pharmaprofessor.com€¦ · Jaypee Brothers Medical Publishers (P) Ltd. Jaypee Brothers Medical...

Essentials of

Pharmacologyfor Dentistry

Essentials of

Pharmacologyfor Dentistry

2ND EDITION

KD TRIPATHI MDEx-Director-Professor and Head of PharmacologyMaulana Azad Medical College and associated

LN and GB Pant HospitalsNew Delhi, India

®

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTDNew Delhi • Panama City • London

Jaypee Brothers Medical Publishers (P) Ltd.

Jaypee Brothers Medical Publishers (P) Ltd4838/24, Ansari Road, DaryaganjNew Delhi 110 002, IndiaPhone: +91-11-43574357Fax: +91-11-43574314Email: [email protected]

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© 2011 KD Tripathi

All rights reserved. No part of this book may be reproduced in any form or by any means without the prior permissionof the publisher.

Inquiries for bulk sales may be solicited at: [email protected]

This book has been published in good faith that the contents provided by the author contained herein are original, andis intended for educational purposes only. While every effort is made to ensure accuracy of information, the publisherand the author specifically disclaim any damage, liability, or loss incurred, directly or indirectly, from the use orapplication of any of the contents of this work. If not specifically stated, all figures and tables are courtesy of the author.Where appropriate, the readers should consult with a specialist or contact the manufacturer of the drug or device.

Publisher: Jitendar P VijPublishing Director: Tarun Duneja

Managing Editor: M. Tripathi

Essentials of Pharmacology for Dentistry

First Edition: 2005

Second Edition: 2011

ISBN-13: 978-93-5025-385-4

Printed at Replika Press, Kundli

Preface to the Second Edition

With phenomenal growth of information on mechanism of action and clinical application of drugs,as well as rapid introduction of new drugs, pharmacology, the science of drugs (medicines), hasbecome increasingly important to all health professionals who prescribe/administer drugs. Practiceof dentistry utilizes drugs both as primary treatment modality as well as facilitator of dentalprocedures. Dentists may have to manage a medical emergency arising in their clinic. Moreover,many dental patients could be receiving other medication that may have orodental implications,or may interact with drugs prescribed by the dentist. As such, a broad knowledge of pharmacologywith emphasis on certain aspects is needed by the dentist.

This book is divided into three sections. The first describes the general pharmacological principleswith which all professionals involved in drug therapy must be conversant. The second on systemicpharmacology presents a brief account of drugs acting on various organ systems and used in thetreatment of common disorders affecting the systems. Each chapter is organised systematically. Theopening sentence defines the class of drugs, followed by their classification. The ‘prototype’ approachis followed by describing the representative drug of the class. In these chapters, matters particularlyrelevant to dental therapeutics have been highlighted by italicizing. Wherever applicable, theimplications in dentistry are prominently elaborated, e.g. drugs and diseases affecting postextractionhaemostasis, dental procedures in patients on corticosteroid therapy or in diabetics, oralcomplications of cancer chemotherapy, conscious sedation in dentistry, etc. Management of medicalemergencies like anaphylactic shock, seizures, angina, or asthmatic attack during dental treatmentis outlined.

The third section covers antimicrobials and other drugs which the dentists prescribe or administerthemselves. However, the allocation of topics in sections two and three does not indicate water-tight distinction, which is impossible, but has been done with a view to focus attention on drugsthat have greater relevance in dentistry. To mention a few, the application of analgesics and NSAIDsin dental pain, dental anaesthesia, role of each class of antimicrobials in orodental infections,prophylaxis of postextraction infection and endocarditis in patients at special risk are emphasized.The highlight of this 2nd edition is a new chapter on drugs and aids having specific applicationin dental disorders and in dental care. Drugs for dental plaque, caries tooth, dentine sensitivityalongwith aids like dentifrices, bleaching agents, disclosing agents, etc. are described pointing outtheir current role in practice. The last chapter on drug interactions highlights those that may beencountered in dental practice.

All chapters in the present edition have been thoroughly updated to include latest informationand new drugs. Presentation and illustrations have been improved. Leading trade names and dosageforms of drugs generally prescribed by dentists are mentioned distinctively. Thus, the book is oriented

to provide core and contemporary pharmacological knowledge based on understanding of therationale. It is designed to meet the specific needs of dental students and practitioners.

I am indebted to my colleagues in pharmacology and dentistry as well as to readers of the 1stedition for their comments and suggestions which helped in orienting the 2nd edition. As always,the motivational influence of Shri J.P. Vij, Chairman and Managing Director, Jaypee Brothers, wascrucial. The meticulous preparation of the manuscript and illustrations by Ms Sunita Katla, Mr ManojPahuja and others in the editorial section is highly appreciated. The participation and cooperationof my wife is sincerely acknowledged.

June, 2011 KD Tripathi

vi Essentials of Pharmacology for Dentistry

1. Introduction, Routes of Drug Administration ............................................................ 3Introduction 3Routes of Drug Administration 5

2. Pharmacokinetics ............................................................................................................. 10Drug Transport 11Drug Absorption 14Drug Distribution 16Drug Biotransformation (Metabolism) 20Drug Excretion 25Kinetics of Elimination 26

3. Pharmacodynamics .......................................................................................................... 31Principles of Drug Action 31Mechanism of Drug Action 31Combined Effect of Drugs 45Drug Dosage 48Factors Modifying Drug Action 50

4. Adverse Drug Effects ...................................................................................................... 56

5. Drugs Acting on Autonomic Nervous System .......................................................... 67(General Considerations, Cholinergic and Anticholinergic Drugs)General Considerations 67Cholinergic Drugs (Cholinomimetic, Parasympathomimetic) 72

Contents

Anticholinesterases 74Anticholinergic Drugs (Parasympatholytic) 76Drugs Acting on Autonomic Ganglia 80

6. Drugs Acting on Autonomic Nervous System .......................................................... 81(Adrenergic and Antiadrenergic Drugs)Adrenergic Transmission 81Adrenergic Drugs (Sympathomimetics) 83Antiadrenergic Drugs (Adrenergic Receptor Antagonists) 90

7. Autacoids and Related Drugs ....................................................................................... 98Histamine 98H1 Antagonists (Conventional Antihistaminics) 1015-hydroxytryptamine (5-HT, Serotonin) 105Drug Therapy of Migraine 107Prostaglandins and Leukotrienes (Eicosanoids) 109Platelet Activating Factor (PAF) 115

8. General Anaesthetics and Skeletal Muscle Relaxants ........................................ 117General Anaesthetics 117Preanaesthetic Medication 125Skeletal Muscle Relaxants 126

9. Drugs Acting on Central Nervous System ............................................................... 133(Sedative-Hypnotics, Alcohols, Antiepileptics and Antiparkinsonian Drugs)Sedative-hypnotics 133Ethyl Alcohol (Ethanol) 139Antiepileptic Drugs 143Antiparkinsonian Drugs 149

10. Drugs Acting on Central Nervous System ............................................................... 155(Psychopharmacological Agents)Psychopharmacological Agents 155Antipsychotic Drugs (Neuroleptics) 156Antimanic (Mood Stabilizing) Drugs 160Antidepressant Drugs 163Antianxiety Drugs 168

11. Cardiovascular Drugs ................................................................................................... 171(Drugs Affecting Renin-Angiotensin System, Calcium Channel Blockers,Drugs for Hypertension, Angina Pectoris and Myocardial Infarction)Angiotensin 171Angiotensin Converting Enzyme Inhibitors 173Calcium Channel Blockers 176Antihypertensive Drugs 178Antianginal Drugs 183Drug Therapy in Myocardial Infarction 188

viii Essentials of Pharmacology for Dentistry

12. Cardiovascular Drugs ................................................................................................... 190(Drugs for Heart Failure and Cardiac Arrhythmia)Cardiac Glycosides 190Treatment of Congestive Heart Failure 195Antiarrhythmic Drugs 197

13. Drugs Acting on Kidney............................................................................................... 203Relevant Physiology of Urine Formation 203Diuretics 205Antidiuretics 212

14. Hormones and Related Drugs .................................................................................... 215(Anterior Pituitary Hormones, Antidiabetic Drugs, Corticosteroids)Introduction 215Anterior Pituitary Hormones 216Antidiabetic Drugs 219Insulin 220Oral Hypoglycaemic Drugs 224Corticosteroids 228

15. Hormones and Related Drugs .................................................................................... 235(Sex Hormones, Contraceptives, Drugs Acting on Uterus)Androgens (Male Sex Hormones) 235Estrogens 237Progestins 239Hormonal Contraceptives 241Uterine Stimulants (Oxytocics, Abortifacients) 243Uterine Relaxants (Tocolytics) 245

16. Hormones and Related Drugs .................................................................................... 246(Thyroid Hormone and Thyroid Inhibitors, Hormones Regulating Calcium Balance)Thyroid Hormone 246Thyroid Inhibitors 249Hormones Regulating Calcium 250

17. Drugs Affecting Blood .................................................................................................. 256Haematinics 256Coagulants 260Anticoagulants 264Fibrinolytics (Thrombolytics) 268Antifibrinolytics 269Antiplatelet Drugs (Antithrombotic Drugs) 269Hypolipidaemic Drugs 271

Contents ix

18. Drugs for Gastrointestinal Disorders ....................................................................... 274Drugs for Peptic Ulcer 274Antiemetics 280Treatment of Gastroesophageal Reflux Disease 284Laxatives (Aperients, Purgatives, Cathartics) 285Treatment of Diarrhoeas 288

19. Drugs for Respiratory Disorders ................................................................................ 291Drugs for Cough 291Drugs for Bronchial Asthma 292

20. Vitamins ........................................................................................................................... 299Fat-soluble Vitamins 300Water-soluble Vitamins 301

21. Anticancer and Immunosuppressant Drugs ........................................................... 305Anticancer Drugs 305Immunosuppressant Drugs 313

22. Antirheumatoid and Antigout Drugs ........................................................................ 317Antirheumatoid Drugs 317Drugs Used in Gout 319

23. Nonsteroidal Antiinflammatory Drugs and Antipyretic-Analgesics ............... 325Analgesic/NSAIDs in Dentistry 339

24. Opioid Analgesics and Antagonists .......................................................................... 341Opioid Analgesics 341Complex Action Opioids and Opioid Antagonists 350

25. Local Anaesthetics ......................................................................................................... 354Uses and Techniques of Local Anaesthesia 361Local Anaesthesia in Dentistry 362

26. Antimicrobial Drugs: General Considerations ...................................................... 364Drug Resistance 367Superinfection 369Choice of an Antimicrobial Agent 370Combined Use of Antimicrobials 373Prophylactic Use of Antimicrobials 375

x Essentials of Pharmacology for Dentistry

27. Sulfonamides, Cotrimoxazole, Quinolones and Nitroimidazoles ..................... 379Sulfonamides 379Cotrimoxazole 381Quinolones 382Nitroimidazoles 387

28. Beta-Lactam Antibiotics ............................................................................................... 390Penicillins 390Cephalosporins 399Monobactams 404Carbapenems 404

29. Tetracyclines, Chloramphenicol and Aminoglycoside Antibiotics .................. 405Tetracyclines 405Chloramphenicol 410Aminoglycoside Antibiotics 413

30. Macrolide and Other Antibacterial Antibiotics ..................................................... 420Macrolide Antibiotics 420Miscellaneous (Lincosamide, Glycopeptide, Oxazolidinone, Polypeptide) Antibiotics 423Urinary Antiseptics 427

31. Antitubercular and Antileprotic Drugs.................................................................... 428Antitubercular Drugs 428Treatment of Tuberculosis 432Antileprotic Drugs 435Multidrug Therapy of Leprosy 436

32. Antifungal and Antiviral Drugs ................................................................................. 438Antifungal Drugs 438Antiviral Drugs 444Treatment of HIV Infection 449Prophylaxis of HIV Infection 450

33. Antiprotozoal and Anthelmintic Drugs ................................................................... 452Antimalarial Drugs 452Antiamoebic Drugs 460Drugs for Giardiasis and Drugs for Trichomoniasis 462Drugs for Leishmaniasis 463Anthelmintic Drugs 463

34. Antiseptics, Disinfectants and Other Locally Acting Drugs .............................. 469Antiseptics and Disinfectants 469Locally Acting Drugs 476

35. Drugs and Aids with Specific Application in Dental Disorders ....................... 477Antiplaque and Antigingivitis Agents 477Antibiotics in Periodontal Disease 479

Contents xi

Anticaries Drugs 480Desensitizing Agents 483Obtundants 484Mummifying Agents 484Bleaching Agents 485Disclosing Agents 485Dentifrices 486

36. Drug Interactions ........................................................................................................... 488Mechanisms of Drug Interactions 489Drug Interactions in Dentistry 491

Index............................................................................................................................................ 495

xii Essentials of Pharmacology for Dentistry

A-I/II/III Angiotensin I/II/IIIAA Amino acidAB Antibody

ABC ATP binding cassettee (trasporter)AC Adenylyl cyclase

ACE Angiotensin II converting enzymeACh Acetylcholine

AChE AcetylcholinesteraseACT Artemisinin combination therapy

ACTH Adrenocorticotropic hormoneA D Alzheimer’s disease

ADH Antidiuretic hormoneADP Adenosine diphosphateAdr AdrenalineAF Atrial fibrillation

AFl Atrial flutterAG Antigen

AIDS Acquired immunodeficiency syndromeAIP Aldosterone induced protein

ALA AlanineAMA Antimicrobial agentAMB Amphotericin Bamp Ampoule

AMP Adenosine monophosphateANC Acid neutralizing capacityANS Autonomic nervous system

ANUG Acute necrotizing ulcerative gingivitisAP Action potential

APD Action potential durationAPF Acidulated phosphate fluoride

aPTT Activated partial thromboplastin timeARB Angiotensin receptor blockerARC AIDS related complexARV Antiretrovirus

5-ASA 5-Amino salicyclic acidAsc LH Ascending limb of Loop of Henle

AT-III Antithrombin IIIATP Adenosine triphosphate

ATPase Adenosine triphosphataseA-V Atrioventricular

AVP Arginine vasopressinAZT Zidovudine

B12 Vitamin B12

BCNU Bischloroethyl nitrosourea (Carmustine)BCRP Breast cancer resistance protein

BD Twice daily

BHP Benign hypertrophy of prostateBMD Bone mineral densityBMR Basal metabolic rate

BP Blood pressureBPN BisphosphonateBRM Biologic response modifierBSA Body surface area

BuChE Butyryl cholinesteraseBW Body weight

BZD Benzodiazepine

C-10 DecamethoniumCA Catecholamine

CaBP Calcium binding proteinCAD Coronary artery diseaseCAM Calmodulin

cAMP 3', 5' Cyclic adenosine monophosphatecap Capsule

CAse Carbonic anhydraseCBS Colloidal bismuth subcitrateCCB Calcium channel blocker

CD Collecting ductcGMP 3', 5' Cyclic guanosine monophosphateCGRP Calcitonin gene-related peptide

CH CholesterolChE Cholinesterase

CHE Cholesterol esterCHF Congestive heart failure

CI Cardiac indexCL Clearance

CLcr Creatinine clearanceClo Clofazimine

CMI Cell-mediated immunityCMV CytomegalovirusCNS Central nervous system

c.o. Cardiac outputCoEn-A Coenzyme-A

COMT Catechol-O-methyl transferaseCOX CyclooxygenaseCPS Complex partial seizuresCPZ ChlorpromazineCRF Corticotropin releasing factorCSF Cerebrospinal fluidCTZ Chemoreceptor trigger zoneCVS Cardiovascular system

CWD Cell wall deficientCYP450 Cytochrome P450

List of Abbreviations

D A DopamineDA-B12 Deoxyadenosyl cobalamin

DAG Diacyl glycerolDAT Dopamine transporterDCI Dichloroisoproterenol

dDAVP DesmopressinDDS Diamino diphenyl sulfone (Dapsone)DEC Diethyl carbamazine citrateDHE Dihydroergotamine

DHFA Dihydro folic acidDHFRase Dihydrofolate reductase

DHP DihydropyridineDI Diabetes insipidus

DIT Diiodotyrosinedl Decilitre

DLE Disseminated lupus erythematosusDMARD Disease modifying antirheumatic drug

DMCM Dimethoxyethyl-carbomethoxy-β-carbolineDMPA Depot medroxyprogesterone acetateDMPP Dimethyl phenyl piperazinium

DNA Deoxyribonucleic acidDOCA Desoxy corticosterone acetate

dopa Dihydroxyphenyl alanineDOSS Dioctyl sulfosuccinateDOTS Directly observed treatment short courseDPP-4 Dipeptidyl peptidase-4

DRC Dose-response curveDT Distal tubule

d-TC d-Tubocurarine

E EthambutolEACA Epsilon amino caproic acid

e.c.f. Extracellular fluidECG Electrocardiogram

EDRF Endothelium dependent relaxing factorEDTA Ethylene diamine tetraacetic acid

EEG Electroencephalogramβ-END β-Endorphin

EPEC Enteropathogenic E. coliEPO ErythropoietinERP Effective refractory period

EPSP Excitatory postsynaptic potentialER Estrogen receptorES Extrasystole

ESR Erythrocyte sedimentation rateETEC Enterotoxigenic E. coli

Etm Ethionamide

FA Folic acid5-FC 5-FlucytosineFEV1 Forced expiratory volume in 1 secondFFA Free fatty acid

FQ FluoroquinoloneFSH Follicle stimulating hormone

5-FU 5-Fluorouracil

GABA Gamma amino butyric acidGC Guanylyl cyclase

GDP Guanosine diphosphateGERD Gastroesophageal reflux disease

g.f.r. Glomerular filtration rateGH Growth hormone

g.i.t. Gastrointestinal tractGITS Gastrointestinal therapeutic system

GLP-1 Glucagon-like peptide-1GLUT Glucose transporterGnRH Gonadotropin releasing hormone

G-6-PD Glucose-6-phosphate dehydrogenaseGTCS Generalised tonic-clonic seizuresGTN Glyceryl trinitrateGTP Guanosine triphosphate

H Isoniazid (Isonicotinic acid hydrazide)HAART Highly active antiretroviral therapy

Hb HaemoglobinHCG Human chorionic gonadotropinHDL High density lipoprotein

5-HIAA 5-Hydroxyindole acetic acidHETE Hydroxyeicosa tetraenoic acid

HIV Human immunodeficiency virusHMG-CoA Hydroxymethyl glutaryl coenzyme AHPA axis Hypothalamo-pituitary-adrenal axis

HPETE Hydroperoxy eicosatetraenoic acidhr Hour

HR Heart rateHRT Hormone replacement therapy

5-HT 5-Hydroxytryptamine5-HTP 5-Hydroxytryptophan

HVA Homovanillic acid

ICSH Interstitial cell stimulating hormoneIDL Intermediate density lipoproteinIGF Insulin-like growth factor

IL InterleukinILEU Isoleucine

i.m. IntramuscularINH Isonicotinic acid hydrazideINR International normalized ratioi.o.t. Intraocular tension

IP3 Inositol trisphosphateIPSP Inhibitory postsynaptic potential

Iso IsoprenalineIU International uniti.v. Intravenous

JAK Janus-kinase

KTZ Ketoconazole

LA Local anaestheticLC-3-KAT Long chain 3-ketoacyl-CoA thiolase

LDL Low density lipoproteinLES Lower esophageal sphincter

leu-ENK Leucine enkephalinLH Luteinizing hormone

xiv Essentials of Pharmacology for Dentistry

liq LiquidLMW Low molecular weightLOX LipoxygenaseLSD Lysergic acid diethylamide

LT Leukotriene

MAC Minimal alveolar concentrationMAC Mycobacterium avium complexMAO Monoamine oxidase

MAPKinase Mitogen activated protein kinasemax Maximum

MBC Minimum bactericidal concentrationMBL Multibacillary leprosyMDI Manic depressive illness

MDR Multidrug resistantMDT Multidrug therapy (of leprosy)

met-ENK Methionine enkephalinmEq milliequivalent

Mf MicrofilariaeMFP Monofluorophosphate

MHC Major histocompatibility complexMI Myocardial infarction

MIC Minimal inhibitory concentrationmin MinimumMIT Monoiodo tyrosine

MLCK Myosin light chain kinase6-MP 6-Mercaptopurine

MRP2 Multidrug resistance associated protein 2MRSA Methicillin resistant Staphylococcus aureus

Mtx MethotrexateMW Molecular weight

NA NoradrenalineNABQI N-acetyl-p-benzoquinoneimineNADP Nicotinamide adenine dinucleotide

phosphateNADPH Reduced nicotinamide adenine dinucleotide

phosphateNAG N-acetyl glucosamineNAM N-acetyl muramic acid

NANC Nonadrenergic noncholinergicNaSSA Noradrenergic and specific serotonergic

antidepressantNAT N-acetyl transferaseNEE Norethindrone enanthateNET Norepinephrine transporter

NFAT Nuclear factor of activated T-cellNIS Na+ iodide symporter

NLEP National leprosy eradication programmeNMDA N-methyl-D-aspartateNNRTI Nonnucleoside reverse transcriptase inhibitor

NPY Neuropeptide-YNR Nicotinic receptor

N-REM Non-rapid eye movement (sleep)NRTI Nucleoside reverse transcriptase inhibitor

NSAID Nonsteroidal antiinflammatory drugNTS Nucleus tractus solitarius

OATP Organic anion transporting polypeptideOC Oral contraceptive

OCD Obsessive-compulsive disorderOCT Organic cation transporter

OD Once dailyORS Oral rehydration salt (solution)ORT Oral rehydration therapy

PABA Paraamino benzoic acidPAE Postantibiotic effect

2-PAM PralidoximePAF Platelet activating factorPAS Paraamino salicylic acid

PBPs Penicillin binding proteinsPBL Paucibacillary leprosyPD Parkinson’s disease

PDE PhosphodiesterasePF Purkinje fibre

PFOR Pyruvate: ferredoxin oxidoreductasePG Prostaglandin

PGI2 ProstacyclinP-gp P-glycoprotein

PI Protease inhibitorPIP2 Phosphatidyl inositol-4, 5-bisphosphate

PKA Protein kinase: cAMP dependentPKC Protein kinase CPLA Phospholipase APLC Phospholipase C

PnG Penicillin GPOMC Pro-opio melanocortin

PP Partial pressurePPARγ Paroxysome proliferator-activated receptor γ

PPH Postpartum haemorrhagePPI Proton pump inhibitor

ppm Part per millionPPNG Penicillinase producing N. gonorrhoeae

Prl ProlactinPSVT Paroxysmal supra-ventricular tachycardia

PT Proximal tubulePTCA Percutaneous transluminal coronary

angioplastyPTH Parathyroid hormonePTP Post-tetanic potentiation

QID Four times a day

R Rifampin (Rifampicin)RAS Renin-angiotensin systemRBP Retinol binding protein

REM Rapid eye movement (sleep)RIMA Reversible inhibitor of MAO-ArINN Recommended international nonproprietary

nameRMP Resting membrane potentialRNA Ribonucleic acid

RNTCP Revised National Tuberculosis ControlProgramme

Abbreviations xv

RP Refractory periodRTF Resistance transfer factor

S StreptomycinSA Sinoatrial (node)

SAARD Slow acting antirheumatic drugSABE Subacute bacterial endocarditis

s.c. SubcutaneousSCh Succinylcholine

SERM Selective estrogen receptor modulatorSERT Serotonin transporterSGA Second generation antihistaminic

s.l. SublingualSLC Solute carrier (transporter)SLE Systemic lupus erythematosus

SMON Subacute myelo-optic neuropathySNRI Serotonin and noradrenaline reuptake

inhibitors.o.s. as required

SPS Simple partial seizuresSR Sustained release

SRS-A Slow reacting substance of anaphylaxisSSRIs Selective serotonin reuptake inhibitorsSTAT Signal transducer and activator of

transcriptionsusp SuspensionSWS Slow wave sleep

syr Syrup

t½ Half-lifeT3 TriiodothyronineT4 Thyroxine

tab TabletTB Tubercle bacilli

TCAs Tricyclic antidepressantsTDS Three times a day

xvi Essentials of Pharmacology for Dentistry

TG Triglyceride6-TG 6-ThioguanineTHC Tetrahydrocannabinol

THFA Tetrahydro folic acidTHR ThreonineTIAs Transient ischaemic attacks

TNF-α Tumour necrosis factor αt.p.r. Total peripheral resistancet-PA Tissue plasminogen activator

TR Thyroid hormone receptorTRH Thyrotropin releasing hormoneTSH Thyroid stimulating hormoneTTS Transdermal therapeutic system

TX Thromboxane

U UnitUDP Uridine diphosphateUFH Unfractionated heparinUGT UDP-glucuronosyl transferase

UT Urea transporter

V Volume of distributionVAL Valine

VF Ventricular fibrillationVit Vitamin

VLDL Very low density lipoproteinVMA Vanillyl mandelic acidVRE Vancomycin resistant enterococci

VRSA Vancomycin resistant Staphylococcus aureusVRUT Vasopressin regulated urea transporter

VT Ventricular tachycardia

WPW Wolff-Parkinson-White syndrome

Z PyrazinamideZollinger-Ellison syndromeZE syndrome

INTRODUCTION

PharmacologyPharmacology is the science of drugs (Greek:Pharmacon—drug; logos—discourse in). In a broadsense, it deals with interaction of exogenouslyadministered chemical molecules (drugs) withliving systems. It encompasses all aspects ofknowledge about drugs, but most importantlythose that are relevant to effective and safe use formedicinal purposes.

In the context of dental practice, a broadunderstanding of pharmacology with emphasison certain aspects is imperative because:

• Dentists have to prescribe/use drugs, albeitfrom a limited range, for the treatment ofdental conditions.

• Many dental patients concurrently sufferfrom other medical conditions, e.g. diabetes,hypertension, arthritis, etc. for which theymay be taking drugs that may have dentalimplications or may interact with drugsprescribed by the dentist.

• The dentist may have to deal with a medicalemergency arising on the dental chair.

For thousands of years most drugs were crudenatural products of unknown composition andlimited efficacy. Only the overt effects of thesesubstances on the body were known, that toorather imprecisely; but how the same wereproduced was entirely unknown. Over the past100 years or so, drugs have been purified,

chemically characterized and a vast variety ofhighly potent and selective new drugs have beendeveloped. The mechanism of action includingmolecular target of many drugs has beenelucidated. This has been possible due to prolificgrowth of pharmacology which forms thebackbone of rational therapeutics.

The two main divisions of pharmacology arepharmacodynamics and pharmacokinetics.

Pharmacodynamics (Greek: dynamis—power) —What the drug does to the body.

This includes physiological and biochemicaleffects of drugs and their mechanism of actionat organ system/subcellular/macromolecularlevels, e.g. adrenaline → interaction with adreno-ceptors → G-protein mediated stimulation of cellmembrane bound adenylyl cyclase → increasedintracellular cyclic 3’,5’AMP → cardiac stimu-lation, hepatic glycogenolysis and hypergly-caemia, etc.

Pharmacokinetics (Greek: Kinesis—movement) —What the body does to the drug.

This refers to movement of the drug in andalteration of the drug by the body; includesabsorption, distribution, binding/localization/storage, biotransformation and excretion of thedrug, e.g. paracetamol is rapidly and almostcompletely absorbed orally attaining peak bloodlevels at 30-60 min; 25% bound to plasma proteins,widely and almost uniformly distributed in thebody (volume of distribution ~ 1 L/kg); extensively

Introduction, Routes ofDrug Administration

1

4 Introduction, Routes of Drug AdministrationS

EC

TIO

NI

metabolized in the liver, primarily by glucuronideand sulfate conjugation into inactive metaboliteswhich are excreted in urine; has a plasma half-life (t½) of 2–3 hours and a clearance value of5 ml/kg/min.

Drug (French: Drogue—a dry herb) It is the singleactive chemical entity present in a medicine that isused for diagnosis, prevention, treatment/cure ofa disease. The WHO (1966) has given a morecomprehensive definition—“Drug is any substanceor product that is used or is intended to be used tomodify or explore physiological systems orpathological states for the benefit of the recipient.”

The term ‘drugs’ is being also used to meanaddictive/abused substances. However, this res-tricted and derogatory sense usage is unfortunatedegradation of a time honoured term, and ‘drug’should refer to a substance that has some thera-peutic/diagnostic application.

Some other important aspects of pharmacologyare:

Pharmacotherapeutics It is the application ofpharmacological information together with know-ledge of the disease for its prevention, mitigationor cure. Selection of the most appropriate drug,dosage and duration of treatment in accordancewith the specific features of a patient are a part ofpharmacotherapeutics.

Clinical pharmacology It is the scientific studyof drugs in man. It includes pharmacodynamicand pharmacokinetic investigation in healthyvolunteers and in patients; evaluation of efficacyand safety of drugs and comparative trials withother forms of treatment; surveillance of patternsof drug use, adverse effects, etc.

The aim of clinical pharmacology is to generatedata for optimum use of drugs and for practice ofmedicine to be ‘evidence based’.

Chemotherapy It is the treatment of systemicinfection/malignancy with specific drugs thathave selective toxicity for the infecting organism/malignant cell with no/minimal effects on the hostcells.

Drugs, in general, can thus be divided into:

Pharmacodynamic agents These are designedto have pharmacodynamic effects in the recipient.

Chemotherapeutic agents These are designed toinhibit/kill invading parasite/malignant cell andhave no/minimal pharmacodynamic effects in therecipient.

Pharmacy It is the art and science of compoun-ding and dispensing drugs or preparing suitabledosage forms for administration of drugs to manor animals. It includes collection, identification,purification, isolation, synthesis, standardizationand quality control of medicinal substances. Thelarge scale manufacture of drugs is called Phar-maceutics. It is primarily a technological science.

Toxicology It is the study of poisonous effect ofdrugs and other chemicals (household, environ-mental pollutant, industrial, agricultural, homi-cidal) with emphasis on detection, prevention andtreatment of poisonings. It also includes the studyof adverse effects of drugs, since the samesubstance can be a drug or a poison, dependingon the dose.

Drug nomenclature

A drug generally has three categories of names:

(a) Chemical name It describes the substancechemically, e.g. 1-(Isopropylamino)-3-(1-naphthy-loxy) propan-2-o1 for propranolol. This is cumber-some and not suitable for use in prescribing. A codename, e.g. RO 15-1788 (later named flumazenil)may be assigned by the manufacturer for con-venience and simplicity before an approved nameis coined.

(b) Nonproprietary name It is the name acceptedby a competent scientific body/authority, e.g. theUnited States Adopted Name (USAN) or theBritish Approved Name (BAN). The nonproprie-tary names of newer drugs are kept uniform by anagreement to use the ‘recommended InternationalNonproprietary Name (rINN)’ only. However,

CH

AP

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R1

Routes of Drug Administration 5

many older drugs have more than one nonpro-prietary names, e.g. meperidine (USA) andpethidine (UK, India) for the same drug. Until thedrug is included in a pharmacopoeia, thenonproprietary name may also be called theapproved name. After its appearance in the officialpublication, it becomes the official name.

In common parlance, the term generic name isused in place of nonproprietary name. Etymolo-gically this is incorrect: ‘generic’ should beapplied to the chemical or pharmacological group(or genus) of the compound, e.g. aminoglycosideantibiotics, tricyclic antidepressants, etc.; but hasbecome synonymous with nonproprietary namedue to wide usage and official acceptance.

(c) Proprietary (Brand) name It is the name assig-ned by the manufacturer(s) and is his property ortrade mark. One drug may have multiple pro-prietary names, e.g. ALTOL, ATCARDIL, ATECOR,ATEN, BETACARD, LONOL, TENOLOL, TENORMIN foratenolol from different manufacturers. Brandnames are designed to be catchy, short, easy toremember and often suggestive, e.g. LOPRESORsuggesting drug for lowering blood pressure.Brand names generally differ in different countries,e.g. timolol maleate eyedrops are marketed asTIMOPTIC in the USA but as GLUCOMOL in India.Even the same manufacturer may market the samedrug under different brand names in differentcountries. In addition, combined formulations havetheir own multiple brand names. This is respon-sible for much confusion in drug nomenclature.

There are many arguments for using thenonproprietary name in prescribing: uniformity,convenience, economy and better comprehension(propranolol, sotalol, timolol, pindolol, meto-prolol, acebutolol, atenolol are all β blockers, buttheir brand names have no such similarity).However, when it is important to ensureconsistency of the product in terms of quality andbioavailability, etc. and especially when officialcontrol over quality of manufactured products isnot rigorous, it is better to prescribe by thedependable brand name.

ROUTES OF DRUG ADMINISTRATION

Most drugs can be administered by a variety ofroutes. The choice of appropriate route in a givensituation depends both on drug as well as patient-related factors. Mostly common sense consi-derations, feasibility and convenience dictate theroute to be used.

Factors governing choice of route

1. Physical and chemical properties of the drug(solid/liquid/gas; solubility, stability, pH,irritancy).

2. Site of desired action—localized and appro-achable or generalized and not approachable.

3. Rate and extent of absorption of the drug fromdifferent routes.

4. Effect of digestive juices and first passmetabolism on the drug.

5. Rapidity with which the response is desired(routine treatment or emergency).

6. Accuracy of dosage required (i.v. andinhalational can provide fine tuning).

7. Condition of the patient (unconscious, vomi-ting).

Routes can be broadly divided into those for(a) local action and (b) systemic action.

LOCAL ROUTES

These routes can only be used for localized lesionsat accessible sites and for drugs whose systemicabsorption from these sites is minimal, slow orabsent. Thus, high concentrations are attained atthe desired site without exposing the rest of thebody. Systemic side effects or toxicity are conse-quently absent or minimal. For drugs (in suitabledosage forms) that are absorbed from these sites/routes, the same can serve as a systemic route ofadministration. The local routes are:

1. Topical This refers to external applicationof the drug to the surface for localized action. It isoften more convenient and efficient mode ofdelivering the drug to skin, oropharyngeal/nasal


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mucosa, eyes, ear canal, anal canal, vagina, etc.Nonabsorbable drugs given orally for action ong.i. mucosa (sucralfate, neomycin), inhalation ofdrugs for action on bronchial mucosa (cromolynsodium) and irrigating solutions/jellys (povidoneiodine, lidocaine) applied to urethra are otherforms of topical medication. In dental practiceantiseptics, astringents, haemostatics are oftenapplied as paints, toothpastes, mouthwashes,gargles or lozenges.

2. Deeper tissues Certain deep areas can beapproached by using a syringe and needle, butthe drug should be such that systemic absorptionis slow, e.g. infiltration around a nerve orintrathecal injection (lidocaine, amphotericin B),intraarticular injection (hydrocortisone acetate),retrobulbar injection (hydrocortisone acetate).

3. Arterial supply Close intra-arterial injectionis used for contrast media in angiography;anticancer drugs can be infused in femoral orbrachial artery to localize the effect for limbmalignancies.

SYSTEMIC ROUTES

The drug administered through systemic routesis intended to be absorbed into bloodstream anddistributed all over, including the site of action,through circulation (see Fig. 1.1).

1. OralOral ingestion is the oldest and commonest modeof drug administration. It is safer, more con-venient, does not need assistance, noninvasive,often painless, the medicament need not be sterileand so is cheaper. Both solid dosage forms(powders, tablets, capsules, spansules, dragees,moulded tablets, gastrointestinal therapeuticsystems—GITs) and liquid dosage forms (elixirs,syrups, emulsions, mixtures) can be given orally.

2. Sublingual (s.l.) or buccalThe tablet or pellet containing the drug is placedunder the tongue or crushed in the mouth andspread over the buccal mucosa. Only lipid-solubleand non-irritating drugs can be so administered.

Absorption is relatively rapid—action can beproduced in minutes. Though it is somewhatinconvenient, one can spit the drug after thedesired effect has been obtained. The chiefadvantage is that liver is bypassed and drugs withhigh first pass metabolism can be absorbed directlyinto systemic circulation. Drugs given sublin-gually are—glyceryl trinitrate, buprenorphine,desamino-oxytocin.

3. RectalCertain irritant and unpleasant drugs can be putinto rectum as suppositories or retention enemafor systemic effect. This route can also be usedwhen the patient is having recurrent vomiting.However, it is rather inconvenient and embar-rassing; absorption is slower, irregular and oftenunpredictable (diazepam solution is dependablyabsorbed from rectum in children). Drug absorbedinto external haemorrhoidal veins (about 50%)bypasses liver, but not that absorbed into internalhaemorrhoidal veins. Rectal inflammation canresult from irritant drugs. Indomethacin, diaze-pam, ergotamine and a few other drugs aresometimes given rectally.

4. CutaneousHighly lipid-soluble drugs can be applied overthe skin for slow and prolonged absorption. The

Limitations of oral route of administration

• Action is slower and thus not suitable foremergencies.

• Unpalatable drugs (chloramphenicol) aredifficult to administer; drug may be filled incapsules to circumvent this.

• May cause nausea and vomiting (emetine).• Cannot be used for uncooperative/uncons-

cious/vomiting patient.• Certain drugs are not absorbed (strepto-

mycin). Absorption of some drugs is erratic.• Others are destroyed by digestive juices

(penicillin G, insulin) or in liver (glyceryltrinitrate, testosterone, lidocaine) by high firstpass metabolism.

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Fig. 1.1: Vascular pathway of drugs absorbed from various systemic routes of administration andsites of first pass metabolismNote: All drug administered orally is subjected to first pass metabolism in intestinal wall and liver, whileapproximately half of that absorbed from rectum passes through liver. Drug entering from any systemicroute is exposed to first pass metabolism in lungs, but its extent is minor for most drugs.


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Fig. 1.2: Illustration of a transdermal drug delivery system

liver is also bypassed. The drug can be incorpo-rated in an ointment and applied over specifiedarea of skin.

Transdermal therapeutic systems These aredevices in the form of adhesive patches of variousshapes and sizes (5–20 cm2) which deliver thecontained drug at a constant rate into systemiccirculation via the stratum corneum (Fig. 1.2).The drug (in solution or bound to a polymer) isheld in a reservoir between an occlusive backingfilm and a rate controlling micropore membrane,the undersurface of which is smeared with anadhesive impregnated with priming dose of thedrug that is protected by another film to be peeledoff just before application. The drug is deliveredat the skin surface by diffusion for percutaneousabsorption into circulation. The microporemembrane is such that rate of drug delivery to skinsurface is less than the slowest rate of absorptionfrom skin. This offsets any variation in the rate ofabsorption according to the properties of differentsites. As such, drug is delivered at constant andpredictable rate irrespective of site of application:usually chest, abdomen, upper arm, lower back,buttock or mastoid region are utilized.

Transdermal patches of glyceryl trinitrate,fentanyl, nicotine and estradiol are available inIndia, while those of isosorbide dinitrate,hyoscine, and clonidine are available in othercountries. These have been designed to last for 1to 7 days in case of different drugs and are becomingincreasingly popular, because they providesmooth plasma concentrations of the drug withoutfluctuations; minimize interindividual variations

(drug is subjected to little first pass metabolism)and side effects. They are also more convenient—many patients prefer transdermal patches to oraltablets of the same drug; patient compliance isbetter. Local irritation and erythema occurs insome, but is generally mild; can be minimized bychanging the site of application each time byrotation. Discontinuation has been necessary in2 to 7% cases.

5. InhalationVolatile liquids and gases are given by inhalationfor systemic action, e.g. general anaesthetics.Absorption takes place from the vast surface ofalveoli—action is very rapid. When administra-tion is discontinued, the drug diffuses back andis rapidly eliminated in expired air. Thus, control-led administration is possible with moment-to-moment adjustment. Irritant vapours (ether) causeinflammation of respiratory tract and increasesecretion.

6. NasalThe mucous membrane of the nose can readilyabsorb many drugs; digestive juices and liver arebypassed. However, only certain drugs like GnRHagonists and desmopressin applied as a spray ornebulized solution have been used by this route.This route is being tried for some other peptidedrugs like insulin.

7. Parenteral(Par—beyond, enteral—intestinal)This refers to administration by injection whichtakes the drug directly into the tissue fluid or bloodwithout having to cross the intestinal mucosa. Thelimitations of oral administration are circum-vented. Drug action is faster and surer (valuablein emergencies). Gastric irritation and vomitingare not provoked. Parenteral route can be emplo-yed even in unconscious, uncooperative or vomi-ting patient. There are no chances of interferenceby food or digestive juices. Liver is bypassed.

Disadvantages of parenteral routes are—thepreparation has to be sterilized and is costlier, thetechnique is invasive and painful, assistance ofanother person is mostly needed (though self-

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injection is possible, e.g. insulin by diabetics),there are chances of local tissue injury and ingeneral it is more risky. The important parenteralroutes are:

(i) Subcutaneous (s.c.) The drug is depositedin the loose subcutaneous tissue which is richlysupplied by nerves (irritant drugs cannot beinjected) but is less vascular (absorption is slower).Self-injection is possible because deep penetrationis not needed. This route should be avoided inshock patients who are vasoconstricted—absorp-tion will be delayed. Repository (depot) prepara-tions—oily solutions or aqueous suspensions canbe injected for prolonged action. Some specialforms of this route are:

(a) Dermojet In this method needle is not used; ahigh velocity jet of drug solution is projected froma microfine orifice using a gun-like implement.The solution passes through the superficial layersand gets deposited in the subcutaneous tissue. Itis essentially painless and suited for massinoculations.

(b) Pellet implantation The drug as solid pellet isintroduced with a trochar and cannula. Thisprovides sustained release of the drug over weeksand months, e.g. DOCA, testosterone.

(c) Sialistic (nonbiodegradable) and biodegradableimplants Crystalline drug is packed in tubes/capsules made of suitable materials and implan-ted under the skin. Slow and uniform leaching ofthe drug occurs over months providing constantblood levels. The nonbiodegradable implant hasto be removed later on but not the biodegradableone. This has been tried for hormones andcontraceptives (e.g. NORPLANT).

(ii) Intramuscular (i.m.) The drug is injected inone of the large skeletal muscles—deltoid, triceps,gluteus maximus, rectus femoris, etc. Muscle isless richly supplied with sensory nerves (mildirritants can be injected) and is more vascular(absorption is faster). It is less painful, but self-injection is often impracticable—deep penetrationis needed. Depot preparations can be injected bythis route.

(iii) Intravenous (i.v.) The drug is injected as abolus (Greek: bolos-lump) or infused slowly overhours in one of the superficial veins. The drugdirectly reaches into the bloodstream and effectsare produced immediately (great value in emer-gency). The intima of veins is insensitive and druggets diluted with blood, therefore, even highlyirritant drugs can be injected i.v., but hazards are—thrombophlebitis of the injected vein and necrosisof adjoining tissues if extravasation occurs. Thesecomplications can be minimized by diluting thedrug or injecting it into a running i.v. line. Onlyaqueous solutions (not suspensions) can beinjected i.v. and there are no depot preparationsfor this route. The dose of the drug required issmallest (bioavailability is 100%) and even largevolumes can be infused. One big advantage withthis route is—in case response is accuratelymeasurable (e.g. BP) and the drug short acting(e.g. sodium nitroprusside), titration of the dosewith the response is possible. However, this is themost risky route—vital organs like heart, brain,etc. get exposed to high concentrations of the drug.

(iv) Intradermal injection The drug is injectedinto the skin raising a bleb (e.g. BCG vaccine,sensitivity testing) or scarring/multiple puncture ofthe epidermis through a drop of the drug is done.This route is employed for specific purposes only.


Pharmacokinetics is the quantitative study ofdrug movement in, through and out of the body.The overall scheme of pharmacokinetic processesis depicted in Fig. 2.1. Intensity of response isrelated to concentration of the drug at the site ofaction, which in turn is dependent on its pharma-cokinetic properties. Pharmacokinetic considera-tions, therefore, determine the route(s) ofadministration, dose, latency of onset, time of peakaction, duration of action and thus frequency ofadministration of a drug.

All pharmacokinetic processes involve trans-port of the drug across biological membranes.

Biological membrane This is a bilayer (about100 Å thick) of phospholipid and cholesterolmolecules, the polar groups of these are orientedat the two surfaces and the nonpolar hydrocarbonchains are embedded in the matrix, with adsor-bed extrinsic and intrinsic protein molecules(Fig. 2.2). The proteins are able to freely floatthrough the membrane: associate and organizeor vice versa. Some of the intrinsic ones, whichextend through the full thickness of the mem-brane, surround fine aqueous pores. Paracellularspaces or channels also exist between certainepithelial/endothelial cells. Other adsorbedproteins have enzymatic or carrier properties.

Fig. 2.1: Schematic depiction of pharmacokinetic processes

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Drugs are transported across the membranes by:(a) Passive diffusion and filtration.(b) Specialized transport.

Passive diffusionThe drug diffuses across the membrane in thedirection of its concentration gradient, themembrane playing no active role in the process.This is the most important mechanism formajority of drugs; drugs are foreign substancesand specialized mechanisms are developed bythe body for normal metabolites only.

Lipid-soluble drugs diffuse by dissolving inthe lipoidal matrix of the membrane (Fig. 2.3), therate of transport being proportional to lipid : waterpartition coefficient of the drug. A more lipid-soluble drug attains higher concentration in themembrane and diffuses quickly. Also, greater thedifference in the concentration of the drug on twosides of the membrane, faster is its diffusion.

Influence of pH Most drugs are weak electro-lytes, i.e. their ionization is pH dependent(contrast strong electrolytes which are nearlycompletely ionized at acidic as well as alkalinepH). The ionization of a weak acid HA is givenby the equation:

[A¯ ]pH = pKa + log —–— ...(1)

[HA]

Fig. 2.2: Illustration of the organisation ofbiological membrane

Transport of Drugs 11

Fig. 2.3: Illustration of passive diffusion and filtration acrossthe lipoidal biological membrane with aqueous pores

pKa is the negative logarithm of acidic disso-ciation constant of the weak electrolyte. If theconcentration of ionized drug [A¯ ] is equal to theconcentration of unionized drug [HA], then—

[A¯ ]—–— = 1[HA]

since log 1 is 0, under this condition

pH = pKa ...(2)

Thus, pKa is numerically equal to the pH at whichthe drug is 50% ionized.If pH is increased by 1, then—

log [A¯ ]/[HA] = 1 or [A¯ ]/[HA] = 10

Similarly, if pH is reduced by 1, then—[A¯ ]/[HA] = 1/10

Thus, weakly acidic drugs, which formsalts with cations, e.g. sod. phenobarbitone, sod.sulfadiazine, pot. penicillin-V, etc. ionize more atalkaline pH and 1 scale change in pH causes 10-fold change in ionization.

Weakly basic drugs, which form salts withanions, e.g. atropine sulfate, ephedrine HCl,chloroquine phosphate, etc. conversely ionize moreat acidic pH. Ions being lipid insoluble, do not

12 PharmacokineticsS

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diffuse and a pH difference across a membranecan cause differential distribution of weaklyacidic and weakly basic drugs on the two sides(Fig. 2.4).

Implications of this consideration are:(a) Acidic drugs, e.g. aspirin (pKa 3.5) are largelyunionized at acid gastric pH and are absorbedfrom stomach, while bases, e.g. atropine (pKa 10)are largely ionized and are absorbed only whenthey reach the intestines.(b) The unionized form of acidic drugs whichcrosses the surface membrane of gastric mucosalcell, reverts to the ionized form within the cell(pH 7.0) and then only slowly passes to theextracellular fluid. This is called ion trapping, i.e.a weak electrolyte crossing a membrane toencounter a pH from which it is not able to escapeeasily. This may contribute to gastric mucosal celldamage caused by aspirin.(c) Basic drugs attain higher concentrationintracellularly (pH 7.0 vs 7.4 of plasma).(d) Acidic drugs are ionized more in alkalineurine—do not back diffuse in the kidney tubulesand are excreted faster. Accordingly, basic drugsare excreted faster if urine is acidified.

Lipid-soluble nonelectrolytes (e.g. ethanol,diethyl-ether) readily cross biological membranesand their transport is pH independent.

FiltrationFiltration is passage of drugs through aqueouspores in the membrane or through paracellularspaces. This can be accelerated if hydrodynamicflow of the solvent is occurring under hydrostaticor osmotic pressure gradient, e.g. across mostcapillaries including glomeruli. Lipid-insolubledrugs cross biological membranes by filtration iftheir molecular size is smaller than the diameterof the pores (Fig. 2.3). Majority of cells (intestinalmucosa, RBC, etc.) have very small pores (4 Å)and drugs with MW > 100 or 200 are not able topenetrate. However, capillaries (except those inbrain) have large paracellular spaces (40 Å) andmost drugs (even albumin) can filter through these(see Fig. 2.8A). As such, diffusion of drugs acrosscapillaries is dependent on rate of blood flowthrough them rather than on lipid-solubility ofthe drug or pH of the medium.

Specialized transportThis can be carrier mediated or by pinocytosis.

Carrier transportAll cell membranes express a host of transmem-brane proteins which serve as carriers ortransporters for physiologically important ions,nutrients, metabolites, transmitters, etc. across themembrane. At some sites, certain transporters alsotranslocate xenobiotics, including drugs and theirmetabolites. In contrast to channels, which openfor a finite time and allow passage of specific ions,transporters combine transiently with theirsubstrate (ion or organic compound)—undergo aconformational change carrying the substrate tothe other side of the membrane where the substratedissociates and the transporter returns back to itsoriginal state (Fig. 2.5). Carrier transport is specificfor the substrate (or the type of substrate, e.g. anorganic anion), saturable, competitively inhibitedby analogues which utilize the same transporter,and is much slower than the flux throughchannels. Depending on requirement of energy,carrier transport is of two types:a. Facilitated diffusion The transporter, belong-ing to the super-family of solute carrier (SLC)

Fig. 2.4: Influence of pH difference on two sides of abiological membrane on the distribution of a weakly acidicdrug with pKa = 6

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transporters, operates passively without needingenergy and translocates the substrate in thedirection of its electrochemical gradient, i.e. fromhigher to lower concentration (Fig. 2.5A). It mearlyfacilitates permeation of a poorly diffusiblesubstrate, e.g. the entry of glucose into muscle andfat cells by the glucose transporter GLUT 4.b. Active transport It requires energy, isinhibited by metabolic poisons, and transportsthe solute against its electrochemical gradient(low to high), resulting in selective accumulationof the substance on one side of the membrane.Drugs related to normal metabolites can utilizethe transport processes meant for these, e.g.levodopa and methyl dopa are actively absorbed

from the gut by the aromatic amino acidtransporter. In addition, the body has developedsome relatively nonselective transporters, likeP-glycoprotein (P-gp), to deal with xenobiotics.Active transport can be primary or secondarydepending on the source of the driving force.i. Primary active transport Energy is obtaineddirectly by the hydrolysis of ATP (Fig. 2.5B). Thetransporters belong to the superfamily of ATPbinding cassettee (ABC) transporters whose intra-cellular loops have ATPase activity.

P-glycoprotein is the most well known primary activetransporter. Others of pharmacological significance aremultidrug resistance associated protein 2 (MRP 2) andbreast cancer resistance protein (BCRP).

Transport of Drugs 13

Fig. 2.5: Illustration of different types of carrier mediated transport across biological membraneABC—ATP-binding cassettee transporter; SLC—Solute carrier transporter; M—MembraneA. Facilitated diffusion: the carrier (SLC) binds and moves the poorly diffusible substrate along its concentration gradient(high to low) and does not require energyB. Primary active transport: the carrier (ABC) derives energy directly by hydrolysing ATP and moves the substrateagainst its concentration gradient (low to high)C. Symport: the carrier moves the substrate ‘A’ against its concentration gradient by utilizing energy from downhillmovement of another substrate ‘B’ in the same directionD. Antiport: the carrier moves the substrate ‘A’ against its concentration gradient and is energized by the downhillmovement of another substrate ‘B’ in the opposite direction


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ii. Secondary active transport In this type ofactive transport effected by another set of SLCtransporters, the energy to pump one solute isderived from the downhill movement of anothersolute (mostly Na+). When the concentrationgradients are such that both the solutes move inthe same direction (Fig. 2.5C), it is called symportor cotransport, but when they move in oppositedirections (Fig. 2.5D), it is termed antiport orexchange transport. Metabolic energy (fromhydrolysis of ATP) is spent in maintaining hightransmembrane electrochemical gradient of thesecond solute.

The organic anion transporting polypeptide (OATP)and organic cation transporter (OCT), highly expressed inliver canaliculi and renal tubules, are secondary activetransporters important in the metabolism and excretionof drugs and metabolites (especially glucuronides). TheNa+,Cl– dependent neurotransmitter transporters forserotonin and dopamine (SERT and DAT) are active SLCtransporters that are targets for action of drugs like tricyclicantidepressants.

Pinocytosis It is the process of transport across the cellin particulate form by formation of vesicles. This is applicableto proteins and other big molecules, and contributes littleto transport of most drugs.

ABSORPTIONAbsorption is the movement of drug from its siteof administration into the circulation. Not onlythe fraction of the administered dose that getsabsorbed, but also the rate of absorption isimportant. Except when given i.v., the drug hasto cross biological membranes; absorption isgoverned by the above described principles. Otherfactors affecting absorption are:

Aqueous solubility Drugs given in solid formmust dissolve in the aqueous biophase before theyare absorbed. For poorly water-soluble drugs(aspirin, griseofulvin) rate of dissolution governsrate of absorption. Obviously, a drug given aswatery solution is absorbed faster than when thesame is given in solid form or as oily solution.

Concentration Passive transport depends onconcentration gradient; drug given as concen-trated solution is absorbed faster than from dilutesolution.

Area of absorbing surface Larger it is, faster isthe absorption.

Vascularity of the absorbing surface Blood circu-lation removes the drug from the site of absorptionand maintains the concentration gradient acrossthe absorbing surface. Increased blood flowhastens drug absorption just as wind hastensdrying of clothes.

Route of administration This affects drug absorp-tion, because each route has its own peculiarities.

OralThe effective barrier to orally administered drugsis the epithelial lining of the gastrointestinal tract,which is lipoidal. Nonionized lipid-solubledrugs, e.g. ethanol are readily absorbed fromstomach as well as intestine at rates proportionalto their lipid : water partition coefficient. Acidicdrugs, e.g. salicylates, barbiturates, etc. arepredominantly unionized in the acid gastric juiceand are absorbed from stomach, while basicdrugs, e.g. morphine, quinine, etc. are largelyionized and are absorbed only on reaching theduodenum. However, even for acidic drugsabsorption from stomach is slower, because themucosa is thick, covered with mucus and thesurface area is small. Thus, faster gastric emptyingaccelerates drug absorption in general. Dissolu-tion is a surface phenomenon, therefore, particlesize of the drug in solid dosage form governs rateof dissolution and in turn rate of absorption.

Presence of food dilutes the drug and retardsabsorption. Further, certain drugs form poorlyabsorbed complexes with food constituents, e.g.tetracyclines with calcium present in milk.Moreover, food delays gastric emptying. Thus,most drugs are absorbed better if taken in emptystomach. Highly ionized drugs, e.g. gentamicin,neostigmine, are poorly absorbed when givenorally.

Certain drugs are degraded in the gastrointes-tinal tract, e.g. penicillin G by acid, insulin bypeptidases, and are ineffective orally. Entericcoated tablets (having acid resistant coating) andsustained release preparations (drug particles

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coated with slowly dissolving material) can beused to overcome acid lability, gastric irritancyand brief duration of action.

Absorption of a drug can be affected by otherconcurrently ingested drugs. This may be aluminal effect: formation of insoluble complexes,e.g. tetracyclines with iron preparations andantacids, ciprofloxacin with sucralfate. This canbe minimized by administering the two drugs at2–3 hour intervals. Alteration of gut flora byantibiotics may disrupt the enterohepatic cyclingof oral contraceptives and digoxin. Drugs can alsoalter absorption by gut wall effects: altering motility(anticholinergics, tricyclic antidepressants,opioids, metoclopramide) or causing mucosaldamage (neomycin, methotrexate, vinblastine).

Subcutaneous and intramuscularBy these routes the drug is deposited directly inthe vicinity of the capillaries. Lipid-soluble drugspass readily across the whole surface of thecapillary endothelium. Capillaries being highlyporous do not obstruct absorption of even largelipid-insoluble molecules or ions (see Fig. 2.8A).Very large molecules are absorbed throughlymphatics. Thus, many drugs not absorbed orallyare absorbed parenterally. Absorption from s.c.site is slower than that from i.m. site, but both aregenerally faster and more consistent/predictablethan oral absorption. Application of heat andmuscular exercise accelerate drug absorption byincreasing blood flow, while vasoconstrictors, e.g.adrenaline injected with the drug (local anaes-thetic) retard absorption. Many depot prepara-tions, e.g. benzathine penicillin, protamine zincinsulin, depot progestins, etc. can be given by theseroutes.

Topical sites (skin, cornea, mucous membranes)Systemic absorption after topical applicationdepends primarily on lipid solubility of drugs.However, only few drugs significantly penetrateintact skin. Glyceryl trinitrate, fentanyl andestradiol (see p. 8) have been used in this manner.Absorption can be promoted by rubbing the drugincorporated in an olegenous base or by use of

occlusive dressing which increases hydration ofthe skin. Organophosphate insecticides comingin contact with skin can produce systemic toxicity.Abraded surfaces readily absorb drugs.

Cornea is permeable to lipid soluble, unioni-zed physostigmine but not to highly ionizedneostigmine. Similarly, mucous membranes ofmouth, rectum, vagina absorb lipophilic drugs.

BIOAVAILABILITY

Bioavailability refers to the rate and extent ofabsorption of a drug from a dosage form asdetermined by its concentration-time curve inblood or by its excretion in urine (Fig. 2.6). It is ameasure of the fraction (F ) of administered doseof a drug that reaches the systemic circulation inthe unchanged form. Bioavailability of druginjected i.v. is 100%, but is frequently lower afteroral ingestion because—(a) the drug may be incompletely absorbed.(b) the absorbed drug may undergo first passmetabolism in intestinal wall/liver or be excretedin bile.

Drug Absorption 15

Fig. 2.6: Plasma concentration-time curves depictingbioavailability differences between three preparations of adrug containing the same amountNote that formulation B is more slowly absorbed than A,and though ultimately both are absorbed to the same extent(area under the curve same), B may not produce therapeuticeffect; C is absorbed to a lesser extent—lower bioavailability.


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DISTRIBUTIONOnce a drug has gained access to the bloodstream,it gets distributed to other tissues that initiallyhad no drug, concentration gradient being in thedirection of plasma to tissues. The extent of dis-tribution of a drug depends on its lipid solubility,ionization at physiological pH (dependent onpKa), extent of binding to plasma and tissueproteins and differences in regional blood flow.Movement of drug proceeds until an equilibriumis established between unbound drug in theplasma and in the tissue fluids. Subsequently,there is a parallel decline in both due toelimination.

Apparent volume of distribution (V) Presumingthat the body behaves as a single homogeneouscompartment with volume V into which the druggets immediately and uniformly distributed

dose administered i.v. V = ——————————– ...(3)

plasma concentrationSince in the example shown in Fig. 2.7 the drugdoes not actually distribute into 20 L of bodywater, with the exclusion of the rest of it, this isonly an apparent volume of distribution whichcan be defined as “the volume that would

Fig. 2.7: Illustration of the concept of apparent volume ofdistribution (V)

In this example, 1000 mg of drug injected i.v. producessteady-state plasma concentration of 50 mg/L, apparentvolume of distribution is 20 L.

Incomplete bioavailability after s.c. or i.m. injectionis less common, but may occur due to localbinding of the drug.

Oral formulation of a drug from differentmanufacturers or different batches from the samemanufacturer may have the same amount of thedrug (chemically equivalent) but may not yieldsame blood levels—biologically inequivalent. Twopreparations of a drug are considered bioequivalentwhen the rate and extent of bioavailability of thedrug from them is not significantly different undersuitable test conditions.

Before a drug administered orally in soliddosage form can be absorbed, it must break intoindividual particles of the active drug (disinte-gration). Tablets and capsules contain a numberof other materials—diluents, stabilizing agents,binders, lubricants, etc. The nature of these as wellas details of the manufacture process, e.g. forceused in compressing the tablet, may affectdisintegration. The released drug must then dissolvein the aqueous gastrointestinal contents. The rateof dissolution is governed by the inherentsolubility, particle size, crystal form and otherphysical properties of the drug. Differences inbioavailability may arise due to variations indisintegration and dissolution rates.

Differences in bioavailability are seen mostlywith poorly soluble and slowly absorbed drugs.Reduction in particle size increases the rate ofabsorption of aspirin (microfine tablets). Theamount of griseofulvin and spironolactone in thetablet can be reduced to half if the drug particle ismicrofined. There is no need to reduce the particlesize of freely water-soluble drugs, e.g.paracetamol.

Bioavailability variation assumes practicalsignificance for drugs with low safety margin(digoxin) or where dosage needs precise control(oral hypoglycaemics, oral anticoagulants). It mayalso be responsible for success or failure of anantimicrobial regimen.

However, for a large number of drugs bioavaila-bility differences are negligible and the risks ofchanging formulation have often been exaggerated.

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accommodate all the drug in the body, if theconcentration throughout was the same as inplasma.” Thus, it describes the amount of drugpresent in the body as a multiple of that containedin a unit volume of plasma. Considered togetherwith drug clearance, this is a very useful pharma-cokinetic concept.

Lipid-insoluble drugs do not enter cells—V approximates extracellular fluid volume, e.g.streptomycin, gentamicin 0.25 L/kg.

Distribution is not only a matter of dilutionbut also binding and sequestration. Drugsextensively bound to plasma proteins are largelyrestricted to the vascular compartment and havelow values, e.g. diclofenac and warfarin (99%bound) V = 0.15 L/kg.

Drugs sequestrated in other tissues may haveV much more than total body water or even bodymass, e.g. digoxin 6 L/kg, chlorpromazine 25 L/kg, morphine 3.5 L/kg, because most of the drugis present in other tissues, and plasma concen-tration is low.

Pathological states, e.g. congestive heartfailure, uraemia, cirrhosis of liver, etc. can alterthe V of many drugs by altering distribution ofbody water, permeability of membranes, bindingproteins or by accumulation of metabolites thatdisplace the drug from binding sites.

Factors governing volume of drug distribution

• Lipid : water partition coefficient of the drug• pKa value of the drug• Degree of plasma protein binding• Affinity for different tissues• Fat : lean body mass ratio• Diseases like CHF, uraemia, cirrhosis

Redistribution Highly lipid-soluble drugs getinitially distributed to organs with high bloodflow, i.e. brain, heart, kidney, etc. Later, lessvascular but more bulky tissues (muscle, fat) takeup the drug—plasma concentration falls and thedrug is withdrawn from brain, etc. If the site ofaction of the drug was in one of the highlyperfused organs, redistribution results in

termination of drug action. Greater the lipidsolubility of the drug, faster is its redistribution.Anaesthetic action of thiopentone injected i.v. isterminated in a few minutes due to redistribution.A relatively short (6-8 hr) hypnotic action due toredistribution is exerted by oral diazepam ornitrazepam despite their elimination half-life of> 30 hr. However, when the same drug is givenrepeatedly or by continuous i.v. infusion over longperiods, the low perfusion high capacity sites getprogressively filled up and the drug becomeslonger acting.

Penetration into brain and CSF The capillaryendothelial cells in brain have tight junctions andlack large intercellular pores. Further, an invest-ment of neural tissue (Fig. 2.8B) covers thecapillaries. Together they constitute the so-calledblood-brain barrier. A similar blood-CSF barrier islocated in the choroid plexus where capillariesare lined by choroidal epithelium having tightjunctions. Both these barriers are lipoidal andlimit the entry of nonlipid-soluble drugs, e.g.gentamicin, neostigmine, etc. Only lipid-solubledrugs, therefore, are able to penetrate and haveaction on the central nervous system. Effluxtransporters like P-glycoprotein present in brainand choroidal vessels extrude many drugs thatenter brain by other processes. Dopamine doesnot enter brain, but its precursor levodopa does;as such, the latter is used in parkinsonism.Inflammation of meninges or brain increasespermeability of these barriers.

There is also an enzymatic blood-brain bar-rier; monoamine oxidase (MAO), cholinesteraseand some other enzymes are present in thecapillary walls or in the cells lining them. Theydo not allow catecholamines, 5-HT, acetylcholine,etc. to enter brain in the active form.

The blood-brain barrier is deficient at the CTZin the medulla oblongata (even lipid-insolubledrugs are emetic) and at certain periventricularsites—(anterior hypothalamus). Exit of drugs fromthe CSF and brain, however, is not dependent onlipid solubility and is rather unrestricted. Bulkflow of CSF (along with the drug dissolved in it)

Drug Distribution 17


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Fig. 2.8: Passage of drugs across capillariesA. Usual capillary with large intercellular pores through which even large lipid-insoluble molecules diffuseB. Capillary constituting blood-brain or blood-CSF barrier. Tight junctions betweencapillary endothelial cells and investment of glial processes or choroidal epitheliumdo not allow passage of nonlipid-soluble molecules/ions

occurs through the arachnoid villi. Further, non-specific organic ion transport processes (similarto those in renal tubule) operate at the choroidplexus.

Passage across placenta Placental membra-nes are lipoidal and allow free passage oflipophilic drugs while restricting hydrophilicdrugs. The placental efflux P-glycoprotein alsoserves to limit foetal exposure to maternallyadministered drugs. However, restricted amountsof nonlipid-soluble drugs, when present in highconcentration or for long periods in maternalcirculation, gain access to the foetus. Thus, it isan incomplete barrier and almost any drug takenby the mother can affect the foetus or the new-born (drug taken just before delivery, e.g.morphine).

Plasma protein bindingMost drugs possess physicochemical affinity forplasma proteins. Acidic drugs generally bind toplasma albumin and basic drugs to α1 acidglycoprotein. Binding to albumin is quantitativelymore important. Extent of binding depends onthe individual compound; no generalization fora pharmacological or chemical class can be made

(even small chemical change can markedly alterprotein binding), for example:

Flurazepam 10% Alprazolam 70%Lorazepam 90% Diazepam 99%

Increasing concentrations of the drug can pro-gressively saturate the binding sites; fractionalbinding may be lower when large amounts of thedrug are given. The generally expressed percen-tage binding refers to the usual therapeutic plasmaconcentrations of a drug. The clinically significantimplications of plasma protein binding are:(i) Highly plasma protein bound drugs arelargely restricted to the vascular compartment andtend to have lower volumes of distribution.(ii) The bound fraction is not available for action.However, it is in equilibrium with the free drug inplasma and dissociates when the concentrationof the latter is reduced due to elimination. Plasmaprotein binding thus tantamounts to temporarystorage of the drug.(iii) High degree of protein binding generallymakes the drug long acting, because boundfraction is not available for metabolism orexcretion, unless it is actively extracted by liver orkidney tubules. Glomerular filtration does not

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well as get metabolized or excreted; the newsteady-state free drug concentration is only mar-ginally higher unless the displacement extendsto tissue binding or there is concurrent inhibitionof metabolism and/or excretion. The overallimpact of many displacement interactions isminimal; clinical significance being attained onlyin case of highly bound drugs with limited volumeof distribution (many acidic drugs bound toalbumin) and where interaction is more complex.Moreover, two highly bound drugs do notnecessarily displace each other—their bindingsites may not overlap, e.g. probenecid andindomethacin are highly bound to albumin butdo not displace each other. Similarly, acidic drugsdo not generally displace basic drugs and viceversa. Some clinically important displacementinteractions are:

• Salicylates displace sulfonylureas.• Indomethacin, phenytoin displace war-

farin.• Sulfonamides and vit K displace bilirubin

(kernicterus in neonates).• Salicylates displace methotrexate.

(vi)In hypoalbuminaemia, binding may be redu-ced and high concentrations of free drug may beattained, e.g. phenytoin and furosemide. Otherdiseases may also alter drug binding, e.g.phenytoin and pethidine binding is reduced inuraemia; propranolol binding is increased inpregnant women and in patients withinflammatory disease (acute phase reactant α1

acid-glycoprotein increases).

Tissue storage Drugs may also accumulate inspecific organs or get bound to specific tissueconstituents, e.g.—Drugs sequestrated in various tissues are diffe-rentially distributed, tend to have large volume ofdistribution and long duration of action. Somemay exert local toxicity due to high concentration,e.g. tetracyclines on bone and teeth, chloroquineon retina, emetine on heart and skeletal muscle.Drugs may also selectively bind to specificintracellular organelle, e.g. tetracycline to mito-chondria, chloroquine to nuclei.

Drug Distribution 19

reduce the concentration of the free form in theefferent vessels because water is also filtered.Active tubular secretion, however, removes thedrug without the attendant solvent → concen-tration of free drug falls → bound drug dissociatesand is eliminated resulting in a higher renalclearance value of the drug than the total renalblood flow (See Fig. 2.10). The same is true of activetransport of highly extracted drugs in liver.Plasma protein binding in this situation acts as acarrier mechanism and hastens drug elimination,e.g. excretion of penicillin; metabolism oflidocaine. Highly protein bound drugs are notremoved by haemodialysis and need specialtechniques for treatment of poisoning.(iv) The generally expressed plasma concentra-tions of the drug refer to bound as well as freedrug. Degree of protein binding should be takeninto account while relating these to concentrationsof the drug that are active in vitro, e.g. MIC of anantimicrobial.

(v) One drug can bind to many sites on thealbumin molecule. Conversely, more than onedrug can bind to the same site. This can give riseto displacement interactions among drugs boundto the same site(s); the drug bound with higheraffinity will displace that bound with loweraffinity. If just 1% of a drug that is 99% bound isdisplaced, the concentration of free form will bedoubled. This, however, is often transient becausethe displaced drug will diffuse into the tissues as

Drugs highly bound to plasma protein

To Albumin To α1-acidglycoprotein

Barbiturates β-blockersBenzodiazepines BupivacaineNSAIDs LignocaineValproic acid DisopyramidePhenytoin ImipraminePenicillins MethadoneSulfonamides PrazosinTetracyclines QuinidineWarfarin Verapamil


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phenicol, propranolol and its active metabolite4-hydroxypropranolol.

(ii) Active metabolite from an active drug Manydrugs have been found to be partially convertedto one or more active metabolite (see box); theeffects observed are the sum total of that due tothe parent drug and its active metabolite(s).

(iii) Activation of inactive drug Few drugs areinactive as such and need conversion in thebody to one or more active metabolite(s). Such adrug is called a prodrug. The prodrug may offeradvantages over the active form in being morestable, having better bioavailability or otherdesirable pharmacokinetic properties or less sideeffects and toxicity. Some prodrugs are activatedselectively at the site of action.

Active drug Active metabolite

Allopurinol — AlloxanthineProcainamide — N-acetyl-procainamidePrimidone — Phenobarbitone,

phenylethylmalonamideCefotaxime — Deacetyl cefotaximeDiazepam — Desmethyl-diazepam,

oxazepamDigitoxin — DigoxinImipramine — DesipramineAmitriptyline — NortriptylineCodeine — MorphineMorphine — Morphine-6-glucuronideSpironolactone — CanrenoneLosartan — E 3174

Biotransformation reactions can be classifiedinto:(a) Nonsynthetic/Phase I reactions: a functionalgroup may be generated/exposed—metabolitemay be active or inactive.(b) Synthetic/Conjugation/ Phase II reactions—metabolite is mostly inactive except few drugs,e.g. morphine-6-glucuronide.

Nonsynthetic reactions

(i) Oxidation This reaction involves additionof oxygen/negatively charged radical or removal

Drugs concentrated in tissues

Skeletal muscle, — digoxin, emetine (toheart muscle proteins).Liver — chloroquine, tetracyclines,

emetine, digoxin.Kidney — digoxin , chloroquine,

emetine.Thyroid — iodine.Brain — chlorpromazine,

acetazolamide, isoniazid.Retina — chloroquine (to

nucleoproteins).Iris — ephedrine, atropine (to

melanin).Bone and teeth — tetracyclines, heavy metals

(to mucopolysaccharidesof connective tissue),bisphosphonates.

Adipose tissue — thiopentone, ether, mino-cycline, DDT dissolve inneutral fat due to highlipid solubility; remainstored due to poor bloodsupply of fat.

BIOTRANSFORMATION(Metabolism)

Biotransformation means chemical alteration ofthe drug in the body. It is needed to rendernonpolar (lipid soluble) compounds polar (lipidinsoluble) so that they are not reabsorbed in therenal tubules and are excreted. Most hydrophilicdrugs, e.g. gentamicin, neostigmine, decametho-nium, etc. are not biotransformed and are excretedunchanged.

The primary site for drug metabolism is liver;others are—kidney, intestine, lungs and plasma.Biotransformation of drugs may lead to thefollowing.

(i) Inactivation Most drugs and their activemetabolites are rendered inactive or less active,e.g. lidocaine, ibuprofen, paracetamol, chloram-

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mercaptopurine are oxidized by mitochondrialor cytoplasmic enzymes.

(ii) Reduction This reaction is the converse ofoxidation and involves cytochrome P-450 enzymesworking in the opposite direction. Drugs prima-rily reduced are chloramphenicol, halothane andwarfarin.

(iii) Hydrolysis This is cleavage of drug mole-cule by taking up a molecule of water.

esteraseEster + H2O ————→→→→→ Acid + Alcohol

Similarly, amides and polypeptides are hydro-lyzed by amidases and peptidases. Hydrolysisoccurs in liver, intestines, plasma and othertissues. Examples are choline esters, procaine,lidocaine, procainamide, pethidine, oxytocin.

Synthetic reactionsThese involve conjugation of the drug or its phaseI metabolite with an endogenous substrate, gene-rally derived from carbohydrate or amino acid, toform a polar highly ionized organic acid, whichis easily excreted in urine or bile.(i) Glucuronide conjugation This is the mostimportant synthetic reaction carried out by agroup of UDP-glucuronosyl transferases (UGTs).Compounds with a hydroxyl or carboxylic acidgroup are easily conjugated with glucuronic acidwhich is derived from glucose. Examples arechloramphenicol, aspirin, morphine, metroni-dazole. Not only drugs but endogenous substrateslike bilirubin, steroidal hormones and thyroxineutilize this pathway. Drug glucuronides excretedin bile can be hydrolyzed by bacteria in the gut—the liberated drug is reabsorbed and undergoesthe same fate. This enterohepatic cycling of thedrug prolongs its action, e.g. phenolphthalein,oral contraceptives.

(ii) Acetylation Compounds having amino orhydrazine residues are conjugated with the helpof acetyl coenzyme-A, e.g. sulfonamides, isonia-zid, PAS, hydralazine. Multiple genes controlthe N-acetyl transferases (NATs) and rate of

Prodrug Active form

Levodopa — DopamineEnalapril — Enalaprilatα-Methyldopa — α-MethylnorepinephrineDipivefrine — EpinephrineProguanil — CycloguanilBacampicillin — AmpicillinSulfasalazine — 5-Aminosalicylic acidAcyclovir — Acyclovir triphosphateCyclophos- — Aldophosphamide,phamide phosphoramide mustard,

acroleinMercaptopurine — Methylmercaptopurine

ribonucleotide

Drug Metabolism 21

of hydrogen/positively charged radical. Oxida-tions are the most important drug metabolizingreactions. Various oxidation reactions are:

hydroxylation; oxygenation at C, N or S atoms;N or O-dealkylation, oxidative deamination, etc.

In many cases, the initial insertion of oxygenatom into the drug molecule produces short livedhighly reactive quinone/epoxide/superoxideintermediates which then convert to more stablecompounds.

Oxidative reactions are mostly carried out bya group of monooxygenases in the liver, which inthe final step involve a cytochrome P-450 haemo-protein, NADPH, cytochrome P-450 reductaseand molecular O2. More than 100 cytochrome P-450 (CYP-450) isoenzymes differing in theiraffinity for various substrates (drugs), have beenidentified. The CYP-450 isoenzymes importantin drug metabolism are CYP3A4, CYP2D6,CYP2C8/9, CYP2C19, CYP1A2.

The relative amount of different cytochrome P-450sdiffers among species and among individuals of the samespecies. These differences largely account for the markedinterspecies and interindividual differences in rate ofmetabolism of drugs.

Barbiturates, phenothiazines, paracetamol,steroids, phenytoin, benzodiazepines, theophyl-line and many other drugs are oxidized in thisway. Some other drugs, e.g. adrenaline, alcohol,


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acetylation shows genetic polymorphism (slowand fast acetylators).

(iii) Methylation The amines and phenols canbe methylated; methionine and cysteine acting asmethyl donors, e.g. adrenaline, histamine, nico-tinic acid.(iv) Sulfate conjugation The phenolic com-pounds and steroids are sulfated by sulfotrans-ferases (SULTs), e.g. chloramphenicol, adrenaland sex steroids.

(v) Glycine conjugation Salicylates and otherdrugs having carboxylic acid group are conju-gated with glycine, but this is not a major pathwayof metabolism.

(vi) Glutathione conjugation Forming a mercap-turate is normally a minor pathway. However, itserves to inactivate highly reactive quinone orepoxide intermediates formed during metabolismof certain drugs, e.g. paracetamol. When a largeamount of such intermediates are formed (inpoisoning or after enzyme induction), glutathio-ne supply falls short—toxic adducts are formedwith tissue constituents → tissue damage.(vii) Ribonucleoside/nucleotide synthesis Itis important for the activation of many purineand pyrimidine antimetabolites used in cancerchemotherapy.

Most drugs are metabolized by manypathways, simultaneously or sequentially asillustrated in Fig. 2.9. As such, a variety ofmetabolities of a drug may be produced.

Only few drugs are metabolized by enzymesof intermediary metabolism, e.g. alcohol by dehy-drogenase, allopurinol by xanthine oxidase,succinylcholine and procaine by plasma choli-nesterase, adrenaline by monoamine oxidase.Majority of drugs are acted on by relativelynonspecific enzymes which are directed to typesof molecules rather than to specific drugs. Thesame enzyme can metabolize many drugs. Thedrug metabolizing enzymes are divided into twotypes:

Microsomal These are located on smoothendoplasmic reticulum (a system of microtubulesinside the cell), primarily in liver, also in kidney,intestinal mucosa and lungs. The monooxyge-nases, cytochrome P 450, UGTs, etc. are micro-somal enzymes.

They catalyze most of the oxidations, reduc-tions, hydrolysis and glucuronide conjugation.Microsomal enzymes are inducible by drugs, dietand other agencies.

Nonmicrosomal These are present in the cyto-plasm and mitochondria of hepatic cells as wellas in other tissues including plasma. The flavo-protein oxidases, esterases, amidases and conju-gases are nonmicrosomal. Reactions catalyzedare:

Some oxidations and reductions, many hydro-lytic reactions and all conjugations exceptglucuronidation.

The nonmicrosomal enzymes are not induciblebut many show genetic polymorphism (acetyltransferase, pseudocholinesterase).

Both microsomal and nonmicrosomal enzy-mes are deficient in the newborn, especiallypremature, making them more susceptible to manydrugs, e.g. chloramphenicol, opioids. This deficitis made up in first few months, more quickly incase of oxidation and other phase I reactions thanin case of glucuronide and other conjugationstaking 3 or more months.

Amount and kind of drug metabolizing enzy-mes is controlled genetically and is also alteredby environmental factors. Thus, marked inter-

Fig. 2.9: Simultaneous and/or sequential metabolismof a drug by phase I and phase II reactions

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species and interindividual differences are seen.Up to 6-fold difference in the rate of metabolismof a drug among normal human adults may beobserved. This is one of the major causes ofindividual variation in drug response.

Hofmann elimination This refers to inactivationof the drug in the body fluids by spontaneousmolecular rearrangement without the agency ofany enzyme, e.g. atracurium.

INHIBITION OF DRUG METABOLISM

One drug can competitively inhibit the meta-bolism of another if it utilizes the same enzyme orcofactors. However, such interactions are not ascommon as one would expect, because oftendifferent drugs are substrates for different CYP-450 isoenzymes. Moreover, a drug may inhibitone isoenzyme while being itself a substrate ofanother isoenzyme, e.g. quinidine is metabolizedby CYP3A4 but inhibits CYP2D6. Also mostdrugs, at therapeutic concentrations aremetabolized by non-saturation kinetics, i.e. theenzyme is present in excess. Clinically significantinhibition of drug metabolism occurs in case ofdrugs having affinity for the same isoenzyme,especially if they are metabolized by saturationkinetics or if kinetics changes from first order tozero order over the therapeutic range (capacitylimited metabolism). Obviously, inhibition of drugmetabolism occurs in a dose-related manner andcan precipitate toxicity of the object drug (whosemetabolism has been inhibited).

Because enzyme inhibition occurs by directeffect on the enzyme, it has a fast time course(within hours) compared to enzyme induction (seebelow).

Metabolism of drugs with high hepaticextraction is dependent on liver blood flow (bloodflow limited metabolism). Propranolol reduces rateof lidocaine metabolism by decreasing hepaticblood flow.

MICROSOMAL ENZYME INDUCTION

Many drugs, insecticides and carcinogens interactwith DNA and increase the synthesis of micro-somal enzyme protein, especially cytochrome P-450 and glucuronyl transferase. As a result, rateof metabolism of inducing drug itself and/or otherdrugs is increased.

Different inducers are relatively selective forcertain cytochrome P-450 enzyme families, e.g.:• Anticonvulsants including phenobarbitone,

rifampin, glucocorticoids induce CYP3Aisoenzymes.

• Phenobarbitone also induces CYP2B1 andrifampin also induces CYP2D6.

• Isoniazid and chronic alcohol consumptioninduce CYP2E1.

• Polycyclic hydrocarbons like 3-methylcholan-threne and benzopyrene found in cigarettesmoke, charcoalbroiled meat and industrialpollutants induce CYP1A isoenzymes.

• Other important enzyme inducers are: chloralhydrate, griseofulvin, DDT.

Since different CYP isoenzymes are involved inthe metabolism of different drugs, every inducerincreases biotransformation of certain drugsbut not that of others. However, phenobarbitonelike inducers of CYP3A and CYP2D6 affect themetabolism of a large number of drugs, becausethese isoenzymes act on many drugs. On theother hand, induction by polycyclic hydrocarbonsis limited to a few drugs (like theophylline)because CYP1A isoenzyme metabolizes only fewdrugs.

Drug Metabolism 23

Drugs that inhibit drug metabolizingenzymes

Allopurinol DiltiazemOmeprazole AmiodaroneErythromycin PropoxypheneClarithromycin IsoniazidChloramphenicol CimetidineKetoconazole QuinidineItraconazole MetronidazoleCiprofloxacin DisulfiramSulfonamides VerapamilFluoxetine Ritonavir


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Table 2.1: Extent of first pass metabolism of some important drugs

Low Intermediate High

not given orally high oral dose

Phenobarbitone Aspirin Isoprenaline PropranololTolbutamide Quinidine Lidocaine AlprenololTheophylline Desipramine Hydrocortisone VerapamilPindolol Nortriptyline Testosterone SalbutamolIsosorbide Chlorpromazine Glyceryl trinitrate

mononitrate Pentazocine MorphineMetoprolol Pethidine

Induction involves microsomal enzymes inliver as well as other organs and increases therate of metabolism by 2–4-fold. Induction takes4–14 days to reach its peak and is maintained tillthe inducing agent is being given. Thereafter, theenzymes return to their original value over 1 to 3weeks.

Consequences of microsomalenzyme induction1. Decreased intensity and/or duration of actionof drugs that are inactivated by metabolism, e.g.failure of contraception with oral contraceptives.2. Increased intensity of action of drugs that areactivated by metabolism. Acute paracetamol toxi-city is due to one of its metabolites—toxicity occursat lower doses in patients receiving enzymeinducers.3. Tolerance—if the drug induces its ownmetabolism (autoinduction), e.g. carbamazepine,rifampin.4. Some endogenous substrates (steroids, bili-rubin) are also metabolized faster.5. Precipitation of acute intermittent porphyria:enzyme induction increases porphyrin synthesisby derepressing δ-aminolevulenic acid synthe-tase.6. Intermittent use of an inducer may interferewith adjustment of dose of another drug pres-cribed on regular basis, e.g. oral anticoagulants,oral hypoglycaemics, antiepileptics, antihyper-tensives.

Drugs whose metabolism is significantlyaffected by enzyme induction are—phenytoin,

warfarin, tolbutamide, imipramine, oralcontraceptives, chloramphenicol, doxycycline,theophylline, griseofulvin.

Possible uses of enzyme induction1. Congenital nonhaemolytic jaundice: pheno-barbitone causes rapid clearance of jaundice.2. Cushing’s syndrome: phenytoin may reducethe manifestations.3. Chronic poisonings.4. Liver disease.

FIRST PASS (PRESYSTEMIC) METABOLISM

This refers to metabolism of a drug during itspassage from the site of absorption into the sys-temic circulation. All orally administered drugsare exposed to drug metabolizing enzymes in theintestinal wall and liver (where they first reachthrough the portal vein). Presystemic metabolismof limited magnitude can also occur in the skin(transdermally administered drug) and in lungs(for drug reaching venous blood through anyroute). The extent of first pass metabolism differsfor different drugs (Table 2.1) and is an importantdeterminant of oral bioavailability.

Attributes of drugs with high first passmetabolism(a) Oral dose is considerably higher than sub-lingual or parenteral dose.(b) There is marked individual variation in theoral dose due to differences in the extent of firstpass metabolism.(c) Oral bioavailability is apparently increasedin patients with severe liver disease.

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(d) Oral bioavailability of a drug is increased ifanother drug competing with it in first passmetabolism is given concurrently, e.g. chlorpro-mazine and propranolol.

EXCRETIONExcretion is the passage out of systemicallyabsorbed drug. Drugs and their metabolites areexcreted in:

1. Urine Through the kidney. It is the mostimportant channel of excretion for majority ofdrugs (see below).

2. Faeces Apart from the unabsorbed fraction,most of the drug present in faeces is derived frombile. Organic acids (especially drug glucuroni-des), organic bases and steroids are actively trans-ported into bile by liver through separate non-specific active transport mechanisms (OATP,MRP2, OCT, P-gP, etc.). Relatively larger mole-cules (MW > 300) are preferentially eliminated inthe bile. Most of the drug, including that releasedby deconjugation of glucuronides by bacteria inintestines is reabsorbed (enterohepatic cycling)and ultimate excretion occurs in urine. Drugs thatattain high concentrations in bile are erythro-mycin, ampicillin, rifampin, tetracycline, oralcontraceptives, phenolphthalein.

Certain drugs are excreted directly in colon,e.g. anthracene purgatives, heavy metals.

3. Exhaled air Gases and volatile liquids(general anaesthetics, alcohol) are eliminated bylungs, irrespective of their lipid solubility.Alveolar transfer of the gas/vapour depends onits partial pressure in the blood. Lungs also serveto trap and extrude any particulate matter injectedi.v.

4. Saliva and sweat These are of minor impor-tance for drug excretion. Lithium, pot. iodide,rifampin and heavy metals are present in thesesecretions. Most of the saliva along with the drugin it, is swallowed and meets the same fate asorally taken drug.

5. Milk The excretion of drug in milk is notimportant for the mother, but the suckling infant

inadvertently receives the drug. Most drugs enterbreast milk by passive diffusion. As such, morelipid soluble and less protein bound drugs crossbetter. Milk has a lower pH (7.0) than plasma,basic drugs are somewhat more concentrated init. However, the total amount of drug reachingthe infant through breastfeeding is generally smalland majority of drugs can be given to lactatingmothers without ill effects on the infant. Never-theless, it is advisable to administer any drug to alactating women only when essential.

RENAL EXCRETION

The kidney is responsible for excreting all water-soluble substances. The amount of drug or itsmetabolites ultimately present in urine is the sumtotal of glomerular filtration, tubular reabsorp-tion and tubular secretion (Fig. 2.10).

Net renal (glomerular filtration + tubularexcretion = secretion) – tubular reabsorption

Glomerular filtration Glomerular capillarieshave pores larger than usual; all nonprotein bounddrug (whether-lipid soluble or insoluble) presen-ted to the glomerulus is filtered. Thus, glomerularfiltration of a drug depends on its plasma proteinbinding and renal blood flow. Glomerularfiltration rate (g.f.r.), normally ~ 120 mL/min,declines progressively after the age of 50 and islow in renal failure.

Tubular reabsorption This depends on lipidsolubility and ionization of the drug at the existingurinary pH. Lipid-soluble drugs filtered at theglomerulus back diffuse passively in the tubulesbecause 99% of glomerular filtrate is reabsorbed,but nonlipid-soluble and highly ionized drugsare unable to do so. Thus, rate of excretion of suchdrugs, e.g. aminoglycoside antibiotics, quaternaryammonium compounds parallels g.f.r. (orcreatinine clearance). Changes in urinary pH affecttubular reabsorption of drugs that are partiallyionized—• Weak bases ionize more and are less reabsor-

bed in acidic urine.• Weak acids ionize more and are less reabsor-

bed in alkaline urine.

Drug Excretion 25


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This principle is utilized for facilitating elimina-tion of drug in poisoning, i.e. urine is alkalinizedin barbiturate and salicylate poisoning.

Tubular secretion This is the active transfer oforganic acids and bases by two separate classesof nonspecific transporters (OATP and OCT)which operate in the proximal tubules. Inaddition efflux transporters P-gp and MRP2 arelocated in luminal membrane of proximal tubularcells. If renal clearance of a drug is greater than120 mL/min (g.f.r.), additional tubular secretioncan be assumed to be occurring.

Active transport of the drug across tubulesreduces the concentration of its free form in thetubular vessels and promotes dissociation ofprotein bound drug, which again is secreted (Fig.2.10). Thus, protein binding, which is a hinde-rance for glomerular filtration of the drug, is notso (may even be facilitatory) to excretion bytubular secretion.

(a) Organic acid transport (by OATP) forpenicillin, probenecid, uric acid, salicylates,

sulfinpyrazone, nitrofurantoin, methotrexate,drug glucuronides, etc.

(b) Organic base transport (through OCT) forthiazides, quinine, procainamide, choline, cimeti-dine, amiloride, etc.

Inherently both transport processes are bi-directional, i.e. they can transport their substratesfrom blood to tubular fluid and vice versa. How-ever, for drugs and their metabolites (exogenoussubstances) secretion into the tubular lumenpredominates, whereas an endogenous substratelike uric acid is predominantly reabsorbed.

Drugs utilizing the same active transport com-pete with each other. Probenecid is an organicacid which has high affinity for the tubular OATP.It blocks the active transport of both penicillinand uric acid, but whereas the net excretion of theformer is decreased, that of the latter is increased.This is because penicillin is primarily secretedwhile uric acid is primarily reabsorbed. Manydrug interactions occur due to competition fortubular secretion, e.g.(i) Salicylates block uricosuric action of probene-cid and sulfinpyrazone and decrease tubularsecretion of methotrexate.(ii) Probenecid decreases the concentration ofnitrofurantoin in urine, increases the duration ofaction of penicillin/ampicillin and impairssecretion of methotrexate.(iii) Quinidine decreases renal and biliary clea-rance of digoxin by inhibiting efflux carrier P-gp.

Tubular transport mechanisms are not welldeveloped at birth. As a result, duration of actionof many drugs, e.g. penicillin, cephalosporins,aspirin is longer in neonates. These systemsmature during infancy. Ranal function againprogressively declines after the age of 50 years.The renal clearance of many drugs is substan-tially lower in the elderly above 75 years of age.

KINETICS OF ELIMINATIONThe knowledge of kinetics of elimination of a drugprovides the basis for, as well as serves to deviserational dosage regimens and to modify themaccording to individual needs. There are three

Fig. 2.10: Schematic depiction of glomerular filtration, tubularreabsorption and tubular secretion of drugsFD—free drug; BD—bound drug; UD—unionized drug; ID—ionized drug, Dx—highly secreted organic acid (or base) drug

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fundamental pharmacokinetic parameters, viz.bioavailability (F), volume of distribution (V) andclearance (CL) which must be understood. Thefirst two have already been considered.

Drug elimination is the sum total of metabolicinactivation and excretion. As depicted in Fig.2.1, drug is eliminated only from the centralcompartment (blood) which is in equilibrium withperipheral compartments including the site ofaction. Depending upon the ability of the body toeliminate a drug, a certain fraction of the centralcompartment may be considered to be totally‘cleared’ of that drug in a given period of time toaccount for elimination over that period.

Clearance (CL) The clearance of a drug is thetheoretical volume of plasma from which the drugis completely removed in unit time (analogy crea-tinine clearance, Fig. 2.11). It can be calculated as

CL = Rate of elimination/C ...(4)where C is the plasma concentration.

For majority of drugs the processes involvedin elimination are not saturated over the clini-cally obtained concentrations, they follow:

First order (exponential) kinetics The rate ofelimination is directly proportional to drug con-centration, CL remains constant; or a constant

fraction of the drug present in the body iseliminated in unit time.

Few drugs, however, saturate eliminatingmechanisms and are handled by—

Zero order (linear) kinetics The rate of elimi-nation remains constant irrespective of drugconcentration, CL decreases with increase inconcentration; or a constant amount of the drug iseliminated in unit time, e.g. ethyl alcohol.

The elimination of some drugs approachessaturation over the therapeutic range, kineticschanges from first order to zero order at higherdoses. As a result, plasma concentration increasesdisproportionately with increase in dose (see Fig.2.13) as occurs in the case of phenytoin,tolbutamide, theophylline, warfarin.

Plasma half-life The plasma half-life (t½) of adrug is the time taken for its plasma concentrationto be reduced to half of its original value.

Taking the simplest case of a drug which hasrapid one compartment distribution and firstorder elimination, and is given i.v., a semilogplasma concentration-time plot as shown in Fig.2.12 is obtained. The plot has two slopes:

(i) initial rapidly declining (α) phase—due todistribution.(ii) later less declined (β) phase—due toelimination.

At least two half-lives (distribution t½ andelimination t½) can be calculated from the twoslopes. The elimination half-life derived from theβ slope is simply called the ‘half-life’ of the drug.Mathematically, elimination t½ is

ln2 t½ = —— ...(5)

kWhere ln2 is the natural logarithm of 2 (or 0.693)and k is the elimination rate constant of the drug, i.e.the fraction of the total amount of drug in the bodywhich is removed per unit time. For example, if 2g of the drug is present in the body and 0.1 g iseliminated every hour, then k = 0.1/2 = 0.05. It iscalculated as:

CLk = —– ...(6)

V

Kinetics of Elimination 27

Fig. 2.11: Illustration of the concept of drug clearance. Afraction of the drug molecules present in plasma are removedon each passage through the organs of elimination. In thecase shown, it requires 50 mL of plasma to account for theamount of drug being eliminated every minute: clearance is50 mL/min


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Vtherefore, t½ = 0.693 × —— ...(7)

CLAs such, half-life is a derived parameter from twovariables V and CL both of which may changeindependently. It, therefore, is not an exact indexof drug elimination. Nevertheless, it is a simpleand useful guide to the sojourn of the drug in thebody, i.e. after

1 t½ – 50% drug is eliminated.2 t½ – 75% (50 + 25) drug is eliminated.3 t½ – 87.5% (50 + 25 + 12.5) drug is eliminated.

4 t½ – 93.75% (50 + 25 + 12.5 + 6.25) drug is eliminated.

Thus, nearly complete drug elimination occursin 4–5 half-lives.For drugs eliminated by—First order kinetics—t½ remains constant becauseV and CL do not change with dose.Zero order kinetics—t½ increases with dosebecause CL progressively decreases as dose isincreased.

Half-life of some representative drugs

Aspirin 4 hr Digoxin 40 hrPenicillin-G 30 min Metronidazole 8 hrDoxycycline 20 hr Phenobarbitone 90 hr

Repeated drug administration

When a drug is repeated at relatively short inter-vals, it accumulates in the body until eliminationbalances input and a steady-state plasma concen-tration (Cpss) is attained—

dose rateCpss = ————— ...(8)

CLFrom this equation it is implied that doubling thedose rate would double the average Cpss and soon. Further, if the therapeutic plasma concen-tration of the drug has been worked out and itsCL is known, the dose rate needed to achieve thetarget Cpss can be determined—

dose rate = target Cpss × CL ...(9)After oral administration, often only a fraction (F)of the dose reaches systemic circulation in theactive form. In such a case—

target Cpss � CLdose rate = ———————— ...(10)

FThe dose rate-Cpss relationship is linear only incase of drugs eliminated by first order kinetics.For drugs (e.g. phenytoin) which follow MichaelisMenten kinetics, elimination changes from firstorder to zero order kinetics over the therapeuticrange. Increase in their dose beyond saturationlevels causes an increase in Cpss which is out ofproportion to the change in dose rate (Fig. 2.13).In their case:

(Vmax) (C)Rate of drug elimination = ————— ...(11)

Km + Cwhere C is the plasma concentration of the drug,Vmax is the maximum rate of drug elimination,and Km is the plasma concentration at whichelimination rate is half maximal.

Plateau principle

When a constant dose of a drug is repeated beforethe expiry of 4 t½, it would achieve higher peakconcentration, because some remnant of theprevious dose will be present in the body. Thiscontinues with every dose until progressivelyincreasing rate of elimination (which increases

Fig. 2.12: Semilog plasma concentration-time plot of a drugeliminated by first order kinetics after intravenous injection

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with increase in concentration) balances theamount administered over the dose interval.Subsequently, plasma concentration plateausand fluctuates about an average steady-state level.This is known as the plateau principle of drugaccumulation. Steady state is reached in 4–5 half-lives unless dose interval is very much longer thant½ (Fig. 2.14).

The amplitude of fluctuations in plasmaconcentration at steady state depends on the doseinterval relative to t½, i.e. the difference betweenthe maximum and minimum levels is less ifsmaller doses are repeated more frequently (doserate remaining constant). Dosage intervals aregenerally a compromise between what amplitudeof fluctuations is clinically acceptable (loss ofefficacy at troughs and side effects at peaks) andwhat frequency of dosing is convenient. However,if the dose rate is changed, a new average Cpss isattained over the next 4–5 half-lives. When thedrug is administered orally (absorption takessome time), average Cpss is approximately 1/3rdof the way between the minimal and maximallevels in a dose interval.Target level strategy For drugs whose effectsare not easily quantifiable and safety margin isnot big, e.g. anticonvulsants, antidepressants,

lithium, some antimicrobials, etc. or those givento prevent an event, it is best to aim at achieving acertain plasma concentration which has beendefined to be in the therapeutic range; such dataare now available for most drugs of this type.

Drugs with short t½ (up to 2–3 hr) adminis-tered at conventional intervals (6–12 hr) achievethe target levels only intermittently and fluctua-tions in plasma concentration are marked. In caseof many drugs (penicillin, ampicillin, chloramp-henicol, erythromycin, propranolol) this, how-ever, is therapeutically acceptable.

For drugs with longer t½ a dose that issufficient to attain the target concentration aftersingle administration, if repeated will accumu-late according to plateau principle and producetoxicity later on. On the other hand, if the dosingis such as to attain target level at steady state, thetherapeutic effect will be delayed by about 4 half-lives (this may be clinically unacceptable). Suchdrugs are often administered by initial loadingand subsequent maintenance doses.

Loading dose This is a single or few quicklyrepeated doses given in the beginning to attain tar-get concentration rapidly. It may be calculated as—

target Cp × VLoading dose = —————— ...(12)

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Kinetics of Elimination 29

Fig. 2.13 Relationship between dose rate and averagesteady-state plasma concentration of drugs eliminated byfirst order and Michaelis Menten (zero order) kinetics

Fig. 2.14: Plateau principle of drug accumulation on repeatedoral dosingNote. The area of the two shaded portions is equal.


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Thus, loading dose is governed only by V and notby CL or t½.

Maintenance dose This dose is one that is to berepeated at specified intervals after the attainmentof target Cpss so as to maintain the same by balan-cing elimination. The maintenance dose rate iscomputed by equation (10) and is governed by CL(or t½) of the drug. If facilities for measurement ofdrug concentration are available, attainment oftarget level in a patient can be verified sub-sequently and dose rate adjusted if required.

Such two phase dosing provides rapid thera-peutic effect with long-term safety; frequentlyapplied to digoxin, chloroquine, doxycycline, etc.However, if there is no urgency, maintenance dosescan be given from the beginning.

PROLONGATION OF DRUG ACTIONIt is sometimes advantageous to modify a drug insuch a way that it acts for a longer period. Bydoing so:(i) Frequency of administration is reduced—more convenient.(ii) Improved patient compliance—a singlemorning dose is less likely to be forgotten/omittedthan a 6 or 8 hourly regimen.(iii) Large fluctuations in plasma concentrationare avoided—side effects related to high peakplasma level just after a dose would be minimized(e.g. nifedipine); better round-the-clock control ofblood sugar, etc.(iv) Drug effect could be maintained overnightwithout disturbing sleep, e.g. antiasthmatics,anticonvulsants, etc.

However, all drugs do not need to be madelong acting, e.g. those used for brief therapeuticeffect (sleep inducing hypnotic, headache remedy)or those with inherently long duration of action(digoxin, amlodipine, doxycycline, omeprazole).Drugs with t½ < 4 hr are suitable for controlledrelease formulations, while there is no need ofsuch formulations for drugs with t½ >12 hr.Methods utilized for prolonging drug action aresummarized below. Some of these have alreadybeen described.

1. By prolonging absorption from site ofadministration(a) Oral Sustained release tablets, spansulecapsules, etc.; drug particles are coated with resins,plastic materials or other substances whichtemporally disperse release of the active ingredientin the g.i.t. The controlled release tablet/capsulepreparation utilizes a semipermeable membraneto control the release of drug from the dosage form.Such preparations prolong the action by 4 to 6hours and no more because in that time drugparticles reach the colon.

(b) Parenteral The s.c. and i.m. injection of drugin insoluble form (benzathine penicillin, lenteinsulin) or as oily solution (depot progestins);pellet implantation, sialistic and biodegradableimplants can provide for its absorption over acouple of days to several months or even years.Inclusion of a vasoconstrictor with the drug alsodelays absorption (adrenaline with local anaes-thetics).

(c) Transdermal drug delivery systems The drugimpregnated in adhesive patches, strips or asointment applied on skin is becoming popular,e.g. glyceryl trinitrate.

2. By increasing plasma protein bindingDrug congeners have been prepared which arehighly bound to plasma protein and are slowlyreleased in the free active form, e.g. sulfadoxine.

3. By retarding rate of metabolism Smallchemical modification can markedly affect the rateof metabolism without affecting the biologicalaction, e.g. addition of ethinyl group to estradiolmakes it longer acting and suitable for use as oralcontraceptive. Inhibition of specific enzyme byone drug can prolong the action of another drug,e.g. allopurinol inhibits degradation of 6-mer-captopurine; ritonavir boosts the action of indina-vir, cilastatin protects imipenem from degradationin kidney.

4. By retarding renal excretion The tubularsecretion of drug being an active process, can besuppressed by a competing substance, e.g. pro-benecid prolongs duration of action of penicillinand ampicillin.

Pharmacodynamics is the study of drug effects.It attempts to elucidate the complete action-effectsequence and the dose-effect relationship.Modification of the effects of one drug by anotherdrug and by other factors is also an aspect ofpharmacodynamics.

PRINCIPLES OF DRUG ACTION

Drugs (except those gene based) do not impartnew functions to any system, organ or cell; theyonly alter the pace of ongoing activity. The basictypes of drug action can be broadly classed as:

1. Stimulation It refers to selective enhance-ment of the level of activity of specialized cells,e.g. adrenaline stimulates heart, pilocarpinestimulates salivary glands. However, excessivestimulation is often followed by depression ofthat function, e.g. high dose of picrotoxin, acentral nervous system (CNS) stimulant,produces convulsions followed by coma andrespiratory depression.

2. Depression It means selective diminutionof activity of specialized cells, e.g. barbituratesdepress CNS, quinidine depresses heart, localanaesthetics depress nerve conduction.

Certain drugs stimulate one type of cells butdepress the other, e.g. acetylcholine stimulatesintestinal smooth muscle but depresses SA nodein heart. Thus, most drugs cannot be just classedas stimulants or depressants.

3. Irritation This connotes a nonselective,often noxious effect and is particularly appliedto less specialized cells (epithelium, connectivetissue). Mild irritation may stimulate associatedfunction, but strong irritation results in inflam-mation, corrosion, necrosis and morphologicaldamage. This may result in diminution or lossof function.

4. Replacement This refers to the use of natu-ral metabolites, hormones or their congeners indeficiency states, e.g. levodopa in parkinsonism,insulin in diabetes mellitus, iron in anaemia.

5. Cytotoxic action Selective cytotoxic actionfor invading parasites or cancer cells, attenuatingthem without significantly affecting the host cellsis utilized for cure/palliation of infections andneoplasms, e.g. penicillin, chloroquine, zido-vudine, cyclophosphamide, etc.

MECHANISM OF DRUG ACTION

Only a handful of drugs act by virtue of theirsimple physical or chemical property; examplesare:• Bulk laxatives—physical mass• Charcoal—adsorptive property• Mannitol—osmotic activity• 131I and other radioisotopes—radioactivity• Antacids—neutralization of gastric HCl• Pot. permanganate—oxidizing property• Dimercaprol—chelation of heavy metals.

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Pharmacodynamics

32 PharmacodynamicsS

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Majority of drugs produce their effects byinteracting with a discrete target biomolecule,which usually is a protein. This also confersselectivity of action to the drug. Functionalproteins that are targets of drug action can begrouped into four basic categories, viz. enzymes,ion channels, transporters and receptors (Fig. 3.1).However, a few drugs do act on other proteins(e.g. colchicine, vinca alkaloids, taxanes bind tothe structural protein tubulin) or on nucleic acids(alkylating agents).

I. ENZYMES

Almost all biological reactions are carried outunder catalytic influence of enzymes; hence,enzymes are a very important target of drugaction. Drugs can either increase or decrease therate of enzymatically mediated reactions. How-ever, in physiological systems enzyme activitiesare often optimally set. Thus, stimulation ofenzymes by drugs, that are truly foreignsubstances, is unusual. Enzyme stimulation isrelevant to some natural metabolites only, e.g.pyridoxine acts as a cofactor and increasesdecarboxylase activity. Several enzymes arestimulated through receptors and secondmessengers, e.g. adrenaline stimulates hepaticglycogen phosphorylase enzyme through βreceptors and cyclic AMP (second messenger).Stimulation of an enzyme increases its affinityfor the substrate so that rate constant (kM) of thereaction is lowered (Fig. 3.2).

Apparent increase in enzyme activity can alsooccur by enzyme induction, i.e. synthesis of moreenzyme protein. This cannot be called stimulationbecause the kM does not change. Many drugsinduce microsomal enzymes (see p. 23).

Inhibition of enzymes is a common mode ofdrug action.

A. Nonspecific inhibition Many chemicalsand drugs are capable of denaturing proteins.They alter the tertiary structure of any enzymewith which they come in contact and thus inhibit

Fig. 3.1: Four major types of biomacromoleculartargets of drug action(A) Enzyme; (B) Transmembrane ion channel;(C) Membrane bound transporter; (D) Receptor (seetext for description)

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it. Heavy metal salts, strong acids and alkalies,alcohol, formaldehyde, phenol inhibit enzymesnonspecifically. Such inhibitors are too dama-ging to be used systemically.

B. Specific inhibition Many drugs inhibit aparticular enzyme without affecting others. Suchinhibition is either competitive or noncompeti-tive.

(i) Competitive (equilibrium type) The drugbeing structurally similar competes with thenormal substrate for the catalytic binding site ofthe enzyme (Fig. 3.1A), so that a new equilibriumis achieved in the presence of the drug. Suchinhibitors increase the kM but the Vmax remainsunchanged (Fig. 3.2), i.e. higher concentrationof the substrate is required to achieve ½ maximalreaction velocity, but if substrate concentrationis sufficiently increased, it can displace the drugand the same maximal reaction velocity can beattained. Examples are:• Physostigmine and neostigmine compete

with acetylcholine for cholinesterase.• Sulfonamides compete with PABA for

bacterial folate synthetase.

• Allopurinol competes with hypoxanthine forxanthine oxidase.

• Carbidopa and methyldopa compete withlevodopa for dopa decarboxylase.

A nonequilibrium type of enzyme inhibition canalso occur with drugs which react with the samecatalytic site of the enzyme but either form strongcovalent bonds or have such high affinity for theenzyme that the normal substrate is not able todisplace the inhibitor, e.g.• Organophosphates react covalently with the

esteretic site of the enzyme cholinesterase.• Methotrexate has 50,000 times higher affinity

for dihydrofolate reductase than the normalsubstrate DHFA.

In these situations, kM is increased and Vmax isreduced.

(ii) Noncompetitive The inhibitor reacts withan adjacent site and not with the catalytic site,but alters the enzyme in such a way that it losesits catalytic property. Thus, kM is unchanged butVmax is reduced. Examples are:

Noncompetitive Enzymeinhibitor

Acetazolamide — Carbonic anhydraseAspirin, — CyclooxygenaseindomethacinDisulfiram — Aldehyde

dehydrogenaseOmeprazole — H+ K+ ATPaseDigoxin — Na+ K+ ATPaseTheophylline — PhosphodiesterasePropylthiouracil — Peroxidase in thyroidLovastatin — HMG-CoA reductase

II. ION CHANNELS

Proteins which act as ion selective channelsparticipate in transmembrane signaling andregulate intracellular ionic composition. Thismakes them a common target of drug action.Drugs can affect ion channels either throughspecific receptors (ligand gated ion channels,

Mechanism of Drug Action 33

Fig. 3.2: Effect of enzyme induction, stimulation andinhibition on kinetics of the reaction

Vmax—Maximum velocity of reaction; Vmax (s) of stimulatedenzyme; Vmax (i)—in presence of noncompetitive inhibitor;kM—rate constant of the reaction; kM (s)—of stimulatedenzyme; kM (i)—in presence of competitive inhibitorNote: Enzyme induction and noncompetitive inhibition donot change the affinity of the enzyme (kM is unaltered),whereas enzyme stimulation and competitive inhibitionrespectively decrease and increase the kM.


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G-protein operated ion channels, see p. 37, 38 and39), or by directly binding to the channel andaffecting ion movement through it, e.g. localanaesthetics which physically obstruct voltagesensitive Na+ channels (see Ch. 25). In addition,certain drugs modulate the opening and closingof channels, e.g.:• Nifedipine blocks L-type of voltage sensitive

Ca2+ channel.• Nicorandil opens ATP-sensitive K+ channels.• Sulfonylurea hypoglycaemics inhibit pan-

creatic ATP- sensitive K+ channels.• Amiloride inhibits renal epithelial Na+

channels.

III. TRANSPORTERS

Several substrates are translocated across mem-branes by binding to specific transporters(carriers) which either facilitate diffusion in thedirection of the concentration gradient or pumpthe metabolite/ion against the concentrationgradient using metabolic energy (see Fig. 2.5).Many drugs produce their action by directlyinteracting with the carrier protein to inhibit theongoing physiological transport of themetabolite/ion. Examples are:• Desipramine blocks neuronal reuptake of

noradrenaline by inhibiting NET.• Fluoxetine selectively inhibits neuronal 5-HT

transporter SERT.• Reserpine blocks the granular reuptake of

noradrenaline and 5-HT by vesicular aminetransporter.

• Furosemide inhibits the Na+-K+-2Cl¯ cotrans-porter in the ascending limb of loop of Henle.

• Hydrochlorothiazide inhibits the Na+-Cl¯symporter in the early distal tubule.

• Probenecid inhibits active transport oforganic acids (uric acid, penicillin) in renaltubules by organic anion transporter (OAT).

IV. RECEPTORS

A large number of drugs do not bind directly tothe effectors like enzymes, channels, transporters

or structural proteins, etc. but act through speci-fic regulatory macromolecules which controlthese effectors. These macromolecules or the siteson them which bind and interact with the drugare called ‘receptors’.Receptor It is defined as a macromolecule orbinding site located on the surface or within theeffector cell that serves to recognize and initiatethe response to a signal molecule or drug, butitself has no other function. In this sense, effectors(enzymes, channels, transporters, etc.) whichbind and interact directly with a drug are notreferred to as receptors; e.g. xanthine oxidase isnot called the receptor for allopurinol.The following terms are used in describing drug-receptor interaction.Agonist An agent which activates a receptor toproduce an effect similar to that of the physio-logical signal molecule.Inverse agonist An agent which activates areceptor to produce an effect in the oppositedirection to that of the agonist.Antagonist An agent which prevents the actionof an agonist on a receptor or the subsequentresponse but does not have any effect of its own.Partial agonist An agent which activates areceptor to produce submaximal effect butantagonizes the action of a full agonist.Ligand (Latin: ligare—to bind) Any moleculewhich attaches selectively to particular receptorsor sites. The term only indicates affinity or abilityto bind without regard to functional change:agonists and competitive antagonists are bothligands of the same receptor.

Basic evidences for drug actionthrough receptors

(i) Many drugs exhibit structural specificity of action, i.e. aspecific chemical configuration is associated with a particularaction, e.g. isopropyl substitution on the ethylamine side chainof sympathetic drugs produces compounds with markedcardiac and bronchial activity—most β adrenergic agonistsand antagonists have this substitution.

Further, many drugs have shown stereospecificity inaction, e.g. levo noradrenaline is 10 times more potent than

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dextro noradrenaline; d-propranolol is about 100 times lesspotent in blocking β receptors than the l-isomer, but bothare equipotent local anaesthetics.

Thus, the cell must have some mechanism to recognizea particular chemical configuration and three-dimensionalstructure.

(ii) Competitive antagonism is seen between specificagonists and antagonists. Langley in 1878 was so impressedby the mutual antagonism among two alkaloids pilocarpineand atropine that he proposed that both reacted with thesame ‘receptive substance’ on the cell.

(iii) It was calculated by Clark that adrenaline andacetylcholine produce their maximal effect on frog’s heartby occupying only 1/6,000th of the cardiac cell surface—thus, special regions of reactivity to such drugs must bepresent on the cell.

Receptor occupation theoryAfter studying quantitative aspects of drugaction, Clark (1937) propounded a theory of drugaction based on occupation of receptors byspecific drugs and that the pace of a cellularfunction can be altered by interaction of thesereceptors with drugs (small molecular ligands).He perceived the interaction between the twomolecular species, viz. drug (D) and receptor (R)to be governed by the law of mass action, and theeffect (E) to be a direct function of the drug-receptor complex (DR) formed:

K1

D + R DR E ...(1)K2

Subsequently, it has been realized that occupa-tion of the receptor is essential but not itselfsufficient to elicit a response; the agonist mustalso be able to activate (induce a conformationalchange in) the receptor. The ability to bind withthe receptor designated as affinity, and thecapacity to induce a functional change in thereceptor designated as intrinsic activity (IA) orefficacy are independent properties. Competitiveantagonists occupy the receptor but do notactivate it. Moreover, certain drugs are partialagonists which occupy and submaximallyactivate the receptor. An all or none action is nota must at the receptor. A theoretical quantity(S)denoting strength of stimulus imparted to thecell was interposed in the Clark’s equation:

K1

D + R DR S E ...(2)K2

Depending on the agonist, DR could generate astronger or weaker S, probably as a function ofthe conformational change brought about by theagonist in the receptor.

Agonists have both affinity and maximalintrinsic activity (IA = 1), e.g. adrenaline,histamine, morphine.

Competitive antagonists have affinity but nointrinsic activity (IA = 0), e.g. propranolol, atro-pine, chlorpheniramine, naloxone.

Partial agonists have affinity and submaximalintrinsic activity (IA between 0 and 1), e.g.dichloroisoproterenol on β adrenergic receptorand pentazocine on opioid receptor.

Inverse agonists have affinity but intrinsic acti-vity with a minus sign (IA between 0 and –1),e.g. DMCM on benzodiazepine receptor.

The two-state receptor model

An alternative ‘two-state receptor’ model of drugaction has also been proposed which does notenvisage intrinsic activity to be an independentattribute of the drug. Instead, the receptor isbelieved to exist in two interchangeable statesRa (active) and Ri (inactive) which are inequilibrium. The agonist binds preferentially tothe Ra state and tilts the equilibrium to generatea response, while the competitive antagonistbinds to Ra and Ri with equal affinity so that theequilibrium is not altered and no response isgenerated. However, fewer Ra are available tobind the agonist. Further, inverse agonist isbelieved to preferentially bind to Ri, while partialagonist is supposed to have only slightly higheraffinity for Ra than for Ri. Several evidencessupport this model.

Nature of receptorsReceptors are regulatory macromolecules, mostlyproteins, though nucleic acids may also serve as



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receptors. They are no longer hypothetical.Hundreds of receptor proteins have been isolated,purified, cloned and their primary amino acid(AA) sequence has been worked out. Molecularcloning has also helped in obtaining the receptorprotein in larger quantity to study its structureand properties, and in subclassifying receptors.The surface receptors with their coupling andeffector proteins are considered to be floating ina sea of membrane lipids; the folding, orientationand topography of the system being determinedby interactions between the lipophilic and hydro-philic domains of the peptide chains with solventmolecules (water on one side and lipids on theother). Nonpolar portions of the AA chain tendto bury within the membrane, while polar groupstend to come out in the aqueous medium. In sucha delicately balanced system, it is not difficult tovisualize that a small molecular ligand bindingto one site in the receptor molecule could becapable of tripping the balance (by alteringdistribution of charges, etc.) and bringing aboutconformational changes at distant sites. Majorityof receptor molecules are made up of several non-identical subunits (heteropolymeric), and agonistbinding has been shown to bring about changesin their quaternary structure or relative align-ment of the subunits, e.g. on activation thesubunits of nicotinic receptor move apart openinga centrally located cation channel (see Fig. 3.3).

Many drugs act upon physiological receptorswhich mediate responses to transmitters, hormo-nes, autacoids and other endogenous signalmolecules; examples are cholinergic, adrenergic,histaminergic, steroid, leukotriene and otherreceptors. In addition, now some truly drugreceptors have been described for which there areno known physiological ligands, e.g. benzo-diazepine receptor, sulfonylurea receptor.

Subtypes of receptors It has been found thatmost receptors exist in multiple types andsubtypes, differing in their affinity for variousagonists and antagonists, ligand binding, tissuedistribution, transducer pathway used andmolecular composition. Illustrative examples are

muscarinic (M) and nicotinic (N) types ofcholinergic receptors and their subtypes (M1,M2....M5), α and β adrenergic receptors and theirsubtypes (α1, α2), (β1, β2, β3). This receptordiversity has been exploited in producing moreselective and more targeted newer drugs.

ACTION-EFFECT SEQUENCE

‘Drug action’ and ‘drug effect’ are often looselyused interchangeably, but are not synonymous.

Drug action It is the initial combination of thedrug with its receptor resulting in a conforma-tional change in the latter (in case of agonists),or prevention of conformational change throughexclusion of the agonist (in case of antagonists).

Drug effect It is the ultimate change in biolo-gical function brought about as a consequenceof drug action, through a series of intermediatesteps (transducer).

Receptors subserve two essential functions,viz, recognition of the specific ligand moleculeand transduction of the signal into a response.Accordingly, the receptor molecule has a ligandbinding domain (spatially and energeticallysuitable for binding the specific ligand) and aneffector domain (Fig. 3.3.) which undergoes a func-tional conformational change. These domainshave now actually been identified in somereceptors. The perturbation in the receptormolecule is variously translated into the response.The sequential relationship between drug action,transducer and drug effect can be seen in Fig. 3.5.

Transducer mechanisms

Considerable progress has been made in theunderstanding of transducer mechanisms whichin most instances have been found to be highlycomplex multistep processes that provide foramplification and integration of concurrentlyreceived extra- and intracellular signals at eachstep. These mechanisms of translation of receptoractivation into functional response can be grou-ped into four major categories. Receptors fallingin one category have also been found to possessconsiderable structural homology, and may be

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Fig. 3.4: Diagrammatic representation of G-proteincoupled receptor molecule

The receptor consists of 7 membrane spanning helicalsegments of hydrophobic amino acids. The interveningsegments connecting the helices form 3 loops on either sideof the membrane. The amino terminus of the chain lies onthe extracellular face, while the carboxy terminus is on thecytosolic side. The approximate location of the agonist andG-protein-binding sites is indicated.

considered to belong to one super family ofreceptors.

1. G-protein coupled receptors These are alarge family of cell membrane receptors whichare linked to the effector (enzyme/channel/car-rier protein) through one or more GTP-activatedproteins (G-proteins) for response effectuation.All such receptors have a common pattern ofstructural organization (Fig. 3.4). The moleculehas 7 α-helical membrane spanning hydrophobicamino acid (AA) segments which run into 3extracellular and 3 intracellular loops. The ago-nist- binding site is located somewhere betweenthe helices on the extracellular face, whileanother recognition site formed by cytosolic seg-ments binds the coupling G-protein. The G-proteins float in the membrane with theirexposed domain lying in the cytosol, and areheterotrimeric in composition (α, β and γsubunits). In the inactive state GDP is bound totheir exposed domain; activation through the

Fig. 3.3: Diagrammatic representation of direct receptor mediated operation of membrane ion channelIn case of nicotinic cholinergic receptor, the molecule (8 nm in diameter) is composed of 5 subunits (2α +β + γ + δ) enclosinga cylindrical ion channel. Normally the channel is closed (A). When two molecules of acetylcholine bind to the two α subunits(B), all subunits move apart opening the central pore to 0.7 nm, enough to allow passage of partially hydrated Na+ ions.Anions are blocked from passage through the channel by positive charges lining it.In other cases, K+, Ca2+ or Cl¯ ions move through the channel depending on its ion selectivity.



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receptor leads to displacement of GDP by GTP.The activated α-subunit carrying GTP dissociatesfrom the other two subunits and either activatesor inhibits the effector. The βγ subunits have alsobeen shown to modulate certain effectors likereceptor operated K+ channels, adenylyl cyclase(AC) and phospholipase C.

The α-subunit has GTPase activity: the boundGTP is slowly hydrolyzed to GDP: the α-subunitthen dissociates from the effector to rejoin itsother subunits, but not before the effector hasbeen activated/inhibited for a few seconds andthe signal has been amplified.

There are three major effector pathways(Table 3.1) through which G-protein coupledreceptors function:(a) Adenylyl cyclase: cAMP pathway Activationof AC results in intracellular accumulation ofsecond messenger cAMP which functions mainlythrough cAMP-dependent protein kinase (PKA).The PKA phosphorylates and alters the functionof many enzymes, ion channels, transporters andstructural proteins to manifest as increasedcontractility/impulse generation (heart, Fig. 3.5),relaxation (smooth muscle), glycogenolysis, lipo-lysis, inhibition of secretion/mediator release,modulation of junctional transmission, hormonesynthesis, etc. The reverse occurs when AC isinhibited through inhibitory Gi-protein.

(b) Phospholipase C: IP3-DAG pathway Activa-tion of phospholipase C (PLc) hydrolyzes themembrane phospholipid phosphatidyl inositol4, 5-bisphosphate (PIP2) to generate the secondmessengers inositol 1,4,5-trisphosphate (IP3) anddiacylglycerol (DAG), IP3 mobilizes Ca2+ fromintracellular organellar depots and DAG enhan-ces protein kinase C (PKc) activation by Ca2+ (Fig.3.6). Cytosolic Ca2+ (third messenger in this set-ting) is a highly versatile regulator acting throughcalmodulin (CAM), PKc and other effectors—mediates/modulates contraction, secretion/transmitter release, neuronal excitability, intra-cellular movements, membrane function, meta-bolism, cell proliferation, etc. Like AC, the PLccan also be inhibited through inhibitory G-proteinwhen directionally opposite responses would beexpected.

(c) Channel regulation The activated G-proteinscan also open or close ionic channels specific forCa2+, K+ or Na+ without the intervention of secondmessengers like cAMP or IP3, and bring abouthyperpolarization/depolarization/changes inintracellular Ca2+; e.g. Gs opens Ca2+ channels inmyocardium and skeletal muscles, while Giand Go open K+ channels in heart and smoothmuscle as well as close neuronal Ca2+ channels.Physiological responses like changes in inotropy,chronotropy, transmitter release, neuronalactivity and smooth muscle relaxation follow.

Table 3.1: Major functional pathways of G-protein coupled receptor transduction

Adenylylcyclase: cAMP Phospholipase Channel regulationIP3-DAG

↑ ↓ Ca2+↑ Ca2+↓ K+↑

Adrenergic-β Adrenergic-α2 Adrenergic-α1 Adrenergic-β1 Dopamine-D2 Adrenergic-α2

Histamine-H2 Muscarinic-M2 Histamine-H1 (Heart, GABA-B Muscarinic-M2

Dopamine-D1 Dopamine-D2 Muscarinic-M1, M3 Sk. muscle) Opioid-κ Dopamine-D2Glucagon 5-HT1 5-HT2 Adenosine-A1 5-HT1A

FSH & LH GABA-B Vasopressin-Oxytocin Somatostatin GABA-B

ACTH Opioid-μ, δ Bradykinin-B2 Opioid-μ, δTSH Angiotensin Angiotensin Adenosine-A1

Prostaglandin-EP2 Prostaglandin-EP3 Prostaglandin-FP, EP1, EP3

Prostacyclin-IP Somatostatin Thromboxane-TPAdenosine-A2 Adenosine-A1 Leukotriene

Cholecystokinin-GastrinPAF

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Fig. 3.5: The action-effect sequence of β adrenergic receptor activation in myocardial cell

Adrenaline (Adr) binds to β-adrenergic receptor (β-R) on the cell surface inducing a conformational change which permitsinteraction of the G-protein binding site with the stimulatory G-protein (Gs). The activated Gs now binds GTP (in place ofGDP), causing its active subunit to dissociate and inturn activate the enzyme adenylyl cyclase (AC) located on the cytosolicside of the membrane: ATP is hydrolyzed to cAMP which phosphorylates and thus activates cAMP-dependent proteinkinase (PKA). The PKA phosphorylates many functional proteins including troponin and phospholamban, so that they interactwith Ca2+, respectively resulting in increased force of contraction and faster relaxation. Calcium is made available by entryfrom outside (direct activation of myocardial membrane Ca2+ channels by Gs and through their phosphorylation by PKA) aswell as from intracellular stores.Action of acetylcholine (ACh) on muscarinic M2 receptor (M2–R), also located in the myocardial membrane, can similarlyactivate an inhibitory G-protein (Gi) which can oppose the activation of AC by Gs.

Receptors found to regulate ionic channelsthrough G-proteins are listed in Table 3.1.2. Receptors with intrinsic ion channel Thesecell surface receptors enclose ion selectivechannels (for Na+, K+, Ca2+ or Cl¯) within theirmolecules. Agonist binding opens the channel(Fig. 3.3) and causes depolarization/hyperpo-larization/changes in cytosolic ionic composi-tion, depending on the ion that flows through.The nicotinic cholinergic, GABA-A, glycine

(inhibitory), excitatory AA (kainate, NMDA orN-methyl-D-aspartate, quisqualate) and 5-HT3

receptors fall in this category.The receptor is usually a pentameric protein; all subunits, inaddition to large intra- and extracellular segments, generallyhave four membrane spanning domains in each of whichthe AA chain traverses the width of the membrane six times.The subunits are thought to be arranged round the channellike a rosette and the α subunits usually bear the agonist-binding sites.

Certain receptor operated ion channels also havesecondary ligands which bind to an allosteric site and



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a single transmembrane stretch of peptide chain.There are two major subgroups of such receptors:(a) Those having intrinsic tyrosine/serineprotein-kinase activity or guanylyl cyclase acti-vity which generates cGMP as second messenger.(b) Those without intrinsic enzymatic activity,but bind a JAK-STAT-Kinase on activation.The general scheme of operation of these twosubgroups of enzyme-linked receptors is illus-trated respectively in Fig. 3.7A and 3.7B.Examples of protein kinase receptors are insulinand various growth factors receptors, while thoseof JAK-STAT-Kinase binding receptors are cyto-kine, interferon and growth hormone receptors.

The enzyme-linked receptors transduceresponses in a matter of minutes to few hours.

4. Receptors regulating gene expression(Transcription factors) In contrast to the above3 classes of receptors, these are intracellularcytoplasmic (as in case of steroidal hormones)or nuclear (in case of thyroid hormone) solubleproteins which respond to lipid-soluble chemicalmessengers that penetrate the cell (Fig. 3.8). Thereceptor protein (specific for each hormone/regulator) is inherently capable of binding tospecific genes, but is kept inhibited till thehormone binds near its carboxy terminus andexposes the DNA binding regulatory segmentlocated in the middle of the molecule. Attachmentof the receptor protein to the genes facilitates theirexpression so that specific mRNA is synthesizedon the template of the gene. This mRNA movesto the ribosomes and directs synthesis of specificproteins which regulate the activity of target cells.All steroidal hormones (glucocorticoids, minera-locorticoids, androgens, estrogens, progeste-rone), thyroxine, vit D and vit A function in thismanner. This transduction mechanism is theslowest in its time course of action.

Receptor regulation

Receptors exist in a dynamic state; their densityand efficacy is subject to regulation by the levelof ongoing activity and other physiopathologicalinfluences. In tonically active systems, prolonged

Fig. 3.6: The important steps of phospholipase C(PLc)pathway of response effectuation (in smooth muscle)

The agonist, e.g. histamine binds to its H1 receptor (H1 R) andactivates the G-protein Gq, which in turn activates membranebound phospholipase C (PLc) that hydrolyzes phosphatidylinositol 4, 5-bisphosphate (PIP2), a membrane bound phos-pholipid. The products inositol 1, 4, 5-trisphosphate (IP3) anddiacylglycerol (DAG) act as second messengers. The primaryaction of IP3 is facilitation of Ca2+ mobilization from intracellularorganellar pools, while DAG in conjunction with Ca2+ activatesprotein kinase C (PKc) which phosphorylates and alters theactivity of a number of functional and structural proteins.Cytosolic Ca2+ is a veritable messenger: combines withcalmodulin (CAM) to activate myosin light chain kinase (MLCK)inducing contraction, and another important regulator calcium-calmodulin protein kinase (CCPK). Several other effectors areregulated by Ca2+ in a CAM dependent or independent manner.

modulate the gating of the channel by the primary ligand, e.g.the benzodiazepine receptor modulates GABAA gatedCl¯channel.

Thus, in these receptors, agonists directly operateion channels, without the intervention of anycoupling protein or second messenger. The onsetand offset of responses through this class ofreceptors is the fastest.

3. Enzyme-linked receptors This class ofreceptors have a subunit with enzymaticproperty or bind a JAK (Janus-Kinase) enzymeon activation. The agonist-binding site and thecatalytic site lie respectively on the outer andinner face of the plasma membrane (Fig. 3.7).These two domains are interconnected through

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deprivation of the agonist (by denervation orcontinued use of an antagonist or a drug whichreduces input) results in supersensitivity of thereceptor as well as the effector system to theagonist. This has clinical relevance in clonidineand CNS depressant/opioid withdrawal syn-dromes, sudden discontinuation of propranololin angina pectoris, etc. The mechanisms involvedmay be unmasking of receptors or their proli-feration (up regulation) or accentuation of signalamplification by the transducer.

Conversely, continued intense receptorstimulation causes desensitization or refractori-ness: the receptor becomes less sensitive to theagonist. This can be easily demonstrated experi-mentally (Fig. 3.9); clinical examples arebronchial asthma patients treated continuouslywith β-adrenergic agonists and parkinsonianpatients treated with high doses of levodopa. Thechanges may be brought about by:

(i) Masking or internalization of the receptor(the receptor becomes inaccessible to theagonist). In this case refractoriness develops aswell as fades quickly.

(ii) Decreased synthesis/increased destruction ofthe receptor (down regulation): refractoriness deve-lops over weeks or months and recedes slowly.Receptor downregulation is particularly exhi-bited by the tyrosine protein kinase receptors.

Sometimes response to all agonists which actthrough different receptors but produce the sameovert effect (e.g. histamine and acetylcholine bothcontract intestinal smooth muscle) is decreasedby exposure to any one of these agonists (hetero-logous desensitization), showing that mecha-nisms of response effectuation have become lessefficient. However, often desensitization is limi-ted to agonists of the receptor being repeatedlyactivated (homologous desensitization).

Functions of receptors These can be summa-rized as:(a) To propagate regulatory signals from outsideto within the effector cell when the molecularspecies carrying the signal cannot itself penetratethe cell membrane.(b) To amplify the signal.(c) To integrate various extracellular and intra-cellular regulatory signals.


Fig. 3.7: Models of enzyme-linked receptorsA. Intrinsic tyrosine protein kinase receptor: On binding the peptide hormone to the extracellular domains, the monomeric

receptors move laterally in the membrane and form diamers. Dimerization activates tyrosine-protein kinase (t-Pr-K) activityof the intracellular domains so that they phosphorylate tyrosine (t) residues on each other, as well as on several SH2 domainsubstrate proteins (SH2-Pr). The phosphorylated substrate proteins then perform downstream signaling function.

B. JAK-STAT kinase binding receptor: The intracellular domain of these receptors lacks intrinsic protein kinase activity.Signal molecule binding to the extracellular domain induces receptor dimerization which activates the intracellular domainto bind free moving JAK (Janus Kinase) molecules. The activated JAK phosphorylate tyrosine residues on the receptorwhich then binds another protein STAT (signal transducer and activator of transcription). Tyrosine residues of STATalso get phosphorylated by JAK. The phosphorylated STAT dimerize, dissociate from the receptor and move to thenucleus to regulate transcription of target genes.


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Fig. 3.8: Operational scheme of intracellular (glucocorticoid) receptor

The glucocorticoid (G) penetrates the cell membrane and binds to the glucocorticoid receptor (GR) protein that normallyresides in the cytoplasm in association with 3 other proteins, viz. heat shock protein 90 (HSP90), HSP70 and immunophilin(IP). The GR has a steroid-binding domain near the carboxy terminus and a mid-region DNA-binding domain having two‘zinc fingers’, each made up of a loop of amino acids with chelated zinc ion. Binding of the steroid to GR dissociates thecomplexed proteins (HSP90, etc.) removing their inhibitory influence on it. A dimerization region that overlaps the steroid-binding domain is exposed, promoting dimerization of the occupied receptor. The steroid bound receptor diamer translocatesto the nucleus and interacts with specific DNA sequences called ‘glucocorticoid responsive elements’ (GREs) within theregulatory region of appropriate genes. The expression of these genes is consequently altered resulting in promotion (orsuppression) of their transcription. The specific mRNA thus produced is directed to the ribosome where the message istranslated into a specific pattern of protein synthesis, which in turn modifies cell function.

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Fig. 3.10: Dose-response and log dose-response curves

(d) To adapt to short-term and long-termchanges in the regulatory melieu and maintainhomeostasis.

DOSE-RESPONSE RELATIONSHIP

When a drug is administered systemically, thedose-response relationship has two components:dose-plasma concentration relationship and plasmaconcentration-response relationship. The former isdetermined by pharmacokinetic considerationsand ordinarily, descriptions of dose-responserelationship refer to the latter, which can be moreeasily studied in vitro.

Generally, the intensity of response increaseswith increase in dose (or more precisely concen-tration at the receptor) and the dose-responsecurve is a rectangular hyperbola (Fig. 3.10). Thisis because drug-receptor interaction obeys lawof mass action, accordingly—

Emax × [D]E = ————— ...(3)

KD + [D]

where E is the observed effect at a dose [D] ofthe drug, Emax is the maximal response, KD isthe dissociation constant of the drug-receptorcomplex, which is equal to the dose of drug atwhich half maximal response is produced. If thedose is plotted on a logarithmic scale, the curvebecomes sigmoid and a linear relationship bet-ween log of dose and the response is seen in theintermediate (30-70% response) zone, as can bepredicted from equation (3). This is not peculiarto drugs. In fact, all stimuli are graded biologi-cally by the fractional change in stimulusintensity, e.g. 1 kg and 2 kg weights held in twohands can be easily differentiated, but not 10 kgand 11 kg weights; though the absolutedifference remains 1 kg, there is a 100% fractionalchange in the former case but only 10% changein the latter case. In other words, response isproportional to an exponential function (log) ofthe dose.

The log dose-response curve (DRC) can becharacterized by its shape (slope and maxima)and position on the dose axis.

Drug potency and efficacy

The position of DRC on the dose axis is the indexof drug potency which refers to the amount ofdrug needed to produce a certain response. ADRC positioned rightward indicates lower

Fig. 3.9: Illustration of the phenomenon of desensitization

Contractile responses of frog’s rectus abdominis muscle toacetylcholine. Note that shortly after exposure to a high (100-fold) dose of the agonist, the response is markedlyattenuated, but is regained if sufficient time is allowed toelapse.

Dose-Response Relationship 43


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(a) Aspirin is less potent as well as less effica-cious analgesic than morphine.(b) Pethidine is less potent but equallyefficacious analgesic as morphine.(c) Furosemide is less potent but moreefficacious diuretic than metolazone.(d) Diazepam is more potent but less efficaciousCNS depressant than pentobarbitone.

Depending on the type of drug, both higherefficacy (as in the case of furosemide: acts evenin renal failure), or lower efficacy (as in the caseof diazepam: safety in overdose) could beclinically advantageous.

The slope of the DRC is also important. Asteep slope indicates that a moderate increase indose will markedly increase the response (doseneeds individualization), while a flat one impliesthat little increase in response will occur over awide dose range (standard doses can be given tomost patients). Hydralazine has a steep, whilehydrochlorothiazide has a flat DRC of anti-hypertensive effect (Fig. 3.12).

Selectivity Drugs seldom produce just oneaction: the DRCs for different effects of a drug

Fig. 3.11: Illustration of drug potency and drug efficacy.Dose-response curve of four drugs producing the samequalitative effectNote:Drug B is less potent but equally efficacious as drug A.Drug C is less potent and less efficacious than drug A, butequally potent and less efficacious than drug B.Drug D is more potent than drugs A, B, & C, but less efficaciousthan drugs A & B, and equally efficacious as drug C.

Fig. 3.12: Steep and flat dose-response curves, illustratedby antihypertensive effect of hydralazine and hydrochloro-thiazide

potency (Fig. 3.11). Relative potency is oftenmore meaningful than absolute potency, e.g. if10 mg of morphine = 100 mg of pethidine,morphine is 10 times more potent thanpethidine. However, a higher potency, in itself,does not confer clinical superiority unless thepotency for therapeutic effect is selectivelyincreased over potency for adverse effect.

The upper limit of DRC is the index of drugefficacy and refers to the maximal response thatcan be elicited by the drug, e.g. morphine pro-duces a degree of analgesia not obtainable withany dose of aspirin—morphine is more effica-cious than aspirin. Efficacy is a more decisivefactor in the choice of a drug.

Often, the terms ‘drug potency’ and ‘drug effi-cacy’ are used interchangeably, but these are notsynonymous and refer to different characteris-tics of the drug. The two can vary independently:

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may be different. The extent of separation ofDRCs of a drug for different effects is a measureof its selectivity, e.g. the DRCs for bronchodila-tation and cardiac stimulation (Fig. 3.13) arequite similar in case of isoprenaline but far apartin case of salbutamol—the latter is a moreselective bronchodilator drug.

The gap between the therapeutic effect DRCand the adverse effect DRC defines the safetymargin or the therapeutic index of a drug. Inexperimental animals, therapeutic index is oftencalculated as:

median lethal doseTherapeutic index = —————————–

median effective dose

LD50 or ——–

ED50

But this is irrelevant in the clinical set up wherethe therapeutic range is bounded by the dosewhich produces minimal therapeutic effect andthe dose which produces maximal acceptableadverse effect (Fig. 3.14). Because of inter-individual variability, the effective dose of a drugfor one subject may be toxic for the other. A drug

may be capable of inducing a higher therapeuticresponse (have higher efficacy), but develop-ment of intolerable adverse effects may precludeuse of higher doses, e.g. prednisolone inbronchial asthma.

Risk-benefit ratio This term is very frequentlyused, and conveys a judgement on the estimatedharm (adverse effects, inconvenience) vsexpected advantages (relief of symptoms, cure,reduction of complications/mortality, improve-ment in quality of life). A drug should beprescribed only when the benefits outweigh therisks. However, risk-benefit ratio can hardly everbe accurately measured for each instance of druguse. The physician has to rely on data from useof drugs in large populations (pharmacoepide-miology) and his own experience of the drug andthe patient.

COMBINED EFFECT OF DRUGS

When two or more drugs are given simulta-neously or in quick succession, they may beeither indifferent to each other or exhibit syner-gism or antagonism. The interaction may takeplace at pharmacokinetic level (see Ch. 2) or atpharmacodynamic level.

Fig. 3.14: Illustrative dose-response curves for therapeuticeffect and adverse effect of the same drug

Fig. 3.13: Illustration of drug selectivityLog dose-response curves of salbutamol for broncho-dilatation (A) and cardiac stimulation (D)Log dose-response curves of isoprenaline for broncho-dilatation (B) and cardiac stimulation (C).

Combined Effect of Drugs 45


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SYNERGISM(Greek: Syn—together; ergon—work)

When the action of one drug is facilitated orincreased by the other, they are said to be syner-gistic. In a synergistic pair both the drugs canhave action in the same direction or given aloneone may be inactive but still enhance the actionof the other when given together. Synergism canbe:

(a) Additive The effect of the two drugs are inthe same direction and simply add up:

effect of drugs A + B = effect of drug A + effect of drug B

Examples are—Aspirin + paracetamol : as analgesic/

antipyreticNitrous oxide + ether : as general

anaestheticAmlodipine + : as antihypertensiveatenolol Glibenclamide + : as hypoglycaemicmetformin

Side effects of components of an additive pairmay be different—do not add up. Thus, thecombination is better tolerated than higher doseof one component.

(b) Supra-additive (potentiation) The effect ofcombination is greater than the individual effectsof the components:

effect of drug A + B > effect of drug A +effect of drug B

This is always the case when one componentgiven alone produces no effect, but enhances theeffect of the other. Examples are given in the box.

ANTAGONISM

When one drug decreases or abolishes the actionof another, they are said to be antagonistic:

effect of drugs A + B < effect of drug A + effect of drug B.

Usually, in an antagonistic pair one drug isinactive as such but decreases the effect of the

other. Depending on the mechanism involved,antagonism may be:

(a) Physical antagonism Based on the physi-cal property of the drugs, e.g. charcoal adsorbsalkaloids and can prevent their absorption—used in alkaloidal poisonings.

(b) Chemical antagonism The two drugs reactchemically and form an inactive product, e.g.• KMnO4 oxidizes alkaloids—used for gastric

lavage in poisoning.• Tannins + alkaloids—insoluble alkaloidal

tannate is formed.• Chelating agents (BAL, Cal. disod. edetate)

complex metals (As, Pb).• Nitrites form methaemoglobin which reacts

with cyanide radical.

Drugs may react when mixed in the samesyringe or infusion bottle:• Thiopentone sod. + succinylcholine chloride• Penicillin-G sod. + succinylcholine chloride• Heparin + penicillin/tetracyclines/strepto-

mycin/hydrocortisone

(c) Physiological / functional antagonism Thetwo drugs act on different receptors or by differentmechanisms, but have opposite overt effects on

Supraadditive drug combinations

Drug pair Basis of potentiation

Acetylcholine + Inhibition of breakphysostigmine downLevodopa + carbidopa/ Inhibition of peri-benserazide pheral metabolismAdrenaline + cocaine/ Inhibition ofdesipramine neuronal uptakeSulfamethoxazole + Sequential blockadetrimethoprimAntihypertensives Tackling two(enalapril+ contributory factorshydrochlorothiazide)Tyramine + MAO Increasing release-inhibitors able CA store

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the same physiological function, i.e. havepharmacological effects in opposite direction, e.g.• Histamine and adrenaline on bronchial

muscles and BP.• Hydrochlorothiazide and triamterene on

urinary K+ excretion.• Glucagon and insulin on blood sugar level.

(d) Receptor antagonism One drug (antagonist)blocks the receptor action of the other (agonist).This is a very important mechanism of drugaction, because physiological signal moleculesact through their receptors, blockade of whichcan produce specific and often profoundpharmacological effects. Receptor antagonists areselective (relatively), i.e. an anticholinergic willoppose contraction of intestinal smooth muscleinduced by cholinergic agonists, but not thatinduced by histamine or 5-HT (they act througha different set of receptors). Receptor antagonismcan be competitive or noncompetitive.

Competitive antagonism (equilibrium type) Theantagonist is chemically similar to the agonist,competes with it (Fig. 3.15A, D) and binds to thesame site to the exclusion of the agonistmolecules. Because the antagonist has affinitybut no intrinsic activity, no response is produced.Since antagonist binding is reversible anddepends on the relative concentration of theagonist and antagonist molecules, higherconcentration of the agonist progressivelyovercomes the block—a parallel shift to the rightof the agonist DRC with no suppression ofmaximal response is obtained (Fig. 3.16a). Theextent of shift is dependent on the affinity andconcentration of the antagonist.

A partial agonist (Fig. 3.15C), having affinityfor the same receptor, also competes with andantagonizes a full agonist, while producing asubmaximal response of its own.

Noncompetitive antagonism The antagonist ischemically unrelated to the agonist, binds to adifferent allosteric site altering the receptor insuch a way that it is unable to combine with theagonist (Fig. 3.15E), or unable to transduce theresponse, so that the downstream chain of events

Fig. 3.15: Illustration of sites of action of agonists andantagonists (A), and the action of full agonist (B), partialagonist (C), competitive antagonist (D) and noncompetitiveantagonist (E) on the receptor

are uncoupled. Because the agonist and the anta-gonist are combining with different sites, thereis no competition between them—even highagonist concentration is unable to reverse theblock completely. Increasing concentrations ofthe antagonist progressively flatten the agonistDRC (Fig. 3.16b).

Combined Effect of Drugs 47


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Fig. 3.16: Dose-response curves showing competitive (a) and noncompetitive (b) antagonismA—agonist, B—competitive antagonist, C—noncompetitive antagonist

Competitive (equilibrium type) Noncompetitive

1. Antagonist binds with the same receptor Binds to another site of receptoras the agonist

2. Antagonist resembles chemically with Does not resemblethe agonist

3. Parallel rightward shift of agonist DRC Flattening of agonist DRC4. The same maximal response can be Maximal response is suppressed

attained by increasing dose of agonist (unsurmountable antagonism)(surmountable antagonism)

5. Intensity of response depends on the concen- Maximal response depends only on the concentrationtration of both agonist and antagonist of antagonist

6. Examples: ACh—Atropine Diazepam—BicucullineMorphine—Naloxone

Nonequilibrium (competitive) antagonismCertain antagonists bind to the receptor withstrong (covalent) bonds or dissociate from itslowly so that agonist molecules are unable toreduce receptor occupancy of the antagonistmolecules—law of mass action cannot apply—an irreversible or nonequilibrium antagonism isproduced. The agonist DRC is shifted to the rightand the maximal response is lowered (if sparereceptors are few). Since flattening of agonistDRC is a feature of noncompetitive antagonism;nonequilibrium antagonism has also been called‘a type of noncompetitive antagonism’.Phenoxybenzamine is a nonequilibrium

antagonist of adrenaline at the α adrenergicreceptors.

Features of competitive and noncompetitiveantagonism are compared in the box.

DRUG DOSAGE

‘Dose’ is the appropriate amount of a drugneeded to produce a certain degree of responsein a patient. Accordingly, dose of a drug has tobe qualified in terms of the chosen response, e.g.the analgesic dose of aspirin for headache is0.3–0.6 g, its antiplatelet dose is 75–150 mg/day,while its anti-inflammatory dose for rheumatoidarthritis is 3–5 g per day. Similarly, there could

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Drug Dosage 49

be prophylactic dose, a therapeutic dose or a toxicdose of the same drug.

The dose of a drug is governed by its inherentpotency, i.e. the concentration at which it shouldbe present at the target site, and its pharmaco-kinetic characteristics. In addition, it is modifiedby a number of factors (see below). However,different strategies are adopted for individua-lizing drug dosage.

1. Standard dose The same dose is appro-priate for most patients—individual variationsare minor or the drug has a wide safety marginso that enough can be given to cover them, e.g.oral contraceptives, penicillin, chloroquine,mebendazole, amantadine.

2. Regulated dose The drug modifies a finelyregulated body function which can be easilymeasured. The dosage is accurately adjusted byrepeated measurement of the affected physiolo-gical parameter, e.g. antihypertensives, hypogly-caemics, anticoagulants, diuretics, generalanaesthetics.

3. Target level dose (see p. 29) The responseis not easily measurable but has been demon-strated to be obtained at a certain range of drugconcentration in plasma. An empirical doseaimed at attaining the target level is given in thebeginning and adjustments are made later bymeasuring the plasma concentration or by obser-ving the patient at relatively long intervals, e.g.antidepressants, antiepileptics, digoxin, lithium,theophylline.

4. Titrated dose The dose needed to producemaximal therapeutic effect cannot be givenbecause of intolerable adverse effects. Optimaldose is arrived at by titrating it with anacceptable level of adverse effect. Low initialdose and upward titration (in most non-criticalsituations) or high initial dose and downwardtitration (in critical situations) can be practised.Often, a compromise between submaximaltherapeutic effect but tolerable side effects canbe struck, e.g. anticancer drugs, corticosteroids,levodopa.

Fixed dose ratio combination preparations

A large number of pharmaceutical preparationscontain two or more drugs in a fixed dose ratio.Advantages offered by these are:

1. Convenience, better patient compliance andmay be cost saving—when all the compo-nents present in a formulation are actuallyneeded by the patient.

2. Certain drug combinations are synergistic,e.g. sulfamethoxazole + trimethoprim; levo-dopa + carbidopa/benserazide; combinationoral contraceptives.

3. The therapeutic effect of two componentsbeing same may add up while the side effectsbeing different may not.

4. The side effect of one component may becounteracted by the other, e.g. a thiazide + apotassium sparing diuretic.

5. Combined formulation ensures that a singledrug will not be taken. This is important inthe treatment of tuberculosis and HIV-AIDS.

Before prescribing a combination, the physicianmust consider whether any of the ingredients isunnecessary; if it is, the combination should notbe prescribed.

There are many inbuilt disadvantages of fixeddose ratio combinations:• The patient may not actually need all the

drugs present in a combination: he is sub-jected to additional side effects and expense(often due to ignorance of the physician aboutthe exact composition of the combinedformulations).

• The dose of most drugs needs to be adjustedand individualized. When a combined for-mulation is used, this cannot be done withoutaltering the dose of the other component(s).

• The time course of action of the componentsmay be different.

• Altered renal or hepatic function of the patientmay differently affect the pharmacokineticsof the components.


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• Adverse effect, when it occurs, cannot beeasily ascribed to the particular drug causingit.

• Contraindication to one component (allergy,other conditions) contraindicates the wholepreparation.

• Confusion of therapeutic aims and false senseof superiority of two drugs over one isfostered, especially in case of antimicrobialswhose combinations should be avoided.Corticosteroids should never be combinedwith any other drug meant for internal use.

Thus, only a handful of fixed dose ratio combi-nations are rational and justified, while far toomany are available and vigorously promoted.

FACTORS MODIFYING DRUG ACTION

Variation in response to the same dose of a drugbetween different patients and even in the samepatient on different occasions is a rule rather thanexception. One or more of the following cate-gories of differences among individuals areresponsible for the variations in drug response:(1) Individuals differ in pharmacokinetic hand-ling of drugs: attain varying plasma/target siteconcentration of the drug. This is more markedfor drugs disposed by metabolism (e.g. pro-pranolol) than for drugs excreted unchanged(e.g. atenolol).(2) Variations in number or state of receptors,coupling proteins or other components ofresponse effectuation.(3) Variations in neurogenic/hormonal tone orconcentrations of specific constituents, e.g. atro-pine tachycardia depends on vagal tone, propra-nolol bradycardia depends on sympathetic tone,captopril hypotension depends on body Na+

status.

A multitude of host and environmental factorsinfluence drug response. Though individualvariation cannot be totally accounted for by thesefactors, their understanding can guide choice ofappropriate drug and dose for an individual

patient. However, final adjustments have to bemade by observing the response in a given patienton a given occasion.

These factors modify drug action either:(a) Quantitatively The plasma concentrationand/or the action of the drug is increased ordecreased. Most of the factors introduce this typeof change and can be dealt with by adjustmentof drug dosage.(b) Qualitatively The type of response is altered,e.g. drug allergy or idiosyncrasy. This is lesscommon but often precludes further use of thatdrug in the affected patient.

The various factors are discussed below—

1. Body size It influences the concentrationof the drug attained at the site of action. Theaverage adult dose refers to individuals ofmedium built. For exceptionally obese or leanindividuals and for children dose may becalculated on body weight (BW) basis:

BW (kg)Individual dose = ———— × average adult dose

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In the case of few drugs, doses are calculatedmore appropriately on the basis of body surfacearea (BSA).

2. Age The dose of a drug for children is oftencalculated from the adult dose

AgeChild dose = ———— × adult dose ... (Young’s

Age + 12 formula) Age

Child dose = –—— × adult dose ...(Dilling’s 20 formula)

Ideal % ofAge BW (kg) Adult dose

6 months 7.5 221 year 10 253 years 14 335 years 18 407 years 23 5012 years 37 75

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Factors Modifying Drug Action 51

It can also be calculated (more accurately) on BWbasis, and for many drugs, manufacturers givedosage recommendations on mg/kg basis.Average figures for children are given in the box.

However, infants and children are not smalladults. They have important physiological diffe-rences from adults.

Children are growing and are susceptible tospecial adverse effects of drugs, e.g. suppressionof growth can occur with corticosteroids;tetracyclines get deposited in growing teeth anddiscolour/deform them. Dystonic reactions tophenothiazines are more common in children.

Elderly In the elderly, renal function progres-sively declines (intact nephron loss) and drugdoses have to be reduced, e.g. daily dose ofstreptomycin is 0.75 g after 50 years and 0.5 gafter 70 years of age compared to 1 g for youngadults. There is also a reduction in the hepaticmicrosomal drug metabolizing activity and liverblood flow: the oral bioavailability of drugs withhigh hepatic extraction is generally increased,but the overall effects on drug metabolism arenot uniform. Other affected aspects of drughandling are slower absorption due to reducedmotility of and blood flow to intestines, lesserplasma protein binding due to lower plasmaalbumin, increased or decreased volume ofdistribution of lipophilic and hydrophilic drugsrespectively. The responsiveness of β adrenergicreceptors to both agonists and antagonists isreduced in the elderly and sensitivity to otherdrugs also may be altered. Due to prostatism inelderly males, even mild anticholinergic activityof the drug can accentuate bladder voidingdifficulty. Elderly are also likely to be on multipledrug therapy for hypertension, ischaemic heartdisease, diabetes, arthritis, etc. which increasesmany fold the chances of drug interactions. Theyare more prone to develop postural instability(e.g. on standing from dental chair), giddinessand mental confusion. In general, the incidenceof adverse drug reactions is much higher in theelderly.

3. Sex Females have smaller body size andrequire doses that are on the lower side of therange. Subjective effects of drugs may differ infemales because of their mental makeup. A num-ber of antihypertensives (clonidine, methyldopa,β-blockers, diuretics) interfere with sexual func-tion in males but not in females. Gynaecomastiais a side effect (of ketoconazole, metoclopramide,chlorpromazine, digitalis) that can occur only inmen. Ketoconazole causes loss of libido in menbut not in women. Obviously, androgens areunacceptable to women and estrogens to men.In women consideration must also be given tomenstruation, pregnancy and lactation.

Drugs given during pregnancy can affect thefoetus (see Ch. 4). There are marked physiologicalchanges during pregnancy, especially in thethird trimester, which can alter drug disposition.

(i) Gastrointestinal motility is reduced →delayed absorption of orally administereddrugs.

(ii) Plasma and extracellular fluid volumeexpands—volume of drug distributionmay increase.

(iii) While plasma albumin level falls, that ofα1 acid glycoprotein increases—theunbound fraction of acidic drugs increasesbut that of basic drugs decreases.

(iv) Renal blood flow increases markedly—polar drugs are eliminated faster.

(v) Hepatic microsomal enzymes undergoinduction—many drugs are metabolizedfaster.

Thus, the overall effect on drug dispositionis complex and often difficult to predict.

4. Species and race There are many examp-les of differences in responsiveness to drugsamong different species.

Among human beings some racial diffe-rences have been observed, e.g. blacks requirehigher and mongols require lower concentra-tions of atropine and ephedrine to dilate theirpupil. β-blockers are less effective as antihyper-tensive in blacks. Indians tolerate thiacetazonebetter than whites. Considering the widespread


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use of chloramphenicol in India and Hong Kong,relatively few cases of aplastic anaemia havebeen reported compared to its incidence in thewest. Similarly, quiniodochlor related cases ofsubacute myelooptic neuropathy (SMON) occu-rred in epidemic proportion in Japan, but thereis no confirmed report of its occurrence in Indiadespite extensive use.

5. Genetics The dose of a drug to produce thesame effect may vary by 4 to 6-fold amongdifferent individuals. This is mainly because ofdiffering rates of drug metabolism, because theamount and isoform pattern of drug metabo-lizing enzymes is genetically controlled. Thereare also differences in target organ sensitivity,transporters, ion channels, etc. The study ofgenetic basis for variability in drug response iscalled Pharmacogenetics;while Pharmacogenomicsis the use of genetic information to guide thechoice of drug and its dose on an individualbasis. A continuous variation with Gaussianfrequency distribution is seen in the case of mostdrugs. However, there are some specific geneticdefects which lead to discontinuous variation indrug responses, e.g.

(i) Atypical pseudocholinesterase—prolong-ed succinylcholine apnoea.

(ii) G-6-PD deficiency—haemolysis with pri-maquine and other oxidizing drugs likesulfonamides, dapsone, quinine, nalidixicacid, nitrofurantoin and menadione, etc.

(iii) Acetylator polymorphism—isoniazid neu-ropathy, procainamide and hydralazineinduced lupus in slow acetylators.

(iv) CYP2D6 abnormality causes poor meto-prolol/debrisoquin metabolizer status.

(v) Precipitation of an attack of angle closureglaucoma by mydriatics in individualswith narrow iridocorneal angle.

6. Route of administration Route of adminis-tration governs the speed and intensity of drugresponse (see Ch. 1). Parenteral administrationis often resorted to for more rapid, morepronounced and more predictable drug action.

7. Environmental factors and time of admi-nistration Several environmental factors affectdrug responses. Exposure to insecticides, carci-nogens, tobacco smoke and consumption ofcharcoal broiled meat are well known to inducedrug metabolism. Type of diet and temporalrelation between drug ingestion and meals canalter drug absorption. Subjective effect of a drugmay be markedly affected by the setup in whichit is taken. It has been shown that corticosteroidstaken as a single morning dose cause less pitui-tary-adrenal suppression. Local anaesthetics havebeen found to produce more prolonged dentalanaesthesia when injected in the afternoon than inthe morning.

8. Psychological factor Efficacy of a drug canbe affected by patient’s beliefs, attitudes andexpectations. This is particularly applicable tocentrally acting drugs, e.g. a nervous and anxiouspatient requires more general anaesthetic; alco-hol generally impairs performance but if punish-ment (which induces anxiety) is introduced, itmay actually improve performance.

Placebo This is an inert substance which isgiven in the garb of a medicine. It works by psy-chological rather than pharmacological meansand often produces responses equivalent to theactive drug. Some individuals are more sug-gestible and easily respond to a placebo—‘placebo reactors’. Placebos are used in twosituations:1. As a control device in clinical trial of drugs

(dummy medication).2. To treat a patient who, in the opinion of the

physician, does not require an active drug.

Placebo is a Latin word meaning ‘I shallplease’. A patient responds to the whole thera-peutic setting; placebo-effect largely depends onthe physician-patient relationship.

Placebos do induce physiological responses,e.g. they can release endorphins in brain—caus-ing analgesia. Naloxone, an opioid antagonist,blocks placebo analgesia. Placebo effects can thussupplement pharmacological effects. However,

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placebo effects are highly variable even in thesame individual, e.g. a placebo may induce sleepon the first night but not subsequently. Thus, ithas a very limited role in practical therapeutics.Substances commonly used as placebo arelactose tablets/capsules and distilled waterinjection.

9. Pathological states Not only drugs modifydisease processes, several diseases can influencedrug disposition and drug action:

Gastrointestinal diseases These can alterabsorption of orally administered drugs. Thechanges are complex and drug absorption mayincrease or decrease, e.g. in coeliac diseaseabsorption of amoxicillin is decreased but thatof cephalexin and cotrimoxazole is increased.Nonsteroidal antiinflammatory drugs canaggravate peptic ulcer disease.

Liver disease Liver disease (especially cirrho-sis) can influence drug disposition in severalways:

(i) Bioavailability of drugs having high firstpass metabolism (see Ch. 2) is increased dueto loss of hepatocellular function andportocaval shunting.

(ii) Serum albumin is reduced—protein bind-ing of acidic drugs (diclofenac, warfarin,etc.) is reduced and more drug is presentin the free form.

(iii) Metabolism and elimination of some drugs(morphine, lidocaine, propranolol) isdecreased: their dose should be reduced.Alternative drugs that do not depend onhepatic metabolism for elimination and/or have shorter t½ should be preferred, e.g.oxazepam or lorazepam in place ofdiazepam; atenolol as β-blocker.

(iv) Prodrugs needing hepatic metabolism foractivation, e.g. prednisone, bacampicillinare less effective and should be avoided.

The changes are complex and there is nosimple test (like creatinine clearance for renaldisease) to guide the extent of alteration in drugdisposition; kinetics of different drugs is affectedto different extents.

Even the action of certain drugs can bealtered in liver disease, e.g.• The sensitivity of brain to depressant action

of morphine and barbiturates is markedlyincreased in cirrhotics—normal doses canproduce coma.

• Brisk diuresis can precipitate mental changesin patients with impending hepatic encep-halopathy because diuretics cause hypo-kalemic alkalosis which favours conversionof NH+

4 to NH3 → enters brain more easily.• Oral anticoagulants can markedly increase

prothrombin time because clotting factors arealready low.

Hepatotoxic drugs should be avoided in liverdisease.

Kidney disease It markedly affects pharmaco-kinetics of many drugs as well as alters the effectsof some drugs.

Clearance of drugs that are primarilyexcreted unchanged (aminoglycosides, digoxin,phenobarbitone) is reduced parallel to thedecrease in creatinine clearance (CLcr). Loadingdose of such a drug is not altered (unless edemais present), but maintenance doses should bereduced or dose interval prolonged proportio-nately. A rough guideline is given in the box:

CLcr (patient) Dose rate to be reduced to

50–70 ml/min 70%30–50 ml/min 50%10–30 ml/min 30%5–10 ml/min 20%

Dose rate of drugs only partly excretedunchanged in urine also needs reduction, but tolesser extents. If the t½ of the drug is prolonged,attainment of steady-state plasma concentrationwith maintenance doses is delayed proportio-nately.

Plasma proteins, especially albumin, areoften low or altered in structure in patients withrenal disease—binding of acidic drugs is reducedbut that of basic drugs is not much affected.


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(iii) Retarding drug elimination as a result ofdecreased perfusion and congestion of liver,reduced glomerular filtration rate and increasedtubular reabsorption; dosing rate of drugs mayneed reduction.(iv) The decompensated heart is more sensitiveto digitalis.

Thyroid disease The hypothyroid patients aremore sensitive to digoxin, morphine and otherCNS depressants. Hyperthyroid patients arerelatively resistant to inotropic action but moreprone to arrhythmic action of digoxin. Theclearance of digoxin is roughly proportional tothe thyroid function, but this only partiallyaccounts for the observed changes in sensitivity.

Other examples of modification of drugresponse by pathological states are:• Antipyretics lower body temperature only

when it is raised (fever).• Thiazides induce more marked diuresis in

edematous patients.• Myocardial infarction patients are more prone

to adrenaline and digitalis induced cardiacarrhythmias.

• Myasthenics are very sensitive to curare.• Schizophrenics tolerate large doses of pheno-

thiazines.• Head injury patients are prone to go into

respiratory failure with normal doses ofmorphine.

• Atropine, imipramine, furosemide can causeurinary retention in individuals with prostatichypertrophy.

• Hypnotics given to a patient in severe painmay cause mental confusion and delirium.

• Cotrimoxazole produces a much higher inci-dence of adverse reactions in AIDS patients.

10.Other drugs Drugs can modify the responseto each other by pharmacokinetic or pharmaco-dynamic interaction between them. The numberof reported interactions is already too large toremember. However, knowledge of drugs andpatients at particular risk and the mechanismunderlying the interaction can avoid most

The permeability of blood-brain barrier isincreased in renal failure; opiates, barbiturates,phenothiazines, benzodiazepines, etc. producemore CNS depression. Pethidine should beavoided because its metabolite norpethidine canaccumulate on repeated dosing and causeseizures. The target organ sensitivity may alsobe increased. Antihypertensive drugs producemore postural hypotension in patients with renalinsufficiency.

Certain drugs worsen the existing clinicalcondition in renal failure, e.g. tetracyclineshave an antianabolic effect and accentuateuraemia; nonsteroidal antiinflammatory drugscause more fluid retention; potentially nephro-toxic drugs, e.g. aminoglycosides, tetracyclines(except doxycycline), sulfonamides (crystalluria),cyclosporine, vancomycin should be avoided.

Antimicrobials needing dose reduction inrenal failure

Even in mild failure Only in severe failure

Aminoglycosides CotrimoxazoleCephalexin CarbenicillinEthambutol CefotaximeVancomycin NorfloxacinAmphotericin B CiprofloxacinAcyclovir Metronidazole

Thiazide diuretics tend to reduce g.f.r.: areineffective in renal failure and can worsen urae-mia. Potassium-sparing diuretics are contraindi-cated; can cause hyperkalaemia → cardiacdepression.

Congestive heart failure It can alter drugkinetics by—(i) Decreasing drug absorption from g.i.t. dueto mucosal edema and splanchnic vasocons-triction.(ii) Modifying volume of distribution which canincrease for some drugs due to expansion ofextracellular fluid volume or decrease for othersas a result of decreased tissue perfusion.

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iatrogenic disasters. That two drugs interact doesnot necessarily mean that their concurrent useis contraindicated: many can be used togetherwith dose adjustments or some other measures.Many drug interactions have already beenconsidered (see pharmacokinetics and combinedeffect of drugs). Drug interactions relevant todental practice are given in Ch. 36.

11.Cumulation Any drug will cumulate in thebody if rate of administration is more than rateof elimination. However, slowly eliminateddrugs are particularly liable to cause cumulativetoxicity, e.g. prolonged use of chloroquine causesretinal damage.

Full loading dose of digoxin should not be givenif patient has received it within the past week.

12.Tolerance It refers to the requirement ofhigher dose of a drug to produce a given response.Tolerance is a widely occurring adaptive biolo-gical phenomenon. Drug tolerance may be:

Natural The species/individual is inherentlyless sensitive to the drug, e.g. rabbits are tolerantto atropine, black races are tolerant to mydriatics.

Acquired This occurs by repeated use of a drugin an individual who was initially responsive.Body is capable of developing tolerance to mostdrugs, but the phenomenon is very easilyrecognized in the case of CNS depressants. Anuninterrupted presence of the drug in the bodyfavours development of tolerance. However,significant tolerance does not develop to atropine,digitalis, cocaine, sodium nitroprusside, etc.Tolerance need not develop equally to all actionsof a drug; consequently, therapeutic index of adrug may increase or decrease with prolongeduse, e.g.:

• Tolerance develops to sedative action of chlor-promazine but not to its antipsychotic action.

• Tolerance occurs to the sedative action ofphenobarbitone but not to its antiepilepticaction.

• Tolerance occurs to analgesic and euphoricaction of morphine but not to its constipatingand miotic actions.

Cross tolerance It is the development of tole-rance to pharmacologically related drugs, e.g.alcoholics are relatively tolerant to barbituratesand general anaesthetics. Closer the two drugsare, more complete is the cross tolerance betweenthem, e.g.There is partial cross tolerance betweenmorphine and barbiturates but complete crosstolerance between morphine and pethidine.Mechanisms responsible for development oftolerance are incompletely understood. How-ever, tolerance may be:

(i) Pharmacokinetic/drug disposition tole-rance—the effective concentration of thedrug at the site of action is decreased, mostlydue to enhancement of drug eliminationon chronic use, e.g. barbiturates, carbama-zepine, amphetamine.

(ii) Pharmacodynamic/cellular tolerance—drug action is lessened; cells of the targetorgan become less responsive, e.g. morp-hine, barbiturates, nitrates. This may be dueto downregulation of receptors (see p. 41),weakening of response effectuation or othercompensatory homeostatic mechanisms(e.g. antihypertensives).

Tachyphylaxis (Tachy-fast, phylaxis-protection)is rapid development of tolerance—doses of adrug repeated in quick succession result inmarked reduction in response. This is usuallyseen with indirectly acting drugs, e.g. ephedrine,tyramine, nicotine: they act by releasingcatecholamines in the body, synthesis of whichis unable to match the rate of release: stores getdepleted. Other mechanisms like slow dissocia-tion of the drug from its receptor, internalizationof receptor, homeostatic adaptation, etc. mayalso be involved.

Drug resistance It refers to tolerance of micro-organisms to inhibitory action of antimicrobials,e.g. Staphylococci to penicillin (see Ch. 26).

Adverse effect is ‘any undesirable or unintendedconsequence of drug administration’. It is a broadterm, includes all kinds of noxious effect—trivial,serious or even fatal.

All drugs are capable of producing adverseeffects and whenever a drug is given a risk istaken. The magnitude of risk has to be consideredalong with the magnitude of expected therapeuticbenefit in deciding whether to use or not to use aparticular drug in a given patient, e.g. even risk ofbone marrow depression may be justified intreating cancer while mild drowsiness caused byan antihistaminic in treating common cold maybe unacceptable.

Adverse effects may develop promptly or onlyafter prolonged medication or even after stoppageof the drug. Adverse effects are not rare; anincidence of 10–25% has been documented indifferent clinical settings. They are more commonwith multiple drug therapy and in the elderly.Adverse effects have been classified in manyways. One may divide them into:

Predictable (Type A) reactions (mechanismbased adverse reactions) these are based onpharmacological properties of the drug, i.e. theyare augmented but qualitatively normal responseto the drug; include side effects, toxic effectsand consequences of drug withdrawal. They aremore common, dose related and mostly preven-table and reversible.

Unpredictable (Type B) reactions These arebased on peculiarities of the patient and not onthe drug’s known actions; include allergy andidiosyncrasy. They are less common, often non-dose related, generally more serious and requirewithdrawal of the drug. Some of these reactionscan be predicted and prevented if their geneticbasis is known and suitable test to characterizethe individual’s phenotype is performed.

Severity of adverse drug reactions has beengraded as:

Minor: No therapy, antidote or prolongation ofhospitalization is required.

Moderate: Requires change in drug therapy,specific treatment or prolongs hospital stay by atleast one day.

Severe: Potentially life threatening, causes perma-nent damage or requires intensive medical treat-ment.

Lethal: Directly or indirectly contributes to deathof the patient.

Prevention of adverse effects to drugs Adversedrug effects can be minimized but not altogethereliminated by observing the following practices:

1. Avoid all inappropriate use of drugs in thecontext of patient’s clinical condition.

2. Use appropriate dose, route and frequencyof drug administration based on patient’sspecific variables.

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3. Elicit and take into consideration previoushistory of drug reactions.

4. Elicit history of allergic diseases andexercise caution (drug allergy is morecommon in patients with allergic diseases).

5. Rule out possibility of drug interactionswhen more than one drug is prescribed.

6. Adopt correct drug administrationtechnique (e.g. NSAIDs not to be given onempty stomach).

7. Carry out appropriate laboratorymonitoring (e.g. prothrombin time withwarfarin, serum drug levels with lithium).

The adverse drug effects may be categorizedinto:

1. Side effects

These are unwanted but often unavoidable phar-macodynamic effects that occur at therapeuticdoses. They can be predicted from the pharma-cological profile of a drug and are known to occurin a given percentage of drug recipients. Reductionin dose generally ameliorates the symptoms.

A side effect may be based on the same actionas the therapeutic effect, e.g. atropine is used inpreanaesthetic medication for its antisecretoryaction—produces dryness of mouth as a sideeffect; antiinflammatory as well as gastric mucosaldamaging effects of NSAIDs are due to inhibitionof prostaglandin synthesis.

Side effect may also be based on a differentfacet of action, e.g. promethazine producessedation which is unrelated to its antiallergicaction. An effect may be therapeutic in one contextbut side effect in another context, e.g. codeine usedfor cough produces constipation as a side effect,but the latter is its therapeutic effect in traveller’sdiarrhoea.

2. Secondary effects

These are indirect consequences of a primaryaction of the drug, e.g. suppression of bacterialflora by tetracyclines paves the way for superin-fections; corticosteroids weaken host defencemechanisms so that latent tuberculosis getsactivated.

3. Toxic effects

These are the result of excessive pharmacologicalaction of the drug due to overdosage or prolon-ged use. Overdosage may be absolute (acciden-tal, homicidal, suicidal) or relative (i.e. usual doseof gentamicin in presence of renal failure). Toxiceffects are predictable and dose related. Theyresult from functional alteration (high dose of atro-pine causing delirium) or drug induced tissuedamage (hepatic necrosis from paracetamoloverdosage). The CNS, CVS, kidney, liver, lung,skin and blood forming organs are most com-monly involved in drug toxicity.

Toxicity may result from extension of thetherapeutic effect itself, e.g. hypoglycaemia dueto insulin, bleeding due to heparin.

Another action may be responsible for toxi-city, e.g.Morphine (analgesic) causes respiratory failurein overdosage.Gentamicin (antibacterial) in high dose causesvestibular damage.

Poisoning Poisoning may result from largedoses of drugs because ‘it is the dose whichdistinguishes a drug from a poison’. Poison is a‘substance which endangers life by severelyaffecting one or more vital functions’. Not onlydrugs but other household and industrial chemi-cals, insecticides, etc. are frequently involved inpoisonings. Specific antidotes such as receptorantagonists, chelating agents or specific antibodiesare available for a few poisons. General supportiveand symptomatic treatment is all that can be donefor others, and this is also important for poisonswhich have a selective antagonist.

These measures are:1. Resuscitation and maintenance of vitalfunctions

a. Ensure patent airway, adequate ventilation,give artificial respiration/100% oxygeninhalation as needed.

b. Maintain blood pressure and heart beat byfluid and crystalloid infusion, pressoragents, cardiac stimulants, etc, as needed.

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58 Adverse Drug EffectsS

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c. Maintain body temperature.d. Maintain blood sugar level by dextrose

infusion, especially in patients with alteredsensorium.

2. Termination of exposure (decontamination) byremoving the patient to fresh air (for inhaledpoisons), washing the skin and eyes (for poisonsentering from the surface), induction of emesiswith syrup ipecac or gastric lavage (for ingestedpoisons). Emesis should not be attempted incomatose or haemodynamically unstable patient.

3. Prevention of absorption of ingested poisonsA suspension of 20–40 g (1g/kg) of activatedcharcoal, which has large surface area and canadsorb many chemicals, should be administeredin 200 ml of water. However, strong acids andalkalies, metallic salts, iodine, cyanide, caustics,alcohol, hydrocarbons and other organic solventsare not adsorbed by charcoal.

4. Hastening elimination of the poison byinducing diuresis (furosemide, mannitol) oraltering urinary pH (alkalinization for acidicdrugs, e.g. barbiturates). However, excretion ofmany poisons is not enhanced by forced diuresisand it is generally not employed now. Haemo-dialysis and haemoperfusion (passage of bloodthrough a column of charcoal or adsorbant resin)are more efficacious procedures.

4. Intolerance

It is the appearance of characteristic toxic effectsof a drug in an individual at therapeutic doses. Itis the converse of tolerance and indicates a lowthreshold of the individual to the action of a drug.These are individuals who fall on the extreme leftside of the Gaussian frequency distribution curvefor sensitivity to the drug. Examples are:• A single dose of triflupromazine induces

muscular dystonias in some individuals,especially children.

• Only few doses of carbamazepine may causeataxia in some people.

• One tablet of aspirin may cause gastricbleeding.

5. Idiosyncrasy

It is genetically determined abnormal reactivityto a chemical. Certain adverse effects of some drugsare largely restricted to individuals with aparticular genotype (see p. 52). In addition, certainuncharacteristic or bizarre drug effects due topeculiarities of an individual (for which nodefinite genotype has been described) are includedamong idiosyncratic reactions, e.g.:• Barbiturates cause excitement and mental

confusion in some individuals.• Chloramphenicol produces non-dose-related

serious aplastic anaemia in rare individuals.

6. Drug allergyIt is an immunologically mediated reactionproducing stereotype symptoms which are unre-lated to the pharmacodynamic profile of the drug,and can occur even with much smaller doses.This is also called drug hypersensitivity; but doesnot refer to increased response which is calledsupersensitivity.

Allergic reactions occur only in a smallproportion of the population exposed to the drugand cannot be produced in other individuals atany dose. Prior sensitization is needed and alatent period of at least 1–2 weeks is required afterthe first exposure. The drug or its metabolite actsas antigen (AG) or more commonly hapten(incomplete antigen: drugs have small moleculeswhich become antigenic only after binding withan endogenous protein) and induce productionof antibody (AB)/sensitized lymphocytes. Pre-sence of AB to a drug is not necessarily followedby allergy to it. Chemically related drugs oftenshow cross sensitivity. One drug can producedifferent types of allergic reactions in differentindividuals, while widely different drugs canproduce the same reaction. The course of drugallergy is variable; an individual previouslysensitive to a drug may subsequently tolerate itwithout a reaction and vice versa.

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Mechanism and Types of Allergic Reactions

A. Humoral

Type-I (anaphylactic) reactions Reaginic anti-bodies (IgE) are produced which get fixed to themast cells. On exposure to the drug, AG: ABreaction takes place on the mast cell surface (seeFig. 7.2) releasing mediators like histamine, 5-HT,leukotrienes, especially LT-C4 and D4, prostaglan-dins, PAF, etc. resulting in urticaria, itching,angioedema, bronchospasm, rhinitis or anaphy-lactic shock. The manifestations occur quicklyafter challenge and are called immediate hyper-sensitivity. This is the only type of allergic drugreaction that the dentist may have to treat himself.

Type-II (cytolytic) reactions Drug + componentof a specific tissue cell act as AG. The resultingantibodies (IgG, IgM) bind to the target cells; onreexposure AG: AB reaction takes place on thesurface of these cells, complement is activated andcytolysis occurs, e.g. thrombocytopenia, agranulo-cytosis, aplastic anaemia, haemolysis, organdamage (liver, kidney, muscle), systemic lupuserythematosus.

Type-III (retarded, Arthus) reactions These aremediated by circulating antibodies (predominan-tly IgG, mopping AB). AG: AB complexes bindcomplement and precipitate on vascular endo-thelium giving rise to a destructive inflammatoryresponse. Manifestations are rashes, serum sick-ness (fever, arthralgia, lymphadenopathy), poly-arteritis nodosa, Stevens-Johnson syndrome(erythema multiforme, arthritis, nephritis, myo-carditis, mental symptoms). The reaction usuallysubsides in 1–2 weeks.

B. Cell mediated

Type-IV (delayed hypersensitivity) reactionsThese are mediated through production ofsensitized T-lymphocytes carrying receptors forthe AG. On contact with AG, these T cells producelymphokines which attract granulocytes and

generate an inflammatory response, e.g. contactdermatitis, some rashes, fever, photosensitization.The reaction generally takes > 12 hours to develop.Dentists may develop contact dermatitis by repeatedhandling of local anaesthetics; though this is nowrare due to replacement of procaine by lidocaineand use of surgical gloves.

Treatment of Drug AllergyThe offending drug must be immediately stopped.Most mild reactions (like skin rashes) subside bythemselves and do not require specific treatment.Antihistamines (H1) are beneficial in some type Ireactions (urticaria, rhinitis, swelling of lips, etc.)and some skin rashes. In case of anaphylacticshock or angioedema of larynx, the resuscitationcouncil of UK has recommended the followingmeasures:• Put the patient in reclining position, admini-

ster oxygen at high flow rate and performcardiopulmonary resuscitation if required.

• Inject adrenaline 0.5 mg (0.5 ml of 1 in 1000solution) i.m.; repeat every 5–10 min in casethe patient does not improve or improvementis transient. This is the only life-savingmeasure. Adrenaline should not be injectedi.v. (can itself be fatal) unless shock isimmediately life threatening. If adrenaline isto be injected i.v., it should be diluted to1:10,000 or 1:100,000 and infused slowly withconstant monitoring.

• Administer a H1 antihistaminic (chlorpheni-ramine 10–20 mg) i.m./slow i.v. It may haveadjuvant value.

• Intravenous glucocorticoid (hydrocortisonesod. succinate 100–200 mg) should be addedin severe/recurrent cases. It acts slowly, butis specially valuable for prolonged reactionsand in asthmatics.

Adrenaline followed by a short course of gluco-corticoids is indicated for bronchospasm atten-ding drug hypersensitivity. Glucocorticoids arethe only drugs effective in type II, type III and typeIV reactions.

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Drugs frequently causing allergic reactions

Penicillins Local anaestheticsCephalosporins SalicylatesSulfonamides CarbamazepineTetracyclines AllopurinolQuinolones ACE inhibitorsAntitubercular drugs MethyldopaPhenothiazines Hydralazine

Skin tests (intradermal, patch) or intranasaltests may forewarn in case of Type I hypersen-sitivity but not in case of other types. However,these tests are not entirely reliable—false positiveand false negative results are not rare.

7. Photosensitivity

It is a cutaneous reaction resulting from druginduced sensitization of the skin to UV radiation.The reactions are of two types:

(a) Phototoxic Drug or its metabolite accumu-lates in the skin, absorbs light and undergoes aphotochemical reaction followed by a photobio-logical reaction resulting in local tissue damage(sunburn like), i.e. erythema, edema, blisteringfollowed by hyperpigmentation and desquama-tion. The shorter wavelengths (290–320 nm, UV-B) are responsible. Drugs involved in acutephototoxic reactions are tetracyclines (especiallydemeclocycline) and tar products. Drugs causingchronic and low-grade sensitization are nalidixicacid, fluoroquinolones, sulfones, sulfonamides,phenothiazines, thiazides, amiodarone. This typeof reaction is more common than photoallergicreaction.

(b) Photoallergic Drug or its metabolite inducesa cell-mediated immune response which onexposure to light of longer wavelengths (320–400nm, UV-A) produces a papular or eczematouscontact dermatitis like picture. Rarely antibodiesmediate photoallergy and the reaction takes theform of immediate flare and wheal on exposureto sun. Drugs involved are sulfonamides, sul-fonylureas, griseofulvin, chloroquine, chlorpro-mazine.

8. Drug dependence

Drugs capable of altering mood and feelings areliable to repetitive use to derive euphoria, with-drawal from reality, social adjustment, etc. Drugdependence is a state in which use of drugs forpersonal satisfaction is accorded a higher prioritythan other basic needs, often in the face of knownrisks to health.

There is a lot of confusion in terminology anddefinitions; the following may serve to describedifferent aspects of the problem.

Psychological dependence It is said to havedeveloped when the individual believes thatoptimal state of wellbeing is achieved onlythrough the actions of the drug. It may start asliking for the drug effects and may progress tocompulsive drug use in some individuals. Theintensity of psychological dependence may varyfrom desire to craving. Obviously, certain degreeof psychological dependence accompanies allpatterns of self-medication.

Reinforcement is the ability of the drug to produceeffects that make the user wish to take it again.Certain drugs (opioids, cocaine) are strongreinforcers, while others (benzodiazepines) areweak reinforcers. Faster the drug acts, morereinforcing it is.

Physical dependence It is an altered physio-logical state produced by repeated administra-tion of a drug which necessitates the continuedpresence of the drug to maintain physiologicalequilibrium. Discontinuation of the drug resultsin a characteristic withdrawal (abstinence) syndrome.Since the essence of the process is adaptation ofthe nervous system to function normally in thepresence of the drug, it has been called‘neuroadaptation’.

Drugs producing physical dependence are—opioids, barbiturates and other depressants inc-luding alcohol and benzodiazepines. Stimulantdrugs, e.g. amphetamines, cocaine produce littleor no physical dependence.

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Drug abuse Refers to use of a drug by self-medi-cation in a manner and amount that deviates fromthe approved medical and social patterns in agiven culture at a given time. The term conveyssocial disapproval of the manner and purpose ofdrug use. For regulatory agencies, drug abuse refersto any use of an ilicit drug.

Drug addiction It is a pattern of compulsivedrug use characterized by overwhelming invol-vement with the use of a drug. Procuring the drugand using it takes precedence over other activities.Even after withdrawal most addicts tend torelapse. Physical dependence, though a strongimpetus for continued drug use, is not an essentialfeature of addiction. Amphetamines, cocaine,cannabis, LSD are drugs which produceaddiction but little/no physical dependence. Onthe other hand, drugs like nalorphine producephysical dependence without imparting addic-tion in the sense that there is little drug seekingbehaviour.

Drug habituation It denotes less intensiveinvolvement with the drug, so that its withdrawalproduces only mild discomfort. Consumption oftea, coffee, tobacco, social drinking are regardedhabituating, physical dependence is absent.

Basically, habituation and addiction implydifferent degrees of psychological dependenceand it may be difficult to draw a clearcut line ofdistinction between the two. Therefore, it is betterto avoid using these terms in describing drugdependence and related conditions.

9. Drug withdrawal reactions

Apart from drugs that are usually recognized asproducing dependence, sudden interruption oftherapy with certain other drugs also results inadverse consequences, mostly in the form ofworsening of the clinical condition for which thedrug was being used, e.g.:

(i) Acute adrenal insufficiency may be precipi-tated by abrupt cessation of corticosteroidtherapy.

(ii) Severe hypertension and sympathetic over-activity may occur shortly after disconti-nuing clonidine.

(iii) Worsening of angina pectoris or myocardialinfarction may result from stoppage of βblockers.

(iv) Frequency of seizures may increase onsudden withdrawal of an antiepileptic.

These manifestations are also due to adaptivechanges and can be minimized by gradualwithdrawal.

10. Teratogenicity

It refers to the capacity of a drug to cause foetalabnormalities when administered to the pregnantmother. The placenta does not strictly constitutea barrier and any drug can cross it to a greater orlesser extent. The embryo is one of the mostdynamic biological systems, and in contrast toadults, drug effects on embryo are often irrever-sible. The thalidomide disaster (1958–61) resul-ting in thousands of babies born with phocomelia(seal-like limbs) and other defects focusedattention to this type of adverse effect.

Drugs can affect the foetus at three stages—

(i) Fertilization and implantation—conception to17 days—failure of pregnancy which oftengoes unnoticed.

(ii) Organogenesis—18 to 55 days of gestation—most vulnerable period, deformities are pro-duced.

(iii) Growth and development—56 days onwards— developmental and functional abnorma-lities can occur, e.g. ACE inhibitors can causehypoplasia of organs, especially lungs andkidneys; NSAIDs may induce prematureclosure of ductus arteriosus.

The type of malformation depends on the drug aswell as stage of exposure to the teratogen. Theproven human teratogens are listed in the box.

Other drugs may be low grade teratogens andit is almost impossible to declare a drug to beabsolutely safe during pregnancy. The US-FDAhas graded the documentation of risk for causingbirth defects into five categories (see box).

Teratogenicity 61


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Human teratogenic drugs

Drug Abnormality

Thalidomide phocomelia, multiple defectsAnticancer drugs cleft palate, hydrocephalus, multiple defects,(methotrexate) foetal deathAndrogens virilization; limb, esophageal, cardiac defectsProgestins virilization of female foetusStilboestrol vaginal carcinoma in teenage female offspringTetracyclines discoloured and deformed teeth, retarded bone growthWarfarin depressed nose; eye and hand defects, growth retardationPhenytoin hypoplastic phalanges, cleft lip/palate, microcephalyPhenobarbitone various malformationsCarbamazepine neural tube defects, other abnormalitiesValproate sod. spina bifida and other neural tube defectsAlcohol low IQ baby, growth retardation, foetal alcohol syndromeACE inhibitors hypoplasia of organs, growth retardation, foetal loss Lithium foetal goiter, cardiac and other abnormalitiesAntithyroid drugs foetal goiter and hypothyroidismIndomethacin/aspirin premature closure of ductus arteriosusIsotretinoin craniofacial, heart and CNS defects

Risk category of drugs during pregnancy

Category Examples

A Adequate studies in pregnant women have failed to demonstrate Inj. Mag. sulfate,a risk to the foetus thyroxine

B Adequate human studies are lacking, but animal studies have failed to Penicillin V,demonstrate a risk to the foetus amoxicillin,

o r cefactor,Adequate studies in pregnant women have failed to demonstrate a risk erythromycin,to the foetus, but animal studies have shown an adverse effect on the paracetamol,foetus lignocaine

C No adequate studies in pregnant women and animal studies are lacking or Morphine,have shown and adverse effect on foetus, but potential benefit may warrant codeine,use of the drug in pregnant women despite potential risk atropine,

corticosteroids,adrenaline,thiopentone,bupivacaine

D There is evidence of human foetal risk, but the potential benefits from use Aspirin,of the drug may be acceptable despite the potential risk phenytoin,

carbamazepine,valproate,lorazepam

X Studies in animals or humans have demonstrated foetal abnormalities, and Estrogens,potential risk clearly outweighs possible benefit isotretinoin,

ergometrine

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It is, therefore, wise to avoid all drugs duringpregnancy unless compelling reasons exist fortheir use regardless of the assigned pregnancycategory, or presumed safety. Only emergencydental treatment should be undertaken duringthe most vulnerable period of organogenesis.

11. Carcinogenicity and mutagenicity

It refers to capacity of a drug to cause cancer andgenetic defects respectively. Usually, oxidationof the drug results in the production of reactiveintermediates which affect genes and may causestructural changes in the chromosomes. Chemi-cal carcinogenesis is a well-recognized pheno-menon but generally takes several (10–40) years

Drug-induced Diseases 63

to develop. Drugs implicated in these adverseeffects are—anticancer drugs, radioisotopes,estrogens, tobacco.

12. Drug-induced diseases

These are also called iatrogenic (physician-indu-ced) diseases, and are functional disturbances(disease) caused by drugs which persist even afterthe offending drug has been withdrawn andlargely eliminated, e.g.:

Peptic ulcer by salicylates and corticosteroids.Parkinsonism by phenothiazines and otherantipsychotics.Hepatitis by isoniazid.DLE by hydralazine.

ORGANIZATION OF AUTONOMICNERVOUS SYSTEM

The autonomic nervous system (ANS) functionslargely below the level of consciousness andcontrols visceral functions. Like the somaticnervous system, the ANS consists of afferents,centre and efferents.

Autonomic afferents are carried in the visceralnerves, most of which are mixed nerves. Theymediate visceral pain and visceral reflexes(cardiovascular, respiratory, vasomotor, etc.).

The highest seat regulating autonomic func-tions is in hypothalamus—posterior and lateralnuclei are primarily sympathetic while anteriorand medial nuclei are primarily parasympathetic.Many autonomic centres (pupillary, vagal,respiratory, etc.) are located in the mid-brain andthe medulla in relation to the cranial nerves. Thelateral column in the thoracic spinal cord containscells which give rise to the sympathetic outflow.

The motor limb of the ANS is anatomicallydivided into sympathetic and parasympathetic.In general, these subdivisions are functionallyantagonistic and most organs receive bothsympathetic and parasympathetic innervation.The level of activity of the innervated organ at agiven moment is the algebraic sum of sympatheticand parasympathetic tone. However, most bloodvessels, spleen, sweat glands and hair folliclesreceive only sympathetic, while ciliary muscle,gastric and pancreatic glands receive only

parasympathetic innervation. The general layoutof ANS is depicted in Fig. 5.1 and the importantdifferences between its two subdivisions are givenin Table 5.1.

The enteric plexus of nerves receives inputsfrom both sympathetic and parasympatheticdivisions, but in addition functions indepen-dently to integrate bowel movements as well asregulate secretion and absorption. As such, it hasalso been labelled as a distinct ‘enteric nervoussystem’.

NEUROHUMORAL TRANSMISSION

Neurohumoral transmission implies that nervestransmit their message across synapses andneuroeffector junctions by the release of humoral(chemical) messengers.

Steps in neurohumoral transmission

I. Impulse conduction The resting transmem-brane potential (70 mV negative inside) isestablished by high K+ permeability of axonalmembrane and high axoplasmic concentration ofthis ion coupled with low Na+ permeability and itsactive extrusion from the neurone. Stimulation orarrival of an electrical impulse causes a suddenincrease in Na+ conductance → depolarizationand overshoot (reverse polarization: insidebecoming 20 mV positive) occurs; K+ ions thenmove out in the direction of their concentration

Drugs Acting on AutonomicNervous SystemGeneral Considerations,

Cholinergic and Anticholinergic Drugs

5

68 Drugs Acting on ANSS

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gradient and repolarization is achieved. Ionicdistribution is normalized during the refractoryperiod by the activation of Na+ K+ pump. The actionpotential (AP) thus generated sets up local circuitcurrents which activate ionic channels at the nextexcitable part of the membrane (next node of

Ranvier in myelinated fibre) and the AP ispropagated without decrement.

II. Transmitter release The transmitter (exci-tatory or inhibitory) is stored in prejunctionalnerve endings within ‘synaptic vesicles’ (Fig. 5.2).

Fig. 5.1: The general outlay of autonomic nervous system. The transmitter released and theprimary postjunctional receptor subtype is shown at each synapse/neuroeffector junction

N = Nicotinic, M = Muscarinic, α = α adrenergic, β = β adrenergic

Table 5.1: Differences between sympathetic and parasympathetic divisions of the autonomic nervous system

Sympathetic Parasympathetic

1. Origin Dorso-lumbar (T1 to L2 or L3) Cranio-sacral (III, VII, IX, X; S2-S4)2. Distribution Wide Limited to head, neck and trunk3. Ganglia Away from the organs supplied On or close to the organ supplied4. Postgang. fibre Long Short5. Pre: post ganglionic 1: 20 to 1: 100 1: 1 to 1: 2 (except in enteric

fibre ratio plexuses)6. Transmitter Noradrenaline (major) Acetylcholine

(neuroeffector) Acetylcholine (minor)7. Stability of transmitter NA stable, diffuses for wider actions ACh—rapidly destroyed locally8. Important function Tackling stress and emergency Assimilation of food, conservation of energy

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Fig. 5.2: Diagrammatic representation of steps in excitatory and inhibitory neurohumoral transmission:EPSP = Excitatory postsynaptic potential; IPSP = Inhibitory postsynaptic potential

Nerve impulse promotes fusion of vesicular andaxonal membranes, through Ca2+ entry whichfluidizes membranes. All contents of the vesicle(transmitter, enzymes and other proteins) areextruded (exocytosis) in the junctional cleft.

The release process can be modulated by thetransmitter itself and by other agents throughactivation of specific receptors located on the pre-junctional membrane, e.g. noradrenaline (NA)release is inhibited by NA (α2 receptors), dopamine,adenosine, prostaglandins and enkephalins whileisoprenaline (β2 receptors) and angiotensin (AT1

receptor) increase NA release. Similarly, α2 andmuscarinic agonists inhibit acetylcholine (ACh)release at autonomic neuroeffector sites (but not inganglia and skeletal muscles).

III. Transmitter action on postjunctional mem-brane The released transmitter combines withspecific receptors on the postjunctional membraneand depending on its nature induces anexcitatory postsynaptic potential (EPSP) or aninhibitory postsynaptic potential (IPSP).

EPSP Increase in permeability to all cations →Na+ or Ca2+ influx (through fast or slow channels)

causes depolarization followed by K+ efflux. Theseionic movements are passive as the flow is downthe concentration gradients.

IPSP Increase in permeability to smaller ions,i.e. K+ and Cl¯ (hydrated K+ ion is smaller thanhydrated Na+ ion) only, so that K+ moves out andCl¯ moves in (in the direction of their concen-tration gradients) resulting in hyperpolarization.

In addition, a trophic influence on junctionalmorphology and functional status is exerted bythe background basal release of the transmitter.

IV. Postjunctional activity A suprathresholdEPSP generates a propagated postjunctional APwhich results in nerve impulse (in neurone),contraction (in muscle) or secretion (in gland).An IPSP stabilizes the postjunctional membraneand resists depolarizing stimuli.

V. Termination of transmitter action Followingits combination with the receptor, the transmitteris either locally degraded (e.g. ACh) or is takenback into the prejunctional neurone by activeuptake as well as diffuses away (e.g. NA, GABA).Rate of termination of transmitter action governs

ANS: General Considerations 69


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the rate at which responses can be transmittedacross a junction (1 to 1000/sec).

Cotransmission

It has now become apparent that the classical ‘oneneurone—one transmitter’ model is an oversimplification. Many peripheral and centralneurones have been shown to release more thanone active substance when stimulated. In the ANS,besides the primary transmitters ACh and NA,neurones have been found to elaborate purines(ATP, adenosine), peptides (vasoactive intestinalpeptide or VIP, neuropeptide-Y or NPY, substanceP, enkephalins, somatostatin, etc.), nitric oxideand prostaglandins as cotransmitters. Thecotransmitter is stored in the same neurone but indistinct synaptic vesicles or locations (Fig. 5.3).However, ATP is stored with NA in the samevesicle. On being released by the nerve impulse,the cotransmitter may serve to regulate the pre-synaptic release of the primary transmitter and/or postsynaptic sensitivity to it (neuromodulatorrole). The cotransmitter may also serve as an alter-native transmitter in its own right and/or exert atrophic influence on the synaptic structures.

CHOLINERGIC TRANSMISSION

Acetylcholine (ACh) is a major neurohumoraltransmitter at autonomic as well as somatic sites(Table 5.2).

Fig. 5.3: CotransmissionThe cotransmitter is stored in the prejunctional nerve terminalalong with the primary transmitter, but in separate vesicles(in some cases in the same vesicle itself). Nerve impulsereleases both the transmitters concurrently. Acting on itsown receptors, the cotransmitter modifies responsivenessof the effector to the primary transmitter or substitutes for it.Cotransmitter may also act on prejunctional receptors andmodulate release of the transmitters

Synthesis, storage and destruction of ACh

The cholinergic neuronal mechanisms are sum-marized in Fig. 5.4.

Table 5.2: Sites of cholinergic transmission and type of receptor involved

Site Type of receptor Selective agonist Selective antagonist

1. a. All postganglionic parasymp.b. Few postganglionic symp (sweat Muscarinic Muscarine Atropine

glands, some blood vessels)

2. a. Ganglia (both symp. andparasymp). Nicotinic (NN) DMPP* Hexamethonium

b. Adrenal medulla

3. Skeletal muscles Nicotinic (NM) PTMA** d-tubocurarine

4. CNS (cortex, basal ganglia, spinal Muscarinic Muscarine/ Atropinecord and other sites) Oxotremorine

Nicotinic Carbachol d-tubocurarine

* DMPP—Dimethyl phenyl piperazinium** PTMA—Phenyl trimethyl ammonium

⎫⎬⎭

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Acetylcholine is synthesized locally in the choli-nergic nerve endings by the following pathway—

ATP + Acetate + CoEn-A

Acetate activating reaction

Acetyl CoEn-A

CHOLINECholine acetylase

ACETYLCHOLINE + CoEn-A

CH3 O | || Cl¯

CH3—N+—CH2—CH2—O—C—CH3

| CH3

Acetylcholine chloride

Choline is actively taken up by the axonalmembrane and acetylated with the help of ATPand coenzyme-A by the enzyme cholineacetylase

present in the axoplasm. Most of the ACh is storedin ionic solution within small synaptic vesicles,but some free ACh is also present in the cytoplasmof cholinergic terminals.

Release of ACh from nerve terminals occursin small quanta—amount contained in individualvesicles is extruded by exocytosis. In responseto a nerve AP synchronous release of multiplequanta triggers postjunctional events. Imme-diately after release, ACh is hydrolyzed by theenzyme cholinesterase and choline is recycled.

A specific (Acetylcholinesterase—AChE or truecholinesterase) and a nonspecific (Butyrylcholi-nesterase—BuChE or pseudocholinesterase) typeof enzyme occurs in the body.

Acetylcholine

Cholinesterase

Choline + Acetate

Acetylcholinesterase is strategically located atall cholinergic sites and serves to hydrolyze AChinstantaneously (in μS). Pseudocholinesterase isa relatively nonspecific esterase present in plasma,liver and some other tissues; hydrolyzes AChslowly and probably serves to metabolize ingestedesters.

Cholinoceptors

Two classes of receptors for ACh are recognized—muscarinic and nicotinic; the former is a G pro-tein coupled receptor, while the latter is a ligandgated cation channel.

Muscarinic These receptors are selectivelystimulated by muscarine and selectively blockedby atropine. They are located primarily onautonomic effector cells in heart, blood vessels,eye, smooth muscles and glands of gastrointes-tinal, respiratory and urinary tracts, sweat glands,etc. and in the CNS. Subsidiary muscarinicreceptors are also present in autonomic gangliawhere they appear to play a modulatory role byinducing a long-lasting late EPSP.

Subtypes of muscarinic receptor The muscarinicreceptors have been divided into 5 subtypes M1,

Cholinergic Transmission 71

Fig. 5.4: Cholinergic neuronal mechanismsMinus sign indicates inhibition while bold arrow indicatesactive transport.Ch = Choline, ACh = Acetylcholine, ChA = Choline acetylase,AChE = Acetylcholinesterase, Anti-ChE = Anticholinesterase,M = Muscarinic receptor, N = Nicotinic receptor, HC3 =Hemicholinium, BoT = Botulinus toxin, Vsa = Vesamicol


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M2, M3, M4 and M5. Out of these, the first 3 havebeen functionally characterized.M1: The M1 is primarily a neuronal receptor located onganglion cells and central neurones: especially in cortex,hippocampus and corpus striatum. It plays a major rolein mediating gastric secretion and relaxation of loweresophageal sphincter (LES) caused by vagal stimulation.

M2: Cardiac muscarinic receptors are predominantly M2and mediate vagal bradycardia. Autoreceptors oncholinergic nerve endings are also of M2 subtype.

M3: Visceral smooth muscle contraction and glandularsecretions are elicited through M3 receptors, which alsomediate vasodilatation through EDRF release. Togetherthe M2 and M3 receptors mediate most of the well-recognizedmuscarinic actions including contraction of LES.

Nicotinic These receptors are selectively acti-vated by nicotine and blocked by tubocurarine orhexamethonium. These are rosette-like pentamericstructures (see Fig. 3.3) which enclose a ligandgated cation channel: their activation causesopening of the channel and rapid flow of cationsresulting in depolarization and an action poten-tial. On the basis of location and selective agonistsand antagonists, two subtypes NM and NN arerecognized.

NM: These are present at skeletal muscle endplate: areselectively stimulated by phenyl trimethyl ammonium(PTMA) and blocked by tubocurarine. They mediate skeletalmuscle contraction.

NN: These are present on ganglionic cells (sympathetic aswell as parasympathetic), adrenal medullary cells, in spinalcord and certain areas of brain. They are selectively stimu-lated by dimethyl phenyl piperazinium (DMPP), blockedby hexamethonium, and constitute the primary pathwayof transmission in ganglia.

CHOLINERGIC DRUGS(Cholinomimetic, Parasympathomimetic)

These are drugs which produce actions similarto that of ACh, either by directly interacting with

cholinergic receptors (cholinergic agonists) or byincreasing availability of ACh at these sites(anticholinesterases).

ACTIONS (of ACh as prototype)

Depending on the type of receptor through whichit is mediated the peripheral actions of ACh maybe classified as muscarinic or nicotinic. Thecentral actions are not so classifiable and aredescribed separately.

A. Muscarinic actions

1. Heart ACh hyperpolarizes the SA nodal cellsand decreases their rate of diastolic depolari-zation. As a result, rate of impulse generation isreduced—bradycardia or even cardiac arrest mayoccur.

At the A-V node and His-Purkinje fibresrefractory period (RP) is increased and conductionis slowed: P-R interval increases and partial tocomplete A-V block may be produced. The force ofatrial contraction is markedly reduced and RP of atrialfibres is abbreviated. Due to nonuniform vagalinnervation, the intensity of effect on RP andconduction of different atrial fibres varies—inducing inhomogeneity and predisposing toatrial fibrillation or flutter.

Ventricular contractility is also decreased butthe effect is not marked.

2. Blood vessels All blood vessels are dilated,though only few (skin of face, neck) receivecholinergic innervation. Thus, fall in BP andflushing, especially in the blush area occurs.Muscarinic receptors (M3) are present on vascularendothelial cells: vasodilatation is primarilymediated through the release of an endothelium-dependent relaxing factor (EDRF) which is nitricoxide (NO).

Stimulation of cholinergic nerves to the peniscauses erection by releasing NO and dilatingcavernosal vessels through M3 receptors.However, this response is minimal with injectedcholinomimetic drugs.

CHOLINERGIC AGONISTS

Choline esters AlkaloidsAcetylcholine MuscarineMethacholine PilocarpineCarbachol ArecolineBethanechol

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3. Smooth muscle Smooth muscle in mostorgans is contracted. Tone and peristalsis in thegastrointestinal tract is increased and sphinctersrelax → abdominal cramps and evacuation ofbowel.

Peristalsis in ureter is increased. The detrusormuscle contracts while the bladder trigone andsphincter relaxes → voiding of bladder.

Bronchial muscles constrict, asthmatics arehighly sensitive → dyspnoea, precipitation of anattack of bronchial asthma.

4. Glands Secretion from all parasympathe-tically innervated glands is increased—sweating,salivation, lacrimation, tracheobronchial andgastric secretion. The effect on pancreatic andintestinal glands is not marked. Secretion of milkand bile is not affected.

5. Eye Contraction of circular muscle of iris →miosis.Contraction of ciliary muscle → spasm of accom-modation, increased outflow facility, reductionin intraocular tension (especially in glaucomatouspatients).

B. Nicotinic actions

1. Autonomic ganglia Both sympathetic andparasympathetic ganglia are stimulated. Thiseffect is manifested at higher doses. High dose ofACh given after atropine causes tachycardia andrise in BP.

2. Skeletal muscles Iontophoretic applicationof ACh to muscle endplate causes contraction ofthe fibre. Intraarterial injection of high dose cancause twitching and fasciculations, but i.v.injection is generally without any effect (due torapid hydrolysis of ACh).

C. CNS actions

ACh injected i.v. does not penetrate blood-brainbarrier and no central effects are seen. However,direct injection into the brain, or other cholinergicdrugs which enter brain, produce a complexpattern of stimulation followed by depression.

The important features of other cholinestersare summarized in Table 5.3.

Table 5.3: Properties of choline esters

Choline ester Hydrolysis by Actions SelectiveAChE BuChE Musc. Nico. action on

Acetylcholine ++ + + + NonselectiveMethacholine + – + ± CVSCarbachol – – + + g.i.t., bladderBethanechol – – + – g.i.t., bladder

Uses Choline esters are rarely if ever usedclinically. ACh is not used because of evanescentand nonselective action. Bethanechol has been usedin postoperative/postpartum nonobstructiveurinary retention, neurogenic bladder, congenitalmegacolon and gastroesophageal reflux.

CHOLINOMIMETIC ALKALOIDS

Pilocarpine It is obtained from the leaves ofPilocarpus microphyllus and other species. It hasprominent muscarinic actions but stimulatesganglia as well—mainly through ganglionic mus-carinic receptors.

Pilocarpine causes marked sweating, sali-vation and increase in other secretions. The cardio-vascular effects of pilocarpine are complex.Applied to the eye, it penetrates cornea andpromptly causes miosis, ciliary muscle contrac-tion and fall in intraocular tension lasting 4–8hours. Pilocarpine is used in the eye as 0.5–4%drops, primarily in open angle glaucoma. It hasalso been used orally for xerostomia, but is notavailable commercially for this purpose.Muscarine It occurs in poisonous mushrooms Amanitamuscaria and Inocybe species and has only muscarinicactions. It is not used therapeutically but is of toxicologicalimportance in mushroom poisoning.

Arecoline It is found in betel nut Areca catechu. It hasmuscarinic as well as nicotinic actions including prominentCNS effects.


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ANTICHOLINESTERASES

Anticholinesterases (anti-ChEs) are agents whichinhibit ChE, protect ACh from hydrolysis—produce cholinergic effects in vivo and potentiateACh both in vivo and in vitro. Some anti- ChEs haveadditional direct action on cholinergic receptors.

ReversibleCarbamates AcridinePhysostigmine (Eserine) TacrineNeostigminePyridostigmineEdrophoniumRivastigmine, Donepezil

IrreversibleOrganophosphates CarbamatesDyflos (DFP) Carbaryl* (SEVIN)Echothiophate Propoxur* (BAYGON)Malathion*Diazinon* (TIK-20)Tabun£, Sarin£, Soman£

Anti-ChEs are either esters of carbamic acid orderivatives of phosphoric acid.

O || R2

R1—O—C—N R3

Carbamates Organophosphates

In carbamates R1 may have a nonpolar tertiaryamino N, e.g. in physostigmine, rendering thecompound lipid soluble. In others, e.g. neostig-mine, R1 has a quaternary N+—rendering it lipidinsoluble. All organophosphates are highly lipidsoluble except echothiophate which is watersoluble.

The anti-ChEs react with the enzyme essen-tially in the same way as ACh. The carbamatesand phosphates respectively carbamylate andphosphorylate the esteratic site of the enzyme.Whereas the acetylated enzyme (producedmomentarily when ACh reacts with ChE) reactswith water extremely rapidly and the esteraticsite is freed in a fraction of a millisecond, the

carbamylated enzyme (reversible inhibitors)reacts slowly and the phosphorylated enzyme(irreversible inhibitors) reacts extremely slowlyor not at all. The half-life of reactivation ofcarbamylated enzyme (about 30 min) is less thanthat of synthesis of fresh enzyme protein, whilethat of phosphorylated enzyme is more than theregeneration time. Thus, apparently reversible andirreversible enzyme inhibition is obtained, thoughthe basic pattern of inhibitor-enzyme interactionremains the same.

Pharmacological actionsThe actions of anti-ChEs are qualitatively similarto that of directly acting cholinoceptor stimulants.However, relative intensity of action onmuscarinic, ganglionic, skeletal muscle and CNSsites varies among the different agents.

Lipid-soluble agents (physostigmine andorganophosphates) have more marked musca-rinic and CNS effects; stimulate ganglia but actionon skeletal muscles is less prominent.

Lipid-insoluble agents (neostigmine and otherquaternary ammonium compounds) producemore marked effect on the skeletal muscles (directaction on muscle endplate cholinoceptors aswell), stimulate ganglia, but muscarinic effectsare less prominent. They do not penetrate CNSand have no central effects.

After treatment with anti-ChEs, the AChreleased by a single nerve impulse in skeletalmuscle is not immediately destroyed—rebinds tothe same receptor and diffuses to act on neigh-bouring receptors as well as on prejunctionalfibres → repetitive firing → twitching andfasciculations. Force of contraction in partiallycurarized and myasthenic muscles is increased.Higher doses cause persistent depolarization ofendplates resulting in blockade of neuromusculartransmission → weakness and paralysis.

The cardiovascular effects of anti-ChEs arecomplex: depend on the agent and its dose.Smooth muscles and glands of the gastrointes-tinal, respiratory, urinary tracts and in the eyeare stimulated.

OR2 ||

P—R1

R3

*Insecticides£Nerve gases forchemical warfare

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Anticholinesterases 75

Pharmacokinetics

Physostigmine is rapidly absorbed from g.i.t. andparenteral sites. Applied to the eye, it penetratescornea freely. It crosses blood-brain barrier and isdisposed after hydrolysis by ChE.

Neostigmine and congeners are poorly absorbedorally; oral dose is 20–30 times higher thanparenteral dose. They do not effectively penetratecornea or cross blood-brain barrier.

Organophosphates are absorbed from all sitesincluding intact skin and lungs. They arehydrolyzed as well as oxidized in the body andlittle is excreted unchanged.

Uses1. Glaucoma: It is a progressive form of optic nervedamage associated with raised intraoculartension (i.o.t.). Miotics like pilocarpine andphysostigmine lower i.o.t. by different mecha-nisms in the two principal types of glaucoma:

Open angle (chronic simple) glaucoma: Mioticsincrease the tone of ciliary muscle which pulls onand improves the outflow facility of trabecularmeshwork. However, they are now 3rd line drugsto ocular β blockers, latanoprost (PGF2α analogue),brimonidine (α2 agonist clonidine congener),dorzolamide (ocular carbonic anhydraseinhibitor) and dipivefrine (prodrug of adrenaline).

Angle closure (narrow angle, acute congestive)glaucoma: Miotics contract sphincter pupillaemuscle changing the direction of forces in the iristo lessen its contact with the lens → pupillaryblock is removed and iridocorneal angle is freed.2. To reverse the effect of mydriatic : After refractiontesting.3. To prevent/break adhesions between iris and lens/cornea: A miotic is alternated with a mydriatic.4. Myasthenia gravis: It is an autoimmunedisorder due to development of antibodies to themuscle endplate nicotinic receptors resulting inweakness and easy fatigability. Neostigmine andits congeners improve muscle contraction bypreserving ACh as well as by directly depolarizingthe endplate.

5. Postoperative decurarization: To reverse the effectof muscle relaxants.6. Postoperative paralytic ileus/urinary retention.7. Cobra bite: To antagonize the curare-like actionof cobra neurotoxin.8. Belladonna poisoning: Physostigmine is thedrug of choice for poisoning with atropine andother anticholinergic drugs.9. Alzheimer’s disease: This is a neurodegenera-tive disorder affecting primarily the cholinergicneurones in the brain. The relatively cerebroselec-tive anti-ChEs tacrine, rivastigmine, donepeziland galantamine afford some symptomaticimprovement.

ANTICHOLINESTERASE POISONING

Anticholinesterases are easily available andextensively used as agricultural and householdinsecticides; accidental as well as suicidal andhomicidal poisoning is common.

Local muscarinic manifestations at the site ofexposure (skin, eye, g.i.t.) occur immediately andare followed by complex systemic effects due tomuscarinic, nicotinic and central actions.

Treatment

1. Termination of further exposure to thepoison—fresh air, wash the skin and mucousmembranes with water, gastric lavageaccording to need.

2. Maintain patent airway, positive pressurerespiration if it is failing.

3. Supportive measures—maintain BP, hydra-tion, control of convulsions with judicious useof diazepam.

4. Specific antidotes—

(a) Atropine It is highly effective in counter-acting the muscarinic symptoms, but higher dosesare required to antagonize the central effects. Itdoes not reverse peripheral muscular paralysiswhich is a nicotinic action.

(b) Cholinesterase reactivators Oximes are usedto restore neuromuscular transmission in caseof organophosphate anti-ChE poisoning. They


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provide more reactive OH groups which reactwith phosphorylated enzyme to form oximephosphonate and release free cholinesterase.Pralidoxime is the most commonly used oxime.

ANTICHOLINERGIC DRUGS(Muscarinic receptor antagonists,

Atropinic, Parasympatholytic)

Conventionally, anticholinergic drugs are thosewhich block actions of ACh on autonomic effec-tors and in the CNS exerted through muscarinicreceptors. Though nicotinic antagonists also blockcertain actions of ACh, they are generally referredto as ‘ganglion blockers’ and ‘neuromuscularblockers’.

Atropine, the prototype drug of this class, ishighly selective for muscarinic receptors, butsome of its synthetic substitutes do possess signi-ficant nicotinic blocking property in addition.All anticholinergic drugs are competitive anta-gonists.

CLASSIFICATION

1. Natural alkaloids Atropine, Hyoscine(Scopolamine).

2. Semisynthetic derivatives Homatropine,Atropine methonitrate, Hyoscine butylbromide, Ipratropium bromide, Tiotropiumbromide.

3. Synthetic compounds(a) Mydriatics: Cyclopentolate, Tropicamide.(b) Antisecretory-antispasmodics:

(i) Quaternary compounds: Propantheline,Oxyphenonium, Clidinium, Glycopyr-rolate.

(ii) Tertiary amines: Dicyclomine, Valetha-mate, Pirenzepine.

(c) Vasicoselective: Oxybutynin, Flavoxate, Toltero-dine.

(d) Antiparkinsonian: Trihexyphenidyl (Benzhe-xol), Procyclidine, Biperiden.

In addition, many other classes of drugs, i.e.tricyclic antidepressants, phenothiazines, anti-histamines, disopyramide possess significantantimuscarinic actions.

The natural alkaloids are found in plants ofthe solanaceae family: atropine in Atropabelladonna and Datura stramonium, hyoscine inHyoscyamus niger. The levo-isomers are much moreactive than the dextroisomers. Atropine is racemicwhile scopolamine is l-hyoscine.

PHARMACOLOGICAL ACTIONS(Atropine as prototype)

The actions of atropine can be largely predictedfrom knowledge of parasympathetic responses.Prominent effects are seen in organs whichnormally receive strong parasympathetic tone. Itblocks all subtypes of muscarinic receptors.

1. CNS Atropine has an overall CNS stimulantaction. However, these effects are not appreciableat low doses which mainly produce peripheraleffects because of restricted entry of atropine intothe brain.• Atropine stimulates many medullary centres

—vagal, respiratory, vasomotor.• It depresses vestibular excitation and has

antimotion sickness property.• By blocking the relative cholinergic overactivity

in basal ganglia, it suppresses tremorand rigidity of parkinsonism.

• High doses cause cortical excitation, restless-ness, disorientation, hallucinations anddelirium followed by respiratory depressionand coma.

Hyoscine differs from atropine in producingdepressant (drowsiness, amnesia, fatigue) effectsat low doses.

2. CVSHeart The most prominent effect of atropine isto cause tachycardia. It is due to blockade of M2

receptors on SA node through which vagal tonedecreases HR. Higher the existing vagal tone—more marked is the tachycardia (maximum inyoung adults, less in children and elderly). Oni.m./s.c. injection, transient initial bradycardiaoften occurs. Earlier believed to be due to vagalcentre stimulation, it is now thought to be causedby blockade of muscarinic autoreceptors (M1) on

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Fig. 5.5: Autonomic control of pupil (A); and site ofaction of mydriatics (B) and miotics (C)

vagal nerve endings augmenting ACh release.Atropine abbreviates refractory period of A-Vnode and facilitates A-V conduction, especially ifit has been depressed by high vagal tone. P-Rinterval is shortened.

BP Since cholinergic impulses are not involvedin maintenance of vascular tone, atropine doesnot have any consistent or marked effect on BP.Tachycardia and vasomotor centre stimulationtend to raise BP while histamine release and directvasodilator action (at high doses) tend to lowerBP.Atropine blocks vasodepressor action of choli-nergic agonists.

3. Eye The autonomic control of iris musclesand the action of mydriatics as well as miotics isillustrated in Fig. 5.5. Topical instillation ofatropine causes mydriasis, abolition of light reflexand cycloplegia lasting 7–10 days. This resultsin photophobia and blurring of near vision.The ciliary muscles recover somewhat earlier thansphincter pupillae. The intraocular tension tendsto rise, especially in narrow angle glaucoma;conventional systemic doses produce minorocular effects.

4. Smooth muscles All visceral smooth musc-les that receive parasympathetic motor innerva-tion are relaxed by atropine (M3 blockade). Toneand amplitude of contractions of stomach andintestine are reduced; the passage of chyme isslowed—constipation may occur, spasm may berelieved. However, peristalsis is only incompletelysuppressed because it is primarily regulated bylocal reflexes and other neurotransmitters (5-HT,enkephalin, etc.).

Atropine causes bronchodilatation and redu-ces airway resistance, especially in COPD andasthma patients. Inflammatory mediators likehistamine, PGs and kinins increase vagal activityin addition to their direct action on bronchialmuscle and glands. Atropine attenuates their actionby antagonizing the reflex vagal component.

Anticholinergic Drugs 77

Atropine has a relaxant action on ureter andurinary bladder; urinary retention can occur inolder males with prostatic hypertrophy. However,the same can be beneficial for increasing bladdercapacity and controlling detrusor hyperreflexiain neurogenic bladder/enuresis. Relaxation of


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biliary tract is less marked and effect on uterus isminimal.

5. Glands Atropine markedly decreases sweat,salivary, tracheobronchial and lacrimal secretion(M3 blockade). Skin and eyes become dry, talkingand swallowing may be difficult.

Atropine decreases secretion of acid, pepsinand mucus in the stomach, but the primary actionis on volume of secretion so that pH of gastriccontents may not be elevated unless diluted byfood. Relatively higher doses are needed andatropine is less efficacious than H2 blockers inreducing acid secretion. Intestinal and pancreaticsecretions are not significantly reduced. Bileproduction is not under cholinergic control, so notaffected.

6. Body temperature Rise in body temperatureoccurs at higher doses. It is due to both inhibitionof sweating as well as stimulation of temperatureregulating centre in the hypothalamus. Childrenare highly susceptible to atropine fever.

The sensitivity of different organs and tissues toatropine varies and can be graded as—

Saliva, sweat, bronchial secretion > eye, bron-chial muscle, heart > smooth muscle of intestine,bladder > gastric glands and smooth muscle.

PHARMACOKINETICS

Atropine and hyoscine are rapidly absorbed fromg.i.t. Applied to eyes, they freely penetrate cornea.Passage across blood-brain barrier is somewhatrestricted. About 50% of atropine is metabolizedin liver and rest is excreted unchanged in urine. Ithas a t½ of 3–4 hours. Hyoscine is morecompletely metabolized and has better blood-brainbarrier penetration.

ATROPINE SUBSTITUTES

Many semisynthetic derivatives of belladonnaalkaloids and a large number of synthetic com-pounds have been introduced with the aim ofproducing more selective action on certain

functions. Most of these differ only marginallyfrom the natural alkaloids.

Hyoscine butyl bromide and atropine methonitrate arequaternary derivatives which do not produce CNS effectsand are used mainly for colics and functional g.i. disorders.

Ipratropium bromide is given by inhalation in bronchialasthma and chronic obstructive pulmonary disease(COPD). Unlike atropine, it does not depress mucociliaryclearance by bronchial epithelium. Tiotropium bromide is along acting and more broncho-selective congener ofipratropium.

Propantheline, oxyphenonium, clidinium are synthetic qua-ternary anticholinergics mainly used as antisecretory-antispasmodic.

Glycopyrrolate acts rapidly and is almost exclusivelyemployed parenterally before and during anaesthesia.

Dicyclomine has additional direct smooth muscle relaxantand antiemetic properties; has been used in morning sick-ness, motion sickness, irritable bowel and dysmenorrhoea.

Valethamate This antispasmodic-anticholinergic is mostlyused to hasten dilatation of cervix during labour.

Oxybutynin, tolterodine and flavoxate are relativelyvasicoselective anticholinergics with direct smooth musclerelaxant property; used for detrusor instability, urinaryfrequency and urge incontinence.

Pirenzepine is a selective M1 antimuscarinic which inhibitsgastric secretion with few atropinic side effects.

Homatropine, cyclopentolate, tropicamide are used exclusivelyas mydriatic and cycloplegic. They have quicker and brieferaction than atropine.

Trihexyphenidyl, procyclidine and biperiden have moreprominent central antimuscarinic action: are used inparkinsonism.

USES (of atropine and its congeners)

1. Preanaesthetic medication: To check increa-sed salivary and tracheobronchial secretions dueto irritant general anaesthetics, prevent reflexlaryngospasm and to block vagal reflexes.Atropine and glycopyrrolate are occasionallyemployed to prevent salivation during dentalprocedures and oral surgery.2. Abdominal cramps/colics, ureteric colic,functional g.i. disorders. Use of atropinic drugsin peptic ulcer is now obsolete.

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3. To relieve urinary frequency and urgency inneurogenic disorders, enuresis in children.4. Pulmonary embolism: Atropine benefits byreducing reflex respiratory secretions.5. Bronchial asthma and COPD: Inhaledipratropium bromide and tiotropium bromide areparticularly useful in COPD and as adjuvant toinhaled β2 agonists in severe/refractory bronchialasthma.6. As mydriatic and cycloplegic for refractiontesting and fundoscopy: tropicamide is preferredbecause of quickest and briefest action. The long-lasting mydriatic-cycloplegic action of atropineis very valuable for giving rest to intraocularmuscles in iritis, iridocyclitis, choroiditis, keratitisand corneal ulcer.7. To block vagal bradycardia in selected casesof myocardial infarction and digitalis toxicity.8. Parkinsonism: Central anticholinergics reducetremor and rigidity by counteracting unbalancedcholinergic activity in striatum.9. Motion sickness: Hyoscine is highly effective,especially valuable for vigorous motions.Dicyclomine is used in milder cases.10. Atropine is the specific antidote for anti-cholinesterase and early mushroom poisoning(due to muscarine). It is also used to block themuscarinic side effects of neostigmine.

SIDE EFFECTS AND TOXICITY

Side effects are quite common with the use ofatropine and its congeners; are due to facets of itsaction other than for which it is being used. Theycause inconvenience but are rarely serious.

The dental implication is that xerostomia(due to reduced salivary flow) caused by atro-pinic drugs can promote dental caries and oralcandidiasis.

Belladonna poisoning may occur due to drugoverdose or consumption of seeds and berries ofbelladonna/datura plant. Children are highlysusceptible. Manifestations are due to exagge-rated pharmacological actions.Dry mouth, difficulty in swallowing and talking.

Dry, flushed and hot skin (especially over faceand neck), fever, difficulty in micturition, a scarletrash may appear.Dilated pupil, photophobia, blurring of nearvision, palpitation.Excitement, psychotic behaviour, ataxia, delirium,hallucinations.Hypotension, weak and rapid pulse, cardiovas-cular collapse with respiratory depression.Convulsions and coma occur only in severepoisoning.

Treatment If poison has been ingested, gastriclavage should be done with tannic acid (KMnO4

is ineffective in oxidizing atropine). The patientshould be kept in a dark quiet room. Cold spon-ging or ice bags are applied for reducing bodytemperature. Physostigmine 1–3 mg s.c. or i.v.antagonizes both central and peripheral effects.It may be repeated 4–6 hourly. Neostigmine is lesssatisfactory.

Other general measures (maintenance of bloodvolume, artificial respiration, diazepam to controlconvulsions) should be taken as appropriate.

Contraindications Atropinic drugs are absolu-tely contraindicated in individuals with a narrowiridocorneal angle—may precipitate acute con-gestive glaucoma. However, marked rise inintraocular tension is rare in patients with wideangle glaucoma.

Caution is advocated in elderly males withprostatic hypertrophy—urinary retention canoccur.

Interactions

1. Absorption of most drugs is slowed becauseatropine delays gastric emptying. Extent ofdigoxin and tetracycline absorption may beincreased due to longer transit time in the g.i.t.

2. Antihistaminics, tricyclic antidepressants,phenothiazines, disopyramide, pethidinehave anticholinergic property—additive sideeffects occur with atropinic drugs.

Anticholinergic Drugs 79


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DRUGS ACTING ON AUTONOMICGANGLIA

Acetylcholine is the primary excitatory neuro-transmitter in both sympathetic and parasym-pathetic ganglia.

Drugs can either stimulate or block the ganglia.

Ganglionic stimulants

Selective nicotinic Nonselective/muscarinicagonists agonists

Nicotine (small dose) AcetylcholineLobeline CarbacholDimethyl phenyl Pilocarpinepiperazinium iodide Anticholinesterases(DMPP) MCN 343-ATetramethyl ammonium(TMA)Varenicline

Nicotine (from Nicotiana tabacum) is important in thecontext of smoking or chewing tobacco, but there is noclinical application of ganglionic stimulants, because nouseful purpose can be served by stimulating bothsympathetic and parasympathetic ganglia concurrently.

Nicotine transdermal and nicotine chewing gum have

become available for treatment of nicotine dependenceand as an aid to smoking cessation.

Varenicline It is a NN subtype selective nicotinic receptorpartial agonist recently approved as an aid to smokingcessation.

Ganglion blocking agentsA. Competitive blockers

Quaternary ammonium compoundsHexamethoniumPentolinium

Amines (secondary/tertiary)MecamylaminePempidine

Monosulfonium compoundTrimethaphan camforsulfonate

B. Persistent depolarising blockersNicotine (large dose)Anticholinesterases (large dose)

The competitive ganglion blockers were used inthe 1950s for hypertension and peptic ulcer,but have been totally replaced now because theyproduce a number of intolerable side effects.

There is at present no clinical relevance ofganglion blockers.

ADRENERGIC TRANSMISSION

Adrenergic (more precisely ‘Noradrenergic’)transmission is restricted to the sympatheticdivision of the ANS. There are three closely relatedendogenous catecholamines (CAs).

Noradrenaline (NA) It acts as transmitter at post-ganglionic sympathetic sites (except sweatglands, hair follicles and some vasodilator fibres)and in certain areas of brain.

Adrenaline (Adr) It is secreted by adrenal medullaand may have a transmitter role in the brain.

Dopamine (DA) It is a major transmitter in basalganglia, limbic system, CTZ, anterior pituitary,etc. and in a limited manner in the periphery.

1. Synthesis of CAs Catecholamines aresynthesized from the amino acid phenylalanineas depicted in Fig. 6.1. Synthesis of NA occurs inall adrenergic neurones, while that of Adr occursonly in the adrenal medullary cells and probablyrequires high concentration of glucocorticoidsthrough intra-adrenal portal circulation forinduction of the methylating enzyme.

2. Storage of CAs NA is stored in synapticvesicles or ‘granules’ within the adrenergicnerve terminal (see Fig. 6.4). The granularmembrane actively takes up DA from thecytoplasm and the final step of synthesis of NAtakes place inside the granule which containsdopamine β-hydroxylase. NA is then stored as a

Fig. 6.1: Steps in the synthesis of catecholamines

6Drugs Acting on Autonomic

Nervous SystemAdrenergic and Antiadrenergic Drugs

complex with ATP (in a ratio of 4:1) which isadsorbed on a protein chromogranin. Thecytoplasmic pool of CAs is kept low by theenzyme monoamine oxidase (MAO) present onthe outer surface of mitochondria.

3. Release of CAs The nerve impulse coupledrelease of CA takes place by exocytosis (see p. 69)and all the granular contents (NA or Adr, ATP,


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Fig. 6.2: Metabolism of catecholamines

it is very important in maintaining the NA contentof the neurone. This uptake is inhibited byreserpine resulting in depletion of CAs.

An extraneuronal uptake (uptake-2) of CAs involvinga different transporter also occurs into nonneural cells.This is not inhibited by cocaine and is of minor importance.

5. Metabolism of CAs The pathways of meta-bolism of CAs are depicted in Fig. 6.2. Part of theNA leaking out from vesicles into cytoplasm aswell as that taken up by axonal transport is firstattacked by MAO, while that which diffuses intocirculation is first acted upon by catechol-o-methyl transferase (COMT) in liver and othertissues. The other enzyme can subsequently actto produce vanillylmandelic acid (VMA). Themajor metabolites excreted in urine are VMA and3-methoxy-4-hydroxy phenylethylene glycol (areduced product) along with some metanephrine,normetanephrine and 3,4 dihydroxy mandelicacid. These metabolites are mostly conjugatedwith glucuronic acid or sulfate before excretionin urine. However, metabolism does not play animportant role in terminating the action ofendogenous CAs.

6. Adrenergic receptors Adrenergic receptorsare membrane bound G-protein coupled receptorswhich function primarily by increasing ordecreasing the intracellular production of secondmessengers cAMP or IP3/DAG. In some cases, the

dopamine β hydroxylase, chromogranin) arepoured out. The release is modulated by pre-synaptic receptors, of which α2 inhibitory controlis dominant.

Indirectly acting sympathomimetic amines (tyramine,etc.) also induce release of NA, but they do so bydisplacing NA from the nerve ending binding sites and byexchange diffusion utilizing norepinephrine transporter(NET) which is the carrier of uptake-1 (see below). This processis not exocytotic and does not require Ca2+.

4. Uptake of CAs There is a very efficientmechanism by which NA released from the nerveterminal is recaptured. This occurs in two steps—

Axonal uptake An active amine pump (NET) ispresent at the neuronal membrane whichtransports NA at a higher rate than Adr (uptake-1). The indirectly acting sympathomimetic aminesalso utilize this pump for entering the neurone.This uptake is the most important mechanism forterminating the postjunctional action of NA andis inhibited by cocaine, desipramine and itscongeners.

Vesicular uptake The membrane of intracellularvesicles has another amine pump which trans-ports CA from the cytoplasm to the interior ofvesicle. The vesicular NA is constantly leakingout into the axoplasm and is recaptured by thismechanism. This carrier also takes up DA formedin the axoplasm for further synthesis to NA. Thus,

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Table 6.1: Differences between α and β adrenergic receptors

α β

1. Rank order of potency of agonists Adr > NA > Iso Iso > Adr > NA

2. Antagonist Phenoxybenzamine Propranolol

3. Effector pathway IP3/DAG↑, cAMP ↓, K+ channel ↑ cAMP↑, Ca2+ channel ↑

Fig. 6.3: Dose-response curves of 3 catecholamines adrenaline (Adr), noradrenaline (NA) andisoprenaline (Iso) on isolated aortic strip and isolated bronchial smooth muscle illustrating twodistinct rank orders of potencies respectively for α and β adrenergic receptors

activated G-protein itself operates K+ or Ca2+

channels, or increases prostaglandin production.Ahlquist (1948), on the basis of two distinct

rank order of potencies of adrenergic agonists (Fig.6.3), classified adrenergic receptors into two typesα and β. This classification was then confirmed bythe development of selective α and β adrenergicantagonists. Important features of α and βreceptors are given in Table 6.1.

On the basis of relative organ specificity ofselective agonists and antagonists, the β receptorswere further subdivided into β1 (cardiac) and β2

(bronchial, vascular, uterine) subtypes. The β1

receptors are preferentially activated by dobuta-mine and blocked by metoprolol, while β2

receptors are selectively activated by salbutamoland blocked by α-methyl propranolol.

Similarly, subtypes of α adrenoceptor havealso been identified. The α1 subtype is locatedonly postjunctionally. Phenylephrine andprazosin respectively are its selective agonist and

antagonist. The α2 subtype is present both pre-and postjuctionally. It is selectively activated byclonidine and blocked by yohimbine.

The adrenergic neuronal mechanisms andaction of drugs which modify them are depicted inFig. 6.4. A summary of drugs acting throughadrenergic neuronal mechanisms is presented inTable 6.2.

ADRENERGIC DRUGS(Sympathomimetics)

These are drugs with actions similar to that of Adror of sympathetic stimulation.

Direct sympathomimetics They act directly asagonists on α and/or β adrenoceptors —Adr, NA,isoprenaline (Iso), phenylephrine, methoxamine,xylometazoline, salbutamol and many others.

Indirect sympathomimetics They act on adre-nergic neurone to release NA which then acts onthe adrenoceptors—tyramine, amphetamine.

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Fig. 6.4: Schematic representation of adrenergic neurotransmission and its modification by drugsTYR—tyrosine; α M-p-TYR—α methyl-p-tyrosine; α M-DOPA—α methyl dopa; MAO— monoamineoxidase;MAOI—monoamine oxidase inhibitor; COMT—catechol-o-methyl transferase; DOH-MA—dihydroxy mandelicacid, NMN—nor-metanephrine; VMA—vanillylmandelic acid

Mixed action sympathomimetics They act direc-tly as well as indirectly—ephedrine, dopamine,mephentermine.

ACTIONS

The peripheral actions of Adr in most tissueshave been clearly differentiated into thosemediated by α or β receptors depending on thepredominant receptor type present in a giventissue. These are tabulated in Table 6.3. The

receptor subtype, wherever defined, has beenmentioned in parenthesis. The actions of aparticular sympathomimetic amine depend on itsrelative activity at different types of adrenergicreceptors.

Adr : α1 + α2 + β1 + β2

NA: α1 + α2 + β1 but no β2 actionIso: β1 + β2 but no α action

Important actions of Adr, NA and isoprenalineare compared in Table 6.4.

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The overall actions are —1. Heart Adr increases heart rate by increa-sing automaticity of SA node. It also activateslatent pacemakers in A-V node and Purkinje fibres;arrhythmias can occur with high doses that raiseBP markedly. Certain anaesthetics (chloroform,halothane) sensitize the heart to the arrhythmicaction of Adr. Idioventricular rate is increased inpatients with complete heart block.

Force of cardiac contraction is increased.Cardiac output and oxygen consumption of theheart are markedly enhanced.

Conduction velocity through A-V node, bun-dle of His, atrial and ventricular fibres isincreased; partial A-V block may be overcome.Refractory period (RP) of all types of cardiac cells

is reduced. All cardiac actions are predominantlyβ1 receptor mediated.

When BP rises markedly, reflex bradycardiaoccurs due to stimulation of vagus— this is theusual response seen when NA is injected i.v.

2. Blood vessels Both vasoconstriction (α)and vasodilatation (β2) can occur depending onthe drug, its dose and vascular bed. Constrictionpredominates in cutaneous, mucous membraneand renal beds. Vasoconstriction occurs throughboth α1 and α2 receptors. Dilatation predominatesin skeletal muscles, liver and coronaries. Thedirect effect on cerebral vessels is not prominent—blood flow through this bed parallels change inBP.

Table 6.2: Summary of drug action through modification of adrenergic transmission

Step/site Action Drug Response

1. Synthesis of NA Inhibition α-methyl-p-tyrosine Depletion of NAUtilisation of α-methyl dopa Replacement of NA bysame synthetic α-methyl NA (falsepathway transmitter)

2. Axonal uptake Blockade Cocaine, desipramine, Potentiation of NAguanethidine (endo-and exogenous),

inhibition of tyramine

3. Granular uptake Blockade Reserpine Depletion of NA(degraded by MAO)

4. Nerve impulse Inhibition Guanethidine, Loss of transmissioncoupled release bretyliumof NA

5. Granular NA Displacement Guanethidine Initially sympathomimetic,depletion later

6. Membrane NA pool Exchange diffusion Tyramine, ephedrine Indirect sympathomimetic7. Metabolism MAO inhibition Nialamide Potentiation of NA (slight),

tranylcypromine —of tyramine (marked)COMT inhibition Tolcapone, Potentiation of NA (slight)

entacapone8. Receptors Mimicking Phenylephrine α1 sympathomimetic

Clonidine α2–inhibition of NA release,↓ sympathetic outflow

Isoprenaline β1 + β2 —sympathomimeticSalbutamol β2—sympathomimetic

Blockade Phenoxybenzamine α1 + α2—blockadePrazosin α1—blockadeYohimbine α2—blockadePropranolol β1 + β2—blockadeMetoprolol β1—blockade

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Table 6.3: Adrenergic responses mediated through α and β receptors

α actions β actions

1. Constriction of arterioles and veins → rise in Dilatation of arterioles and veins → fall in BP (β2)BP (mainly α1)

2. Heart—little action, arrhythmia at high dose Cardiac stimulation (β1), ↑ rate, force and conduction(α1) velocity

3. — Bronchodilatation (β2)

4. Contraction of radial muscles of iris → No effect on iris and ciliary musclemydriasis (α1), decreased aqueous secretion Enhanced aqueous secretion

5. Intestinal relaxation, contraction of sphincters Intestinal relaxation (β2)

6. Bladder trigone—contraction Detrusor—relaxation

7. Uterus—contraction Relaxation (β2)

8. Splenic capsule—contraction Relaxation (β2) (slight)

9. Neuromuscular transmission facilitated, Active state—prolonged in fast contracting muscle,↑ ACh release abbreviated in slow contracting muscle; tremors (β2)

10. Insulin secretion inhibited (α2) (dominant) Augmented insulin (mild) and glucagon secretion (β2)

11. Liver—glycogenolysis (α in some species) Liver—glycogenolysis (β2) → hyperglycaemiaMuscle—glycogenolysis (β2) → hyperlactacidaemiaFat—lipolysis (β3) → increased blood FFA, calorigenesis

12. — Renin release from kidney (β1)

13. Male sex organs—ejaculation —

14. Salivary gland—K+ and water secretion (α1) Ptylin secretion

15. — ADH secretion from posterior pituitary (β1)

16. Nictitating membrane—contraction (in —animals)

Action is most marked on arterioles; largerarteries and veins are affected at higher doses.

3. BP The effect depends on the amine, its doseand rate of administration.• NA causes rise in systolic, diastolic and mean

BP; it does not cause vasodilatation (noβ2 action), peripheral resistance increasesconsistently due to α action.

• Isoprenaline causes rise in systolic but markedfall in diastolic BP (β1—cardiac stimulation,β2— vasodilatation). The mean BP generallyfalls.

• Adr given by slow i.v. infusion or s.c. injectioncauses rise in systolic but fall in diastolic BP;peripheral resistance decreases because vas-cular β2 receptors are more sensitive than α receptors. Mean BP generally rises. Pulsepressure is increased.

When an α blocker has been given, only fall in BPis seen—vasomotor reversal of Dale.

4. Respiration Adr and Isoprenaline but not NAare potent bronchodilators (β2). This action is moremarked when the bronchi are constricted. Adr candirectly stimulate respiratory centre (RC), butthis action is seldom manifest at clinically useddoses.

5. Eye Mydriasis occurs due to contraction ofradial muscles of iris (α1), but this is minimal aftertopical application because Adr penetrates corneapoorly. The intraocular tension tends to fall,especially in wide angle glaucoma due to bothreduction in aqueous formation and facilitation ofoutflow.

6. GIT In isolated preparations of gut relaxationoccurs through activation of both α and β

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receptors. In intact animals and man, peristalsisis reduced and sphincters are constricted, but theeffects are brief and of no clinical import.

7. Bladder Detrusor is relaxed (β) and trigoneis constricted (α): both actions tend to hindermicturition.

8. Uterus Adr can both contract or relax uterinemuscle through respectively α and β receptors;effect varies with hormonal and gestationalstatus. Human uterus at term of pregnancy isrelaxed by Adr; while at other times, itscontractions are enhanced.

9. Skeletal muscle Adr facilitates neuromus-cular transmission. However, incomplete fusionof individual muscle fibre contractions along withenhanced firing of muscle spindles is responsiblefor the tremors produced by β2 agonists.

10. CNS Adr, in clinically used doses, does notproduce any marked CNS effects because of poorpenetration in brain, but restlessness, apprehen-sion and tremor may occur. Activation of α2

receptors in the brainstem results in decreasedsympathetic outflow → fall in BP and brady-cardia.

11. Metabolic Adr produces glycogenolysis—hyperglycaemia, hyperlactacidaemia (β2); lipoly-sis—rise in plasma free fatty acid (FFA), calori-genesis (β2 + β3) and transient hyperkalaemiafollowed by hypokalaemia due to direct action onliver, muscle and adipose tissue cells. In addition,metabolic effects result from reduction of insulin(α2) and augmentation of glucagon (β2) secretion.

Biochemical mediation of adrenergic responses

β actions The β actions are mediated through cAMP (seeFig. 3.5). Adr activates membrane bound enzyme adenylylcyclase through a regulatory protein Gs → ATP is brokendown to cAMP at the inner face. This in turn phosphorylatesa number of intracellular cAMP-dependent protein kinasesand initiates a series of reactions.

α actions The mediation of α actions is varied and lesswell defined. Vascular and other muscle contractions aremediated through IP3/DAG production and mobilizationof intracellular Ca2+. In other tissues, inhibition of cAMPproduction and hyperpolarization through K+ channelactivation mediates the α adrenergic responses.

Administration CAs are absorbed from theintestine but are rapidly degraded by MAO andCOMT present in the intestinal wall and liver.They are thus orally inactive. For systemic effectsAdrenaline (epinephrine) is administered by s.c. ori.m. injection in a dose of 0.2–0.5 mg; action lasts0.5–2 hours. In dental practice, it is used as a localvasoconstrictor added to lidocaine in a concentrationof 1 in 200,000 to 100,000 for dental anaesthesia.

ADRENALINE 1 mg/ml inj.; in XYLOCAINE withADRENALINE: Lidocaine 21.3 mg + Adrenaline 0.005mg per ml inj, 30 ml vial.

Noradrenaline (norepinephrine, levarterenol) isadministered only by slow i.v. infusion at the rateof 2–4 μg/min, for raising BP in emergencysituations.

Adverse effects and contraindications

• Transient restlessness, palpitation, anxiety,tremor, pallor may occur after s.c./i.m. injectionof Adr.

• Marked rise in BP leading to cerebral haemor-rhage, ventricular tachycardia/fibrillation,angina, myocardial infarction are thehazards of large doses or inadvertant i.v.injection of Adr.

Table 6.4: Comparative effects of adrenaline,noradrenaline and isoprenaline

Adr NA Iso

1. Heart rate ↑ ↓ ↑↑2. Cardiac output ↑↑ – ↑↑3. BP—Systolic ↑↑ ↑↑ ↑

Diastolic ↓↑ ↑↑ ↓↓ Mean ↑ ↑↑ ↓

4. Blood flowSkin and mm ↓ ↓ –Sk. muscle ↑↑ –, ↓ ↑Kidney ↓ ↓ –Liver ↑↑ – ↑Coronary ↑ ↑ ↑

5. Bronchial muscle ↓↓ – ↓↓6. Intestinal muscle ↓↓ ↓ ↓7. Blood sugar ↑↑ –, ↑ ↑

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• Adr is contraindicated in hypertensive, hyper-thyroid and angina patients.

• Adr mixed local anaesthetic should be used verycautiously for dental anaesthesia in patients withheart disease.

• It should not be given during anaesthesiawith halothane (risk of arrhythmias) and topatients receiving β blockers (marked rise inBP can occur).

THERAPEUTIC CLASSIFICATION OFADRENERGIC DRUGS

I. Pressor agentsNoradrenaline PhenylephrineEphedrine MethoxamineDopamine Mephentermine

II. Cardiac stimulantsAdrenaline DobutamineIsoprenaline

III. BronchodilatorsIsoprenaline TerbutalineSalbutamol Bambuterol(Albuterol) Salmeterol

Formoterol

IV. Nasal decongestantsPhenylephrine NaphazolineXylometazoline PseudoephedrineOxymetazoline Phenyl propanolamine

V. CNS stimulantsAmphetamine MethamphetamineDexamphetamine

VI. AnorecticsFenfluramine SibutramineDexfenfluramine

VII. Uterine relaxant and vasodilatorsRitodrine SalbutamolIsoxsuprine Terbutaline

Salient features of important adrenergic drugs aresummarized below:

Dopamine (DA) It is a dopamine (D1 and D2

receptors) as well as adrenergic α and β1 (but not

β2) agonist. The D1 receptors in renal andmesenteric blood vessels are the most sensitive: i.v.infusion of low dose of DA dilates these vesselsincreasing g.f.r. and Na+ excretion. Moderatelyhigh doses produce a positive inotropic effect onthe heart. Vasoconstriction (α1 action) occurs onlywhen large doses are infused. At doses normallyinfused i.v. (0.2–1 mg/min), it raises cardiacoutput and systolic BP with little effect on diastolicBP. This is useful in cardiogenic and septic shock.

Dobutamine A derivative of DA, but not a D1 orD2 receptor agonist. Though it acts on both α andβ adrenergic receptors, the only prominent actionof clinically employed doses (2-8 μg/kg/min i.v.infusion) is increase in force of cardiac contractionand output. It is used as an inotropic agent inpump failure accompanying myocardial infarc-tion, cardiac surgery, and for short-term manage-ment of severe congestive heart failure.

Ephedrine It is an alkaloid obtained fromEphedra vulgaris. Mainly acts indirectly but hassome direct action on α and β receptors also.Repeated injections produce tachyphylaxis,primarily because the neuronal pool of NAavailable for displacement is small. It is resistantto MAO, therefore, effective orally. It crosses tobrain and causes stimulation.

Ephedrine is now occasionally used in mildchronic bronchial asthma and for hypotensionduring spinal anaesthesia.

Amphetamines These are synthetic compoundshaving the same pharmacological profile asephedrine; orally active with long duration (4–6hr). The CNS actions are more prominent;maximal selectivity is exhibited by dextroamphe-tamine and methamphetamine, which in theusual doses produce few peripheral effects.

The central effects include alertness, increasedconcentration and attention span, euphoria,talkativeness, increased work capacity. Fatigue isallayed. Athletic performance is improved tempo-rarily followed by deterioration. It is one of thedrugs included in the ‘dope test’ for athletes. Thereticular activating system is stimulated resulting

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in wakefulness and postponement of sleep depri-vation induced physical disability. But this isshort lived and may be accompanied by anxiety,restlessness, tremor, dysphoria and agitation.

Amphetamines stimulate respiratory centre,especially if it has been depressed. Hunger is sup-pressed as a result of inhibition of hypothalamicfeeding centre. Peripheral effects on heart and BPare not significant at the usual doses, but tone ofvesical sphincter is definitely increased.

Amphetamines are drugs of abuse and arecapable of producing marked psychological butlittle or no physical dependence. Amphetamineabusers are generally teenagers seeking thrill orkick which is obtained on rapid i.v. injection. Highdoses produce euphoria, marked excitementwhich may progress to mental confusion, deli-rium, hallucinations and an acute psychotic state.

Repeated use is likely to produce long-lastingbehavioural abnormalities; psychosis may beprecipitated.

Phenylephrine It is a selective α1 agonist, hasnegligible β action. It raises BP by causing vaso-constriction. Topically, it is used as a nasaldecongestant and for producing mydriasis whencycloplegia is not required. It is also a constituentof orally administered nasal decongestant pre-parations.

Methoxamine Another selective α1 stimulantwith no β actions; occasionally used as a pressoragent.

Mephentermine It produces both cardiac stimu-lation and vasoconstriction by directly activatingα and β adrenergic receptors as well as byreleasing NA. Administered orally as well asparenterally, it is used to prevent and treat hypo-tension due to spinal anaesthesia, shock and otherhypotensive states.

SELECTIVE β2 STIMULANTS

These include, salbutamol, terbutaline and itslong acting prodrug bambuterol, salmeterol,formoterol and ritodrine. They cause bronchodila-tation, vasodilatation and uterine relaxation,

without producing significant cardiac stimula-tion. β2 selectivity is only relative. Salbutamolhas β2:β1 action ratio of about 10 . They areprimarily used in bronchial asthma (see Ch. 19).Occasionally ritodrine is employed to depressuterine contractions and delay premature labour.

The most important side effect is muscletremor.

NASAL DECONGESTANTS

These are α agonists which on topical appli-cation as dilute solution (0.05–0.1%) producelocal vasoconstriction. The imidazoline com-pounds—xylometazoline and oxymetazoline arerelatively selective α2 agonist (like clonidine).They have a longer duration of action (12 hr) thanephedrine. Rise in BP can occur in hypertensivesafter nasal instillation.

Phenylpropanolamine (PPA) Chemically andpharmacologically similar to ephedrine; causesvasoconstriction and has some amphetaminelike CNS effects. It is included in a large number oforal cold/decongestant combination remedies,though it has been banned in the USA because ofpossible risk of haemorrhagic stroke when usedas appetite suppressant in relatively larger doses.

ANORECTIC AGENTS

A number of drugs related to amphetamine havebeen developed which inhibit feeding centre buthave little/no CNS stimulant action or abuseliability. All of them act by inhibiting the reuptakeof NA/DA or 5-HT, enhancing monoaminergictransmission in the brain.

Fenfluramine and its dextroisomer dexfenflu-ramine reduce food seeking behaviour by enhan-cing serotonergic transmission in the hypo-thalamus, and have no stimulant property. Assuch, they were extensively used by slimmingcentres, but are banned now due to a possibleassociation with cardiac valvular defects andpulmonary hypertension.

Sibutramine is a newer antiobesity drug whichinhibits both NA and 5-HT reuptake. It reduces

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appetite and may in addition stimulate thermo-genesis resulting in weight loss. The safety of thisdrug too has been questioned, but it is still widelyused.

THERAPEUTIC USES

1. Hypotensive states (shock, spinal anaesthe-sia, hypotensive drugs) One of the pressor agentscan be used along with volume replacement forneurogenic and haemorrhagic shock, also as anexpedient measure to maintain cerebral circula-tion in other hypotensive states. Slow i.v. infusionof dopamine is more appropriate, while use of NAis practically obsolete. Adr 0.5 mg injectedpromptly i.m. is the drug of choice for anaphy-lactic shock (see p 59). It not only raises BP, butcounteracts bronchospasm/laryngeal edema thatmay accompany. Because of the rapidity andprofile of action, Adr is the only life-savingmeasure.

2. Along with local anaesthetics Adr 1 in100,000 or 1 in 200,000 for infiltration, nerve blockand spinal anaesthesia. Duration of anaesthesiais prolonged and systemic toxicity of localanaesthetic is reduced. It is routinely included indental anaesthesia (unless contraindicated); serves toreduce bleeding as well.

3. Control of local bleeding From skin, mucousmembranes, tooth socket, epistaxis, etc: compressesor packs of Adr 1 in 10,000, soaked in cotton cancontrol arteriolar and capillary bleeding.

4. Nasal decongestant In colds, rhinitis, sinusi-tis, blocked eustachian tube—one of the α-agonists is used as nasal drops.

5. Cardiac arrest (drowning, electrocution,Stokes-Adams syndrome and other causes) Adrinjected i.v. may be used to stimulate the heartalong with external cardiac massage.

6. Partial or complete A-V block Isoprenalinemay be used as temporary measure to maintainsufficient ventricular rate.

7. Congestive heart failure Adrenergic inotropicdrugs are not useful in the routine treatment of

CHF. However, controlled short-term i.v. infusionof DA/dobutamine can tide over acute cardiacdecompensation during myocardial infarction,cardiac surgery and in resistant CHF.

8. Bronchial asthma Adrenergic drugs, espe-cially β2 stimulants, are the primary drugs forrelief of reversible airway obstruction (see Ch. 19).

9. Allergic disorders Adr is life saving inlaryngeal edema and anaphylaxis, and can affordquick relief in urticaria, angioedema of mouth/face, etc., because it is a physiological antagonistof histamine.

10. Mydriatic Phenylephrine is used to facilitatefundus examination; cycloplegia is not required.It tends to reduce intraocular tension in wide angleglaucoma. The ester prodrug of Adr dipivefrine isan adjuvant drug for open angle glaucoma.

11. Narcolepsy Narcolepsy is sleep occurring infits, and is adequately controlled by ampheta-mines.

12. Hyperkinetic children (minimal brain dys-function, attention deficit hyperkinetic disorder):Amphetamines have an apparently paradoxicaleffect to calm down hyperkinetic children. Byincreasing attention span, they improvebehaviour and performance in studies.

13. Obesity The anorectic drugs can help theobese to tolerate a reducing diet for short periods.Their use (for 2–3 months) may be considered insevere obesity.

14. Uterine relaxant Selective β2 stimulants,especially ritodrine, infused i.v. have beensuccessfully used to postpone labour.

15. Insulin hypoglycaemia Adr may be used asan expedient measure, but glucose should begiven as soon as possible.

ANTIADRENERGIC DRUGS(ADRENERGIC RECEPTOR ANTAGONISTS)

These are drugs which antagonize the receptoraction of adrenaline and related drugs. They are

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competitive antagonists at α or β or both types ofadrenergic receptors.

ααααα ADRENERGIC BLOCKING DRUGS

These drugs inhibit adrenergic responses media-ted through the α adrenergic receptors withoutaffecting those mediated through β receptors.

CLASSIFICATION

I. Nonequilibrium typeβ-Haloalkylamines—Phenoxybenzamine.

II. Equilibrium type (competitive)

A. Nonselective(i) Ergot alkaloids—Ergotamine, Ergotoxine.

(ii) Hydrogenated ergot alkaloids—Dihydroergo-tamine (DHE), Dihydroergotoxine.

(iii) Imidazolines—Tolazoline, Phentolamine.(iv) Miscellaneous—Chlorpromazine.

B. α1 selective—Prazosin, Terazosin, Doxazosin,Tamsulosin, Alfuzosin.

C. α2 selective—Yohimbine.

GENERAL EFFECTS OF α BLOCKERS

1. Blockade of vasoconstrictor α1 (also α2) recep-tors reduces peripheral resistance and causespooling of blood in capacitance vessels → venousreturn and cardiac output are reduced → fall inBP. Postural reflex is interfered with → markedhypotension occurs on standing → dizziness andsyncope. Hypovolemia accentuates the hypoten-sion. Special care must be taken to ensure thatpatients receiving an α blocker (e.g. prazosin forhypertension or benign prostatic hypertrophy) do notsuddenly stand up after being supine on the dentalchair. Also, these patients are more prone todevelop hypotension if they bleed during thedental procedure. The α blockers abolish pressoraction of Adr (injected i.v. in animals) which thenproduces only fall in BP due to β2 mediatedvasodilatation—vasomotor reversal of Dale. Pressorand other actions of selective α agonists (NA,phenylephrine) are suppressed.

2. Reflex tachycardia occurs due to fall in meanarterial pressure and increased release of NA dueto blockade of presynaptic α2 receptors.3. Nasal stuffiness and miosis result fromblockade of α receptors in nasal blood vessels andin radial muscles of iris respectively.4. Intestinal motility is increased due to partialinhibition of relaxant sympathetic influences—diarrhoea may occur.5. Hypotension produced by α blockers canreduce renal blood flow → g.f.r. is reducedand more complete reabsorption of Na+ and wateroccurs in the tubules → Na+ retention andincrease in blood volume. This is accentuated byreflex increase in renin release mediated throughβ1 receptors.6. Tone of smooth muscle in bladder trigone,sphincter and prostate is reduced by blockade ofα1 receptors (mostly of the α1A subtype) → urineflow in patients with benign hypertrophy ofprostate (BHP) is improved.7. Contractions of vas deferens and relatedorgans which result in ejaculation are coordina-ted through α receptors—α blockers can inhibitejaculation; this may manifest as impotence.

The α blockers have no effect on adrenergicallyinduced cardiac stimulation, bronchodilatation,vasodilatation and most of the metabolic changes,because these are predominantly mediatedthrough β receptors.

Apart from these common effects, most ofwhich manifest as side effects, individual αblockers have some additional actions. Theirpharmacological profile is also governed by theircentral effects and by the relative activity on α1

and α2 receptor subtypes.Side effects that may occur with any α blocker

are—palpitation, postural hypotension, nasalblockage, loose motions, fluid retention, inhibi-tion of ejaculation and impotence.

Distinctive features of important α adrenergicblockers are given below:

Phenoxybenzamine It cyclizes spontaneouslyin the body giving rise to a highly reactiveethyleniminium intermediate which reacts with

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α adrenoceptors and other biomolecules byforming strong covalent bonds. The α blockade isof nonequilibrium type and develops gradually(even after i.v. injection). It lasts 3–4 days.

Phenoxybenzamine has been used primarilyin pheochromocytoma; occasionally in secondaryshock and peripheral vascular disease.

Natural and hydrogenated ergot alkaloids The aminoacid alkaloids ergotamine and ergotoxine are partial agonistsand antagonists at α adrenergic, serotonergic and dopami-nergic receptors. The amine alkaloid ergometrine has no αblocking activity.

The natural ergot alkaloids produce long-lastingvasoconstriction which predominates over their α blockingaction—peripheral vascular insufficiency and gangrene oftoes and fingers occurs in ergotism. Hydrogenation reducesvasoconstrictor and increases α blocking activity.

Their principal use is in migraine. Dihydroergotoxinehas been used as a cognition enhancer.

Phentolamine It is a rapidly acting α blockerwith short duration of action (in minutes) whichhas been utilized for diagnosis and intraoperativemanagement of pheochromocytoma and for con-trol of hypertension due to clonidine withdrawal,cheese reaction, etc.

Prazosin It is first of the highly selective α1

blockers having α1 : α2 selectivity ratio 1000:1. Itblocks sympathetically mediated vasoconstric-tion and produces fall in BP which is attended byonly mild tachycardia; NA release is not increaseddue to absence of α2 blockade.

Prazosin dilates arterioles more than veins.Postural hypotension occurs, especially in thebeginning—dizziness and fainting may becaused as ‘first dose effect’. This can be minimizedby starting with a low dose and taking it atbedtime.

Prazosin is primarily used as an anti-hypertensive. Other uses are—LVF, Raynaud’sdisease and prostatic hypertrophy—blocks α1

receptors in bladder trigone and prostate and thusimproves urine flow, reduces residual urine inbladder.

Terazosin and doxazosin are longer actingcongeners of prazosin suitable for once dailydosing, particularly in BHP.

Tamsulosin is relatively uroselective due tohigher affinity for α1A subtype of α1 receptorswhich predominate in the bladder base andprostate. Thus, it does not cause significantchanges in BP or HR at doses which relieveurinary symptoms of BHP. Dizziness andretrograde ejaculation are the only significant sideeffects. Its modified release (MR) capsule needsonly once daily dosing.

Yohimbine An alkaloid from West African plantYohimbehe. It is a relatively selective α2 blocker withshort duration of action. It may cause congestion ofgenitals and has been claimed to be an aphrodisiac. Thiseffect probably is only psychological.There are no valid indications for clinical use of yohimbine.

USES OF α BLOCKERS1. Pheochromocytoma It is a tumour of adre-nal medullary cells. Excess CAs are secretedwhich can cause intermittent or persistent hyper-tension. Estimation of urinary CA metabolites(VMA, normetanephrine) is diagnostic. In addi-tion, a pharmacological test can be performed byinjecting phentolamine 5 mg i.v. A fall in BP> 35 mmHg systolic or > 25 mmHg diastolic isindicative of pheochromocytoma.

Phenoxybenzamine can be used as definitivetherapy for inoperable and malignant tumours. Itis also employed before and during surgicalremoval of the tumour. Alternatively, phentola-mine drip can be instituted during the operation.

2. Hypertension Prazosin and other selectiveα1 blockers are useful antihypertensive drugs, butthe nonselective α1 + α2 blockers have been afailure. However, phentolamine/phenoxybenza-mine are of great value in controlling episodesof rise in BP during clonidine withdrawal andcheese reaction in patients on MAO inhibitors.

3. Benign hypertrophy of prostate (BHP) Theurinary obstruction caused by BHP has a staticcomponent due to increased size of prostate anda dynamic component due to increased tone ofsmooth muscle in bladder neck and prostaticurethra. Since this increase in tone is mediatedneurogenically through α1 receptors, their

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blockade relaxes these structures, reducingdynamic obstruction, increasing urinary flow rateand causing more complete emptying of bladderin many patients of BHP.

Terazosin, doxazosin and tamsulosin are thepeferred α1

blockers because of once daily dosing.Tamsulosin appears to cause fewer vascular sideeffects because of relative α1A

selectivity.

4. Secondary shock Shock due to blood or fluid loss isaccompanied by reflex vasoconstriction. If volumereplacement fails to reverse this, therapy with an α blocker(phenoxybenzamine i.v.) can help by counteractingvasoconstriction and improving tissue perfusion, shiftingblood from extravascular to vascular compartment andfrom pulmonary to systemic circuit.

5. Peripheral vascular diseases The α blockers affordsymptomatic relief when vasoconstriction is prominent asin Raynaud’s phenomenon, but not when vascularobstruction is organic as in Buerger’s disease.

βββββ ADRENERGIC BLOCKING DRUGS

These drugs inhibit adrenergic responses media-ted through the β receptors. All β blockers arecompetitive antagonists.

CLASSIFICATION

Nonselective (β1 and β2)a. Without intrinsic sympathomimetic activity

Propranolol, Sotalol, Timolol.b. With intrinsic sympathomimetic activity

Pindolol.c. With additional α blocking property

Labetalol, Carvedilol.Cardioselective (β1)

Metoprolol, Atenolol, Acebutolol, Bisoprolol,Esmolol, Betaxolol, Celiprolol, Nebivolol.

The pharmacology of propranolol is describedas prototype.

PHARMACOLOGICAL ACTIONS

1. CVS

(a) Heart Propranolol decreases heart rate, forceof contraction (at relatively higher doses) andcardiac output (c.o.). The effects on a normalresting subject are not appreciable, but becomeprominent under sympathetic overactivity(exercise, emotion).

Cardiac work and oxygen consumption arereduced as the product of heart rate and aorticpressure decreases. Overall effect in anginapatients is improvement of O2 supply/demandstatus: exercise tolerance is increased.

Propranolol suppresses ectopic automaticity,especially if it has been augmented by adrenergicstimuli. The A-V conduction is delayed. At highdoses, a direct depressant and membrane stabi-lizing (quinidine like) action is exerted, but thiscontributes little to the antiarrhythmic effect atusual doses. Propranolol blocks cardiac stimulantaction of adrenergic drugs but not that of digoxin,methylxanthines or glucagon.

(b) Blood vessels Propranolol blocks vasodila-tation and fall in BP evoked by isoprenaline andenhances the rise in BP caused by Adr—there is

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First generation Second generation Third generation(older, nonselective) (β1 selective) (with additional α blocking

and/or vasodilator property)

Propranolol Metoprolol LabetalolTimolol Atenolol CarvedilolSotalol Acebutolol CeliprololPindolol Bisoprolol Nebivolol

Esmolol

Another system classifies β blockers into 3 generations:


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re-reversal of vasomotor reversal that is seen afterα blockade. It has no direct effect on blood vesselsand there is little acute change in BP. Onprolonged administration, BP gradually falls inhypertensive subjects but not in normotensives.Total peripheral resistance (t.p.r.) is increasedinitially (due to blockade of β mediated vaso-dilatation) and c.o. is reduced so that there is littlechange in BP. With continued treatment,resistance vessels gradually adapt to chronicallyreduced c.o. and t.p.r. decreases—both systolicand diastolic BP fall. This is considered to be themost likely explanation of the antihypertensiveaction. Other mechanisms that may contribute are:(i) Reduced NA release from sympathetic termi-nals.(ii) Decreased renin release from kidney (β1

mediated).(iii) Central action reducing sympathetic outflow.

2. Respiratory tract Propranolol increasesbronchial resistance by blocking β2 receptors. Theeffect is hardly discernible in normal individualsbecause sympathetic bronchodilator tone isminimal. In asthmatics, however, the conditionis consistently worsened and a severe attack maybe precipitated.

3. CNS No overt central effects are producedby propranolol. However, subtle behaviouralchanges, forgetfulness, increased dreaming andnightmares have been reported with long-termuse of relatively high doses.

4. Local anaesthetic Propranolol is as potenta local anaesthetic as lidocaine, but is notclinically used for this purpose because of itsirritant property.

5. Metabolic Propranolol blocks adrenergi-cally induced lipolysis and consequent increasein plasma free fatty acid levels. Plasma trigly-ceride level and LDL/HDL ratio is increased. Italso inhibits glycogenolysis—recovery frominsulin action is delayed. Though there is no effecton normal blood sugar level, prolonged

propranolol therapy may reduce carbohydratetolerance by decreasing insulin release.

6. Skeletal muscle Propranolol inhibits adre-nergically provoked tremor. This is a peri-pheral action exerted directly on muscle fibrethrough β2 receptors.

7. Eye Instillation of β blockers reducessecretion of aqueous humor: i.o.t. is lowered. Thereis no consistent effect on pupil size or accom-modation.

PHARMACOKINETICS

Propranolol is well absorbed after oral adminis-tration, but has low bioavailability due to highfirst pass metabolism in liver. Oral: parenteral doseratio of up to 40:1 has been found.

Metabolism of propranolol is dependent onhepatic blood flow. Chronic use of propranololitself decreases hepatic blood flow—oral bio-availability is increased and its t½ is prolonged.Metabolites of propranolol, one of which is active,are excreted in urine.

INTERACTIONS

1. Additive depression of sinus node and A-Vconduction with digitalis and verapamil—cardiac arrest can occur.2. Propranolol delays recovery from hypoglycae-mia due to insulin and oral antidiabetics.Warning signs of hypoglycaemia mediatedthrough sympathetic stimulation (tachycardia,tremor) are suppressed.3. Phenylephrine, ephedrine and other αagonists present in cold remedies can causemarked rise in BP in β blocked subjects.4. Though only low concentrations of Adr areadded to lidocaine for dental anaesthesia, it mayproduce some pressor action in patients receivingnonselective β blockers.5. Indomethacin and other NSAIDs attenuatethe antihypertensive action of β blockers.6. Propranolol retards lidocaine metabolism byreducing hepatic blood flow.

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ADVERSE EFFECTS ANDCONTRAINDICATIONS

1. Propranolol can accentuate myocardial insuffi-ciency and worsen CHF. However, when compen-sation has been restored, careful addition of a β1

blocker is now established therapy to prolongsurvival.2. Bradycardia: resting HR may be reduced to60/min or less.3. Propranolol worsens chronic obstructive lungdisease; can precipitate life-threatening attack ofbronchial asthma: contraindicated in asthmatics.4. Propranolol exacerbates variant (vasospastic)angina due to unopposed α mediated coronaryconstriction.5. Carbohydrate tolerance may be impaired inprediabetics.6. Plasma lipid profile is altered on long-termuse.7. Withdrawal of propranolol after chronic useshould be gradual, otherwise rebound hyper-tension, worsening of angina and even suddendeath can occur.8. Propranolol is contraindicated in partial andcomplete heart block: arrest may occur.9. Tiredness and reduced exercise capacity.10. Cold hands and feet due to blockade ofvasodilator β2 receptors.11. Side effects not overtly due to β blockade are—g.i.t. upset, lack of drive, nightmares, forgetfulness,rarely hallucinations. Male patients more fre-quently complain of sexual distress.

OTHER β BLOCKERS

A number of β blockers have been developedhaving some special features. The associatedproperties along with their significance can besummarized as:

Cardioselectivity (in metoprolol, atenolol, acebu-tolol, bisoprolol, nebivolol).These drugs are more potent in blocking cardiac(β1) than bronchial (β2) receptors. Their featuresare:1. Lower propensity to cause bronchoconstric-tion.

2. Less interference with carbohydrate meta-bolism.3. Lower incidence of cold hands and feet.4. No/less deleterious effect on blood lipidprofile.5. Ineffective in suppressing essential tremor.6. Less liable to impair exercise capacity.

Partial agonistic (intrinsic sympathomimetic)action (in pindolol, acebutolol). They themselvesactivate β1 and/or β2 receptors submaximally.1. Bradycardia and depression of contractilityat rest are not prominent.2. Withdrawal is less likely to exacerbate hyper-tension or angina.3. Not effective in migraine prophylaxis—theydilate cerebral vessels.4. Less suitable for secondary prophylaxis of MI.

Salient features of important β blockers are givenbelow:

1. Sotalol Nonselective β blocker that hasadditional K+ channel blocking and class IIIantiarrhythmic property.

2. Timolol It is a β blocker used topically inthe eye for glaucoma.

Betaxolol and Levobunolol are other β blockers employedtopically for glaucoma.

3. Pindolol A potent β blocker with prominentintrinsic sympathomimetic activity.

4. Metoprolol It is the prototype of cardio-selective (β1) blockers. Its potency to block cardiacstimulation is similar to propranolol, but nearly50 times higher dose is needed to block isoprenalineinduced vasodilatation. It is less likely to worsenasthma and it may be preferred in diabeticsreceiving insulin or oral hypoglycaemics.

5. Atenolol A relatively selective β1 blockerhaving low lipid solubility. It is incompletelyabsorbed orally, but first pass metabolism is notsignificant. Because of longer duration of action,once daily dose is often sufficient. It is one of themost commonly used β blockers for hypertensionand angina.

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6. Esmolol It is an ultrashort acting β1 blockerdevoid of partial agonistic or membrane stabili-zing actions. It is inactivated by esterases in blood;plasma t½ is < 10 min; action lasts 15–20 minafter terminating i.v. infusion—degree of β block-ade can be titrated by regulating rate of infusion.

Esmolol has been used to terminate supra-ventricular tachycardia, episodic atrial fibrillationor flutter, arrhythmia during anaesthesia, toreduce HR and BP during and after cardiacsurgery, and in early treatment of myocardialinfarction.

7. Nebivolol This cardioselective β blocker alsoacts as a nitric oxide (NO) donor: producesvasodilatation and has the potential to improveendothelial function.

USES

1. Hypertension β blockers are relatively mildantihypertensives. All agents, irrespective of asso-ciated properties, are nearly equally effective. Theyare one of the first choice drugs because of goodpatient acceptability and cardioprotectivepotential (see Ch. 11).

2. Angina pectoris All β blockers benefit anginaof effort. Taken on a regular schedule, they dec-rease frequency of attacks and increase exercisetolerance (see Ch. 11).

3. Cardiac arrhythmias β blockers suppressextrasystoles and tachycardias, especially thosemediated adrenergically (during anaesthesia,digitalis induced)—may be used i.v. for thispurpose. Esmolol is an alternative drug forparoxysmal supraventricular tachycardia (seeCh. 12).

4. Myocardial infarction (MI) In relation to MI,β blockers are used for two purposes:(a) Secondary prophylaxis of MI: there is now firmevidence of benefit. Long-term use after recoveryfrom MI has been found to decrease subsequentmortality by 20%.(b) Myocardial salvage during evolution of MI:administered i.v. within 4–6 hours of an attackfollowed by continued oral therapy. β blockers—

(i) May limit infarct size by reducing O2 con-sumption—marginal tissue which ispartially ischaemic may survive.

(ii) May prevent arrhythmias including ventri-cular fibrillation.

However, β blockers can be given to only thosepatients not in shock or cardiac failure. Inmegatrials such therapy has been found to reducemortality by 20–25%.

5. Congestive heart failure Although β blockerscan worsen heart failure, several studies havereported beneficial haemodynamic effects of lowdoses of β1 blockers in selected patients withdilated cardiomyopathy. Introduced graduallyand maintained for long term, these drugs retardthe progression of CHF and prolong life. Thebenefit may result from antagonism of deleteriouseffects of sympathetic overactivity on myocar-dium. Certain β1 blockers used appropriatelyalong with other measures under expert super-vision is now considered standard therapy formost mild-to-moderate CHF patients.

6. Dissecting aortic aneurysm β blockers helpby reducing cardiac contractile force and aorticpulsation.

7. Pheochromocytoma β blockers may beadded to α blockers to control tachycardia andarrhythmia.

8. Thyrotoxicosis Propranolol rapidly controlssymptoms (palpitation, nervousness, tremor,fixed stare, severe myopathy and sweating)without significantly affecting thyroid status. Itis used preoperatively and while awaiting res-ponse to antithyroid drugs/radioactive iodine.

9. Migraine Propranolol is the most effectivedrug for chronic prophylaxis of migraine (seep. 109).

10. Anxiety Propranolol exerts an apparentantianxiety effect, especially under conditionswhich provoke nervousness and panic, e.g.examination, unaccustomed public appearance,etc. This is probably due to blockade of peripheral

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manifestations of anxiety (palpitation, tremor)which have a reinforcing effect on anxiety.

11. Essential tremor Nonselective β blockershave an established place in treating essentialtremor.

12. Glaucoma Timolol and other ocular βblockers are one of the first choice drugs forchronic simple (wide angle) glaucoma; also usedas adjuvant in angle closure glaucoma.

13. Hypertrophic obstructive cardiomyopathy Thesubaortic region is hypertrophic. β blockersimprove c.o. in these patients during exercise, byreducing left ventricular outflow obstruction.

ααααα + βββββ ADRENERGIC BLOCKERS

Labetalol It is the first adrenergic antagonistcapable of blocking both α and β receptors. Theβ blocking potency is about 1/3rd that of propra-nolol, while the α blocking potency is about1/10th of phentolamine.

Labetalol is 5 times more potent in blockingβ than α receptors. As such, effects of a low doseresemble those of propranolol alone; while at highdoses, they are like a combination of propranololand prazosin. It causes fall in BP which isattended by no change or slight decrease in heartrate.

Labetalol is orally effective but undergoesconsiderable first pass metabolism. It is amoderately potent hypotensive and is speciallyuseful in pheochromocytoma, clonidine with-drawal; can also be used in essential hyper-tension. Most important side effect is posturalhypotension, though other side effects of α and βblockers can also occur.

Carvedilol It is a β1 + β2 + α1 adrenoceptorblocker; produces vasodilatation due to α1

blockade as well as calcium channel blockade,and has antioxidant property. It has been used inhypertension and is the β blocker especiallyemployed as cardioprotective in CHF.

α + β Adrenergic Blockers 97

Autacoid This term is derived from Greek:autos—self, akos—healing substance or remedy.These are diverse substances produced by a widevariety of cells in the body, having intensebiological activity, but generally act locally (e.g.within inflammatory pockets) at the site ofsynthesis and release.

They have also been called ‘local hormones’.However, they differ from ‘hormones’ in twoimportant ways—hormones are produced byspecific cells, and are transported through circu-lation to act on distant target tissues.

Autacoids are involved in a number of phy-siological and pathological processes (especiallyinflammation and immunological reaction).They even serve as transmitters or modulatorsin the nervous system, but their role at many sitesis not precisely known. A number of useful drugsact by modifying their action or metabolism. Theclassical autacoids are—

Amine autacoids Histamine, 5-Hydroxytryp-tamine (Serotonin).

Lipid-derived autacoids Prostaglandins, Leuko-trienes, Platelet activating factor.

Peptide autacoids Plasma kinins (Bradykinin,Kallidin), Angiotensin.

In addition, cytokines (interleukins, TNFα,GM-CSF, etc.) and several peptides like gastrin,somatostatin, vasoactive intestinal peptideand many others may be considered asautacoids.

HISTAMINE

Histamine, meaning ‘tissue amine’ (histos—tissue) is almost ubiquitously present in animaltissues and in certain plants, e.g. stinging nettle.

Histamine is present mostly within storagegranules of mast cells. Tissues rich in histamineare skin, gastric and intestinal mucosa, lungs, liverand placenta. Nonmast cell histamine occurs inbrain, epidermis, gastric mucosa and growingregions. Turnover of mast cell histamine is slow,while that of nonmast cell histamine is fast.Histamine is also present in blood, most bodysecretions, venoms and pathological fluids.

Synthesis, storage and destruction Histamineis β imidazolylethylamine. It is synthesizedlocally from the amino acid histidine anddegraded rapidly by oxidation and methylation(Fig. 7.1). In mast cells, histamine (positivelycharged) is held by an acidic protein and heparin(negatively charged) within intracellular

Fig. 7.1: Synthesis and degradation of histamine

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classified into H1 and H2. A third H3 receptor,which serves primarily as an autoreceptorcontrolling histamine release from neurones inbrain, has been lately identified, but is not of clini-cal importance. The important features of H1 andH2 histamine receptors are given in Table 7.1.


1. Blood vessels Histamine causes markeddilatation of smaller blood vessels, includingarterioles, capillaries and venules. On s.c. injec-tion flushing, especially in the blush area, heat,increased heart rate and cardiac output, withlittle or no fall in BP are produced. Rapid i.v.injection causes fall in BP which has an earlyshort-lasting H1 and a slow but more persistentH2 component. Dilatation of cranial vesselscauses pulsatile headache.

Like many other autacoids and ACh, vasodi-latation caused by histamine is partly (H1 compo-nent) indirect, mediated through ‘endothelium-dependent relaxing factor’ (EDRF): the receptorbeing located on the endothelial cells. H2 receptorsmediating vasodilatation are located directly onthe vascular smooth muscle. Histamine alsocauses increased capillary permeability due toseparation of endothelial cells → exudation ofplasma. This is primarily a H1 response.Injected intradermally, it elicits the triple responseconsisting of:

Red spot: due to intense capillary dilatation.Wheal: due to exudation of fluid from

capillaries and venules.Flare: i.e. redness in the surrounding

area due to arteriolar dilatationmediated by axon reflex.

2. Heart Direct effects of histamine on in situheart are not prominent, but the isolated heartis stimulated.

3. Visceral smooth muscle Histaminecauses bronchoconstriction; guineapigs andpatients of asthma are highly sensitive. Largedoses cause abdominal cramps and colic byincreasing intestinal contractions. Other visceralsmooth muscles are not much affected.

Fig. 7.2: Mechanism of antigen-antibody reaction inducedrelease of histamine from mast cell

In sensitized atopic individual, specific reaginic (IgE) antibodyis produced and gets bound to Fc epsilon receptor I (FcεRI)on the surface of mast cells. On challenge, the antigenbridges IgE molecules resulting in transmembrane activationof a tyrosine-protein kinase (t-Pr-K) which phosphorylatesand activates phospholipaseCγ. Phosphatidyl inositolbisphosphate (PIP2) is hydrolysed and inositol trisphosphate(IP3) is generated which triggers intracellular release of Ca2+.The Ca2+ ions induce fusion of granule membrane withplasma membrane of the mast cell resulting in exocytoticrelease of granule contents. In the granule, positively chargedhistamine (Hist+) is held complexed with negatively chargedprotein (Prot–) and heparin (Hep–) molecules. Cationicexchange with extracellular Na+ (and Ca2+) sets histaminefree to act on the target cells.

granules. When the granules are extruded byexocytosis, Na+ ions in e.c.f. exchange withhistamine to release it free (Fig. 7.2). Increase inintracellular cAMP inhibits histamine release.Histamine is inactive orally because liverdegrades all histamine that is absorbed from theintestines.

Histamine receptors Analogous to adrenergicα and β receptors, histaminergic receptors are

Histamine 99

100 Autacoids and Related DrugsS

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4. Glands Histamine causes marked increasein gastric secretion—primarily of acid but alsoof pepsin (see Ch. 18). This is a direct actionexerted on parietal cells through H2 receptorsand is mediated by increased cAMP generation,which in turn activates the membrane protonpump (H+ K+ ATPase).

5. Sensory nerve endings Itching occurs whenhistamine is injected i.v. or intracutaneously.Higher concentrations injected more deeplycause pain.

6. Autonomic ganglia and adrenal medullaThese are stimulated and release of Adr occurs,which can cause a secondary rise in BP.

7. CNS Histamine does not penetrate blood-brain barrier—no central effects are seen oni.v. injection. However, intracerebroventricular

administration produces rise in BP, cardiacstimulation, behavioural arousal, hypothermia,vomiting and ADH release.

PATHOPHYSIOLOGICAL ROLES

1. Gastric secretion Histamine has dominantphysiological role in mediating secretion of HClin the stomach (see Fig. 18.1). Histamine isreleased locally under the influence of all stimulithat evoke gastric secretion (feeding, vagalstimulation, cholinergic drugs and gastrin) andactivates the proton pump (K+H+ATPase)through H2 receptors to secrete HCl.

2. Allergic phenomena Released from mast cellsfollowing AG : AB reaction, histamine is causativein urticaria, angioedema, bronchoconstrictionand anaphylactic shock. The H1 antagonists areeffective in controlling these manifestations to a

Table 7.1: Distinctive features of H1 and H2 histaminergic receptors

H1 H2

1. Selective agonists 2-Methyl histamine (8:1) 4-Methyl histamine (1:170)(relative selectivity H1: H2) 2-Pyridylethylamine(30:1) Dimaprit (1:2000)

2-Thiazolyl ethylamine (90: 1 ) Impromidine (1:10,000)

2. Selective antagonists Mepyramine (6000:1) Cimetidine (1: 500)(relative selectivity H1: H2) Chlorpheniramine (15000:1) Ranitidine ( l : >500)

3. Receptor type G-protein coupled G-protein coupled

4. Effector pathway PIP2 hydrolysis → IP3/DAG : Adenylyl cyclase activation —Release of Ca2+ from intracellular stores; cAMP ↑ — phosphorylation ofProtein Kinase-C activation specific proteins

5. Distribution in body: a) Smooth muscle (intestine, airway, a) Gastric glands — acid secretionactions mediated uterus) — contraction b) Blood vessels (smooth

b) Blood vessels muscle) — dilatationi) Endothelium: Release of EDRF, c) Heart

PGI2 — vasodilatation. Atria: +ive chronotropy widening of gap junctions — Ventricles: +ive inotropy increased capillary permeability d) Uterus (rat)—relaxation

ii) Smooth muscle — vasoconstriction. e) Brain — transmitterc) Afferent nerve endings — stimulationd) Ganglionic cell — stimulation.e) Adrenal medulla — release of CAs.f) Brain—transmitter.

PIP2 — Phosphatidyl inositol bisphosphate; IP3 — Inositol trisphosphate; DAG — Diacylglycerols:

EDRF— Endothelium dependent relaxing factor: PGI2 — Prostacyclin;

CAs — Catecholamines: cAMP —Cyclic 3', 5' adenosine monophosphate; ACh — acetylcholine

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considerable extent, except asthma and to a lesserextent anaphylactic fall in BP in which leuko-trienes (especially LTD4) and PAF appear to bemore important. Histamine is not involved indelayed or retarded type of allergic reactions.

3. As transmitter Histamine is believed to bethe afferent transmitter which initiates the sen-sation of itch and pain at sensory nerve endings.

In the brain, it is involved in maintainingwakefulness; (H1 antihistaminics owe theirsedative action to blockade of this function) andappears to regulate many other functions.

4. Inflammation Histamine has been implica-ted as a mediator of vasodilatation and otherchanges that occur during inflammation. It mayalso regulate microcirculation according to thelocal needs.

5. Headache Histamine has been implicatedin certain vascular headaches, but there is noconclusive evidence.

Histamine has no therapeutic use.

H1 ANTAGONISTS(Conventional antihistaminics)

These drugs competitively antagonize actions ofhistamine at the H1 receptors.

Pharmacological actions

Qualitatively all H1 antihistaminics have similaractions, but there are quantitative differences,especially in the sedative property.

1. Antagonism of histamine They effectivelyblock histamine induced bronchoconstriction,contraction of intestinal and other smooth muscleand triple response—especially wheal, flare anditch. Fall in BP produced by low doses of hista-mine is blocked, but additional H2 antagonistsare required for complete blockade of higherdoses. Action of histamine on gastric secretion issingularly not affected by these drugs.

2. Antiallergic action Many manifestations ofimmediate hypersensitivity (type I reactions) aresuppressed. Urticaria, itching and angioedema

are well controlled. Anaphylactic fall in BP isonly partially prevented. Asthma in man ispractically unaffected.

3. CNS The older antihistamines producevariable degree of CNS depression. This appearsto depend on the compound’s ability to penetrateblood-brain barrier and its affinity for the central(compared to peripheral) H1 receptors. Individualsusceptibility to different agents varies consi-derably, but an overall grading of the sedativeproperty is presented in Table 7.2. Some indivi-duals also experience stimulant effects likerestlessness and insomnia. Excitement and con-vulsions are frequently seen at toxic doses. Thesecond generation antihistaminics are practicallynonsedating.

Certain (see below) H1 antihistamines areeffective in preventing motion sickness. Prome-thazine also controls vomiting of pregnancy andother causes.

Promethazine and a few other antihistami-nics reduce tremor, rigidity and sialorrhoea ofparkinsonism. Anticholinergic and sedativeproperties underlie the benefit. Some H1 anti-histamines are used as antitussives (see Ch. 19).

4. Anticholinergic action Many H1 blockers inaddition antagonize muscarinic actions of ACh.The anticholinergic action can be graded as:

High Low Minimal/Absent

Promethazine Chlorpheniramine FexofenadineDiphenhydramine Hydroxyzine AstemizoleDimenhydrinate Triprolidine LoratadinePheniramine Cyclizine CetirizineCyproheptadine Mizolastine

5. Local anaesthetic Some drugs have strongwhile others have weak membrane stabilizingproperty. However, they are not used clinicallyas local anaesthetic because they cause irritationwhen injected s.c.

Membrane stabilizing activity also confersantiarrhythmic property to these compounds.

6. BP Most antihistaminics cause a fall in BPon i.v. injection (direct smooth muscle

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Table 7.2: Clinical classification, doses and preparations of H1 antihistaminics

Drug Dose and route Preparations

I. HIGHLY SEDATIVE

Diphenhydramine 25–50 mg oral BENADRYL 25 mg cap., 12.5 mg/5 ml syr.

Dimenhydrinate 25–50 mg oral, DRAMAMINE 16 mg/5 ml syr, 50 mg tab

Promethazine 25–50 mg oral, PHENERGAN 10, 25 mg tab., 5 mg/ml elixer,i.m. (1 mg/kg) 25 mg/ml inj

Hydroxyzine 25–50 mg oral, ATARAX 10, 25 mg tab., 10 mg/5 ml syr, 6 mg/mli.m. drops, 25 mg/ml inj.

II. MODERATELY SEDATIVE

Pheniramine 20–50 mg oral, AVIL 25 mg, 50 mg tab, 15 mg/5 ml syr,i.m. 22.5 mg/ml inj.

Cyproheptadine 4 mg oral PRACTIN, CIPLACTIN 4 mg tab., 2 mg/5 ml syrup,

Meclozine (Meclizine) 25–50 mg oral In DILIGAN 12.5 mg + niacin 50 mg tab

Cinnarizine 25–50 mg oral STUGERON, VERTIGON 25 and 75 mg tab.

III. MILD SEDATIVE

Chlorpheniramine 2–4 mg (0.1 mg/kg) PIRITON, CADISTIN 4 mg taboral, i.m.

Dexchlorpheniramine 2 mg oral POLARAMINE 2 mg tab, 0.5 mg/5 ml syr

Triprolidine 2.5–5 mg oral ACTIDIL 2.5 mg tab.

Mebhydroline 100–300 mg oral INCIDAL 50 mg (base) tab.

Cyclizine 50 mg oral MAREZINE 50 mg tab.Clemastine 1-2 mg oral TAVEGYL 1 mg tab, 0.5 mg/5 ml syr.

IV. SECOND GENERATION ANTIHISTAMINICS

Fexofenadine 120–180 mg oral ALLEGRA, ALTIVA, FEXO 120, 180 mg tab

Astemizole 10 mg oral STEMIZOLE, HISTALONG, STEMIZ, 5 mg,10 mg tab., 1 mg/ml susp.

Loratadine 10 mg oral LORFAST, LORIDIN, LORMEG, 10 mg tab,1 mg/ml susp.

Desloratadine 5 mg oral DESLOR, LORDAY 5 mg tab

Cetirizine 10 mg oral ALERID, CETZINE, ZIRTIN, SIZON 10 mg tab,5 mg/5 ml syr.

Levocetirizine 5-10 mg oral LEVOSIZ, LEVORID, TECZINE 5, 10 mg tab.

Azelastine 4 mg oral AZEP NASAL SPRAY 0.14 mg per puff nasal spray0.28 mg intranasal

Mizolastine 10 mg oral ELINA 10 mg tab

Ebastine 10 mg oral EBAST 10 mg tab

relaxation). However, this is not evident on oraladministration.Pharmacokinetics The classical H1 antihistami-nics are well absorbed from oral and parenteralroutes, metabolized in the liver and excreted in

urine. They are widely distributed in the bodyand enter brain. The newer compounds pene-trate brain poorly. Duration of action of mostagents is 4–6 hours, except astemizole, lorata-dine, cetirizine and fexofenadine which act for

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12–24 hours or more. On repeated use, manyantihistamines induce their own metabolism.

Side effects and toxicity Side effects with firstgeneration H1 antihistaminics are frequent, butare generally mild. Individuals show markeddifferences in susceptibility to side effects withdifferent drugs. Some tolerance to side effectsdevelops on repeated use.

Sedation, diminished alertness and concen-tration, light headedness, motor incoordination,fatigue and tendency to fall asleep are the mostcommon. Objective testing shows impairment ofpsychomotor performance. Patients should becautioned not to operate motor vehicles ormachinery requiring constant attention. Alcoholsynergises in producing these effects as do otherCNS depressants. Few individuals become rest-less, nervous and are unable to sleep. Secondgeneration compounds are largely free of CNSeffects.Dryness of mouth, alteration of bowel movement,urinary hesitancy and blurring of vision can beascribed to anticholinergic property.Epigastric distress and headache are alsocommon.Local application can cause contact dermatitis.

SECOND GENERATION ANTIHISTAMINICS

The second generation antihistaminics (SGAs)may be defined as those H1 receptor blockersmarketed after 1980 which have one or more ofthe following properties:• Absence of CNS depressant property.• Higher H1 selectivitiy: no anticholinergic side

effects.• Additional antiallergic mechanisms apart

from histamine blockade.These newer drugs have the advantage of not

impairing psychomotor performance (driving,etc. need not be contraindicated), produce nosubjective effects, no sleepiness, do not potentiatealcohol or benzodiazepines. Some patients docomplain of sedation, but incidence is similar toplacebo. However, they have a narrow spectrumof therapeutic usefulness which is limited by the

extent of involvement of histamine (actingthrough H1 receptors) in the disease state. Theirprincipal indications are:

(i) Allergic rhinitis and conjunctivitis, hayfever, pollinosis—control sneezing, runnybut not blocked nose, and red, watering,itchy eyes.

(ii) Urticaria, dermographism, atopic eczema.(iii) Acute allergic reactions to drugs and foods.

They have poor antipruritic, antiemetic andantitussive actions.

A life-threatening adverse effect due to overdose or druginteraction occurred with some SGAs. Terfenadine, the firstSGA introduced clinically, was found to cause polymorphicventricular tachycardia (Torsades de pointes) in a few patients.The risk was markedly increased in liver disease or whenerythromycin, clarithromycin, ketoconazole or itraconazole(inhibitors of CYP 3A4) were given concurrently. This adverseeffect occurs due to blockade of cardiac K+ channels by highconcentrations of terfenadine (but not by its active metabolite).Similar incidences have been reported with astemizole andare possible with ebastine, but not with other SGAs.Terfenadine has been withdrawn by the manufacturers.

Fexofenadine It is the active metabolite ofterfenadine that does not block delayed rectifierK+ channels in the heart—does not prolong QTcinterval. Therefore, it has been introduced as asubstitute of terfenadine free of arrhythmogenicpotential.

Astemizole It has slow onset (2–4 hr) and longduration (2–5 days) of action. An activemetabolite is produced whose t½ is 12–19 days.Astemizole is better used for maintenancetherapy and is not suitable for rapid control ofsymptoms. In perennial rhinitis it has showngood efficacy. However, it shares the ventriculartachycardia producing potential of terfenadine.

Loratadine Another long-acting selective peri-pheral H1 antagonist which lacks CNS depres-sant effects and is faster acting than astemizole.Good efficacy has been reported in urticaria andatopic dermatitis.Desloratadine is the active metabolite ofloratadine with similar properties.

Cetirizine This nonsedating antihistamine inaddition inhibits release of histamine and

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cytotoxic mediators from platelets as well as eosi-nophil chemotaxis during the secondary phaseof the allergic response. Thus, it may benefitallergic disorders by other actions as well. It isindicated in upper respiratory allergies, polli-nosis, urticaria and atopic dermatitis; also usedas adjuvant in seasonal asthma.

Its active R(–) enantiomer has been marketedas Levocetirizine, claimed to produce fewer sideeffects.

Azelastine This newer H1 blocker has goodtopical activity. Given by nasal spray for seasonaland perennial allergic rhinitis it provides quicksymptomatic relief lasting 12 hr. Stinging in thenose and altered taste perception are the localside effects.

USES

The uses of H1 antihistaminics are based on theirability to block certain effects of histamine relea-sed endogeneously, as well as on sedative andanticholinergic properties.

1. Allergic disorders They do not suppressAG: AB reaction, but block the effects of releasedhistamine—are only palliative. They effectivelycontrol certain immediate type of allergies, e.g.itching, urticaria, seasonal hay fever, allergicconjunctivitis and angioedema of lips, eyelids,etc. However, their action is slow—Adr alone islife saving in laryngeal angioedema. Similarly,they cannot be relied upon in anaphylactic shockand have a secondary place to Adr. Benefits areless marked in perennial vasomotor rhinitis,atopic dermatitis and chronic urticarias.Certain newer compounds like cetirizine haveadjuvant role in seasonal asthma.

Type I hypersensitivity reactions to drugs(except asthma and anaphylaxis) are suppressed.Some skin rashes also respond.

2. Other conditions involving histamine Theyafford symptomatic relief in insect bite andivy poisoning. Abnormal dermographism issuppressed. They have prophylactic value inblood/saline infusion induced rigor.

3. Pruritides Though relief is often incomplete,older antihistaminics remain the first choicedrugs for idiopathic pruritus.

4. Common cold Antihistaminics do not affectthe course of the illness but may afford symptoma-tic relief by anticholinergic (reduce rhinorrhoea)and sedative actions. The newer nonsedating anti-histamines are less effective in this respect.

5. Motion sickness Promethazine, diphenhy-dramine, dimenhydrinate and cyclizine haveprophylactic value in milder types of motionsickness; should be taken one hour beforestarting journey. Promethazine can also be usedin morning sickness, drug induced and post-operative vomiting.

6. Vertigo Cinnarizine is the H1 antihistaminehaving additional anticholinergic, anti-5-HT,sedative and vasodilator properties which hasbeen widely used in vertigo. It inhibits vestibularsensory nuclei in the inner ear, possibly byreducing stimulated influx of Ca2+ from endo-lymph into the vestibular sensory cells.7. Preanaesthetic medication Promethazinehas been used, especially in children, for itsanticholinergic and sedative properties.8. Cough Antihistaminics like chlorphenira-mine, diphenhydramine, promethazine areconstituents of many popular cough remedies.They have no selective cough suppressant action,but may afford symptomatic relief by sedativeand anticholinergic action.9. Parkinsonism Promethazine and some othersafford mild symptomatic relief in early cases—based on anticholinergic and sedative property.10. Acute muscle dystonia Caused by antieme-tic-antipsychotic drugs is promptly relieved byparenteral promethazine or hydroxyzine. Thisis again based on central anticholinergic actionof the drugs.11. As sedative, hypnotic, anxiolytic Antihista-mines with CNS depressant action have beenused as sedative and to induce sleep, but are notas dependable as benzodiazepines. Prometha-

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zine, commonly used to sedate children, has pro-duced severe respiratory depression in someyoung children. It is contraindicated below 2 yearsage.

H2 antagonists They are primarily used inpeptic ulcer and other gastric hypersecretorystates (see Ch. 18).

5-HYDROXYTRYPTAMINE(5-HT, Serotonin)

Serotonin was the name given to the vasocons-trictor substance which appeared in serum whenblood clotted, and was shown to be 5-hydroxytry-ptamine (5-HT). About 90% of body’s content of5-HT is localized in the intestines; most of therest is in platelets and brain. It is also found inwasp and scorpion sting and widely distributedin invertebrates and plants (banana, pear,pineapple, tomato, stinging nettle, cowhage).

Synthesis, storage and destruction

5-HT is β-aminoethyl-5-hydroxyindole. It is syn-thesized from the amino acid tryptophan anddegraded primarily by MAO and to a smallextent by a dehydrogenase (Fig. 7.3).

Like NA, 5-HT is actively taken up by anamine pump serotonin transporter (SERT) whichoperates at the membrane of platelets (therefore,5-HT does not circulate in free form in plasma)and serotonergic nerve endings. It is inhibitedby tricyclic antidepressants. Platelets do not

synthesize but acquire 5-HT by uptake duringpassage through intestinal blood vessels. Again,like CAs, 5-HT is stored within storage vesiclesand its uptake at the vesicular membrane isinhibited by reserpine.

Serotonergic (5-HT) receptors

Four families of 5-HT receptors (5-HT1, 5-HT2,5-HT3, 5-HT4-7) comprising of 14 receptorsubtypes have so far been recognized. However,only some of these have been functionallycorrelated or their selective agonists/antagonistsdefined. Knowledge of subtypes of 5-HT recep-tors has assumed importance because somenewly developed therapeutically useful drugscan only be described as 5-HT receptor subtypeselective agonists or antagonists.

Important 5-HT receptor subtypes

5-HT1 : Autoreceptors; inhibit serotonergicneural activity in brain.5-HT1A—present in raphe nuclei andhippocampus; buspirone appears toexert antianxiety action through thesereceptors.5-HT1B/1D—Constricts cranial bloodvessels and inhibits release ofinflammatory neuropeptides in them;sumatriptan controls migrainethrough these receptors.

5-HT2A : Most important postjunctionalreceptor mediating direct actions of 5-HT like vascular and visceral smoothmuscle contraction, platelet aggre-gation, neuronal activation in brain;ketanserin blocks these receptors.

5-HT3 : Depolarizes neurones by gating cationchannels; elicits reflex effects of 5-HT—emesis, gut peristalsis, brady-cardia, transient hypotension, apnoea,pain, itch; ondansetron acts asantiemetic by blocking these receptors.

5-HT4 : Mediate intestinal secretion, augmen-tation of peristalsis. Renzapride is aselective 5-HT4 agonist.

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All 5-HT receptors (except 5-HT3) are Gprotein coupled receptors which functionthrough decreasing (5-HT1) or increasing (5-HT4,5-HT6, 5-HT7) cAMP production or by generatingIP3/DAG (5-HT2) as second messengers. The 5-HT3 is a ligand gated cation (Na+, K+) channelwhich on activation elicits fast depolarization.

Actions

5-HT is a potent depolarizer of nerve endings.It thus exerts direct as well as reflex and indirecteffects. Tachyphylaxis is common with repeateddoses of 5-HT. The overall effects, therefore, areoften variable; important ones are:1. Constriction of larger arteries and veins, butdilatation of arterioles: variable and phasic effecton BP.2. Isolated heart is stimulated, but in the intactanimal bradycardia due to coronary chemoreflexpredominates.3. Enhanced peristalsis and secretion in gut →diarrhoea.4. Inhibition of gastric acid and pepsinsecretion; augmentation of mucus production:ulceroprotective.5. Activation of afferent nerve endings—tingling or pricking sensation, pain; cardiovas-cular and respiratory reflexes are elicited.6. Proaggregatory action on platelets.

Pathophysiological roles ascribed to 5-HT are:1. Neurotransmitter in brain, especially raphenuclei, substantia nigra, limbic system, cortex,etc; involved in sleep, temperature regulation,cognitive function, behavior and mood,vomiting and pain perception.2. Regulation of gut peristalsis by 5-HTcontaining neurones on enteric plexuses andenterochromaffin cells.3. Precursor of melatonin in pineal gland:regulation of biological clock.4. Control of anterior pituitary hormonefunction by hypothalamus.5. Nausea and vomiting, especially that evokedby cancer chemotherapy/radiotherapy.

6. Migraine: probably involved in initiatingconstriction of cranial vessels and inducingneurogenic inflammation of vessel wall.7. Haemostasis by promoting platelet aggre-gation and blood vessel retraction.8. Vasospastic disorders like Raynaud’sphenomenon and variant angina.9. Carcinoid syndrome: mediates bowelhypermotility and bronchoconstriction.

5-HT ANTAGONISTS

The ability to antagonize at least some actionsof 5-HT is found in many classes of drugs, e.g.ergot derivatives (ergotamine, LSD, 2-bromoLSD, methysergide), adrenergic α blockers(phenoxybenzamine), antihistaminics (cypro-heptadine, cinnarizine), chlorpromazine, mor-phine, etc., but these are nonselective and interactwith several other receptors as well. Drugs thathave been used as 5-HT antagonists and somenewer subtype selective agents are:

1. Cyproheptadine It primarily blocks 5-HT2A

receptors and has additional H1 antihistaminic,anticholinergic and sedative properties. Likeother antihistaminics, it has been used inallergies and is a good antipruritic. It increasesappetite and has been recommended in childrenand poor eaters to promote weight gain.

The anti-5-HT activity of cyproheptadine hasbeen utilized in controlling intestinal manifes-tations of carcinoid and postgastrectomy dump-ing syndromes.

2. Methysergide Methysergide is a potent 5-HT2A/2C andweak 5-HT1 antagonist. It has been used for migraine pro-phylaxis, carcinoid and postgastrectomy dumping syndrome.

3. Ketanserin It has 5-HT2 receptor blocking propertywith negligible action on 5-HT1, 5-HT3 and 5-HT4 receptorsand no partial agonistic activity.

Ketanserin is an effective antihypertensive, but α1

adrenergic blockade appears to be causative rather than 5-HT2A blockade.

4. Clozapine In addition to being a dopami-nergic antagonist (weaker than the typicalneuroleptics), this atypical antipsychotic is a5-HT2A/2C blocker (see Ch. 10).

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5. Risperidone This atypical antipsychotic isa combined 5-HT2A + dopamine D2 antagonist,similar to clozapine.

6. Ondansetron It is the prototype of selective5-HT3 antagonists that have shown remarkableefficacy in controlling nausea and vomitingfollowing administration of highly emeticanticancer drugs and radiotherapy (see Ch. 18).

ERGOT ALKALOIDSErgot is a fungus Claviceps purpurea which grows on rye,millet and some other grains. Epidemics of ergot poisoning(ergotism), due to consumption of contaminated grains, havebeen recorded from the beginning of history. It still occursin epidemic and sporadic forms. Dry gangrene of hands andfeet which become black (as if burnt) is the most prominentfeature. Miscarriages occur in women and cattle. Aconvulsive type is also described.

Ergot contains a host of pharmacologicallyactive substances—alkaloids, LSD, histamine,ACh, tyramine and other amines, sterols, etc.

Ergot alkaloids are tetracyclic indole contain-ing compounds which may be considered as deri-vatives of lysergic acid. They are divided into—

(a) Amine alkaloid Ergometrine (Ergonovine):which is oxytocic.

(b) Amino acid alkaloids Ergotamine, Ergotoxine(mixture of ergocristine + ergocornine +ergocryptine): that are vasoconstrictor andα adrenergic blocker.

The ergot alkaloid-related compounds havediverse pharmacological properties. They act asagonists, partial agonists and antagonists oncertain subtypes of α adrenergic, serotonergicand dopaminergic receptors: activity differingdepending on the tissue and the compound.

Ergotamine It acts as a partial agonist andantagonist at α adrenergic and all subtypes of5-HT1 and 5-HT2 receptors, produces sustainedvasoconstriction, visceral smooth muscle con-traction, vasomotor centre depression andantagonizes the action of NA and 5-HT onsmooth muscles. It is a potent emetic (throughCTZ) and moderately potent oxytocic.

Dihydroergotamine (DHE) Hydrogenation ofergotamine reduces serotonergic and α-adrener-gic agonistic actions, but enhances α-receptorblocking property. Consequently, DHE is a lesspotent vasoconstrictor.

Dihydroergotoxine (Codergocrine) This hydro-genated mixture of ergotoxine group of alkaloidsis a more potent α blocker and a very weakvasoconstrictor. It has been advocated fortreatment of dementia.

Bromocriptine The 2 bromo derivative of ergo-cryptine is a relatively selective dopamine D2agonist on pituitary lactotropes (inhibits pro-lactin release), in striatum (antiparkinsonian)and in CTZ (emetic—but less than ergotamine).

Ergometrine (Ergonovine) This amine ergotalkaloid has a very weak agonistic and prac-tically no antagonistic action on α adrenergicreceptors: vasoconstriction is not significant.Partial agonistic action on 5-HT receptors hasbeen demonstrated in uterus, placental andumbilical blood vessels. The most prominentaction is contraction of myometrium. It is usedexclusively in obstetrics (see Ch. 15).

DRUG THERAPY OF MIGRAINEMigraine is a mysterious disorder characterized by pulsatingheadache, usually restricted to one side, which comes inattacks lasting 4–48 hours and is often associated with nausea,vomiting, sensitivity to light and sound, vertigo, loosemotions and other symptoms. Two major types are—migrainewith aura (classical migraine) in which headache is precededby visual or other neurological symptoms, and migrainewithout aura (common migraine). Pulsatile dilatation ofcertain large cranial vessels is the immediate cause of pain.The pathogenic mechanisms are not well understood. Sometriggering event appears to produce neurogenicinflammation of the affected blood vessel wall which isamplified by retrograde transmission in the afferentnerves and release of mediators like 5-HT, neurokinin,substance P, calcitonin gene-related peptide (CGRP), nitricoxide, etc.

Changes in blood/urinary levels of 5-HT and itsmetabolites during migraine attack, its precipitation by 5-HT releasers and efficacy of drugs having actions in theserotonergic system to prevent/abort/terminate migraineattacks suggests a pivotal role of 5-HT in this disorder.

Drug Therapy of Migraine 107


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Drug therapy of migraine has to be individua-lized: severity and frequency of attacks andresponse of individual patients to various drugsdetermine the choice. The strategy mostlyadopted is summarized in the box.

Mild migraine Cases having fewer than oneattack per month of throbbing but tolerableheadache lasting up to 8 hours which does notincapacitate the individual may be classified asmild migraine.(i) Simple analgesics like paracetamol (500mg) or aspirin (300–600 mg) taken at the firstindication of an attack and repeated 4–6 hourlyabort and suppress most mild attacks.(ii) Nonsteroidal antiinflammatory drugs(NSAIDs) and their combinations Drugs likeibuprofen (400–800 mg 8 hourly), diclofenac (50mg 8 hourly), mephenamic acid (500 mg 8 hourly),either alone or combined with paracetamol/codeine/diazepam/diphenhydramine/caffeineare found more satisfactory by some patients.Drugs are taken only till the attack passes off.Taken in the prodromal stage they also have aprophylactic effect.(iii) Antiemetics Metoclopramide (10 mgoral/i.m.) is frequently used. Domperidone (10–20 mg oral) and prochlorperazine (10–25 mgoral/i.m.) are also effective.

Moderate migraine Migraine may be labelledas moderate when the throbbing headache ismore intense, lasts for 6–24 hours, nausea/

vomiting and other features are more prominentand the patient is functionally impaired.

Simple analgesics are usually not effective,but stronger NSAIDs or their combinations men-tioned above are beneficial in many cases. Theremaining patients are treated with an ergotpreparation or sumatriptan. Antiemetics arealmost regularly needed. Prophylactic therapyis advised only when attacks are more frequentthan 2 to 3 per month.

Severe migraine These patients suffer morethan 2 to 3 attacks per month of severe throbbingheadache lasting 12–48 hours, often accom-panied by vertigo, vomiting and othersymptoms; the subject is grossly incapacitatedduring the attack.

Analgesics/NSAIDs and their combinationsusually do not afford adequate relief—specificdrugs like ergot alkaloids/sumatriptan have tobe prescribed along with antiemetics. Prophylac-tic regimens lasting 6 months or more are recom-mended.

Ergotamine It is the most effective ergotalkaloid for migraine. Given early in attack, reliefis often dramatic and lower doses suffice, butwhen pain has become severe—larger doses areneeded and control may be achieved only aftera few hours.

Ergotamine probably acts by constricting thedilated cranial vessels. It has also been shownto reduce neurogenic inflammation and leakage

Drug therapy of migraine

Severity Drug therapy

Mild : Simple analgesics/NSAIDs or their combinations (± antiemetic)Moderate : NSAIDs combinations/ergot alkaloids/sumatriptan (+ antiemetic)Severe : Ergot alkaloids/sumatriptan/rizatriptan (+ antiemetic)

+ Prophylaxis • Propranolol/other β blockers• Amitriptyline/other tricyclic antidepressants• Flunarizine/other Ca2+ channel blockers• Valproate/topiramate• Methysergide/cyproheptadine

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of plasma in duramater that occurs due toretrograde stimulation of perivascular afferentnerves. These actions appear to be mediatedthrough partial agonism at 5-HT1B/1D receptorsin and around cranial vessels.

Dihydroergotamine (DHE) It is nearly as effec-tive as ergotamine and preferred for parenteraladministration because injected DHE is lesshazardous. Orally, it is a safer alternative toergotamine in patients who respond to this drug.

Ergot alkaloids should be discontinued whenrelief is obtained. They have no prophylacticvalue. Caffeine 100 mg taken with ergotamine en-hances its absorption from oral and rectal routesand adds to the cranial vasoconstricting action.

Sumatriptan This novel selective 5-HT1B/1D

receptor agonist does not interact with 5-HT2,5-HT3, 5-HT4-7, α or β adrenergic, dopaminergic,cholinergic or GABA receptors. Administered atthe onset of an attack of migraine sumatriptanis as effective and better tolerated than ergo-tamine. It tends to suppress nausea and vomitingof migraine, while ergotamine accentuates thesesymptoms. The antimigraine activity of sumatri-ptan has been ascribed to 5-HT1B/1D receptormediated constriction of dilated cranialextracerebral blood vessels. Like ergotamine, thetriptans have been found to suppress neurogenicinflammation of cranial vessels.

Side effects to sumatriptan are usually mild.Tightness in head and chest, feeling of heat andother paresthesias in limbs, dizziness, weaknessare short lasting but dose-related side effects.Bradycardia, coronary vasospasm and risk ofmyocardial infarction are the serious butinfrequent adverse effects.

It is contraindicated in patients with ischaemicheart disease, hypertension, epilepsy, hepatic orrenal impairment and during pregnancy.Rizatriptan is a more potent and slightly fasteracting congener of sumatriptan.

Prophylaxis of migraineRegular medication to reduce the frequencyand/or severity of attacks is recommended for

Prostaglandins and Leukotrienes 109

moderate-to-severe migraine when more than2 to 3 attacks occur per month. Diverse classesof drugs are used but none is effective in all cases,and none abolishes the attacks totally.

(i) β-Adrenergic blockers Propranolol is themost commonly used drug: reduces frequencyas well as severity of attacks in up to 70%patients. Effect is generally seen in 4 weeks andis sustained during prolonged therapy.

(ii) Tricyclic antidepressants Many tricycliccompounds, of which amitriptyline has beenmost extensively tried, reduce migraine attacks.It is effective in many patients but produces moreside effects than propranolol.

(iii) Calcium channel blockers Flunarizine isclaimed to be a cerebro-selective Ca2+ channelblocker which may benefit migraine by reducingintracellular Ca2+ overload due to brain hypoxiaand other causes. It may reduce frequency ofattacks, but effect on intensity and duration ofattacks is less marked.

(iv) Anticonvulsants Valproic acid and topira-mate can reduce the frequency of migraineattacks, but are less effective than propranolol;may be tried when the latter is contraindicated.

The 5-HT antagonists methysergide andcyproheptadine have less impressive prophy-lactic effect in migraine and produce more sideeffects than propranolol.

PROSTAGLANDINS AND LEUKOTRIENES(Eicosanoids)

Prostaglandins (PGs) and Leukotrienes (LTs) arebiologically active derivatives of 20 carbon atompolyunsaturated essential fatty acids that arereleased from cell membrane phospholipids.They are the major lipid-derived autacoids.

In the 1930s, human semen was found to contract isolateduterine and other smooth muscle strips and to cause fall in BPin animals. The active principle was termed ‘prostaglandin’,thinking that it was derived from prostate. Only in 1960s, itwas shown to be a mixture of closely related compounds, thechemical structures were elucidated and widespreaddistribution was revealed. In 1970s, it became clear that


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aspirin-like drugs act by inhibiting PG synthesis, and that inaddition to the classical PGs (Es and Fs), thromboxane (TX),prostacyclin (PGI) and leukotrienes (LTs) were of greatbiological importance. Bergstrom, Samuelsson and Vane gotthe Nobel prize in 1982 for their work on PGs and LTs.

CHEMISTRY, BIOSYNTHESIS ANDDEGRADATION

Chemically, PGs may be considered to be deri-vatives of prostanoic acid, though prostanoic aciddoes not naturally occur in the body. It has a fivemembered ring and two side chains projectingin opposite directions at right angle to the planeof the ring. There are many series of PGsdesignated A, B, C,..., I, and thromboxanes (TXs)depending on the ring structure and thesubstituents on it. Each series has members withsubscript 1, 2, 3 indicating the number of doublebonds in the side chains.

Leukotrienes are so named because theywere first obtained from leukocytes (leuko) andhave 3 conjugated double bonds (triene). Theyhave also been similarly designated A, B, C,..., Fand given subscripts 1, 2, 3, 4.

In the body PGs, TXs and LTs are all derived

from 5,8,11,14 eicosa tetraenoic acid (arachidonicacid). During PG, TX and prostacyclin synthesis,2 of the 4 double bonds of arachidonic acid getsaturated in the process of cyclization, leaving 2double bonds in the side chain. Thus, subscript2 PGs are most important in man, e.g. PGE2,PGF2α, PGI2, TXA2. No cyclization or reductionof double bonds occurs during LT synthesis—the LTs of biological importance are LTB4, LTC4,LTD4.

Eicosanoids are the most universally distri-buted autacoids in the body. Practically, everycell and tissue is capable of synthesizing one or

more types of PGs or LTs. The pathways ofbiosynthesis of eicosanoids are summarized inFig. 7.4.

There are no preformed stores of PGs andLTs. They are synthesized locally at ratesgoverned by the release of arachidonic acid frommembrane lipids in response to appropriatestimuli. These stimuli activate hydrolases,including phospholipase A.

The cyclooxygenase (COX) pathway generateseicosanoids with a ring structure (PGs, TXs,prostacyclin) while lipoxygenase (LOX) producesopen chain compounds (LTs). All tissues haveCOX—can form cyclic endoperoxides PGG2 andPGH2 which are unstable compounds. Furthercourse in a particular tissue depends on the typeof isomerases or other enzymes present in it.PGE2 and PGF2α are the primary prostaglandins.Lung and spleen can synthesize the whole rangeof COX products. Platelets primarily synthesizeTXA2 which is chemically unstable, sponta-neously changes to TXB2. Endothelium mainlygenerates prostacyclin (PGI2) that is alsochemically unstable and rapidly converts to 6-keto PGF1α.

Cyclooxygenase is now known to exist in twoisoforms COX-1 and COX-2. While both isoformscatalyse the same reactions, COX-1 is a consti-tutive enzyme in most cells—its activity is notchanged once the cell is fully grown. On the otherhand, COX-2 normally present in insignificantamounts is inducible by cytokines, growth factorsand other stimuli during the inflammatoryresponse. It is believed that eicosanoids producedby COX-1 participate in physiological (housekeeping) functions such as secretion of mucusfor protection of gastric mucosa, haemostasis andmaintenance of renal function, while thoseproduced by COX-2 lead to inflammatory andother pathological changes. However, certainsites in kidney and brain constitutively expressCOX-2 which may play physiological role.

Lipoxygenase pathway appears to operatemainly in the lung, WBC and platelets. Its mostimportant products are the LTs, (generated by

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Fig. 7.4: Biosynthesis of prostaglandins (PG) and leukotrienes (LT). Less active metabolites are shown in italicsTX—Thromboxane, PGI—Prostacyclin; HPETE—Hydroperoxy eicosatetraenoic acid (Hydroperoxy arachidonic acid);HETE—Hydroxyeicosatetraenoic acid (Hydroxy arachidonic acid); SRS-A—Slow-reacting substance of anaphylaxis

5-LOX) particularly LTB4 (potent chemotactic)and LTC4, LTD4 which together constitute the‘slow reacting substance of anaphylaxis’ (SRS-A).

Inhibition of synthesis Synthesis of COXproducts can be inhibited by nonsteroidalantiinflammatory drugs (NSAIDs). Aspirinacetylates COX at a serine residue and causesirreversible inhibition, while other NSAIDs arecompetitive and reversible inhibitors. MostNSAIDs are nonselective COX-1 and COX-2inhibitors, but some newer ones like celecoxib,etoricoxib are selective for COX-2.

NSAIDs do not inhibit the production of LTs:this may even be increased since all the arachido-nic acid becomes available to the LOX pathway.

Glucocorticosteroids inhibit the release ofarachidonic acid from membrane lipids (bystimulating production of proteins called annexinsor lipocortins which inhibit phospholipase A2) —indirectly reduce production of all eicosanoids—PGs, TXs and LTs. Moreover, they inhibit the

induction of COX-2 by cytokines at the site ofinflammation.

Degradation of arachidonates occurs rapidlyin most tissues, but fastest in the lungs. Most PGs,TXA2 and prostacyclin have plasma t½ of a fewseconds to a few minutes. First a specific carriermediated uptake into cells occurs, the side chainsare then oxidized and double bonds are reducedin a stepwise manner to yield inactivemetabolites. Metabolites are excreted in urine.PGI2 is catabolized mainly in the kidney.

PROSTAGLANDINS, THROMBOXANES ANDPROSTACYCLIN

Actions

The cyclic eicosanoids produce a wide variety ofactions depending upon the particular PG (or TXor PGI), species on which tested, tissue, hormonalstatus and other factors. PGs differ in theirpotency to produce a given action and different



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PGs sometimes have opposite effects. Even thesame PG may have opposite effects underdifferent circumstances. The actions of importantPGs, PGI2 and TXA2 are summarized in Table 7.3.

Patho-physiological roles

Since virtually all cells and tissues are capableof forming PGs, these autacoids have been imp-licated as mediators or modulators of a numberof physiological processes and pathologicalstates.1. PGI2 is probably involved in the regulationof local vascular tone as a dilator.2. PGE2 and PGI2 are believed to be conti-nuously produced locally in the ductusarteriosus during foetal life—keep it patent. Atbirth their synthesis stops and closure occurs.Aspirin and indomethacin have been found toinduce closure when it fails to occurspontaneously. These PGs may also be impor-tant in maintaining placental blood flow.3. PGs, along with LTs and other autacoids maymediate vasodilatation and exudation at the siteof inflammation.4. TXA2 (produced by platelets) and PGI2

(produced by vascular endothelium) probablyconstitute a mutually antagonistic system:preventing aggregation of platelets while incirculation and inducing aggregation on injury,when plugging and thrombosis are needed.

Aspirin interferes with haemostasis byinhibiting platelet aggregation which is due toTXA2 production. Before it is deacetylated inliver, aspirin acetylates COX in platelets whilethey are in portal circulation. Further, plateletsare unable to regenerate fresh COX (lack nucleus:do not synthesize protein), while vessel wall isable to do so (fresh enzyme is synthesized withinhours). Thus, in low doses, aspirin selectivelyinhibits TXA2 production and has antithromboticeffect lasting > 3 days.5. PGs produced by foetal tissues at termprobably mediate initiation and progression oflabour. Aspirin has been found to delay the ini-tiation of labour and also prolongs its duration.

6. Because PGs are present in high concen-tration in semen and can be rapidly absorbedwhen lodged in the vagina at coitus, it is believedthat they so coordinate movements of the femalegenital tract that transport of sperms andfertilization is facilitated.7. Dysmenorrhoea in many women is asso-ciated with increased PG synthesis by the endo-metrium. This apparently induces uncoordi-nated uterine contractions which compressblood vessels → uterine ischaemia → pain.Aspirin group of drugs are highly effective inrelieving dysmenorrhoea in most women.8. Asthma may be due to an imbalance bet-ween constrictor PGs (F2a, PGD2, TXA2) and LTson one hand and dilator ones (PGE2, PGI2) onthe other. However, in allergic human asthma,LTs are more important and COX inhibitors arewithout any effect in most patients.9. PGs may be involved in mediating toxininduced increased fluid movement in secretorydiarrhoeas. PGs appear to play a role in thegrowth of colonic polyps and cancer. Associationof low incidence of colon cancer with regularintake of aspirin is now established.10. PGs (especially PGI2) appear to be involvedin the regulation of gastric mucosal blood flowand PGE2 enhances gastric mucus production.They may be functioning as natural ulcerprotectives. The ulcerogenic action of NSAIDsmay be due to loss of this protective influence.11. PGs appear to function as intrarenalregulators of blood flow as well as tubularreabsorption in kidney. The NSAIDs tend toretain salt and water. The diuretic action offurosemide is blunted by indomethacin—indica-ting a facilitatory role of PGs by increasing renalblood flow and/or augmenting inhibition oftubular reabsorption.12. PGE2 may mediate bacterial or otherpyrogen-induced fever and malaise at the levelof hypothalamus. Aspirin and other inhibitorsof PG synthesis are antipyretic.13. PGs may be functioning as neuromodulatorsin the brain by regulating neuronal excitability.

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Tab

le 7

.3:

A s

umm

ary

of th

e ac

tions

of m

ajor

pro

stag

land

ins,

pro

stac

yclin

and

thro

mbo

xane

Org

anP

rost

agla

ndin

E2

(PG

E2)

Pro

stag

land

in F

2α (

PG

F 2α)

Pro

stac

yclin

(P

GI 2

)T

hrom

boxa

ne A

2 (T

XA

2)

1.B

lood

Vas

odila

tati

on, ↓

BP

Vas

odila

tati

on (m

ostl

y), l

arge

r ve

ins

Vas

odila

tati

on (m

arke

d a

ndV

asoc

onst

rict

ion

vess

els

cons

tric

t, lit

tle

effe

ct o

n B

Pw

ides

prea

d),

↓ ↓

BP

2.H

eart

Wea

k in

otro

pic,

ref

lex

Wea

k in

otro

pic

——

card

iac

stim

ulat

ion

3.Pl

atel

ets

Var

iabl

e ef

fect

—A

ntia

ggre

gato

ryA

ggre

gati

on a

ndre

leas

e re

acti

on

4.U

teru

sC

ontr

acti

on (i

n vi

vo),

rela

xes

Con

trac

tion

(in

vivo

and

in v

itro

),—

—no

ngra

vid

hum

an u

teru

s in

soft

enin

g of

cer

vix

vitr

o, s

ofte

ning

of c

ervi

x

5.B

ronc

hiD

ilata

tion

, inh

ibit

his

tam

ine

Con

stri

ctio

nD

ilata

tion

(mild

), in

hibi

tC

onst

rict

ion

rele

ase

hist

amin

e re

leas

e

6.St

omac

h↓

acid

sec

reti

on,

—↓

acid

sec

reti

on (w

eak)

,—

↑ m

ucus

pro

duc

tion

muc

osal

vas

odila

tati

on

7.In

test

ine

Con

trac

ts lo

ngit

udin

al &

rel

axes

Spas

mog

enic

, ↑ fl

uid

& e

lect

roly

teW

eak

spas

mog

enic

, inh

ibit

Wea

k sp

asm

ogen

icci

rcul

ar m

uscl

es, ↑

per

ista

lsis

,se

cret

ion

(wea

k)to

xin-

ind

uced

flui

d s

ecre

tion

↑ C

l¯ &

wat

er s

ecre

tion

8.K

idne

yN

atri

ures

is, ↓

Cl¯

rea

bsor

p-—

Nat

riur

esis

, vas

odila

tati

on,

Vas

ocon

stri

ctio

nti

on, i

nhib

it A

DH

act

ion,

reni

n re

leas

eva

sod

ilata

tion

, ren

in r

elea

se

9.C

NS

Pyro

geni

c, v

arie

ty o

f eff

ects

on i.

c.v.

inj.

10.

Rel

ease

↑ o

r ↓

↑

or ↓

of N

A

11.

Aff

eren

tSe

nsit

ize

to n

oxio

us s

tim

uli

—Sa

me

as P

GE

2—

nerv

es→

tend

erne

ss

12.

End

ocri

neR

elea

se o

f ant

. pit

uita

ryR

elea

se o

f gon

adot

ropi

ns &

——

syst

emho

rmon

es, s

tero

ids,

insu

lin;

prol

acti

n, lu

teol

ysis

(in

anim

als)

TSH

-lik

e ac

tion

13.

Met

abol

ism

Ant

ilipo

lyti

c, in

sulin

-lik

e ac

tion

,—

——

mob

iliza

tion

of b

one

Ca2+



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They may also modulate sympathetic neuro-transmission in the periphery.14. PGs (especially E2 and I2) sensitize afferentnerve endings to pain inducing chemical andmechanical stimuli (Fig. 7.5). They irritatemucous membranes and produce long lastingdull pain on intradermal injection.

PGs appear to serve as algesic agents duringinflammation. They cause tenderness andamplify the action of other algesics. Inhibition ofPG synthesis is a major antiinflammatorymechanism.15. PG F2α lowers i.o.t. by enhancing uveoscleraloutflow of aqueous humor. Several nonirritatingPG congeners like latanoprost are first line drugsfor open angle glaucoma.

LEUKOTRIENES

The straight chain lipoxygenase products ofarachidonic acid are produced by a more limitednumber of tissues (LTB4 mainly by neutrophils;LTC4 and LTD4—the cysteinyl LTs—mainly bymacrophages) but probably they are pathophy-siologically as important as PGs.

1. CVS and blood LTC4 and LTD4 injected i.v.evoke a brief rise in BP followed by a moreprolonged fall. The fall in BP is not due tovasodilatation because no relaxant action hasbeen seen on blood vessels. It is probably a resultof coronary constriction induced decrease in

Fig. 7.5: Sensitization of nociceptors (pain receptors) tomediators of pain by prostaglandins at the inflammatory site

cardiac output and reduction in circulatingvolume due to increased capillary permeability.These LTs markedly increase capillarypermeability and are more potent than histaminein causing local edema formation.

LTB4 is highly chemotactic for neutrophilsand monocytes. Migration of neutrophilsthrough capillaries and their clumping at sitesof inflammation in tissues is also promoted byLTB4.

Role LTs are important mediators of inflam-mation. They are produced (along with PGs)locally at the site of injury. While LTC4 and D4

cause exudation of plasma, LTB4 attracts theinflammatory cells which reinforce the reaction.5-HPETE and 5-HETE may facilitate local releaseof histamine from mast cells.

2. Smooth muscle LTC4 and D4 contractmost smooth muscles. They are potentbronchoconstrictors and induce spasticcontraction of g.i.t. at low concentrations.

They also increase mucus secretion in theairways.

Role The cysteinyl LTs (C4 and D4) are the mostimportant mediators of human allergic asthma.They are released along with PGs and otherautacoids during AG: AB reaction in the lungs.In comparison to other mediators, they are morepotent and are metabolized slowly in the lungs,exert a long lasting action. LTs may also beresponsible for abdominal colics during systemicanaphylaxis.

3. Afferent nerves Like PGE2 and I2, the LTB4

also sensitizes afferents carrying pain impulses—contributes to pain and tenderness of inflam-mation.

PROSTANOID RECEPTORS

PGs, TX and prostacyclin act on their own specific receptorslocated on cell membrane. Five major types of prostanoidreceptors have been designated, each after the natural PGfor which it has the greatest affinity. All prostanoid receptorsare G-protein coupled receptors which utilize the IP3/DAGor cAMP transducer mechanisms. Some selective antagonistsof prostanoid receptors have been produced. The prostanoidreceptors are:

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DP Has greatest affinity for PGD2, but PGE2 also acts on it.

EP Has greatest affinity for PGE2; enprostil is a selectiveagonist. It mediates both smooth muscle contraction andrelaxation.

FP Has greatest affinity for PGF2α; fluprostenol is a selectiveagonist. The most prominent effect of activation of thisreceptor is smooth muscle contraction mediated through IP3/DAG formation.

IP Has greatest affinity for PGI2; PGE also acts on it andcicaprost is a selective agonist. It functions by activatingadenylyl cyclase in platelets (inhibiting aggregation) andsmooth muscles (relaxation).

TP Has greatest affinity for TXA2; PGH2 also acts on it. Itutilizes IP3/DAG as second messengers which mediateplatelet aggregation and smooth muscle contraction.

LEUKOTRIENE RECEPTORS

Separate receptors for LTB4 and for the cysteinyl LTs (LTC4,LTD4) have been defined. Two subtypes cysLT1 andcys LT2 of the cysteinyl LT receptor have been cloned. AllLT receptors function through the IP3/DAG transducermechanism. Many cysLT1 receptor antagonists, viz.Montelukast, Zafirlukast, etc. are now valuable drugs forbronchial asthma (see Ch 19).

USES

Clinical use of PGs and their analogues is ratherrestricted because of limited availability, shortlasting action, cost, side effects and other prac-tical considerations. Their approved indicationsare:1. Abortion: Single oral dose of misoprostol after2 days of mifepristone (antiprogestin) priming isused to terminate pregnancy of upto 7 weeksduration. Extra or intra amniotic injection of PGE2

or PGF2α can be used for 2nd trimester abortion.2. Induction/augmentation of labour: Intra-vaginal PGE2 or PGF2α are alternative to i.v.oxytocin, but less reliable.3. Cervical priming: Low doses of PGE2 appliedin cervical canal/vagina make the cervix soft andmore compliant for abortion/delivery.4. Postpartum haemorrhage: Carboprost (15-methyl PGF2α) i.v. is an alternative toergometrine/oxytocin.5. Peptic ulcer: Misoprostol (PGE1 analogue) canbe used to heal NSAID-associated peptic ulcer.

Platelet Activating Factor 115

6. Glaucoma: Topical latanoprost (PGF2α ana-logue) is a first line drug.7. To maintain patency of ductus arteriosus inneonates with congenital heart disease:alprostadil (PGE1) i.v. infusion.8. To avoid platelet damage during haemo-dialysis/cardiopulmonary bypass.

PLATELET ACTIVATING FACTOR (PAF)

Like eicosanoids, platelet activating factor (PAF)is a cell membrane- derived polar lipid withintense biological activity; discovered in 1970sand now recognized to be an important signalmolecule. PAF is acetyl-glyceryl ether-phosphoryl choline.

Synthesis and degradation PAF is synthesized fromprecursor phospholipids present in cell membrane by thefollowing reactions:

PAF-acetylPhospholipase A2 transferase

MembraneAcyl-glycero- Lyso PAF PAFphosphocholine

Fatty acid Acetyl CoA CoA

The second step is rate limiting. Antigen-antibody reactionand a variety of mediators stimulate PAF synthesis ondemand: there are no preformed stores of PAF. In contrastto eicosanoids, the types of cells which synthesize PAF isquite limited—mainly WBC, platelets, vascular endotheliumand kidney cells.

PAF is degraded by reversal of the above reactions andthe product is incorporated back into the membrane.

Actions PAF has potent actions on many tissues/organs.

Platelets Aggregation and release reaction; also releasesTXA2; i.v. injection results in intravascular thrombosis.

WBC PAF is chemotactic to neutrophils, eosinophils andmonocytes. It stimulates neutrophils to aggregate, to stickto vascular endothelium and migrate across it to the site ofinfection. It also prompts release of lysosomal enzymes andLTs and generation of superoxide radical by the polymorphs.

Blood vessels Vasodilatation occurs mediated by releaseof EDRF → fall in BP on i.v. injection.

PAF is the most potent agent known to increase vascularpermeability. Wheal and flare occur at the site of intradermalinjection.

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Aerosolized PAF is a potent bronchoconstrictor. In addition,it produces mucosal edema, secretion and a delayed andlong-lasting bronchial hyper-responsiveness. It alsostimulates intestinal and uterine smooth muscle.

Stomach Ulcerogenic: erosions and mucosal bleeding occurshortly after i.v. injection of PAF. The gastric smooth musclecontracts.

Mechanism of action Membrane bound specific PAFreceptors have been identified. The PAF receptor is aG-protein coupled receptor which exerts most of theactions through intracellular messengers IP3/DAG → Ca2+

release.

PAF antagonists A number of natural and synthetic PAFreceptor antagonists have been investigated. Importantamong these are ginkgolide B (from a Chinese plant), and

some structural analogues of PAF. The PAF antagonists havemanyfold therapeutic potentials but none has been foundworth marketing. Alprazolam and triazolam antagonizesome actions of PAF.

Pathophysiological roles PAF has been implicated inmany physiological processes and pathological states,especially those involving cell-to-cell interaction. These are:1. Inflammation2. Bronchial asthma3. Anaphylactic (and other) shock conditions4. Haemostasis and thrombosis5. Rupture of mature graafian follicle and implantation6. Labour7. Ischaemic states of brain, heart and g.i.t., including

g.i. ulceration.

GENERAL ANAESTHETICS

General anaesthetics (GAs) are drugs whichproduce reversible loss of all sensation andconsciousness. The cardinal features of generalanaesthesia are:

• Loss of all sensation, especially pain• Sleep (unconsciousness) and amnesia• Immobility and muscle relaxation• Abolition of reflexes.

In the modern practice of balanced anaesthesia,these modalities are achieved by using combi-nation of drugs, each drug for a specific purpose.Anaesthesia has developed as a highly specia-lized science in itself. In dental practice, generalanaesthesia is employed occasionally; is admini-stered and managed by a qualified anaesthetist,and not by the dental surgeon himself.

Mechanism of general anaesthesia

The mechanism of action of GAs is not preciselyknown. A wide variety of chemical agents pro-duce general anaesthesia. Therefore, GA actionhad been related to some common physicoche-mical property of the drugs. Mayer and Overton(1901) pointed out a direct parallelism betweenlipid/water partition coefficient of the GAs andtheir anaesthetic potency.

Minimal alveolar concentration (MAC) is thelowest concentration of the anaesthetic in pul-

monary alveoli needed to produce immobility inresponse to a painful stimulus (surgical incision)in 50% individuals. It is accepted as a validmeasure of potency of inhalational GAs becauseit remains fairly constant for a given species evenunder varying conditions.

The MAC of a number of GAs showsexcellent correlation with their oil/gas partitioncoefficient. However, this only reflects capacityof the anaesthetic to enter into CNS and attainsufficient concentration in the neuronal mem-brane, but not the mechanism by which anaes-thesia is produced.

Recent evidence favours a direct interactionof the GA molecules with hydrophobic domainsof membrane proteins or the lipid-proteininterface.

Different anaesthetics may be acting throughdifferent molecular mechanisms and variouscomponents of the anaesthetic state involveaction at discrete loci in the cerebrospinal axis.The principal locus of causation of unconscious-ness appears to be in the thalamus or reticularactivating system, amnesia may result fromaction in hippocampus, while spinal cord isthe likely seat of immobility on surgicalstimulation.

Recent findings show that ligand gated ion channels(but not voltage sensitive ion channels) are the majortargets of anaesthetic action. The GABAA receptor gatedCl¯ channel is the most important of these. Manyinhalational anaesthetics, barbiturates, benzodiazepines

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General Anaesthetics andSkeletal Muscle Relaxants

118 General Anaesthetics and Skeletal Muscle RelaxantsS

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and propofol potentiate the action of inhibitory trans-mitter GABA to open Cl¯ channels. Each of the aboveanaesthetics appears to interact with its own specificbinding site on the GABAA receptor-Cl¯ channel complex,but none binds to the GABA binding site as such. Actionof glycine (another inhibitory transmitter which alsoactivates Cl¯ channels) in the spinal cord and medullais augmented by barbiturates, propofol and many inhala-tional anaesthetics. This action may block responsivenessto painful stimuli resulting in immobility of theanaesthetic state. Certain fluorinated anaesthetics andbarbiturates, in addition, inhibit neuronal cation channelgated by nicotinic cholinergic receptor which may mediateanalgesia and amnesia.

On the other hand, N2O and ketamine do not affectGABA or glycine gated Cl¯ channels. Rather they selec-tively inhibit the excitatory NMDA type of glutamatereceptor. This receptor gates mainly Ca2+ selective cationchannels in the neurones and their inhibition appears tobe the primary mechanism of anaesthetic action ofketamine as well as N2O. The volatile anaesthetics havelittle action on this receptor.

Unlike local anaesthetics which act primarilyby blocking axonal conduction, the GAs appearto act by depressing synaptic transmission.

Stages of anaesthesia

GAs cause an irregularly descending depressionof the CNS, i.e. the higher functions are lost firstand progressively lower areas of the brain areinvolved, but in the spinal cord lower segmentsare affected somewhat earlier than the highersegments. The vital centres located in themedulla are paralysed the last as the depth ofanaesthesia increases. Guedel (1920) describedfour stages with ether anaesthesia.I. Stage of analgesia From beginning ofanaesthetic inhalation to loss of consciousness;pain is progressively abolished; some minorprocedures can be performed, but it is difficult tomaintain.II. Stage of delirium From loss of consciousnessto beginning of regular respiration; excitement,struggling, breath-holding, jerky breathing,sympathetic stimulation occur. No procedure canbe carried out. This stage is inconspicuous inmodern anaesthesia.III. Surgical anaesthesia From onset of regularrespiration to cessation of spontaneous breathing.This stage has been divided into 4 planes as

anaesthesia becomes light to deep. Most dental/surgical procedures are carried out at plane 1 or 2.IV. Medullary paralysis From cessation ofbreathing to failure of circulation and death. It isnever attempted.

These clear-cut stages are not seen now-a-days with the use of faster acting GAs,premedication and employment of many drugstogether. The precise sequence of events differssomewhat with anaesthetics other than ether.

The modern anaesthetist has to depend onseveral other observations to gauge the depth ofanaesthesia.• If eyelash reflex is present and patient is

making swallowing movements—Stage II hasnot been reached.

• Incision of the skin causes reflex increase inrespiration, BP rise or other effects; insertionof endotracheal tube is resisted and inducescoughing, vomiting, laryngospasm; tearsappear in eye; passive inflation of lungs isresisted—anaesthesia is light.

• Fall in BP, cardiac and respiratory depressionare signs of deep anaesthesia.In the present-day practice, anaesthesia is

generally kept light; adequate analgesia, amnesiaand muscle relaxation are produced by the useof intravenous drugs. Concentrations of inhala-tional anaesthetics exceeding 1.2 MAC are rarelyused.

Pharmacokinetics of inhalational anaesthetics

Inhalational anaesthetics are gases or vapoursthat diffuse rapidly across pulmonary alveoliand tissue barriers. The depth of anaesthesiadepends on the potency of the agent (MAC is anindex of potency) and its partial pressure (PP)in the brain, while induction and recoverydepend on the rate of change of PP in the brain.Transfer of the anaesthetic between lung andbrain depends on a series of tension gradientswhich may be summarized as—

Alveoli Blood Brain

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Factors affecting the PP of anaesthetic attainedin brain are—

1. PP of anaesthetic in the inspired gas Higherthe inspired tension more anaesthetic will betransferred to the blood hastening induction.

2. Pulmonary ventilation It governs delivery ofthe GA to the alveoli. Hyperventilation will bringin more anaesthetic per minute and quickeninduction.

3. Alveolar exchange The GAs diffuse freelyacross alveoli, but if alveolar ventilation andperfusion are mismatched (as occurs in emphy-sema and other lung diseases) the attainment ofequilibrium between alveoli and blood will bedelayed. Induction and recovery both areslowed.

4. Solubility of anaesthetic in blood This is themost important property determining inductionand recovery. Large amount of an anaestheticthat is highly soluble in blood (ether) mustdissolve before its PP is raised. The rise as wellas fall of PP in blood and consequently inductionas well as recovery are slow. Drugs with lowblood solubility, e.g. N2O, sevoflurane, desfluraneinduce quickly.

5. Solubility of anaesthetic in tissues Relativesolubility of anaesthetic in blood and tissuesdetermines its concentration in tissues atequilibrium. Most of GAs are equally soluble inlean tissues as in blood but more soluble in fattytissue. Anaesthetics with higher lipid solubility(halothane) continue to enter adipose tissue forhours and also leave it slowly.

6. Cerebral blood flow Brain is a highly per-fused organ; as such GAs are quickly deliveredto it. This can be hastened by CO2 inhalationwhich causes cerebral vasodilatation—inductionand recovery are accelerated.

Elimination When anaesthetic administrationis discontinued, gradients are reversed and thechannel of absorption (pulmonary epithelium)becomes the channel of elimination. Same factors

which govern induction also govern recovery.Anaesthetics, in general, persist for long periodsin adipose tissue because of their high lipid solu-bility and low blood flow through fatty tissues.Muscles occupy an intermediate positionbetween brain and adipose tissue. Most GAs areeliminated unchanged. Metabolism is significantonly for halothane which is about 20% meta-bolized in liver.

Second gas effect and diffusion hypoxia Inthe initial part of induction, diffusion gradientfrom alveoli to blood is high and larger quantityof anaesthetic is entering blood. If the inhaledconcentration of anaesthetic is high, substantialloss of alveolar gas volume will occur and thegas mixture will be sucked in, independent ofventilatory exchange—gas flow will be higherthan tidal volume. This is significant only withN2O since it is given at 70–80% concentration.Though it has low solubility in blood, about 1litre/min of N2O enters blood in the first fewminutes—gas flow is 1 litre/min higher thanminute volume. If another potent anaesthetic, e.g.halothane (given at 1–2% concentration) is beinggiven at the same time, it also will be deliveredto blood at a rate 1 litre/min higher than minutevolume and induction will be faster—second gaseffect.

The reverse occurs when N2O is dis-continued after prolonged anaesthesia—N2Ohaving low blood solubility rapidly diffuses intoalveoli and dilutes the alveolar air—PP ofoxygen in alveoli is reduced. The resultinghypoxia, called diffusion hypoxia, is not of muchconsequence if cardiopulmonary reserve isnormal, but may be dangerous if it is low. Thiscan be prevented by continuing 100% O2

inhalation for a few minutes after discontinuingN2O, instead of straight away switching over toair. Diffusion hypoxia is not significant withother anaesthetics because they are administeredat low concentrations (0.2–4%) and cannot dilutealveolar air by more than 1–2%.

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Table 8.1: Physical and anaesthetic properties of inhalational anaesthetics

Anaesthetic Boiling Inflamma- Irritancy Oil: Gas Blood: Gas MAC Induction Musclepoint (°C) bility (odour) partition partition (%) relaxation

coefficient* coefficient*

1. Ether 35 Infl. + +++ 65 12.1 1.9 Slow V. goodExplo. (Pungent)

2. Halothane 50 Noninfl. – 224 2.3 0.75 Interm. Fair(Pleasant)

3. Isoflurane 48 Noninfl. ± 99 1.4 1.2 Fast Good(Not pleasant)

4. Desflurane 24 Noninfl. + 19 0.42 6.0 Fast Good(Unpleasant)

5. Sevoflurane 59 Noninfl. – 50 0.68 2.0 Fast Good(Pleasant)

6. Nitrous oxide Gas Noninfl. – 1.4 0.47 105 Fast Poor

* At 37oCMAC—Minimal alveolar concentration; Infl.—Inflammable; Explo.—Explosive; Interm.—Intermediate

Properties of an ideal anaesthetic

A. For the patient It should be pleasant, non-irritating, should not cause nausea or vomiting.Induction and recovery should be fast with noafter effects.B. For the surgeon It should provide adequateanalgesia, immobility and muscle relaxation.It should be noninflammable and nonexplosiveso that cautery may be used.

C. For the anaesthetist Its administrationshould be easy, controllable and versatile.• Margin of safety should be wide—no fall in

BP. Heart, liver and other organs should notbe affected.

• It should be potent so that low concentrationsare needed and oxygenation of the patientdoes not suffer.

• Rapid adjustments in depth of anaesthesiashould be possible.

• It should be cheap, stable and easily stored.• It should not react with rubber tubing or soda

lime.

The inhalational anaesthetics have a steep con-centration-response relationship: increasing theconcentration only by 10% over MAC immo-

bilizes>90 individuals (at MAC only 50% areimmobilized), and 2–3 MAC is often lethal.

The important physical and anaestheticproperties of inhalational anaesthetics arepresented in Table 8.1.

CLASSIFICATION

Inhalational

Gas LiquidsNitrous oxide Ether

HalothaneIsofluraneDesfluraneSevoflurane

Intravenous

Inducing agents Slower acting drugsThiopentone sod. BenzodiazepinesMethohexitone sod. DiazepamPropofol Lorazepam

MidazolamDissociative anaesthesia

KetamineOpioid analgesia

Fentanyl

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INHALATIONAL ANAESTHETICS

1. Nitrous oxide (N2O) It is a colourless,odourless, heavier than air, noninflammable gassupplied under pressure in steel cylinders. It isa nonirritating but low potency anaesthetic;unconsciousness cannot be produced in allindividuals without concomittent hypoxia: MACis 105% implying that even pure N2O cannotproduce adequate anaesthesia at 1 atmospherepressure.

Nitrous oxide is a good analgesic (even 20%produces moderate analgesia) but poor musclerelaxant. Onset of N2O action is quick andsmooth (but thiopentone is often used forinduction), recovery is rapid. Second gas effectand diffusion hypoxia occur with N2O only.Post-anaesthetic nausea is not marked.

Nitrous oxide is generally used as a carrierand adjuvant to other anaesthetics. A mixture of70% N2O + 25–30% O2 + 0.2–2% another potentanaesthetic is employed for most surgicalprocedures.

As the sole agent, N2O (50%) has been usedwith O2 for obstetric analgesia. In dental practiceN2O is now used to provide ‘conscious sedation’for allaying anxiety and apprehension (seep. 125). It is nontoxic to liver, kidney and brain.It is cheap and very commonly used.

2. Ether (Diethyl ether) It is a highly volatile liquid,produces irritating vapours which are inflammable andexplosive. Ether is a potent anaesthetic, produces goodanalgesia and marked muscle relaxation—the dose ofcompetitive neuromuscular blockers should be reducedto about 1/3rd.

It is highly soluble in blood—induction is prolongedand unpleasant with struggling, breath-holding, saliva-tion and marked respiratory secretions (atropine mustbe given as premedication to prevent the patient fromdrowning in his own secretions). Recovery is slow; post-anaesthetic nausea, vomiting and retching are marked.

Ether has gone out of use because of its unpleasantand inflammable properties. However, it is occasionallyused in peripheral areas because it is—cheap, can be givenby open drop method without the need for any equip-ment, and is relatively safe even in inexperienced hands.

3. Halothane (FLUOTHANE) It is a volatileliquid with sweet odour, nonirritant and nonin-

flammable. Solubility in blood is intermediate—induction is reasonably quick and pleasant.

It is a potent anaesthetic. For induction 2–4%and for maintenance 0.5–1% is delivered by theuse of a special vaporizer. It is not a goodanalgesic or muscle relaxant; however, it poten-tiates competitive neuromuscular blockers.

Halothane causes direct depression of myo-cardial contractility. Cardiac output is reducedwith deepening anaesthesia. BP starts fallingearly and parallels the depth. Heart rate is oftenreduced by direct depression of SA nodal auto-maticity and lack of baroreceptor activation evenwhen BP falls. It tends to sensitize the heart tothe arrhythmogenic action of Adr. Halothanecauses relatively greater depression of respira-tion; breathing is shallow and rapid. Ventilatorysupport with added oxygen is frequentlyrequired.

Pharyngeal and laryngeal reflexes are aboli-shed early and coughing is suppressed whilebronchi dilate—preferred for asthmatics. Itinhibits intestinal and uterine contractions.

Hepatitis occurs in susceptible individuals(approximately 1 in 10,000) especially afterrepeated use. A genetically determined reactionmalignant hyperthermia occurs rarely. It is due tointracellular release of Ca2+ from sarcoplasmicreticulum through an abnormal RyR calciumchannel causing persistent muscle contractionand increased heat production.

About 20% of halothane that enters blood ismetabolized in the liver, the rest is exhaled out.Recovery from halothane anaesthesia is smoothand reasonably quick; shivering may occur butnausea and vomiting are rare. Psychomotor per-formance and mental ability remain depressedfor several hours after regaining consciousness.

Halothane is a routinely used anaesthetic inIndia, but in affluent countries it has beenreplaced by the newer and costlier congeners.

4. Isoflurane (SOFANE) This potent fluorinatedanaesthetic has properties similar to halothane,but is less soluble in blood—produces rapid

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induction and recovery. Fall in BP is likehalothane, but it tends to increase heart rate.Isoflurane does not sensitize the heart toadrenergic arrhythmias.

Respiratory depression is prominent andassistance is usually needed to avoid hyper-carbia. Secretions are slightly increased. Renaland hepatic toxicity has not been encountered.Postanaesthetic nausea and vomiting is low.

Though slightly irritant, isoflurane has manyadvantages, i.e. better adjustment of depth ofanaesthesia and low toxicity. It does not provokeseizures and is preferred for neurosurgery. Inmany hospitals it has become the routineanaesthetic.

5. Desflurane It is a recently developed allfluorinated congener of isoflurane which hasgained popularity as an anaesthetic for out-patient surgery in western countries. Itsdistinctive properties are high volatility, loweroil: gas partition coefficient and very lowsolubility in blood as well as tissues because ofwhich induction and recovery are very fast.Depth of anaesthesia changes rapidly withchange in inhaled concentration. Postanaestheticcognitive and motor impairment is shortlived—patient can be discharged a few hours aftersurgery.

Desflurane is less potent than isoflurane;higher concentration has to be used forinduction—irritates air passage—may inducecoughing, breath-holding and laryngospasmbecause of somewhat pungent odour making itdifficult to use for induction. Degree of respiratorydepression, muscle relaxation, vasodilatation andfall in BP, as well as maintained cardiac contrac-tility and coronary circulation are like isoflurane.Desflurane can serve as a good alternative toisoflurane for routine surgery as well, especiallyprolonged operations.

6. Sevoflurane It is the latest polyfluorinatedanaesthetic with properties intermediate bet-ween isoflurane and desflurane. Solubility inblood and tissues as well as potency are less

than isoflurane but more than desflurane.Induction and emergence from anaesthesia arefast and rapid changes in depth can be achieved.Absence of pungency makes it pleasant andadministrable through face mask. Unlikedesflurane, it poses no problem in induction;acceptability is good even by pediatric patients.Recovery is smooth; orientation, cognitive andmotor functions are regained almost as quicklyas with desflurane. Sevoflurane is suitable forboth outpatient and inpatient surgery, but itshigh cost and need for high flow open systemmakes it very expensive to use.

INTRAVENOUS ANAESTHETICS

INDUCING AGENTS

These are drugs which on i.v. injection produceloss of consciousness in one arm-brain circu-lation time (~11 sec); are generally used forinduction because of rapidity of onset of action.Anaesthesia is then usually maintained by aninhalational agent. They also serve to reduce theamount of maintenance anaesthetic. Supple-mented with analgesics and muscle relaxants,they can also be used as the sole anaesthetic.

1. Thiopentone sod It is an ultrashort actingthiobarbiturate, highly soluble in water yieldinga very alkaline solution, which must be preparedfreshly before injection. Extravasation of thesolution or inadvertent intraarterial injectionproduces intense pain—necrosis and gangrenemay occur.

Injected i.v. (3–5 mg/kg) it produces uncons-ciousness in 15–20 sec. Its undissociated formhas high lipid solubility—enters brain almostinstantaneously. Initial distribution depends onorgan blood flow—brain gets large amounts.However, as other less vascular tissues (muscle,fat) gradually take up the drug, blood concen-tration falls and it back diffuses from the brain;consciousness is regained in 6–10 min (t½ ofdistribution phase is 3 min).

On repeated injection, the extracerebral sitesare gradually filled up—lower doses produce

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anaesthesia which lasts longer. Its ultimatedisposal occurs mainly by hepatic metabolism(elimination t½ is 7–12 hr). Residual CNS dep-ression may persist for > 12 hr. The patientshould not be allowed to leave the hospitalwithout an attendant before this time.

Thiopentone is a poor analgesic. Painfulprocedures should not be carried out under itsinfluence unless an opioid or N2O has beengiven; otherwise, the patient may struggle, shoutand show reflex changes in BP and respiration.

It is a weak muscle relaxant. BP fallsimmediately after injection mainly due to vaso-dilatation, but recovers rapidly.

Thiopentone is a commonly used inducingagent, but seldom employed in dentistry.

Adverse effects Laryngospasm occurs gene-rally when respiratory secretions or other irri-tants are present, or when intubation is attemp-ted while anaesthesia is light. This can beprevented by atropine premedication.

Shivering and delirium may occur duringrecovery. Postanaesthetic nausea and vomitingare uncommon.

2. Methohexitone sod. It is a more potent and shorteracting thiopentone congener that is more rapidlymetabolized—patient becomes roadworthy earlier.

3. Propofol It is an oily liquid employed as a1% emulsion for i.v. induction and shortduration anaesthesia. Unconsciousness afterpropofol injection occurs in 15–45 sec and lasts~10 min. Propofol distributes rapidly (distribu-tion t½ 2–4 min). Elimination t½ (100 min) ismuch shorter than that of thiopentone due torapid metabolism. As such, propofol has largelysuperseded thiopentone.

Intermittent injection or continuous infu-sion of propofol has been used for total i.v.anaesthesia when supplemented by fentanyl. Itlacks airway irritancy and is particularly suitedfor outpatient surgery because residual impair-ment is less marked and incidence of post-operative nausea and vomiting is low. Excitatoryeffects and involuntary movements are noted in

few patients. Induction apnoea lasting ~1 minis common. Fall in BP due primarily to vasodila-tation occurs consistently and is occasionallysevere, but short lasting. Bradycardia is alsofrequent.

In subanaesthetic doses it has been used forsedating intubated patients in intensive careunits.

SLOWER ACTING DRUGS

1. Benzodiazepines (BZDs) In addition topreanaesthetic medication, BZDs are nowfrequently used for inducing, maintaining andsupplementing anaesthesia as well as for cons-cious sedation. Relatively large doses (diazepam0.2–0.5 mg/kg or equivalent) injected i.v. producesedation, amnesia and then unconsciousness in5–10 min. If no other anaesthetic or opioid isgiven, the patient becomes responsive in 1 hr orso due to redistribution of the drug (distributiont½ of diazepam is 15 min), but amnesia persistsfor 2–3 hr and sedation for 6 hr or more. BZDsare poor analgesics : an opioid or N2O is usuallyadded if the procedure is painful.

By themselves, BZDs do not markedly dep-ress respiration, cardiac contractility or BP; butwhen opioids are also given, these functions areconsiderably compromised. They do not provokepostoperative nausea or vomiting. Involuntarymovements are not stimulated.

BZDs are now the preferred drugs for endo-scopies, cardiac catheterization, angiographies,conscious sedation during local/regional anaes-thesia for dental procedures, fracture setting, etc.They are a frequent component of balancedanaesthesia employing several drugs. Theanaesthetic action of BZDs can be rapidlyreversed by flumazenil 0.5–2 mg i.v.

Diazepam 0.2–0.5 mg/kg by slow undilutedinjection in a running i.v. drip: this techniquereduces the burning sensation in the vein andincidence of thromboflebitis.Lorazepam Three times more potent, sloweracting and less irritating than diazepam. It

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distributes more gradually—awakening may bedelayed. Amnesia is more profound.

Midazolam Water soluble, nonirritating toveins, faster and shorter acting and 3 times morepotent than diazepam. It is being preferred overdiazepam for anaesthetic use and for sedationof dental patients, intubated and mechanicallyventilated patients, etc.

2. Ketamine It induces a so- called ‘dissociativeanaesthesia’—profound analgesia, immobility,amnesia with light sleep and feeling of dis-sociation from one’s own body and thesurroundings. The primary site of action is in thecortex and subcortical areas; not in the reticularactivating system.

Respiration is not depressed, airway reflexesare maintained and muscle tone increases. Heartrate, cardiac output and BP are elevated due tosympathetic stimulation. The above effects areproduced within a min and recovery starts after10–15 min, but the patient remains amnesic for1–2 hr. Emergence delirium, hallucinations andinvoluntary movements occur in up to 50%patients, but the injection is not painful. Childrentolerate the drug better. Its elimination t½ is3–4 hr.

Ketamine has been employed for dental andother operations on the head and neck, inpatients who have bled, in asthmatics (relievesbronchospasm), in those who do not want to loseconsciousness and for short operations. It is goodfor repeated use; particularly suitable for burndressing. Combined with diazepam, it hasfound use in angiographies, cardiac catheteriza-tion and trauma surgery. It may be dangerousfor hypertensives and in ischaemic heart disease,but is good for hypovolemic patients.

3. Fentanyl This short acting (30–50 min)potent opioid analgesic related to pethidine isgenerally given i.v. at the beginning of painfulsurgical procedures. It is frequently used tosupplement anaesthetics in balanced anaes-thesia. This permits use of lower anaestheticconcentrations with better haemodynamic

stability. Combined with benzodiazepines, it canobviate the need for inhaled anaesthetics fordiagnostic, endoscopic, angiographic, dental andother minor procedures in poor risk patients, aswell as for burn dressing.

After i.v. fentanyl (2–4 μg/kg) the patientremains drowsy but conscious and his co-operation can be commanded. Respiratorydepression is marked, but predictable; the patientmay be encouraged to breathe and assistancemay be provided. Heart rate decreases, becausefentanyl stimulates vagus. Fall in BP is slight andheart is not sensitized to Adr.

Nausea, vomiting and itching often occurduring recovery. The opioid antagonist naloxonecan be used to counteract persisting respiratorydepression and mental clouding.

COMPLICATIONS OF GENERALANAESTHESIA

A. During anaesthesia1. Respiratory depression and hypercarbia.2. Salivation, respiratory secretions—less

problematic now as nonirritant anaestheticsare mostly used.

3. Cardiac arrhythmias, asystole.4. Fall in BP.5. Aspiration of gastric contents: acid pneumo-

nitis.6. Laryngospasm and asphyxia.7. Awareness: dreadful perception and recall of

events during surgery—by use of light anaes-thesia + analgesics and muscle relaxants.

8. Delirium, convulsions, excitatory effects.9. Fire and explosion—rare now due to use of

non-inflammable agents.

B. After anaesthesia1. Nausea and vomiting.2. Persisting sedation: impaired psychomotor

function.3. Pneumonia, atelectasis.4. Organ toxicities: liver, kidney damage.5. Nerve palsies—due to faulty positioning.6. Emergence delirium.

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7. Cognitive defects: prolonged excess cognitivedecline has been observed in some patients,especially the elderly.

DRUG INTERACTIONS

1. Patients on antihypertensives given generalanaesthetics—BP may fall markedly.

2. Neuroleptics, opioids, clonidine and mono-amine oxidase inhibitors potentiate anaes-thetics.

3. Halothane sensitizes heart to Adr.4. If a patient on corticosteroids is to be

anaesthetized, give 100 mg hydrocortisoneintraoperatively because anaesthesia is astress—can precipitate adrenal insufficiency.

5. Insulin need of a diabetic is increased duringGA: switch over to plain insulin even if thepatient is on oral hypoglycaemics.

CONSCIOUS SEDATION

In place of general anaesthesia ‘conscioussedation’ (a monitored state of alteredconsciousness) can be employed, supplementedwith local anaesthesia, to carry out dentalprocedures/surgery in apprehensive children (oradults) and in medically compromised patients.It allows operative procedure to be performedwith minimal physiologic and psychologic stress.Conscious sedation is a technique in which drugsare used to produce a state of CNS depression(but not unconsciousness) enabling surgicalprocedure to be carried out while maintainingcommunication with the patient who is able torespond to commands and maintain a patentairway throughout. The difference betweenconscious sedation and anaesthesia is one ofdegree. The protective airway and other reflexesare not lost during conscious sedation; therefore,it is safer. However, by itself, conscious sedationis not able to suppress pain of dental procedure;local anaesthetic must be injected in addition.Drugs used for conscious sedation are:1. Diazepam It is injected i.v. in small (1–2 mg)repeated doses or by slow infusion until thedesired level of sedation is produced indicated

by relaxation, indifference, slurring of speech,ptosis, etc. Further injection is stopped, after whichthis state lasts for about 1 hour and psychomotorimpairment persists for 6–24 hours; an escort isneeded to take back the patient home. Flumazenilcan be used to reverse the sedation, but repeateddoses are needed.

Midazolam (i.v.) is a shorter acting alternativeto diazepam. Oral diazepam administered 1 hrbefore is also used with the limitation that level ofsedation cannot be titrated. The patient remainssedated (not roadworthy) for several hours.2. Propofol Because of brief action, it has to beadministered by continuous i.v. infusionregulated by infusion pump throughout theprocedure. However, level of sedation can bealtered during the procedure and recovery isrelatively quick, permitting early discharge of thepatient.3. Nitrous oxide The patient is made to breathe100 oxygen through a nose piece or hood andN2O is added in 10% increments (to a maximumof 50%, rarely 70%) till the desired level of sedationassessed by constant verbal contact is obtained.This is maintained till the procedure is performed.Thereafter, N2O is switched off but 100% O2 iscontinued for next 5 min. The patient is generallyroadworthy within 30–60 min.4. Fentanyl Injected i.v. (1-2 μg/kg every 15-30min), it can be used alone as well as incombination with propofol.

PREANAESTHETIC MEDICATION

Preanaesthetic medication refers to the use ofdrugs before anaesthesia to make it morepleasant and safe. The aims are:1. Relief of anxiety and apprehension preopera-

tively and to facilitate smooth induction.2. Amnesia for pre- and postoperative events.3. Supplement analgesic action of anaesthetics

and potentiate them so that less anaestheticis needed.

4. Decrease secretions and vagal stimulationcaused by the anaesthetic.

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5. Antiemetic effect extending to the postope-rative period.

6. Decrease acidity and volume of gastric juiceso that it is less damaging if aspirated.

Different drugs achieve different purposes. Oneor more drugs may be used in a patient depen-ding on the needs.

1. Sedative-antianxiety drugs Benzodiaze-pines like diazepam or lorazepam have becomepopular drugs for preanaesthetic medicationbecause they produce tranquility and smootheninduction with little respiratory depression. Theycounteract CNS toxicity of local anaesthetics.

Promethazine is an antihistaminic with sedative,antiemetic and anticholinergic properties. Itcauses little respiratory depression and has beenused particularly in children.

2. Opioids Morphine or pethidine, i.m. allay anxietyand apprehension of the operation, produce pre- andpostoperative analgesia, smoothen induction, andsupplement poor analgesic (thiopentone, halothane) orweak (N2O) anaesthetics but have disadvantages likerespiratory depression, greater fall in BP due to theanaesthetic, interference with pupillary signs, lack ofamnesic action, delayed recovery, more postoperativeconstipation and urinary retention, etc.

Use of opioids is now mostly restricted to thosehaving preoperative pain.

3. Anticholinergics Atropine or hyoscine (0.6 mgi.m./i.v.) have been used, primarily to reduce salivaryand bronchial secretions. They are infrequently needednow, because only non-irritant anaesthetics are used.However, they must be given before hand when ether isused. The main aim of their use now is to prevent vagalbradycardia, hypotension and prophylaxis of laryngo-spasm.

Glycopyrrolate This quaternary atropine substitute isa potent antisecretory and antibradycardiac drug; actsrapidly and is less likely to produce central effects (seeCh. 5).

4. Neuroleptics Chlorpromazine, triflupromazine orhaloperidol i.m. are infrequently used in premedication.They allay anxiety and have antiemetic action. However,they potentiate respiratory depression and hypotensioncaused by the anaesthetics and delay recovery.

5. H2 blockers Patients undergoing prolongedoperations and obese patients are at increased

SKELETAL MUSCLE RELAXANTS

Skeletal muscle relaxants are drugs that actperipherally at neuromuscular junction/ musclefibre itself or centrally in the cerebrospinal axisto reduce muscle tone and/or cause paralysis.

The neuromuscular blocking agents are usedin conjunction with general anaesthetics toprovide muscle relaxation for surgery, whilecentrally acting muscle relaxants are usedprimarily for painful muscle spasms and spasticneurological diseases.

PERIPHERALLY ACTING MUSCLERELAXANTS

I. Neuromuscular Blocking Agents

A. Nondepolarizing (Competitive) blockers

1. Long acting: d-Tubocurarine, Pancuronium,Doxacurium, Pipecuronium.

2. Intermediate acting: Vecuronium, Atracurium,Cisatracurium, Rocuronium, Rapacuronium.

3. Short acting: Mivacurium.

B. Depolarizing blockers

Succinylcholine (SCh., Suxamethonium),Decamethonium (C-10)

II. Directly Acting Agents

Dantrolene sodium, Quinine

risk of gastric regurgitation and aspirationpneumonia. Ranitidine or famotidine benefit byraising pH of gastric juice; may also reduce itsvolume and thus chances of regurgitation.Prevention of stress ulcers is another advantage.

The proton pump inhibitor omeprazole/pantoprazole is an alternative.

6. Antiemetics Metoclopramide injected pre-operatively is effective in reducing postoperativevomiting. By enhancing gastric emptying andtone of LES, it reduces the chances of reflux andits aspiration.

Domperidone and Ondansetron (5-HT3 antagonist)can be used as alternatives.

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NEUROMUSCULAR BLOCKING AGENTS

Curare It is the generic name for certain plant extractsused by south American tribals as arrow poison for gamehunting. The animals got paralysed even if not killed bythe arrow. Natural sources of curare are Strychnostoxifera, Chondrodendron tomentosum and related plants.Muscle paralysing active principles of these are tubocura-rine, toxiferins, etc.

MECHANISM OF ACTION

The site of action of both competitive anddepolarizing blockers is the endplate of skeletalmuscle fibres.Competitive block (Nondepolarizing block)This is produced by curare and related drugs.

The competitive blockers have affinity for thenicotinic (NM) cholinergic receptors at the muscleendplate but have no intrinsic activity. The NM

receptor has been isolated and studied in detail.It is a protein with 5 subunits (α2 β ε or γ andδ) which are arranged like a rosette surroundingthe Na+ channel (see Fig. 3.3). The two α subunitscarry 2 ACh binding sites; these have negativelycharged groups which combine with the cationichead of ACh → opening of the Na+ channel.Most of the competitive blockers have two ormore quaternary N+ atoms which provide thenecessary attraction to the same site, but the bulkof the antagonist molecule does not allowconformational changes in the subunits neededfor opening the channel. The ACh released frommotor nerve endings is not able to combine withits receptors to generate endplate potential (EPP)and muscle fails to contract in response to nerveimpulse. The antagonism is surmountable byincreasing the concentration of ACh in vitro andby anticholinesterases in vivo.

The competitive blockers also block theprejunctional nicotinic receptors located onmotor nerve endings and supplement the postjunctional block.

Depolarizing block Decamethonium and SChhave affinity as well as submaximal intrinsicactivity at the NM cholinoceptors. They depola-rize muscle endplates by opening Na+ channels

(just as ACh does) and initially produce twitch-ing and fasciculations. These drugs do notdissociate rapidly from the receptor → induceprolonged partial depolarization of the regionaround muscle endplate → Na+ channels getinactivated (because transmembrane potentialdrops to about –50 mV) → ACh released frommotor nerve endings is unable to generatepropagated muscle action potential (MAP) →flaccid paralysis in mammals. In other words, azone of inexcitability is created around the end-plate preventing activation of muscle fibre. Inbirds, the area of depolarization is moreextensive and spastic paralysis occurs.

Fig. 8.1: Illustration of characteristics of competitive (A)and depolarizing (B) neuromuscular blockade in sciatic

nerve-gastrocnemius muscle of catA. Tubocurarine (d-TC) produces progressive decreasein twitch tension; tetanic stimulation (TET) produces poorlysustained contracture, which is followed by post-tetanicpotentiation (PTP); Neostigmine (Neo) restores the twitchcontractions.B. Succinylcholine (SCh) produces initial augmentation oftwitches followed by progressive block; tetanus is wellsustained, but there is no PTP; block is not reversed (ratherworsened) by neostigmine.

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Table 8.2: Features of competitive and typical depolarizing block

Competitive block Depolarizing block(d-TC) (C-10)

1. Paralysis in man Flaccid Fasciculations → flaccid2. Paralysis in chick Flaccid Spastic3. Effect on isolated No contraction, Contraction

frog’s rectus muscle Antagonism of ACh4. Species sensitivity Rat > Rabbit > Cat Cat > Rabbit > Rat5. Human neonates More sensitive Relatively resistant6. Tetanic stimulation Poorly sustained contraction Well-sustained contraction

during partial block7. Neostigmine Antagonises block No effect8. Ether anaesthesia Synergistic No effect9. Order of paralysis Fingers, eyes → limbs → neck, Neck, limbs → face, jaw, eyes,

face → trunk → respiratory pharynx → trunk → respiratory10. Effect of lowering Reduces block Intensifies block

temperature11. Effect of cathodal Lessens block Enhances block

current to endplate

Depolarizing blockers also have 2 quaternaryN+ atoms but the molecule is long, slender andflexible. The features of classical depolarizingblock differ markedly from that of nondepo-larizing block (see Fig. 8.1 and Table 8.2).

In many species, e.g. dog, rabbit, rat, monkey, in slowcontracting soleus muscle of cat, and under certainconditions in man the classical depolarizing blockdescribed above (phase I block) is followed by phase IIblock, which is due to desensitization of the NM receptorto ACh, and superficially resembles nondepolarizingblock in features. SCh readily produces phase II blockin patients with atypical or deficient pseudocho-linesterase.

ACTIONS

1. Skeletal muscles Intravenous injection ofnondepolarizing blockers rapidly producesmuscle weakness followed by flaccid paralysis.Small fast response muscles (fingers, extraocular)are affected first; paralysis spreads to hands,feet—arm, leg, neck, face—trunk—finally inter-costal muscles—diaphragm: respiration stops.Recovery occurs in the reverse sequence;diaphragmatic contractions resume first.

Depolarizing blockers typically produce fas-ciculations lasting a few seconds before inducing

flaccid paralysis, but fasciculations are not promi-nent in well-anaesthetized patients. Though thesequence in which muscles are involved issomewhat different from the competitive blockers(Table 8.2), the action of SCh develops with suchrapidity that this is not appreciated. Apnoeagenerally occurs within 45–90 sec, but lasts only2–5 min; recovery is rapid.2. Autonomic ganglia Because the cholinergicreceptors in autonomic ganglia are nicotinic(though of a different subclass NN), competitiveneuromuscular blockers produce some degree ofganglionic blockade. SCh may cause ganglionicstimulation.3. Histamine release d-TC releases histaminefrom mast cells resulting in hypotension, flush-ing, bronchospasm and increased respiratorysecretions. Histamine releasing potential of otherneuromuscular blockers is graded in Table 8.3.

4. C.V.S.d-Tubocurarine produces a significant fall in BP.This is due to—(a) ganglionic blockade,(b) histamine release, and(c) reduced venous return—a result of paralysis

of limb and respiratory muscles.

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Table 8.3: Comparative properties of neuromuscular blocking drugs

Drug Dose£ Onset* Duration@ Hist. Gang. Vagal(mg/kg) (min) (min) release block block

LONG ACTING1. d-Tubocurarine 0.2–0.4 4–6 30–60 +++ ++ ±

2. Pancuronium 0.04–0.1 4–6 60–120 ± ± +

3. Doxacurium 0.03–0.08 4–8 60–120 + – –

4. Pipecuronium 0.05–0.08 2–4 50–100 ± – –

INTERMEDIATE ACTING5. Vecuronium 0.08–0.1 2–4 30–60 ± – ±

6. Atracurium 0.3–0.6 2–4 20–35 + – –

7. Rocuronium 0.6–0.9 1–2 25–40 – – ±

SHORT ACTING8. Mivacurium 0.07–0.15 2–4 12–20 + – –

9. Succinylcholine 0.5–0.8 1–1.5 3–6 ++ St. St.

£Initial paralysing dose for opioid/nitrous oxide/oxygen anaesthesia. In patients anaesthetised withether/halothane/isoflurane, the dose may be 1/3–1/2 of the figure given.*Time to maximal block after i.v. injection.@Duration of surgical grade relaxation after usual clinical doses; time to 95% recovery of muscle twitchis nearly double of the figure given (especially for long-acting drugs). Duration is also dose dependent.St. — Stimulation

Heart rate may increase due to vagal ganglionicblockade. Pancuronium and vecuronium alsotend to cause tachycardia. All newer nondepolar-izing drugs have negligible effects on BP and HR.

Cardiovascular effects of SCh are variable.BP occasionally falls on account of its muscarinicaction causing vasodilatation.

5. G.I.T. The ganglion blocking activity ofcompetitive blockers may enhance postoperativeparalytic ileus after abdominal operations.

6. C.N.S. All neuromuscular blockers are qua-ternary compounds—do not cross blood-brainbarrier—no CNS effects.

PHARMACOKINETICS

All neuromuscular blockers are quaternarycompounds—not absorbed orally. They are practi-cally always given i.v. Muscles with higher bloodflow receive more drug and are affected earlier.Redistribution to non-muscular tissues plays asignificant role in the termination of action of a

single dose. They do not cross placenta or pene-trate brain. d-TC, pancuronium, doxacurium andpipecuronium are partly metabolized whilevecuronium, atracurium, rocuronium andmivacurium are largely metabolized in the body.Atracurium is inactivated in plasma by spon-taneous nonenzymatic degradation (Hofmannelimination) in addition to that by cholinesterases.The unchanged drug is excreted in urine as wellas in bile.

SCh is rapidly hydrolysed by plasmapseudocholinesterase—action lasts for 3 to 5 min.Some patients have genetically determinedabnormality (low affinity for SCh) or deficiencyof pseudocholinesterase. In them, SCh causesdominant phase II blockade resulting in muscleparalysis and apnoea lasting for hours.

INTERACTIONS

1. Thiopentone sod and SCh solutions shouldnot be mixed in the same syringe—react chemi-cally.

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2. General anaesthetics potentiate competitiveblockers.3. Anticholinesterases reverse the action of com-petitive blockers. Neostigmine 0.5–2 mg i.v. isalmost routinely used after pancuronium andother long acting blockers to hasten recovery atthe end of operation.4. Antibiotics Aminoglycoside antibiotics re-duce ACh release from prejunctional nerveendings and have a weak stabilizing action onthe postjunctional membrane. In clinically useddoses they do not by themselves produce musclerelaxation but potentiate competitive blockers.Tetracyclines (by chelating Ca2+) polypeptideantibiotics, clindamycin and lincomycin alsosynergise with competitive blockers.5. Calcium channel blockers Verapamil andothers potentiate both competitive and depola-rizing neuromuscular blockers.6. Diuretics produce hypokalaemia whichenhances competitive block.7. Diazepam, propranolol and quinidine intensifycompetitive block, while high dose of cortico-steroids reduce it.

TOXICITY

1. Respiratory paralysis and prolonged apnoeais the most important problem.

2. Flushing can occasionally occur with atra-curium and mivacurium.

3. Fall in BP and cardiovascular collapse canoccur, especially in hypovolemic patients.

4. Cardiac arrhythmias and even arrest haveoccurred, especially with SCh.

5. Precipitation of asthma with histaminereleasing neuromuscular blockers.

6. Postoperative muscle soreness after SCh.

USES

1. The most important use of neuromuscularblockers is as adjuvants to general anaesthesia;adequate muscle relaxation can be achievedat lighter planes. They are specially valuablein abdominal and thoracic surgery. In dentistry

they may be needed for setting of mandibular frac-tures.

Succinylcholine is employed for brief proce-dures, e.g. endotracheal intubation, laryngo-scopy, bronchoscopy, esophagoscopy, reductionof fractures and to treat laryngospasm, etc.2. Assisted ventilation of critically ill patientsin intensive care units can be facilitated bycontinuous infusion of a competitive neuro-muscular blocker which reduces chest wallresistance to inflation.3. Convulsions and trauma from electrocon-vulsive therapy can be avoided by the use ofmuscle relaxants.4. Severe cases of tetanus and status epilep-ticus, may be paralysed by a neuromuscularblocker (repeated doses of a competitive blocker)and maintained on intermittent positive pressurerespiration.

DIRECTLY ACTING MUSCLE RELAXANTS

Dantrolene This muscle relaxant is chemically andpharmacologically entirely different from neuromuscularblockers. It does not affect neuromuscular transmissionor MAP, but uncouples contraction from depolarizationof the muscle membrane; depolarization triggered releaseof Ca2+ from sarcoplasmic reticulum is reduced.

Used orally dantrolene reduces spasticity in uppermotor neurone disorders, hemiplegia, paraplegia, cerebralpalsy and multiple sclerosis.

Used i.v. it is the drug of choice for malignanthyperthermia which is due to persistent release of Ca2+

from sarcoplasmic reticulum (induced by fluorinatedanaesthetics and SCh in genetically susceptibleindividuals).

Muscular weakness is the dose limiting side effect.Troublesome diarrhoea is another problem. Long-term usecan cause serious liver toxicity.

Quinine This antimalarial drug increases refractoryperiod and decreases excitability of motor endplates.Muscle tone in myotonia congenita is reduced. Taken atbed time it may abolish nocturnal leg cramps in somepatients.

CENTRALLY ACTING MUSCLE RELAXANTS

These are drugs which reduce skeletal muscle toneby a selective action in the cerebrospinal axis,without altering consciousness. They selectively

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depress spinal and supraspinal polysynapticreflexes involved in the regulation of muscle tonewithout significantly affecting monosynapticallymediated stretch reflex. Polysynaptic pathwaysin the ascending reticular formation which areinvolved in the maintenance of wakefullness arealso depressed, though to a lesser extent. Allcentrally acting muscle relaxants do have somesedative property and they overlap with anti-anxiety drugs. They have no effect on neuro-muscular transmission and on muscle fibres, butreduce decerebrate rigidity, upper motor neuronespasticity and hyperreflexia. Prominent diffe-rences between centrally and peripherally actingmuscle relaxants are listed in Table 8.4.

CLASSIFICATION

(i) Mephenesin Mephenesin,congeners Carisoprodol,

Chlorzoxazone,Chlormezanone,Methocarbamol.

(ii) Benzodiazepines Diazepam and others.(iii) GABA derivative Baclofen.(iv) Central α2 agonist Tizanidine.

Mephenesin was the first drug found to reducemuscle tone by depressing spinal internuncialneurones, which modulate polysynaptic reflexesthat maintain muscle tone. It is not used clinicallybecause of toxicity. Its congeners like carisoprodol,chlorzoxazone, chlormezanone and methocarbamolhave low toxicity and are used for musculoskeletaldisorders associated with muscle spasm. Theyare often combined with NSAIDs. However,

clinical efficacy of none of the above drugs asmuscle relaxant is well established. Gastricirritation and sedation are the most important sideeffects.

Diazepam (see Ch. 9) is the prototype ofbenzodiazepines (BZDs) which act in the brainon specific receptors enhancing GABAergictransmission. It reduces muscle tone by supra-spinal rather than spinal action. Sedation limitsthe dose which can be used for reducing muscletone but gastric tolerance is very good. It isparticularly valuable in spinal injuries andtetanus. Combined with analgesics, it is popularfor rheumatic disorders associated with musclespasm.

Baclofen It is an analogue of the inhibitorytransmitter GABA; acts as selective GABAB

receptor agonist.The GABA receptors have been divided into:

GABAA receptor Intrinsic ion channel receptor—increasesCl¯ conductance; blocked by bicuculline; facilitated byBZDs.

GABAB receptor G-protein coupled receptor; hyper-polarizes neurones by increasing K+ conductance andaltering Ca2+ flux; bicuculline insensitive.

Baclofen does not affect Cl¯ transport and itsactions are not antagonized by bicuculline.

The primary site of action of baclofen is inthe spinal cord where it depresses both poly-synaptic and monosynaptic reflexes. As such, itdoes produce muscle weakness. It reducesspasticity in many neurological disorders likemultiple sclerosis, amyotropic lateral sclerosis,spinal injuries and flexor spasms but is relatively

Table 8.4: Comparative features of centrally acting and peripherally acting muscle relaxants

Centrally acting Peripherally acting

1. Decrease muscle tone without reducing Cause muscle paralysis, voluntary movementsvoluntary power lost

2. Selectively inhibit polysynaptic reflexes in CNS Block neuromuscular transmission

3. Cause some CNS depression No effect on CNS

4. Given orally, sometimes parenterally Practically always given i.v.

5. Used in chronic spastic conditions, Used for short-term purposesacute muscle spasms, tetanus (surgical operations)

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ineffective in stroke, cerebral palsy, rheumaticand traumatic muscle spasms and parkinso-nism.

Tizanidine This recently introduced clonidinecongener is a central α2 adrenergic agonist—inhibits release of excitatory amino acids inspinal interneurones. Facilitation of inhibitorytransmitter glycine has also been demonstrated.It inhibits polysynaptic reflexes; reduces muscletone and frequency of muscle spasms withoutreducing muscle strength.

It is indicated in spasticity due to neuro-logical disorders and in painful muscle spasmsof spinal origin. Side effects are dry-mouth,drowsiness, night-time insomnia and hallucina-tions. Dose-dependent elevation of liver testvalues has been noted.

Uses of centrally acting muscle relaxants

1. Acute muscle spasms Overstretching of amuscle, sprain, tearing of ligaments and tendons,dislocation, fibrositis, bursitis, etc. cause painfulspasm of muscles. The mephenesin like and BZDmuscle relaxants are often combined with

analgesics. They may help to relieve trismus occurringafter a dental procedure. However, efficacy of thesedrugs is not impressive.

2. Torticollis, lumbago, backache, neuralgiasrespond in the same way as acute musclespasms.

3. Anxiety and tension associated with increa-sed tone of muscles and bruxism (involuntarygrinding of teeth during sleep; often stress related)may be benefited.4. Spastic neurological diseases like hemiple-gia, paraplegia, spinal injuries, multiplesclerosis, and cerebral palsy are somewhatbenefited by baclofen, diazepam, tizanidine anddantrolene.5. Tetanus Most commonly diazepam is infu-sed i.v. and the dose is titrated by the response.Methocarbamol is an alternative.6. Electroconvulsive therapy Diazepam maybe used to suppress convulsions.7. Orthopaedic manipulations may be per-formed under the influence of diazepam ormethocarbamol given i.v.

SEDATIVE-HYPNOTICS

Sedative A drug that subdues excitement andcalms the subject without inducing sleep, thoughdrowsiness may be produced. Sedation refers todecreased responsiveness to any level of stimula-tion; is associated with some decrease in motoractivity and ideation.

Hypnotic A drug that induces and/or main-tains sleep, similar to normal arousable sleep. Thisis not to be confused with ‘hypnosis’ meaning atrans like state in which the subject becomespassive and highly suggestible.

The sedatives and hypnotics are more or lessglobal CNS depressants with somewhat differingtime-action and dose-action relationships. Thosewith quicker onset, shorter duration and steeperdose-response relationships are prefered ashypnotics, while more slowly acting drugs withflatter dose-response curves are employed assedatives. However, there is considerable overlap;a hypnotic at lower dose may act as sedative.Thus, sedation—hypnosis—general anaesthesiamay be regarded as increasing grades of CNSdepression. Hypnotics given in high doses canproduce general anaesthesia. However, benzo-diazepines (BZDs) cannot be considered non-selective or global CNS depressants like barbitu-rates.

Treatment of insomnia is the most importantuse of this class of drugs.

Sleep

The duration and pattern of sleep varies considerablyamong individuals. Age has an important effect onquantity and depth of sleep. It has been recognized thatsleep is an architectured cyclic process in which the subjectpasses from stage 0 (awake) to stage 4 (cerebral sleep)through stage 1 (dozing), stage 2 (unequivocal sleep) andstage 3 (deep sleep transition) of non-rapid eye movement(N-REM) sleep interspersed with REM (paradoxical) sleep(Fig. 9.1). About 20–30% of sleep time is spent in REM,while stage 2 occupies the major part of NREM sleep.Dreams and nightmares occur during REM sleep. Thecyclic pattern of sleep stages, particularly REM, is consi-dered to be essential for sleep to be refreshing.

CLASSIFICATION

1. Barbiturates For practical reasons dividedinto—Long acting PhenobarbitoneShort acting PentobarbitoneUltrashort acting Thiopentone sod.

2. Benzodiazepines May be divided accordingto primary use—

Hypnotic AntianxietyDiazepam DiazepamFlurazepam ChlordiazepoxideNitrazepam OxazepamAlprazolam LorazepamTemazepam AlprazolamTriazolam Anticonvulsant

DiazepamClonazepamClobazam

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Drugs Acting on Central Nervous SystemSedative-Hypnotics, Alcohols, Antiepileptics and

Antiparkinsonian Drugs

134 Drugs Acting on CNSS

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3. Newer nonbenzodiazepine hypnoticsZopiclone, Zolpidem, Zaleplon

Chloral hydrate, Triclophos, Paraldehyde, Methaqualoneand Meprobamate are historical sedative-hypnotics nolonger used.In addition, some antihistaminics (promethazine, diphen-hydramine), some neuroleptic/antidepressants (chlorpro-mazine, amitriptyline), some anticholinergic (hyoscine) andopioids (morphine, pethidine) have significant sedativeaction, but are not reliable for treatment of insomnia.

BARBITURATES

Barbiturates have been popular hypnotics andsedatives of the last century up to 1960s but arenot used now. However, they are described firstas they are the prototype of CNS depressants.

Barbiturates are substituted derivatives ofbarbituric acid (malonyl urea). They have variablelipid solubility, the more lipid soluble ones aremore potent and shorter acting. They are insolublein water but their sodium salts dissolve yieldinghighly alkaline solution.


Barbiturates are general depressants for allexcitable cells, the CNS is most sensitive wherethe effect is almost global, but certain areas aremore susceptible.

1. CNS Barbiturates produce dose-dependenteffects:

sedation → sleep → anaesthesia → coma.

Hypnotic dose shortens the time taken to fallasleep and increases sleep duration. The sleep isarousable, but the subject may feel confused andunsteady if waken early. REM and stage 3, 4 sleepare decreased; REM-NREM sleep cycle is dis-rupted. The effects on sleep become progressivelyless marked if the drug state given every nightconsecutively. A rebound increase in REM sleepand nightmares is often noted when the drug isdiscontinued after a few nights of use. Hangover(dizziness, distortions of mood, irritability andlethargy) may occur in the morning after a nightlydose.

Sedative dose (smaller dose of a longer actingbarbiturate) given at daytime can producedrowsiness, reduction in anxiety and excitability.However, barbiturates do not have selective anti-anxiety action. They can impair learning, short-term memory and judgement, and have no anal-gesic action; small doses may even cause hyper-algesia. Euphoria may be experienced by addicts.

Barbiturates have anticonvulsant property.The 5-phenyl substituted agents (phenobarbitone)have higher anticonvulsant : sedative ratio, i.e.they have specific anticonvulsant action.

Fig. 9.1: A normal sleep cycle

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Barbiturates depress all areas of the CNS, butreticular activating system is the most sensitive;its depression is primarily responsible forinability to maintain wakefulness.

Mechanism of action Barbiturates appear to actprimarily at the GABA : BZD receptor–Cl¯channel complex (see Fig. 9.2) and potentiateGABAergic inhibition by increasing the lifetimeof Cl¯ channel opening induced by GABA. Theydo not bind to the BZD receptor, but bind toanother site on the same macromolecular complexto exert the GABA-facilitatory action. At highconcentrations, barbiturates directly increase Cl¯conductance (GABA-mimetic action; contrastBZDs which have only GABA-facilitatory action)and inhibit Ca2+ dependent release of neurotrans-mitters. In addition, they depress glutamate-induced neuronal depolarization through AMPAreceptors (a type of excitatory amino acidreceptors). At very high concentrations, barbitu-rates depress Na+ and K+ channels directly.

2. Other systemsRespiration is depressed by relatively higher doses.Barbiturates do not have selective antitussiveaction.

Hypnotic doses of barbiturates produce aslight decrease in BP and heart rate: magnitudeof change not differing from that during normalsleep. Toxic doses produce marked fall in BP dueto ganglionic blockade, vasomotor centre depres-sion and direct decrease in cardiac contractility.However, the dose producing cardiac arrest isabout 3 times larger than that causing respiratoryfailure.

Tone and motility of bowel is decreasedslightly by hypnotic doses; more profoundlyduring intoxication.

Barbiturates tend to reduce urine flow bydecreasing BP and increasing ADH release.

Pharmacokinetics

Barbiturates are well absorbed from the g.i. tract. They arewidely distributed in the body. The rate of entry into CNSis dependent on lipid solubility: highly lipid solublethiopentone has practically instantaneous entry while lesslipid soluble ones (pentobarbitone) take longer; phenobar-

bitone enters very slowly. Plasma protein binding varieswith the compound, e.g. thiopentone 75%, phenobarbitone20%.

Three processes are involved in termination of actionof barbiturates: the relative importance of each varies withthe compound.

(a) Redistribution It is important in the case of highlylipid soluble thiopentone and other ultrashort actingbarbiturates. After their i.v. injection, consciousness isregained in 6–10 min due to redistribution (see Ch. 2),while the ultimate disposal occurs by metabolism (t½ ofelimination phase is 9 hours).

(b) Metabolism Drugs with intermediate lipid solubility(short acting barbiturates) are primarily metabolized inliver by oxidation, dealkylation and conjugation. Theirplasma t½ ranges from 12–40 hours.

(c) Excretion Barbiturates with low lipid solubility (longacting agents) are significantly excreted unchanged in urine.The t½ of phenobarbitone is 80–120 hours. Alkalinizationof urine increases ionization and excretion. This is mostsignificant in the case of long acting agents.

Barbiturates induce hepatic microsomal enzymes andincrease the rate of their own metabolism as well as that ofmany other drugs.

Uses

Except for phenobarbitone in epilepsy and thio-pentone in anaesthesia, barbiturates are seldomused now. They are occasionally employed asadjuvants in psychosomatic disorders.

Adverse effects

Side effects Hangover, mental confusion, impairedperformance and traffic accidents.

Idiosyncrasy In an occasional patient barbituratesproduce excitement.

Hypersensitivity Rashes, swelling of eyelids, lips, etc.

Tolerance and dependence Both cellular and pharmaco-kinetic tolerance develops on repeated use.

Psychological as well as physical dependence occursand barbiturates have considerable abuse liability—oneof their major disadvantages. Withdrawal symptomsare—excitement, hallucinations, delirium, convulsions;deaths have occurred.

Acute barbiturate poisoningManifestations are due to excessive CNS depression—patient is flabby and comatose with shallow and failingrespiration, fall in BP and cardiovascular collapse, renalshut down, pulmonary complications, bullous eruptions.

Lethal dose depends on lipid solubility. It is 2–3 g forthe more lipid soluble agents (short acting barbiturates)and 5–10 g for less lipid soluble phenobarbitone.

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TreatmentGastric lavage; supportive measures such as patentairway, assisted respiration, oxygen, maintenance of bloodvolume by fluid infusion and use of vasopressors.Alkaline diuresis: with mannitol and sodium bicarbonatein the case of long acting barbiturates only. Haemodialysisand haemoperfusion is highly effective in removing longacting as well as short acting barbiturates.

There is no specific antidote for barbiturates. Theapproach is to keep the patient alive till the poison hasbeen eliminated.

Interactions

1. Barbiturates induce the metabolism of manydrugs and reduce their effectiveness—warfarin,steroids (including contraceptives), tolbutamide,griseofulvin, chloramphenicol, theophylline.2. Additive action with other CNS depressants—alcohol, antihistamines, opioids, etc.3. Sodium valproate increases plasma concen-tration of phenobarbitone.4. Phenobarbitone competitively inhibits as wellas induces phenytoin and imipramine meta-bolism: complex interaction.5. Phenobarbitone decreases absorption ofgriseofulvin from the g.i.t.

BENZODIAZEPINES (BZDs)

Chlordiazepoxide and diazepam were intro-duced around 1960 as antianxiety drugs. Sincethen, this class has proliferated and has gainedpopularity over barbiturates as hypnotic andsedative as well, because—1. BZDs have a high therapeutic index. Inges-tion of even 20 hypnotic doses does not usuallyendanger life.2. Hypnotic doses do not affect respiration orcardiovascular functions.3. BZDs have practically no action on other bodysystems. Only on i.v. injection the BP falls andcardiac contractility decreases.4. BZDs cause less distortion of sleep architec-ture.5. BZDs do not alter disposition of other drugsby microsomal enzyme induction.6. They have lower abuse liability: tolerance ismild, psychological and physical dependenceand withdrawal syndrome are less marked.

7. A specific BZD antagonist flumazenil has beendeveloped which can be used in case of poisoning.

CNS actions The overall action of all BZDs isqualitatively similar, but there are prominentdifferences in selectivity and time course of action:different members are used for different purposes.In contrast to barbiturates, they are not generaldepressants, but exert relatively selective anxio-lytic, hypnotic, muscle relaxant and anticon-vulsant effects. Even when apparently anaestheticdose of diazepam is administered i.v., some degreeof awareness is maintained.

They hasten onset of sleep, reduce intermittentawakening and increase total sleep time. Timespent in stage 2 is increased while that in stage3 and 4 is decreased. They tend to shortenREM phase, but effect is less marked than withbarbiturates. Most subjects wake up with a feelingof refreshing sleep. Some degree of tolerancedevelops to the sleep promoting action of BZDsafter repeated nightly use.

Given i.v., diazepam causes analgesia. Incontrast to barbiturates, BZDs do not producehyperalgesia. They also produce centrallymediated skeletal muscle relaxation and exertanticonvulsant activity (see p. 131 and 147).

Other actions Diazepam decreases nocturnalgastric secretion and prevents stress ulcers. BZDsdo not significantly affect bowel movement.

Site and mechanism of actionBenzodiazepines act preferentially on midbrainascending reticular formation (which maintainswakefulness) and on limbic system (thought andmental functions). Muscle relaxation is producedby a primary medullary site of action and ataxiais due to action on cerebellum.

BZDs act by enhancing presynaptic/post-synaptic inhibition through a specific BZDreceptor which is an integral part of the GABAA

receptor–Cl¯ channel complex. The subunits ofthis complex form a pentameric transmembraneanion channel (Fig. 9.2) gated by the primaryligand (GABA), and modulated by secondaryligands which include BZDs. The modulatoryBZD receptor increases the frequency of Cl¯

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channel opening induced by submaximalconcentrations of GABA. The GABAA antagonistbicuculline antagonizes BZD action in a non-competitive manner. It is noteworthy that theBZDs do not themselves increase Cl¯ conduc-tance; have only GABA facilitatory but no GABAmimetic action. This probably explains the lowerceiling CNS depressant effect of BZDs.The BZD receptor exhibits a considerable degree ofconstitutive activation. As such, it is capable of fine tuningGABA action in either direction. While the BZD-agonistsenhance GABA induced hyperpolarization (due to influxof Cl¯ ions), and decrease firing rate of neurones, othercompounds called BZD-inverse agonists like dimethoxy-ethyl-carbomethoxy-β-carboline (DMCM) inhibit GABAaction and are convulsants. The competitive BZD-antagonist flumazenil blocks the sedative action of BZDsas well as the convulsant action of DMCM.

Recently, several subtypes of the BZD receptor have beendescribed which may explain the differing pharmacologicalprofile of individual BZD compounds.

Pharmacokinetics

There are marked pharmacokinetic differencesamong BZDs because they differ in lipid solubilityby > 50-fold. Oral absorption of some is rapidwhile that of others is slow. Absorption from i.m.sites is irregular except for lorazepam. Plasmaprotein binding also varies markedly (flurazepam10% to diazepam 99%). BZDs are widelydistributed in the body. The more lipid solublemembers enter brain rapidly and have a twophase plasma concentration decay curve; first dueto distribution and later due to elimination. Arelatively short duration of action is obtained withsingle dose of a drug that is rapidly redistributed,even though it may have a long elimination t½.Using the elimination t½ alone to predict durationof action may be misleading. However, elimi-nation t½ determines duration of action in case of

Fig. 9.2: Schematic depiction of GABAA-benzodiazepine receptor-chloride channel complex The chloride channel is gated by the primary ligand GABA. The benzodiazepine (BZD) receptor modulates GABAA

receptor in either direction : agonists like diazepam facilitate, while inverse agonists like DMCM hinder GABA mediated Cl¯channel opening, and BZD antagonist flumazenil blocks the action of both. The barbiturate receptor, located elsewhere,also facilitates GABA and is capable of opening Cl¯ channel directly as well. Bicuculline blocks GABAA receptor, whilepicrotoxine blocks the Cl¯ channel directly



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Table 9.1: Some pharmacokinetic and clinical features of benzodiazepines used as hypnotics

Drug t½ (hr)* Redistribution$ Hypnotic Clinical indicationsdose (mg)

I. LONG ACTINGFlurazepam 50–100 – 15–30 Chronic insomnia, short-term insomniaDiazepam 30–60 + 5–10 with anxiety; Frequent nocturnal awakening;Nitrazepam 30 ± 5–10 Night before operation or dental procedure

II. SHORT ACTINGAlprazolam 12 + 0.25-0.5 Individuals who react unfavourably toTemazepam 8–12 + 10–20 unfamiliar surroundings or unusual timingsTriazolam 2–3 - 0.125–0.25 of sleep. Sleep onset difficulties.

* t½ of elimination phase, including that of active metabolite$ + indicates that redistribution contributes to termination of action of single dose

drugs whose elimination is by far the dominantfeature or when the drug is given repeatedly.

Benzodiazepines are metabolized in liver bydealkylation and hydroxylation to many meta-bolites, some of which may be active. Thebiological effect half-life of these drugs may belonger than the plasma t½ of the administeredcompound. Some BZDs (e.g. diazepam) undergoenterohepatic circulation. BZDs and their phaseI metabolites are excreted in urine as glucuronideconjugates. BZDs cross placenta and are secretedin milk.

Drugs with a long t½ or those which generateactive metabolites cumulate on nightly use; theiraction may then extend into the next day. Somefeatures of BZDs used as hypnotic are given inTable 9.1.

Adverse effects

Benzodiazepines are relatively safe drugs. Sideeffects of hypnotic doses are dizziness, ataxia,disorientation, amnesia, prolongation of reactiontime—impairment of psychomotor skills (shouldnot drive). Hangover is less common. Weakness,blurring of vision, dry mouth and urinaryincontinence are sometimes complained. Like anyhypnotic, BZDs can aggravate sleep apnoea.

Tolerance to the sedative effects developsgradually, but there is little tendency to increasethe dose. Cross tolerance to alcohol and otherCNS depressants occurs.

The dependence producing liability of BZDsis low. They are seldom abused alone. Drugabusers find them rather bland and prefer otherCNS depressants. Withdrawal syndrome isgenerally mild. Drug seeking behaviour is notprominent. Anxiety, insomnia, restlessness,malaise, loss of appetite, bad dreams is all thatoccurs in most cases. Agitation, panic reaction,tremors and delirium are occasional; convulsionsare rare.

Interactions

BZDs synergise with alcohol and other CNSdepressants leading to excessive impairment.Concurrent use with sod. valproate has provokedpsychotic symptoms.

Drug interactions due to microsomal enzymeinduction are not significant.

Action of BZDs can be prolonged by CYP 3A4inhibitors like ketoconazole, erythromycin andothers. Cimetidine, isoniazid and oral contra-ceptives also retard BZD metabolism.

NON-BENZODIAZEPINE HYPNOTICS

Zopiclone This newer cyclopyrrolone hypno-tic is an agonist at a subtype of BZD receptorinvolved in the hypnotic action. The effect on sleepresemble those of BZDs, but it does not alter REMsleep and tends to prolong stages 3 and 4. It isreported not to disturb sleep architecture; butsome degree of next morning impairment can

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occur. Zopiclone has been used to weanoffinsomniacs taking regular BZD medication. Itst½ is 5-6 hours.

Zopiclone is indicated for short-term treatmentof insomnia.

Zolpidem An imidazopyridine which pre-ferentially acts on a subtype of BZD receptors thatare important in mediating hypnotic effect . Onlysome BZD like actions but not others areprominent. Hypnotic effect is pronounced, butanticonvulsant, muscle relaxant and antianxietyeffects are not evident. Its advantages are: relativelack of effect on sleep stages; minimal residualdaytime sedation and fading of hypnotic actionon repeated nightly use; no/little reboundinsomnia on discontinuation; near absence oftolerance or physical dependence and low abusepotential combined with safety in overdose likeBZDs. The t½ is short (2 hr).

Zaleplon This is the shortest acting of the newernon-BZD hypnotics that selectively act on a subsetof BZD receptors which appear to mediate thehypnotic action. It is rapidly absorbed and rapidlycleared by hepatic metabolism with a t½ of 1 hour.As such, it is effective only in sleep-onsetinsomnia; does not prolong total sleep time orreduce the number of awakenings. Because ofbrevity of action, it can be taken late at nightwithout causing morning sedation. No toleranceor dependence has been reported and hypnoticeffect does not fade on nightly use. However, itsuse should be limited to 1-2 weeks.

USES

Currently, BZDs are one of the most frequentlyprescribed drugs. They have also been combinedwith many other categories of drugs with a viewto improve efficacy by relieving attendant anxiety.

1. As hypnotic When indicated, BZDs are thehypnotic of choice and the newer non-BZDcompounds zopiclone, zolpidem or zaleplon arealso being used.

Insomnia arises under a variety of circum-stances. It could be a long term (months-years),

short term (weeks) or transient (a day or two,mostly situational) problem.

Dentists are likely to need to prescribe ahypnotic either to ensure sleep night before thedental procedure in an apprehensive patient, orto supplement analgesics before and after dentalsurgery. A longer acting BZD, like diazepam, ismostly preferred. Because of rapid onset of actionoral zolpidem can be given to anxious patients inthe dentist’s office before carrying out the dentalprocedure.

2. Other uses• As anxiolytic and for daytime sedation.• As anticonvulsant, especially emergency con-

trol of status epilepticus, febrile convulsions,tetanus, etc.

• As centrally acting muscle relaxant formuscular spasms.

• For preanaesthetic medication, i.v. anaes-thesia or conscious sedation.

• Alcohol withdrawal in dependent subjects.• Along with analgesics, NSAIDs, spasmolytics,

antiulcer and many other drugs.

BENZODIAZEPINE ANTAGONIST

Flumazenil It is a BZD analogue which haslittle intrinsic activity (practically no effect onnormal subjects), but competes with BZD agonistsas well as inverse agonists for the BZD receptorand reverses their depressant or stimulant effectsrespectively.

Flumazenil abolishes the hypnogenic, psycho-motor, cognitive and EEG effects of BZDs. On i.v.injection action of flumazenil starts in secondsand lasts for 1–2 hr; elimination t½ is 1 hr. It hasbeen used to reverse the effect of BZD employedfor i.v. anaesthesia or conscious sedation, and asan antidote for BZD overdose/poisoning.

ETHYL ALCOHOL (Ethanol)

Alcohols are hydroxy derivatives of aliphatichydrocarbons. When unqualified, ‘alcohol’ refersto ethyl alcohol or ethanol. Pharmacology of alcoholis important for its presence in beverages (which



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have been used since recorded history) and foralcohol intoxication, rather than as a drug.


Local actions Ethanol is a mild rubefacient andcounterirritant when rubbed on skin. By eva-poration it produces cooling. Applied to delicateskin (scrotum) or mucous membranes (oralmucosa) it produces irritation and burningsensation: should not be applied in the mouth.Injected s.c. it causes intense pain, inflammationand necrosis followed by fibrosis. Injected arounda nerve it produces permanent damage.

Alcohol is an astringent—precipitates surfaceproteins and hardens skin. By precipitatingbacterial proteins it acts as an antiseptic. Theantiseptic action increases with concentrationfrom 20 to 70%, remains constant from 70 to 90%and decreases above that.

CNS Alcohol is a neuronal depressant. Sincethe highest areas are most easily deranged andthese are primarily inhibitory—apparent exci-tation and euphoria are experienced at lowerplasma concentrations (30–100 mg/dl). Hesita-tion, caution, self-criticism and restraint are lostfirst. Mood and feelings are altered; anxietymay be allayed. With increasing concentration(100–150 mg/dl) mental clouding, disorganiza-tion of thought, impairment of memory and otherfaculties, alteration of perception and drowsinesssupervene. At 150–200 mg/dl the person issloppy, ataxic and drunk; 200–300 mg/dl resultin stupor and above this unconsciousnessprevails, medullary centres are paralysed anddeath may occur. Though alcohol can produceanaesthesia, margin of safety is narrow.

Any measurable concentration of alcohol pro-duces a measurable slowing of reflexes: drivingis dangerous. Performance is impaired, fine dis-crimination and precise movements are oblitera-ted; errors increase.

Alcohol can induce sleep but is not adependable hypnotic. Some individuals reportpoor quality of sleep and early morning awaken-ing. Sleep architecture may be disorganized andsleep apnoea aggravated. It raises pain thresholdand also alters reaction to it, but is not a depen-dable analgesic—severe pain can precipitateconfusion and convulsions. During the timealcohol is acting on brain, it exerts anticonvulsantaction, but this is followed by lowering of seizurethreshold: seizures may be precipitated inepileptics. Chronic alcohol abuse damages brainneurones.

Other actions Alcohol affects many bodyfunctions in a dose-dependent manner.1. Vasodilatation, flushing, tachycardia, mildrise in BP at low doses (due to sympatheticstimulation), but fall in BP at high levels (due tovasodilatation, cardiac and vasomotor centredepression).2. Respiratory centre is depressed at highconcentrations.3. Though alcohol is reputed to combat coldbecause it produces a sense of warmth due tocutaneous vasodilatation, heat loss is actuallygreater in cold surroundings.4. Dilute alcohol (10%) stimulates gastricsecretion, but high concentrations inhibit it andcause mucosal congestion progressing to gastritis.Gastroesophageal reflux is worsened due todecrease in the tone of lower esophagealsphincter. Bowel movement may be altered.5. Moderate amounts of alcohol do not causeliver damage in well nourished individuals, butchronic alcoholism along with nutritional defi-ciencies may cause alcoholic cirrhosis of liver.6. Regular intake of small to moderate amountsof alcohol raises HDL-cholesterol level: risk ofcoronary artery disease is reduced by 15–35%.7. Urine flow may increase due to inhibition ofADH secretion.

Alcohol : conscious anaesthesia death.

Ether : conscious anaesthesia death.

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8. Though reputed as an aphrodisiac, alcoholactually impairs performance of sexual act.9. Uterine contractions are dampened atmoderate blood levels.10. Hyperglycaemia (due to Adr release) occursinitially, but high levels deplete hepatic glycogenand cause hypoglycaemia.

PHARMACOKINETICS

Though some alcohol is absorbed from stomach,very rapid absorption occurs when it reachesduodenum and small intestine. Limited first passmetabolism takes place in stomach wall and inliver. Alcohol gets distributed widely in the body(vol of distribution 0.7 L/kg), crosses blood-brainbarrier efficiently: concentration in brain is verynear blood concentration. It also crosses placentafreely. It is oxidized in liver to the extent of 98%.Even with high doses, not more than 10% escapesmetabolism.

Alcohol AldehydeEthyl Acetaldehyde Acetate CO2+alcohol dehydro- dehydro- H2O

genase genase

Metabolism of alcohol follows zero order kinetics,i.e. a constant amount (8–12 ml of absolutealcohol/hour) is degraded in unit time,irrespective of blood concentration. Thus, rate ofconsuming drinks governs whether a person willget drunk.

Excretion occurs though kidney and lungs,but neither is quantitatively significant. Concen-tration in exhaled air is about 0.05% of bloodconcentration: this is utilized for medicolegaldetermination of drunken state. The subject blowsin a balloon and alcohol is measured by a portablebreath analyser.

INTERACTIONS

1. Alcohol synergises with tranquilizers, anti-depressants, antihistaminics, hypnotics,opioids → marked CNS depression withmotor impairment can occur: Chances ofaccidents increase.

2. Individuals taking sulfonylureas (especiallychlorpropamide), certain cephalosporins(cefoperazone) or metronidazole have expe-rienced bizarre, somewhat disulfiram likereactions when they consume alcohol.

3. Acute alcohol ingestion inhibits, while chro-nic intake induces tolbutamide, phenytoin(and many other drugs) metabolism.

4. Insulin and sulfonylureas: alcohol enhanceshypoglycaemia acutely.

5. Aspirin and other NSAIDs cause more gastricbleeding when taken with alcohol.

6. Alcoholics are more prone to paracetamoltoxicity due to enhanced generation of its toxicmetabolite.

FOOD VALUE

Alcohol requires no digestion and is metabolized rapidly.It is an energy yielding substrate: 7 Cal/g, but these cannotbe stored. It also does not supply body building and otheressential constituents of food. Those who consumesubstantial part of their caloric intake as alcohol, oftensuffer from nutritional deficiencies. Thus, alcohol is animperfect and expensive food.

TOXICITY

A. Side effects of moderate drinking Nausea,vomiting, flushing, hangover, traffic accidents.B. Acute alcoholic intoxication Hypotension,gastritis, hypoglycaemia, collapse, respiratorydepression, coma and death.

Treatment: Institute gastric lavage, maintainpatent airway and take steps to prevent aspirationof vomitus. Positive pressure respiration may beneeded if it is markedly depressed. Most patientswill recover with supportive treatment, mainte-nance of fluid and electrolyte balance andcorrection of hypoglycaemia by glucose infusiontill alcohol is metabolized.

C. Chronic alcoholism On chronic intake,tolerance develops to subjective and behavioraleffects of alcohol, but is generally of a low degree.It is both pharmacokinetic (reduced rate ofabsorption due to gastritis and faster metabolismdue to enzyme induction) and cellular tolerance.

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Psychic dependence often occurs even withmoderate drinking; depends a lot on individual’slikings and attitudes.

Physical dependence occurs only on heavyand round-the-clock drinking (if alcohol ispresent in the body continuously). Heavydrinking is often associated with nutritionaldeficiencies, because food is neglected andmalabsorption may occur. In addition to impairedmental and physical performance, neurologicalafflictions are common—polyneuritis, pellagra,tremors, seizures, loss of brain mass, Wernicke’sencephalopathy, Korsakoff’s psychosis andmegaloblastic anaemia. Alcoholic cirrhosis ofliver, hypertension, cardiomyopathy, CHF,arrhythmias, stroke, acute pancreatitis, impo-tence, gynaecomastia, infertility and skeletalmyopathy are other complications. Incidence oforopharyngeal, esophageal and hepatic malig-nancy and respiratory infections is high; immunefunction is depressed.

Dental implications Alcoholics have higherincidence of heavy dental plaque, calculusdeposits, chronic periodontitis and tooth loss dueto poor oral hygiene. Dentists, while prescribingmetronidazole or certain cephalosporins for perio-dontal infections should warn patients not to drink.Concurrent ingestion of NSAIDs and alcohol shouldbe prohibited.

Treatment: Psychological and medical suppor-tive measures are needed during withdrawal.Substitution therapy with BZDs like diazepamor chlordiazepoxide is given to suppresswithdrawal syndrome, followed by their gradualdiscontinuation. The long acting opioid anta-gonist naltrexone helps to prevent relapse ofalcoholism.Disulfiram It is an aldehyde dehydrogenase inhibitorwhich prevents further oxidation of acetaldehyde generatedfrom ingested alcohol. As a result, when the subject drinksa small quantity of alcohol after taking disulfiram, heexperiences distressing symptoms like flushing, burningsensation, throbbing headache, sweating, uneasiness,tightness in chest, vomiting, etc. (aldehyde syndrome).This has been used as an aversion technique in chronicalcoholics who have been motivated and have stopped

drinking. However, because of risk of severe reaction, it israrely employed.

CLINICAL USES

Medicinal uses of ethanol are primarily restrictedto external application and as a vehicle for liquidpreparations used internally.1. As antiseptic and disinfectant: because of good

cleansing property and that it evaporateswithout leaving any residue, alcohol is used todisinfect working surfaces in dentistry. Beingirritant, it is not suitable for application to oralmucosa.

2. Rubefacient and counterirritant for sprains,joint pains, etc.

3. Rubbed into the skin to prevent (but not totreat) bedsores. Astringent action of alcoholis utilized in antiperspirant and aftershavelotions.

4. Alcoholic sponges to reduce body tempera-ture in fever.

5. Intractable neuralgias (trigeminal and others),severe cancer pain—injection of alcoholaround the nerve causes permanent loss oftransmission.

6. To ward off cold—may benefit by causingvasodilatation of blanched mucosae.

7. As appetite stimulant and carminative.8. To treat methanol poisoning.

METHYL ALCOHOL (Methanol, Wood alcohol)

Methyl alcohol is added to rectified spirit to render it unfitfor drinking. It is only of toxicological importance.Unscrupulous mixing of methylated spirit with alcoholicbeverages or its inadvertent ingestion results in methanolpoisoning.

Methanol is metabolized to formaldehyde and formicacid by alcohol and aldehyde dehydrogenases respectively,but the rate is 1/7th that of ethanol. Like ethanol, it followszero order kinetics and t½ of 20–60 hours has beenmeasured.

Methanol also is a CNS depressant, but less potentthan ethanol. Toxic effects of methanol are largely due toformic acid, since its further metabolism is slow and folatedependent.

Manifestations of methanol poisoning are vomiting,headache, epigastric pain, uneasiness, dyspnoea, brady-cardia and hypotension. Delirium may occur and thepatient may suddenly pass into coma. Acidosis is

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prominent and entirely due to production of formic acid.The specific toxicity of formic acid is retinal damage.Blurring of vision, congestion of optic disc followed byblindness always precede death which is due to respiratoryfailure.

Treatment

1. Keep the patient in a quiet, dark room; protect theeyes from light.

2. Gastric lavage with Sod. bicarbonate, supportivemeasures to maintain ventilation and BP.

3. Combat acidosis by i.v. Sod. bicarbonate infusion—themost important measure; prevents retinal damageand other symptoms.

4. Pot. chloride infusion is needed only when hypo-kalaemia occurs due to alkali therapy.

5. Ethanol retards methanol metabolism. This helps byreducing the rate of generation of toxic metabolites.

6. Haemodialysis: clears methanol as well as its toxicmetabolite formate and hastens recovery.

7. Fomepizole (4-methylpyrazole) is a specific inhibitorof alcohol dehydrogenase—retards methanol meta-bolism. It has several advantages over ethanol, but isnot available commercially.

8. Folate therapy: Calcium leucovorin injected repeatedlyhas been shown to reduce blood formate levels byenhancing its metabolism.

ANTIEPILEPTIC DRUGS

Epilepsies These are a group of disorders ofthe CNS characterized by paroxysmal cerebraldysrhythmia, manifesting as brief episodes(seizures) of loss or disturbance of consciousness,with or without characteristic body movements(convulsions), sensory or psychiatric phenomena.Epilepsy has a focal origin in the brain,manifestations depend on the site of the focus,regions into which the discharges spread andpostictal depression of these regions. Epilepsieshave been classified variously; major types are:

1. Generalised seizures

1. Generalised tonic-clonic seizures (GTCS, major epi-lepsy, grand mal): commonest, lasts 1–2 min.The usual sequence is aura—cry—unconsciousness—tonicspasm of all body muscles—clonic jerking followed byprolonged sleep and depression of all CNS functions.

2. Absence seizures (minor epilepsy, petit mal):prevalent in children, lasts about 1/2 min.Momentary loss of consciousness, patient apparentlyfreezes and stares in one direction, no muscular component

or little bilateral jerking. EEG shows characteristic 3 cyclesper second spike and wave pattern.

3. Atonic seizures (Akinetic epilepsy): Unconsciousnesswith relaxation of all muscles due to excessive inhibitorydischarges. Patient may fall.

4. Myoclonic seizures Shock-like momentary contrac-tion of muscles of a limb or the whole body.

II. Partial seizures

1. Simple partial seizures (SPS, cortical focal epilepsy):lasts 1/2–1 min. Often secondary. Convulsions areconfined to a group of muscles or localized sensorydisturbance depending on the area of cortex involved inthe seizure, without loss of consciousness.

2. Complex partial seizures (CPS, temporal lobe epilepsy,psychomotor): attacks of bizarre and confused behaviourand purposeless movements, emotional changes lasting 1–2 min along with impairment of consciousness. An aura oftenprecedes. The seizure focus is located in the temporal lobe.

3. Simple partial or complex partial seizures secondarilygeneralized The partial seizure occurs first and evolvesinto generalized tonic-clonic seizures with loss ofconsciousness.

Most of the cases are primary (idiopathic), somemay be secondary to trauma/surgery on head,intracranial tumour, tuberculoma, cysticercosis,cerebral ischaemia, etc. Treatment is symptomaticand the same whether epilepsy is primary orsecondary.

CLASSIFICATION

1. Barbiturate Phenobarbitone2. Deoxybarbiturate Primidone3. Hydantoin Phenytoin4. Iminostilbene Carbamazepine

Oxcarbazepine5. Succinimide Ethosuximide6. Aliphatic carboxylic Valproic acid

acid (sodium valproate)Divalproex

7. Benzodiazepines Clonazepam,Diazepam,LorazepamClobazam

8. Phenyltriazine Lamotrigine9. Cyclic GABA analogue Gabapentin

Pregabalin

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10. Newer drugs Vigabatrin,TopiramateZonisamideLevetiracetam

PhenobarbitonePhenobarbitone is the first efficacious anti-epileptic introduced in 1912. Enhancement ofGABAA receptor mediated synaptic inhibitionappears to be its most important mechanism ofsedative as well as anticonvulsant action.Phenobarbitone has specific anticonvulsantactivity which is not entirely dependent on generalCNS depression. This may be due to its lessmarked effect on Ca2+ channels and glutamaterelease compared to hypnotic barbiturates. Withcontinued use of phenobarbitone sedation wanesoff but not the anticonvulsant action.

The major drawback of phenobarbitone as anantiepileptic is its sedative action. Long-termadministration (as needed in epilepsy) mayproduce additional side effects like—behavioralabnormalities, diminution of intelligence, impair-ment of learning and memory, hyperactivity inchildren, mental confusion in older people.

Uses Phenobarbitone is one of the cheapest andleast toxic antiepileptics. It has broad-spectrumefficacy in generalized tonic-clonic (GTC), simplepartial (SP) and complex partial (CP) seizures:but is less popular than carbamazepine, pheny-toin or valproate.

Status epilepticus: Phenobarbitone may be injectedi.m. or i.v. but response is slow to develop.It is not effective in absence seizures.

Primidone A deoxybarbiturate, converted byliver to phenobarbitone and phenylethyl malona-mide (PEMA). Activity is mainly due to these activemetabolites. Antiepileptic efficacy and side effectsare similar to phenobarbitone. However, it maycontrol seizures in some patients refractory toother drugs.

Phenytoin (Diphenylhydantoin)

Phenytoin is a major antiepileptic drug, but is nota CNS depressant; some sedation occurs at

therapeutic doses, that does not increase furtherwith dose; rather toxic doses produce excitement.Tonic-clonic epilepsy is suppressed but paroxys-mal focal EEG discharge and ‘aura’ persist.

Mechanism of action: Phenytoin has a stabili-zing influence on neuronal membrane—preventsrepetitive detonation of normal brain cells during‘depolarization shift’. This is achieved by pro-longing the inactivated state of voltage sensitiveneuronal Na+ channel (Fig. 9.3) that governs therefractory period of the neurone. As a result, highfrequency discharges are inhibited with little effecton normal low frequency discharges. Intracel-lular accumulation of Na+ that occurs duringrepetitive firing is prevented.

Its ability to selectively inhibit high frequencyfiring confers efficacy in trigeminal neuralgia aswell.

Pharmacokinetics Absorption of phenytoin byoral route is slow, and it is 80–90% bound toplasma proteins.

Phenytoin is metabolized in liver by hydroxy-lation and glucuronide conjugation. The kineticsof metabolism is capacity limited; changes fromfirst order to zero order over the therapeuticrange—small increments in dose produce dispro-portionately high plasma concentrations. The t½(normally 12–24 hr) progressively increases (upto 60 hr) when plasma concentration rises.

Adverse effects These are numerous; someoccur at therapeutic plasma concentration afterprolonged use, while others are a manifestationof toxicity due to overdose.

At therapeutic levels(a) Gum hypertrophy: Commonest (20% inci-

dence), more in younger patients and is dueto overgrowth of gingival collagen fibres. Itcan be minimized by maintaining good oralhygiene. In some patients it may be so massiveas to require surgery.

(b) Hirsutism, coarsening of facial features(troublesome in young girls), acne.

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Fig. 9.3: Major mechanisms of anticonvulsant actionm: Activation gate; h: Inactivation gate; GAT-1: GABA transporter;

GABA-T: GABA transaminase; SSA: Succinic semialdehyde

(c) Hypersensitivity reactions are—rashes, DLE,lymphadenopathy; neutropenia is rare butrequires discontinuation of therapy.

(d) Megaloblastic anaemia: phenytoin decreasesfolate absorption and increases its excretion.

(e) Osteomalacia(f) Used during pregnancy—can produce foetal

hydantoin syndrome (hypoplastic phalanges,cleft palate, hare lip, microcephaly).

At high plasma levels (dose-related toxicity)(a) Cerebellar and vestibular manifestations:

ataxia, vertigo, diplopia, nystagmus are themost characteristic features.

(b) Drowsiness, behavioral alterations, mentalconfusion and hallucinations.

(c) Epigastric pain, nausea and vomiting.

Interactions Phenobarbitone competitivelyinhibits phenytoin metabolism, while by enzyme

induction both enhance each other’s degra-dation—unpredictable overall interaction.

• Carbamazepine and phenytoin increase eachother’s metabolism.

• Valproate displaces protein bound phenytoinand decreases its metabolism: plasma level ofunbound phenytoin increases.

• Chloramphenicol, isoniazid, cimetidine, dicu-marol, and warfarin inhibit phenytoin meta-bolism—can precipitate its toxicity.

• Phenytoin induces microsomal enzymes andincreases degradation of steroids (failure of oralcontraceptives), doxycycline, theophylline.

Uses Phenytoin is one of the most widely usedantiepileptic drugs for—1. Generalized tonic-clonic, simple and comp-lex partial seizures. It is ineffective in absenceseizures.



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2. Status epilepticus: occasionally used by slowi.v. injection.3. Trigeminal neuralgia: second choice drug tocarbamazepine.

Fosphenytoin This water soluble prodrug ofphenytoin has replaced phenytoin for i.v. use,because it is less damaging to the intima of thevein.

Carbamazepine

Chemically related to imipramine, it was intro-duced in the 1960s for trigeminal neuralgia; isnow a first line antiepileptic drug. Its pharmacolo-gical actions resemble phenytoin but manydifferences have been noted. Though its actionon Na+ channels (prolongation of inactivatedstate) is similar to phenytoin, the profile of actionon neuronal systems in brain is different.

Carbamazepine has a therapeutic effect inmood disorders and an antidiuretic action,probably by enhancing ADH action on renaltubules.

Oral absorption of carbamazepine is slow andvariable. It is 75% bound to plasma proteins andmetabolized in liver by oxidation to an activemetabolite (10-11 epoxy carbamazepine) as wellas by hydroxylation and conjugation to inactiveones. Initially, its plasma t½ is 20–40 hours butdecreases to 10–20 hr on chronic medication dueto autoinduction of metabolism.

Adverse effects Carbamazepine producesdose-related neurotoxicity—sedation, dizziness,vertigo, diplopia and ataxia. Vomiting, diarrhoea,worsening of seizures are also seen with higherdoses.Hypersensitivity reactions are rashes, photosen-sitivity, hepatitis, lupus like syndrome and rarelyagranulocytosis, aplastic anaemia.Increased incidence of minor foetal malforma-tions has been reported. Its combination withvalproate doubles teratogenic frequency.

Interactions Carbamazepine is an enzymeinducer: can reduce efficacy of haloperidol andoral contraceptives. Metabolism of carbamazepine

is induced by phenobarbitone, phenytoin,valproate and vice versa.

Erythromycin, fluoxetine, isoniazid inhibitmetabolism of carbamazepine.

Uses It is the most effective drug for CPS andshares first choice drug status with phenytoin forGTCS and SPS.

Trigeminal and related neuralgias: carbamazepineis the drug of choice. These neuralgias arecharacterized by attacks of high intensity electricshock-like or stabbing pain set off by even trivialstimulation of certain trigger zones in the mouthor on the face. Drugs benefit by interruptingtemporal summation of afferent impulses (by aselective action on high frequency nerve impulses).Carbamazepine is not an analgesic but has a spe-cific action (almost diagnostic) in these neuralgias.About 60% patients respond well. Phenytoin andbaclofen are less efficacious alternatives.Manic depressive illness and acute mania: as analternative to lithium.

Oxcarbazepine This newer congener of carba-mazepine does not generate the epoxide meta-bolite, so that toxic effects and drug interactionsdue to this metabolite are avoided. Indicationsare similar to carbamazepine, but doses requiredare 1½ times larger.

Ethosuximide

It has an entirely different profile of anticonvulsant actionthan phenytoin and is clinically effective only in absenceseizures. The primary action appears to be exerted onthalamocortical system which is involved in the generationof absence seizures. Thalamic neurones exhibit prominent‘T’ (transient) current which is low threshold Ca2+ currentthat amplifies repetitive spikes. Ethosuximide selectivelysuppresses T current without affecting other types of Ca2+

or Na+ currents. It also does not potentiate GABA. Thiscorrelates well with its selective action in absence seizures,which is its only indication.

Valproic acid (Sodium valproate)

It is a broad-spectrum anticonvulsant effective inseveral experimental models of epilepsy.Remarkably, valproate produces little sedationor other central effects. It is effective in partialseizures, GTCS as well as absence seizures.

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Valproate appears to act by multiple mechanisms:(i) A phenytoin-like frequency dependentprolongation of Na+ channel inactivation.(ii) Attenuation of Ca2+ mediated ‘T’ current(ethosuximide like).(iii) Augmentation of release of inhibitory trans-mitter GABA by inhibiting its degradation (byGABA-transaminase).

Adverse effects Toxicity of valproate is low.Anorexia, vomiting, drowsiness, ataxia andtremor are dose-related side effects. However,cognitive and behavioral effects are not pro-minent.Alopecia, curling of hair, and increased bleedingtendency have been observed. The dentist may faceexcess bleeding while executing a dental procedure.A rare but serious adverse effect is fulminanthepatitis; occurs only in children (especially below3 yr age).Used during pregnancy, it has produced neuraltube defects (spina bifida) in the offspring.

Uses Valproic acid is the drug of choice forabsence seizures.It is an alternative/adjuvant drug for GTCS, SPSand CPS.Myoclonic and atonic seizures—control is oftenincomplete, but valproate is the drug of choice.Mania and bipolar illness: as alternative tolithium.

Interactions• Valproate increases plasma levels of phenob-

arbitone by inhibiting its metabolism.• It displaces phenytoin from protein binding

site and decreases its metabolism → pheny-toin toxicity.

• Valproate and carbamazepine induce eachother’s metabolism.

• Concurrent administration of clonazepam andvalproate is contraindicated because absencestatus may be precipitated.

• Foetal abnormalities are more common ifvalproate and carbamazepine are given con-currently.

Divalproex This coordination compound ofvalproic acid with sodium valproate has bettergastric tolerance, but is absorbed more slowly.

Clonazepam

It is a benzodiazepine with prominent anticon-vulsant properties, but is singularly ineffective inGTCS.

Benzodiazepines potentiate GABA inducedCl– influx to produce sedation and the samemechanism has been held responsible for theanticonvulsant property. At large doses, highfrequency discharges are inhibited akin tophenytoin.

The most important side effect of clonazepamis sedation and dullness. Motor disturbances andataxia are dose-related adverse effects.

Clonazepam has been primarily employed inabsence seizures. It is also useful as an adjuvantin myoclonic and akinetic epilepsy. However, itsvalue is limited by development of tolerance.

Clobazam This BZD analogue is generally usedas adjuvant to other antiepileptic drugs inrefractory epilepsy.

Diazepam

It has anticonvulsant activity in a variety ofmodels but is not used for long-term therapy ofepilepsy because of prominent sedative actionand rapid development of tolerance to the anti-epileptic effect. However, administered i.v., it isthe drug of choice for emergency control ofconvulsions, e.g. status epilepticus, tetanus,eclampsia, convulsant drug poisoning, etc.

Rectal instillation of diazepam is the prefer-red therapy for febrile convulsions in children.

Lorazepam Injected i.v., it is an alternative todiazepam for emergency control of seizures withthe advantage of more sustained effect.

Lamotrigine A new anticonvulsant havingcarbamazepine-like action profile. Prolongationof Na+ channel inactivation and suppression ofhigh frequency firing has been demonstrated. In


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addition, it may directly block voltage sensitiveNa+ channels, thus stabilizing the presynapticmembrane and preventing release of excitatoryneurotransmitters, mainly glutamate andaspartate.

Lamotrigine is a broad-spectrum antiepileptic.Initially found useful as add-on therapy inrefractory cases of partial seizures and GTCS, ithas now been shown effective as monotherapyas well. Absence and myoclonic or akineticepilepsy cases have also been successfully treated.

Side effects are sleepiness, dizziness, diplopia,ataxia and vomiting.

Gabapentin This lipophilic GABA derivativecrosses to the brain and enhances GABA release,but does not act as agonist at GABAA receptor.Added to a first line drug, it reduces seizurefrequency in refractory partial seizures with orwithout generalization. Beneficial effects in manicdepressive illness and migraine have also beenreported. Gabapentin is now considered to be thefirst line drug for pain due to diabetic neuropathy,postherpetic and other neuralgias.

Pregabalin This newer congener of gabapentinhas been particularly used for neuropathic pain,

but has similar antiseizure property as well. Itappears to cause less sedation than gabapentin.

Vigabatrin (γ vinyl GABA) It is an inhibitor of GABA-transaminase, the enzyme which degrades GABA. Itsanticonvulsant action may be due to increase in synapticGABA concentration. It is effective in many patients withrefractory epilepsy, especially partial seizures with orwithout generalization. It is used only as adjuvantmedication.

Topiramate This weak carbonic anhydraseinhibitor has broad-spectrum anticonvulsantactivity and appears to act by multiplemechanisms, viz phenytoin-like prolongation ofNa+ channel inactivation, GABA potentiationand antagonism of certain glutamate receptors.

Topiramate is indicated for supplementingprimary antiepileptic drug in refractory SPS, CPSand GTCS. Promising results have been obtainedin myoclonic epilepsy also.

Zonisamide Another newer weak carbonic anhydraseinhibitor with multiple anticonvulsant actions. It isindicated as ‘add on’ therapy for refractory partial seizures.

Levetiracetam This new anticonvulsant drug has aunique profile of action in experimental seizures andlacks all the major anticonvulsant mechanisms of action.It is used as adjuvant medication for refractory partialseizures.

Table 9.2: Choice of antiseizure drugs

Type of seizure First choice drugs Second choice drugs Alternative/Add-on drugs

1. Generalised tonic-clonic/ Carbamazepine, Valproate, Lamotrigine, Gabapentin,simple partial with or Phenytoin Phenobarbitone Topiramatewithout generalization

2. Complex partial with or Carbamazepine, Gabapentin, Clobazam, Zonisamidewithout generalization Valproate, Lamotrigine Topiramate

Phenytoin

3. Absence Valproate Lamotrigine ClobazamClonazepam

4. Myoclonic Valproate Lamotrigine Primidone, Clobazam,Topiramate Clonazepam

5. Atonic Valproate Clonazepam, LamotrigineClobazam

6. Febrile seizures Diazepam (rectal) — —

7. Status epilepticus Diazepam (i.v.) Fosphenytoin (i.v.) Gen. anaestheticsLorazepam (i.v.) Phenobarbitone

(i.v., i.m.)

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TREATMENT OF EPILEPSIES

Antiepileptic drugs suppress seizures but do notcure the disorder; the disease may fade out thoughafter years of successful control. The aim of drugsis to control and totally prevent all seizure activityat an acceptable level of side effects. The cause ofepilepsy should be searched in the patient; iffound and treatable, an attempt to remove itshould be made. Some general principles of sym-ptomatic treatment with antiepileptic drugs are:(i) Choice of drug (Table 9.2) and dose isaccording to the seizure type(s) and need of theindividual patient.(ii) Initiate treatment early, because each seizureepisode increases the propensity to furtherattacks. Start with a single drug, graduallyincrease dose till full control of seizures or sideeffects appear. Use combinations when all reason-able monotherapy fails.

(iii) Therapy should be as simple as possible. Aseizure diary should be maintained.

(iv) All drug withdrawals should be gradual(except in case of toxicity). Prolonged therapy(may be life long, or at least 3 years after the lastseizure) is needed. Withdrawal may be attemptedin selected cases.

(v) Dose regulation may be facilitated by monito-ring of steady-state plasma drug levels.

(vi) When women on antiepileptic therapy con-ceive, antiepileptic drugs should not be stopped.Though most antiseizure drugs have been shownto increase the incidence of birth defects, disconti-nuation of therapy carries a high risk of statusepilepticus. It may be advisable to substitutevalproate and give folic acid supplementation.

(vii) In an epileptic patient dental procedure should becarried out only after ensuring that the patient is underadequate anticonvulsant drug cover.

(viii) In the event of a patient developing an attack oftonic-clonic seizures during dental procedure, the firstpriority is to prevent injuries due to biting or fall. Anydenture or instrument should be immediately removedfrom the mouth and a gag placed between the teeth.

The head should be turned to the side to prevent thetongue from falling back and obstructing the airway.

The seizure usually passes off in a fewminutes. Continuation or postponement of theprocedure after the fit is over depends on thecircumstances. The patient must be sent backhome with an escort. In case the seizures do not stop,management is as for status epilepticus.

Status epilepticus When seizure activity occursfor >30 min, or two or more seizures occur withoutrecovery, it is labelled status epilepticus. Recurrenttonic-clonic convulsions without recovery ofconsciousness is an emergency; fits have to becontrolled as quickly as possible to prevent deathand permanent brain damage.(a) Diazepam 10 mg i.v. bolus injection (2 mg/min) followed by fractional doses every 10 min,or slow infusion titrated to control the fits hasbeen the standard treatment. However, itredistributes rapidly so that anticonvulsant effectstarts fading after 20 min. Lorazepam is less lipidsoluble with slow redistribution: anticonvulsanteffect of i.v. dose lasts for 6-12 hours. It is thereforepreferred; 0.1 mg/kg (injected at 2 mg/min) iseffective in 75-90% cases.(b) Phenobarbitone (100-200 mg i.m./i.v.) orfosphenytoin (maximum 1000 mg phenytoinequivalent) act more slowly; may be usedalternatively to diazepam/lorazepam or substi-tuted for them after the convulsions have beencontrolled.(c) Refractory cases may be treated with i.v.midazolam/propofol/thiopentone anaesthesia,with or without curarization.(d) General measures, including maintenance ofairway (intubation if required), oxygenation, fluidand electrolyte balance, BP, normal cardiacrhythm, euglycaemia and care of the unconsciousmust be taken.

ANTIPARKINSONIAN DRUGS

These are drugs that have a therapeutic effect inparkinsonism.

Parkinsonism It is an extrapyramidal motordisorder characterized by rigidity, tremor and

Antiparkinsonian Drugs 149


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hypokinesia with secondary manifestations likedefective posture and gait, mask-like face andsialorrhoea; dementia may accompany. If untrea-ted, the symptoms progress over several years toendstage disease in which the patient is rigid,unable to move, unable to breathe properly;succumbs mostly to chest infections/embolism.

Parkinson’s disease (PD) is a progressive degenerativedisorder, mostly affecting older people, first described byJames Parkinson in 1817.

The most consistent lesion in PD is degeneration ofneurones in substantia nigra pars compacta and thenigrostriatal (dopaminergic) tract. This results in deficiencyof dopamine (DA) in the striatum which controls muscletone and coordinates movements. An imbalance betweendopaminergic (inhibitory) and cholinergic (excitatory)system in the striatum (Fig. 9.4) occurs giving rise to themotor defect. Though the cholinergic system is notprimarily affected, its suppression (by anticholinergics)tends to restore balance.

Drug-induced temporary parkinsonism due to neuro-leptics, metoclopramide (dopaminergic blockers) is nowfairly common.

CLASSIFICATION

I. Drugs affecting brain dopaminergic system(a) Dopamine precursor : Levodopa (l-dopa)(b) Peripheral decarboxylase inhibitors :

Carbidopa, Benserazide.(c) Dopaminergic agonists: Bromocriptine,

Ropinirole, Pramipexole(d) MAO-B inhibitor: Selegiline(e) COMT inhibitors: Entacapone, Tolcapone(f) Dopamine facilitator: Amantadine.

II. Drugs affecting brain cholinergic system(a) Central anticholinergics : Trihexyphenidyl

(Benzhexol), Procyclidine, Biperiden.(b) Antihistaminics : Orphenadrine,

Promethazine.

LEVODOPA

Levodopa has a specific salutary effect in PD:efficacy exceeding that of any other drug usedalone. It is inactive by itself, but is the immediateprecursor of the transmitter DA. More than 95%of an oral dose is decarboxylated in the peripheraltissues (mainly gut and liver). DA thus formed

acts on heart, blood vessels, other peripheralorgans and on CTZ (though located in the brain,i.e. floor of IV ventricle, it is not bound by blood-brain barrier). About 1–2% of administeredlevodopa crosses to the brain, is taken up by thesurviving dopaminergic neurones, converted toDA which is stored and released as a transmitter.

Actions

1. CNS Levodopa hardly produces any effectin normal individuals. Marked symptomaticimprovement occurs in parkinsonian patients.Hypokinesia and rigidity resolve first, later tremoras well. Secondary symptoms of posture, gait,handwriting, speech, facial expression, mood,self-care and interest in life are graduallynormalized.

The effect of levodopa on behaviour has beendescribed as a ‘general alerting response’. In somepatients this progresses to excitement—frankpsychosis may occur. Embarrassingly dispropor-tionate increase in sexual activity has also beennoted.

2. CVS The peripherally formed DA can causetachycardia by acting on β adrenergic receptors.Postural hypotension due to central andganglionic action is quite common.

3. CTZ The peripherally formed DA gains accessto the CTZ without hindrance—elicits nausea andvomiting by stimulating dopaminergic D2receptors. Tolerance occurs gradually to this action.

4. Endocrine DA acts on pituitary mammotro-pes to inhibit prolactin release → blood prolactinlevel falls.

Pharmacokinetics

Levodopa is rapidly absorbed from the smallintestines by utilizing the active transport processmeant for aromatic amino acids.

It undergoes high first pass metabolism in g.i.mucosa and liver. The peripheral and centralpathway of metabolism of levodopa is depictedin Fig. 9.5.

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Fig. 9.4: Simplified scheme of side loop circuits in the basal ganglia that provide modulatory input to the motor cortex.The striatal GABAergic neurones receive side-loop excitatory glutamatergic (Glu) input from the motor cortex andmodulatory dopaminergic (DA) projections from the substantia nigra pars compacta (SN-PC). There are also balancingcholinergic (ACh) interneurones. The striatal neurones express both excitatory D1 and inhibitory D2 receptors. The outputfrom the striatum to substantia nigra pars reticulata (SN-PR) and internal globus pallidus (GP-I) follows a direct and anindirect pathway. The direct pathway modulated by DI receptors releases inhibitory transmitter GABA, while the dominantindirect pathway modulated by D2 receptors has two inhibitory (GABAergic) relays and an excitatory (glutamatergic)terminal. Due to this arrangement, dopaminergic action in the striatum exerts inhibitory influence on SN-PR and GP-I viaboth the pathways. The output neurones from SN-PR and GP-I feedback on the motor cortex through the thalamus usingan inhibitory GABAergic link and an excitatory glutametergic terminal. The basal ganglia modulatory loop serves tosmoothen output to the spinal motor neurone and reduce basal tone.

The degenerative lesion (in SN-PC) of Parkinson’s disease (PD) decreases dopaminergic input to the striatum,producing an imbalance between DA and ACh, resulting in hypokinesia, rigidity and tremor.

About 1% of administered dose that entersbrain, aided by amino acid carrier mediated activetransport across brain capillaries, also undergoesthe same transformation. The plasma t½ oflevodopa is 1–2 hours. Pyridoxal is a cofactor forthe enzyme dopa-decarboxylase. The metabolitesare excreted in urine mostly after conjugation.

Adverse effectsSide effects of levodopa therapy are frequent andoften troublesome. Some are prominent in thebeginning of therapy while others appear late.1. Nausea and vomiting: Tolerance graduallydevelops and then the dose can be progressivelyincreased.



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Fig. 9.5: Metabolic pathways of levodopa in the periphery and the brain3-OMD—3-O-methyldopa; COMT—catechol-O-methyl transferase; MAO—monoamineoxidase; 3-MT—3-methoxytyramine; DOPAC—3,4 dihydroxy phenylacetic acid; HVA—homovanillic acid (3-methoxy-4-hydroxy phenylacetic acid), DDC—dopa decarboxylase

2. Postural hypotension: It occurs in about 1/3rdof patients, but is mostly asymptomatic; somepatients experience dizziness, few have faintingattacks. Tolerance develops with continued treat-ment. Care should be taken by the dentist that patientson levodopa therapy do not sit up and leave the dentalchair abruptly from a reclining position.3. Cardiac arrhythmias4. Exacerbation of angina5. Alteration in taste sensation6. Abnormal movements: Facial tics, grimacing,tongue thrusting, choreoathetoid movements oflimbs, etc. start appearing after a few months ofuse of levodopa. They may become as disablingas the original disease itself—are the mostimportant dose limiting side effects. Orofacialdyskinesias may make brushing difficult—damageteeth and pose difficulty in wearing dentures.7. Behavioral effects: Range from mild anxiety,nightmares, etc. to severe depression, mania,hallucinations, mental confusion or frank psy-chosis.3. Fluctuation in motor performance: After 2–5years of therapy, the level of control ofparkinsonian symptomatology starts showing

fluctuation. ‘End of dose’ deterioration, developsinto rapid ‘switches’ or ‘on-off’ effect. With time‘all or none’ response develops, i.e. the patient isalternately well and disabled. This is probably areflection of progression of the disorder: withprogressive degeneration of DA neurones theability to regulate storage and release of DA maybe largely lost.

Interactions

1. Pyridoxine: Abolishes therapeutic effect byenhancing peripheral decarboxylation of levo-dopa.2. Phenothiazines, butyrophenones, metoclopra-mide reverse the therapeutic effect of levodopa byblocking DA receptors.3. Antihypertensives: postural hypotension isaccentuated.

PERIPHERAL DECARBOXYLASE INHIBITORS

Carbidopa and benserazide are extracerebral dopadecarboxylase inhibitors; they do not penetrateblood-brain barrier and do not inhibit conversionof levodopa to DA in brain. Administered along

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with levodopa, they increase its t½ in theperiphery and make more of it available to crossblood-brain barrier to reach its site of action.

Benefits obtained on combining with levodopa are—1. The plasma t½ of levodopa is prolonged and

its dose is reduced to approximately 1/4th.2. Systemic concentration of DA is reduced,

nausea and vomiting are not prominent.3. Cardiac complications are minimized.4. Pyridoxine reversal of levodopa effect does not

occur.5. ‘On-off’ effect is minimized.6. Degree of improvement may be higher.

Problems not resolved or accentuated are—

1. Involuntary movements2. Behavioral abnormalities

3. Postural hypotension.

Currently, levodopa is practically always usedalong with a decarboxylase inhibitor

DOPAMINERGIC AGONISTS

The DA agonists can act on striatal DA receptorseven in advanced patients who have largely lostthe capacity to synthesize, store and release DAfrom levodopa. Moreover, they can be longeracting, exert subtype selective activation of DAreceptors involved in parkinsonism and not sharethe concern expressed about levodopa ofcontributing to dopaminergic neuronal damageby oxidative metabolism.

Bromocriptine It is an ergot derivative whichacts as potent agonist on D2, but as partial agonistor antagonist on D1 receptors. Improvement inparkinsonian symptoms occurs within ½–1 hr ofan oral dose and lasts 6–10 hours. If used alone,doses needed in parkinsonism are high, expen-sive and often produce intolerable side effects—vomiting, hallucinations, hypotension, nasalstuffiness, conjunctival injection.

In parkinsonism, bromocriptine is used onlyin advanced cases as a supplement to levodopa.

It serves to improve control and smoothen ‘end ofdose’ and ‘on-off’ fluctuations. Dyskinesias areless prominent with bromocriptine compared tolevodopa.

Ropinirole and Pramipexole These are twononergoline, selective D2/D3 receptor agonistswith negligible affinity for D1 and nondopami-nergic receptors. The therapeutic effect as supple-mentary drugs to levodopa in advanced cases ofPD, as well as side effect profile is similar tobromocriptine; but they are better tolerated withfewer g.i. symptoms.

Ropinirole and pramipexole are beingincreasingly used as monotherapy for early PDas well with the possible advantage of lowerincidence of dyskinesias and motor fluctuations.

MAO-B INHIBITOR

Selegiline (Deprenyl) It is a selective andirreversible MAO-B inhibitor. Two isoenzymeforms of MAO, termed MAO-A and MAO-B arerecognized; both are present in peripheraladrenergic structures and intestinal mucosa,while the latter predominates in brain and bloodplatelets. Unlike nonselective MAO inhibitors,selegiline in low doses (10 mg/day) does notinterfere with peripheral metabolism of dietaryamines; CA accumulation and hypertensivereaction does not develop, while intracerebraldegradation of DA is retarded. This is responsiblefor the therapeutic effect in parkinsonism. Higherdoses can produce hypertensive interactions.

Selegiline alone has mild antiparkinsonianaction in early cases. Administered with levodopait prolongs levodopa action, attenuates motorfluctuations and decreases ‘wearing off’ effect.However, advanced cases with ‘on-off’ effect arenot improved and the peak dose levodopa sideeffects such as dyskinesias, mental confusion orhallucinations may be worsened.

Selegiline interacts with pethidine causingexcitement, rigidity, hyperthermia, respiratorydepression. It may interact with tricyclic anti-depressants and selective serotonin reuptakeinhibitors as well.


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COMT INHIBITORS

Two selective, potent and reversible COMT inhibitorsEntacapone and Tolcapone have been introduced asadjuvants to levodopa-carbidopa for advanced PD. Whenperipheral decarboxylation of levodopa is blocked bycarbidopa/benserazide, it is mainly metabolized by COMTto 3-O-methyldopa (see Fig. 9.5). Blockade of this pathwayby entacapone/tolcapone prolongs the t½ of levodopaand allows a larger fraction of administered dose to crossto brain. Since COMT plays a role in the degradation ofDA in the brain as well, COMT inhibitors could preserveDA formed in the striatum and supplement the peripheraleffect. However, entacapone acts only in the periphery(probably because of short duration of action ~2 hr). Fortolcapone also the central action is less important.

Entacapone may be used to smoothen ‘wearing off’effect or increase ‘on’ time with levodopa-carbidopa.Because of reports of acute fatal hepatitis andrhabdomyolysis, use of tolcapone is highly restricted.

DOPAMINE FACILITATOR

Amantadine Developed as an antiviral drug forprophylaxis of influenza A2, it was foundserendipitiously to benefit parkinsonism. It actsrapidly but has lower efficacy than levodopa,though higher than anticholinergics. About2/3rd patients derive some benefit. However,tolerance develops over few months and theefficacy is lost. While amantadine is believed toact by promoting presynaptic synthesis andrelease of DA in brain its antagonistic action onNMDA type of glutamate receptors, through

which striatal dopaminergic system exerts itsinfluence, is now considered to be more important.

Amantadine can be used in milder cases, orin short courses to supplement submaximal dosesof levodopa.

CENTRAL ANTICHOLINERGICS

These are drugs having a higher central : peri-pheral anticholinergic action ratio than atropine,but the pharmacological profile is similar to it. Inaddition, certain H1 antihistaminics havesignificant central anticholinergic property. Thereis little to choose clinically among these drugs,though individual preferences vary.

They act by reducing the unbalanced choli-nergic activity in striatum of parkinsonianpatients. Generally, tremor is benefited more thanrigidity; hypokinesia is affected the least.Sialorrhoea is controlled by their peripheralaction. The overall efficacy is much lower thanlevodopa. However, they are cheap and produceless side effects than levodopa. They may be usedalone in mild cases. In others, they can becombined with levodopa.

Anticholinergics are the only drugs effectivein drug (phenothiazine) induced parkinsonism.The side effect profile is similar to atropine.Xerostomia caused by them may aggravate dentalcaries.

The psychopharmacological agents or psycho-tropic drugs are those having primary effects onpsyche (mental processes) and are used fortreatment of psychiatric disorders.

Psychiatric diagnostic categories are often imprecise. Thecriteria adopted overlap in individual patients. Nevertheless,broad divisions have to be made, primarily on the basis ofpredominant manifestations, to guide the use of drugs.

Psychoses These are severe psychiatric illness with seriousdistortion of thought, behaviour, capacity to recognise realityand of perception (delusions and hallucinations). There isinexplicable misperception and misevaluation; the patientis unable to meet the ordinary demands of life.

(a) Acute and chronic organic brain syndromes (cognitivedisorders) Such as delirium and dementia; some toxic orpathological basis can often be defined; prominent featuresare confusion, disorientation, defective memory anddisorganized behaviour.

(b) Functional disorders No underlying cause can bedefined; memory and orientation are mostly retained butemotion, thought and behaviour are seriously altered.(i) Schizophrenia (split mind), i.e. splitting of perceptionand interpretation from reality—hallucinations, inabilityto think coherently.(ii) Paranoid states with marked persecutory or other kindsof fixed delusions (false beliefs) and loss of insight intothe abnormality.

Affective disorders The primary symptom is change inmood state; may manifest as:

Mania—elation, hyperactivity, uncontrollable thoughtand speech, may be associated with violent behaviour, or

Depression—sadness, loss of interest and pleasure,worthlessness, guilt, physical and mental slowing, melan-cholia, self destructive ideation.

It may be bipolar (manic-depressive) with cyclicallyalternating manic and depressive phases or unipolar(mania or depression) with waxing and waning course.

Neuroses These are less serious; ability to comprehendreality is not lost, though the patient may undergo extremesuffering. Depending on the predominant feature, it maybe labelled as:(a) Anxiety An unpleasant emotional state associatedwith uneasiness and concern for the future.(b) Phobic states Fear of the unknown or of some specificobjects, person or situations.(c) Obsessive compulsive Limited abnormality ofthought or behaviour (ritual like) which the patient is notable to overcome even on voluntary effort.(d) Reactive depression due to physical illness, loss,blow to self-esteem or bereavement, but is excessive ordisproportionate.(e) Post-traumatic stress disorder Varied symptomsfollowing distressing experiences like war, riots, earth-quakes, etc.(f) Hysterical Dramatic symptoms resembling seriousphysical illness, but situational, and always in the presenceof others; the patient does not feign but actually undergoesthe symptoms, though the basis is only psychic and notphysical.

Pathophysiology of mental illness is not clear,though some ideas have been formed, e.g. dopa-minergic overactivity in the limbic system may beinvolved in schizophrenia and mania; mono-aminergic (NA, 5-HT) deficit may underliedepression. Treatment is empirical, symptomoriented and not disease specific. However, it ishighly effective in many situations. Dependingon the primary use, the psychotropic drugs maybe grouped into:

1. Antipsychotic (neuroleptic, ataractic, majortranquillizer) useful in all types of functionalpsychosis, especially schizophrenia.

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2. Antianxiety (anxiolytic-sedative, minor tran-quillizer) used for anxiety and phobic states.3. Antidepressants used for minor as well asmajor depressive illness, phobic states, obsessive-compulsive behaviour, and certain anxietydisorders.4. Antimanic (mood stabiliser) used to controlmania and to break into cyclic affective disorders.5. Psychotomimetic (psychedelic, psychodys-leptic, hallucinogen). These are seldom usedtherapeutically but produce psychosis like states,majority are drugs of abuse like LSD, cannabis.

Tranquillizer It is an old term meaning “a drug whichreduces mental tension and produces calmness withoutinducing sleep or depressing mental faculties.” It has beeninterpreted differently by different people; some extend itto cover both chlorpromazine like and antianxiety drugs,others feel that it should be restricted to the antianxietydrugs only. The term ‘tranquillizer’ is therefore best avoided.

ANTIPSYCHOTIC DRUGS(Neuroleptics)

These are drugs having a salutary therapeuticeffect in psychoses.

CLASSIFICATION

1. PhenothiazinesAliphatic side chain: Chlorpromazine

TriflupromazinePiperidine side chain: ThioridazinePiperazine side chain: Trifluoperazine

Fluphenazine2. Butyrophenones Haloperidol

TrifluperidolPenfluridol

3. Thioxanthenes Flupenthixol4. Other heterocyclics Pimozide

Loxapine5. Atypical antipsychotics Clozapine

RisperidoneOlanzapineQuetiapineAripiprazoleZiprasidone

Pharmacology of chlorpromazine (CPZ) isdescribed as prototype. Comparative features ofother drugs are presented in Table 10.1.


1. CNS Effects differ in normal and psychoticindividuals.

In normal individuals CPZ produces indifferenceto surroundings, paucity of thought, psychomotorslowing, emotional quietening, reduction ininitiative and tendency to go off to sleep fromwhich the subject is easily arousable. Sponta-neous movements are minimized, but slurring ofspeech, ataxia or motor incoordination does notoccur.

In a psychotic CPZ reduces irrational beha-viour, agitation and aggressiveness and controlspsychotic symptomatology. Disturbed thoughtand behaviour are gradually normalised, anxietyis relieved. Hyperactivity, hallucinations anddelusions are suppressed.

All phenothiazines, thioxanthenes and buty-rophenones have the same antipsychotic efficacy,but potency differs in terms of equieffective doses.The aliphatic and piperidine side chain pheno-thiazines (CPZ, triflupromazine, thioridazine)have low potency, produce more sedation andcause greater potentiation of hypnotics, opioids,etc. The sedative effect is produced immediatelywhile antipsychotic effect takes weeks to develop.Moreover, tolerance develops to the sedative butnot to the antipsychotic effect. Thus, the twoappear to be independent actions.

Performance and intelligence are relativelyunaffected but vigilance is impaired. Extrapyra-midal motor disturbances (see adverse effects) areintimately linked to the antipsychotic effect butare more prominent in the high potency com-pounds and least in thioridazine, clozapine andother atypical antipsychotics. No consistent effecton sleep architecture has been noted.

Chlorpromazine lowers seizure thresholdand can precipitate fits in untreated epileptics.

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Table 10.1: Comparative properties of antipsychotic drugs

Drug Antipsychotic Relative activity Trade namedose (mg/day)

Extrapyramidal Sedative Hypotensive Antiemetic

1. Chlorpromazine 100–800 ++ +++ ++ ++ LARGACTIL

2. Triflupromazine 50–200 ++± +++ ++ +++ SIQUIL

3. Thioridazine 100–400 + +++ +++ ± MELLERIL, THIORIL

4. Trifluoperazine 2–20 +++ + + +++ TRINICALM

5. Fluphenazine 1–10 +++ + + +++ ANATENSOL

6. Haloperidol 2–20 +++ + + +++ SERENACE, HALOPIDOL

7. Trifluperidol 1–8 +++ + + +++ TRIPERIDOL

8. Flupenthixol 3–15 +++ + + + FLUANXOL

9. Pimozide 2–6 +++ + + + ORAP, NEURAP

10. Loxapine 20–100 ++ + ++ + LOXAPAC

11. Clozapine 50–300 – +++ +++ – LOZAPIN, SIZOPIN

12. Risperidone 2–12 ++ ++ +++ – RESPIDON, SIZODON

13. Olanzapine 2.5–10 + + ++ – OLACE, OLZAP

14. Quetiapine 50-400 ± +++ ++ – QUEL, SOCALM

15. Aripiprazole 5-30 ± ± ± – ARIPRA, BILIEF

16. Ziprasidone 40-160 + + + – AZONA, ZIPSYDON

The piperazine side chain compounds have alower propensity for this action. Temperaturecontrol is knocked off at relatively higher dosesrendering the individual poikilothermic—bodytemperature falls if surroundings are cold. Themedullary respiratory and other vital centres arenot affected, except at very high doses. It is verydifficult to produce coma with these drugs.Neuroleptics, except thioridazine, have potentantiemetic action exerted through the CTZ.However, they are ineffective in motion sick-ness.

Mechanism of action All antipsychotics (exceptclozapine like) have potent dopamine D2 receptorblocking action; antipsychotic potency has showngood correlation with their capacity to bind toD2 receptor. Phenothiazines and thioxanthenesalso block D1, D3 and D4 receptors. Blockade of

dopaminergic projections to the temporal andprefrontal areas constituting the ‘limbic system’and in mesocortical areas is probably responsiblefor the antipsychotic action.

The atypical antipsychotics like clozapinehave weak D2 blocking action. However,clozapine has additional 5-HT2 and α1 adrenergicblocking action, and is relatively selective for D4receptors. Thus, antipsychotic property maydepend on a specific profile of action of the drugson several neurotransmitter receptors.

Dopaminergic blockade in the basal gangliaappears to cause the extrapyramidal symptoms,while that in CTZ is responsible for antiemeticaction.

2. ANS Neuroleptics have varying degrees ofα adrenergic blocking activity which may begraded as:

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CPZ = triflupromazine > thioridazine > fluphe-nazine > haloperidol > trifluoperazine > cloza-pine > pimozide, i.e. more potent compoundshave lesser α blocking activity.

Anticholinergic property of neuroleptics isweak and may be graded as:

thioridazine > chlorpromazine > trifluproma-zine > trifluoperazine = haloperidol.

The phenothiazines have weak H1-antihista-minic and anti-5-HT actions as well.

3. Local anaesthetic Chlorpromazine is aspotent a local anaesthetic as procaine. Othershave weaker membrane stabilizing action.

4. CVS Neuroleptics produce hypotension (pri-marily postural) by a central as well as periphe-ral action on sympathetic tone. The hypotensiveaction is more marked after parenteral adminis-tration and roughly parallels the α adrenergicblocking potency. Partial tolerance develops afterchronic use. Reflex tachycardia accompanieshypotension.

High doses of CPZ directly depress the heartand produce ECG changes (Q-T prolongation andsuppression of T wave). CPZ exerts someantiarrhythmic action, probably due to membranestabilization. Arrhythmia may occur in overdose,especially with thioridazine.

5. Endocrine Neuroleptics consistently inc-rease prolactin release by blocking the inhibitoryaction of DA on pituitary lactotropes. This mayresult in galactorrhoea and gynaecomastia.

They reduce gonadotropin secretion, butamenorrhoea and infertility occur only occa-sionally. ACTH release in response to stress isdiminished—corticosteroid levels fail to increaseunder such circumstances. Release of GH is alsoreduced, but this is not sufficient to cause growthretardation in children or to be beneficial in acro-megaly.

Tolerance and dependence Tolerance to thesedative and hypotensive actions develops withindays or weeks, but the antipsychotic, extra-pyramidal and other actions based on DAantagonism do not display tolerance.

Neuroleptics are hedonically (pertaining topleasure) bland drugs. Physical dependence isprobably absent. No drug seeking behaviour isimparted.

PHARMACOKINETICS

Oral absorption of CPZ is somewhat unpredic-table and bioavailability is low. More consistenteffects are produced after i.m. or i.v. administra-tion. It is highly bound to plasma as well as tissueproteins. Volume of distribution is large (20 L/kg). It is metabolized by liver into a number ofmetabolites. The acute effects of a single dosegenerally last for 6–8 hours. The elimination t½ isvariable, but mostly is in the range of 18–30 hours.

Atypical (second generation) neurolepticsLately some antipsychotic drugs like clozapine,risperidone, olanzapine, quetiapine, aripiprazole andziprasidone have been developed which have apharmacological profile distinct from CPZ,produce few extrapyramidal symptoms, no/mildhyperprolactinaemia; tardive dyskinesia israre. They tend to suppress both positive andnegative symptoms of schizophrenia (the olderdrugs have little effect on negative symptoms).Many patients refractory to the typical anti-psychotics respond to these drugs. The atypicalantipsychotics have only weak D2, but potent5-HT2 antagonistic activity alongwith variableα adrenergic, muscarinic and H1 histaminergicblocking property. These features may accountfor the above differences.

The major limitation of clozapine is higherincidence of agranulocytosis and other blooddyscrasias. This is not the case with olanzapine ,risperidone and others. Currently, they are beingincreasingly prescribed. Though, there is noconvincing evidence of higher efficacy, theyproduce fewer side effects and neurologicalcomplications. Some atypical antipsychotics arealso effective in mania and bipolar disorder.

ADVERSE EFFECTSNeuroleptics are very safe drugs in single or infre-quent doses, but side effects are common.

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I. Based on pharmacological actions(dose related)

1. CNS Drowsiness, lethargy, mental con-fusion: more with low potency agents; increasedappetite and weight gain; aggravation of seizuresin epileptics.2. α Adrenergic blockade Postural hypotension,palpitation, inhibition of ejaculation (especiallywith thioridazine) are more common withlow potency phenothiazenes. Dentists shouldinstruct patients to get up slowly from a reclining dentalchair.

3. Anticholinergic Dry mouth (may promotecaries tooth), blurring of vision, constipation,urinary hesitancy in elderly males (thioridazinehas the highest propensity); absent in highpotency agents.4. Endocrine Amenorrhoea, infertility, gynae-comastia, galactorrhoea—due to hyperprolac-tinaemia.5. Extrapyramidal disturbances These are themajor dose limiting side effects; more prominentwith high potency drugs like fluphenazine,haloperidol, pimozide, etc., least with thiori-dazine and atypical antipsychotics. These are offollowing types.

(a) Parkinsonism with typical manifestations—rigidity, tremor, hypokinesia, mask like facies,shuffling gait. Anticholinergic antiparkinsoniandrugs may counteract these symptoms.

A rare form of extrapyramidal side effect isperioral tremors ‘rabbit syndrome’ that generallyoccurs after few years of therapy.

(b) Acute muscular dystonias Bizarre musclespasms, mostly involving linguo-facial muscles—grimacing, tongue thrusting, torticollis, lockedjaw; occurs within a few hours of a single dose orat the most in the first week of therapy. It is morecommon in children below 10 years and in girls,particularly after parenteral administration;overall incidence is 2%. It lasts for one to few hoursand then resolves spontaneously. One of thecentral anticholinergics, promethazine or hyd-

roxyzine injected i.m. clears the reaction within10–15 minutes.

(c) Akathisia Restlessness, feeling of discomfort,apparent agitation manifested as a compellingdesire to move about but without anxiety is seenin some patients. A central anticholinergic mayreduce the intensity in some cases; propranolol ismore effective, but most cases require reductionof dose.

(d) Malignant neuroleptic syndrome It occursrarely with high doses of potent agents; the patientdevelops marked rigidity, immobility, tremor, fever,semiconsciousness, fluctuating BP and heart rate;lasts for 5–10 days after drug withdrawal and maybe fatal. Anticholinergics are of no help.Intravenous dantrolene may benefit. Bromocrip-tine in large doses has been found to be useful.

(e) Tardive dyskinesia It occurs late in therapy,sometimes even after withdrawal of the neuro-leptic: manifests as purposeless involuntary facialand limb movements like constant chewing,pouting, puffing of cheeks, lip licking, choreo-athetoid movements. Dental problems may arisebecause of involvement of orofacial muscles. Attritionof teeth may result from grinding. It is probably amanifestation of progressive neuronal degenera-tion along with supersensitivity to DA. There isno satisfactory solution of the problem.

6. Miscellaneous Weight gain, blue pigmen-tation of exposed skin, corneal and lenticularopacities, retinal degeneration, cardiac arrhyth-mia are rare complications. Impairment of glucosetolerance and worsening of diabetes has beenreported with some drugs like clozapine andolanzapine.

II. Hypersensitivity reactions These are notdose related.1. Cholestatic jaundice.2. Skin rashes, urticaria, contact dermatitis,photosensitivity.3. Agranulocytosis is rare; more common withclozapine.

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INTERACTIONS

1. Neuroleptics potentiate all CNS depressants —hypnotics, anxiolytics, alcohol, opioids and anti-histaminics. Dentists should be careful whileprescribing any of these drugs to patients receivingneuroleptics.2. Neuroleptics block the actions of levodopa anddirect DA agonists in parkinsonism.3. CPZ and few others abolish the antihyper-tensive action of clonidine and methyldopa,probably due to central α2 adrenergic blockade.4. Enzyme inducers (barbiturates, anticon-vulsants) can reduce blood levels of neuroleptics.

USES

1. Schizophrenia The neuroleptics are usedprimarily in functional psychoses: haveindefinable but definite therapeutic effect: producea wide range of symptom relief. They controlpositive symptoms (hallucinations, delusions,disorganized thought, restlessness, insomnia,anxiety, fighting, aggression) better than negativesymptoms (apathy, loss of insight and volition,affective flattening, poverty of speech, social with-drawal). Some patients do not respond, andvirtually none responds completely. They are onlysymptomatic treatment, do not remove the cause ofillness.

2. Mania Antipsychotics are required for rapidcontrol, may be given i.m. Lithium or valproatemay be started simultaneously or after the acutephase.

3. Organic brain syndromes Neuroleptics arenot very effective. May be used on a short-termbasis.

4. Anxiety Neuroleptics should not be used forsimple anxiety. Patients not responding to BZDs,or those having a psychotic basis for anxiety maybe treated with a neuroleptic.

5. As antiemetic Neuroleptics are potentantiemetics—control a wide range of drug anddisease induced vomiting at doses much lowerthan those needed in psychosis. They are

ineffective in motion sickness: probably becausedopaminergic pathway through the CTZ is notinvolved in this condition.

ANTIMANIC (MOOD STABILIZING) DRUGS

LITHIUM CARBONATE

Lithium is a small monovalent cation. In 1949, itwas found to exert beneficial effects in manicpatients.

Later, the importance of maintaining anarrow range of serum lithium concentration wasrealized and unequivocal evidence of its efficacywas obtained. At present, lithium is a drug of itsown kind to exert a prophylactic effect in bipolarmanic depressive illness (MDI). Over the past2 decades antiepileptics like carbamazepine,valproate, etc. and atypical antipsychotics haveemerged as alternatives to lithium.

Actions and mechanism

1. CNS Lithium has practically no acute effectsin normal individuals as well as in MDI patients.It is neither sedative nor euphorient; but onprolonged administration, it acts as a moodstabiliser in bipolar disease. Given to patients inacute mania, it gradually suppresses the episodetaking 1–2 weeks; continued treatment preventscyclic mood changes. The markedly reduced sleeptime in manic patients is normalized.

The mechanism of antimanic and moodstabilizing action of lithium is not known. It hasbeen proposed that:(a) Li+ partly replaces body Na+ and is nearlyequally distributed inside and outside the cells(contrast Na+ and K+); this may affect ionic fluxesacross brain cells or modify the property of cellularmembranes.(b) Li+ may correct imbalance in the turnover ofbrain monoamines.(c) The above hypothesis cannot explain whyLi+ has no effect on people not suffering frommania. An attractive hypothesis has been putforward based on the finding that lithium inhibitshydrolysis of inositol-1-phosphate. As a result,

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the supply of free inositol for regeneration ofmembrane phosphatidyl-inositides, which arethe source of IP3 and DAG, is reduced (Fig. 10.1).The hyperactive neurones involved in the manicstate may be preferentially affected, becausesupply of inositol from extracellular sources ismeagre. Thus, lithium may ignore normallyoperating receptors, but ‘search out’ andselectively, though indirectly, dampen signaltransduction in the overactive ones.

2. Other actions Lithium inhibits the action ofADH on distal tubules and causes a diabetesinsipidus like state.It has some insulin-like action on glucose meta-bolism.Leukocyte count is increased by lithium therapy.Lithium reduces thyroxine synthesis by inter-fering with iodination of tyrosine.

Pharmacokinetics and control of therapy

Lithium is well absorbed orally and is neitherprotein bound nor metabolized. It first distributes

in the extracellular water and then graduallyenters cells and slowly penetrates into the CNS,ultimately attaining a rather uniform distributionin total body water.

Lithium is handled by the kidney in much thesame way as Na+. Most of the filtered Li+ isreabsorbed in the proximal convoluted tubule.After a single dose of Li+, urinary excretion israpid for 10–12 hours followed by a much slowerphase lasting several days. The t½ of the latterphase is 16–30 hours.

There is marked individual variation in therate of lithium excretion. Since the margin ofsafety is narrow, monitoring of serum lithiumconcentration is essential for optimal therapy.Serum lithium level 0.5–0.8 mEq/L is consideredoptimum for maintenance therapy in bipolardisorder, while 0.8–1.1 mEq/L is required forepisodes of mania. Toxicity symptoms occurfrequently when serum levels exceed 1.5 mEq/L.

Adverse effects Side effects are common but aremostly tolerable. Toxicity occurs at levels onlymarginally higher than therapeutic levels.

Antimanic Drugs 161

Fig. 10.1: Proposed mechanism of antimanic action of lithiumPIP-Phosphatidyl inositol phosphate; PIP2-Phosphatidyl inositol bisphosphate; IP3-Inositol trisphosphate; IP-Inositol-1-phosphate; PLc-Phospholipase C; DAG-Diacylglycerol; PKc-Protein kinase C; Gq-Coupling Gq protein; R- Neurotransmitter receptor


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1. Nausea, vomiting and mild diarrhoea.2. Thirst and polyuria are experienced by most.3. Fine tremors and rarely seizures.4. CNS toxicity manifests as plasma concen-tration rises—coarse tremors, giddiness, ataxia,motor incoordination, nystagmus, mental confu-sion, slurred speech, hyper-reflexia. In acuteintoxication, these symptoms progress to muscletwitchings, drowsiness, delirium, coma and con-vulsions. Vomiting, severe diarrhoea, albumi-nuria, hypotension and cardiac arrhythmias arethe other features.There is no specific antidote to lithium.5. On long-term use, some patients develop renaldiabetes insipidus and goiter.6. Lithium is contraindicated during pregnancy;foetal goiter and other congenital abnormalitiescan occur.

Interactions1. Diuretics (thiazide, furosemide) raise plasmalevels of lithium.2. NSAIDs also cause Li+ retention (along withNa+ retention). Dentists should refer patients formonitoring and adjusting Li+ therapy when theyprescribe NSAIDs. Tetracyclines and ACE inhi-bitors are other drugs capable of producingLi+ retention.3. Lithium tends to enhance insulin/sulfonyl-urea induced hypoglycaemia.

Use

1. Acute manic episode (inappropriate cheer-fullness, motor restlessness, nonstop talking,flight of ideas and progressive loss of contact withreality; sometimes violent behaviour): thoughlithium is effective, response is slow. Mostpsychiatrists prefer to use a neuroleptic, generallyby i.m. route, with or without diazepam, and startlithium after the episode is under control.Maintenance lithium therapy is generally givento prevent recurrences.

2. Prophylaxis in bipolar disorder Lithium hasproven efficacy in bipolar disorder. It lengthens

the interval between cycles of mood swings:episodes of mania as well as depression areattenuated, if not totally prevented.

Recurrent unipolar depression also responds tolithium therapy. Combination of antidepressant+ lithium is often used initially, and lithium aloneis continued in the maintenance phase.

3. Lithium is sporadically used in many otherrecurrent neuropsychiatric illness, cluster headache,etc. and as an adjuvant to tricyclic antidepres-sants in patients of major depression not fullyrelieved by the latter.

Alternatives to lithium

Approximately 50% patients of mania and bipolardisorder show incomplete or poor response tolithium. Many do not tolerate it or are at specialrisk of toxicity. Alternatives are:

1. Carbamazepine Soon after its introductionas antiepileptic carbamazepine (CBZ) was foundto prolong remission in bipolar disorder. Itsefficacy in mania and bipolar disorder has nowbeen confirmed and is rated almost equal tolithium. Patients with rapid cycling of mood statedo better on combined Li + CBZ treatment.

2. Sodium valproate A reduction in manicrelapses is noted when valproate is used inbipolar disorder. High dose valproate is a rapidlyacting alternative to oral antipsychotic ±benzodiazepine for acute mania. For bipolarillness it can be useful in those not responding toLi or CBZ or not tolerating these drugs. Valproatehas a favourable tolerability profile.

The newer anticonvulsants like lamotrigineand topiramate have also been found effective inbipolar disorder: can serve as alternative drugs.

3. Atypical antipsychotics Olanzapine, ris-peridone, aripiprazole and quetiapine ± a BZDare now among the first line drugs for mania notrequiring parenteral medication. Olanzapine isapproved for maintenance therapy of bipolarillness as well.

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Antidepressant Drugs 163

ANTIDEPRESSANT DRUGS

These are drugs which can elevate mood indepressive illness. Practically all antidepressantsaffect monoaminergic transmission in the brainin one way or the other and many of them haveother associated properties. Particularly over thepast two decades, a large number of antidepres-sants with an assortment of effects on reuptake/metabolism of biogenic amines and on pre/post-junctional aminergic/cholinergic receptors havebecome available so that a cogent classification isdifficult. The following working classification maybe adopted.

CLASSIFICATION

I. Reversible inhibitors of MAO-A (RIMAs)Moclobemide, Clorgyline

II. Tricyclic antidepressants (TCAs)A. NA + 5-HT reuptake inhibitors

Imipramine, Amitriptyline,Trimipramine, Doxepin, Dothiepin,Clomipramine

B. Predominantly NA reuptake inhibitorsDesipramine, Nortriptyline, Amoxapine,Reboxetine

III. Selective serotonin reuptake inhibitors(SSRIs)Fluoxetine, Fluvoxamine, Paroxetine,Sertraline, Citalopram, Escitalopram

IV. Atypical antidepressantsTrazodone, Mianserin, Mirtazapine,Venlafaxine, Duloxetine, Tianeptine,Amineptine, Bupropion.

MAO INHIBITORS

MAO is a mitochondrial enzyme involved in the oxidativedeamination of biogenic amines (Adr, NA, DA, 5-HT).Two isoenzyme forms of MAO have been identified.

MAO-A: Preferentially deaminates 5-HT and NA, andis inhibited by clorgyline, moclobemide.

MAO-B: Preferentially deaminates phenylethylamineand is inhibited by selegiline.Dopamine is degraded equally by both isoenzymes.

Their distribution also differs. Peripheral adrenergicnerve endings, intestinal mucosa and human placenta

contain predominantly MAO-A, while MAO-B predo-minates in certain areas of brain and in platelets. Livercontains both isoenzymes.

Iproniazid, a congener of the antitubercular drugisoniazid, was found to cause mood elevation that wasascribed to its ability to inhibit MAO. Iproniazid andrelated drugs that were nonselective and irreversible MAOinhibitors were used briefly as antidepressants, but wereabandoned because of high toxicity and interaction withseveral foods and drugs. The most important interactionknown as cheese reaction occurs when the subject receivingMAO inhibitor ingests tyramine rich foods including certaincheese, beer, wines, etc. The indirectly acting sympatho-mimetic amine escapes degradation in the intestinal walland liver → reaches systemic circulation in high concentra-tion and displaces large amounts of NA from transmitterloaded sympathetic nerve endings → hypertensive crisis,cerebrovascular accident and other complications. Similarhypertensive reaction can occur with cold remedies,levodopa, tricyclic antidepressants as well. Because theseMAO inhibitors in addition inhibit drug metabolizingenzymes, several drugs get potentiated. The opioidpethidine produces excitation, delirium, high fever,convulsions, etc. because its metabolism is diverted togenerate excess of norpethidine.

Recently, some MAO-A selective and reversi-ble inhibitors have been developed which haveuseful antidepressant property coupled with lowtoxicity and freedom from dangerous interactionsin the recommended dose range.

Reversible inhibitors of MAO-A (RIMAs)

Moclobemide It is a reversible and selectiveMAO-A inhibitor with short duration of action;full MAO activity is restored within 1–2 days ofstopping the drug. Because of competitive enzymeinhibition, tyramine is able to displace it from theenzyme so that potentiation of pressor responseto ingested amines is weak and dietary restrictionsare not required. Clinical trials have shown moclo-bemide to be an efficacious antidepressant,comparable to TCAs, except in severe cases. Itlacks the anticholinergic, sedative, cognitive,psychomotor and cardiovascular adverse effectsof typical TCAs and is safer in overdose. Thismakes it a particularly good option in elderlypatients and in those with heart disease.

Adverse effects are nausea, dizziness,headache, insomnia, rarely excitement and liver


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damage. Chances of interaction with other drugsand alcohol are remote, but caution is advisedwhile coprescribing pethidine, SSRIs and TCAs.

TRICYCLIC ANTIDEPRESSANTS (TCAs)

Imipramine, an analogue of CPZ, was foundduring clinical trials (1958) to selectively benefitdepressed but not agitated psychotics. In contrastto CPZ, it inhibited NA and 5-HT reuptake intoneurones. A large number of congeners were soonadded and are collectively called tricyclic anti-depressants (TCAs).


The TCAs inhibit monoamine uptake and interactwith a variety of receptors viz. muscarinic, αadrenergic, histamine H1, 5-HT1, 5-HT2 andoccasionally dopamine D2. However, relativepotencies at these sites differ among differentcompounds. The newer selective serotonin reup-take inhibitors (SSRIs) and atypical antidepres-sants interact with fewer receptors and have morelimited spectrum of action (produce fewer sideeffects). The actions of imipramine are describedas prototype.

Table 10.2: Comparative properties and trade names of tricyclic and related antidepressants

Drug Sedation Antimuscarinic Hypotension Cardiac Seizure Daily Trade namearrhythmia precipitation dose (mg)

Tricyclic antidepressants

1. Imipramine + ++ ++ +++ ++ 50–200 DEPSONIL,ANTIDEP

2. Amitriptyline +++ +++ +++ +++ ++ 50–200 AMLINE, TRYPTOMER

3. Trimipramine +++ +++ ++ +++ ++ 50–150 SURMONTIL

4. Doxepin +++ ++ ++ ++ ++ 50–150 SPECTRA, DOXIN

5. Clomipramine ++ +++ ++ +++ +++ 50–150 CLOFRANIL, CLONIL

6. Dothiepin ++ ++ ++ ++ ++ 50–150 PROTHIADEN

7. Nortriptyline + ++ + ++ + 50–150 SENSIVAL

8. Amoxapine + + ++ ++ ++ 100–300 DEMOLOX

Selective 5-HT reuptake inhibitors

1. Fluoxetine ± — — — ± 20–50 FLUDAC, FLUNIL

2. Fluvoxamine ± — — — — 50–200 FLUVOXIN

3. Paroxetine ± ± — — — 20–50 XET

4. Sertraline ± — — — — 50–200 SERENATA

5. Citalopram — — — — — 20–40 CELICA

6. Escitalopram — — — — — 10-20 ESDEP, FELIZ-S

Atypical antidepressants

1. Trazodone +++ — ± ± — 50–200 TRAZODAC

2. Mianserin ++ + ++ + ++ 30–100 TETRADEP

3. Bupropion –, ↑ — — — +++ 150–300 SMOQUIT

4. Mirtazapine +++ — ± — — 15–45 MIRT, MIRTAZ

5. Venlafaxine — — — ± — 75–150 VENLOR

6. Duloxetine — — — — — 30-80 DELOK

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1. CNS Effects differ in normal individuals andthe depressed.In normal individuals it induces a peculiar clumsyfeeling, tiredness, light-headedness, sleepiness,difficulty in concentrating and thinking, unsteadygait. These effects tend to provoke anxiety. Thereis no mood elevation or euphoria; effects are ratherunpleasant and may become more so on repeatedadministration.In depressed patients little acute effects are pro-duced, except sedation. After 2–3 weeks ofcontinuous treatment, the mood is graduallyelevated, patients become more communicativeand start taking interest in self and surroundings.Thus, TCAs are not euphorients but only anti-depressants. Sedative property varies amongdifferent compounds (see Table 10.2). The moresedative ones are suitable for depressed patientsshowing anxiety and agitation. The less sedativeor stimulant ones are better for withdrawn andretarded patients.

The TCAs lower seizure threshold and pro-duce convulsions in overdose. Clomipramine andbupropion have the highest seizure precipitatingpotential. Amitriptyline and imipramine depressrespiration in overdose only.

Mechanism of action The TCAs and relateddrugs inhibit NET and SERT the transporterswhich mediate active uptake of biogenic aminesNA and 5-HT into their respective neurones andthus potentiate them. They, however, differmarkedly in their selectivity and potency fordifferent amines (see classification above). Most ofthe compounds do not inhibit DA uptake, exceptbupropion.

Uptake inhibition results in increased concen-tration of the amines in the synaptic cleft in theCNS and periphery. Tentative conclusions drawnare:• Inhibition of DA uptake correlates with stimu-

lant action; but is not primarily involved inantidepressant action.

• Inhibition of NA and 5-HT uptake is associatedwith antidepressant action.

Uptake blockade appears to initiate a series oftime-dependent changes in the number andsensitivity of aminergic receptors that culminatein antidepressant effect after a few weeks.

None of these compounds, except amoxapine,block DA receptors or possess antipsychoticactivity.

2. ANS Most tricyclic antidepressants are potentanticholinergics—cause dry mouth, blurring ofvision, constipation and urinary hesitancy as sideeffect. The anticholinergic potency is graded inTable 10.2. They potentiate exogenous andendogenous NA by blocking uptake.

3. CVS Effects on cardiovascular function areprominent, and may be dangerous in overdose.Tachycardia: due to anticholinergic and NA poten-tiating actions.Postural hypotension: due to inhibition of cardio-vascular reflexes and α1 blockade.ECG changes and cardiac arrhythmias: T wave sup-pression or inversion is the most consistentchange. Arrhythmias occur in overdose due tointerference with intraventricular conduction,combination of NA potentiating + ACh blockingactions and direct myocardial depression. Olderpatients are more susceptible. The SSRIs andatypical antidepressants are safer in this regard.

Tolerance and dependence

Tolerance to the anticholinergic and hypotensiveeffects of imipramine like drugs develops gradually,though antidepressant action is sustained.

Psychological dependence on these drugs israre because their acute effects are not pleasant.

There is some evidence of physical depen-dence occurring when high doses are used forlong periods, but they do not carry abuse potential.

PHARMACOKINETICS

The oral absorption of TCAs is good, though oftenslow. They are highly bound to plasma and tissueproteins—have large volumes of distribution(~20 L/kg). They are extensively metabolizedin liver; the major route for imipramine and



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amitriptyline is demethylation whereby activemetabolites—desipramine and nortriptyline res-pectively are formed. Metabolites are excreted inurine over 1–2 weeks. The plasma t½ of amitrip-tyline, imipramine and doxepin range between16–24 hours.

ADVERSE EFFECTS

Side effects are common with tricyclic antidep-ressants.1. Anticholinergic: dry mouth, bad taste, consti-

pation, epigastric distress, urinary retention(especially in males with enlarged prostate),blurred vision, palpitation. Decreased sali-vation increases risk of dental caries, oral thrush,etc.

2. Sedation, mental confusion and weakness,especially with amitriptyline and more seda-tive congeners.

3. Increased appetite and weight gain is notedwith most TCAs and trazodone, but not withSSRIs and bupropion.

4. Some patients may switch to hypomania ormania. Probably, this reflects a basic bipolarillness, the other pole being unmasked by theantidepressant.

5. Sweating and fine tremors are relativelycommon.

6. Seizure threshold is lowered—fits may be pre-cipitated, especially in children.

7. Postural hypotension, especially in olderpatients; less severe with desipramine likedrugs and insignificant with SSRIs. Patientsshould not abruptly sit up or stand from a recliningposition on the dental chair.

8. Cardiac arrhythmias, especially in patientswith ischaemic heart disease—may be respon-sible for sudden death in these patients.

9. Rashes and jaundice due to hypersensitivityare rare.

Acute poisoning It is frequent; usually self-attempted by the depressed patients, and mayendanger life. Manifestations are:Excitement, delirium and other anticholinergicsymptoms followed by muscle spasms, convul-

sions and coma. Respiration is depressed, bodytemperature may fall, BP is low, tachycardia isprominent. ECG changes and ventriculararrhythmias are common.Treatment is primarily supportive with gastriclavage, respiratory support, fluid infusion,maintenance of BP and body temperature. Aci-dosis must be corrected by bicarbonate infusion.

Diazepam may be injected i.v. to controlconvulsions and delirium. Most important istreatment of cardiac arrhythmias, for whichpropranolol / lidocaine may be used.

INTERACTIONS

1. TCAs potentiate directly acting sympathomi-metic amines (in cold/asthma remedies).Adrenaline containing local anaesthetic should beavoided for dental anaesthesia due to risk ofpotentiation and precipitation of cardiac arrhy-thmia.

2. TCAs abolish the antihypertensive actionof clonidine by preventing its transport intoadrenergic neurones.

3. Chances of Q-T prolongation and cardiacarrhythmia increase when erythromycin isgiven to patients on TCA therapy.

4. TCAs potentiate CNS depressants, includingalcohol and antihistaminics.

5. Phenobarbitone induces as well as competi-tively inhibits imipramine metabolism.Carbamazepine and other enzyme inducersenhance metabolism of TCAs.

6. SSRIs inhibit metabolism of many drugsincluding TCAs—dangerous toxicity canoccur if the two are given concurrently.

7. When used together, the anticholinergicaction of neuroleptics and TCAs may add up.

SELECTIVE SEROTONIN REUPTAKEINHIBITORS (SSRIs)

The major limitations of standard TCAs are:• Frequent anticholinergic, cardiovascular and

neurological side effects.• Relatively low safety margin, hazardous in

overdose; fatalities common.

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• Lag time of 2–4 weeks before antidepressantaction manifests.

• Significant number of patients respondincompletely and some do not respond.To overcome these shortcomings, a large

number of newer antidepressants have beendeveloped since 1980s. The most significant ofthese are the SSRIs which selectively inhibitmembrane associated 5-HT transporter SERT.Though, none of the newer drugs has surpassedolder TCAs in overall efficacy, some patients notresponding to one type of drug may respond tothe other. More importantly, the newer drugs haveimproved tolerability, both in therapeutic use aswell as in overdose.

The relative safety and better acceptability ofSSRIs has made them 1st line drugs in depressionand allowed their extensive use in anxiety,phobias, OCD and related disorders. The SSRIs,produce little or no sedation, do not interfere withcognitive and psychomotor function or produceanticholinergic side effects. They are devoid of αadrenergic blocking action—postural hypoten-sion does not occur—suitable for elderly patients.They have practically no seizure precipitatingpropensity and do not inhibit cardiac conduc-tion—overdose arrhythmias are not a problem.However, they frequently produce nausea. Weightgain is not a problem with SSRIs, but they morecommonly interfere with ejaculation or orgasm.A new constellation of mild side effects, viz.nervousness, restlessness, insomnia, anorexia,dyskinesia, headache and diarrhoea is associatedwith them, but patient acceptability is good.Increased incidence of epistaxis and ecchymosishas been reported, probably due to impairment ofplatelet function. Gastric blood loss due to NSAIDsmay be increased by SSRIs.

The SSRIs inhibit drug metabolizing iso-enzymes CYP2D6 and CYP3A4: elevate plasmalevels of TCAs, haloperidol, clozapine, terfena-dine, astemizole, warfarin, β blockers, some BZDsand carbamazepine. Use of tramadol to relievedental pain should be avoided in patients receivingSSRIs due to risk of ‘Serotonin syndrome’ mani-

festing as agitation, muscle rigidity, twitchings,convulsions and hyperthermia.

The overall antidepressant efficacy of SSRIsis similar to that of TCAs, but in severe depression,TCAs appear to be more efficacious.

Other uses of SSRIs The SSRIs are now 1stchoice drugs for OCD, panic disorder, socialphobia, eating disorders and post-traumatic stressdisorder. They are also being increasingly usedfor many anxiety disorders, body dysmorphicdisorder, compulsive buying and kleptomania.Elevation of mood and increased work capacityhas been reported in postmyocardial infarctionand other chronic somatic illness patients. Thus,SSRIs are being used to improve outlook on lifeand to feel good, even in apparently nondepressedpatients. Wisdom of such use though isquestionable.

ATYPICAL ANTIDEPRESSANTS

The distinctive features of some atypicalantidepressants are outlined below.1. Trazodone It is the first atypical anti-depressant; selectively but less efficiently blocks5-HT uptake and has prominent α blocking aswell as weak 5-HT2 antagonistic action. It issedative but not anticholinergic, causes brady-cardia rather than tachycardia, does not interferewith intracardiac conduction—less prone to causearrhythmia. Inappropriate, prolonged and pain-ful penile erection (priapism) occurs in a fewrecipients as does postural hypotension.

2. Mianserin It is unique in not inhibitingeither NA or 5-HT uptake; but blocks presynapticα2 receptors—increases release and turnover ofNA in brain which may be responsible forantidepressant effect. Blood dyscrasias and liverdysfunction have restricted its use.

3. Tianeptine This antidepressant is reportedto increase rather than inhibit 5-HT uptake, andhas shown efficacy in anxiodepressive statesparticularly with psychosomatic symptoms aswell as in endogenous depression.



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4. Amineptine Like tianeptine, it enhances 5-HT uptake but has antidepressant property. Itproduces anticholinergic side effects, posturalhypotension, conduction disturbances andarrhythmias.

5. Venlafaxine A novel antidepressantreferred to as ‘serotonin and noradrenaline reuptakeinhibitor’ (SNRI), because it inhibits uptake of boththese amines; but, in contrast to older TCAs, doesnot interact with cholinergic, adrenergic orhistaminergic receptors or have sedative property.Venlafaxine does not produce the usual sideeffects of TCAs; tends to raise rather than depressBP and is safer in overdose.

6. Duloxetine This is another SNRI similar inproperties to venlafaxine. In addition to depres-sion, duloxetine is useful in panic attacks,neuropathic pain and stress urinary incontinencein women.

7. Mirtazapine It acts by a novel mechanismviz. blocks α2 auto- (on NA neurones) and hetero-(on 5-HT neurones) receptors enhancing bothNA and 5-HT release. Accordingly, it has beenlabelled as “noradrenergic and specific serotonergicantidepressant” (NaSSA). It is a H1 blocker andquite sedative, but not anticholinergic or anti-dopaminergic. Efficacy in depression is reportedto be comparable to TCAs and benefit may startearlier.

8. Bupropion This inhibitor of DA and NAuptake has excitant rather than sedative property.It is metabolized into an amphetamine likecompound. It is marketed in a sustained releaseformulation as an aid to smoking cessation. Sideeffects are insomnia, agitation, dry mouth andnausea. Seizures occur in overdose.

USES

1. Endogenous (major) depression: The aim isto relieve symptoms of depression and restorenormal social behaviour. The tricyclic and relatedantidepressants are of proven value. Responsetakes at least 2–3 weeks to appear, full benefits

take still longer. The SSRIs are currently usedas first choice for their good tolerability and safety.The newer atypical agents also offer someadvantages. However, the TCAs are still themost effective in severely depressed patients. Aftera depressive episode has been controlled, conti-nued treatment at maintenance doses for monthsis recommended to prevent relapse. Therapy isgenerally not continued beyond one year.

2. Obsessive-compulsive and phobic states: TheSSRIs are the drugs of choice due to better patientacceptability. TCAs, especially clomipramine, arehighly effective in OCD and panic disorders.SSRIs and TCAs also reduce compulsive eatingin bulimia, and help patients with body dysmorphicdisorder, compulsive buying and kleptomania,though these habits may not completely die.

3. Anxiety disorders: Antidepressants, especiallySSRIs, exert a delayed but sustained beneficialeffect in many patients of generalized anxietydisorder; may be used along with a short courseof BZDs to cover exacerbations. SSRIs have alsoproven helpful in post-traumatic stress disorder.

4. Neuropathic pain: Imipramine/amitriptylineafford considerable relief in post-herpeticneuralgia, diabetic and some other types ofchronic pain.

5. Attention deficit-hyperactivity disorder inchildren: TCAs with less depressant propertieslike imipramine and amoxapine are emerging asalternatives to amphetamine like drugs.

6. Enuresis: Imipramine 25 mg at bedtimereduces bedwetting in children above 5 years.

7. Migraine: Amitriptyline has some prophylacticvalue.

8. Pruritus: Some tricyclics have antipruriticproperty.

ANTIANXIETY DRUGS

Anxiety Some degree of anxiety is a part ofnormal life. Treatment is needed when it isdisproportionate to the situation and excessive.Some psychotics also exhibit pathological anxiety.

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Antianxiety drugs These are an ill-definedgroup of drugs, mostly mild CNS depressantswhich are aimed to control the symptoms ofanxiety, produce a restful state of mind withoutinterfering with normal mental or physicalfunctions. In dentistry, the most important applicationof antianxiety drugs is for premedication ofapprehensive patients and as adjuncts to localanaesthesia. BZDs also counteract the CNS toxi-city of local anaesthetics. The anxiolytic-sedativedrugs differ markedly from antipsychotics, andmore closely resemble sedative-hypnotics. They:1. Have no therapeutic effect to control thought

disorder of schizophrenia.2. Do not produce extrapyramidal side effects.3. Have anticonvulsant property.4. Produce physical dependence and carry

abuse liability.

CLASSIFICATION

1. Benzodiazepines DiazepamChlordiazepoxideOxazepamLorazepamAlprazolam

2. Azapirones BuspironeIspapironeGepirone

3. Sedative Hydroxyzineantihistaminic

4. β blocker Propranolol

In addition to the above drugs, antidepres-sants, especially the selective serotonin reuptakeinhibitors (SSRIs), are effective in obsessive-compulsive disorder (OCD), phobias, panic andmany types of severe generalized anxietydisorders.

Benzodiazepines

The pharmacology of benzodiazepines (BZDs) asa class is described in Ch. 9. Some members havea slow and prolonged action, relieve anxiety atlow doses without producing significant CNSdepression. In contrast to barbiturates, they are

more selective for the limbic system and haveproven clinically better in both quality andquantity of improvement in anxiety and stress-related symptoms. At antianxiety doses,cardiovascular and respiratory depression isminor.

Because anxiety is a common complaint, is apart of most physical and mental illness, andbecause BZDs:

(i) have little effect on other body systems,(ii) have lower dependence producing liability,

(iii) are relatively safe even in gross overdosage,

they are presently one of the most widely usedclass of drugs. Potent BZDs like lorazepam andclonazepam injected i.m. have adjuvant role inthe management of acutely psychotic and manicpatients. Higher doses induce sleep and impairperformance.

Adverse effects of BZDs noted in their use ashypnotics are described in Ch. 9. Side effectsthat occur in their use to relieve anxiety are—sedation, light-headedness, psychomotor andcognitive impairment, vertigo, confusional state(especially in elderly), increased appetite andweight gain, alterations in sexual function. Somewomen fail to ovulate while on regular use ofBZDs. The major constraint in their long-term usefor anxiety disorders is their potential to producedependence.

Differences between individual BZDs recom-mended for anxiety are primarily pharmaco-kinetic: choice of one over the other is largelyempirical.

BuspironeIt is the first azapirone, a new class of antianxietydrugs, distinctly different from BZDs. It:• Does not produce significant sedation or

cognitive/functional impairment.• Does not interact with BZD receptor or modify

GABAergic transmission.• Does not produce tolerance or physical depen-

dence.• Does not suppress BZD or barbiturate with-

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• Has no muscle relaxant or anticonvulsantactivity.Buspirone relieves mild-to-moderate

generalized anxiety, but is ineffective in severecases, in those showing panic reaction and inOCD. The therapeutic effect develops slowly:maximum benefit may be delayed up to 2 weeks.The mechanism of anxiolytic action is not clearlyknown, but may be dependent on its selectivepartial agonistic action on 5-HT1A receptors. Bystimulating presynaptic 5-HT1A autoreceptors, itreduces activity of dorsal raphe serotonergicneurones.

Side effects of buspirone are minor: dizziness,nausea, headache, light-headedness, rarelyexcitement. It does not potentiate CNS depres-sants. Though most patients on buspirone remainalert, those operating machinery/motor vehiclesshould be cautioned.

Hydroxyzine A H1 antihistaminic with sedative, anti-emetic, antimuscarinic and spasmolytic properties. It maybe used in reactive anxiety or that associated with markedautonomic symptoms.

βββββ Blockers (see Ch. 6)

Many symptoms of anxiety (palpitation, rise inBP, shaking, tremor, gastrointestinal hurrying,etc.) are due to sympathetic overactivity and thesesymptoms reinforce anxiety. Propranolol andother nonselective β blockers help anxiouspatients troubled by these symptoms, by cuttingthe vicious cycle and provide symptomatic relief.They do not affect the psychological symptomssuch as worry, tension and fear, but are valuablein acutely stressful situations (examination fear,unaccustomed public appearance, etc.). They maybe used for performance/situational anxiety oras adjuvant to BZDs.

Drugs having their major action on heart or bloodvessels, or those used primarily for cardiovasculardisorders are designated ‘Cardiovascular drugs’.They can act directly on the cardiovascularstructures or through the autonomic/centralnervous system, kidney, autacoids or hormoneswhich regulate cardiovascular function.

ANGIOTENSIN

Angiotensin II (AII) is an octapeptide generatedin the plasma from a precursor plasma α2 globulin,and is involved in electrolyte, blood volume andpressure homeostasis. Drugs that interfere withthe generation or action of AII have assumed greatimportance in the treatment of cardiovasculardiseases.

Renin-angiotensin system (RAS) The gene-ration and metabolism of AII in circulation isdepicted in Fig. 11.1. The enzyme renin secretedby kidney splits off a decapeptide Angiotensin I(AI) from angiotensinogen. AI is largely inactivebut is rapidly converted to AII by angiotensin-converting enzyme (ACE) which removes 2 aminoacids from the carboxy terminus of thedecapeptide. The ACE is located primarily on theluminal surface of vascular endothelial cells(especially in lungs). Circulating AII has a veryshort t½ (1 min); due to serial degradation bypeptidases termed angiotensinases.

Many tissues, especially heart, blood vessels,brain, kidneys, adrenals generate AII inside their

cells. Thus, local renin-angiotensin systemsappear to operate in several organs in addition tothe circulating one.

ACTIONS

1. The most prominent action of AII is vasocons-triction—produced directly as well as by enhan-cing Adr/NA release from adrenal medulla/adrenergic nerve endings and by increasing centralsympathetic outflow. BP rises acutely. As a pressoragent, AII is much more potent than NA.2. AII increases force of myocardial contractionby promoting Ca2+ influx. Reflex bradycardiapredominates in the intact animal. Cardiac outputis often reduced and cardiac work is increased(due to rise in peripheral resistance).3. Acting on a chronic basis AII induces hyper-trophy, hyperplasia and increased intercellularmatrix production in the myocardium andvascular smooth muscle by direct cellular effects.Indirectly, volume overload and increased t.p.r.caused by AII contributes to the hypertrophy andremodeling (abnormal redistribution of musclemass) in heart and blood vessels. Fibrosis anddilatation of infarcted area with hypertrophy ofthe noninfarcted ventricular wall is seen aftermyocardial infarction. Progressive cardiac myo-cyte death and fibrotic transformation occursin CHF. These changes are important risk factorsfor cardiovascular morbidity and mortality.ACE inhibitor therapy retards/reverses many of

11Cardiovascular Drugs

Drugs Affecting Renin-Angiotensin System, Calcium ChannelBlockers, Drugs for Hypertension, Angina Pectoris and

Myocardial Infarction

172 Cardiovascular DrugsS

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Fig. 11.1: Physiological regulation of electrolyte balance, plasma volumeand blood pressure by the renin-angiotensin system

these changes imparting a pivotal role to AII invascular and ventricular hypertrophy, apoptosisand remodeling.4. AII contracts many visceral smooth musclesin vitro, but in vivo effects are insignificant.5. AII and AIII are trophic to zona glomerulosaof the adrenal cortex—enhance synthesis andrelease of aldosterone. This acts on distal tubuleto promote Na+ reabsorption and K+/H+ excretion.These effects are exerted at concentrations lowerthan those required to cause vasoconstriction.6. In addition to exerting indirect effect on kidneythrough aldosterone, AII promotes Na+/H+

exchange in proximal tubule → increased Na+,Cl– and HCO3¯ reabsorption.

Angiotensin receptors Specific angiotensinreceptors are present on the surface of target cells.Two subtypes (AT1 and AT2) have beendifferentiated pharmacologically: Losartan is aselective AT1 antagonist, while PD 123177 is aselective AT2 antagonist. Both subtypes are G-protein coupled receptors. However, all knowneffects of AII appear to be mediated by AT1

receptor. Though AT2 receptors have beendetected in several tissues and their activation

causes NO-dependent vasodilatation, promotesapoptosis and myocardial fibrosis, the functionsubserved by them is not clear.

PATHOPHYSIOLOGICAL ROLES

1. Mineralocorticoid secretion AII (also AIII)is the physiological stimulus for aldosteronesecretion from adrenal cortex.

2. Electrolyte, blood volume and pressure homeo-stasis The RAS plays an important role inmaintaining electrolyte composition and volumeof extracellular fluid (see Fig. 11.1). Changes thatlower blood volume or pressure, or decrease Na+

content induce renin release by:(i) Decreasing tension in the afferent glomeru-

lar arterioles: the intrarenal baroreceptor path-way.

(ii) Low Na+ concentration in the tubular fluidsensed by macula densa cells: the maculadensa pathway.

(iii) Baroreceptor and other reflexes whichincrease sympathetic impulses to JG cells—activated through β1 receptors: the β adreno-ceptor pathway.

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Angiotensin Converting Enzyme Inhibitors 173

Increased renin is translated into increasedplasma AII which produces acute rise in BP byvasoconstriction, and more longlasting effects bydirectly as well as indirectly increasing Na+ andwater reabsorption in the kidney. Rise in BP inturn inhibits renin release.

3. Development of hypertension The RAS isdirectly involved in renovascular hypertension:plasma renin activity (PRA) is raised in mostpatients. In essential hypertension andpregnancy-induced hypertension also it appearsto have a permissive role.

4. Secondary hyperaldosteronism The RAS isinstrumental in the development of secondaryhyperaldosteronism.

5. CNS AII can be formed locally in the brainand may function as transmitter or modulator.Regulation of thirst, hormone release and sym-pathetic flow may be the responses mediated.

Inhibition of renin-angiotensin system It canbe achieved by:1. Sympathetic blockers (β blockers, adrenergic

neurone blockers, central sympatholytics)—decrease renin release.

2. Renin inhibitory peptides and renin specificantibodies block renin action—interfere withgeneration of AI from angiotensinogen (ratelimiting step).

3. Angiotensin converting enzyme inhibitors—prevent generation of the active principle AII.

4. Angiotensin receptor (AT1) antagonists—block the action of AII on target cells.

5. Aldosterone antagonists—block mineralocor-ticoid receptors.

ANGIOTENSIN CONVERTINGENZYME INHIBITORS

Captopril, an orally active dipeptide ACE inhi-bitor, was introduced in 1977 and quickly gainedwide usage. A multitude of ACE inhibitors likeenalapril, lisinopril, benazepril, ramipril, perindopril,trandolapril, imidapril, and fosinopril, etc. are nowavailable. The pharmacology of captopril is

described as prototype since most of its effects areclass effects common to all ACE inhibitors.

Captopril

It is a sulfhydryl containing dipeptide surrogateof proline which abolishes the pressor actionof AI but not that of AII: does not block AIIreceptors.

By inhibiting their degradation it can alsoincrease plasma kinin levels and potentiate thehypotensive action of exogenously administeredbradykinin. Elevated kinins (and PGs whosesynthesis is enhanced by kinins) may be respon-sible for the cough and angioedema induced byACE inhibitors in susceptible individuals, butkinins do not appear to be important for theirhypotensive action in the long term.

Captopril lowers BP. This effect is moremarked in Na+ depleted subjects and in thosewith overactive RAS. Captopril-inducedhypotension is a result of decrease in totalperipheral resistance. Both systolic and diastolicBP fall. It has no effect on cardiac output.Cardiovascular reflexes are not interfered withand there is little dilatation of capacitance vessels.Because of these features, postural hypotensionis not a problem.

Reflex (postural) changes in plasma aldoste-rone are abolished and basal levels are decreasedas a consequence of loss of its regulation by AII.However, physiologically sufficient mineralo-corticoid is still secreted under the influence ofACTH and plasma K+.

Pharmacokinetics About 70% of orally adminis-tered captopril is absorbed. Presence of food instomach reduces its bioavailability. Penetrationin brain is poor. It is partly metabolized and partlyexcreted unchanged in urine. The plasma t½ is~2 hours, but actions last for 6–12 hours.

Adverse effects The adverse effect profile of allACE inhibitors is similar. Captopril is welltolerated by most patients; adverse effects are:1. Hypotension.


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2. Hyperkalemia more likely in patients withimpaired renal function and in those takingK+ sparing diuretics, NSAIDs or β blockers.

3. Cough: a persistent brassy cough occurs in4-16% patients within 1–8 weeks. This is notdose related and appears to be caused byinhibition of bradykinin/substance P break-down in the lungs of susceptible individuals.

4. Rashes, urticaria.5. Angioedema: resulting in swelling of lips,

mouth, nose, larynx may develop withinhours to a few days.

6. Dysguesia: reversible loss or alteration of tastesensation.

7. Foetopathic: foetal growth retardation, hypo-plasia of organs and foetal death may occur ifACE inhibitors are given during later half ofpregnancy.

8. Headache, dizziness, nausea and bowel upset.9. Granulocytopenia and proteinurea: are rare.10. Acute renal failure: is precipitated by ACE

inhibitors in patients with bilateral renal arterystenosis.

Interactions Indomethacin (and other NSAIDs)attenuate the hypotensive action. Hyperkalemiacan occur if K+ supplements/K+ sparing diureticsare given with captopril. Antacids reducebioavailability of captopril, while ACE inhibitorsreduce Li+ clearance and predispose to its toxicity.

Other ACE inhibitors Differences among ACEinhibitors are primarily pharmacokinetic reflectedin time course of their action; no single drug is

superior to others. Their important features aregiven in Table 11.1. Enalapril is a prodrug: has tobe converted in the body to the active form.Therefore, it acts slowly; is less likely to causeabrupt hypotension and is longer acting. OtherACE inhibitors are also slow acting, longer actingand more potent than captopril. Ramipril isclaimed to cause greater inhibition of tissue RASbecause of extensive tissue distribution.

USES

1. Hypertension ACE inhibitors are now firstline drugs in all grades of hypertension. About50% patients respond to monotherapy with ACEinhibitors, and majority of the rest to theircombination with diuretics or β blockers or both.They offer many advantages:

(i) Lack of postural hypotension, electrolytedisturbances, feeling of weakness and CNSeffects.

(ii) Safety in asthmatics, diabetics and peri-pheral vascular disease patients.

(iii) Reverse left ventricular hypertrophy andincreased wall-to-lumen ratio of bloodvessels that occurs in hypertensive patients.

(iv) No hyperuricaemia, no deleterious effect onplasma lipid profile.

(v) No rebound hypertension on withdrawal.(vi) Minimum worsening of quality of life

parameters like general wellbeing, workperformance, sleep, sexual performance,etc.

Table 11.1: Comparative features of ACE inhibitors

Captopril Enalapril Lisinopril Perindopril Ramipril

1. Chemical nature Sulfhydryl Carboxyl Carboxyl Carboxyl Carboxyl

2. Activity status Active Prodrug Active Prodrug Prodrug

3. Bioavailability 70% 50% 25% 20% 60%(as active form)

4. Time to peak action 1 hr 4–6 hr 6–8 hr 6 hr 3–6 hr

5. Elimination t½ 2 hr 11 hr 12 hr 25–30 hr 8–48 hr

6. Mode of excretion Renal Renal Renal Renal Renal

7. Duration of action 6–12 hr 24 hr > 24 hr > 24 hr >24 hr

8. Daily dose (mg) 25–150 2.5–40 5–40 2–8 1.25–10

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2. CHF ACE inhibitors cause both arteriolarand venodilatation in CHF patients: reduce after-load as well as preload. Though they have nodirect myocardial action, stroke volume andcardiac output are increased while heart rate isreduced. Considerable symptomatic relief isobtained in nearly all grades of CHF.

ACE inhibitors also retard the progression ofleft ventricular systolic dysfunction and prolongsurvival of CHF patients. Long-term benefits ofACE inhibitors may also accrue from withdrawalof AII mediated ventricular hypertrophy, remodel-ing, accelerated myocyte apoptosis and fibrosis.

Thus, ACE inhibitors are the first line drugsin CHF.

3. Myocardial infarction (MI) ACE inhibitorsadministered while MI is evolving (within 24 hrof an attack) and continued for 6 weeks to severalyears reduce early as well as long-term mortality.

4. Prophylaxis in high cardiovascular risksubjects ACE inhibitors are protective in highcardiovascular risk subjects even when there isno associated hypertension or left ventriculardysfunction. Protective effect is exerted both onmyocardium as well as vasculature and isindependent of hypotensive action.

5. Diabetic nephropathy Prolonged ACE inhibi-tor therapy has been found to prevent or delayend-stage renal disease in type I as well as type IIdiabetics.

Chronic renal failure due to nondiabeticcauses may also be improved by ACE inhibitors.

6. Scleroderma crisis ACE inhibitors producedramatic improvement and are life saving.

ANGIOTENSIN ANTAGONISTS

Over the past 2 decades, several nonpeptide orallyactive AT1 receptor antagonists have beendeveloped as alternatives to ACE inhibitors. Theseinclude losartan, candesartan, irbesartan, valsartan,telmisartan and few others. Selective antagonistsof AT2 receptors as well as combined AT1 + AT2

antagonists have also been produced but none isin clinical use.

Losartan It is a competitive antagonist andinverse agonist of AII and 10,000 times moreselective for AT1 than for AT2 receptor; does notblock any other receptor or ion channel. It blocksall overt actions of AII viz. vasoconstriction,central and peripheral sympathetic stimulation,release of aldosterone and Adr from adrenals,renal actions promoting salt and waterreabsorption, central actions like thirst, vaso-pressin release and growth-promoting actions onheart and blood vessels. No inhibition of ACEhas been noted.

Pharmacologically, AT1 antagonists differfrom ACE inhibitors in that they do not interferewith degradation of bradykinin and other ACEsubstrates: no rise in level or potentiation ofbradykinin occurs. Consequently, many patientswho develop cough with ACE inhibitors, tolerateit well.

Losartan causes fall in BP in hypertensivepatients which lasts for 24 hours, while HRremains unchanged and cardiovascular reflexesare not interfered. No significant effect on plasmalipid profile, carbohydrate tolerance, insulinsensitivity has been noted. It is also a milduricosuric. Data so far suggests that losartan hasthe same potential for regressing hypertensive leftventricular hypertrophy as ACE inhibitors.

Pharmacokinetics Oral bioavailability of losartanis only 33% due to first pass metabolism. It ispartially carboxylated in liver to an activemetabolite (E3174) which is a 10-30 times morepotent noncompetitive AT1 antagonist. Bothcompounds are 98% plasma protein bound, donot enter brain and are excreted by the kidney.The plasma t½ of losartan is 2 hours, but that ofE3174 is 6–9 hours.

Adverse effects Losartan is well tolerated; hasside effect profile similar to placebo. Like ACEinhibitors, it can cause hypotension andhyperkalemia, but first dose hypotension isuncommon and losartan is largely free of coughand dysguesia inducing potential. Headache,dizziness, weakness and upper g.i. side effectsare mild and occasional.

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Candesartan is dose to dose more potent, val-sartan and telmisartan nearly equipotent, whileIrbesartan is less potent than losartan, but theirpharmacological profile and uses are similar.

Uses of AT1 antagonists Losartan and otherAT1 antagonists are now first line antihyper-tensive drugs as alternative to ACE inhibitors,comparable in efficacy and other desirablefeatures, with the advantage of not inducingcough and a low incidence of angioedema, rashand dysguesia. AT1 antagonists are as effectiveas ACE inhibitors in CHF, MI and diabeticnephropathy as well.

CALCIUM CHANNEL BLOCKERS

These are an important class of cardiovasculardrugs which act by inhibiting L-type of voltagesensitive calcium channels in smooth musclesand heart. There are 3 pharmacologically distinctsubclasses of calcium channel blockers (CCBs):(a) Phenylalkylamines: Verapamil(b) Benzothiazepines: Diltiazem(c) Dihydropyridines: Nifedipine, Felodipine,Amlodipine, Nitrendipine, Lacidipine, Nimo-dipine, Lercanidipine, Benidipine.

The two most important actions of CCBs are:(i) Smooth muscle (especially vascular) relaxa-

tion.(ii) Negative chronotropic, inotropic and dromo-

tropic action on heart.

Smooth muscle Smooth muscles depolariseprimarily by inward Ca2+ movement throughvoltage sensitive channel. These Ca2+ ions triggerrelease of more Ca2+ from intracellular stores andtogether bring about excitation-contractioncoupling (see Fig. 11.4). The CCBs cause relaxationby decreasing intracellular availability of Ca2+.They markedly relax arterioles but have mildeffect on veins. Extravascular smooth muscle(bronchial, biliary, intestinal, vesical, uterine) isalso relaxed.

Heart In the working atrial and ventricularfibres, Ca2+ moves in during the plateau phase ofAP and elicits contraction through binding totroponin. The CCBs would thus have negativeinotropic action.

The 0 phase depolarization in SA and A-Vnodes is largely Ca2+ mediated. Automaticity andconductivity of these cells appear to be dependenton the rate of recovery of the Ca2+ channel.

Recovery

Resting channel Activated channel Inactivated channel(Non-conducting) (Conducts Ca2+) (Non-conducting)

The L-type Ca2+ channels activate as well asinactivate at a slow rate. Consequently, Ca2+ depo-larized cells (SA and A-V nodal) have aconsiderably less steep 0 phase and longerrefractory period. The recovery process whichrestores the channel to the state from which it can

Table 11.2: Comparative properties of representative calcium channel blockers

Verapamil Nifedipine Diltiazem

1. Channel blocking potency ++ +++ +2. Frequency dependence of ++ – +

channel blockade3. Channel recovery rate Much delayed No effect Delayed4. Cardiac effects (In vivo

at usual clinical doses)Heart rate ↓ ↑ ↓, –A-V Conduction velocity ↓↓ – ↓Contractility –, ↓ ↑ ↓,↑Output –, ↓ ↑ –, ↑

5. Vascular smooth muscle ++ +++ +relaxation

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again be activated is delayed by verapamil and toa lesser extent by diltiazem (resulting indepression of pacemaker activity and conduction)but not by DHPs (they have no negativechronotropic/dromotropic action). Moreover,channel blockade by verapamil is enhanced athigher rates of stimulation, that by nifedipine isindependent of frequency, while diltiazem isintermediate. Thus, verapamil slows sinus rateand A-V conduction, but nifedipine does not.Effect of diltiazem on sinus node automaticity andA-V conduction is similar to that of verapamil.

The relative potencies to block slow channelsin smooth muscle do not parallel those in heart.The DHPs are more selective for smooth muscleL channels: at concentrations which cause vaso-dilatation they have negligible negative inotropicaction. Diltiazem causes less depression ofcontractility than verapamil. Important differen-ces between the three representative CCBs aresummarized in Table 11.2.

Verapamil causes vasodilatation as well ascardiac depression. Along with lowering of BP, itproduces bradycardia, depresses A-V conductionand may worsen heart failure. It should not beused concurrently with β blockers or other cardiacdepressants.

Diltiazem has less marked cardiodepressantactivity: fall in BP is attended by little change ordecrease in the HR. Though it produces milderside effects, drug interactions and contraindi-cations remain the same as for verapamil.

Nifedipine is a rapidly acting dihydropyridine(DHP) with short duration of action. It frequentlyproduces flushing, palpitation, headache andankle edema. Direct depression of heart is minimaland overshadowed by reflex sympathetic stimu-lation. Nifedipine has paradoxically worsenedangina pectoris in some patients and has beenassociated with higher mortality amongpostmyocardial infarct subjects. The slow andlong-acting DHPs have replaced nifedipine.

Amlodipine is pharmacokinetically the mostdistinct DHP. It is absorbed very slowly (peakafter 6–9 hours) and acts for > 24 hours. The early

vasodilator side effects like flushing, palpitation,headache, postural dizziness are largely avoided.A single daily dose is sufficient.

Felodipine, nitrendipine, lercanidipine, benidi-pine and lacidipine are the other highlyvasoselective long-acting DHPs.

Nimodipine is a short-acting DHP whichselectively relaxes cerebral vasculature; hasbeen specifically indicated for prevention of neuro-logical deficit following subarachnoid haemor-rhage.

An occasional adverse effect of prolonged CCBtherapy having implications in dentistry is gumhyperplasia.

USES

1. Angina pectoris All CCBs are effective inreducing frequency and severity of classical aswell as variant angina. Benefit in classical anginaappears to be primarily due to reduction in cardiacwork: mainly as a result of reduced afterload.Though they can increase coronary flow in normalindividuals, this is unlikely to be significant inpatients with fixed arterial obstruction. Exercisetolerance is increased.

However, myocardial ischaemia may beaggravated by short-acting DHPs. This may bedue to decreased coronary flow secondary to fallin mean arterial pressure, reflex tachycardia andcoronary steal. Trials using high dose regularshort-acting nifedipine formulation have reportedincreased mortality among MI patients. Thesudden rush of sympathetic activity evoked byeach dose of these preparations has been heldresponsible for the deleterious effect. The directcardiac effect of verapamil and diltiazem to reduceO2 requirement as well as less marked reflexsympathetic stimulation makes these drugs lesslikely to aggravate ischaemia.

The capacity of CCBs to prevent arterial spasmis undoubtedly responsible for the beneficial effectin variant angina.

2. Hypertension CCBs are one of the first lineantihypertensive drugs. Though all 3 subgroups

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of CCBs are equally efficacious, the long-actingDHPs (e.g. amlodipine) are most commonly usedfollowed by diltiazem. The CCBs lower BP byreducing peripheral resistance without compro-mising cardiac output. Their advantages are:1. Do not compromise haemodynamics: no

impairment of physical and mental workcapacity, no sedation.

2. Can be used in asthma, angina and peripheralvascular disease patients.

3. Do not affect male sexual function.4. No deleterious effect on plasma lipid profile,

uric acid level or electrolyte balance.5. Do not impair renal perfusion.6. No impairment of quality of life.7. No adverse foetal effects when given during

pregnancy.Verapamil and diltiazem are not suitable for

patients with CHF or cardiac conduction defectsbecause of their negative inotropic and dromo-tropic actions. On the other hand, DHPs mayaccentuate bladder voiding difficulty in elderlymales and gastroesophageal reflux.

3. Arrhythmias Verapamil and diltiazem arehighly effective in PSVT and for control ofventricular rate in supraventricular arrhythmias.4. Hypertrophic cardiomyopathy The negativeinotropic action of verapamil can be salutary inthis condition.

ANTIHYPERTENSIVE DRUGS

These are drugs used to lower BP in hypertension.Hypertension is a very common disorder,

particularly past middle age. As such, manypatients presenting for dental treatment are likelyto be on long-term antihypertensive drug therapy.

Hypertension is not a disease in itself but isan important risk factor for cardiovascularmorbidity and mortality. Though the risk appearsto increase progressively with BP values over 120(systolic)/80 (diastolic) mm Hg, hypertension hasbeen defined by WHO-ISH* guidelines to be valuesabove 140/90 mm Hg.

Majority of cases are of essential (primary)hypertension, i.e. the cause is not known. Sympa-thetic and renin-angiotensin systems may or maynot be overactive, but they do contribute to tone ofblood vessels and c.o. in hypertensives, as theydo in normotensives. Many antihypertensivedrugs interfere with these regulatory systems atone level or the other.

CLASSIFICATION

1. DiureticsThiazides: Hydrochlorothiazide,

Chlorthalidone, IndapamideHigh ceiling: Furosemide, etc.K+ Sparing: Spironolactone,

Triamterene, Amiloride2. ACE Inhibitors

Captopril, Enalapril, Lisinopril,Perindopril, Ramipril, Fosinopril, etc.

3. Angiotensin (AT1) AntagonistsLosartan, Candesartan, Irbesartan, etc.

4. Calcium Channel BlockersVerapamil, Diltiazem, Nifedipine, Felodipine,Amlodipine, Nitrendipine, Lacidipine, etc.

5. β Adrenergic BlockersPropranolol, Metoprolol, Atenolol, etc.

6. β + α Adrenergic BlockersLabetalol, Carvedilol

7. α Adrenergic BlockersPrazosin, Terazosin, Doxazosin,Phentolamine, Phenoxybenzamine

8. Central SympatholyticsClonidine, Methyldopa

9. VasodilatorsHydralazine, Sodium nitroprussideThe ACE inhibitors, angiotensin antagonists

and CCBs have already been described.

DIURETICS

Diuretics have been the standard antihyperten-sive drugs over the past 4 decades, but they donot lower BP in normotensives. Their pharma-cology is described in Ch. 13.

*WHO-ISH—World Health Organization and InternationalSociety of Hypertension.

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Antihypertensive Drugs 179

Thiazides and related drugs (chlorthalidone,etc.) are the diuretic of choice in uncomplicatedhypertension. The proposed mechanism of anti-hypertensive action is:1. Initially, the diuresis reduces plasma and e.c.f.volume by about 10% → decreased c.o.2. Subsequently, compensatory mechanismsoperate to almost regain Na+ balance and plasmavolume; c.o. is restored, but the fall in BP ismaintained by a slowly developing reduction int.p.r.3. The reduction in t.p.r. is most probably anindirect consequence of a small (~5%) persistingNa+ and volume deficit. Decrease in intracellularNa+ concentration in the vascular smooth musclemay decrease stiffness of vessel wall, increasetheir compliance and dampen responsiveness toconstrictor stimuli (NA, AII). Similar effects areproduced by salt restriction.

The fall in BP develops gradually over 2–4weeks. During long-term treatment with thia-zides, the heart rate and c.o. remain unaffected,while t.p.r. is reduced despite compensatoryincrease in plasma renin activity which confirmspersisting Na+ deficit. Thiazides have no effecton capacitance vessels, sympathetic reflexes arenot impaired: postural hypotension is rare.Thiazides are mild antihypertensives, average fallin mean arterial pressure is ~10 mm Hg. Theypotentiate all other antihypertensives (exceptDHPs) and prevent development of tolerance tothese drugs by not allowing expansion of plasmavolume. Maximal antihypertensive efficacy isreached at doses equivalent to 25 mg ofhydrochlorothiazide which has minimal diureticeffect. At 12.5–25 mg/day doses, complicationsof diuretic therapy like hypokalaemia, fatigue, lossof energy, impotence, carbohydrate intolerance,dyslipidemia, hyperuricaemia are absent or mild.As such, thiazides are a first choice antihyper-tensive, alone or in combination.

High ceiling diuretics Furosemide is a strongdiuretic, but a weaker antihypertensive thanthiazides. The explanation of this paradox maylie in its brief duration of action. The natriuretic

action lasting only for 4–6 hours after theconventional morning dose may not maintainNa+ deficient state in vascular smooth muscleround the clock. They are indicated in hyper-tension only when it is complicated by:(a) Chronic renal failure: thiazides are ineffective.(b) Coexisting refractory CHF.(c) Resistance to combination regimens contain-

ing a thiazide, or marked fluid retention dueto use of potent vasodilators.

Potassium sparing diuretics Spironolactoneor amiloride themselves lower BP slightly, butthey are used only in conjunction with a thiazidediuretic to prevent K+ loss and to augment theantihypertensive action.

Indapamide It is a mild diuretic, chemicallyrelated to chlorthalidone; reduces BP at doseswhich cause little diuresis or K+ loss.

β-ADRENERGIC BLOCKERS

The pharmacology and mechanism of antihyper-tensive action of β blockers is described in Ch. 6.They are mild antihypertensives; do not signifi-cantly lower BP in normotensives. Used alone theysuffice in 30–40% patients—mostly mild-to-moderate cases. In the large majority of the rest,they can be usefully combined with other drugs.

Their hypotensive response develops over 1–3 weeks and is well sustained. Despite short anddiffering plasma half-lives, the antihypertensiveaction of most β blockers is maintained over 24hours with single daily dose.

All β blockers, irrespective of associated pro-perties, exert similar antihypertensive effect.

There are several contraindications to βblockers, including cardiac, pulmonary andperipheral vascular disease and diabetes. Thenonselective β blockers have an unfavourableeffect on lipid profile (raise triglyceride level andLDL/HDL ratio). They have also fared less wellon quality of life parameters like decreased workcapacity, fatigue, loss of libido and subtle cogni-tive effects (forgetfulness, low drive). However,most of these drawbacks are minimized in the β1


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selective agents and in those which penetratebrain poorly. Thus, there are several reasons toprefer a β1 selective hydrophilic drug like atenololover propranolol.

Because of absence of postural hypotension,bowel alteration, salt and water retention; a lowincidence of side effects, low cost; once a dayregimen and cardioprotective potential, β blockerscontinue to be one of the first line antihypertensivedrugs.

β + α ADRENERGIC BLOCKERS

Labetalol It is a combined α and β blocker;reduces t.p.r. and acts faster than pure β blockers.It has been used i.v. for rapid BP reduction incheese reaction, clonidine withdrawal, etc. Orallabetalol therapy is restricted to moderately severehypertension not responding to pure β blocker.Side effects of both α blocker and β blocker occurwith it.

Carvedilol This nonselective β + selective α1

blocker produces vasodilatation and hasadditional antioxidant/free radical scavengingproperties.

α-ADRENERGIC BLOCKERS

Prazosin (See Ch. 6)This prototype of selective α1 antagonists dilatesboth resistance and capacitance vessels; effect onthe former predominating. The haemodynamiceffects—reduction in t.p.r. and mean BPaccompanied by only slight decrease in venousreturn and c.o. are similar to that produced by adirect acting vasodilator. However, there is littlereflex cardiac stimulation and renin releaseduring long-term therapy. Tachycardia does notcompensate for the fall in BP because releaseinhibitory α2 (presynap-tic) receptors are notblocked: autoregulation of NA release remainsintact.

Renal blood flow and g.f.r. are maintained butfluid retention may attend fall in BP. Cardio-vascular reflexes are not appreciably impairedby chronic therapy, but postural hypotension and

fainting may occur in the beginning—called ‘firstdose effect’

Other advantages of prazosin are:1. Improves carbohydrate metabolism.2. Has favourable effect on lipid profile.3. No impairment of cardiac contractility. Does

not alter exercise capacity and uric acid levels.4. Affords symptomatic improvement in coexis-

ting PVD or benign prostatic hypertrophy.Prazosin is a moderately potent antihypertensivewith many desirable features, but is not used as afirst choice drug because fluid retention and tole-rance gradually develops; risk of CHF is increased.

Terazosin, Doxazosin These are long-actingcongeners of prazosin with similar properties andare suitable for once daily dosing.

Nonselective α blockers (Phentolamine,Phenoxybenzamine)

The conventional α blockers have been disappointing forroutine treatment of hypertension and are reserved forspecial situations like pheochromocytoma, clonidinewithdrawal, cheese reaction, etc., where circulating CAsare responsible for the rise in BP.

CENTRAL SYMPATHOLYTICS

Clonidine It is an imidazoline derivative having complexactions. Clonidine is a partial agonist with high affinityand high intrinsic activity at α2 receptors, especially α2A

subtype in brainstem. The major haemodynamic effectsresult from stimulation of α2A receptors present mainlypostjunctionally in medulla (vasomotor centre) → decreasesympathetic outflow → fall in BP and bradycardia (alsodue to enhanced vagal tone). In addition, clonidineactivates specific imidazoline receptors in the brain that alsomediate reduction in central sympathetic tone.Clonidine is a moderately potent antihypertensive.

Clonidine is active orally; metabolized as well asexcreted unchanged in urine with a t½ of 8-12 hours. Effectof a single dose lasts for 6–24 hours.

Adverse effects Side effects with clonidine are relativelycommon and disturbing.• Sedation, mental depression, disturbed sleep; dryness

of mouth, nose and eyes, constipation.• Impotence, salt and water retention, bradycardia.• Postural hypotension occurs, but is mild.• Rebound hypertension with tachycardia, restlessness,

headache, sweating occurs on sudden stoppage ofclonidine therapy due to:

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Antihypertensive Drugs 181

(a) Sudden removal of central sympathetic inhibitionresulting in release of large quantities of storedCAs.

(b) Supersensitivity of peripheral adrenergic struc-tures to CAs.

Regular schedule of drug administration must bemaintained to prevent rebound phenomena.

Interactions Tricyclic antidepressants and chlorpromazineabolish the antihypertensive action of clonidine, probablyby blocking α receptors on which clonidine acts.

Use Moderate hypertension: relatively higher incidenceof side effects, impairment of quality of life and risk ofwithdrawal hypertension limit use of clonidine.

Other possible uses of clonidine are opioid withdrawalsyndrome, postoperative epidural analgesia and meno-pausal syndrome.

Methyldopa It is the α-methyl analogue of dopa, theprecursor of dopamine (DA) and NA. The α methyl-NA(a selective α2 agonist) formed in the brain frommethyldopa acts on central α2 receptors to decrease efferentsympathetic activity. Because methyldopa decreases t.p.r.more than HR or c.o., it may be acting on a differentpopulation of neurones in the vasomotor centre thanclonidine. In large doses it inhibits the enzyme dopadecarboxylase in brain and periphery → reduces NAsynthesis and forms the false transmitter methyl-NA inperiphery as well.

Methyldopa is a moderate efficacy antihypertensive.Circulating levels of NA and renin tend to fall due toreduction in sympathetic tone.

Adverse effects Sedation, lethargy and reduced mentalcapacity are common side effects. Cognitive impairmentmay develop. Dryness of mouth, nasal stuffiness,headache, fluid retention, weight gain, impotence andpostural hypotension are the other side effects.

Hypersensitivity phenomena are positive Coombs’test, haemolytic anaemia, fever, rash, hepatitis, ‘flu’ likeillness, thrombocytopenia and rarely lupus syndrome.

Use Methyldopa was widely used for mild-to-moderatehypertension, but use has declined now because of theavailability of better tolerated agents. It is safe duringpregnancy.

VASODILATORS

Hydralazine/Dihydralazine It is a directly acting arte-riolar vasodilator with little action on venous capacitancevessels; reduces t.p.r. and causes greater reduction ofdiastolic than systolic BP. Reflex compensatory mecha-nisms are evoked which cause tachycardia, increase in c.o.and renin release → increased aldosterone → Na+ andwater retention. The disproportionate cardiac stimulationappears to involve direct augmentation of NA release and

myocardial contractility as well. Angina may be precipi-tated due to increased cardiac work as well as stealphenomenon. Tolerance to the hypotensive action developsunless diuretics or β blockers or both are given together toblock the compensatory mechanisms. The mechanism ofvascular smooth muscle relaxant action is not clearlyknown.

Hydralazine is well absorbed orally. The chiefmetabolic pathway is acetylation, and there are slow orfast acetylators.

The hypotensive effect lasts for 12 hours.

Adverse effects are frequent and mainly due tovasodilatation.1. Facial flushing, conjunctival injection, throbbingheadache, dizziness, palpitation, nasal stuffiness, fluidretention, edema, CHF.2. Angina and MI may be precipitated in patients withcoronary artery disease.3. Paresthesias, tremor, muscle cramps, edema, rarelyperipheral neuritis.4. Lupus erythematosus or rheumatoid arthritis likesymptoms develop on prolonged use of doses above 100mg/day.

Use Hydralazine is occasionally used in moderate-to-severe hypertension not controlled by the first line drugs.Usually, low doses are added to diuretics andβ blockers.

It is one of the preferred antihypertensives duringpregnancy.

Sodium nitroprusside It is a rapidly (withinseconds) and consistently acting vasodilator: hasbrief duration of action (2–5 min)—vascular tonecan be titrated with the rate of i.v. infusion. Itrelaxes both resistance and capacitance vessels:reduces t.p.r. as well as c.o. (by decreasing venousreturn). Myocardial work is reduced—ischaemiais not accentuated, as occurs with selective arte-riolar dilators (hydralazine). Little reflex tachy-cardia is produced in supine posture.

Endothelial cells, RBCs (and may be othercells) split nitroprusside to generate NO whichrelaxes vascular smooth muscle. The enzymesinvolved are different from those that produce NOfrom glyceryl trinitrate. Moreover, nitroprussideis spontaneously converted to NO (and CN) byglutathione. This may be responsible for thedifferent pattern of vasodilator action comparedto nitrates, as well as for the fact that no nitratelike tolerance develops to nitroprusside action.


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Nitroprusside has gained popularity in themanagement of hypertensive emergencies: 50 mgis added to a 500 ml bottle of saline. The infusionis started at 0.02 mg/min and titrated upwardwith the response.

Side effects due to the vasodilator action ofnitroprusside are—palpitation, nervousness,vomiting, perspiration, pain in abdomen, weak-ness, disorientation, and lactic acidosis.

Nitroprusside has also been used to producecontrolled hypotension and in refractory CHF,pump failure accompanying MI, acute mitralregurgitation. The ventricular performance isimproved by reducing both pre- and afterload.

TREATMENT OF HYPERTENSION

The aim of antihypertensive therapy is to preventmorbidity and mortality associated with persis-tently raised BP by lowering it to an acceptablelevel, with minimum inconvenience to the patient.Both systolic and diastolic BP predict the likeli-hood of target organ damage and complicationssuch as:(a) Cerebrovascular disease, transient ischaemic

attacks, stroke.(b) Hypertensive heart disease—left ventricular

hypertrophy, CHF.(c) Coronary artery disease, angina, myocardial

infarction, sudden cardiac death.(d) Arteriosclerotic peripheral vascular disease,

retinopathy.(e) Dissecting aneurysm.(f) Glomerulopathy, renal failure.Nonpharmacological measures (life style modi-fication—diet, exercise, weight reduction, mentalrelaxation, etc.) should be tried first and con-currently with drugs.

With the establishment of at least five groups(ACE inhibitors, AT1 antagonists, CCBs, βblockers, diuretics) of first choice drugs and theirevaluation in large multicentric trials, an‘individualized care approach’ can be adoptedfor the selection of initial monotherapy, followedif needed, by stepped combination therapy. The

principle of this approach is to match therequirements of individual patients with thepharmacological and clinical properties of anappropriate antihypertensive agent. For each classof antihypertensive drugs, certain patients canbe identified who are best suited to be treated withthat drug as first choice therapy, and those inwhom it should be avoided.

Combination therapy Though ~50% hyperten-sives can be successfully treated, at least initially,with a single drug, the addition of a second (andthird) drug when monotherapy fails or is nottolerated, is often required. In practice a largemajority of hypertensives ultimately require 2 ormore drugs.

It is rational in such cases to combine drugswith different mechanisms of action or differentpatterns of haemodynamic effects:(a) Drugs which increase plasma renin activity—

diuretics, vasodilators, CCBs, ACE inhibitorsmay be combined with drugs which lowerplasma renin activity—β blockers, clonidine,methyldopa.

(b) All sympathetic inhibitors (except β blockers)and vasodilators cause fluid retention: usedalone tolerance develops. Addition of a diure-tic checks fluid retention and development oftolerance.

(c) Hydralazine and DHPs cause tachycardiawhich is counteracted by β blockers, whilethe initial increase in t.p.r. caused by non-selective β blockers is counteracted by thevasodilator.

(d) ACE inhibitors/AT1 antagonists are particu-larly synergistic with diuretics; this combi-nation is very good for patients with asso-ciated CHF and left ventricular hypertrophy.

(e) Other useful combinations are:ACE inhibitor + CCB or β blocker or clonidineor methyldopa.β blocker + prazosinA three drug combination therapy may be

needed in a few patients (of severe or nonrespon-sive or malignant hypertension).

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Combinations to be avoided are:1. An α or β adrenergic blocker with clonidine:

apparent antagonism of clonidine action hasbeen observed.

2. Nifedipine (or other DHPs) with diuretic:synergism between these is unproven.

3. Hydralazine with a DHP or prazosin: similarpattern of haemodynamic action.

4. Verapamil or diltiazem with β blocker: mar-ked bradycardia, A-V block.

5. Methyldopa with clonidine or any two drugsof the same class.

Hypertensive emergencies and urgencies

Controlled reduction of BP over minutes (inemergencies) or hours (in urgencies) is requiredto counter threat to organ function and life in:1. Cerebrovascular accident (haemorrhage) or

head injury with high BP.2. Hypertensive encephalopathy.3. Hypertensive acute LVF and pulmonary

edema.4. Unstable angina or MI with raised BP.5. Dissecting aortic aneurysm.6. Eclampsia.7. Hypertensive episodes in pheochromocytoma,

cheese reaction or clonidine withdrawal.The practice of using rapidly acting oral drugslike nifedipine (soft gelatine capsule), Captopril orClonidine for urgent BP reduction has beenfound unsatisfactory and therefore abandoned.Parenteral drugs with controllable action are nowused. Mean BP should be lowered by no morethan 25% over minutes or a few hours and thengradually to not lower than 160/100 mmHg.Drugs employed are:1. Sodium nitroprusside Because of predictable,

instantaneous, titratable and balanced arterio-venous vasodilatory action which persistswithout tolerance till infused, nitroprussideis the drug of choice for most hypertensiveemergencies. However, it needs an infusionpump and constant monitoring.

2. Glyceryl trinitrate Given by i.v. infusion GTNalso acts within 2–5 min and has brief

titratable action. Its predominant venodilatoraction makes it particularly suitable forlowering BP after cardiac surgery and in acuteLVF, MI, unstable angina.

3. Esmolol This β blocker given as bolusfollowed by slow i.v. injection acts in 1–2 min;action lasts for 10–20 min. It is particularlyuseful when cardiac contractility and work isto be reduced, such as in aortic dissection(nitroprusside may be given concurrently) andduring/after anaesthesia.

4. Phentolamine This α1 + α2 blocker is the drugof choice for hyperadrenergic states—hypertensive episodes in pheochromocytoma,cheese reaction, clonidine withdrawal.

Antianginal Drugs 183

ANTIANGINAL DRUGS

Antianginal drugs are those that prevent, abortor terminate attacks of angina pectoris.

Angina pectoris Is a pain syndrome due to induction ofan adverse oxygen supply/demand situation in a portionof the myocardium. Two principal forms are recognized:

(a) Classical angina (common form) Attacks arepredictably (stable angina) provoked by exercise, emotion,eating or coitus and subside when the increased energydemand is withdrawn. The underlying pathology is—severe arteriosclerotic affliction of larger coronary arteries(conducting vessels) which run epicardially and send per-forating branches to supply the deeper tissue (Fig. 11.2).The coronary obstruction is ‘fixed’; blood flow fails toincrease during increased demand despite local factorsmediated dilatation of resistance vessels (Fig. 11.3) andischaemic pain is felt. Due to inadequacy of ischaemic left

Fig. 11.2: Diagrammatic representation of subendocardial‘crunch’ during an attack of angina


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Fig. 11.3: Diagrammatic representation of coronary arterycalibre changes in classical and variant angina

ventricle, the end diastolic left ventricular pressure risesfrom 5 to about 25 mm Hg—produces subendocardial‘crunch’ during diastole (blood flow to the subendocardialregion occurs only during diastole) and aggravatesischaemia in this region.

Drugs that are useful, primarily reduce cardiac work(directly by acting on heart or indirectly by reducingpreload hence end diastolic pressure, and afterload). Theymay also cause favourable redistribution of blood flow tothe ischaemic areas.

(b) Variant/Prinzmetal’s/Vasospastic angina (uncommonform) Attacks occur at rest or during sleep and areunpredictable. They are due to recurrent localized(occasionally diffuse) coronary vasospasm (Fig. 11.3)which may be superimposed on arteriosclerotic coronaryartery disease. Abnormally reactive and hypertrophiedsegments in the coronary arteries have been demonstrated.Drugs are aimed at preventing and relieving the coronaryvasospasm.

Unstable angina with rapid increase in duration andseverity of attacks is mostly due to rupture of anatheromatous plaque attracting platelet deposition and

progressive occlusion of the coronary artery; occasionallywith associated coronary vasospasm.

Antianginal drugs relieve cardiac ischaemiabut do not alter the course of coronary arterypathology: no permanent benefit is afforded.

CLASSIFICATION

1. Nitrates(a) Short acting: Glyceryl trinitrate (GTN, Nitro-

glycerine)(b) Long acting: Isosorbide dinitrate (short acting

by sublingual route), Isosorbide mononitrate,Erythrityl tetranitrate, Penta erythritoltetranitrate

2. β Blockers Propranolol, Metoprolol, Atenololand others.

3. Calcium channel blockers: Verapamil,Diltiazem, Nifedipine, Felodipine, Amlodipine,Nitrendipine, Lacidipine, etc.

4. Potassium channel opener Nicorandil5. Others Dipyridamole, Trimetazidine,

Ranolazine.

Clinical Classification

A. Used to abort or terminate attack GTN,Isosorbide dinitrate (sublingually).

B. Used for chronic prophylaxis All other drugs.

NITRATES (GTN as prototype)

All organic nitrates share the same action; differonly in time course. The only major action is directnonspecific smooth muscle relaxation.

Preload reduction The most prominent action isexerted on vascular smooth muscle. Nitrates dilateveins more than arteries → peripheral pooling ofblood → decreased venous return, i.e. preload onheart is reduced → end diastolic size and pressureare reduced → decreased cardiac work.

The decrease in end diastolic pressureabolishes the subendocardial crunch by restoringthe pressure gradient across ventricular wall dueto which subendocardial perfusion occurs duringdiastole. It is through their action on peripheral

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veins that nitrates exert major beneficial effects inclassical angina.

After load reduction Nitrates also produce somearteriolar dilatation → slightly decrease totalperipheral resistance (t.p.r.) or afterload on heart;BP falls somewhat; systolic more than diastolic(reflex sympathetic activity tends to maintain dia-stolic BP). This action contributes to the reductionof cardiac work which is directly proportional toaortic impedance.

Redistribution of coronary flow In the arterialtree, nitrates preferentially relax bigger conduc-ting (angiographically visible) coronary arteriesthan arterioles or resistance vessels. This patternof action may cause favourable redistribution ofblood flow to ischaemic areas in angina patients.Dilatation of conducting vessels all over by thenitrate along with ischaemia induced dilatationof autoregulatory resistance vessels only in theischaemic zone increases blood flow to this area;while in the non-ischaemic zones, resistancevessels maintain their tone → flow does notincrease, or may decrease to compensate forincreased flow to ischaemic zone. In fact, nitratesdo not appreciably increase total coronary flowin angina patients.

Mechanism of relief of angina The dilator effecton larger coronary vessels is the principal actionof nitrates benefiting variant angina by counter-acting coronary spasm. In classical angina,undoubtedly, the primary action is to reducecardiac work by action on peripheral vasculature,though increased blood supply to ischaemic areamay contribute. Exercise tolerance of anginapatients is increased because the same amount ofexercise causes lesser augmentation of cardiacwork.

Heart and peripheral blood flow Nitrates haveno direct stimulant or depressant action on theheart. They dilate cutaneous (especially over faceand neck → flushing) and meningeal vessels →headache. Splanchnic and renal blood flowdecreases to compensate for vasodilatation in

other areas. Nitrates tend to decongest lungs byshifting blood to systemic circulation.

Other smooth muscles Bronchi, biliary tractand esophagus are relaxed; effect on intestine,ureter and uterus is variable and insignificant.

Mechanism of action Organic nitrates arerapidly denitrated enzymatically in the smoothmuscle cell to release the reactive free radical nitricoxide (NO) which activates cytosolic guanylylcyclase → increased cGMP → causes dephos-phorylation of myosin light chain kinase (MLCK)through a cGMP-dependent protein kinase (Fig.11.4). Reduced availability of phosphorylated(active) MLCK interferes with activation of myosin→ it fails to interact with actin to causecontraction. Consequently, relaxation occurs.Raised intracellular cGMP may also reduce Ca2+

entry—contributing to relaxation.

Pharmacokinetics Organic nitrates are lipidsoluble: well absorbed from buccal mucosa, intes-tines and skin. All except isosorbide mononitrate

Fig. 11.4: Mechanism of vascular smooth muscle relaxantaction of nitrodilators like glyceryl trinitrate and calciumchannel blockers; (- - - →) InhibitionCAM—Calmodulin; NO—Nitric oxide; MLCK—Myosin lightchain kinase; MLCK-P—Phosphorylated MLCK; GTP—Guanosine triphosphate; cGMP—Cyclic guanosine mono-phosphate


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undergo extensive but variable first passmetabolism in liver. They are rapidly denitratedby a glutathione reductase.

Adverse effects These are mostly due to vaso-dilatation.1. Fullness in head, throbbing headache; some

degree of tolerance develops on continued use.2. Flushing, weakness, sweating, palpitation,

dizziness and fainting; these are mitigated bylying down and accentuated by erect postureand alcohol.

3. Methemoglobinemia: is not marked withclinically used doses.

4. Rashes are rare.

Tolerance Attenuation of haemodynamic andantiischaemic effect of nitrates occurs if they arecontinuously present in the body. This toleranceweans off rapidly (within hours) when the bodyis free of the drug. Clinically, no significant tole-rance develops on intermittent use of sublingualGTN for attacks of angina. However, it maybecome important when GTN is used orally,transdermally or by continuous i.v. infusionround the clock.

The most practical way to prevent nitratetolerance is to provide nitrate free intervals everyday.

Interactions Sildenafil (a drug used for erectiledysfunction) causes dangerous potentiation ofnitrate action: severe hypotension, MI and deathsare on record. Additive hypotension is alsopossible when nitrate is given to a patientreceiving other vasodilators.

1. Glyceryl trinitrate (GTN, Nitroglycerine) Itis a volatile liquid which is absorbed on the inertmatrix of the tablet. The sublingual route is usedwhen terminating an attack or aborting animminent one is the aim. It acts within 1–2 min(peak blood level in 3–6 min) because of directabsorption into systemic circulation (bypassingliver where almost 90% is metabolized).

Plasma t½ is 2 min, duration of action dependson the period it remains available for absorptionfrom buccal mucosa. The remaining part of the

tablet may be spit or swallowed when no longerneeded. Sustained release oral capsules con-taining much larger amounts of GTN can be usedfor chronic prophylaxis.

Nitroglycerine is readily absorbed from theskin. A transdermal patch in which the drug isincorporated into a polymer bonded to adhesiveplaster (see p. 8) has been developed whichprovides steady delivery for 24 hours. However,development of tolerance and dependence mayjeopardise its value. It is advised that the patch betaken off for 8 hours daily.

Intravenous infusion of GTN has beensuccessfully used for unstable angina, coronaryvasospasm, LVF accompanying MI, hypertensionduring cardiac surgery, etc.

2. Isosorbide dinitrate It can be usedsublingually at the time of attack (slightly slowerin action than GTN, peak in 5–8 min) as well asorally for chronic prophylaxis. The t½ is 40 min,but sustained release formulation may affordprotection for 6–10 hours.

3. Isosorbide mononitrate This is an activemetabolite of isosorbide dinitrate. When adminis-tered orally, it undergoes little first pass meta-bolism: bioavailability is high, interindividualdifferences are minimal and it is longer acting (t½4–6 hr).

4. Erythrityl tetranitrate and pentaerythritoltetranitrate These are longer acting nitrates usedonly for chronic prophylaxis.

USES

1. Angina pectoris Nitrates are effective inclassical as well as variant angina. For abortingor terminating an attack, sublingual GTN tabletor isosorbide dinitrate is taken on ‘as and whenrequired’ basis. Since dental procedures are oftenan emotional stress, anginal attack may beprecipitated. Sublingual GTN tablet should be readilyavailable to abort/terminate such an attack on the dentalchair. Nitrates increase exercise tolerance andpostpone ECG changes of ischaemia. Longeracting formulations (oral, transdermal) of GTN

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or other nitrates are used on regular schedule forchronic prophylaxis. Nitrates are effective inunstable angina as well. However, antiplateletdrugs are the primary measure in unstableangina.2. CHF and acute LVF Nitrates afford relief byvenous pooling of blood → reduced venous return(preload) → decreased end diastolic volume →improvement in left ventricular function.Intravenous GTN is the preparation of choice foremergency use.3. Myocardial infarction Carefully titrated i.v.infusion of GTN to avoid tachycardia and startedsoon after the arterial occlusion can relievepulmonary congestion and limit the area ofnecrosis by favourably altering O2 balance in themarginal partially ischaemic zone by reducingcardiac work.4. Interventional cardiac procedures Such aspercutaneous coronary angioplasty to dilatecoronaries.5. Biliary colic due to disease or morphine—res-ponds to sublingual GTN or isosorbide dinitrate.6. Esophageal spasm Sublingual GTN prom-ptly relieves pain.7. Cyanide poisoning Nitrates generate met-haemoglobin which has high affinity for cyanideradical and forms cyanomethaemoglobin.Cytochrome and other oxidative enzymes are thusprotected from cyanide.

βββββ BLOCKERS

These drugs do not dilate coronaries or otherblood vessels; total coronary flow is rather reduceddue to blockade of dilator β2 receptors. However,flow to the ischaemic subendocardial area is notreduced because of favourable redistribution anddecrease in ventricular wall tension. They act byreducing cardiac work and O2 consumption(decreased heart rate, inotropic state and meanBP). This is marginal at rest. More importantly,they limit increase in these modalities that occursduring exercise or anxiety (due to antiadrenergicaction on heart).

All β blockers are nearly equally effective indecreasing frequency and severity of attacks andincreasing exercise tolerance in classical angina,but cardioselective agents (e.g. atenolol, meto-prolol) are preferred over nonselective β1 + β2

blockers (e.g. propranolol) which may worsenvariant angina. Long-term β blocker therapylowers risk of sudden cardiac death amongischaemic heart disease patients. β blockers areto be taken on a regular schedule; not on ‘as andwhen required’ basis.

β blockers are routinely used in unstableangina provided there are no contraindications.

CALCIUM CHANNEL BLOCKERS

Described earlier (see p. 177).

POTASSIUM CHANNEL OPENERS

Since intracellular concentration of K+ is much higher (150mM) compared to extracellular (4–5 mM), K+ channelopening results in outflow of K+ ions and hyperpola-rization. There are multiple types of K+ channels, e.g.voltage dependent, Ca2+ activated, receptor operated, ATPsensitive, Na+ activated and cell volume sensitive whichserve diverse functions and exhibit different sensitivitiesto drugs. As such, K+ channel openers exhibit considerablediversity in action. The most prominent action of K+

channel openers is smooth muscle relaxation—vascularas well as visceral.

Nicorandil This novel antianginal drug activa-tes ATP sensitive K+ channels— hyperpolarizingvascular smooth muscle. Like nitrates it also actsas a NO donor—relaxes blood vessels byincreasing cGMP. Thus, arterial dilatation iscoupled with venodilatation. Coronary flow isincreased; dilatation of both epicardial conduc-ting vessels and deeper resistance vessels hasbeen demonstrated. No significant cardiac effectson contractility and conduction have been noted.

Beneficial effects on angina frequency andexercise tolerance that are comparable to nitrates,β blockers and CCBs have been obtained in stableas well as vasospastic angina.

Side effects are flushing, palpitation, weakness,headache, dizziness, mouth ulcers, nausea andvomiting.


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OTHER ANTIANGINAL DRUGS

1. Dipyridamole It is a powerful coronary dilator withprimary action on arterioles, but does not afford sympto-matic benefit or avert ECG changes of angina. Thepharmacological success but therapeutic failure ofdipyridamole has been explained on the basis of ‘coronarysteal’ phenomenon. By dilating resistance vessels innonischaemic zone as well, it diverts the already reducedblood flow away from ischaemic zone.

Dipyridamole inhibits platelet aggregation. Thoughnot useful as an antianginal drug, it is being employed forprophylaxis of coronary and cerebral thrombosis in post-MI and post-stroke patients, as well as to preventthrombosis in patients with prosthetic heart valves.

2. Trimetazidine This novel antianginal drugacts by nonhaemodynamic mechanisms. Thereis no effect on determinants of myocardial O2

consumption, such as HR and BP, both at rest aswell as during exercise, but angina frequency isreduced and exercise capacity is increased. Inpatients not fully controlled by long-actingnitrate/β blocker/CCB, addition of trimetazidinefurther reduced anginal attacks and increasedexercise duration. The mechanism of action oftrimetazidine is not known, but it may improvecellular tolerance to ischaemia by:• Inhibiting a key enzyme LC 3-KAT of fatty acid

oxidation, thus shifting back ischaemicmyocardial metabolism to utilize glucose andsave O2.

• Limiting Na+, Ca2+ accumulation in ischaemiccells.Trimetazidine is generally well tolerated; side

effects are—gastric burning, dizziness, fatigueand muscle cramps.

Trimetazidine is popular in Europe and India,but not in UK and USA. It is mostly used asadditional medication to conventional therapyin angina and post-MI patients.3. Ranolazine This recently introducedinhibitor of LC 3-KAT or ‘metabolic modifier’ isindicated in chronic angina pectoris patients whofail to respond adequately to the standard therapy.It has been shown to shift ATP production inischaemic myocardium from fatty acid oxidationto more O2 efficient carbohydrate oxidation. It alsoreduces Ca2+ overload in myocardium during

ischaemia, and decreases frequency of anginalattacks. Currently, it is used only in combinationwith conventional therapy.

DRUG THERAPY IN MYOCARDIALINFARCTION

Myocardial infarction (MI) is ischaemic necrosisof a portion of the myocardium due to suddenocclusion of a branch of coronary artery. An acutethrombus at the site of atherosclerotic obstructionis the usual cause. About ¼ patients die beforetherapy can be instituted. The remaining are besttreated in specialized coronary care units withcontinuous monitoring of the haemodynamicparameters and ECG to guide the selection ofdrugs and dosage. Those who receive such facilitycan be greatly benefitted by drug therapy, whichaccording to individual needs is directed to:

1. Pain, anxiety and apprehension Opioid anal-gesics (morphine/pethidine), diazepam.

2. Oxygenation By O2 inhalation and assistedrespiration, if needed.

3. Maintenance of blood volume, tissue perfu-sion and microcirculation Slow i.v. infusion ofsaline/low molecular weight dextran (avoidvolume overload).

4. Correction of acidosis Due to lactic acidproduction—sod. bicarbonate by i.v. infusion.

5. Prevention and treatment of arrhythmiasProphylactic i.v. infusion of β blocker as soon asthe MI patient is seen and its continuation for afew days has been shown to reduce the incidenceof arrhythmias and mortality. β blockers usedearly in evolving MI can reduce the infarct size(myocardial salvage) and subsequent compli-cations.

Tachyarrhythmias may be treated with lido-caine, procainamide or other antiarrhythmics.Bradycardia and heart block may be managedwith atropine or electrical pacing.

6. Pump failure The objective is to increase c.o.and/or decrease filling pressure without unduly

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Drug Therapy in Myocardial Infarction 189

increasing cardiac work or reducing BP. Drugsused for this purpose are:(a) Furosemide: indicated if pulmonary wedge pres-sure is > 20 mm Hg. It decreases cardiac preload.(b) Vasodilators: arteriolar, venous or combineddilator is selected according to the monitoredhaemodynamic parameters. Drugs like GTN(i.v.), captopril, or nitroprusside have been mainlyused.(c) Inotropic agents: dopamine or dobutamine maybe needed to augment the pumping action of heartand tide over crisis.

7. Prevention of thrombus extension, embolism,venous thrombosis Heparin followed by oralanticoagulants. However, value is disputed. Anybenefit is short term; anticoagulants are notprescribed on long-term basis now.

8. Thrombolysis Fibrinolytic agents, i.e. plas-minogen activators—streptokinase/urokinase/alteplase to achieve reperfusion of the infarctedarea.

9. Prevention of remodeling and subsequentCHF ACE inhibitors have proven efficacy andafford long-term survival benefit.

10. Prevention of future attacks(a) Platelet function inhibitors—aspirin givenon long-term basis is routinely prescribed.(b) β blockers—reduce risk of reinfarction, CHFand mortality. All patients not having anycontraindication are put on a β blocker for atleast 2 years.(c) Control of hyperlipidaemia—dietary substi-tution with unsaturated fats, hypolipidemicdrugs.

CARDIAC GLYCOSIDES

These are glycosidic drugs having cardiac inotro-pic property. They increase myocardial contrac-tility and output in a hypodynamic heart withouta proportionate increase in O2 consumption.Thus, efficiency of failing heart is increased. Incontrast, ‘cardiac stimulants’ (Adr, theophylline)increase O2 consumption rather disproportiona-tely and tend to decrease myocardial efficiency,i.e. increase in O2 consumption is more thanincrease in contractility.

The cardiac glycosides are obtained fromDigitalis lanata (Digoxin), Digitalis purpurea(Digitoxin) and many other plants; some havebeen prepared semisynthetically. They consist ofan aglycone moiety made of cyclopentanoper-hydrophenanthrene (steroid) ring with attached5 or 6 membered unsaturated lactone ring and asugar moiety. Digoxin is the most commonly usedglycoside, therefore described as prototype.


Heart Digitalis has direct effects on myocardialcontractility and electrophysiological properties.In addition, it has vagomimetic action, reflexeffects due to alteration in haemodynamics anddirect CNS effects altering sympathetic activity.

1. Digitalis causes a dose dependent increase inforce of contraction of heart—a positive inotropicaction. This is specially seen in the failing heart.

When a normal heart is subjected to increasedimpedance to outflow, it generates increasedtension so that stroke volume is maintained up toconsiderably higher values of impedance (Fig.12.1), while the failing heart is not able to do soand the stroke volume progressively decreases.The digitalized failing heart regains some of itscapacity to contract more forcefully whensubjected to increased resistance to ejection. Thereis more complete emptying of failing and dilatedventricles—cardiac output is increased.

Fig. 12.1: Relationship between peripheral resistance andstroke output in normal and failing heart, and the action ofdigitalis on failing heart

2. Therapeutic doses of digoxin do not increasemyocardial tone or resting tension which isdefined by the maximum length of the musclefibre at a given filling pressure. However, toxicdoses do produce myocardial contracture.

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Cardiovascular DrugsDrugs for Heart Failure and Cardiac Arrhythmia

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Fig. 12.2: Mechanism of positive inotropic action of cardiac glycosides. SR—Sarcoplasmicreticulum; TnC—Troponin C; NCX—Na+-Ca2+ exchanger; RyR—Ryanodine receptor calciumchannel; PL—Phospholamban; SERCA—Sarcoplasmic-endoplasmic reticulum calcium ATPase

3. The heart rate is decreased by digitalis. Itproduces bradycardia by increasing vagal tone aswell as by a direct extravagal action exerted on SAand A-V nodes. In CHF patients improved cir-culation (due to positive inotropic action) restoresthe diminished vagal tone and abolishes sympa-thetic overactivity: decrease in heart rate is moremarked.

4. The electrophysiological properties of differenttypes of cardiac fibres are affected differently bydigitalis.• SA and A-V nodal automaticity is depressed

while that in Purkinje fibres (PFs) and otherpacemakers it is enhanced: arrhythmias maybe produced.

• Effective refractory period (ERP) of A-V nodeand bundle of His is prolonged: the maximalrate at which impulses can be transmitted fromatrium to ventricle is reduced.

• A-V conduction is slowed. Partial to completeA-V block can occur.

• Atrial ERP is abbreviated and made moreinhomogeneous: atria become more prone tofibrillation. Ventricular ERP is also reduced.

• Myocardial excitability is enhanced, but maybe depressed at toxic doses.

Mechanism of action Digitalis increases forceof cardiac contraction by inhibiting membraneassociated Na+K+ ATPase of myocardial fibres(Fig. 12.2). Inhibition of this cation pump resultsin progressive accumulation of Na+ intra-cellularly. This indirectly results in intracellularCa2+ accumulation by Na+ : Ca2+ exchange.

The excess Ca2+ remaining in cytosol is takenup into sarcoplasmic reticulum (SR) whichprogressively get loaded with more Ca2+ → sub-sequent calcium transients (brief bursts of Ca2+

release attending action potentials) are augmented→ better excitation-contraction coupling →increased force of contraction.

Binding of glycoside to Na+K+ATPase is slow.Moreover, after Na+K+ATPase inhibition, Ca2+

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loading occurs gradually. As such, inotropic effectof digitalis takes hours to develop, even after i.v.administration.

Inhibition of Na+K+ ATPase is clearly invol-ved in the toxic actions of digitalis. At high doses,there is depletion of intracellular K+; toxicity ispartially reversed by infusing K+. Excessive Ca2+

loading of SR results in spontaneous cycles ofCa2+ release and uptake producing oscillatoryafter-depolarizations and after-contractions.

Blood vessels Digitalis has mild direct vaso-constrictor action—peripheral resistance isincreased in normal individuals. However, inCHF patients this is more than compensated bythe indirect effect of improvement in circulationwhereby reflex sympathetic overactivity is with-drawn and a net decrease in peripheral resistanceoccurs. Digitalis has no prominent effect on BP.Hypertension is no contraindication to the use ofdigitalis.

Therapeutic doses of digitalis have no signi-ficant effect on coronary circulation—coronaryinsufficiency is no contraindication to its use.

Kidney Diuresis is seen promptly in CHFpatients, secondary to improvement in circulationand renal perfusion. The retained salt and wateris gradually excreted. No diuresis occurs innormal individuals or in patients with edema dueto other causes.

CNS Digitalis has little apparent CNS effect intherapeutic dose. Higher doses cause CTZactivation → nausea and vomiting. Still higherdoses produce hyperapnoea, central sympatheticstimulation, mental confusion, disorientation andvisual disturbances.

PHARMACOKINETICS

The pharmacokinetic properties of digoxin anddigitoxin are presented in Table 12.1.

Digitoxin is the most lipid soluble, digoxinis relatively polar. Bioavailability of digoxintablets from different manufacturers differs consi-derably.

The volume of distribution of cardiac glyco-sides is large, e.g. 6–8 L/kg in case of digoxin. Allare concentrated in the heart (~20 times thanplasma), skeletal muscle, liver and kidney.

Digoxin is primarily excreted unchanged bythe kidney: mainly by glomerular filtration; rateof excretion is altered parallel to creatinineclearance.

Cardiac glycosides are cumulative drugs.When maintenance doses are given from thebeginning, steady-state levels and full therapeuticeffect are attained after 4 × t½, i.e. 6–7 days fordigoxin and 4 weeks for digitoxin.

ADVERSE EFFECTS

Toxicity of digitalis is high, margin of safety islow (therapeutic index 1.5–3) and fatalities haveoccurred occasionally. The manifestations are:

Extracardiac Anorexia, nausea, vomiting andabdominal pain are usually reported first: are dueto gastric irritation, mesenteric vasoconstrictionand CTZ stimulation. Fatigue, malaise, headache,mental confusion, restlessness, hyperapnoea, dis-orientation, psychosis and visual disturbancesare the other complaints. Skin rashes and gynae-comastia are rare.

Cardiac Almost every type of arrhythmia can beproduced by digitalis: pulsus bigeminus, nodal

Table 12.1: Pharmacokinetic properties ofdigoxin and digitoxin

DIGITOXIN DIGOXIN

1. Oral absorption V. good Good(90–100%) (60–80%)

2. Plasma protein 95% 25%binding

3. Duration of action 2–3 weeks 2–6 days4. Plasma t½ 5–7 days 40 hr

5. Daily maintenance 0.05–0.2 mg 0.125–0.5 mgdose

6. Daily elimination* 10–15% 35%7. Route of elimination Hepatic Renal

(predominant) metabolism excretion8. Administration Oral Oral, i.v.

* fraction of total amount present in the body.

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and ventricular extrasystoles, ventricular tachy-cardia and terminally ventricular fibrillation.Partial to complete A-V block may be the solecardiac toxicity or it may accompany otherarrhythmias. Severe bradycardia, atrial extra-systoles, AF or AFl have also been noted.

Treatment Further doses of digitalis must bestopped at the earliest sign of toxicity; nothingmore needs to be done in many patients, especiallyif the manifestations are only extracardiac.

Tachyarrhythmias can be treated with KClinfusion. For ventricular arrhythmias lidocaineis preferred, while propranolol is generally givenfor atrial arrhythmias. Atropine may be tried incase of severe bradycardia/A-V block. The Fabfragment of digoxin antibody is used to bind theglycoside and accelerate its elimination.

PRECAUTIONS AND CONTRAINDICATIONS

(a) Hypokalemia: enhances digitalis toxicity.(b) Elderly, renal or severe hepatic disease: patientsare more sensitive.(c) Myocardial infarction: arrhythmogenic dose ofdigitalis may be reduced.(d) Thyrotoxicosis: patients are more prone todevelop digitalis arrhythmias.(e) Myxoedema: these patients eliminate digoxinmore slowly; cumulative toxicity can occur.(f) Ventricular tachycardia: digitalis is contraindi-cated.(g) Partial A-V block: may be converted to comp-lete A-V block.(h) Acute myocarditis: Diphtheria, acute rheumaticcarditis, toxic carditis—response is poor, moreprone to arrhythmias.(i) Wolff-Parkinson-White syndrome: Digitalis iscontraindicated.

INTERACTIONS

1. Diuretics: cause hypokalemia which can preci-pitate digitalis arrhythmias.2. Calcium: synergises with digitalis → precipi-tates toxicity.

3. Quinidine: reduces binding of digoxin to tissueproteins as well as its renal and biliary clearance→ toxicity can occur.4. Adrenergic drugs: can induce arrhythmias indigitalized patients. Plain lidocaine without Adrshould be injected for dental anaesthesia.5. Digoxin absorption can be reduced bymetoclopramide (gastrointestinal hurrying) andsucralfate which adsorbs digoxin. Antacids,neomycin, sulfasalazine: can also reduce digoxinabsorption. Absorption is increased by atropinicdrugs, including tricyclic antidepressants (whichdelay gastric emptying). Erythromycin, omepra-zole and tetracycline increase bioavailability ofdigoxin.6. Propranolol, verapamil, diltiazem and disopyra-mide: may additively depress A-V conduction andoppose positive inotropic action.

USES

The two main indications of digitalis are CHFand control of ventricular rate in atrial fibrilla-tion/flutter.

1. Congestive heart failure

CHF occurs when cardiac output is insufficientto meet the demands of tissue perfusion. Heartfailure may primarily be due to systolic dysfunc-tion or diastolic dysfunction.

Systolic dysfunction The ventricles are dilatedand unable to develop sufficient wall tension toeject adequate quantity of blood. This occurs inischaemic heart disease, valvular incompetence,dilated cardiomyopathy, etc.

Diastolic dysfunction The ventricular wall isthickened and unable to relax properly duringdiastole; ventricular filling is impaired because ofwhich output is low. It occurs in sustained hyper-tension, hypertrophic cardiomyopathy, etc.

However, most patients, especially long-standing CHF, have both systolic and diastolicdysfunction. Cardiac glycosides primarily miti-gate systolic dysfunction. Because of lower

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inotropic state, the failing heart is able to pumpmuch less blood at the normal filling pressure(Fig. 12.3), more blood remains in the ventricles atthe end of systole. The normal venous return isadded to it and Frank-Starling compensation isutilized to increase filling pressure: the heart maybe able to achieve the required stroke volume, butat a filling pressure which produces congestivesymptoms (venous engorgement, edema,enlargement of liver, pulmonary congestion →dyspnoea, renal congestion → oliguria).

Fig. 12.3: Relationship between filling pressure and cardiacoutput in normal and failing heart. Digitalis tends to shift thecurve towards normal

Digitalis induced enhancement of contrac-tility increases ventricular ejection and shiftsthe curve relating stroke output to filling pressuretowards normal, so that adequate output may beobtained at a filling pressure that does not producecongestive symptoms. Improved tissue perfusionresults in withdrawal of sympathetic overactivity→ heart rate and central venous pressure (CVP)are lowered towards normal. Compensatory mec-hanisms retaining Na+ and water are inactivated→ diuresis → edema is cleared. Liver regresses,pulmonary congestion is reduced → dyspnoeaabates, cyanosis disappears. Low output

symptoms like decreased capacity for muscularwork are mitigated.

Before the introduction of modern high ceilingdiuretics and ACE inhibitors, digitalis wasconsidered an indispensible part of anti-CHFtreatment. It is not so now. Many mild-to-moderatecases can be managed without digitalis, i.e. withdiuretics and vasodilators, especially an ACEinhibitor. Lately, β blockers have got added to thestandard therapy. However, digitalis is still themost effective drug capable of restoring cardiaccompensation in decompensated patients.Continued digitalis therapy is the best course inCHF patients with atrial fibrillation.

The two major limitations in the use of cardiacglycosides are low margin of safety and inabilityto reverse/retard the processes which cause theheart to fail.

2. Cardiac arrhythmias

A. Atrial fibrillation (AF) Digitalis is the drug ofchoice for controlling ventricular rate in AF,whether associated with CHF or not. However, itdoes not revert AF to sinus rhythm, evenperpetuates it.

Digitalis reduces ventricular rate in AF bydecreasing the number of impulses that are ableto pass down the A-V node and bundle of His.

B. Atrial flutter (AFI) The atrial rate is 200–350/min (less than that in AF), but contractions areregular and synchronous. A variable degree ofA-V block, depending on the mean ERP of A-Vnode, is naturally established. Digitalis enhancesthis A-V block, reduces ventricular rate andprevents sudden tachycardia due to shift of A-Vblock to a lower degree (as may occur duringexercise or sympathetic stimulation—commonduring dental procedure). Digitalis may convertAFl to AF by reducing atrial ERP and making itinhomogeneous.

C. Paroxysmal supraventricular tachycardia(PSVT) It is a common arrhythmia with a rate150–200/min and 1 : 1 A-V conduction. It is mostlydue to re-entry involving the SA or A-V node.

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A parenteral glycoside injected i.v. may terminatethe arrhythmia by increasing vagal tone, butverapamil/adenosine are more effective, less toxicand act faster. Digitalis is now reserved forpreventing recurrences in selected cases.

TREATMENT OF CHF

There are two distinct goals of drug therapy inCHF:(a) Relief of congestive/low output symptoms

and restoration of cardiac performance. Thisis afforded by:Inotropic drugs—Digoxin, dobutamine/dopamine, amrinone/milrinoneDiuretics—Furosemide, thiazidesVasodilators—ACE inhibitors/AT1 antago-nists, hydralazine, nitrateβ blocker—Metoprolol, bisoprolol, carvedilol,etc.

(b) Arrest/reversal of disease progression andprolongation of survival. This is achieved by:ACE inhibitors/AT1 antagonistsβ blockersAldosterone antagonist—Spironolactone.

Important nonpharmacological measures are restand salt restriction. The pathophysiologicalmechanisms which perpetuate heart failure andcontribute to disease progression, along with thesites of action of different categories of drugs aredepicted in Fig. 12.4.

Diuretics Almost all cases of symptomatic CHFare treated with a diuretic. High ceiling diuretics(furosemide, bumetanide) are the diuretics ofchoice for mobilizing edema fluid. Diuretics:(a) Decrease preload and improve ventricularefficiency by reducing circulating volume.(b) Remove peripheral edema and pulmonarycongestion.

However, diuretics do not influence theprimary disease process in CHF, though they maydramatically improve symptoms. Despite decadesof experience, no prognostic benefit has beendemonstrated for diuretics.

Vasodilators They are used i.v. to treat acuteheart failure that occurs in advanced cases, inmyocardial infarction and cardiogenic shock, aswell as orally for long-term therapy of chronic

Fig. 12.4: The vicious cycle in CHF: compensatory mechanisms evoked in response to reduced cardiac output themselvesperpetuate failure and contribute to remodeling responsible for disease progression. The parameter which is improved bydifferent therapeutic measures is indicated

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In the long term, survival benefit has beenobtained only with a combination of hydralazine+ isosorbide dinitrate or with ACE inhibitors/ARBs, the latter performing better than the former.Only ACE inhibitors and ARBs alter the course ofpathological changes in CHF; afford symptomaticas well as disease modifying benefits byretarding/reversing ventricular hypertrophy,myocardial cell apoptosis and remodeling.

βββββ1-Adrenergic blockers Though the earlyhaemodynamic action of β blockers is to depresscardiac contractility and ejection fraction, theseparameters gradually improve over weeks whencertain β blockers (metoprolol, bisoprolol,carvedilol) are given to selected CHF patients.After a couple of months, ejection fraction isgenerally higher than baseline, and slow upwardtitration of dose further improves cardiacperformance. The haemodynamic benefit ismaintained over long term and hospitalization/mortality due to worsening cardiac failure, aswell as all cause mortality is reduced. The benefitsappear to be due to antagonism of ventricular wallstress enhancing, apoptosis promoting andpathological remodeling effects of excesssympathetic activity in CHF, as well as due toprevention of sinister arrhythmias.

However, β blocker therapy in CHF requirescaution, proper patient selection and observanceof several guidelines.

Aldosterone antagonist (Spironolactone) Overthe past 2 decades, it has been realized that risein plasma aldosterone in CHF, in addition to itswell known Na+ and water retaining action, is animportant contributor to disease progression bydirect and indirect effects:(a) Expansion of e.c.f. volume → increasedcardiac preload.(b) Fibrotic change in myocardium → worseningsystolic dysfunction and pathological remode-ling.(c) Hypokalemia and hypomagnesemia →increased risk of ventricular arrhythmias andsudden cardiac death.

CHF, and have become the mainstay of anti-CHFmeasures. This class of drugs have been shownto improve life expectancy of CHF patients.Vasodilators with differing profiles of arteriolarand venodilator action are available.

Arteriolar dilators (primarily ↓↓↓↓↓ afterload)

HydralazineCa2+ channel blockers (Nifedipine)Pot. channel openers (Nicorandil)

Venodilators (primarily ↓↓↓↓↓ preload)

Nitrates:Glyceryl trinitrateIsosorbide dinitrate

Mixed dilators (↓↓↓↓↓ pre-and afterload)

ACE InhibitorsAT1 antagonists (ARBs)Prazosin (α1 blocker)PhentolamineNitroprusside.

(i) Preload reduction: Nitrates cause pooling ofblood in systemic capacitance vessels and reduceventricular end-diastolic presure and volume.Controlled i.v. infusion of glyceryl trinitrateaffords rapid relief in acute left ventricular failure.(ii) Afterload reduction: Hydralazine dilatesresistance vessels and reduces aortic impedanceso that even weaker ventricular contraction is ableto pump more blood. It is effective in forwardfailure, but tachycardia and fluid retention limitsits long term use. Other arteriolar dilators haveunproven efficacy in CHF.(iii) Pre-and afterload reduction: ACE inhibitors(captopril, enalapril and others) and AT1

antagonists (losartan, etc.) are orally activemedium efficacy nonselective arterio-venousdilators, while Sod. nitroprusside is high efficacyi.v. dilator with equal action on the two types ofvessels. These drugs act by both the abovemechanisms. Titrated infusion of nitroprussideis employed in conjunction with a loop diuretic +inotropic drug to tideover crisis in severelydecompensated patients.

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(d) Enhancement of cardiotoxic effect ofsympathetic overactivity.

The aldosterone antagonist spironolactone isa weak diuretic but can benefit CHF by anta-gonising the above effects of aldosterone. It isindicated as add-on therapy to ACE inhibitors ±other drugs in moderate-to-severe CHF. It canretard disease progression, reduce episodes ofdecompensation and death due to heart failureas well as sudden cardiac deaths over and abovethe protection afforded by ACE inhibitors/ARBs+ β blockers.

Sympathomimetic inotropic drugs

Drugs with β adrenergic and dopaminergic D1

agonistic actions have positive inotropic andvasodilator properties which may be utilized tocombat emergency pump failure. Dobutamine,a relatively selective β1 agonist with prominentinotropic action, is the preferred drug for i.v.infusion in acute heart failure accompanyingmyocardial infarction (MI), cardiac surgery aswell as to tide over crisis in advanced CHF.Dopamine has been used in cardiogenic shockdue to MI and other causes. These drugs affordadditional haemodynamic support over andabove vasodilators, digitalis and diuretics, butbenefits are short lasting. They have no role in thelong-term management of CHF.

Phosphodiesterase III inhibitors

Amrinone (Inamrinone), Milrinone These arebipyridine derivatives, and selective phospho-diesterase III (PDE III) inhibitors. This isoenzymeis specific for intracellular degradation of cAMPin heart, blood vessels and bronchial smoothmuscles. They increase myocardial cAMP andtransmembrane influx of Ca2+.

The two most important actions of amrinoneand milrinone are positive inotropy and directvasodilatation: have been called ‘inodilators’.

They are indicated only for short-term i.v. usein severe and refractory CHF, as additional drugto conventional therapy with digitalis, diureticsand vasodilators. Though active orally, theyafford no long-term benefits.

ANTIARRHYTHMIC DRUGS

These are drugs used to prevent or treat irregula-rities of cardiac rhythm.

Cardiac arrhythmias arise due to abnormalimpulse generation or abnormal impulseconduction or both. Ischaemia, electrolyte and pHimbalance, stretching, injury, neurogenic and druginfluences, including antiarrhythmic drugsthemselves, can cause arrhythmia by alteringelectrophysiological properties of cardiac fibres.The types of electrophysiological changesresulting in arrhythmias are:

Antiarrhythmic Drugs 197

Fig. 12.5: Normal action potential in a ventricular fibre (in red) followed byearly or delayed after-depolarizations


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Fig. 12.6: Diagrammatic representation of circusmovement re-entry in atrium

1. Enhanced or ectopic pacemaker activity.2. ‘Early after-depolarizations’ (associated with long

Q-T interval due to slow repolarization) and ‘delayedafter-depolarizations’ (due to Ca2+ overload) whichare triggered by a normal or premature action potential(AP) — hence called ‘triggered arrhythmias’ (Fig. 12.5).

3. Re-entry due to unidirectional conduction block of theimpulse and its recirculation around an obstacle(infarcted or refractory myocardium) causing repetitiveactivation of the adjacent fibres (Fig. 12.6).

4. Fractionation of the impulse due to inhomogeneousrefractory periods (RP) of different fibres. The impulsemoves rapidly through fibres with short RP, slowlythrough fibres with longer RP and not at all throughthose still refractory; different fibres get activatedasynchronously.

5. Slowing of impulse conduction through the A-V nodeproducing partial to complete heart block.The main categories of cardiac arrhythmias and their

characteristics are:1. Extrasystoles (ES) are premature beats due to

abnormal automaticity or after-depolarization arisingfrom an ectopic focus in the atrium (atrial ES), A-Vnode (nodal ES) or ventricle (ventricular ES).

2. Paroxysmal supraventricular tachycardia (PSVT) issudden onset episodes of atrial tachycardia (rate 150–200/min) with 1:1 atrio-ventricular conduction: mostlydue to circus movement type of re-entry involving theA-V node or SA node.

3. Atrial flutter (AFl) Atria beat at a rate of 220–350/min and there is a physiological 2:1 to 4:1 or higher,A-V block (because A-V node cannot transmitimpulses faster than 200/min). This is mostly due toa self-perpetuating re-entrant circuit in the atrium,but some cases may be due to rapid discharge of anatrial focus.

4 . Atrial fibrillation (AF) Atrial fibres are activatedasynchronously at a rate of 350–550/min (due to

electrophysiological inhomogeneity of atrial fibres),associated with grossly irregular and often fast (100–160/min) ventricular response. Atria remain dilatedand quiver like a bag of worms.

5. Ventricular tachycardia is a run of 4 or moreconsecutive ventricular extrasystoles. It may be asustained or nonsustained arrhythmia, and is dueeither to discharges from an ectopic focus, after-depolarizations or circus movement of a re-entrantimpulse.

6. Torsades de pointes (French: twisting of points) is alife-threatening form of polymorphic ventriculartachycardia with an undulating baseline on ECG. It isgenerally associated with long Q-T interval.

7. Ventricular fibrillation (VF) is grossly irregular, rapidand fractionated activation of ventricles resulting inincoordinated contraction of its fibres with loss ofpumping function. It is fatal unless reverted within2–5 min. It is the most common cause of suddencardiac death.

8. Atrio-ventricular (A-V) block is due to depression ofimpulse conduction through the A-V node and bundleof His.First degree A-V block: Slowed conduction resulting inprolonged P-R interval.Second degree A-V block: Some supraventricularcomplexes are not conducted : drop beats.Third degree A-V block: No supraventricular complexesare conducted; ventricle generates its own impulse;complete heart block.

CLASSIFICATION

Antiarrhythmic drugs act by blocking myocardialNa+, K+ or Ca2+ channels. Some have additionalor even primary autonomic effects. Classificationof antiarrhythmic drugs has been unsatisfactorybecause many drugs have more than one action.Vaughan Williams and Singh (1969) proposed a4 class system which takes into account the mostimportant property of a drug that is apparentlyresponsible for its antiarrhythmic action in theclinical setting. This system is arbitrary, but it hasbeen widely accepted.

CLASS I

The primary action of drugs in this class is tolimit the conductance of Na+ (and K+) across cellmembrane—a local anaesthetic action. They alsoreduce rate of phase-4 depolarization responsiblefor impulse generation in automatic cells.

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fall in BP, decrease contractility of skeletalmuscles, augment uterine contractions, inducevomiting and diarrhoea and produce neurolo-gical effects like ringing in ears, vertigo, deafness,visual disturbances and mental changes. Like itslevoisomer quinine, it has antimalarial action. Thedrug interactions of quinidine are:• Rise in blood levels and toxicity of digoxin

due to displacement from tissue binding andinhibition of excretion.

• Marked fall in BP in patients receivingvasodilators.

• Risk of torsades de pointes is increased byhypokalaemia caused by diuretics.

• Synergistic cardiac depression with β-blockers, verapamil, K+ salts.Though quinidine is effective in many atrial

and ventricular arrhythmias, it is not used toterminate them because of risk of adverse effects,

Subclass IA

The subclass IA containing the oldest anti-arrhythmic drugs quinidine and procainamide areopen state Na+ channel blockers which alsomoderately delay channel recovery (1–10 s),suppress A–V conduction and prolong refractori-ness. The Na+ channel blockade is greater athigher frequency so that premature depolari-zation is affected more. These actions serve toextinguish ectopic pacemakers that are oftenresponsible for triggered arrhythmias and abolishre-entry by converting unidirectional block intobidirectional block.

Quinidine in addition has antivagal action,which augments prolongation of atrial RP andminimises RP disparity of atrial fibres. Quinidinealso decreases myocardial contractility: mayprecipitate failure in damaged hearts. It can cause


Antiarrhythmic drugs

Class Actions Drugs

I. Membrane stabilizing agents(Na+ channel blockers)A. Moderately decrease dv/dt of 0 phase Quinidine, Procainamide

DisopyramideB. Little decrease in dv/dt of 0 phase Lidocaine, MexiletineC. Marked decrease in dv/dt of 0 phase Propafenone, Flecainide

II. Antiadrenergic agents Propranolol, Esmolol(β blockers) Sotalol (also class III)

III. Agents widening AP Amiodarone, Bretylium (also class II)(prolong repolarization and ERP) Dofetilide, Ibutilide

IV. Calcium channel blockers Verapamil, Diltiazem

Note: Class IA agents also have Class III property; Propranolol has Class I action as well; sotalol andbretylium have both Class II and Class III actions.

In addition1. For PSVT : Adenosine, Digitalis.2. For A-V block : Sympathomimetics—Isoprenaline, etc.

Anticholinergics—Atropine.


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including that of torsades de pointes, suddencardiac arrest or VF. It is occasionally used tomaintain sinus rhythm after termination of AF orAFl.

Procainamide This orally active amide of thelocal anaesthetic procaine has cardiac electro-physiological actions similar to quinidine but hasminimal antivagal action, causes less depressionof contractility, A-V conduction and BP.Prolonged use of procainamide can causesystemic lupus erythematosus. Cardiac toxicityis similar to quinidine; clinical use therefore ishighly restricted.

Disopyramide is a quinidine-like class IA drugwhich has prominent cardiac depressant andanticholinergic actions, but no α adrenergicblocking property. However, disopyramide pro-duces less g.i. side effects and is better tolerated.Cardiac decompensation and hypotension canoccur in patients with damaged hearts, becauseit also increases peripheral resistance to furtherdecrease cardiac output. It is a second linedrug for preventing recurrences of ventriculararrhythmia and may be a better toleratedmaintenance drug after cardioversion of AF orAFl.

Subclass IB

Lidocaine This most widely used localanaesthetic is the prototype member of subclassIB. It is a blocker of inactivated Na+ channels morethan that of open state. As such, it is relativelyselective for partially depolarized fibres and thosewith longer action potential duration (APD),whose Na+ channels remain inactivated forlonger period. Unlike quinidine, channel recoveryis not delayed. While normal ventricular andconducting tissues are minimally affected,depolarized/damaged fibres are particularlydepressed. The most prominent action oflidocaine is suppression of automaticity inventricular ectopic foci and after-depolarizations.Brevity of atrial AP and lack of prolongation ofchannel recovery makes lidocaine ineffective in

atrial arrhythmias. It does not depress A-Vconduction and ventricular contractility orprolong refractoriness.

Lidocaine is inactive orally due to high firstpass metabolism. Action of an i.v. bolus dose lastsonly for 10–20 minutes because of rapiddistribution, while elimination t½ is 1.5–2 hoursdue to metabolism. Lidocaine is used only inventricular tachyarrhythmias by repeated i.v.injections or continuous i.v. infusion. Because ofrapidly developing and titratable action, it is agood drug in the emergency setting, e.g.arrhythmias following MI or during cardiacsurgery. It is also useful in digitalis toxicity.

Mexiletine is an orally active congener of lidocainewith similar cardiac electrophysiological actions.Parenterally, it has been used as an alternative tolidocaine for postinfarction ventricular arrhy-thmias. Orally, it is used to keep VES and VTsuppressed over long-term.

Subclass IC

The subclass IC drugs like propafenone andflecainide are the most potent Na+ channel blockerswith more prominent action on the open stateand the longest channel recovery time (>10 s).They markedly delay conduction in A-V nodeas well as accessory pathway: have been usedin WPW re-entrant tachycardias. Propafenonehas additional β adrenergic blocking property —can precipitate CHF and bronchospasm. Thoughthese drugs are effective in many refractoryarrhythmias, they also have high proarrhythmicpotential. Chronic therapy in postinfarct patientshas paradoxically increased the incidence ofsudden cardiac death. Therefore, they are usedonly as reserve drugs for resistant arrhythmias.

CLASS II

The primary action of class II durgs is to suppressadrenergically mediated ectopic activity anddelayed after-depolarizations. Though some βblockers, e.g. propranolol have quinidine like directmembrane stabilizing action at high doses,

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antiarrhythmic action is exerted clinicallyprimarily by cardiac adrenergic blockade. Theother important action is to prolong RP of A-Vnode. This impedes A-V conduction: re-entrantarrhythmias that involve SA or A-V node (manyPSVT) may be abolished.

The β blockers are very useful in treatingin- appropriate sinus tachycardia, atrial and nodalextrasystoles provoked by emotion, exercise or stress(e.g. of dental procedure). They rarely abolish AF orAFl, but can be used to control ventricular rate.β blockers are highly effective in sympatheticallymediated arrhythmias occurring in pheochromo-cytoma or during anaesthesia with halothane.Digitalis-induced tachyarrhythmias mayrespond. However, efficacy in chronic ventriculararrhythmias is low. Prophylactic treatmentwith β blockers reduces mortality in post-MIpatients.

Sotalol is a β blocker with prominent class IIIproperty of prolonging repolarization by blockingcardiac K+channels. It delays A-V conduction andprolongs nodal RP. Sotalol is effective in somecases of VT as well as for prophylaxis of AF andAFl. Risk of torsades de pointes is the majorlimitation

Esmolol is a quick and short-acting β1 blockerthat is used i.v. for emergency control of ventricularrate in AF/AFl. It can also terminate supra-ventricular tachycardia and arrhythmias asso-ciated with anaesthesia.

CLASS III

The characteristic action of class III antiarrhy-thmics is prolongation of repolarization: AP iswidened which increases RP. Myocardial fibresremain refractory even after repolarization: re-entrant arrhythmias are terminated. Prolongationof APD is attributable to blockade of delayedrectifier K+ channels, which open duringrepolarization. The most important member of thisclass amiodarone is an unusual iodine containingcompound which in addition blocks Na+ chan-nels during inactivation and has noncompetitiveβ adrenergic blocking property. Amiodarone is

highly lipophilic, extensively bound in tissuesand exceptionally long acting (t½ 3–8 weeks).Given orally, its full action takes weeks to develop,but i.v. loading doses can rapidly terminate life-threatening arrhythmias. Amiodarone is effectivein a wide range of ventricular and supraven-tricular arrhythmias, particularly resistant VT andrecurrent VF. Despite prolongation of APD, theproarrhythmic potential of amiodarone is low.This, together with its broad spectrum efficacyand long duration of action makes it a commonlyused antiarrhythmic. However, close supervisionis needed because long term use carries the risk ofhypothyroidism, photosensitization, peripheralneuropathy and pulmonary fibrosis.

Bretylium is an adrenergic neurone blockingdrug which prolongs APD by blocking cardiacK+ channels. It can facilitate reversal of VF, but israrely used now.

Dofetilide is a recently developed pure class IIIantiarrhythmic which has no other action thanblocking delayed rectifier K+ channels. Its primaryindication is to maintain sinus rhythm afterconversion of AF and AFl.

Ibutilide Another similar drug, mainly usedi.v. to terminate AF or AFl.

CLASS IV

The Ca2+ channel blockers verapamil and diltia-zem (but not DHPs) exert antiarrhythmic actionby depressing Ca2+ mediated depolarization.They slow SA node pacemaker, A-V conductionand suppress re-entry through A-V node as wellas in partially depolarized (ischaemic) tissue.Verapamil and diltiazem are used i.v. to terminateepisodes of PSVT, as well as orally to prevent itsrecurrences. The other use of verapamil is tocontrol ventricular rate in AF and AFl asalternative to or in addition to digitalis. Efficacyof calcium channel blockers in ventriculararrhythmias is poor.

Adenosine Administered by rapid i.v. injection(over 1–3 sec) either as the free base or as ATPadenosine terminates within 30 seconds more



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than 90% episodes of PSVT involving the A-Vnode. It activates ACh sensitive K+ channels andcauses membrane hyperpolarization throughinteraction with A1 type of adenosine receptorson SA node (pacemaker depression →bradycardia), A-V node (prolongation of RP →slowing of conduction) and atrium (shorteningof AP, reduced excitability). It indirectly reducesCa2+ current in A-V node; depression of the re-entrant circuit through A-V node is responsiblefor termination of PSVT.

Adenosine has a very short t½ in blood (~10sec) due to uptake into RBCs and endothelialcells where it is converted to 5-AMP and inosine.Almost complete elimination occurs in a singlepassage through coronary circulation.

Adverse effects of adenosine are transientdyspnoea, chest pain, fall in BP and flushing in30–60% patients; ventricular standstill for afew seconds or VF occurs in some patients.Bronchospasm may be precipitated in asthmatics.Adenosine has to be rapidly injected in a largevein and has brief action, not suitable for recurrentcases.

Other drugs that can be used i.v. to terminatePSVT are verapamil, diltiazem, esmolol or digoxin.

Drugs for A-V block

Atropine: When A-V block is due to vagaloveractivity, e.g. digitalis toxicity, some cases ofMI; it can be improved by atropine 0.6–1.2 mg i.m.Atropine abbreviates A-V node RP and increasesconduction velocity in bundle of His.

Sympathomimetics (Adr, isoprenaline): Thesedrugs may overcome partial heart block byfacilitating A-V conduction and shortening RP ofconducting tissues.

They may also be used in complete heart blockto maintain a sufficient idioventricular rate (byincreasing automaticity of ventricular pacemakers)till external pacemaker can be implanted.

Relevance to dentistryPatients with history of recurrent cardiacarrhythmias, ischaemic heart disease or chronicdigitalis therapy are at greater risk of precipitationof arrhythmias during dental procedure due tothe stress and/or use of Adr containing localanaesthetic. A cardiologist may be consultedbeforehand and the dentist should be preparedto provide first-line treatment of emergencyarrhythmias such as PSVT, VT, VF, complete heartblock, cardiac arrest, etc.

13

Drugs Acting on Kidney

RELEVANT PHYSIOLOGY OFURINE FORMATION

Urine formation starts from glomerular filtration(g.f.) in a prodigal way. Normally, about 180 L offluid is filtered every day: all soluble constituentsof blood minus the plasma proteins (along withsubstances bound to them) and lipids, are filteredat the glomerulus. More than 99% of the glomeru-lar filtrate is reabsorbed in the tubules; about 1.5L urine is produced in 24 hours. The diuretics actprimarily by inhibiting tubular reabsorption: just1% decrease in tubular reabsorption would morethan double urine output.

The mechanisms that carry out ion movementacross tubular cells are complex and involve avariety of energy dependent transmembranepumps as well as channels in between the loosefitting cells of the proximal tubule (PT). All Na+

that enters tubular cells through the luminalmembrane is pumped out of it into the renal intersti-tium at the basolateral membrane by Na+K+ATPaseenergised Na+-K+ antiporter (see Figs 13.3 and 13.4).Because there is a large intracellular to extracellulargradient for K+, it diffuses out through K+ channelsto be recirculated by the Na+-K+ antiporter. Forsimplification, tubular reabsorption can bedivided into four sites (Fig. 13.1).

Site I: Proximal tubule Four mechanisms ofNa+ transport have been defined in this segment.

(a) Direct entry of Na+ along a favourableelectrochemical gradient. This is electrogenic.

(b) Transport of Na+ and K+ coupled to activereabsorption of glucose, amino acids, other orga-nic anions and PO4

3¯ through specific symporters.

(c) Exchange with H+: The PT cells secrete H+ withthe help of carbonic anhydrase (CAse) Fig. 13.2,which exchanges with Na+ present in tubularfluid through Na+-H+ antiporter located in theluminal membrane. There is also net reabsorptionof HCO3¯due to the activity of brush border CAseand Na+- HCO3¯ symporter at the basolateralmembrane.

(d) The disproportionately large HCO3̄ , acetate,PO4

3¯, amino acid and other anion reabsorptioncreate passive driving forces for Cl¯ which alsotakes Na+ and water along. Reabsorption in PT isisotonic.

Major part of filtered K+ is reabsorbed in thePT.Site II: Ascending limb of loop of Henle (AscLH) The thick AscLH is relatively impermeableto water but absorbs salt actively and thus dilutesthe tubular fluid.

In the medullary portion a distinct luminalmembrane carrier transports ions in the stoichio-metric ratio of Na+-K+-2Cl¯ (see Fig. 13.3). TheNa+ that enters the cell is pumped to e.c.f. by Na+

K+ ATPase at the basolateral membrane. In

204 Drugs Acting on KidneyS

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Fig. 13.2: The carbonic anhydrase (C.Ase) mediatedbicarbonate absorption in proximal tubule (PT)

Fig. 13.1: Diagrammatic representation of nephron showing the four sites of solute reabsorptionThe thick ascending limb of loop of Henle is impermeable to water; Glu.—Glucose; A.A.—Amino acid;Org. An.—Organic anions.

addition, a Na+-Cl¯ symporter moves Cl¯ downits electrochemical gradient into e.c.f. and carriesNa+ along. As the tubular fluid traverses AscLH,

it progressively becomes hypotonic. Accumu-lation of NaCl in the medullary interstitiumwithout accompanying water makes it hyper-tonic: a corticomedullary osmotic gradient is setup which is essential for production of bothconcentrated as well as dilute urine.

Site III: Cortical diluting segment of loop ofHenle This segment, also impermeable towater, continues to absorb salt, but here it isthrough a Na+-Cl¯ symporter. Tubular fluid getsfurther diluted.

Site IV: Distal tubule (DT) and collecting duct(CD) In the late DT and CD, Na+ is againactively reabsorbed; the cation-anion balancebeing maintained partly by passive Cl¯ diffusion

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and partly by secretion of K+ and H+. Absorptionof Na+ at this site occurs through a specificamiloride sensitive Na+ channel and is control-led to a large extent by aldosterone (see Fig. 13.5).This provides fine tuning to electrolyte excretionaccording to body needs.

Any diuretic acting proximal to the aldo-sterone sensitive ion exchange site causes anincreased delivery of Na+ to the distal nephron—more exchange with K+ takes place. The net K+

loss is regulated by variations in the secretoryprocess and depends on:

(i) The Na+ load delivered to distal segment(ii) Presence or absence of aldosterone

(iii) Availability of H+

(iv) Intracellular K+ stores.The characteristic feature of cells lining CD istheir responsiveness to antidiuretic hormone(ADH). If ADH is absent, the hypotonic fluidentering CD is passed as such → dilute urine isproduced during water loading. If ADH levelsare high, CD cells become fully permeable towater → equilibrate with hyperosmotic medulla→ concentrated urine is passed, as occurs duringwater deprivation or hypertonic saline infusion.ADH also promotes reabsorption of urea byinserting more urea transporter (UT1 or VRUT)into the luminal membrane of CD cells. Duringwater deprivation more urea is transported to themedullary interstitium, reinforcing the hyperto-nocity.

Relation to diuretic actionThe relative magnitudes of Na+ reabsorption atdifferent tubular sites are:

PT 65–70%; AscLH 20–25%;DT 8–9%; CD 1–2%.

The maximal natriuretic response to a diureticcan give a clue to its site of action. It may appearthat diuretics acting on PT should be the mostefficacious. However, these agents are either tooweak or cause distortion of acid-base balance(CAse inhibitors). Further, their effect may beobscured by compensatory increase in reabsorp-tion further down the nephron, because the

reserve reabsorptive capacity of diluting seg-ments is considerable and can overshadow moreproximal actions.

A diuretic having primary action onmedullary AscLH (furosemide) can producesubstantial effect because of limited capacity forsalt absorption in DT and CD. This also explainswhy agents acting on DT and CD (K+ sparingdiuretics) evoke only mild saluretic effect.Diuretics acting on cortical diluting segment(thiazides) are intermediate between these two.

DIURETICS

These are drugs which cause a net loss of Na+

and water in urine.

CLASSIFICATION

1. High efficacy diuretics (Inhibitors of Na+-K+-2Cl¯ cotransport)

Furosemide, Bumetanide, Torasemide2. Medium efficacy diuretics (Inhibitors of Na+-Cl¯ symport)

(a) Benzothiadiazines (thiazides):Hydrochlorothiazide, Benzthiazide,Hydroflumethiazide, Clopamide

(b) Thiazide like (related heterocyclics):Chlorthalidone, Metolazone, Xipamide,Indapamide.

3. Weak or adjunctive diuretics(a) Carbonic anhydrase inhibitors:

Acetazolamide(b) Potassium sparing diuretics

(i) Aldosterone antagonist:Spironolactone, Eplerenone

(ii) Inhibitors of renal epithelial Na+ channel:Triamterene, Amiloride.

(c) Osmotic diuretics:Mannitol, Isosorbide, Glycerol.

HIGH CEILING (LOOP) DIURETICS(Inhibitors of Na+-K+-2Cl¯ Cotransport)

Furosemide (Frusemide) Prototype drugThe development of this orally and rapidlyacting highly efficacious diuretic was a break-

Diuretics 205


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(AscLH) cell, and site of action of furosemide on the Na+-K+-2Cl¯ cotransporter

through. Its maximal natriuretic effect is muchgreater than that of other classes. The diureticresponse goes on increasing with increasingdose: up to 10 L of urine may be produced in aday. It is active even in patients with relativelysevere renal failure. The onset of action is prompt(i.v. 2–5 min, i.m. 10–20 min, oral 20–40 min) andduration short (3–6 hours).

The major site of action is the thick AscLH(site II) where furosemide inhibits Na+- K+-2Cl¯cotransport (Fig. 13.3). It abolishes the cortico-medullary osmotic gradient and blocks positiveas well as negative free water clearance. K+

excretion is increased mainly due to high Na+

load reaching DT.Furosemide has weak CAse inhibitory action

and increases HCO3¯ excretion as well. Its actionis independent of acid-base balance of the bodyand it causes little distortion of the same.

In addition to its prominent tubular action,furosemide causes acute changes in renal andsystemic haemodynamics. After 5 min of i.v.injection, renal blood flow is transiently increased,

the result of which is decreased PT reabsorption.The intrarenal haemodynamic changes arebrought about by increased local PG synthesis.

Intravenous furosemide causes promptincrease in systemic venous capacitance anddecreases left ventricular filling pressure, evenbefore the saluretic response is apparent. This isresponsible for the quick relief it affords in LVFand pulmonary edema. This action may be PGmediated.

Furosemide increases Ca2+ excretion (contrastthiazides which reduce it) as well as Mg2+

excretion. It tends to raise blood uric acid levelby decreasing its renal excretion. Hyperglycae-mic action of furosemide is less marked thanthiazides.

Molecular mechanism of action: A glycoproteinwith 12 membrane spanning domains has beenfound to function as the Na+-K+-2Cl¯ cotrans-porter in many epithelia including AscLH.Furosemide attaches to the Cl¯ binding site ofthis protein to inhibit its transport function.

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Pharmacokinetics Furosemide is rapidly absor-bed orally but bioavailability is about 60%. It ishighly bound to plasma proteins. It is partlyconjugated with glucuronic acid and mainlyexcreted unchanged by glomerular filtrationas well as tubular secretion. Plasma t½ is 1-2hours.

Bumetanide It is similar to furosemide in allrespects, but is 40 times more potent. It inducesvery rapid diuresis and is highly effective inpulmonary edema. Hyperuricaemia, K+ loss,glucose intolerance and ototoxicity are claimedto be less than with furosemide. However, it mayrarely cause myopathy.

Torasemide This high ceiling diuretic is 3times more potent than furosemide and longeracting.

Use of high ceiling diuretics

1. Edema Diuretics are used irrespective ofetiology of edema—cardiac, hepatic or renal. Thehigh ceiling diuretics are preferred initially in

CHF for rapid mobilization of edema fluid. Theyare the diuretic of choice for nephrotic and otherforms of resistant edema.

2. Acute pulmonary edema (acute LVF, followingMI) Intravenous administration of furosemideproduces prompt relief. This is due to vasodilatoraction that precedes the saluretic action.

3. Cerebral edema Though osmotic diureticsare preferred, furosemide may be employed byi.m. route.

4. Hypertension High ceiling diuretics areindicated only in presence of renal insufficiency,CHF, in resistant cases or hypertensive emer-gencies; otherwise thiazides are preferred

THIAZIDE AND RELATED DIURETICS(Inhibitors of Na+-Cl¯ symport)

These are medium efficacy diuretics withprimary site of action in the cortical dilutingsegment or the early DT (Site III). Here theyinhibit Na+–Cl¯ symport at the luminal mem-brane. They do not affect the corticomedullary

Fig. 13.4: Mechanism of salt reabsorption in early distal tubular cell and site ofaction of thiazide diuretics on Na+Cl¯ symporter

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osmotic gradient indicating lack of action at themedullary thick AscLH. Positive free waterclearance is reduced (very dilute urine cannot bepassed in the absence of ADH), but negative freewater clearance (in the presence of ADH) is notaffected. Like the Na+-K+-2Cl¯ cotransporter, theNa+-Cl¯ symporter is also a glycoprotein with 12membrane spanning domains that bindsthiazides but not furosemide or any other classof diuretics. The site of action of thiazide diureticsis shown in Fig. 13.4.

Some of the thiazides and related drugshave additional CAse inhibitory action whichmay confer a secondary proximal tubular actionto the compounds.

Under their action, increased amount of Na+

is presented to the distal nephron, more of itexchanges with K+ → urinary K+ excretion isincreased in parallel to the natriuretic response.The different thiazide and related diuretics havenearly the same maximal efficacy as hydro-chlorothiazide, though potency (reflected in dailydose) differs markedly. Nevertheless, they aremoderately efficacious diuretics because nearly90% of the glomerular filtrate has already beenreabsorbed before it reaches their site of action.They have a flat dose response curve; littleadditional diuresis occurs when the dose isincreased beyond 100 mg of hydrochloro-thiazide or equivalent. No significant alterationin acid-base balance of the body is produced.

Renal Ca2+ excertion is diminished whileMg2+ excertion is enhanced by direct tubularaction. They also decrease urate excretion by thesame mechanism as furosemide.

The extrarenal actions of thiazides consist ofa slowly developing fall in BP in hypertensivesand elevation of blood sugar in some patientsdue to decreased insulin release.

All thiazides and related drugs are wellabsorbed orally, and are administered only bythis route. Their action starts within 1 hour, butthe duration varies from 8–48 hours. Most of theagents undergo little hepatic metabolism and areexcreted as such. They are filtered at the

glomerulus as well as secreted in the PT byorganic anion transport. Tubular reabsorptiondepends on lipid solubility: the more lipidsoluble ones are highly reabsorbed—prolongingduration of action.

Uses

1. Edema Thiazides may be used for mild-to-moderate cases. For mobilization of edema fluidmore efficacious diuretics are employed initially,but thiazides are considered better for main-tenance therapy. They are powerless in thepresence of renal failure. Cirrhotics often developrefractoriness to thiazides due to development ofsecondary hyperaldosteronism.

2. Hypertension They are one of the first linedrugs.

3. Diabetes insipidus They reduce urinevolume.

Complications of high ceiling andthiazide-type diuretic therapy

Most of the adverse effects of these drugs arerelated to fluid and electrolyte changes causedby them. They are remarkably safe in low dosesused over short periods.

1. Hypokalaemia This is the most significantproblem. It is rare at low doses, but may be ofgrave consequence when brisk diuresis is indu-ced or on prolonged therapy. The usual mani-festations are weakness, fatigue, muscle cramps;cardiac arrhythmias are the serious complica-tions. It can be prevented and treated by:(a) High dietary K+ intake or(b) Supplements of KCl (24–72 mEq/day) or(c) Concurrent use of K+ sparing diuretics.

2. Acute saline depletion Over enthusiastic useof diuretics, particularly high ceiling ones, maycause dehydration and fall in BP

3. Dilutional hyponatremia Occurs in CHFpatients in whom vigorous diuresis is inducedwith high ceiling agents, rarely with thiazides.

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4. GIT and CNS disturbances Nausea, vomi-ting, diarrhoea, headache, giddiness, weakness,paresthesias, impotence are the occasionalcomplaints.

5. Hearing loss Occurs rarely, only with highceiling diuretics.

6. Allergic manifestations Rashes, photosen-sitivity occur specially in patients hypersensitiveto sulfonamides.

7. Brisk diuresis induced in cirrhotics mayprecipitate mental disturbances and hepatic coma.

8. Hyperuricaemia Long-term use of thiazidesin hypertension has caused rise in blood uratelevel, but is rare now due to use of lower doses.

9. Hyperglycaemia and hyperlipidemia Haveoccurred in the use of diuretics as antihyper-tensive. Use of lower doses now has minimizedthis complication.

10. Magnesium depletion It may develop afterprolonged use of thiazides as well as loop diure-tics.

Interactions

1. Thiazides and high ceiling diuretics poten-tiate all other antihypertensives.

2. Hypokalaemia induced by these diuretics:(a) Enhances digitalis toxicity.(b) Increases the incidence of polymorphic

ventricular tachycardia due to quinidine andother antiarrhythmics.

(c) Potentiates competitive neuromuscularblockers and reduces sulfonylurea action.

3. High ceiling diuretics and aminoglycosideantibiotics are both ototoxic; produce additivetoxicity.

4. High ceiling diuretics enhance nephrotoxicityof aminoglycosides.

5. Indomethacin and most NSAIDs diminishthe action of high ceiling diuretics by inhibitingPG synthesis in the kidney. Antihypertensive

action of thiazides and furosemide is alsodiminished by NSAIDs.

6. Probenecid competitively inhibits tubularsecretion of furosemide and thiazides: decreasestheir action.

7. Serum lithium level rises when diuretictherapy is instituted. This is due to enhancedreabsorption of Li+ in PT.

CARBONIC ANHYDRASE INHIBITORS

AcetazolamideIt is a sulfonamide derivative which noncompeti-tively but reversibly inhibits CAse in PT cellsresulting in slowing of hydration of CO2 →decreased availability of H+ to exchange withluminal Na+. Inhibition of brush border CAseretards dehydration of H2CO3 in the tubularfluid so that less CO2 diffuses back into the cells.The net effect is inhibition of HCO3̄ (andaccompanying Na+) reabsorption in PT → mildalkaline diuresis.

Secretion of H+ in DT and CD is alsoinhibited. The distal Na+ exchange takes placeonly with K+ which is lost in excess. The urineproduced under acetazolamide action is alkalineand rich in HCO3̄ which is matched by both Na+

and K+. Continued action of acetazolamidedepletes body HCO3̄ and causes acidosis; lessHCO3̄ (on which its diuretic action depends) isfiltered at the glomerulus → self-limiting diureticaction.The extrarenal actions of acetazolamide are:

(i) Lowering of intraocular tension due todecreased formation of aqueous humour (itis rich in HCO3̄ ).

(ii) Raised level of CO2 in brain and loweringof pH → elevation of seizure threshold.

Uses Because of self-limiting action, productionof acidosis and hypokalaemia, acetazolamide isnot used as diuretic. Its current clinical uses are:

1. Glaucoma: as adjuvant to other ocularhypotensives.

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Aldosterone (AL) penetrates the cell from the interstitial side and combines with the mineralocorticoid receptor (MR). Thecomplex translocates to the nucleus—promotes gene mediated mRNA synthesis. The mRNA then directs synthesis ofaldosterone-induced proteins (AIPs). The AIPs include Na+K+ ATPase and amiloride sensitive Na+ channels. The AIPsalso activate Na+ channel, translocate Na+ channels from cytosolic site to luminal membrane and Na+K+ATPase tobasolateral membrane, increase ATP production by mitochondria. All these changes promote Na+ reabsorption—more K+

and H+ is secreted indirectly. Spironolactone binds to MR, prevents AL action and produces opposite effects.Amiloride approaches the Na+ channel from the luminal side and blocks it—reducing the lumen negative transepithelial

potential difference which governs K+ and H+ secretion.

2. To alkalinise urine.3. Epilepsy: as adjuvant in absence seizures.4. Acute mountain sickness: for symptomatic

relief as well as prophylaxis: benifitsprobably by lowering CSF formation andits pH.

Adverse effects are frequent.Acidosis, hypokalaemia, drowsiness, paresthe-sias, fatigue, abdominal discomfort.Hypersensitivity reactions—fever, rashes.Bone marrow depression is rare but serious.

POTASSIUM SPARING DIURETICS

These are either aldosterone antagonists orinhibit Na+ channels in DT and CD cells toindirectly conserve K+.

Spironolactone (Aldosterone antagonist)

It is a steroid, chemically related to the minera-locorticoid aldosterone. Aldosterone acts onthe late DT and CD cells (Fig. 13.5) by combiningwith an intracellular mineralocorticoid receptor→ induces the formation of ‘aldosterone-inducedproteins’ (AIPs) which promote Na+ reabsorp-tion by a number of mechanisms (see legend toFig. 13.5) and K+ secretion. Spironolactone com-bines with the mineralocorticoid receptor andinhibits the formation of AIPs in a competitivemanner. It has no effect on Na+ and K+ transportin the absence of aldosterone; while undernormal circumstances, it increases Na+ anddecreases K+ excretion.

Spironolactone is a mild saluretic becausemajority of Na+ has already been reabsorbed

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proximal to its site of action. However, itantagonises K+ loss induced by other diureticsand slightly adds to their natriuretic effect.

Pharmacokinetics The oral bioavailability ofspironolactone from microfine powder tablet is75%. It is highly bound to plasma proteins andcompletely metabolized in liver; converted toactive metabolites, the most important of whichis Canrenone.

Use Spironolactone is a weak diuretic in itsown right and is used only in combination withother more efficacious diuretics.1. To counteract K+ loss due to thiazide andloop diuretics.2. Edema: to break resistance to thiazide diure-tics that develops due to secondary hyperaldo-steronism.3. Hypertension: as adjuvant to thiazides.4. CHF: As additional drug to conventionaltherapy in moderate-to-severe CHF; can retarddisease progression and lower mortality.

Interactions Given together with K+ supple-ments—dangerous hyperkalaemia can occur.Aspirin blocks spironolactone action byinhibiting tubular secretion of canrenone.

Adverse effects Drowsiness, confusion, abdo-minal upset, hirsutism, gynaecomastia, impo-tence and menstrual irregularities.

Most serious is hyperkalaemia.

Eplerenone A new more selective aldosteroneantagonist that is less likely to cause gynae-comastia, impotence or menstrual irregularities.

Inhibitors of renal epithelial Na+ channel

Triamterene and amiloride are two nonste-roidal organic bases with identical actions. Theirmost important effect is to decrease K+ excretion,particularly when it is high due to large K+

intake or use of a diuretic that enhances K+ loss,along with a small increase in Na+ excretion. Theeffect on urinary electrolyte pattern is superfi-cially similar to spironolactone, but their actionis independent of aldosterone.

Mechanism of action: The luminal membrane oflate DT and CD cells expresses a distinct‘amiloride sensitive’ or ‘renal epithelial’ Na+

channel through which Na+ enters the cell downits electro-chemical gradient which is generatedby Na+K+ ATPase operating at the basolateralmembrane (Fig. 13.5). This Na+ entry partiallydepolarizes the luminal membrane creating a–15 mV transepithelial potential differencewhich promotes secretion of K+ into the lumenthrough K+ channels. Though there is no directcoupling between Na+ and K+ channels, more thedelivery of Na+ to the distal nephron—greater isits entry through the Na+ channel—luminalmembrane is depolarized more —driving forcefor K+ secretion is augmented. Amiloride andtriamterene block the luminal Na+ channels—indirectly inhibit K+ excretion, while the netexcess loss of Na+ is minor (most of it hasalready been absorbed).

Both triamterene and amiloride are used inconjunction with thiazide type or high ceilingdiuretics: prevent hypokalaemia and slightlyaugment the natriuretic and antihypertensiveresponse. They should not be given with K+

supplements, dangerous hyperkalaemia maydevelop. Hyperkalaemia is also more likely inpatients receiving ACE inhibitors, and those withrenal impairment.

Both drugs elevate plasma digoxin levels.Amiloride blocks entry of Li+ through Na+

channels in the CD cells and mitigates diabetesinsipidus induced by lithium.

OSMOTIC DIURETICS

Mannitol

Mannitol is a nonelectrolyte of low molecularweight (182) that is pharmacologically inert—can be given in large quantities sufficient to raiseosmolarity of plasma and tubular fluid. It is notmetabolized in the body; freely filtered at theglomerulus and undergoes limited reabsorption;therefore, excellently suited to be used as osmoticdiuretic. Mannitol appears to limit tubular waterand electrolyte reabsorption by:

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Table 13.1: Urinary electrolyte pattern and natriuretic efficacy of some diuretics

Urinary electrolyte excretion Max. % of filtered EfficacyDiuretic Na+ K+ Cl¯ HCO 3̄ Na+ excreted

1. Furosemide ↑↑↑ ↑ ↑↑ ↑,− 25% High

2. Thiazide ↑↑ ↑ ↑ ↑ 8% Intermediate

3. Acetazolamide ↑ ↑↑ ↑,− ↑↑ 5% Mild

4. Spironolactone ↑ ↓ ↑ -,↑ 3% Low

5. Triamterene ↑ ↓ ↑ -,↑ 3% Low

6. Mannitol ↑↑ ↑ ↑ ↑ 20% High

1. Retaining water isoosmotically in PT—dilutes luminal fluid which opposes NaClreabsorption.

2. Inhibiting transport processes in the thickAscLH by an unknown mechanism—quantitatively this appears to be the mostimportant cause of diuresis.

3. Expanding extracellular fluid volume—this increases g.f.r. and inhibits reninrelease.

Administration Mannitol is not absorbed orally;has to be given i.v. as 10–20% solution. It isexcreted with a t½ of 0.5–1.5 hours.

Uses Mannitol is never used for the treatmentof chronic edema or as a natriuretic. Its indica-tions are:1. Increased intracranial or intraocular tension(acute congestive glaucoma, head injury, stroke,etc.): by osmotic action it encourages movementof water from brain parenchyma, CSF andaqueous humour. Also, before and after eye/brain surgery to prevent acute rise in intra-ocular/intracranial pressure.2. To maintain g.f.r. and urine flow in impen-ding acute renal failure.Isosorbide and glycerol These are orally active osmoticdiuretics which may be used to reduce intraocular orintracranial tension.

ANTIDIURETICS

These are drugs that reduce urine volume,particularly in diabetes insipidus (DI) which is theirprimary indication. Drugs are:

1. Antidiuretic hormone (ADH, Vasopressin),Desmopressin, Lypressin, Terlipressin

2. Thiazide diuretics, Amiloride.

ANTIDIURETIC HORMONE

It is a nonapeptide secreted by posterior pituitary(neurohypophysis) along with oxytocin. Osmo-receptors present in hypothalamus and volumereceptors present in left atrium, ventricles andpulmonary veins primarily regulate the rate ofADH release governed by body hydration. Thetwo main physiological stimuli for ADH releaseare rise in plasma osmolarity and contraction ofe.c.f. volume.

The mammalian ADH is 8-arginine-vasopres-sin (AVP); 8-lysine-vasopressin (lypressin) isfound in swine and has been syntheticallyprepared. Other more potent and longer actingpeptide analogues of ADH having agonistic aswell as antagonistic action have been prepared.

ADH (Vasopressin) receptors These are Gprotein coupled cell membrane receptors; twosubtypes V1 and V2 have been identified, clonedand structurally characterized.

V1 Receptors All vasopressin receptors except thoseon renal CD cells and some blood vessels are of theV1 type.

V2 Receptors These are located primarily on the collectingduct (CD) cells in the kidney—regulate their waterpermeability through cAMP production. Vasodilatory V2

receptors are present in blood vessels.The V2 receptors are more sensitive to ADH than are

V1 receptors.

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Actions

Kidney ADH acts on the collecting duct (CD)cells to increase their water permeability—waterfrom the lumen diffuses to the interstitium by equi-librating with the hyperosmolar renal medulla. Inman, maximal osmolarity of urine that can beattained is 4 times higher than plasma. When ADHis absent, CD cells remain impermeable to water →dilute urine (produced by the diluting segment) ispassed as such. Graded effect occurs at lowerconcentration of ADH: urine volume closelybalances fluid intake.

Mechanism of action The V2 subtype of ADHreceptors are present on the basolateral side ofCD cell membrane. Activation of these receptorsincreases cAMP formation intracellularly →phosphorylation of relevant proteins whichpromote exocytosis of ‘aquaporin–2’ water channelcontaining vesicles (WCVs) through the apicalmembrane → more aqueous channels get insertedinto the apical membrane. The water permeabilityof CD cells is increased in proportion to the popu-lation of aquaporin–2 channels in the apicalmembrane at any given time. Secondary V2 actionson urea transporter (VRUT) in CD cells and onNa+K+2Cl cotransporter in AscLH augmentmedullary hypertonocity enhansing theantidiuresis.

Blood vessels AVP constricts blood vesselsthrough V1 receptors and can raise BP (hence thename vasopressin), but much higher concen-tration is needed than for maximal antidiuresis.

A V2 receptor mediated vasodilatation can beunmasked when AVP is administered in thepresence of a V1 antagonist. It can also bedemonstrated by the use of selective V2 agonistdesmopressin, and appears to be EDRF (NO)mediated.

Other actions Most visceral smooth musclescontract. Increased peristalsis in gut (especiallylarge bowel), evacuation and expulsion of gasesmay occur.

Uterus is contracted by AVP acting onoxytocin receptors.

AVP is recognized as a peptide neurotrans-mitter in many areas of brain and spinal cord:may be involved in regulation of temperature,circulation, ACTH release, and in learning oftasks.

AVP induces platelet aggregation and hepaticglycogenolysis. It releases coagulation factor VIIIand von Willebrand’s factor from vascular endo-thelium through V2 receptors.

Pharmacokinetics AVP is inactive orallybecause it is destroyed by trypsin. It can beadministered by any parenteral route or byintranasal application. The peptide chain of AVPis rapidly cleaved enzymatically in many organs,especially in liver and kidney; plasma t½ is short~25 min.

VASOPRESSIN ANALOGUESLypressin It acts on both V1 and V2 receptorsand has longer duration of action (4–6 hours). Itis being used in place of AVP—mostly for V1

receptor mediated actions.

Terlipressin This synthetic prodrug of vaso-pressin is specifically used for bleedingesophageal varices.

Desmopressin (dDAVP) This synthetic peptideis a selective V2 agonist; 12 times more potentantidiuretic than AVP, but has negligible vaso-constrictor activity. It is also longer acting; t½1–2 hours; duration of action 8–12 hours.Desmopressin is the preparation of choice for allV2 receptor related indications. The intranasalroute is preferred, though bioavailability is only10–20%. An oral formulation has been recentlymarketed with a bioavailability of 1–2%.

Uses

A. Based on V2 actions (Desmopressin is thedrug of choice)1. Diabetes insipidus DI of pituitary origin(neurogenic) is the most important indication forvasopressin. It is ineffective in renal (nephrogenic)DI since kidney is unresponsive to ADH.

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2. Bedwetting in children and nocturia in adultsIntranasal or oral desmopressin at bed-time con-trols primary nocturia by reducing urine volume.3. Renal concentration test 5–10 U i.m. ofaqueous vasopressin or 2 μg of desmopressincauses maximum urinary concentration.4. Haemophilia, von Willebrand’s diseaseDesmopressin may check bleeding by releasingcoagulation factor VIII and von Willebrand’sfactor.

B. Based on V1 actionsBleeding esophageal varices Vasopressin/terlipressin often stops bleeding by constrictingmesenteric blood vessels and reducing blood flowthrough the liver to the varices.

Adverse effects Because of V2 selectivity, des-mopressin produces fewer adverse effects thanvasopressin, lypressin or terlipressin. Headacheand flushing may be felt briefly.

Nasal irritation, congestion, rhinitis, ulcera-tion and epistaxis can occur on local application.Belching, nausea, abdominal cramps, palor, urgeto defecate, backache in females (due to uterinecontraction). Fluid retention and hyponatraemiamay develop.

THIAZIDES

Diuretic thiazides paradoxically exert anantidiuretic effect in DI. High ceiling diuretics arealso effective but are less desirable because of theirshort and brisk action. Thiazides reduce urinevolume in both pituitary origin as well as renalDI; especially valuable for the latter in whichADH is ineffective. However, their efficacy is low;urine can never become hypertonic as can occurwith ADH in neurogenic DI. The mechanism ofaction is not well understood, possibleexplanation is:

Thiazides induce a state of sustainedelectrolyte depletion so that glomerular filtrate ismore completely reabsorbed iso-osmotically in PT.Further, because of reduced salt absorption in thecortical diluting segment, a smaller volume of lessdilute urine is presented to the CDs and the sameis passed out.

Amiloride is the drug of choice for lithium-inducednephrogenic DI.

Indomethacin has also been found to reducepolyuria in renal DI to some extent by reducingrenal PG synthesis.

INTRODUCTION

Hormone (Greek hormaein—to stir up) is a sub-stance of intense biological activity that isproduced by specific cells in the body and istransported through circulation to act on its targetcells.

Hormones regulate body functions to bringabout a programmed pattern of life events andmaintain homeostasis in the face of markedlyvariable external/internal environment.

Body function Major regulatorhormone(s)

1. Availability of fuel : Insulin, Glucagon,Growth hormone

2. Metabolic rate : Triiodothyronine,Thyroxine

3. Somatic growth : Growth hormone,Insulin-like growthfactors

4. Sex and : Gonadotropins,reproduction Androgens, Estrogens,

Progestins5. Circulating : Aldosterone,

volume Antidiuretic hormone6. Adaptation to : Glucocorticoids,

stress Adrenaline7. Calcium balance : Parathormone,

Calcitonin, Vitamin D

Hormones are secreted by the endocrine or ductlessglands. These are:

1. Pituitary

(a) Anterior—Growth hormone (GH),Prolactin (Prl),Adrenocorticotropic hormone (ACTH),Thyroid stimulating hormone (TSH),Gonadotropins—Follicle stimulating hor-mone (FSH) and Luteinizing hormone (LH).

(b) Posterior—Oxytocin,Antidiuretic hormone (ADH, Vasopressin).

2. Thyroid Thyroxine (T4), Triiodothyronine(T3), Calcitonin.

3. Parathyroid Parathormone (PTH).

4. Pancreas (Islets of Langerhans) Insulin,Glucagon.

5. Adrenals(a) Cortex Glucocorticoids (hydrocortisone)

Mineralocorticoids (aldosterone)Sex steroids (dehydroepiandro-sterone)

(b) Medulla Adrenaline, Noradrenaline6. Gonads Androgens (testosterone)

Estrogens (estradiol)Progestins (progesterone)

In addition, hypothalamus, which is a part of theCNS and not a gland, produces many releasingand inhibitory hormones which control thesecretion of anterior pituitary hormones.

14

Hormones and Related DrugsAnterior Pituitary Hormones, Antidiabetic Drugs,

Corticosteroids

216 Hormones and Related DrugsS

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Placenta also secretes many hormones:Chorionic gonadotropin ProlactinEstrogens ProgesteronePlacental lactogen

The natural hormones and in many cases theirsynthetic analogues which may be more suitabletherapeutically, are used as drugs for substitutiontherapy as well as for pharmacotherapy. Inaddition, hormone antagonists and synthesis/release inhibitors are of therapeutic importance.

ANTERIOR PITUITARY HORMONES

Anterior pituitary (adenohypophysis), the masterendocrine gland, elaborates a number ofimportant regulatory hormones. All of these arepeptide in nature and act at extracellular recep-tors located on their target cells. Their secretion iscontrolled by the hypothalamus through releasingand release-inhibitory hormones that are trans-ported via hypothalamohypophyseal portalsystem, and is subjected to feedback inhibition byhormones of their target glands. Each anteriorpituitary hormone is produced by a separategroup of cells, which according to their stainingcharacteristic are either acidophilic or basophilic.The acidophils are either somatotropes → GH; orlactotropes → Prl.The basophils are gonadotropes → FSH and LH;thyrotropes → TSH; and corticotrope-lipotropes→ ACTH. The latter in addition to ACTH alsoproduce two melanocyte stimulating hormones(MSHs) and two lipotropins, but these areprobably not important in man.

GROWTH HORMONE (GH)

It is a 191 amino acid, single chain peptide ofMW 22,000.

Physiological functions GH promotes growthof all organs by inducing hyperplasia. In general,there is a proportionate increase in the size andmass of all parts; but in the absence of gonado-tropins, sexual maturation does not take place.The growth of brain and eye is independent ofGH. It promotes retention of nitrogen and other

tissue constituents: more protoplasm is formed.The positive nitrogen balance results fromincreased uptake of amino acids by tissues andtheir synthesis into proteins. GH promotes utili-zation of fat and spares carbohydrates: uptake ofglucose by muscles is reduced while its outputfrom liver is enhanced causing hyperglycaemia.Fat is broken down.

The growth promoting, nitrogen retaining andcertain metabolic actions of GH are exertedindirectly through the elaboration of peptidescalled Somatomedins or Insulin-like growth factors(IGF-1, also IGF-2) which are extracellular media-tors of GH response (see Fig. 14.1).

GH acts directly as well to induce lipolysis inadipose tissue, glycogenolysis in liver anddecreased glucose utilization by muscles. Theseeffects are opposite to those of IGF-1 and insulin.As such, GH accentuates the metabolic derange-ment in diabetes.Pathological involvements Excess production of GHis responsible for gigantism in childhood and acromegaly inadults. Hyposecretion of GH in children results in pituitarydwarfism.

Use The primary indication for GH is pituitary dwarfism.Human GH produced by recombinant DNA technique(somatrem and somatropin) is used.

GH has also been tried in children with constitutionalshort stature (only if epiphyses are open) with encouragingresults. In adult GH deficient patients it increases leanbody mass and decreases body fat and may reudce excessmorbidity and mortality but stature is unaffected. Otherpossible indications are catabolic states like severe burns,bedridden patients, chronic renal failure, osteoporosis, etc.It is now approved for AIDS-related wasting.

Somatostatin It is a 14 amino acid peptide producedby hypothalamus, pancreatic islets, etc. which inhibits thesecretion of GH, prolactin, TSH, insulin, glucagon, gastrinand most gastrointestinal juices—can be beneficial inpancreatic, biliary and intestinal fistulae. It also constrictssplanchnic, hepatic and renal blood vessels. Therefore, itcan be used to control bleeding from esophageal varicesand peptic ulcer.

Octreotide This synthetic octapeptide congener ofsomatostatin is longer acting and 40 times more potentexcept in inhibiting insulin secretion. It is preferred oversomatostatin for acromegaly, diarrhoea associated withcarcinoid, AIDS or chemotherapy and for esophagealvariceal bleeding.

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growth and development of breast during preg-nancy. It promotes proliferation of ductal as wellas acinar cells in the breast and induces synthesisof milk proteins and lactose. After parturition, Prlinduces milk secretion since the inhibitoryinfluence of high estrogen and progesterone levelsis withdrawn.

Prl has an inhibitory effect on hypothalamo-pituitary-gonadal axis. Continued high level ofPrl during breastfeeding is responsible forlactational amenorrhoea, inhibition of ovulationand infertility for several months postpartum. Prlmay affect immune response through action on T-lymphocytes.

Prl is under predominant inhibitory controlof hypothalamus through PRIH which is dopa-mine that acts on pituitary lactotrope D2 receptor.Dopaminergic agonists (DA, bromocriptine,cabergoline, apomorphine) decrease plasma Prllevels, while dopaminergic antagonists (chlorpro-mazine, haloperidol, metoclopramide) and DAdepleter (reserpine) cause hyperprolactinaemia.

Physio-pathological involvement Hyperpro-lactinaemia is responsible for the galactorrhoea-amenorrhoea-infertility syndrome in women. Inmales it causes loss of libido and depressedfertility.

Use There are no clinical indications for Prl.

Bromocriptine

This synthetic ergot derivative, 2-bromo-α-ergocryptine, is a potent dopamine agonist. It hasgreater action on D2 receptors, while at certaindopamine sites in the brain, it acts as a partialagonist or antagonist of D1 receptor. It is also aweak α adrenergic blocker but not an oxytocic.

Actions

1. Decreases prolactin release from pituitary byactivating dopaminergic receptors on lacto-trope cells—a strong antigalactopoietic.

2. Increases GH release in normal individualsbut decreases the same from pituitary tumoursthat cause acromegaly.

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Fig. 14.1: Action of growth hormone (GH) and regulationof its secretion

GHRH—Growth hormone releasing hormone; IGF-1: Insulinlike growth factor-1; Stimulation (——→); Inhibition (- - - -→)

PROLACTIN (Prl)

It is a 198 amino acid, single chain peptide ofMW 23,000; quite similar chemically to GH. It wasoriginally described as the hormone which cau-ses secretion of milk from crop glands of pigeonand later to be of considerable importance inhuman beings as well.

Physiological function Prl is the primarystimulus which, in conjunction with estrogens,progesterone and several other hormones, causes


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3. Has levodopa like actions in the CNS—anti-parkinsonian and behavioral effects.

4. Produces nausea and vomiting by stimulatingdopaminergic receptors in CTZ.

5. Hypotension—due to central suppression ofpostural reflexes and weak peripheral αadrenergic blockade.

6. Decreases gastrointestinal motility.

Uses Bromocriptine is indicated in hyperpro-lactinaemia causing galactorrhoea, amenorrhoeaand infertility in women; gynaecomastia, impo-tence and sterility in men. It is an alternative drugfor acromegaly and an adjuvant drug forparkinsonism.

Cabergoline This newer bromocriptine congeneris a longer acting (t½ > 60 days), more potent andmore selective D2 receptor agonist. It has largelysuperseded bromocriptine in the treatment ofhyperprolactinaemia and acromegaly.

GONADOTROPINS (Gns)

The anterior pituitary secretes two Gns viz. FSHand LH. Both are glycoproteins having a total of207 amino acid residues in two chains. FSH hasMW 32,000 while LH has MW 30,000.

Physiological functions FSH and LH act inconcert to promote gametogenesis and secretionof gonadal hormones.

FSH In the female it induces follicular growth,development of ovum and secretion of estrogens.In the male it supports spermatogenesis and hasa trophic influence on seminiferous tubules.Ovarian and testicular atrophy occurs in theabsence of FSH.

LH It induces preovulatory swelling of the ripegraafian follicle and triggers ovulation in females.It then brings about luteinization of the rupturedfollicle and maintains corpus luteum till the nextmenstrual cycle. It is also probably responsiblefor atresia of the remaining follicles. Progesteronesecretion occurs under the influence of LH. In themale LH stimulates testosterone secretion by theinterstitial cells and is designated interstitial cellstimulating hormone (ICSH).

Pathological involvement Disturbances of Gn secretionfrom pituitary may be responsible for delayed puberty orprecocious puberty both in girls and boys.

Inadequate Gn secretion results in amenorrhoea andsterility in women; oligozoospermia, impotence and inferti-lity in men. Excess production of Gn in adult womencauses polycystic ovaries.

Uses

Gonadotropins are obtained either from urine ofpostmenopausal women (Menotropins FSH+LHor pure FSH) or urine of pregnant women (Humanchorionic gonadotropin—HCG, which isequivalent to LH). Recombinant human FSH(Follitropin), recombinant human LH (Lutropin)and recombinant HCG (Choriogonadotropin)have also been produced. They can be used for:1. Amenorrhoea and infertility in women due to

deficient production of Gns by pituitary.2. Hypogonadotrophic hypogonadism in males

manifesting as delayed puberty or malesterility.

3. Cryptorchidism: HCG given before 7 years ofage can favour descent of testes.

4. To aid in vitro fertilization.

Superactive / long acting GnRH agonists Manyanalogues of GnRH, e.g. Buserelin, Leuprorelin, Triptorelin,Nafarelin, have been developed: are 15–150 times morepotent than natural GnRH and longer acting because ofhigh affinity for GnRH receptor and resistance to enzymatichydrolysis. They acutely increase Gn secretion, but after1–2 weeks cause desensitization and down-regulation ofGnRH receptors → inhibition of FSH and LH secretion →suppression of gonadal function. Spermatogenesis orovulation cease and testosterone or estradiol levels fall tocastration levels. Recovery occurs within 2 months ofstopping treatment.

The superactive GnRH agonists are used as nasalspray or injected s.c. The resulting reversible pharmaco-logical oophorectomy/orchiectomy is being used inprecocious puberty, prostatic carcinoma, endometriosis,premenopausal breast cancer, uterine leiomyoma,polycystic ovarian disease and to assist induced ovulation.It also has potential to be used as contraceptive for bothmales and females.

THYROID STIMULATING HORMONE (TSH,THYROTROPIN)

It is a 210 amino acid, two chain glycoprotein,MW 30,000.

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Physiological function TSH stimulates thyroidto synthesize and secrete thyroxine (T4) andtriiodothyronine (T3).

(i) It induces hyperplasia and hypertrophy ofthyroid follicles and increases blood supplyto the gland.

(ii) It promotes trapping of iodide by thyroid.(iii) It promotes organification of trapped iodine

and its incorporation into T3 and T4 byincreasing peroxidase activity.

(iv) It enhances endocytotic uptake of thyroidcolloid by the follicular cells and proteolysisof thyroglobulin to release more of T3 andT4. This action starts within minutes of TSHadministration.

Pathological involvement Only few cases of hypo-orhyperthyroidism are due to inappropriate TSH secretion.In majority of cases of myxoedema TSH levels are markedlyelevated because of deficient feedback inhibition. Graves’disease is due to an immunoglobulin of the IgG classwhich attaches to the thyroid cells and stimulates them inthe same way as TSH. Consequently, TSH levels are low.

Use Thyrotropin has no therapeutic use.

ADRENOCORTICOTROPIC HORMONE(ACTH, CORTICOTROPIN)

It is a 39 amino acid single chain peptide, MW4,500, derived from a larger peptide pro-opiomelanocortin (MW 30,000) which also gives rise toendorphins, two lipotropins and two MSHs.

Physiological function ACTH promotes steroi-dogenesis in adrenal cortex by stimulating cAMPformation in cortical cells (through specific cellsurface G protein coupled receptors) → rapidlyincreases the availability of cholesterol forconversion to pregnenolone which is the ratelimiting step in the production of gluco, mineraloand weakly androgenic steroids. The stores ofadrenal steroids are very limited and rate ofsynthesis primarily governs the rate of release.ACTH also exerts trophic influence on adrenalcortex (again through cAMP): high doses causehypertrophy and hyperplasia. Absence of ACTHresults in adrenal atrophy. However, zona glo-merulosa is little affected because angiotensin II

also exerts trophic influence on this layer andsustains aldosterone secretion.Regulation of secretion Hypothalamus regulatesACTH release from pituitary through corticotropin-releasing hormone (CRH). Secretion of ACTH has acircadian rhythm. Peak plasma levels occur in the earlymorning, decrease during day and are lowest at midnight.Corticosteroids exert inhibitory feedback influence onACTH production by acting directly on the pituitary aswell as indirectly through hypothalamus.

Pathological involvement Excess production of ACTHfrom basophil pituitary tumours is responsible for somecases of Cushing’s syndrome. Hypocorticism occurs inpituitary insufficiency due to low ACTH production.Iatrogenic suppression of ACTH secretion and pituitaryadrenal axis is the most common form of abnormalityencountered currently due to the use of pharmacologicaldoses of glucocorticoids in nonendocrine diseases.

ACTH is used primarily for the diagnosis ofdisorders of pituitary adrenal axis. Injected i.v.25 IU causes increase in plasma cortisol if theadrenals are functional.

ANTIDIABETIC DRUGS

Diabetes mellitus (DM) It is a metabolic disordercharacterized by hyperglycaemia, glycosuria,hyperlipidaemia, negative nitrogen balance andsometimes ketonaemia. A widespread patholo-gical change is thickening of capillary basementmembrane, increase in vessel wall matrix andcellular proliferation resulting in vascular comp-lications like lumen narrowing, early atheroscle-rosis, sclerosis of glomerular capillaries, retino-pathy, neuropathy and peripheral vascularinsufficiency.

The two major types of diabetes mellitus are:

Type I Insulin-dependent diabetes mellitus(IDDM)/juvenile onset diabetes mellitus:There is β cell destruction in pancreatic islets;majority of cases are autoimmune (type 1A)antibodies that destroy β cells are detectable inblood, but some are idiopathic (type 1B)—no βcell antibody is found. In all type 1 casescirculating insulin levels are low or very low, andpatients are more prone to ketosis. This type is

Antidiabetic Drugs 219


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less common and has a low degree of geneticpredisposition.

Type II Noninsulin-dependent diabetes mellitus(NIDDM)/maturity onset diabetes mellitus:There is no loss or moderate reduction in β cellmass; insulin in circulation is low, normal or evenhigh, no anti-β-cell antibody is demonstrable; hasa high degree of genetic predisposition; generallyhas a late onset (past middle age). Over 90% casesare type 2 DM. Causes may be:• Abnormality in gluco-receptor of β cells so that

they respond at higher glucose concentration.• Reduced sensitivity of peripheral tissues to

insulin; down regulation of insulin receptors.• Excess of hyperglycaemic hormones (glucagon,

etc.)/obesity.

INSULIN

The hypoglycaemic hormone insulin is synthe-sized in the β cells of pancreatic islets. It is a twochain polypeptide having 51 amino acids andMW about 6,000. The A-chain has 21 while B-chain has 30 amino acids. There are minor differ-ences between human, pork and beef insulins:

Species A-chain B-chain

8th AA 10th AA 30th AAHuman THR ILEU THRPork THR ILEU ALABeef ALA VAL ALA

Under basal condition ~1 U insulin is secretedper hour by human pancreas. Much larger quantityis secreted after every meal. Secretion of insulinfrom β cells is regulated by chemical (primarilyglucose, but also amino acids, fatty acids, ketonebodies), hormonal (growth hormone, cortico-steroids, thyroxine, glucagon, somatostatin) andneural (adrenergic, cholinergic) mechanisms.

Actions of Insulin

The overall effects of insulin are to favour storageof fuel. The most prominent action of insulin ishypoglycaemia. It facilitates glucose transportacross cell membrane (by enhancing insertionof glucose transporter GLUT4 into the cellmembrane) and alters the activity of enzymesinvolved in carbohydrate, fat and proteinmetabolism in liver, muscle and adipose tissue tolower blood glucose level. Concurrently, theactions prevent rise in free fatty acid level, ketonebody production and protein breakdown of thediabetic state (see box on page 221).

Most of the metabolic actions of insulin areexerted within seconds or minutes and are calledthe rapid actions. Others involving DNA mediatedsynthesis of glucose transporter and someenzymes of amino acid metabolism have a latencyof few hours—the intermediate actions. Inaddition, insulin exerts major long-term effectson multiplication and differentiation of cells.

Approaches to drug therapy in type 2 DM

Improve insulin availability Overcome insulin resistance

Exogenous insulin BiguanidesSulfonylureas ThiazolidinedionesMeglitinide/phenylalanine analogues α glucosidase inhibitors

Major limitations Major limitations

Hypoglycaemic episodes Inability to achieve normoglycaemia by themselvesWeight gain in many patients, especially moderate-to-severe casesConcern about premature atherosclerosisdue to hyperinsulinaemia

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Actions of insulin producing hypoglycaemia

Liver Muscle Adipose tissue▲ Increases glucose uptake ▲ Increases glucose uptake ▲ Increases glucose uptake and

and glycogen synthesis and utilization storage as fat and glycogen▲ Inhibits glycogenolysis ▲ Inhibits proteolysis and ▲ Inhibits lipolysis and

and glucose output release of amino acids, release of FFA + glycerol▲ Inhibits gluconeogenesis pyruvate, lactate into blood which form substrate

from protein, pyruvate, FFA which form substrate for for gluconeogenesisand glycerol gluconeogenesis in liver in liver

Mechanism of action Insulin acts on specific receptorslocated on the cell membrane of practically all cells, liverand fat cells are very rich. The insulin receptor is aheterotetrameric glycoprotein consisting of 2 extracellularα and 2 transmembrane β subunits linked together bydisulfide bonds. Its orientation across the membrane isdepicted in Fig. 14.2. The α subunits carry insulin binding

sites, while the β subunits have tyrosine protein kinaseactivity.

Binding of insulin to α subunits induces aggregationand internalization of the receptor along with the boundinsulin molecules. This activates tyrosine kinase activityof the β subunits to phosphorylate tyrosine residues ofeach other and then of Insulin Receptor Substrate proteins


Fig. 14.2: A model of insulin receptor and mediation of its metabolic and cellular actions; T—Tyrosine residue;GLUT—Glucose transporter; IRS—Insulin receptor substrate proteins; PIP3—Phosphatidyl inositol trisphosphate;MAP-kinase—Mitogen activated protein kinase; T-PrK—Tyrosine protein kinase


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Table 14.1: Types of insulin preparations and insulin analogues

Type Onset Peak Duration Can be mixed(hr) (hr) (hr) with

Rapid actingInsulin lispro 0.2–0.4 1–2 3–5 Regular, NPHInsulin aspart 0.2–0.4 1–1.5 3–5 Regular, NPHInsulin glulisine 0.3–0.5 1–2 2–4 Regular, NPH

Short actingRegular (soluble) insulin 0.5–1 2–4 6–8 All preparations

Intermediate actingInsulin zinc suspension or Lente* 1–2 8–10 20–24 RegularNeutral protamine hagedorn 1–2 8–10 20–24 Regular(NPH) or isophane insulin

Long actingProtamine zinc insulin (PZI) 4–6 14–20 24–36 Regular

Insulin glargine 2–4 5–12 24 None

* Lente insulin is a 7:3 mixture of ultralente (crystalline) and semilente (amorphous) insulin zinc suspension. Ultralente(long-acting) and semilente (short-acting) are not separately marketed in India.

(IRS1, IRS2). In turn, a cascade of phosphorylation anddephosphorylation reactions is set into motion resultingin stimulation or inhibition of enzymes involved in therapid metabolic actions of insulin.

Certain second messengers like phosphatidyl inositoltris-phosphate (PIP3) also mediate the action of insulin onmetabolic enzymes.

Through the phosphorylation cascade insulin activatesGLUT4 and promotes its translocation to the cellmembrane. In the long term, the genes for GLUT4 andmany enzymes as well as carriers are upregulated whilesome are down regulated.

The internalized receptor-insulin complex is partlyrecycled to the surface and partly degraded intracellularly.

Fate of insulin Insulin is distributed only extra-cellularly. It is a peptide, therefore degraded inthe g.i.t. if given orally. Injected insulin or thatreleased from pancreas is metabolized primarilyin liver and to a smaller extent in kidney andmuscles. The plasma t½ is 5–9 min.

Preparations of insulin

The conventional commercial preparations areobtained from pork and beef pancreas. Theycontain about 1% (10,000 ppm) of proinsulin andother peptides which are potentially antigenic.These have now been largely replaced by highly

purified (monocomponent) pork insulins/humaninsulins/insulin analogues.

Regular (soluble) insulin is a buffered solutionof unmodified insulin which needs to be injecteds.c. 2-3 or more times daily. Therefore, it has beenmodified by adding more zinc with or withoutprotamine (a nonantigenic protein) to yield slowlyabsorbed and longer acting ‘modified’ or ‘retard’preparations (Table 14.1).

Human insulin produced by recombinant DNAtechnology or by enzymatic modification of porkinsulin, has the same amino acid composition asthat produced by human pancreas. It is now morepopular than highly purified pork/beef insulins.The human and purified pork insulin produceless allergic reaction, insulin resistance andinjection site lipodystrophy.

Several analogues of human insulin producedby replacing 1-3 amino acids have the samepharmacodynamic actions but exhibit greaterstability and consistency in time-course of action.Insulin lispro, insulin aspart and insulin glulisinehave a more rapid and predictable onset, peakand shorter duration of action than regularinsulin. On the other hand, insulin glargine is long

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acting; produces relatively low smooth and‘peakless’ blood insulin level. Once daily s.c.injection yields relatively constant backgroundinsulin action. The meal time glycaemia may becontrolled by injecting a short acting insulinpreparation or by ingesting an oral hypoglycaemicbefore food.

Reactions to insulin

1. Hypoglycaemia is the most frequent andpotentially the most serious reaction to insulin.Hypoglycaemia can occur in any diabeticfollowing inadvertent injection of large doses, bymissing a meal (e.g. after a dental procedure) or byperforming vigorous exercise. The symptoms canbe divided into those due to counter-regulatorysympathetic stimulation—sweating, anxiety,palpitation, tremor; and those due to deprivationof brain of its essential nutrient—glucose(neuroglucopenic symptoms)—dizziness, head-ache, behavioural changes, visual disturbances,hunger, fatigue, weakness, muscular incoordi-nation and sometimes fall in BP. Generally, thereflex sympathetic symptoms occur before theneuroglucopenic.

Finally, when blood glucose falls further (to< 40 mg/dl) mental confusion, seizures andcoma occur.

Treatment Glucose must be given orally or i.v.(for severe cases)—reverses the symptoms rapidly.2. Local reactions Swelling, erythema andstinging sometimes occur at the injection site,especially in the beginning. Localized lipodystrophyoccurs in the subcutaneous fat after long usage.

3. Allergy This is infrequent; is due to contami-nating proteins; very rare with human/highlypurified insulins. Urticaria, angioedema andanaphylaxis are the manifestations.

Drug interactions

1. β adrenergic blockers prolong hypoglycaemiaby inhibiting compensatory mechanisms opera-ting through β2 receptors (β1 selective agents are

less liable). Warning signs of hypoglycaemia likepalpitation, tremor and anxiety are masked.2. Thiazides, furosemide, corticosteroids, oralcontraceptives, salbutamol tend to raise bloodsugar and reduce effectiveness of insulin.3. Acute ingestion of alcohol can precipitatehypoglycaemia by depleting hepatic glycogen.4. Lithium, theophylline and high dose aspirinmay also accentuate hypoglycaemia by enhan-cing insulin secretion and peripheral glucose utili-zation.

Use of insulin in diabetes mellitus Thepurpose of therapy in diabetes mellitus is to restoremetabolism to normal, avoid symptoms due tohyperglycaemia and glucosuria, prevent short-term complications (infection, ketoacidosis, etc.)and long-term sequelae (cardiovascular, retinal,neurological, renal, etc.)

Insulin is effective in all forms of diabetesmellitus and is a must for type 1 cases. Many type2 cases can be controlled by diet, reduction inbody weight and appropriate exercise supple-mented, if required, by oral hypoglycaemics.Insulin is needed by such cases when:

(i) Not controlled by diet and exercise.(ii) Primary or secondary failure of oral hypo-

glycaemics.(iii) Underweight patients.(iv) Temporarily to tide over infections, trauma,

surgery, pregnancy. In the perioperativeperiod and during labour, monitored i.v.insulin infusion is preferable.

(v) Any complication of diabetes, e.g. ketoaci-dosis, diabetic or non-ketotic hyperosmolarcoma, gangrene of extremities.

Insulin resistance This is said to havedeveloped when insulin requirement is increased(by definition > 200 U/day, but physiologically> 100 U/day). Relative insulin resistance isintegral to the ‘metabolic syndrome, of whichhyperinsulinemia (with latent or overt type 2diabetes), dyslipidaemia, hyperuricaemia andhypertension are important components. Stress ofdental procedure may produce low grade acute insulinresistance. It can be overcome by increasing insulin



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dose. Insulin antibody mediated chronic highgrade resistance is now rare due to use of morepurified preparations.

ORAL HYPOGLYCAEMIC DRUGS

These drugs lower blood glucose levels and areeffective orally.

SULFONYLUREASFirst generation Second generationTolbutamide GilbenclamideChlorpropamide (Glyburide)

GlipizideGliclazideGlimepiride

BIGUANIDEMetformin

MEGLITINIDE/PHENYLALANINE ANALOGUESRepaglinide Nateglinide

THIAZOLIDINEDIONESRosiglitazone Pioglitazone

ααααα GLUCOSIDASE INHIBITORSAcarbose Miglitol

DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORSitagliptin Vildagliptin

SULFONYLUREAS

The generic formula of sulfonylureas is:

All have similar pharmacological profile—solesignificant action being lowering of blood glu-cose level in normal subjects and in type 2diabetics, but not in type 1 diabetics.

Sulfonylureas provoke release of insulin frompancreas. They act on the so-called ‘sulfonylureareceptors’ (SUR1) on the pancreatic β cellmembrane—cause depolarization by reducingconductance of ATP sensitive K+ channels. Thisenhances Ca2+ influx → degranulation andinsulin release. They primarily augment the 2ndphase insulin secretion. That they do not cause

hypoglycaemia in pancreatectomised animalsand in type 1 diabetics (presence of at least 30%functional β cells is essential for their action)confirms their indirect action through pancreas.

After chronic administration, the insulinae-mic action of sulfonylureas declines probably dueto downregulation of sulfonylurea receptors on βcells, but improvement in glucose tolerance ismaintained. In this phase, they sensitize the targettissues (especially liver) to the action of insulin.This is due to increase in the number of insulinreceptors and/or a postreceptor action—improving translation of receptor activation.

Pharmacokinetics All sulfonylureas are wellabsorbed orally. Their pharmacokinetic anddistinctive features are given in Table 14.2.

Interactions

Drugs that enhance sulfonylurea action (mayprecipitate hypoglycaemia) are:(a) Inhibit metabolism/excretion: Cimetidine, sulfo-namides, ketoconazole, warfarin, chloramphe-nicol, acute alcohol intake (also synergises bycausing hypoglycaemia).(b) Synergise with or prolong pharmacodynamicaction: Propranolol, sympatholytic antihyperten-sives, lithium, theophylline, high dose aspirin.

Drugs that decrease sulfonylurea action (vitiatediabetes control) are:(a) Induce metabolism: Phenobarbitone, phenytoin,rifampicin, chronic alcoholism.(b) Opposite action/suppress insulin release: Cortico-steroids, thiazides, furosemide, oral contra-ceptives.

Adverse effects

1. Hypoglycaemia It is the commonest problem,may occasionally be severe and rarely fatal.

Treatment is to give glucose, may be for a fewdays because hypoglycaemia may recur.

2. Nonspecific side effects Nausea, vomiting,flatulence, diarrhoea or constipation, headache,paresthesias and weight gain.

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Table 14.2: Important features of oral hypoglycaemics

Drug Plasma Duration Clearance Daily Remarkst½ (hr) of action route* dose

(hr)

SULFONYLUREAS1. Tolbutamide 6–8 6–8 L 0.5–3g Weaker, shorter acting, flexible dosage, safer in those

prone to hypoglycaemia2. Chlorpropamide 30–36 36–48 K,L 0.1–0.5g Longest acting, can cause prolonged hypoglycaemia,

potentiates ADH action, more cholestatic jaundice,alcohol flush

3. Glibenclamide 4–6 18–24 L 5–15mg Potent but slow acting, marked initial insulinaemic(Glyburide) action, may work when others fail, higher incidence of

hypoglycaemia, single daily dose possible despite shortt½

4. Glipizide 3–5 12–18 L 5–20mg Fast acting, insulinaemic action persists even afterprolonged use, can be given once daily despiteshort t½, hypoglycaemia and weight gain less likely

5. Gliclazide 8–20 12–24 L 40–240mg Has antiplatelet action, reduces free radicals, maydelay diabetic retinopathy, less weight gain

6. Glimepiride 5–7 24 L 1–6mg Stronger extrapancreatic action; less hyper-insulinaemia. Divide in two if daily dose > 4 mg

BIGUANIDES1. Metformin 1.5–3 6–8 K 0.5–2g Not metabolized at all, lactic acidosis less common

MEGLITINIDE / PHENYLALANINE ANALOGUES1. Repaglinide < 1 3-5 L 1.5–8mg Given ½ hr before each meal for limiting p.p.

hyperglycaemia2. Nateglinide 1.5 2–3 L 180–480 Stimulates 1st phase insulin secretion, less likely

mg to cause delayed hypoglycaemiaTHIAZOLIDINEDIONES

1. Rosiglitazone 4 12–24 L 4–8mg Reverses insulin resistance. No hypoglycaemia,C/I in liver and heart disease

2. Pioglitazone 3–5 24 L 15–45mg -do-; May improve lipid profile

*L—Metabolized in liver, K—Excreted unchanged by kidney, p.p.—postprandial

3. Hypersensitivity Rashes, photosensitivity,purpura, transient leukopenia, rarely agranulo-cytosis.

BIGUANIDES

The generic formula of biguanides is:

R1 — N — C — N — C — N — R2

| || | || |H NH H NH H

The only biguanide in clinical use now ismetformin. It differs markedly from sulfonylureas:

causes little or no hypoglycaemia in nondiabeticsubjects.

Mechanism of action of biguanides is not clearlyunderstood. They do not cause insulin release,but presence of some insulin is essential for theiraction. Explanations offered for their hypogly-caemic action are:

1. Suppress hepatic gluconeogenesis andglucose output from liver: the major action.

2. Enhance insulin-mediated glucose disposalin muscle and fat.

3. Retard intestinal absorption of glucose,other hexoses, amino acids and vit B12.



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4. Promote peripheral glucose utilization byenhancing anaerobic glycolysis. This actionon mitochondrial respiratory chain is veryweak in metformin.

Adverse effects Abdominal pain, anorexia,nausea, metallic taste, mild diarrhoea andtiredness are the frequent side effects. Metformindoes not cause hypoglycaemia except in overdose.

Lactic acidosis is the most serious complication.It is rare with metformin, but risk is increased inliver disease and in alcoholics.

Vit B12 deficiency due to interference with itsabsorption can occur—especially with high doseof metformin.

MEGLITINIDE/PHENYLALANINE ANALOGUES

These are recently developed quick and short-acting insulin releases.

Repaglinide Though not a sulfonylurea, it actsin an analogous manner by binding tosulfonylurea receptor as well as to other distinctreceptors → closure of ATP dependent K+

channels → depolarisation → insulin release.Repaglinide induces rapid onset short-lasting

insulin release. It is administered before eachmajor meal to control postprandial hypergly-caemia; the dose may be omitted if a meal ismissed. Because of short-lasting action, it mayhave a lower risk of serious hypoglycaemia. Sideeffects are mild headache, dyspepsia, arthralgiaand weight gain.

Repaglinide is indicated only in type 2 DM asan alternative to sulfonylureas, or to supplementmetformin/long-acting insulin.

Nateglinide It stimulates the 1st phase insulinsecretion and has more rapid onset and shorterduration of hypoglycaemic action than repag-linide. There is little effect on fasting blood glucoselevel. Episodes of hypoglycaemia are less frequentthan with sulfonylureas. It is used only to controlpostprandial hyperglycaemia in type 2 diabetics.

THIAZOLIDINEDIONES

This novel class of oral antidiabetic drugs areselective agonists for the nuclear peroxisomeproliferator-activated receptor γ (PPARγ) whichenhances the transcription of several insulinresponsive genes. They tend to reverse insulinresistance by stimulating GLUT4 expression andtranslocation: entry of glucose into muscle andfat is improved. Hepatic gluconeogenesis isalso suppressed. Used alone they are weakerhypoglycaemics than sulfonylureas and bigua-nides, but when added to one of these—improvedglycaemic control results in lowering ofcirculating insulin levels in type 2 DM patients.

Two members Rosiglitazone and Pioglitazoneare available for clinical use. Both are welltolerated; adverse effects are plasma volumeexpansion, edema, weight gain, headache,myalgia and mild anaemia. An increase incardiovascular events and CHF has been linkedto their long term use. Risk of fractures in theelderly may be increased by rosiglitazone.Monotherapy with glitazones is not associatedwith hypoglycaemic episodes.

Failure of oral contraception may occur duringpioglitazone therapy. Ketoconazole inhibitsmetabolism of pioglitazone.

The thiazolidinediones are indicated in type2 DM, but not in type 1 DM. They are primarilyused to supplement sulfonylureas/metforminand in case of insulin resistance.

α GLUCOSIDASE INHIBITORS

Acarbose It is a complex oligosaccharide whichreversibly inhibits α-glucosidases, the finalenzymes for the digestion of carbohydrates in thebrush border of small intestine mucosa. It slowsdown and decreases digestion and absorption ofpolysaccharides and sucrose: postprandial gly-caemia is reduced without increasing insulinlevels.

Acarbose is a mild antihyperglycaemic andnot a hypoglycaemic: may be used as an adjuvant

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to diet (with or without a sulfonylurea) in obesediabetics.

DIPEPTIDYL PEPTIDASE-4 (DPP-4)INHIBITORS

The enzyme DPP-4 rapidly degrades glucagonlike peptide-1 (GLP-1) which is released from thegut in response to oral glucose. The GLP-1 is animportant incretin which serves to limit post-prandial glycaemia by inducing insulin releasefrom pancreas and suppressing glucagon release.It also slows gastric emptying and reducesappetite.

Sitagliptin and Vildagliptin are recentlyintroduced orally active DPP-4 inhibitors which

potentiate endogenous GLP-1 and other incretinsby preventing their degradation. They have beenfound to limit postprandial hyperglycaemia aswell as lower basal blood glucose level in type 2diabetics without producing hypoglycaemia.Because of their good tolerability, they havequickly become popular add-on drugs fordiabetics not fully controlled by sulfonylureas ±biguanides alone.

Oral hypoglycaemics in diabetes mellitusOral hypoglycaemics are indicated only in type 2diabetes, when not controlled by diet and exercise.They are best used in patients with—1. Age above 40 years at onset of disease.2. Obesity at the time of presentation.

Fig. 14.3: Flow chart of management approach in diabetes mellitusBG: Biguanide; SU: Sulfonylureas; TZD: Thiazolidinedione; PP: Postprandial; DPP-4I: Dipeptidyl peptidase-4 inhibitor



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3. Duration of disease < 5 years when startingtreatment.

4. Fasting blood sugar < 200 mg/dl.5. Insulin requirement < 40 U/day.6. No ketoacidosis or a history of it, or any other

complication.A simplified treatment approach for diabetesmellitus is presented in Fig. 14.3.

Implications in dentistry Diabetes mellitus isassociated with increased incidence of manydental problems like caries tooth, periodontaldisease, oral candidiasis and other infections, etc.Dental extractions and other simple proceduresunder local anaesthesia do not usually pose anyspecial problems in diabetics, provided bloodsugar levels are well controlled. If the diabeticwho is being treated with insulin/oralhypoglycaemics is to miss the meals after a dentalprocedure, care should be taken that he/she doesnot develop hypoglycaemia. For more extensivedental procedures or those to be done undergeneral anaesthesia, it is advisable to monitorurine and blood sugar levels and cover theperioperative period with regular insulin injecteds.c. Severe/uncontrolled diabetics may be givenan i.v. infusion of regular insulin along with 5%glucose solution during the procedure.

Prophylactic antibiotics should be given tocover dental procedures in diabetics, particularlyif they are poorly controlled.

GLUCAGON

The hyperglycaemic hormone glucagon is a single chainpolypeptide containing 29 amino acids, MW 3,500. It issecreted by the α cells of the islets of Langerhans inpancreas.

Blood glucose level has opposite effects on insulinand glucagon release, i.e. high glucose level inhibitsglucagon secretion.

Glucagon is hyperglycaemic; most of its actions areopposite to that of insulin. Glucagon causes hyper-glycaemia primarily by enhancing glycogenolysis andgluconeogenesis in liver. Suppression of glucose utilizationin muscle and fat contributes modestly.

Glucagon increases the force and rate of cardiaccontraction and this is not antagonized by β blockers.

Mechanism of action Glucagon, through its own receptorand coupling Gs protein activates adenylyl cyclase and

increases cAMP in liver, fat cells, heart and other tissues;most of its actions are mediated through this cyclicnucleotide.

Uses Glucagon can be used to counteract insulinhypoglycaemia as an expedient measure, and occasionallyto stimulate the heart in cardiogenic shock.

CORTICOSTEROIDS

The adrenal cortex secretes steroidal hormoneswhich have glucocorticoid, mineralocorticoid andweakly androgenic activities. Conventionally, theterm ‘corticosteroid’ or ‘corticoid’ includes natu-ral gluco- and mineralocorticoids and theirsynthetic analogues.

The corticoids (both gluco and mineralo) are21 carbon compounds having a cyclopentanoper-hydro-phenanthrene (steroid) nucleus. They aresynthesized in the adrenal cortical cells fromcholesterol. Adrenal steroidogenesis takes placeunder the influence of ACTH which makes morecholesterol available for conversion to preg-nenolone and induces steroidogenic enzymes.Since adrenal cortical cells store only minutequantities of the hormones, rate of release isgoverned by the rate of biosynthesis.

The normal rate of secretion of the two principalcorticoids in man is—

Hydrocortisone—10-20 mg daily (nearly half ofthis in the few morning hours).

Aldosterone— 0.125 mg daily.

ACTIONS

The corticoids have widespread actions. Theymaintain fluid-electrolyte, cardiovascular andenergy substrate homeostasis and functionalstatus of skeletal muscles and nervous system.They prepare the body to withstand effects of allkinds of noxious stimuli and stress. Theinvolvement of hypothalamo-pituitary-adrenalaxis in stress response is depicted in Fig. 14.4.

Actions of corticoids are divided into:

Glucocorticoid Effects on carbohydrate, proteinand fat metabolism, and other actions that areinseparably linked to these.

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corticosteroid production and response to stress

Mineralocorticoid Effects on Na+, K+ and fluidbalance.

Marked dissociation between these two typesof actions is seen among natural as well assynthetic corticoids. Accordingly, compounds arelabelled as ‘glucocorticoid’ or ‘mineralocorticoid’.

Mineralocorticoid actions

Enhancement of Na+ reabsorption in distalconvoluted tubule of kidney associated withincreased K+ and H+ excretion is the principalaction. Excessive action leads to Na+ and waterretention, edema, progressive rise in BP,hypokalaemia and alkalosis. Mineralocorticoiddeficiency results in progressive Na+ loss →dilutional hyponatraemia → cellular hydration→ decreased blood volume. Hyperkalaemia andacidosis accompany. These distortions of fluidand electrolyte balance progress and contribute

to the circulatory collapse that occurs in adrenalinsufficiency if excess salt is not ingested. It isthis action which makes adrenal cortex essentialfor survival.

The action of aldosterone is expressed by genemediated increased transcription of m-RNA inrenal tubular cells which directs synthesis ofproteins (aldosterone-induced proteins—AIP).The Na+K+ ATPase of tubular basolateralmembrane responsible for generating gradientsfor movement of cations in these cells is the majorAIP (see Ch. 13). Aldosterone also promotesmyocardial fibrosis in CHF, contributing todisease progression.

Glucocorticoid actions

1. Carbohydrate and protein metabolism Gluco-corticoids promote glycogen deposition in liver

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by inducing hepatic glycogen synthetase andpromoting gluconeogenesis. They inhibit glucoseutilization by peripheral tissues. This along withincreased glucose release from liver results inhyperglycaemia, resistance to insulin and adiabetes-like state. They also cause proteinbreakdown and amino acid mobilization fromperipheral tissues—responsible for side effects likemuscle wasting, lympholysis, loss of osteoid frombone and thinning of skin. The amino acids somobilized funnel into liver → used up in gluco-neogenesis, excess urea is produced → negativenitrogen balance. Glucocorticoids are thuscatabolic. Their function appears to be orientedto maintaining blood glucose levels duringstarvation—so that brain continues to get itsnutrient.

They also increase uric acid excretion.

2. Fat metabolism Corticoids promote lipolysis.Fat depots in different areas respond differently—redistribution of body fat occurs. Subcutaneoustissue over extremities loses fat which is depositedover face, neck and shoulder —‘moon face’, ‘fishmouth’, ‘buffalo hump’.

3. Calcium metabolism They inhibit intestinalabsorption and enhance renal excretion of Ca2+.There is also loss of calcium from bone indirectlydue to loss of osteoid. Spongy bones (vertebrae,ribs, etc.) are more sensitive. Osteoporosis occurs.

4. Water excretion Glucocorticoids, but notaldosterone, maintain g.f.r. and help excretingexcess water load.

5. CVS Glucocorticoids restrict capillary per-meability, maintain tone of arterioles and myo-cardial contractility. They play a permissive rolein the development of hypertension.

Adrenal insufficiency is attended by low car-diac output, arteriolar dilatation, poor responseto Adr and increased permeability of capillaries.

6. Skeletal muscles Optimum level of cortico-steroids is needed for normal muscular activity.Weakness occurs in both hypo-and hypercor-ticism, but the causes are different.

Hypocorticism: diminished work capacity andweakness are primarily due to hypodynamiccirculation.Hypercorticism: excess mineralocorticoid action →hypokalaemia → weakness;Excess glucocorticoid action → muscle wastingand myopathy → weakness.

7. CNS Mild euphoria is quite common withsupraphysiological doses of glucocorticoids. Thissometimes progresses to cause insomnia, anxietyor depression as side effect of corticosteroidtherapy.

8. Stomach Secretion of gastric acid and pep-sin is increased—may aggravate peptic ulcer.

9. Lymphoid tissue Glucocorticoids enhancethe rate of destruction of lymphoid cells (T cellsare more sensitive than B cells). A marked lyticresponse is shown by malignant lymphatic cells.Corticosteroids are palliative in lymphomas.

10. Inflammatory responses Irrespective of thetype of injury or insult, the attending inflamma-tory response is suppressed by glucocorticoids.This is the basis of most of their clinical uses. Theaction is nonspecific and includes reduction of—increased capillary permeability, local exudation,cellular infiltration, phagocytic activity and lateresponses like capillary proliferation, collagendeposition, fibroblastic activity and ultimatelyscar formation. The action is direct and local.Therefore, topical use is possible. The cardinalsigns of inflammation—redness, heat, swellingand pain are suppressed.

Glucocorticoids interfere at several steps inthe inflammatory response, but the most impor-tant overall mechanism appears to be limitationof recruitment of inflammatory cells at the localsite.

Production of PGs and several other mediatorsof inflammation like LTs, PAF, TNFα andcytokines is interfered by negative regulation ofCOX and other relevant enzymes. They alsoinduce formation of anti-inflammatory proteinlipocortin, which inhibits phospholipase A that

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is responsible for release of arachidonic acidfrom membrane phospholipids for PG and LTsynthesis.

Corticoids are only palliative, do not removethe cause of inflammation; the underlying diseasecontinues to progress while manifestations aredampened. They favour spread of infectionsbecause capacity of defensive cells to killmicroorganisms is impaired. They also interferewith healing and scar formation: peptic ulcer mayperforate asymptomatically.

11. Immunological and allergic responses Gluco-corticoids impair immunological competence.They suppress all types of hypersensitization andallergic phenomena. The clinical effect appearsto be due to suppression of recruitment of leuko-cytes at the site of contact with antigen andof inflammatory response to immunologicalinjury.

They cause greater suppression of CMI in whichT cells are primarily involved, e.g. delayedhypersensitivity and graft rejection—basis of usein autoimmune diseases and organ transplan-tation. Factors involved may be inhibition of IL-1release from macrophages; inhibition of IL-2formation and action → T cell proliferation isnot stimulated; suppression of natural killer cells,etc. Overall, corticosteroids interrupt cooperativecell-to-cell communication between immuno-logical cells.

Mechanism of action at cellular level

Corticosteroids penetrate cells and bind to a highaffinity cytoplasmic receptor protein → astructural change occurs in the steroid-receptorcomplex that allows its migration into thenucleus and binding to glucocorticoid responseelements (GRE) on the chromatin → transcriptionof specific m-RNA → regulation of proteinsynthesis (see Fig. 3.8). This process takes at least30-60 min : effects of corticosteroid are notimmediate, and once the appropriate proteins aresynthesized—effects persist much longer than the

steroid itself. In many tissues, the overall effect iscatabolic, i.e. inhibition of protein synthesis. Thismay be a consequence of steroid directed syn-thesis of an inhibitory protein. The glucocorticoidreceptor (GR) is very widely distributed (inpractically all cells).

PHARMACOKINETICS

All natural and synthetic corticoids are absorbedby the oral route.

Hydrocortisone undergoes high first pass meta-bolism, has low oral: parenteral activity ratio. Oralbioavailability of synthetic corticoids is high.

Hydrocortisone is 90% bound to plasma pro-tein, mostly to a specific cortisol-binding globulin(CBG; transcortin) as well as to albumin.

The steroids are metabolized primarily byhepatic microsomal enzymes. The metabolites areexcreted in urine.

The plasma t½ of hydrocortisone is 1.5 hours.However, biological effect t½ is longer because ofaction through intracellular receptors and regu-lation of protein synthesis—effects that persistlong after the steroid is removed from plasma.

The synthetic corticosteroids are moreresistant to metabolism and are longer acting.

Phenobarbitone and phenytoin induce meta-bolism of hydrocortisone, prednisolone and dexa-methasone, etc. to decrease their therapeutic effect.

DISTINCTIVE FEATURES

The relative potency and activity of differentnatural and synthetic corticosteroids employedsystemically is compared in Table 14.3.

1. Hydrocortisone (cortisol) In addition toprimary glucocorticoid, it has significant minera-locorticoid activity with rapid and short lastingaction.

2. Prednisolone It is 4 times more potent thanhydrocortisone; also more selective glucocor-ticoid, but fluid retention does occur with highdoses. Has intermediate duration of action: causesless pituitary-adrenal suppression when a single

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It is used for allergic, inflammatory, autoimmunediseases and in malignancies.

3. Methylprednisolone Slightly more potent andmore selective than prednisolone.

Pulse therapy with high dose methylpredni-solone (1 g infused i.v. every 6–8 weeks) hasbeen tried in nonresponsive active rheumatoidarthritis, renal transplant, pemphigus, etc.

4. Triamcinolone Slightly more potent thanprednisolone but highly selective glucocorticoid.

5. Dexamethasone Very potent and highlyselective glucocorticoid. Long acting, causesmarked pituitary-adrenal suppression, but fluidretention and hypertension are not a problem.

It is used for inflammatory and allergic condi-tions, shock, cerebral edema, etc.

6. Betamethasone Similar to dexamethasone.Dexamethasone or betamethasone are preferredin cerebral edema and other states in which fluidretention must be avoided.

7. Deflazacort It is a highly selective gluco-corticoid, dose-to-dose slightly less potent than

prednisolone, but claimed to cause less adverseeffects.

ADVERSE EFFECTS

These are extension of the pharmacological actionthat become prominent with prolonged therapy,and are a great limitation to the use of corticoidsin chronic diseases.

A. Mineralocorticoid Sodium and waterretention, edema, hypokalaemic alkalosis and aprogressive rise in BP.

Gradual rise in BP occurs due to excessglucocorticoid action as well.

B. Glucocorticoid1. Cushing’s habitus: characteristic appea-

rance with rounded face, narrow mouth,supraclavicular hump, obesity of trunk withrelatively thin limbs.

2. Fragile skin, purple striae—easy bruising,telengiectasis, hirsutism. Cutaneous atro-phy occurs with topical use also.

3. Hyperglycaemia, precipitation of diabetes.4. Muscular weakness; myopathy occurs occa-

sionally.

Table 14.3: Relative activity of systemic corticosteroids

Compound Gluco Mineralo Equiv. dose(antiinflammatory)

Short acting, 1. Hydrocortisone 1 1 20 mg(Biological (cortisol)t½ < 12 hr)

Intermediate 2. Prednisolone 4 0.8 5 mgacting, 3. Methyl- 5 0.5 4 mg(Biological prednisolonet½ 12–36 hr) 4. Triamcinolone 5 0 4 mg

Long acting, 5. Dexamethasone 25 0 0.75 mg(Biological 6. Betamethasone 25 0 0.75 mgt½ > 36 hr) 7. Deflazacort ~4 0 6 mg

Equiv. saltretaining dose

8. Desoxycortico- 0 100 2.5 mgsterone acetate (DOCA) (sublingual)

9. Fludrocortisone 10 150 0.2 mg10. Aldosterone 0.3 3,000 not used clinically

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5. Susceptibility to infection; opportunisticinfections with low-grade pathogens(Candida, etc.).

6. Delayed healing of wounds.7. Peptic ulceration.8. Osteoporosis: Specially involving vertebrae

and other flat spongy bones.9. Growth retardation: in children occurs even

with small doses if given for long periods.10. Foetal abnormalities: cleft palate and other

defects are produced in animals, but havenot been encountered in pregnant women.

11. Psychiatric disturbances.12. Suppression of hypothalamo-pituitary-

adrenal (HPA) axis: occurs depending bothon dose and duration of therapy. In time,adrenal cortex atrophies and stoppage ofexogenous steroid precipitates a withdra-wal syndrome and reactivation of thedisease. Subjected to stress, these patientsmay go into acute adrenal insufficiency.

Any patient who has received > 20–25 mg/day hydrocortisone or equivalent for longer than2–3 weeks should be put on a scheme of gradualwithdrawal. Such patients may need protectionwith steroids if a stressful situation develops upto one year after withdrawal.

If a patient on steroid therapy develops aninfection—the steroid should not be discontinueddespite its propensity to weaken host defence.Rather, the dose may have to be increased to meetstress of the infection.Measures that minimise HPA axis suppressionare:(a) Use shorter acting steroids (hydrocortisone,

prednisolone) at the lowest possible dose.(b) Use steroids for the shortest period of time

possible.(c) Give the entire daily dose at one time in the

morning.(d) Switch to alternate-day therapy if possible.(e) If appropriate, use local (dermal, inhaled, ocu-

lar, nasal, buccal, rectal, intrasynovial)preparations.

USES

Systemic as well as topical corticosteroids haveone of the widest spectrum of medical uses fortheir antiinflammatory and immunosuppressiveproperties. They are powerful drugs: have thepotential to cause dramatic improvement in manysevere diseases, but can produce equally seriousadverse effects. Important conditions in whichthey are used are:

1. Collagen and autoimmune diseases: syste-mic lupus erythematosus, polyarteritisnodosa, nephrotic syndrome, glomerulo-nephritis, rheumatoid arthritis, rheumaticfever, acute gouty arthritis, haemolytic anae-mia, thrombocytopenia, myasthenia gravis,etc.

2. Severe allergic reactions: anaphylaxis,angioneurotic edema, urticaria, serumsickness.

3. Bronchial asthma, aspiration pneumonia,allergic rhinitis.

4. Eye diseases: allergic conjunctivitis,iridocyclitis, keratitis, uveitis, retinitis, opticneuritis, etc.

5. Skin diseases: mostly topical use indermatitis; systemic steroids are needed inpemphigus vulgaris, exfoliative dermatitis,Stevens-Johnson syndrome and otherserious disorders.

6. Inflammatory bowel disease: ulcerativecolitis, Crohn’s disease.

7. Infective diseases: only in serious/life-threatening infective diseases undereffective antimicrobial cover, e.g. inbacterial/tubercular meningitis, miliarytuberculosis, severe lepra reaction, etc.

8. Neurological conditions: like cerebraledema due to tubercular meningitis/cerebral tumours, Bells palsy, neurocysti-cercosis.

9. Malignancies: acute lymphatic leukaemia,Hodgkin’s disease, lymphomas, etc.

10. Renal and other organ transplantation, skinallograft.

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11. Substitution therapy in acute and chronicadrenal insufficiency and congenitaladrenal hyperplasia.

CONTRAINDICATIONS

The following diseases are aggravated by corti-costeroids. Since steroids may have to be used asa life-saving measure, all of these are relativecontraindications:

1. Peptic ulcer2. Diabetes mellitus3. Hypertension4. Viral and fungal infections5. Tuberculosis and other infections6. Osteoporosis7. Herpes simplex keratitis8. Psychosis9. Epilepsy

10. CHF11. Renal failure.

Implications in dentistry

Application of corticosteroids in dental conditionsis rather limited. Recurrent oral ulceration maybe treated with topical steroids, but maintaininglong enough contact between the steroid and the

oral lesion is often difficult. Severe oral lesionslike pemphigus, erosive lichen planus, etc. needto be treated with systemic corticosteroids. Painfrom exposed dental pulp is occasionally treatedwith locally applied steroids. Intra-articularhydrocortisone is sometimes injected in thetemporomandibular joint to relieve refractory painand stiffness. Only rarely a corticosteroid isneeded to suppress pain and swelling due todental surgery, (e.g. impacted third molarextraction), for which NSAIDs are the first linedrugs.

In the case of patients who are/have been inrecent past on long-term corticosteroid therapy,consideration has to be given to the need forsupplementary prophylactic corticoid to cover adental procedure. In general, simple extractionsand other mildly traumatic surgeries do notwarrant additional steroid dose. For traumaticprocedures and those to be performed undergeneral anaesthesia, supplementary steroids maybe needed, particularly if the dose and durationof steroid therapy are such as to have causedsignificant adrenal suppression, or the patient isexcessively anxious. Monitoring of BP of suchpatients during surgery is required. In case BPfalls, hydrocortisone should be injected i.v.immediately.

The gonads produce steroidal hormones whichhave androgenic, estrogenic and progestationalactivities. Their synthetic analogues have similaror antagonistic actions and form an importantclass of drugs.

ANDROGENS(Male sex hormones)

These are substances which cause developmentof secondary sex characters in the castrated male.Testosterone produced by the testes is the principalandrogen, a part of which is converted in extra-glandular tissues by the enzyme steroid 5αreductase to the more active compounddihydrotestosterone. Whereas in most target tissuesdihydrotestosterone is the active androgen,testosterone itself is active at the spermatogenic(in testes) and erythropoietic (in bone marrow)cells, and for feedback inhibition of LH at thehypothalamic/pituitary site.

Actions

1. Sex organs and secondary sex characters(Androgenic) Testosterone is responsible for allthe changes that occur in a boy at puberty:Growth of genitals—penis, scrotum, seminalvesicles, prostate.Growth of hair—pubic, axillary, beard, moust-ache, body hair and male pattern of its distribution.Thickening of skin, proliferation and increasedactivity of sebaceous glands—especially on the

face, acne vulgaris.Larynx grows and voice deepens.Behavioral effects are—increased physical vigour,aggressiveness, penile erections.Testosterone is also important for the intrauterinedevelopment of the male phenotype.

2. Testes Testosterone is needed for normalspermatogenesis and maturation of spermatozoa.However, larger doses administered exogenouslycause testicular atrophy by inhibiting Gnsecretion from pituitary.

3. Skeleton and skeletal muscles (Anabolic)Testosterone is responsible for the pubertal spurtof growth in boys and to a smaller extent in girls.There is rapid bone growth. After puberty, theepiphyses fuse and linear growth comes to a halt.Testosterone also promotes muscle building,especially if aided by exercise. There is accretionof nitrogen, minerals (Na, K, Ca, P, S) and water—body weight increases rapidly, more protoplasmis built.

4. Erythropoiesis Testosterone accelerates ery-thropoiesis by increasing erythropoietin pro-duction and probably direct action on haemesynthesis.

Pharmacokinetics

Testosterone is inactive orally due to high firstpass metabolism in liver. Slowly absorbed estersof testosterone are used by the i.m. route.

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The major metabolic products of testosteroneare androsterone and etiocholanolone which areexcreted in urine. Small quantities of estradiol arealso produced from testosterone by aromatizationof A ring in extraglandular tissues. Plasma t½ oftestosterone is 10–20 min.

Side effects

1. Virilization and menstrual irregularities inwomen.2. Acne: in males and females.3. Frequent, sustained and often painful erec-tions.4. Oligozoospermia with moderate doses givenfor a few weeks.5. Precocious puberty and shortening of stature.6. Cholestatic jaundice: occurs with 17-alkylsubstituted derivatives but not with parenterallyused esters of testosterone. Long-term use of thesederivatives also increases incidence of hepaticcarcinoma.

Androgens accelerate growth of carcinomaprostate and that of male breast.

Uses

Testosterone is used for replacement therapy incase of primary or secondary testicular failureresulting in delayed puberty, loss of libido andimpotence. However, impotence due to psycho-logical and other factors, and not testosteronedeficiency, does not respond.

The anabolic effect of testosterone can be usedto improve weakness and muscle wasting in AIDSpatients.

Attacks of hereditary angioneurotic edema canbe prevented by 17α-alkylated androgens (methyl-testosterone, stanozolol, danazol) but not bytestosterone. They act by increasing synthesis ofcomplement (C1) esterase inhibitor.

ANABOLIC STEROIDS

These are synthetic androgens with supposedlyhigher anabolic and lower androgenic activity.Drugs are Nandrolone, Oxymetholone, Stanozolol,Methandienone and others.

The anabolic steroids have been used forosteoporosis in elderly males, in catabolic stateslike severe trauma, major surgery, duringconvalescence and in hypoplastic/malignancyassociated anaemia. They may reduce nitrogenload in renal insufficiency. Use for promotingsuboptimal growth in children is controversial,and misuse by athletes to enhance physical abilityis illegal.

IMPEDED ANDROGENS / ANTIANDROGENS

Danazol It is an orally active ethisteronederivative having weak androgenic, anabolic andprogestational activity. Though labelled as animpeded/attenuated androgen, the most pro-minent action is suppression of Gn secretionfrom pituitary in both men and women →inhibition of testicular/ovarian function. Itsuppresses gonadal function directly as well byinhibiting steroidogenic enzymes. Endometrialatrophy occurs over a few weeks andamenorrhoea may supervene.

Danazol is used in endometriosis wherein itrelieves dysmenorrhoea, dyspareunia andexcessive bleeding. It reduces blood loss inmenorrhagia and affords symptomatic relief infibrocystic breast disease and hereditary angio-neurotic edema.

Flutamide A nonsteroidal drug having specificantiandrogenic, but no other hormonal activity.Its active metabolite 2-hydroxyflutamide compe-titively blocks androgen action on accessory sexorgans as well as on pituitary—increases LHsecretion by blocking feedback inhibition. Plasmatestosterone levels increase in males whichpartially overcome the direct antiandrogenicaction of flutamide. Palliative effect may occur inadvanced prostatic carcinoma, but it is better usedin conjunction with a GnRH agonist (to suppressgonadotropin secretion) or after castration.Reports of liver damage have restricted its use.

Bicalutamide It is a longer acting and morepotent congener of flutamide that is also lesshepatotoxic and better tolerated. As such, it is

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being preferred over flutamide for palliativetreatment of metastatic carcinoma prostate.

5 α-REDUCTASE INHIBITOR

Finasteride A competitive inhibitor of theenzyme 5 α-reductase which converts testosteroneinto more active dihydrotestosterone responsiblefor androgen action in many tissues includingthe prostate gland and hair follicles. Plasma LHand testosterone levels remain unchanged duringfinasteride treatment, because testosterone itselfmediates feedback pituitary LH inhibition: libidoand potency are largely preserved.

Treatment with finasteride has resulted indecreased prostate size and increased peakurinary flow rate in ~50% patients with sympto-matic benign hypertrophy of prostate (BHP).

The relief of obstructive symptoms, however,is less marked compared to surgery andadrenergic α1-blockers. Concurrent treatment withα1 blocker + finasteride produces greatersymptomatic relief.

Finasteride has also been found effective inmale pattern baldness.

Dutasteride An exceptionally long acting(plasma t½ ~ 9 weeks) congener of finasteride,similarly useful in BHP and male pattern baldness.

ESTROGENS

These are substances which can induce estrus inspayed (ovariectomised) animals.

Estradiol is the major estrogen secreted by theovary. It is synthesized in the graafian follicle,corpus luteum and placenta from cholesterol.Estradiol is rapidly oxidized in liver to estronewhich is hydroxylated to form estriol. All threeare found in the blood, but estradiol is the mostpotent.

Natural estrogens are inactive orally and havea short duration of action due to rapid metabolismin liver. Synthetic estrogens are:

Steroidal Ethinylestradiol, Mestranol,Tibolone.

Nonsteroidal Diethylstilbestrol (stilbestrol):Hexestrol, Dienestrol.

Actions

1. Sex organs The estrogens bring about puber-tal changes in the female—growth of uterus,fallopian tubes and vagina. Vaginal epitheliumgets thickened, stratified and cornified. They areresponsible for the proliferation of endometriumin the preovulatory phase, and it is only in concertwith estrogens that progesterone brings aboutsecretory changes.

Estrogens increase rhythmic contractions ofthe fallopian tubes and uterus, and induce awatery alkaline secretion from the cervix—favourable to sperm penetration. They alsosensitize the uterus to oxytocin. Deficiency ofestrogens is responsible for atrophic changes inthe female reproductive tract that occur aftermenopause.

2. Secondary sex characters Estrogens produ-ced at puberty cause growth of breasts. The pubicand axillary hair appear, feminine body contoursand behaviour are influenced.

3. Metabolic effects Estrogens are anabolic,similar to but weaker than testosterone. Continuedaction of estrogen promotes fusion of epiphyses.They are important in maintaining bone massprimarily by retarding bone resorption andpromoting positive calcium balance.

Combination contraceptives containinghigher doses of estrogens and progestins impairglucose tolerance. However, amounts used forhormone replacement therapy (HRT) and lowdose contraception do not affect carbohydratemetabolism.

Estrogens decrease plasma LDL cholesterolwhile HDL and triglyceride levels are raised. Theraised HDL : LDL ratio is probably responsiblefor rarity of atherosclerosis in premenopausalwomen. However, blood coagulability is increa-sed due to induction of synthesis of clottingfactors. They increase lithogenicity of bile.

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Mechanism of action Estrogens act by bindingto specific nuclear estrogen receptors (ERs) in thetarget cells and regulating protein synthesis.Two ERs designated ERα and ERβ have beenidentified.

Pharmacokinetics Estrogens are well absorbedorally and transdermally, but natural estrogensare inactive orally due to rapid metabolism inliver. Transdermal estradiol (Estradiol-TTS)bypasses first pass metabolism in liver; the patchapplied over skin is active for 3-4 days. Estradiolesters injected i.m. are slowly absorbed and exertprolonged action.

Estradiol is converted to estrone and vice versain liver. Estriol is derived from estrone. All threeare conjugated with glucuronic acid and sulfate—excreted in urine and bile. Considerable entero-hepatic circulation occurs due to deconjugationin intestines and reabsorption—ultimate disposaloccurs mostly in urine.

Ethinylestradiol is metabolized very slowly.It is orally active and more potent.

Adverse effects

Most of the adverse effects of estrogens aredescribed with oral contraceptives (see p. 243).In addition, adverse effects noted when use is madefor other indications are:1. Suppression of libido, gynaecomastia andfeminization when given to males.2. Fusion of epiphyses and reduction of adultstature when given to children.3. In postmenopausal women, estrogens canincrease the risk of endometrial carcinoma. Aprogestin given concurrently blocks the risk.4. Increased incidence of breast cancer is a riskwith higher doses.5. Long-term estrogen therapy doubles theincidence of gallstones.6. Estrogens increase the incidence of thrombo-embolic diseases.7. Migraine and endometriosis may be worsenedby estrogens.

Uses

Currently, the two most common uses of estrogensare as contraceptives and for hormone replace-ment therapy (HRT) in postmenopausal women.The dose of estrogen used for HRT is substantiallylower than that for contraception. Estrogen HRTis highly efficacious in suppressing the meno-pausal syndrome.

Hot flushes, palpitation, mood changes andother symptoms are mitigated. HRT improvesgeneral physical, mental and sexual well being.Atrophic genital changes are arrested. The vulvaland urinary symptoms are effectively relieved.

HRT restores calcium balance, further boneloss is prevented.

However, the benefits of HRT must be weighedagainst the risks (predisposition to endometrial/breast cancer, gallstones, venous thromboembo-lism, worsening of migraine, etc.) in individualwomen.

Other indications of estrogens are senilevaginitis, dysfunctional uterine bleeding (asadjuvant to progestin), advanced carcinomaprostate and as substitution therapy for delayedpuberty in girls.

Antiestrogen

1. Clomiphene citrate It acts as a pure estrogenantagonist in all human tissues and induces Gnsecretion in women by blocking estrogenic feed-back inhibition of pituitary. In response, theovaries enlarge and ovulation occurs if theovaries are responsive to Gn. Antagonism ofperipheral actions of estrogen results in hotflushes. Endometrium and cervical mucus maybe modified.

The chief use of clomiphene is in sterility dueto failure of ovulation. Conception occurs in manywomen who previously were amenorrhoeic orhad anovular cycles.

Polycystic ovaries, multiple pregnancy, hotflushes are the adverse effects.

Oligozoospermia: Clomiphene increases Gnsecretion in men as well → promotes spermato-

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genesis and testosterone secretion. It may be usedfor male infertility.

Fulvestrant It is a new drug designated as ‘pure estrogenantagonist’ or ‘selective estrogen receptor downregulator’(SERD); used for palliative treatment of metastatic ERpositive breast cancer in postmenopausal women.

Selective estrogen receptor modulators(SERMs)

Tamoxifen citrate It acts as potent estrogenantagonist in breast carcinoma cells, blood vesselsand at some peripheral sites, but as partial agonistin uterus, bone, liver and pituitary. Inhibition ofhuman breast cancer cells and hot flushes reflectantiestrogenic action, while the weak estrogenagonistic action manifests as stimulation ofendometrial proliferation, lowering of Gn andprolactin levels in postmenopausal women aswell as improvement in their bone density. Similarto estrogen HRT, it increases the risk of deep veinthrombosis by 2–3 times.

Tamoxifen is the first choice hormonaltreatment of breast cancer in both pre- and post-menopausal women. It is also approved forprimary prophylaxis of breast cancer in high-riskwomen.

Improvement in bone mass due to anti-resorptive effect, and in lipid profile (loweringcoronary artery disease risk) are the other benefitsof tamoxifen therapy. However, endometrialthickening occurs and risk of endometrialcarcinoma is increased 2 to 3-fold.

Side effects are hot flushes, vomiting, vaginalbleeding and menstrual irregularities.

Raloxifene This SERM is an estrogen partialagonist in bone and cardiovascular system, butan antagonist in endometrium and breast.

Raloxifene prevents bone loss in postmeno-pausal women; bone mineral density (BMD) mayeven increase. It also reduces the risk of breastcancer.

Raloxifene does not stimulate endometrialproliferation and there is no increase in risk ofendometrial carcinoma.

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Hot flushes, leg cramps are mild side effects.The only serious concern is 3-fold increase inrisk of deep vein thrombosis and pulmonaryembolism.

Raloxifene is an effective alternative to HRTfor prevention and treatment of osteoporosis inpostmenopausal women.

Aromatase inhibitorsAromatization (introduction of double bonds) of‘A’ ring in testosterone produces estradiol.Inhibition of the aromatase enzyme leads to arrestof estrogen production in the body, which canhave palliative effect in breast cancer. Letrozole,Anastrozole and Exemestane are recently introducedaromatase inhibitors which have demonstratedclinical superiority in the treatment of breastcancer. While letrozole and anastrozole are non-steroidal, exemestane is a steroidal compound.However, all are orally active. They cause nearlytotal estrogen deprivation of breast carcinomacells arresting their proliferation. Hot flushes,nausea, dyspepsia, acceleration of bone loss andjoint pain are the important side effects.

In India, letrozole is also approved for treat-ment of female infertility by inducing ovulation.

PROGESTINS

These are substances which convert the estrogenprimed endometrium to secretory and maintainpregnancy in animals spayed after conception(Progestin = favouring pregnancy).

Progesterone, a 21 carbon steroid, is thenatural progestin. It is secreted by the corpusluteum in the later half of menstrual cycle underthe influence of LH. Its production declines a fewdays before the next menstrual flow. If the ovumgets fertilized and implants—the blastocystimmediately starts producing chorionic gonado-tropin which is absorbed into maternal circulationand sustains the corpus luteum in earlypregnancy. Placenta starts secreting lots ofestrogens and progesterone from 2nd trimestertill term.

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either progesterone derivatives (21 C) or 19-nortestosterone derivatives (18 C). Whereas theprogesterone derivatives are almost pureprogestins, have weaker antiovulatory action andare used primarily as adjuvants to estrogens forHRT, threatened abortion, endometriosis, etc.some of the 19-nortestosterone derivatives haveadditional weak estrogenic, weak androgenic,anabolic and potent antiovulatory action: are usedprimarily in combined contraceptive pills.

Progesterone derivatives

Medroxyprogesterone acetateDydrogesteroneHydroxyprogesterone caproateNomegestrol acetate

19-Nortestosterone derivatives

Norethindrone (Norethisterone)Lynestrenol (Ethinylestrenol)AllylestrenolLevonorgestrelDesogestrelNorgestimateGestodene

Actions

The main function of progesterone is preparationof uterus for nidation and maintenance of preg-nancy. The latter is due to prevention ofendometrial shedding, decreased uterine motilityand inhibition of immunological rejection of thefoetus: progesterone depresses T-cell function andcell-mediated immunity (CMI).1. Progesterone brings about secretory changes

in the estrogen primed endometrium whileepithelial proliferation is suppressed. It is lackof progestational support which causesmucosal shedding during menstruation.

2. It converts the watery cervical secretioninduced by estrogens to viscid, scanty andcellular secretion which is hostile to spermpenetration.

3. Progesterone induces pregnancy like changesin the vaginal mucosa. The pregnancy associated

increased incidence of gingival inflammationhas been ascribed to high levels of progesterone.

4. Progesterone causes proliferation of acini inthe mammary glands. Acting in concert withestrogens, it prepares breast for lactation.Withdrawal of these hormones after deliverycauses release of prolactin from pituitary andmilk secretion starts.

5. It causes a slight (0.5oC) rise in body tem-perature by resetting hypothalamic thermostatand increasing heat production. This isresponsible for the higher body temperatureseen during the luteal phase.

6. Prolonged use of oral contraceptives impairsglucose tolerance in some women. This hasbeen ascribed to the progestational compo-nent. Progestins tend to raise LDL and lowerHDL levels.

7. Progesterone is a weak inhibitor of Gnsecretion from pituitary. Administration ofprogestin during follicular phase suppressesthe preovulatory LH surge and preventsovulation; synergises with estrogen for thisaction.

Pharmacokinetics

Progesterone, unless specially formulated, isinactive orally because of high first passmetabolism in liver. It is primarily injected i.m. inoily solution. Even after an i.m. dose, it is rapidlycleared from plasma, has a short t½ (5–7 min). Itis nearly completely degraded in the liver.

A micronized formulation of progesterone(referred to as ‘natural progesterone’) has beendeveloped for oral administration.

Most of the synthetic progestins are orallyactive and are metabolized slowly; have plasmat½ ranging from 8–24 hours.

Adverse effects

• Breast engorgement, headache, rise in bodytemperature, esophageal reflux, and moodswings may occur with higher doses.

• Irregular bleeding or amenorrhoea can occurif a progestin is given continuously.

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• Blood sugar may rise and diabetes may beprecipitated.

• Long-term use of progestin in HRT mayincrease the risk of breast cancer.

Uses

1. As contraceptive: Most common use.

2. Hormone replacement therapy (HRT): To counter-act the risk of inducing endometrial carcinomaby the estrogen given alone.

3. Dysfunctional uterine bleeding: A progestin inrelatively large doses promptly stops bleeding andkeeps it in abeyance as long as given.

4. Endometriosis: It is due to the presence ofectopic endometrium; manifestations are dysme-norrhoea, painful pelvic swellings and infertility.Continued administration of progestins affordssymptomatic relief.

5. Threatened/habitual abortion: Progestins arealmost routinely prescribed, but benefit only whenthere is progestin deficiency.

6. Endometrial carcinoma: Progestins are pallia-tive.

7. Progesterone treatment may improve oralaphthous ulcers that are related to menstruation inwomen.

ANTIPROGESTIN

Mifepristone It is a 19-norsteroid with potentcompetitive antiprogestational and significantantiglucocorticoid as well as antiandrogenicactivity.

Given during the follicular phase, its antipro-gestin action results in attenuation of the midcycleGn surge from pituitary → slowing of folliculardevelopment and delay/failure of ovulation.During the luteal phase, it prevents secretorychanges normally brought about by progesterone.Later in the cycle, it blocks progesterone supportto the endometrium, unrestrains PG release fromit—this stimulates uterine contractions. Mifepris-

tone also sensitizes myometrium to PGs andinduces menstruation. If implantation hasoccurred, it blocks decidualization, so thatconceptus is dislodged.

The antiglucocorticoid action is usually notmanifest because antagonism of the negative feed-back at hypothalamic-pituitary level elicits ACTHrelease → plasma cortisol rises and overcomesthe direct antiglucocorticoid action. Larger dosesdo ameliorate Cushing’s syndrome.

Uses of mifepristone are:1. Termination of pregnancy of up to 7 weeks.2. To induce cervical ripening before attempting

abortion/ induction of labour.3. As postcoital contraceptive. It has also been

tried as once-a-month contraceptive.4. Cushing’s syndrome: for its antiglucocor-

ticoid property.

HORMONAL CONTRACEPTIVES

These are hormonal preparations used forreversible suppression of fertility.

Over 100 million women worldwide are cur-rently using hormonal contraceptives. With thesedrugs, fertility can be suppressed at will, for aslong as desired, with almost 100% confidence andcomplete return of fertility on discontinuation. Theefficacy, convenience, low cost and overall safetyof oral contraceptives (OCs) has allowed womento decide whether and when they will becomepregnant and to plan their activities. A variety oforal and parenteral preparations are nowavailable offering individual choices.

TYPES OF METHODS

1. Combined pill It contains an estrogen and aprogestin. With accumulated experience, it hasbeen possible to reduce the amount of estrogenand progestin in the ‘second generation’ OC pillswithout compromising efficacy, but reducing sideeffects and complications. Ethinylestradiol 30 μgdaily is considered threshold but can be reducedto 20 μg/day if a progestin with potent antiovu-

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latory action (such as desogestrel) is included.While both estrogens and progestins synergise toinhibit ovulation, the progestin ensures promptbleeding at the end of a cycle and blocks the riskof developing endometrial carcinoma due to theestrogen. One tablet is taken daily for 21 days,starting on the 5th day of menstruation. The nextcourse is started after a gap of 7 days in whichbleeding occurs. Thus, a cycle of 28 days ismaintained. Calendar packs of pills are available.This is the most popular and most efficaciousmethod.2. Phased regimens These have been introdu-ced to permit reduction in total steroid dose. Theestrogen dose is kept constant (or varied slightlybetween 30–40 μg), while the amount of progestinis low in the first phase and progressively higherin the second and third phases.

3. Minipill (luteal supplement) A low-doseprogestin only pill is taken daily continuouslywithout any gap. The menstrual cycle tends tobecome irregular and ovulation occurs in 20–30%women, but other mechanisms contribute to thecontraceptive action. The efficacy is lower (96–98%) compared to 98–99.9% with combined pill.

4. Postcoital (emergency) contraception

Currently 3 regimens are available:(a) Levonorgestrel 0.75 mg × 2 doses taken at 12hour interval (or 1.5 mg single dose) within 72hours of unprotected intercourse. This is the mostpopular method; recommended by WHO as well.(b) Levonorgestrel 0.5 mg + ethinylestradiol 0.1mg (2 OVRAL tablets) × 2 doses 12 hours aparttaken as early as possible, but within 72 hours ofunprotected intercourse. This regimen, called the‘Yuzpe method’ has become less popular due tolower efficacy and more side effects.(c) Mifepristone 600 mg single dose taken within72 hours of intercourse.

Emergency postcoital contraception should bereserved for unexpected or accidental exposure(rape, condom rupture) only and not practicedroutinely.

Injectable These have been developed toobviate the need for daily ingestion of pills. Theyare given i.m. as oily solution; are highly effective.

Two types of preparations have been tested:(i) Long acting progestin alone:

(a) Depot medroxyprogesterone acetate(DMPA) 150 mg at 3-month intervals.(b) Norethindrone (Norethisterone) enanthate(NEE) 200 mg at 2-month intervals.

The most important draw back is completedisruption of menstrual bleeding pattern and totalamenorrhoea in many cases.(ii) Long acting progestin + long acting estrogen —once a month. One such combination is:

DMPA + Estradiol cypionate.These have been tested to a more limited extent.Main advantage is that they allow a reasonablemenstrual bleeding pattern in most cases. Theirobvious disadvantage is that they contain a long-acting estrogen which has potential to harm.

MECHANISM OF ACTION

Hormonal contraceptives interfere with fertilityin many ways; the relative importance dependson the type of method.1. Inhibition of Gn release from pituitary. Whenthe combined pill is taken, both FSH and LH arereduced and the midcycle surge is abolished. Asa result, follicles fail to develop and fail torupture—ovulation does not occur.2. Thick cervical mucus secretion hostile to spermpenetration is evoked by progestin action. Thismechanism does not operate in case of postcoitalpill.3. Even if ovulation and fertilization occur, theblastocyst may fail to implant because endomet-rium is out of phase with fertilization—not suitablefor nidation. This action is most important in caseof mini pill and postcoital pill.4. Uterine and tubal contractions may be modifiedto disfavour fertilization.5. The postcoital pill may dislodge a just implan-ted blastocyst.

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ADVERSE EFFECTS

Since contraceptives are used in otherwisehealthy and young women, adverse effects,especially long-term consequences, assume greatsignificance. The present-day low-dose prepara-tions carry relatively minor risk.

A. Nonserious side effects These are frequent,especially in the first 1–3 cycles and then dis-appear gradually.1. Nausea and vomiting.2. Headache; migraine may be precipitated orworsened.3. Breakthrough bleeding or spotting. Amenor-rhoea may occur in few.4. Breast discomfort.

B. Side effects that appear later1. Weight gain, acne and increased body hair.2. Chloasma: pigmentation of cheeks.3. Pruritus vulvae.4. Carbohydrate intolerance and precipitationof diabetes.5. Mood swings, abdominal distention.

C. Serious complications1. Leg vein and pulmonary thrombosis: Significantrisk in women >35 years of age, diabetics,hypertensives and in those who smoke.2. Coronary and cerebral thrombosis resulting inmyocardial infarction or stroke: A 2 to 6-fold increasein risk was estimated earlier, but recent studieshave found no increased incidence with the lowdose pills in the absence of other risk factors.3. Rise in BP: This again is less frequent andsmaller in magnitude with the low-dose pills oftoday.4. Genital carcinoma: Risk is increased inpredisposed individuals but not in the generalpopulation. Growth of already existing hormone-dependent tumour may be hastened.

Epidemiological data has recorded minorincrease in breast cancer incidence among currentOC users.5. Gallstones: Incidence of gallstones is slightlyhigher in women on OCs.

Contraindications

The combined oral contraceptive pill is absolu-tely contraindicated in:1. Thromboembolic, coronary and cerebrovas-cular disease or a history of it.2. Moderate-to-severe hypertension; hyperlipi-daemia.3. Active liver disease, hepatoma or h/o jaun-dice during past pregnancy.4. Suspected/overt malignancy of genitals/breast.5. Impending major surgery—to avoid post-operative thromboembolism.

Interactions Contraceptive failure may occur ifthe following drugs are used concurrently:(a) Enzyme inducers: phenytoin, phenobarbitone,primidone, carbamazepine, rifampin.(b) Suppression of intestinal microflora: tetracyclines,ampicillin, etc. Deconjugation of estrogensexcreted in bile does not occur → theirenterohepatic circulation is interrupted → bloodlevels fall.

Centchroman (Ormeloxifene) It is a nonsteroi-dal estrogen antagonist or SERM developed atCDRI, India and introduced in the National FamilyWelfare Programme as an oral contraceptive. Itprobably acts as an anti-implantation agent byinducing embryo-uterine asynchrony, acceleratedtubal transport and suppression of decidua-lization. It prevents conception as long as taken,with return of fertility on withdrawal. Failure rateof 1–3% has been recorded.

UTERINE STIMULANTS(Oxytocics, Abortifacients)

These drugs increase uterine motility, especiallyat term.1. Posterior pituitary hormone Oxytocin,

Desamino-oxytocin2. Ergot alkaloids Ergometrine (Ergonovine),

Methylergometrine3. Prostaglandins PGE2, PGF2α, 15-methyl

PGF2α, Misoprostol4. Miscellaneous Ethacridine, Quinine.

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Oxytocin

Oxytocin is a nonapeptide secreted by theposterior pituitary along with ADH.

Both oxytocin and ADH are synthesized withinthe nerve cell bodies in supraoptic and paraven-tricular nuclei of hypothalamus. They aretransported down the axon and stored in the nerveendings within the neurohypophysis. Both arereleased by stimuli appropriate for oxytocin, i.e.coitus, parturition, suckling; or for ADH, i.e.hypertonic saline infusion, water deprivation,haemorrhage, etc. However, the proportion ofoxytocin to ADH can vary depending upon thenature of the stimulus.

Oxytocin increases the force and frequency ofuterine contractions. With low doses, fullrelaxation occurs inbetween contractions.

The increased contractility is restricted to thefundus and body; lower segment is not contracted,may even be relaxed at term. Oxytocin plays afacilitatory role in labour, but does not appear tobe essential for its initiation.

Initiated by suckling, oxytocin plays anessential role in ‘milk ejection reflex’ bycontracting the myoepithelium of mammaryalveoli which forces milk into the bigger milksinusoids.

Conventional doses used in obstetrics haveno effect on BP, but higher doses cause vasodila-tation → brief fall in BP, reflex tachycardia andflushing. Oxytocin in high doses exerts an ADH-like action—urine output is decreased.

Being a peptide, oxytocin is inactive orally andis administered by i.m. or i.v. routes. It is rapidlydegraded in the liver and kidney; plasma t½ is~ 6 min. It is used to induce labour in case ofpostmaturity or to augment it in case of uterineinertia. It can also be used to control postpartumhaemorrhage as an alternative to ergometrine.Intranasal spray of oxytocin may be employed torelieve breast engorgement in women withinadequate milk ejection reflex.

Injudicious use of oxytocin during labour canproduce too strong uterine contractions forcing

the presenting part through incompletely dilatedbirth canal, causing maternal and foetal soft tissueinjury, rupture of uterus, foetal asphyxia anddeath.

Desamino-oxytocin This formulation of oxytocin hasbeen developed for buccal administration—is absorbedfrom the oral mucosa. Its actions are similar to injectedoxytocin, but less consistent.

Ergometrine, Methylergometrine

The amine ergot alkaloid ergometrine (ergono-vine) and its derivative methylergometrineincrease force, frequency and duration of uterinecontractions. At low doses, contractions arephasic with normal relaxation in between, butonly moderate increase in dose raises the basaltone, contracture occurs with high doses. Graviduterus is more sensitive, especially at term and inearly puerparium. Their stimulant action involvesthe lower segment also. The uterotonic action isbelieved to result from partial agonistic action on5-HT2 and α adrenergic receptors.

They are much weaker vasoconstrictors thanthe amino acid ergot alkaloid ergotamine.

Methylergometrine is 1½ times more potent thanergometrine on the uterus and has replacedergometrine at many obstetric units.

Ergometrine and methylergometrine arerapidly and nearly completely absorbed from theoral route. They are partly metabolized in liverand excreted in urine. Plasma t½ is 1–2 hours.

Use

1. The primary indication of ergometrine/methylergometrine is to control and preventpostpartum haemorrhage (PPH). For this purpose,these drugs are preferred over oxytocin becausethey produce sustained tonic contraction:perforating uterine arteries are compressed by themyometrial meshwork—bleeding stops.2. After cesarean section/instrumental delivery—to prevent uterine atony.3. To ensure normal involution: because a firmand active uterus involutes rapidly.

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Prostaglandins PGE2, PGF2α and 15-methylPGF2α are potent uterine stimulants, especiallyin the later part of pregnancy and cause ripeningof cervix. Their actions and use in obstetrics aredescribed in Ch. 7.

UTERINE RELAXANTS (Tocolytics)

These are drugs which decrease uterine motility.They have been used to delay or postpone labourand arrest threatened abortion. Suppression oflabour may be needed to allow foetus to mature,to initiate glucocorticoid therapy for foetal lungmaturation or to transfer the mother in labour to acentre with proper facilities.

1. Adrenergic agonists (see Ch. 6) Ritodrine,the β2 selective agonist having major uterinerelaxant action is preferred to suppress prematurelabour and to delay delivery in case of someexigency or acute foetal distress. For dependableaction, it is given by i.v. infusion. However, cardio-vascular (hypotension, tachycardia, arrhythmia,pulmonary edema) and metabolic (hypergly-caemia, hyperinsulinaemia, hypokalaemia)complications occur frequently.

Salbutamol and terbutaline are the alter-natives. Isoxsuprine oral/i.m. has been used tostop threatened abortion, but efficacy is uncertain.

2. Calcium channel blockers Because influxof Ca2+ ions plays an important role in uterinecontractions, Ca2+ channel blockers (see Ch. 11)reduce the tone of myometrium and oppose con-tractions. These drugs, especially nifedipine,which has prominent smooth muscle relaxantaction, can postpone labour if used early enough.Tachycardia and hypotension are prominent atdoses which suppress uterine contractions.

3. Magnesium sulfate Given by i.v. infusion,it has been used to control convulsions and toreduce BP in toxaemia of pregnancy. It alsosuppresses uterine contraction effectively, but cancause cardiac arrhythmias, muscular paralysis,CNS and respiratory depression. Its use astocolytic is risky.

Ethyl alcohol, nitrates, progesterone, generalanaesthetics (especially halothane), atosiban(oxytocin antagonist) and PG synthesis inhibitorsare other drugs which can depress uterinecontractions.

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THYROID HORMONE

The thyroid gland secretes 3 hormones—thyro-xine (T4), triiodothyronine (T3) and calcitonin. Theformer 2 are produced by thyroid follicles, havesimilar biological activity and the term ‘thyroidhormone’ is restricted to these only. Calcitoninproduced by interfollicular ‘C’ cells is chemicallyand biologically entirely different: regulatescalcium metabolism.

Chemistry and synthesis

Both T4 and T3 are iodine containing derivativesof thyronine which is a condensation productof two molecules of the amino acid tyrosine.

The thyroid hormones are synthesized andstored in the thyroid follicles as part of thyroglo-bulin molecule—which is a glycoprotein. Thesynthesis, storage and release of T4 and T3 issummarized in Fig. 16.1 and involves thefollowing processes:1. Iodide uptake into the thyroid by active

transport through Na+: Iodide symporter (NIS)which is activated by TSH.

2. Oxidation of the trapped iodide by thyroidperoxidase enzyme to forms of iodine viz.iodinium ions (I+), hypoiodous acid (HOI) orenzyme-linked hypoiodate (E-OI) whichcombine avidly with tyrosil residues ofthyroglobulin to form monoiodotyrosine (MIT)and diiodotyrosine (DIT).

3. Coupling of MIT and DIT with the aid of thesame peroxidase to form T3 and T4.

4. Storage of thyroglobulin containing T3 , T4, MITand DIT residues as thyroid colloid in theinterior of the follicles till it is taken back intothe cells by endocytosis and broken down bylysosomal proteases. The T4 and T3 so releasedare secreted into the circulation.

5. Peripheral conversion of a portion of T4 intoT3 by deiodination in several tissues,especially liver and kidney.Thyroid hormones are avidly bound to

plasma proteins—only 0.03–0.08% of T4 and 0.2–0.5% of T3 are in the free form.

Only the free hormone is available for action aswell as for metabolism and excretion. Metabolicinactivation of T4 and T3 occurs by deiodinationand glucuronide/sulfate conjugation of thehormones as well as of their deiodinated products.Liver is the primary site. The conjugates are excretedin bile. A significant fraction is deconjugated inintestines and reabsorbed (enterohepatic circula-tion) to be finally excreted in urine.

Plasma t½ of T4 is 6–7 days, while that of T3 is1–2 days.

Actions

The actions of T4 and T3 are qualitatively similarand are nicely depicted in the features of hypo-and hyperthyroidism. They affect the function ofpractically all body cells.

16Hormones and Related Drugs

Thyroid Hormone and Thyroid Inhibitors,Hormones Regulating Calcium Balance

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Fig. 16.1: Synthesis, storage and secretion of thyroid hormoneTG—Thyroglobulin; MIT—Monoiodotyrosine; DIT—Diiodotyrosine; T3—Triiodothyronine; T4—Thyroxine (Tetraiodothyronine); HOI—Hypoiodous acid; EOI—Enzyme-linked hypoiodateThyroid-stimulating hormone (TSH) activates steps 1, 2, 3, 4, and 5; Ionic inhibitors block step 1;Excess iodide interferes with steps 1, 2, 3 and 5 with primary action on step 3 and 5; Propylthiouracilinhibits steps 2 and 6; Carbimazole inhibits step 2 only.

1. Growth and development T4 and T3 areessential for normal growth and development.The action is exerted through a critical control ofprotein synthesis in the translation of the geneticcode. Congenital deficiency of T4 and T3 resultingin cretinism emphasizes their importance. Themilestones of development are delayed andpractically every organ and tissue of the bodysuffers. The greatest sufferer, however, is the ner-vous system. Retardation and nervous deficit is aconsequence of paucity of axonal and dendriticramification, synapse formation and impairedmyelination. In adult hypothyroidism also, intel-ligence is impaired and movements are slow.

2. Intermediary metabolism Thyroid hormoneshave marked effect on lipid, carbohydrate and

protein metabolism. Lipolysis and cholesterolmetabolism are accelerated, more cholesterol isconverted to bile acids.

Though utilization of sugar by tissues isincreased, glycogenolysis and gluconeogenesisin liver more than compensate it → hypergly-caemia and diabetic like state results.

Synthesis of certain proteins is increased, butthe overall effect of T3 is catabolic—increasedamounts of protein being used as energy source.Prolonged action results in negative nitrogenbalance and tissue wasting.

3. Calorigenesis T3/T4 increase BMR by stimu-lation of cellular metabolism and resetting of theenergystat. This is important for maintainingbody temperature.

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4. Organ systems Heart rate, contractility andoutput are increased resulting in a fast, boundingpulse. T3/T4 stimulate heart by direct action oncontractile elements as well as by upregulation ofβ adrenergic receptors. Atrial fibrillation andother irregularities are common in hyper-thyroidism. Angina and CHF may be precipitateddue to the hyperdynamic state of circulation.T3/T4 have profound functional effect on CNS.Mental retardation is the hallmark of cretinism;sluggishness and other behavioral features areseen in myxoedema. Hyperthyroid individualsare anxious, nervous, excitable, exhibit tremorsand hyperreflexia.

Muscles are flabby and weak in myxoedema,while thyrotoxicosis produces increased muscletone. Propulsive activity of gut is increased byT3/T4. Hypothyroid patients are often consti-pated, while diarrhoea is common in hyper-thyroidism. Thyroid hormones are facilitatory toerythropoiesis and reproduction.

Mechanism of action T3 (and T4) penetrate cellsby active transport and combine with a nuclearthyroid hormone receptor (TR). A specific DNAsequence called ‘thyroid hormone response element’has been identified in the regulatory region ofspecific genes to which the T3-receptor complexbinds → derepression of gene transcription or insome cases direct activation of gene transcriptionoccurs (Fig. 16.2). This results in expression ofpredetermined genetically coded pattern ofprotein synthesis producing various metabolicand anatomic effects.

Many of the manifestations, e.g. tachycardia,arrhythmias, raised BP, tremor, hyperglycaemiaare mediated, at least partly, by sensitization ofadrenergic receptors to catecholamines. In thethyrotoxic patient, Adr mixed local anaestheticshould be avoided for dental anaesthesia.

Because T3 binds more avidly to the intra-cellular receptor and is 5 times more potent aswell as faster acting than T4, in most tissues, it is

Fig. 16.2: Mechanism of action of thyroid hormone on nuclear thyroid hormone receptor (TR)T3—Triiodothyronine; T4—Thyroxine; TRE—Thyroid hormone response element; RXR—Retinoid X receptor; mRNA—

Messenger ribonucleic acid; 5’DI—5’Deiodinase (See text for explanation).

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the major active hormone, while T4 is mainly thetransport form or prohormone.

Uses The most important uses of thyroidhormone are as replacement therapy in cretinism(congenital hypothyroidism) and myxoedema(adult hypothyroidism). Levothyroxine (T4) givenorally is the preparation of choice and the benefitsare most gratifying. Nontoxic goiter is due torelative thyroid hormone deficiency resulting inexcess TSH → thyroid enlargement, more efficientiodide trapping and T3 synthesis → enoughhormone to meet peripheral demand is produced→ the patient is clinically not hypothyroid.Treatment with T4 normalises TSH level andtends to regress the goiter if the enlargement wasrecent and diffuse. Endemic goiter and endemiccretinism can be prevented by iodizing table salt.T4 has palliative effect in certain benignfunctioning thyroid nodules and in papillarycarcinoma of thyroid by lowering TSH levels.Myxoedema coma is an emergency that is treatedwith l-thyroxine (T4) injected i.v. followed by oraldosing. Due to higher risk of arrhythmias andangina, i.v. liothyronine (T3) is not employed now,though it acts faster.

THYROID INHIBITORS

These are drugs used to lower the functionalcapacity of the hyperactive thyroid gland.

Thyrotoxicosis is due to excessive secretion ofthyroid hormones. The two main causes are Graves’disease and toxic nodular goiter. Graves’ disease isan autoimmune disorder: IgG class of antibodiesto the TSH receptor bind to and stimulate thyroidcells, and produce other TSH like effects. Due tofeedback inhibition, TSH levels are low.

Toxic nodular goiter, which produces thyroidhormone independent of TSH, mostly superveneson old nontoxic goiters.

CLASSIFICATION

1. Inhibit hormone synthesis (Antithyroid drugs)Propylthiouracil, Methimazole, Carbimazole.

2. Inhibit hormone releaseIodine, Iodides of Na and K, Organic iodide

3. Destroy thyroid tissueRadioactive iodine (131I).

ANTITHYROID DRUGS

By convention, only the synthesis inhibitors arecalled antithyroid drugs, though this term hasalso been applied to all thyroid inhibitors.

Antithyroid drugs bind to the thyroid peroxi-dase and prevent oxidation of iodide/iodotyrosylresidues, thereby;

(i) Inhibit iodination of tyrosine residues inthyroglobulin

(ii) Inhibit coupling of iodotyrosine residues toform T3 and T4.

Thyroid colloid is gradually depleted andblood level of T4/T3 is lowered. Effects ofantithyroid drugs are not apparent till thyroid isdepleted of its hormone content.

Propylthiouracil also inhibits peripheralconversion of T4 to T3: this may partly contributeto its effects. Methimazole and carbimazole donot have this action.

Pharmacokinetics All antithyroid drugs arequickly absorbed orally, widely distributed in thebody, enter milk and cross placenta, are meta-bolized in liver and excreted in urine, primarilyas metabolites.

Adverse effects Hypothyroidism and goitercan occur due to overtreatment, but is reversibleon stopping the drug.Important side effects are: g.i. intolerance, skinrashes and joint pain.A rare but serious adverse effect is agranulo-cytosis.

Use Antithyroid drugs control thyrotoxicosis inboth Graves’ disease and toxic nodular goiter.Clinical improvement starts after 1–2 weeks ormore and may take 1–3 months for full control.These drugs may be used for short periods beforepartial thyroidectomy (surgery in thyrotoxicpatient is risky) or while awaiting response to

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radioactive iodine. They can also be used asdefinitive therapy at lower (maintenance) doses.

IODINE AND IODIDES

Though iodine is a constituent of thyroid hormone,it is the fastest acting thyroid inhibitor. It is reducedin the intestines to iodide and the response toiodine or iodides is identical. In Graves’ diseasethe gland, if enlarged, shrinks, becomes firm andless vascular. The thyroid status starts returningto normal at a rate commensurate with completestoppage of hormone release from the gland. Peakeffects are seen in 10–15 days, after which ‘thyroidescape’ occurs and thyrotoxicosis may return withgreater vengeance.

All facets of thyroid function seem to be affec-ted, but the most important action is inhibition ofhormone release. Endocytosis of colloid andproteolysis of thyroglobulin comes to a halt.

In thyrotoxicosis, iodine is primarily used forabout 10 days just preceding thyroid surgery tomake the gland firm, less vascular and easier tooperate on. It may also be given to stop thyroidstorm. Incidence of endemic goiter in iodinedeficient areas has been reduced by iodizing tablesalt.

Potassium iodide is an expectorant. Tinctureiodine is used externally as an antiseptic.

Adverse effects Long-term ingestion of highdoses of iodine/iodides can cause hypothyroi-dism and goiter. Chronic overdose also results ininflammation of mucous membranes. An acutereaction consisting of swelling of lips, eyes,angioedema, fever, thrombocytopenia, etc. candevelop in sensitive individuals.

RADIOACTIVE IODINE

The stable isotope of iodine is 127I. Its radioactiveisotope 131I has a physical half-life of 8 days—most commonly used in medicine.

131I emits X-rays as well as β particles. Theformer are useful in tracer studies, while the latterare utilized for their destructive effect on thyroidcells. 131I is concentrated by thyroid, incorporatedin the colloid—emits radiation from within the

follicles. The β particles penetrate only 0.5–2 mmof tissue. The thyroid follicular cells are affectedfrom within, undergo pyknosis and necrosisfollowed by fibrosis when a sufficiently large dosehas been administered, without damage to neigh-bouring tissues. With carefully selected doses, itis possible to achieve partial ablation of thyroid.

It is used as sodium salt of 131I dissolved in waterand taken orally.

Diagnostic 25–100 μ curie is given; counting orscanning is done at intervals. No damage tothyroid cells occurs at this dose.

Therapeutic The most common indication ishyperthyroidism. The average therapeutic dose is3–6 m curie—calculated on the basis of previoustracer studies and thyroid size. The response isslow—starts after 2 weeks and graduallyincreases, reaching peak at 3 months or so.

Treatment with 131I is simple, convenientlygiven on outpatient basis and inexpensive. Oncehyperthyroidism is controlled, cure is permanent.

The biggest disadvantage of 131I therapy isdevelopment of life-long hypothyroidism in manyrecipients. Long latent period of response isanother drawback. Radioactive iodine may bepalliative in metastatic carcinoma of thyroid.

β ADRENERGIC BLOCKERS

Propranolol (and other nonselective β blockers)have emerged as an important form of therapy torapidly alleviate manifestations of thyrotoxicosisthat are due to sympathetic overactivity: palpi-tation, tremor, nervousness, severe myopathy,sweating. They have little effect on thyroidfunction and the hypermetabolic state; are usedfor symptomatic relief only.

HORMONES REGULATING CALCIUM

CALCIUM

After C, O, H and N, calcium is the most abun-dant body constituent, making up about 2% ofbody weight: 1–1.5 kg in an adult. Over 99% of

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Fig. 16.3: Regulation of plasma level of calcium————→ stimulation, - - - - - -→Inhibition; Bold arrow—major action.PTH—Parathormone; 25-OHD3—Calcifediol; 1,25 (OH)2D3—Calcitriol

this is stored in bones (and teeth), the rest beingdistributed in plasma, all tissues and cells, andserves important physiological roles.1. Controls excitability of nerves and musclesand regulates permeability of cell membranes andcell adhesion.2. Ca2+ ions are essential for excitation-contrac-tion coupling in all types of muscles andexcitation-secretion coupling in exocrine andendocrine glands, release of transmitters fromnerve ending and other release reactions.3. Intracellular messenger for hormones, auta-coids and transmitters.4. Impulse generation in heart—determines levelof automaticity and A-V conduction.5. Coagulation of blood.6. Calcium serves structural function in bone andteeth; abnormalities of calcium balance affect teethindirectly.

Plasma calcium level is precisely regulatedby 3 hormones almost exclusively devoted to thisfunction viz. parathormone (PTH), calcitonin andcalcitriol (active form of vit D). These regulatorscontrol its intestinal absorption, exchange withbone and renal excretion as summarized in Fig.16.3.

Normal plasma calcium is 9–11 mg/dl. Ofthis, about 40% is bound to plasma proteins—chiefly albumin; 10% is complexed with citrate,phosphate and carbonate in an undissociableform; the remaining (about 50%) is ionized andphysiologically important.

Calcium turnover Major fraction of calcium in the boneis stored as crystalline hydroxyapatite deposited on theorganic bone matrix osteoid, while a small labile pool is indynamic equilibrium with plasma. Even the fully laid downparts of the bone undergo constant remodeling by way of twoclosely coupled but directionally opposite processes ofresorption and new bone formation (Fig. 16.4). Millions oftiny remodeling units are working on the surface of bone tra-beculae and Haversian canals to dig micropits by osteoclasticactivity and then repair by osteoblastic activity in which firstcollagen and other proteins (osteoid) are deposited followedby mineralization; the full cycle taking 4–6 months.

Absorption and excretion Calcium is absorbedby facilitated diffusion from the entire smallintestine as well as from duodenum by a carrier-mediated active transport under the influenceof vit D. Phytates, phosphates, oxalates, tetra-cyclines, glucocorticoids and phenytoin reducecalcium absorption.

All ionized calcium is filtered at the glome-rulus and most of it is reabsorbed in the tubules.Vit D increases and calcitonin decreases proximal

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Fig. 16.4: Hormonal regulation of bone remodeling unitThe monocyte osteoclast precursor cells in the marrow near the bony surface are activated to proliferate and fuse to formmultinucleated osteoclasts. The osteoclast-precursors express a ‘receptor for activation of nuclear factor-κ B’ (RANK) ontheir surface. The osteoblasts on activation release a protein RANK-ligand (RANKL). When RANKL is bound to RANK onthe surface of osteoclast-precursors they are transformed into mature osteoclasts and develop bone lysing ruffledsurface. A bone resorption pit is dug out by secretion of acid and proteolytic acid hydrolases.

Osteoblasts produce another protein osteoprotegerin (OPG) as well, which can bind RANKL and prevent it fromcombining with RANK to activate osteoclasts. Thus, osteoblasts by producing RANKL and OPG regulate bone resorption.

After formation of the remodeling pit, preosteoblasts from bone marrow stem cells proliferate, migrate to the base of thepit, transform into mature osteoblasts and laydown new osteoid, which is later mineralized.

Parathormone (PTH) acts on PTH-receptor located on the osteoblast membrane and induces RANKL production—indirectly activating osteoclast differentiation and function. Subsequently PTH promotes new bone formation as well.

Calcitriol also induces RANKL in osteoblasts to indirectly activate osteoclasts. Similarly, it promotes laying of osteoidas well as bone mineralization.

Calcitonin directly inhibits osteoclast function and probably enhances osteoblastic new bone formation.

tubular reabsorption, while PTH increases distaltubular reabsorption of Ca2+. About 300 mg ofendogenous calcium is excreted daily: half in urineand half in faeces. To maintain calcium balance,the same amount has to be absorbed in the smallintestine from the diet. Because normally only1/3rd of ingested calcium is absorbed, the dietaryallowance for calcium is 0.8–1.5 g per day.

Side effects Calcium supplements are usuallywell tolerated; only g.i. side effects like constipation,bloating and excess gas have been reported.

Use

1. As dietary supplement especially in growingchildren, pregnant, lactating and menopausal

women. Abnormalities of dentition can be reduced byavoiding calcium deficiency.2. Osteoporosis Calcium + vit D3 have adjuvantrole to HRT/raloxifene/bisphosphonates inprevention and treatment of osteoporosis.3. To prevent and treat tetany which occurs dueto hypocalcaemia.4. As antacid (Calcium carbonate).

PARATHYROID HORMONE (Parathormone)

Parathyroid hormone (PTH) is a single chain 84amino acid polypeptide, MW 9,500. Secretion ofPTH is regulated by plasma Ca2+ concentration;there is no trophic hormone for it. Fall in plasmaCa2+ induces PTH release and rise inhibits

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secretion. Changes in phosphate concentration inplasma affect PTH secretion indirectly by alteringCa2+ concentration.PTH increases plasma calcium levels by:1. Increasing resorption of calcium from bone.This is the most prominent action of PTH.2. Increasing calcium reabsorption in the distaltubule. It also promotes phosphate excretionwhich tends to supplement the hypercalcaemiceffect.3. Enhancing the formation of calcitriol (activeform of vit D) in the kidney, which then increasesintestinal absorption of calcium.

Hypoparathyroidism Manifestations are:Low plasma calcium levels, tetany, convulsions,laryngospasm, paresthesias, cataract and psy-chiatric changes. Pseudohypoparathyroidismoccurs due to reduced sensitivity of target cells toPTH. Hypoparathyroidism is treated with Vit D.

Hyperparathyroidism It is mostly due to para-thyroid tumour. It produces:Hypercalcaemia, decalcification of bone—defor-mities and fractures (osteitis fibrosa generalisata),metastatic calcification, renal stones, muscleweakness, constipation and anorexia.Treatment is surgical removal of the parathyroidtumour.Teriparatide is a recombinant preparation of 1-34 aminoacids of human PTH which duplicates the actions of PTH,and has been recently approved for the treatment of severeosteoporosis.

CALCITONIN

Calcitonin is the hypocalcaemic hormone. It is a 32amino acid single chain polypeptide (MW 3,600)produced by parafollicular ‘C’ cells of thyroidgland.

Synthesis and secretion of calcitonin is regu-lated by plasma Ca2+ concentration itself: rise inplasma Ca2+ increases, while fall in plasma Ca2+

decreases calcitonin release. However, the phy-siological role of calcitonin in regulating plasmaCa2+ appears to be minor. The plasma t½ of calcito-nin is 10 min, but its action lasts for ~ 8 hours.

The actions of calcitonin are generallyopposite to that of PTH.

It inhibits bone resorption by direct action onosteoclasts—decreasing their ruffled surfacewhich forms contact with the resorptive pit.

Calcitonin inhibits proximal tubular calciumand phosphate reabsorption by direct action onthe kidney.

Calcitonin is rarely used clinically; indicationsare Paget’s disease of bone and hypercalcaemicstates like hypervitaminosis D, osteolytic bonymetastasis, etc. It has to be injected i.m. or s.c.

A nasal spray formulation of calcitonin hasbeen used for postmenopausal osteoporosis whenother drugs cannot be given.

VITAMIN D

Vitamin D is the collective name given toantirachitic substances synthesized in the bodyand found in foods activated by UV radiation.

7-DEHYDROCHOLESTEROL ERGOSTEROL(Synthesized in skin) (yeast, bread, milk)

UV Light

CHOLECALCIFEROL (Vit D3) CALCIFEROL (Vit D2)

Liver microsomes

CALCIFEDIOL (25-OH-D3) 25-OH-D2

Kidney mitochondria

CALCITRIOL (1, 25 (OH)2D3) 1, 25 (OH)2D2

ACTIVE FORMS

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D3 : cholecalciferol — synthesized in the skinunder the influence of UV rays.

D2 : calciferol—present in irradiated food—yeasts, fungi, bread, milk.

In man, vit D2 and D3 are equally active andcalcitriol (active form of D3) is more importantphysiologically; 25-OH D3 is released in bloodfrom liver. Its final hydroxylation in kidney is ratelimiting and controlled by many factors. This stepis activated or induced by calcium/vit D defi-ciency as well as by PTH, estrogens and prolactin,while calcitriol inhibits it in a feedback manner.

Thus, vit D should be considered a hormonebecause:(a) It is synthesized in skin: (under ideal condi-tions, it is not required in diet).(b) It is transported by blood, activated and thenacts on specific receptors in target tissues.(c) Feedback regulation of vit D activation occursby plasma Ca2+ level and by the active form itself.

Actions1. Calcitriol enhances absorption of calcium andphosphate from intestine. This is brought aboutby increasing synthesis of calcium channels anda carrier protein for Ca2+ called ‘calcium bindingprotein’ (Ca BP) or Calbindin. The action ofcalcitriol is analogous to that of steroid hormoneswhich bind to a cytoplasmic receptor → trans-locate to the nucleus → increase synthesis ofspecific mRNA → regulation of protein synthesis.At least part of vit D action is quick (withinminutes) and, therefore, appears to be exerted bymechanisms not involving gene regulation.2. Calcitriol enhances resorption of calcium andphosphate from bone. It appears to help bonemineralization indirectly by maintaining normalplasma calcium and phosphate level. Its action isindependent of but facilitated by PTH.3. It enhances tubular reabsorption of bothcalcium and phosphate in kidney.

Vit D deficiency Plasma calcium and phosphatetend to fall due to inadequate intestinalabsorption. As a consequence, PTH is secreted →calcium is mobilized from bone in order to restore

plasma Ca2+. The bone fails to mineralizenormally in the newly laid area, becomes soft →rickets in children and osteomalacia in adults.However, in contrast to osteoporosis, the organicmatrix (osteoid) is normal in osteomalacia.

Retarded development of mandible, delayed/ faultyeruption of teeth and defective tooth enamel are thedental complications of vit D deficiency.

Hypervitaminosis D It may occur due to chronic ingestionof large doses (~50,000 IU/day) or due to increasedsensitivity of tissues to vit D. Manifestations are due toelevated plasma calcium and its ectopic deposition.

Hypercalcaemia, weakness, fatigue, vomiting, diarrhoea,sluggishness, polyuria, albuminuria, ectopic Ca2+ depo-sition (in soft tissues, blood vessels, parenchymal organs),renal stones, hypertension, growth retardation in children.Treatment: consists of withholding the vitamin, low calciumdiet, plenty of fluid and corticosteroids.

Pharmacokinetics Vit D is well absorbed fromintestines in the presence of bile salts. Malabsorp-tion and steatorrhoea interfere with its absorption.

In the circulation, it is bound to a specific αglobulin and is stored in the body, mostly inadipose tissues, for many months. It is hydroxy-lated in liver to active and inactive metabolites.The t½ of different forms varies from 1–18 days:25-OHD3, having the longest t½, constitutes theprimary circulating form.Metabolites of vit D are excreted mainly in bile.1 μg of cholecalciferol = 40 IU of vit D.The daily requirement varies, depending on exposure tosunlight. It is estimated that if no vit D3 is synthesized inthe body, a dietary allowance of 400 IU/day will preventdeficiency symptoms.

Use

1. Prophylaxis (400 IU/day) and treatment(3,000–4,000 IU/day) of nutritional vit D deficiencywhich causes rickets in children and osteo-malacia in adults.

2. Metabolic rickets These are a group of condi-tions in which tissues do not respond to normaldoses of vit D. The active forms of vit D Calcitriolor Alfacalcidol, which do not need hydroxylationby kidney, are effective in these conditions.

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3. Senile or postmenopausal osteoporosis Age-related decrease in calcium absorption from guthas been noted. Vit D3 + calcium have been shownto improve calcium balance in osteoporoticfemales and elderly males.

4. Hypoparathyroidism Calcitriol/alfacalcidol aremore effective than vit D2 or D3 because they actquickly and directly without the need forhydroxylation in kidney which needs PTH.

Interactions Long-term treatment with pheny-toin and phenobarbitone can cause rickets/osteo-malacia, probably by reducing tissue response tocalcitriol.

BISPHOSPHONATES

Bisphosphonates (BPNs) are analogues ofpyrophosphate: carbon atom replacing oxygenin the P-O-P skeleton. They inhibit bone resorptionand have recently attracted considerable attentionbecause of their ability to prevent osteoporosis inaddition to their usefulness in metabolic bonediseases and hypercalcaemia. They are the mosteffective antiresorptive drugs. Chronologically andaccording to potency, the BPNs can be groupedinto 3 generations (see box).

The BPNs have strong affinity for calciumphosphate, therefore exert selective action incalcified tissue. They have also been shown toaffect isoprenoid lipid synthesis. The net result is:

• Accelerated apoptosis of osteoclasts reducingtheir number.

• Disruption of cytoskeleton and ruffled borderof osteoclasts.In addition, BPNs appear to affect osteoclast

precursors and inhibit their differentiation bysuppressing IL-6. Interference with mevalonatepathway may also impart antitumor action onbony metastasis.

The BPNs are useful in conditions characteri-zed by enhanced bone turnover.1. Osteoporosis The second and third generationBPNs (alendronate; risedronate) are effective inpreventing and treating postmenopausal osteo-porosis in women as well as idiopathic andsteroid-induced osteoporosis in both men andwomen.2. Paget’s disease This disease due to abnormalosteoclast function producing disordered bonearchitecture is benefited by BPNs. They arrestosteolytic lesions, reduce bone pain and improvesecondary symptoms. BPNs (along with Calcium+ Vit D) may have adjuvant value in the treatmentof attrition or tooth decay due to osteoporosis,particularly in postmenopausal women.3. Osteolytic bone metastasis Parenteral pamid-ronate/zoledronate arrest osteolytic lesions andreduce bone pain (most commonly secondary toprostate cancer).4. Hypercalcaemia of malignancy Pamidronateand zoledronate injected i.v. normalise plasmaCa2+ level in this medical emergency.

The first generation BPN etidronate is infre-quently used now. Alendronate and risedronate areoral BPNs used mainly in osteoporosis. They areto be taken on empty stomach in the morning withplenty of water. The patient is instructed not to liedown or take food for at least 30 min, to preventcontact of the BPN with esophageal mucosa toavoid esophagitis. Calcium and iron preparationsas well as NSAIDs should not be administeredwith these drugs.

Pamidronate and Zoledronate are administeredonly by i.v. infusion. They are indicated in bonymetastasis, hypercalcaemia of malignancy andin Pagets’ disease. Bone pain and a flu-likereaction are the common adverse effects.

O R1 OHO || | | | OH

P — C — PNaO | ONa

R2

Bisphosphonate

Bisphosphonate Relative potency

First generation BPN

Etidronate 1Second generation BPNsPamidronate 100Alendronate 100–500Third generation BPNsRisedronate 1000Zoledronate 5000

Bisphosphonates 255

be early manifestations of iron deficiency. Thedaily iron requirement is:

Adult male : 0.5–1 mg (13 μg/kg)Adult female : 1–2 mg (21 μg/kg)Infants : 60 μg/kgChildren : 25 μg/kgPregnancy : 3–5 mg (80 μg/kg).

Iron absorption, transport and excretion

Iron absorption occurs all over the intestine, butmajority in the upper part. Dietary iron is presenteither as haeme or as inorganic iron. Haeme ironis absorbed better (upto 35%) and without the aidof a carrier (Fig. 17.1), than inorganic (~5%), butthe former is a smaller fraction of the dietary iron.Inorganic iron is mostly in the ferric form; needsto be reduced to ferrous form before absorptioncan take place. Two separate iron transporters inthe intestinal mucosal cells function to effect ironabsorption. At the luminal membrane the divalentmetal transporter 1 (DMT1) carrys ferrous iron intothe mucosal cell. This along with the iron releasedfrom haeme is transported across the basolateralmembrane by another iron transporter ferroportin(FP). These iron transporters are regulatedaccording to the body needs. Absorption of haemeiron is largely independent of other foodssimultaneously ingested, but that of inorganiciron is affected by several factors. Gastric acid,reducing substances (ascorbic acid) and aminoacids facilitate iron absorption, while antacids,

HAEMATINICS

Haematinics are substances required in theformation of blood, and are used for treatment ofanaemias.

Anaemia occurs when the balance betweenproduction and destruction of RBCs is disturbedby:(a) Blood loss (acute or chronic).(b) Impaired red cell formation due to:• Deficiency of essential factors, i.e. iron, vitamin

B12, folic acid.• Bone marrow depression (hypoplastic anae-

mia), erythropoietin deficiency.(c) Increased destruction of RBCs (haemolytic

anaemia).

IRON

Iron is an essential body constituent. Total bodyiron in an adult is 2.5–5 g (average 3.5 g). It ismore in men (50 mg/kg) than in women (38 mg/kg) and is distributed into:

Haemoglobin (Hb) 66%Iron stores as ferritin and haemosiderin 25%Myoglobin (in muscles) 3%Parenchymal iron (enzymes, etc.) 6%

To raise the Hb level of blood by 1 g/dl—about200 mg of elemental iron is needed. Though theprimary reflection of iron deficiency occurs inblood, severe deficiency affects practically everycell. Oral ulceration, stomatitis, glossitis may even

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tetracyclines, phosphates and phytates impedeiron absorption.

Mucosal block The gut has a mechanism toprevent entry of excess iron in the body. Ironreaching inside mucosal cell is either transportedto plasma or oxidised to ferric form and com-plexed with apoferritin to form ferritin (Fig. 17.1).This ferritin generally remains stored in the muco-sal cells and is lost when they are shed (lifespan2–4 days). This is called the ‘Ferritin Curtain’.

The iron status of the body and erythropoieticactivity govern the balance between these twoprocesses, a larger percentage is absorbed duringiron deficiency.

Iron is transported in blood in combinationwith a glycoprotein transferrin (Tf). It is transportedinto cells through attachment of transferrin tospecific membrane bound transferrin receptors(TfRs). In iron deficiency the erythron becomesselectively more efficient in trapping iron. Iron isstored in RE cells in liver, spleen, bone marrow,also in hepatocytes and myocytes as ferritin andhaemosiderin. Plasma iron derived fromdestruction of old RBCs (lifespan–120 days), fromstores and from intestinal absorption forms acommon pool that is available for erythropoiesis,to all other cells and for restorage.

Oral iron preparations The preferred route ofiron administration is oral in the form ofdissociable ferrous salts.1. Ferrous sulfate: (hydrated salt 20% iron, driedsalt 32% iron) is the cheapest. It often leaves ametallic taste in mouth.2. Ferrous gluconate (12% iron).3. Ferrous fumarate (33% iron): is less watersoluble than ferrous sulfate and tasteless.4. Colloidal ferric hydroxide (50% iron).Other forms of iron present in oral formulationsare:

Ferrous succinate (35% iron)Iron calcium complex (5% iron)Ferric ammonium citrate (scale iron)Iron hydroxy polymaltoseFerrous aminoate (10% iron)Carbonyl iron (metallic iron as very finepowder)

These are claimed to be better absorbed and/orproduce less bowel upset, but this is primarilydue to lower iron content.

The elemental iron content and not thequantity of iron compound per dose unit shouldbe taken into consideration.

A total of 200 mg elemental iron (infants andchildren 3–5 mg/kg) given daily in 3 divideddoses produces the maximal haemopoieticresponse. Prophylactic dose is 30 mg iron daily.

Fig. 17.1: Schematic depiction of intestinal absorption, transport, utilization and storage of iron (see text for description)Fe2+—Ferrous iron; Fe3+—Ferric iron; DMT1—Divalent metal transporter 1; Hb—Haemoglobin; RE cell—Reticuloendothelialcell; FP1—Ferroportin; Tf—Transferrin; TfR—Transferrin receptor

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Adverse effects of oral iron These are common,but individuals differ in susceptibility.Epigastric pain, heart burn, nausea, vomiting,staining of teeth, metallic taste.Constipation is more common (believed to be dueto astringent action of iron) than diarrhoea(thought to reflect irritant action). However, thesemay be caused by alteration of intestinal flora aswell.

Parenteral iron preparations

Iron therapy by injection is indicated only when:1. Oral iron is not tolerated: bowel upset is too

much.2. Failure to absorb oral iron.3. Non-compliance to oral iron.4. In presence of severe deficiency with chronic

bleeding.5. Along with erythropoietin: to meet the acce-lerated demand.

Rate of response with parenteral iron is not fasterthan that with optimal doses given orally.However, stores can be replenished in a shortertime by parenteral therapy.

Two organically complexed preparations forparenteral use are:

(i) Iron-dextran: as a colloidal solution contain-ing 50 mg elemental iron/ml is thepreparation of choice.

(ii) Iron-sorbitol-citric acid complex: 50 mgiron/ml.

Both are injected i.m. using Z track technique. Irondextran can also be infused i.v., but this is morerisky.

Pain at site of i.m. injection, pigmentation ofskin, sterile abscess are the local complications.

Fever, headache, joint pains, flushing,palpitation, chest pain, dyspnoea are the systemicadverse effects.

An anaphylactoid reaction resulting invascular collapse and death occurs rarely.

Use

Prophylaxis and treatment of iron deficiencyanaemia is the most important indication for

medicinal iron. A rise in Hb level by 0.5–1 g/dlper week is an optimum response to iron therapy.Treatment should be continued till normal Hblevel is attained (generally takes 1–3 monthsdepending on the severity) and 2–4 monthsthereafter to replenish the stores because aftercorrection of anaemia, iron absorption is slow.

Iron is given in megaloblastic anaemia alongwith vit B12/folic acid so that existing irondeficiency may not be unmasked when briskhaemopoiesis is induced by the maturationfactors.

Ferric chloride is used in throat paint as anastringent.

VITAMIN B12

Cyanocobalamin and hydroxocobalamin arecomplex cobalt containing compounds presentin the diet and referred to as vit B12.

Vit B12 occurs as water soluble, thermostablered crystals. It is synthesized in nature only bymicroorganisms; plants and animals acquire itfrom them. Vit B12 is synthesized by the colonicmicroflora, but this is not available for absorptionin man.

Daily requirement: is 1–3 μg; in pregnancy andlactation it is 3–5 μg.

Metabolic functions Vit B12 is intricately linkedwith folate metabolism in many ways; megalo-blastic anaemia occurring due to deficiency ofeither is indistinguishable. In addition, vit B12 hassome independent metabolic functions as well.The active coenzyme forms of B12 generated inthe body are deoxyadenosyl-cobalamin (DAB12) andmethyl-cobalamin (methyl B12).

(i) Vit B12 is essential for the conversion of homo-cysteine to methionine

methyl-THFA B12 methionine

THFA methyl-B12 homocysteine

Methionine is needed as a methyl group donor inmany metabolic reactions and for proteinsynthesis. This reaction is also critical in making

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Folic Acid 259

tetrahydrofolic acid (THFA) available for reutili-zation. In B12 deficiency THFA gets trapped inthe methyl form and a number of one carbontransfer reactions suffer.

(ii) Purine and pyrimidine synthesis is affectedprimarily due to defective ‘one carbon’ transferbecause of ‘folate trap’.

(iii) Malonic acid Succinic acid:is an important step in propionic acid metabolism.This reaction does not require folate and has beenconsidered to be responsible for demyelinationseen in B12 deficiency, but not in pure folatedeficiency.(iv) Now it appears that interference with thereaction:

Methionine S-adenosyl methionine

may be more important in the neurologicaldamage of B12 deficiency, because it is needed inthe synthesis of phospholipids and myelin.(v) Vit B12 is essential for cell growth and multi-plication.

Utilization of vit B12 Intrinsic factor (aglycoprotein) secreted by stomach is essential forthe absorption of B12 ingested in physiologicalamounts. The B12-intrinsic factor complexattaches to specific mucosal receptors and isinternalized by an active carrier. Vit B12 istransported in blood in combination with aspecific β globulin transcobalamin II (TCII).

Vit B12 is not degraded in the body. It isexcreted mainly in bile (3–7 μg/day), all but 0.5–1 μg of this is reabsorbed. Thus, in the absence ofintrinsic factor or when there is malabsorption,B12 deficiency develops much more rapidly thanwhen it is due to nutritional deficiency.

Vit B12 is completely absorbed after i.m. ordeep s.c. injection. Normally, only traces of B12

are excreted in urine, but when pharmacologicaldoses (> 100 μg) are given orally or parenterally—a large part is excreted in urine.

Deficiency B12 deficiency occurs due to absenceof intrinsic factor secretion by stomach (perni-

cious anaemia in which there is autoimmunegastric mucosal damage, or chronic gastritis,gastric carcinoma, etc.), malabsorption, increaseddemand or nutritional deficiency.Manifestations of deficiency are:

(a) Megaloblastic anaemia, neutrophils withhypersegmented nuclei, giant platelets.(b) Glossitis, g.i. disturbances: damage to epi-thelial structures.(c) Neurological: subacute combined degenera-tion of spinal cord; peripheral neuritis,paresthesias, depressed stretch reflexes; mentalchanges—poor memory, mood changes,hallucinations, etc.

Uses

1. Prevention and treatment of B12 deficiency.When B12 deficiency is due to lack of intrinsicfactor (pernicious anaemia, gastric carcinoma,etc.), it should be given by i.m./s.c. injection, tobypass the defective absorptive mechanism. It iswise to add 1–5 mg of oral folic acid and an ironpreparation, because reinstitution of briskhaemopoiesis may unmask deficiency of thesefactors.2. Mega doses of B12 have been used inneuropathies, psychiatric disorders, cutaneoussarcoid and as a general tonic to allay fatigue,improve growth—value is questionable.

Methylcobalamine, an active coenzyme formof vit B12 has been especially advocated forneurological defects in diabetic and other formsof neuropathy.

FOLIC ACID

Chemically, it is Pteroyl glutamic acid (PGA)consisting of pteridine + paraaminobenzoic acid(PABA) + glutamic acid, which occurs as yellowcrystals.

Daily requirement of an adult is < 0.1 mg, butdietary allowance of 0.2 mg/day is recommen-ded. During pregnancy, lactation or any condi-tion of high metabolic activity, 0.8 mg/ day isconsidered appropriate.

DAB12

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Utilization Small, physiological amounts of folicacid are absorbed by specific carrier-mediatedactive transport in the intestinal mucosa. Largepharmacological doses may gain entry by passivediffusion, but only a fraction is absorbed.

Folic acid is rapidly extracted by tissues andstored in cells as polyglutamates. Liver takes upa large part and secretes methyl-THFA in bilewhich is mostly reabsorbed. Normally, only tracesare excreted, but when pharmacological doses aregiven, 50–90% of a dose may be excreted in urine.

Metabolic functions Folic acid is inactive as suchand is reduced to the coenzyme form in two steps:FA → DHFA → THFA by folate reductase (FRase)and dihydrofolate reductase (DHFRase). THFAmediates a number of one carbon transfer reactionsby carrying a methyl group as an adduct.1. Conversion of homocysteine to methionine.2. Generation of thymidylate, an essentialconstituent of DNA:

Deoxyuridylate methylene-THFA Glycine

Thymidylate DHFA THFA Serine

DHFRase

3. Conversion of serine to glycine: needs THFAand results in the formation of methylene-THFAwhich is utilized in thymidylate synthesis.4. Purine synthesis: de novo building of purinering requires formyl-THFA and methenyl-THFA.5. Generation and utilization of ‘formate pool’.6. Histidine metabolism.

Deficiency Folate deficiency occurs due to:(a) Inadequate dietary intake(b) Malabsorption: coeliac disease, tropical sprue,regional ileitis, etc.(c) Chronic alcoholism.(d) Increased demand: pregnancy, lactation,rapid growth periods, haemolytic anaemia.(e) Drug induced: prolonged therapy with anti-convulsants (phenytoin, phenobarbitone, primi-done) and oral contraceptives—interfere withabsorption and storage of folate.

Manifestations of deficiency are:(i) Megaloblastic anaemia, indistinguishablefrom that due to B12 deficiency.(ii) Epithelial damage: glossitis, enteritis, diar-rhoea, steatorrhoea.(iii) General debility, weight loss, sterility.

Uses

1. Megaloblastic anaemias due to nutritional folatedeficiency, periods of increased folate demand,malabsorption or antiepileptic therapy.

Folic acid should never be given alone topatients with B12 deficiency—haematologicalresponse may occur, but neurological defect mayprogress due to diversion of meagre amount ofB12 present in body to haemopoiesis.

2. Prophylaxis of folate deficiency: only whendefinite predisposing factors are present. Routinefolate supplementation is advised duringpregnancy to reduce the risk of neural tube defectsin the newborn.

3. Methotrexate toxicity: Folinic acid (Leucovorin,citrovorum factor, 5-formyl-THFA) an activecoenzyme form is used. Methotrexate is aDHFRase inhibitor; its toxicity is not counteractedby folic acid, but antagonized by folinic acid.

4. Citrovorum factor rescue: In certain malignan-cies, high dose of methotrexate is injected i.v. andis followed within ½–2 hours with 1–3 mg i.v. offolinic acid to rescue the normal cells.

ERYTHROPOIETINErythropoietin (EPO) is a sialoglycoprotein hormoneproduced by peritubular cells of the kidney that is essentialfor normal erythropoiesis. It stimulates erythroid colonyforming cells, induces haemoglobin production andreleases reticulocytes into the circulation. Recombinanthuman EPO (Epoetin α, β) infused i.v. or injected s.c. isused to treat anaemia of chronic renal failure and that inAIDS patients.

COAGULANTSThese are substances which promote coagulation,and are indicated in haemorrhagic states.

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Haemostasis (arrest of blood loss) and bloodcoagulation involve complex interactions betweenthe injured vessel wall, platelets and coagulationfactors. A cascading series of proteolytic reactions(Fig. 17.2) is started by:(i) Contact activation of Hageman factor: intrin-sic system, in which all factors needed forcoagulation are present in the plasma. This isslow and takes several minutes to activate factorX.(ii) Tissue thromboplastin: extrinsic system, needsa tissue factor, but activates factor X in seconds.

The subsequent events are common in the twosystems and result in the formation of fibrinmeshwork in which blood cells are trapped andclot is formed.

Most clotting factors are proteins present inplasma in the inactive (zymogen) form. By partial

proteolysis, they themselves become activeproteases and activate the next factor. On the otherhand, factors like antithrombin, protein C, anti-thromboplastin and the fibrinolysin system tend tooppose coagulation and lyse formed clot. Thus, acheck and balance system operates to maintainblood in a fluid state while in circulation andallows rapid haemostasis following injury.

Fresh whole blood or plasma provide all thefactors needed for coagulation and are the besttherapy for deficiency of any clotting factor; alsothey act immediately. Drugs used to restorehaemostasis are:1. Vitamin K

K1 : Phytonadione (Phylloquinone)K3 (synthetic)

Fat soluble : Menadione,Acetomenaphthone

Fig. 17.2: The coagulation cascade. The vit. K dependent factors have been encircled;* Inactivated byheparin; a—activated form; Pl.Ph.—Platelet phospholipid; HMW—High molecular weight

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Water : Menadione sod. bisulfitesoluble Menadione sod.

diphosphate2. Fibrinogen (human)3. Antihaemophilic factor4. Ethamsylate.

Vitamin K

It is a fat-soluble dietary principle required forthe synthesis of clotting factors.

Vit K has a basic naphthoquinone structure,with or without a side chain.

Daily requirement of vit K is uncertain, becausea variable amount becomes available from colonicbacteria. Even 3–10 μg/day external source maybe sufficient. However, the total requirement ofan adult has been estimated to be 50–100 μg/day.

Vit K acts as a cofactor at a late stage in thesynthesis by liver of coagulation proteins—prothrombin, factors VII, IX and X. The vit Kdependent change (γ carboxylation of glutamateresidues of these zymogen proteins; see Fig. 17.3)confers on them the capacity to bind Ca2+ and toget bound to phospholipid surfaces—propertiesessential for participation in the coagulationcascade.

Fat-soluble forms of vit K are absorbed fromintestine via lymph and require bile salts forabsorption, while water-soluble forms areabsorbed directly into portal blood. Vit K is onlytemporarily concentrated in liver, but there areno significant stores in the body. It is metabolizedin liver by side chain cleavage and glucuronideconjugation; metabolites are excreted in bile andurine.

Deficiency Deficiency of vit K occurs due to liverdisease, obstructive jaundice, malabsorption,long-term antimicrobial therapy which altersintestinal flora. However, deficient diet is rarelyresponsible. The most important manifestation isbleeding tendency due to lowering of the levels ofprothrombin and other clotting factors in blood.Haematuria is usually first to occur; other common

sites of bleeding are g.i.t., nose and under theskin—ecchymoses.

Use The only use of vit K is in prophylaxis andtreatment of bleeding due to deficiency of clottingfactors in the above situations.

All newborns have low levels of prothrombinand other clotting factors. Vit K 1 mg i.m. soonafter birth has been recommended routinely.Menadione (K3) should not be used for this purpose(see below).

The most important indication of vit K is toreverse the effect of overdose of oral anti-coagulants: Phytonadione (K1) is the preparationof choice, because it acts most rapidly; dosedepends on the severity of hypoprothrombinae-mia (measured INR) and bleeding. Unnecessaryhigh dose is to be avoided because it will renderthe patient unresponsive to oral anticoagulantsfor several days.

Menadione and its water-soluble derivativescan cause haemolysis in a dose-dependentmanner. Patients with G-6-PD deficiency andneonates are specially susceptible. In the newbornmenadione or its salts can precipitate kernicterus:(a) by inducing haemolysis and increasingbilirubin load.(b) by competitively inhibiting glucuronidationof bilirubin.

Fibrinogen The fibrinogen fraction of human plasma isemployed to control bleeding in haemophilia, antihaemo-philic globulin (AHG) defi-ciency and acute afibrino-genemic states; 0.5 g is infused i.v.

Antihaemophilic factor It is concentrated human AHGprepared from pooled human plasma. It is indicated (alongwith human fibrinogen) in haemophilia and AHGdeficiency. It is highly effective in controlling bleedingepisodes, but action is short lasting (1 to 2 days).

Ethamsylate It reduces capillary bleeding whenplatelets are adequate; probably exerts anti-hyaluronidase action—improves capillary wallstability, but does not stabilize fibrin (not anantifibrinolytic). Ethamsylate has been used inthe prevention and treatment of capillary bleedingin menorrhagia, after abortion, epistaxis, malena,hematuria and after tooth extraction. Side effects

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are nausea, rash, headache, and fall in BP (onlyafter i.v. injection).

Dose: 250-500 mg TDS oral/i.v.; ETHAMSYL, HEMSYL,

K. STAT 250, 500 mg tabs, 250 mg/2 ml inj.

Haemostasis in dentistry

Many dental procedures cause at least somebleeding: the dentist has to routinely deal withhaemostasis (arrest of blood loss). After toothextraction or similar procedures, bleeding occursdue to disruption of arterioles and smaller bloodvessels that cannot be sutured. Normal haemo-stasis occurs successively by• contraction of injured vessel wall (lasting few

minutes)• adhesion and aggregation of platelets to form

a plug• formation of a blood clot, and finally in due

course• dissolution of the clot by fibrinolysis.

Postextraction bleeding from the tooth socketis usually arrested by a cotton-gauze pressure packheld for 20 to 30 min. Suturing may be required ifbleeding is due to tear around the socket.However, control of bleeding may need to be aidedby the use of local haemostatics.

Local Haemostatics (styptics) are substancesused to stop bleeding from a local andapproachable site. They are particularly effectiveon oozing surfaces, e.g. tooth socket, abrasions,etc. Absorbable materials like fibrin (prepared fromhuman plasma and dryed as sheet or foam),gelatin foam, oxidized cellulose (as strips which canbe cut and placed in the socket) provide a mesh-work which activates the clotting mechanism andchecks bleeding. Left in situ these materials areabsorbed in 1–4 weeks and generally cause noforeign body reaction. Thrombin obtained frombovine plasma may be applied as dry powder orfreshly prepared solution to the bleeding surfacein haemophiliacs. Vasoconstrictors like 1% Adrsolution may be soaked in sterile cotton-gauzeand packed in the bleeding socket (or nose in

case of epistaxis) to check bleeding whenvasoconstriction is inadequate. Astringents suchas tannic acid or metallic salts (e.g. alum, ferricchloride) are occasionally applied for bleedinggums, bleeding piles, etc.

Many diseases and drugs can affect thevascular response to injury, platelet function orcoagulation to create haemostatic problems.When dental surgery is contemplated in patientswith such defects, careful planning and consul-tation with their physician are needed.1. Vitamin C deficiency impairs collagen syn-

thesis and causes bleeding gums, excessivepostextraction blood loss. Scurvy should becorrected before elective dental surgery. In caseof emergency surgery, careful packing andpressure can stop the bleed. Long-termcorticosteroid therapy can also compromisehaemostasis by impairing vessel retraction aswell as by reducing platelet count.

2. Platelet function may be deficient due tothrombocytopenia (count<100,000/mL) oruse of drugs which inhibit platelet aggre-gation. Transfusion of platelet-rich plasma isindicated before dental surgery in patientswith low platelet count. Corticosteroid therapyhelps to restore platelet count in idiopathicthrombocytopenic purpura. Aspirin and otherNSAIDs are the most important drugs thatinhibit platelet aggregation. A large numberof older individuals now receive long-termlow-dose aspirin prophylaxis for ischaemicheart disease or stroke. Many others receivelong term clopidogrel/ticlopidine for a varietyof thromboembolic disorders. Several patientsof arthritis regularly take NSAIDs. Disconti-nuation of aspirin for 5 days (other antiplateletdrugs for periods appropriate to their durationof action) before dental surgery should beconsidered. In case this is not possible, properpacking and use of local haemostatics isneeded to prevent excess bleeding.

3. Even minor dental procedures (like scaling)put the haemophiliac patient at great risk of

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bleeding. The patient should be covered beforeand after the procedure with i.v. infusion ofantihaemophilic factor (AHG or factor VIII)along with fibrinogen. The antifibrinolyticdrug tranexaemic acid has adjuvant valueby reducing the requirement of AHG.Desmopressin injected i.v. also helps inchecking dental bleeding in haemophiliacs aswell as in von Willebrand’s disease byreleasing factor VIII and von Willebrand’sfactor from the vascular endothelium.

4. Any oral surgery in patients on anticoagulantmedication requires due care to avoid exces-sive bleeding. Since the action of i.v. heparinlasts for only 4–6 hours, the extraction can bescheduled at a time when anticoagulation isminimal. Low dose s.c. heparin and LMWheparin therapy ordinarily does not increasedental surgery associated bleeding. Theheparin antagonist protamine may be giveni.v. in case of emergency bleed.In patients treated with oral anticoagulants,

due consultation with their physician andmonitoring of their INR prior to dental surgery isessential. An INR of <3 generally does not increasebleeding due to simple extractions, but in case ofmore invasive procedures, it may be advisable tostop the anticoagulant for 2–3 days or temporarilyswitch over the patient to heparin. In case ofemergency dental bleed, the effect of oralanticoagulant is reversed by i.v. infusion of freshfrozen plasma (containing all coagulationfactors). Vit. K may be injected in addition.Adequate packing and local measures must beapplied.

ANTICOAGULANTS

These are drugs used to reduce the coagulabilityof blood. They may be classified into:

1. Used in vivoA. Parenteral anticoagulant

Heparin, Low molecular weight heparin,Heparan sulfate

B. Oral anticoagulants(i) Coumarin derivatives: Bishydroxycoumarin

(Dicumarol), Warfarin sod, Acenocoumarol(Nicoumalone), Ethylbiscoumacetate

(ii) Indandione derivative: Phenindione.

2. Used in vitroA. HeparinB. Calcium complexing agents:

Sodium citrate: used to keep blood in the fluidstate for transfusion;Sodium oxalateSodium edetate

HEPARIN

Heparin is a non-uniform mixture of straightchain mucopolysaccharides with MW 10,000 to20,000. It contains polymers of two sulfateddisaccharide units:

D-glucosamine-L-iduronic acidD-glucosamine-D-glucuronic acid

It carries strong electronegative charges and isthe strongest organic acid present in the body. Itoccurs in mast cells and is loosely bound to thegranular protein. Commercially, it is producedfrom ox lung and pig intestinal mucosa.

Actions

1. Anticoagulant Heparin is a powerful andinstantaneously acting anticoagulant, effectiveboth in vivo and in vitro. It acts indirectly byactivating plasma antithrombin III (AT III, a serineproteinase inhibitor). The heparin-AT III complexthen binds to clotting factors of the intrinsic andcommon pathways (Xa, IIa, IXa, XIa, XIIa andXIIIa) and inactivates them but not factor VIIaoperative in the extrinsic pathway. At lowconcentrations of heparin, factor Xa mediatedconversion of prothrombin to thrombin isselectively affected. The anticoagulant action isexerted mainly by inhibition of factor Xa as wellas thrombin (IIa) mediated conversion offibrinogen to fibrin.

⎫⎬⎭

used in blood taken forinvestigations

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chain length and proportionof the two disaccharide unitsvaries. Some glucosamineresidues are N-acetylated.

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Low concentrations of heparin prolongactivated partial thromboplastin time (aPTT)without significantly prolonging prothrombintime (PT). High concentrations prolong both. Thus,low concentrations interfere selectively with theintrinsic pathway, affecting amplification andcontinuation of clotting, while high concentra-tions affect the common pathway as well.

2. Antiplatelet Heparin in higher doses inhi-bits platelet aggregation and prolongs bleedingtime.

3. Lipaemia clearing Injection of heparin clearsturbid post-prandial lipaemic plasma byreleasing a lipoprotein lipase from the vessel walland tissues, which hydrolyses triglycerides ofchylomicra and very low density lipoproteins tofree fatty acids; these then pass into tissues andthe plasma looks clear.

Pharmacokinetics: Heparin is a large, highlyionized molecule; therefore not absorbed orally.Injected i.v. it acts instantaneously, but after s.c.injection anticoagulant effect develops after ~60min. Heparin does not cross blood-brain barrieror placenta. It is metabolized in liver by heparinaseand fragments are excreted in urine. Heparin isnot a physiologically circulating anticoagulant.

After i.v. injection, dose-dependent inactiva-tion is seen and t½ varies from 1–4 hours.Heparin is conventionally given i.v. in bolus doses of 5,000–10,000 U every 4–6 hours, or the initial bolus dose isfollowed by continuous infusion. The dose and frequencyis controlled by aPTT measurement which is kept at 50–80 sec. or 1.5–2.5 times the patient’s pretreatment value.

Low dose (s.c.) regimen 5,000 U is injected s.c. every8–12 hours; started before surgery and continued for 7–10 days or till the patient starts moving about. This regimenhas been found to prevent postoperative deep veinthrombosis without increasing surgical bleeding. It alsodoes not prolong aPTT or clotting time.

Adverse effects

1. Bleeding due to overdose is the most seriouscomplication of heparin therapy. Aspirin, otherNSAIDs and antiplatelet drugs enhance heparin-induced bleeding. They should be used verycautiously in heparinized patients.

2. Thrombocytopenia is another common prob-lem.3. Osteoporosis and alopecia are infrequent.

Low molecular weight (LMW) heparinsHeparin has been fractionated into LMW forms(MW 3,000–7,000) by different techniques. LMWheparins have a different anticoagulant profile;selectively inhibit factor Xa with little effect onIIa. As a result, LMW heparins have smaller effecton aPTT and whole blood clotting time thanunfractionated heparin (UFH) relative toantifactor Xa activity. Also, they appear to havelesser antiplatelet action—less interference withhaemostasis. The more important advantages ofLMW heparins are pharmacokinetic:• Better subcutaneous bioavailability; less

variable response• Longer and more consistent monoexponential

t½: once daily s.c. administration.• Since aPTT/clotting times are not prolonged,

laboratory monitoring is not needed.Indications of LMW heparins are:1. Prophylaxis of deep vein thrombosis andpulmonary embolism in high-risk patientsundergoing surgery, stroke or other immobilizedpatients.2. Treatment of established deep vein throm-bosis.3. Unstable angina.4. To maintain patency of cannulae and shuntsin dialysis patients, and in extracorporealcirculation.

A number of LMW heparins (Enoxaparin,Raviparin, Dalteparin, Nadroparin, etc.) havebeen marketed.

Heparan sulfate It is a heparin-like substance found inthe intercellular matrix in many tissues. Though less potent,it may be used as a heparin substitute.

Heparin antagonist

Protamine sulfate is a strongly basic, lowmolecular weight protein obtained from the spermof certain fish. Given i.v. it neutralises heparinweight for weight, i.e. 1 mg is needed for every100 U of heparin. It is used when heparin action

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Table 17.1: Pharmacokinetic and adverse effect profile of oral anticoagulants

Drug t ½ Duration Dose (mg) Adverse side effectsof action (other than bleeding)

Loading Maintenance*

1. Bishydroxycoumarin 25–100 hr 4–7 days 200 for 50–100 Frequent g.i.t. disturbances(dose dependent) 2 days

2. Warfarin sod. 36–48 hr 3–6 days 10–15 2–10 Alopecia, dermatitis, diarrhoea

3. Acenocoumarol 18–24 hr 2–3 days 8–12 2–8 Oral ulceration, g.i.t. distur-(Nicoumalone) bances, dermatitis, urticaria,

alopecia

4. Ethylbiscoumacetate 2 hr 1–3 days 900 300–600 Alopecia, bad taste

5. Phenindione 5 hr 1–3 days 200 50–100 Orange urine, rashes, fever,leukopenia, hepatitis, nephro-pathy, agranulocytosis

* Daily maintenance dose: to be adjusted by measurement of prothrombin time.

Fig. 17.3: Mechanism of action of oral anticoagulantsNAD—Nicotinamide adenine dinucleotide; NADH—itsreduced form

needs to be terminated rapidly, e.g. after cardiacor vascular surgery and for heparin-inducedbleeding.

ORAL ANTICOAGULANTS

Warfarin and its congeners act as anticoagulantsonly in vivo, not in vitro. This is so because theyact indirectly by interfering with the synthesis ofvit K dependent clotting factors in liver. Theyapparently behave as competitive antagonists ofvit K and reduce the plasma levels of functionalclotting factors in a dose-dependent manner. Infact, they interfere with regeneration of the activehydroquinone form of vit K (Fig. 17.3) whichcarries out the final step of γ carboxylatingglutamate residues of prothrombin and factorsVII, IX and X. This carboxylation is essential forthe ability of the clotting factors to bind Ca2+ andto get bound to phospholipid surfaces, necessaryfor the coagulation sequence to proceed.

Factor VII has the shortest plasma t½ (6 hr), itslevel falls first when warfarin is given, followedby factor IX (t½ 24 hr), factor X (t½ 40 hr) andprothrombin (t½ 60 hr). The anticoagulant effectdevelops gradually over 1–3 days as the levels ofthe clotting factors already present in plasmadecline progressively. Thus, there is always adelay between administration of these drugs and

the anticoagulant effect. Therapeutic effect occurswhen the synthesis of clotting factors is reducedto ~50%.

The differences between different oral anti-coagulants are primarily pharmacokinetic andin the adverse side effects produced by them.These are summarized in Table 17.1.

Bleeding as a result of extension of the desiredpharmacological action is the most importantproblem, causing ecchymosis, epistaxis, hema-turia, bleeding in the g.i.t., intracranial or otherinternal haemorrhages, which may be fatal.

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Treatment: of bleeding due to oral anticoagulantsconsists of:• Withhold the anticoagulant.• Give fresh blood transfusion. Alternatively,

fresh frozen plasma may be used as a sourceof clotting factors.

• Give vit K1—specific antidote, but it takes6–24 hours for the clotting factors to beresynthesized and released in blood after vitK administration.

Dose regulation The dose of oral anticoagulantmust be individualized by repeated measurementof prothrombin time; the aim is to achieve atherapeutic effect without unduly increasing thechances of bleeding. A standardized systemcalled the International Normalized Ratio (INR)based on the use of human brain thromboplastinhas been developed by WHO to quantify the effectof oral anticoagulants. An INR of 2–4.5 isconsidered therapeutic for different indications.

Drug interactions A large number of drugs inter-act with oral anticoagulants and either enhanceor decrease their effect. These interactions areclinically important (may be fatal if bleedingoccurs).

A. Enhanced anticoagulant action1. Broad-spectrum antibiotics: inhibit gut flora

and reduce vit K production.2. Newer cephalosporins (cefamandole, moxa-

lactam, cefoperazone) cause hypoprothrom-binaemia by the same mechanism as warfarin—additive action.

3. Aspirin: inhibits platelet aggregation andcauses g.i. bleeding—this may be hazardousin anticoagulated patients.

4. Sulfonamides, indomethacin, phenytoin dis-place warfarin from plasma protein binding.

5. Metronidazole, chloramphenicol, erythro-mycin, celecoxib, cimetidine, allopurinol andamiodarone inhibit warfarin metabolism.

B. Reduced anticoagulant action1. Barbiturates and other hypnotics (but not

benzodiazepines), rifampin and griseofulvininduce the metabolism of oral anticoagulants.

2. Oral contraceptives: increase blood levels ofclotting factors.

Uses of anticoagulants The aim of usinganticoagulants is to prevent thrombus extensionand embolic complications by reducing the rateof fibrin formation. They do not dissolve alreadyformed clot, but prevent recurrences.

1. Deep vein thrombosis and pulmonary embo-lism Because venous thrombi are mainly fibrinthrombi, anticoagulants are highly effective.Prophylaxis is needed by bedridden, elderly,postoperative, postpartum, poststroke and legfracture patients. When deep vein thrombosis/pulmonary embolism has occurred, 3 months orlonger anticoagulant therapy has been recom-mended.

2. Myocardial infarction (MI) Arterial thrombiare mainly platelet thrombi; anticoagulants areof questionable value. Their use in acute MI hasdeclined.

Heparin (followed by oral anticoagulant) isgenerally given after recanalization of coronaryartery by fibrinolytic therapy. Heparin cover isgenerally provided during coronary angioplastyand stent placement.

3. Unstable angina Short-term use of heparin hasreduced the occurrence of MI. Current recom-mendation is to give aspirin + heparin followedby warfarin.

4. Rheumatic heart disease, atrial fibrillation(AF) Warfarin is particularly effective inpreventing stroke (due to embolism fromfibrillating atria) while low dose heparin andaspirin are the alternatives. Anticoagulants aregiven for 3–4 weeks before and after attemptingconversion of AF to sinus rhythm.

5. Vascular surgery, prosthetic heart valves, retinalvessel thrombosis, extracorporeal circulation,haemodialysis Anticoagulants are indicatedalong with antiplatelet drugs for prevention ofthromboembolism.

The important features of heparin and oralanticoagulants are compared in Table 17.2.

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Table 17.2: Some comparative aspects of heparin and oral anticoagulants

Heparin Warfarin

1. Chemistry Mucopolysaccharide Coumarin derivative2. Source Hog lung, pig intestine Synthetic3. Route of admin. Parenteral (i.v., s.c.) Oral4. Onset of action Immediate Delayed (1–3 days)5. Duration of action 4–6 hrs 3–6 days6. Activity In vitro and in vivo In vivo only7. Mechanism Blocks action of factor X and Inhibits synthesis of clotting factors

thrombin8. Antagonist Protamine sulphate Vit K9. Variability in response Little Marked

10. Lab. control aPTT/clotting time Prothrombin time/INR(desirable) (essential)

11. Drug interactions Few and not significant Many and significant12. Use To initiate therapy For maintenance

FIBRINOLYTICS(Thrombolytics)

These are drugs used to lyse thrombi/clot torecanalize occluded blood vessels (mainlycoronary artery). They are therapeutic rather thanprophylactic; work by activating the naturalfibrinolytic system.

Haemostatic plug of platelets formed at the site of injuryto blood vessels is reinforced by fibrin deposition to forma thrombus. Once repair is over, the fibrinolytic system isactivated to remove the fibrin. The enzyme responsiblefor digesting fibrin is a serine protease Plasmin generatedfrom plasminogen by tissue plasminogen activator (t-PA),which is produced primarily by vascular endothelium.Plasminogen circulates in plasma as well as remains boundto fibrin. The t-PA selectively activates fibrin boundplasminogen within the thrombus.

Fibrinolytics like Streptokinase, Urokinase, Alteplase(rt-PA), Reteplace and Tenecteplase have beenproduced. All are administered by i.v. injection.Haemorrhage is their major complication.

Streptokinase It is obtained from β haemolyticStreptococci group C and is inactive as such:combines with circulating plasminogen to forman activator complex which then causes limitedproteolysis of other plasminogen molecules toplasmin. Its t½ is estimated to be 30–80 min.

Streptokinase is antigenic; can cause hyper-sensitivity reactions and anaphylaxis. Fever is

common; hypotension and arrhythmias arereported. Because of these drawbacks, it has beenlargely superseded, but for cost considerations.

Urokinase It is an enzyme isolated from humanurine; now prepared from cultured human kidneycells. It activates plasminogen directly and has aplasma t½ of 10–15 min. It is nonantigenic. Feveroccurs during treatment, but hypotension andallergic phenomena are rare.

Alteplase (recombinant tissue plasminogenactivator (r t-PA) Produced by recombinantDNA technology from human tissue culture, itspecifically activates gel-phase plasminogenalready bound to fibrin, and has little action oncirculating plasminogen. It is rapidly cleared byliver and has a plasma t½ of 4–8 min. It isnonantigenic, but nausea, mild hypotension andfever may occur.

Reteplase and Tenecteplase These are modified/mutantforms of rt-PA with a longer duration of action permitingbolus i.v. dosing, in contrast to alteplase which requiresslow i.v. infusion.

Uses of fibrinolytics

1. Acute myocardial infarction is the chiefindication. It is now considered one of the firstline approaches if fibrinolytic therapy can be

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instituted within 12 hours of symptom onset. Timelag in starting i.v. infusion is critical for reducingarea of necrosis, preserving ventricular functionand reducing mortality. Heparin with or withoutaspirin is generally started concurrently or soonafter thrombolysis to prevent reocclusion.

Fibrinolytic therapy has also been used inunstable angina.

2. Deep vein thrombosis in leg, pelvis, shoulder,etc.; up to 60% patients can be successfully treated.

3. Pulmonary embolism Fibrinolytic therapy isindicated in large, life-threatening pulmonaryembolism.

Fibrinolytics have also been used in certaintypes of peripheral arterial occlusions, but haveno clearcut role in stroke.

ANTIFIBRINOLYTICS

These are drugs which inhibit plasminogenactivation and dissolution of clot.

Epsilon amino-caproic acid (EACA) It is ananalogue of the amino acid lysine: combines withthe lysine binding sites of plasminogen andplasmin so that the latter is not able to bind tofibrin and lyse it. It is a specific antidote forfibrinolytic agents and has been used in manyhyperplasminaemic states associated with exces-sive intravascular fibrinolysis resulting inbleeding.

Tranexaemic acid Like EACA, it binds to thelysine binding site on plasminogen and preventsits combination with fibrin, and is 7 times morepotent.

Antifibrinolytics are used to prevent/controlexcessive bleeding in the following situations:• To counteract the effect of fibrinolytics• After cardio-pulmonary bypass surgery.• After tooth extraction, tonsillectomy, prostatic

surgery in haemophiliacs.• Menorrhagia, especially due to IUCD.• Recurrent epistaxis, ocular trauma, bleeding

peptic ulcer.

Main side effects are nausea and diarrhoea. Head-ache, giddiness and thromboflebitis of injectedvein are other adverse effects.

ANTIPLATELET DRUGS(Antithrombotic drugs)

These are drugs which interfere with plateletfunction and are useful in the prophylaxisof thromboembolic disorders. However, all ofthem are likely to accentuate dental surgery relatedbleeding.

Platelets stick to the damaged vessel wall, thenthey stick to each other (aggregate) and releaseADP, thromboxane A2 (TXA2) which promotefurther aggregation. Thus, a ‘platelet plug’ isformed.

Prostacyclin (PGI2), synthesized in the intimaof blood vessels, is a strong inhibitor of plateletaggregation. A balance between TXA2 releasedfrom platelets and PGI2 released from vessel wallappears to control intravascular thrombus forma-tion.Drugs interfering with platelet function are:

Aspirin GP IIb/IIIa antagonistsDipyridamole AbciximabTiclopidine EptifibatideClopidogrel Tirofiban

Aspirin It acetylates the enzyme cyclooxyge-nase (COX) and TX-synthetase—inactivatingthem irreversibly. Because platelets are exposedto aspirin in the portal circulation before it isdeacetylated during first pass in liver, and becauseplatelets cannot synthesize fresh enzyme (haveno nuclei), TXA2 formation is suppressed at verylow doses and till fresh platelets are formed. Thus,aspirin induced prolongation of bleeding timelasts for 5–7 days. Effect of daily doses cumulatesand it has now been shown that doses as low as40 mg/day have an effect on platelet aggregation.Maximal inhibition of platelet function occurs at~160 mg aspirin per day.

Aspirin also inhibits PGI2 synthesis in vesselwall. However, since intimal cells can synthesizefresh enzyme, activity returns rapidly. It is

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possible that at low doses (75–150 mg/day),TXA2 formation by platelets is selectively sup-pressed, whereas higher doses (> 900 mg/day)may decrease both TXA2 and PGI2 production.

Aspirin inhibits the release of ADP fromplatelets and their sticking to each other.However, it has no effect on platelet survival timeand their adhesion to damaged vessel wall.

Other NSAIDs are reversible inhibitors of COX, produceshort-lasting inhibition of platelet function—are notclinically useful but can prolong bleeding time for variableperiods.

Dipyridamole It is a vasodilator which wasintroduced for angina pectoris (see Ch.11). Itinhibits phosphodiesterase and blocks uptake ofadenosine to increase platelet cAMP whichpotentiates PGI2 and interferes with aggregation.Levels of TXA2 or PGI2, are not altered, but plate-let survival time reduced by disease is norma-lized.

Dipyridamole used along with warfarindecreases the incidence of thromboembolism inpatients with prosthetic heart valves.

It has also been used to enhance theantiplatelet action of aspirin. Risk of stroke inpatients with transient ischaemic attacks (TIAs)may be additively reduced.

Ticlopidine It is the first thienopyridine whichalters surface receptors on platelets and inhibitsADP as well as fibrinogen-induced plateletaggregation. It blocks the subtype of purinergicreceptors through which ADP inhibits adenylylcyclase in platelets. As a result, platelet activationis interfered. Ticlopidine prevents fibrinogenbinding to platelets without modifying GPIIb/IIIareceptor. There is no effect on platelet TXA2, butbleeding time is prolonged and platelet survivalin extra-corporeal circulation is increased.Because of different mechanism of action, it hassynergistic effect on platelets with aspirin. Theircombination is a potent platelet inhibitor.

Ticlopidine has produced beneficial effects instroke prevention, TIAs, intermittent claudication,unstable angina, coronary artery bypass graftsand secondary prophylaxis of MI. Combined with

aspirin, it has markedly lowered incidence ofrestenosis after percutaneous transluminal coro-nary angioplasty (PTCA) and stent thrombosis.

Side effects: Diarrhoea, vomiting, abdominal pain,headache, tinnitus, skin rash. Serious adverseeffects are bleeding, neutropenia, thrombocyto-penia and jaundice, because of which use ofticlopidine is restricted.

Clopidogrel This newer congener of ticlopidinehas similar mechanism of action, ability to inhibitplatelet function and therapeutic efficacy, butappears to be safer and better tolerated. Side effectsare diarrhoea, epigastric pain and rashes.As such, it has largely replaced ticlopidine.

Glycoprotein (GP) IIb/IIIa receptor antagonists

GP IIb/IIIa antagonists are a new class of potentplatelet aggregation inhibitors which act byblocking the key receptor involved in plateletaggregation. The GP IIb/IIIa is an adhesivereceptor on platelet surface for fibrinogen and vonWillebrand’s factor through which agonists likecollagen, thrombin, TXA2, ADP, etc. induceplatelet aggregation. Thus, GP IIb/IIIa antagonistsblock aggregation induced by all platelet agonists.

Abciximab It is the Fab fragment of a chimericmonoclonal antibody against GP IIb/IIIa, which is givenalong with aspirin + heparin during PTCA. It has markedlyreduced the incidence of restenosis, subsequent MI anddeath. Unstable angina is another indication.

Abciximab is nonantigenic. The main risk is haemor-rhage. Thrombocytopenia is another complication.

Eptifibatide (a peptide) and Tirofiban (a nonpeptide) aretwo GPIIb/IIIa receptor antagonists that have been recentlyintroduced as alternatives to abciximab for i.v. infusionbefore and after coronary angioplasty and in acute coronarysyndromes.

Uses of antiplatelet drugs

1. Coronary artery diseaseMI: Low dose aspirin started immediately afterMI has been found to reduce mortality andprevent reinfarction. Ticlopidine and clopidogrelare alternatives. Aspirin is now routinely usedto prevent reocclusion after thrombolytic therapy.

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Unstable angina Antiplatelet drugs used singlyor in combination including a GPIIb/IIIa anta-gonist reduce the risk of MI and sudden death.

Primary and secondary prevention of MI It has beenrecommended that aspirin 75–150 mg/day begiven to all individuals with evidence of coronaryartery disease and in those with risk factors forthe same, but routine use in the whole populationis not warranted.

2. Cerebrovascular disease Antiplatelet drugsdo not alter the course of stroke due to cerebralthrombosis. However, aspirin has reduced theincidence of TIAs, of stroke in patients with TIAsor persistent atrial fibrillation and in those withhistory of stroke in the past. Ticlopidine andclopidogrel also reduce TIAs and stroke.3. Coronary angioplasty, stents, bypass implantsThe patency of recanalized/stented coronaryantery or implanted bypass vessel is improvedand incidence of reocclusion is reduced by aspirinand/or ticlopidine/clopidogrel. Addition ofGPIIb/IIIa antagonist markedly reduces restenosis.4. Prosthetic heart valves and arteriovenousshunts Antiplatelet drugs, used with warfarinreduce formation of microthrombi on artificialheart valves and the incidence of embolism.Antiplatelet drugs also prolong the patency ofchronic arteriovenous shunts.5. Peripheral vascular disease Aspirin/ticlopi-dine/clopidogrel may produce some improve-ment in intermittent claudication and reduce theincidence of thromboembolism.

HYPOLIPIDAEMIC DRUGS

These are drugs which lower the levels of lipidsand lipoproteins in blood.

The hypolipidaemic drugs have attractedconsiderable attention because of their potentialto prevent cardiovascular disease by retardingthe accelerated atherosclerosis in hyperlipi-daemic individuals.

Whereas, raised low density lipoprotein-cholesterol (LDL-CH) is atherogenic, an increased

level of high density lipoprotein-cholesterol(HDL-CH) is either itself protective or indicates alow atherogenic state. It is now recognized thatelevated plasma triglyceride (TG) level posesindependent risk of coronary artery disease(CAD) and stroke.

CLASSIFICATION

1. HMG-CoA reductase inhibitors (Statins):Lovastatin, Simvastatin, Pravastatin,Atorvastatin, Rosuvastatin

2. Bile acid sequestrants (Resins):Cholestyramine, Colestipol

3. Lipoprotein lipase activators (Fibric acid deri-vatives): Clofibrate, Gemfibrozil, Bezafibrate,Fenofibrate.

4. Inhibitor of triglyceride synthesis and lipolysis:Nicotinic acid.

5. Others: EzetimibeThe mechanism of action and profile of lipid

lowering effect of important hypolipidaemicdrugs is summarized in Table 17.3.

HMG-CoA reductase inhibitors (Statins)These are the most efficacious and best toleratedhypolipidaemic drugs. They competitively inhibitconversion of 3-Hydroxy-3-methyl glutarylcoenzyme A (HMG-CoA) to mevalonate, the ratelimiting step in cholesterol (CH) synthesis, by theenzyme HMG-CoA reductase. Therapeutic dosesreduce CH synthesis by 20–50%. This results incompensatory increase in LDL receptor expres-sion on liver cells → increased receptor mediateduptake and catabolism of intermediate densitylipoprotein (IDL) and LDL. They cause dose-dependent lowering of LDL-CH levels.

At their maximum recommended doses,simvastatin, atorvastatin and rosuvastatin canreduce LDL-CH by up to 45–55%, while theceiling effect of lovastatin and pravastatin is 35–40% LDL-CH reduction.

A concurrent fall by 10–30% in plasma TGlevel, probably due to reduction of very lowdensity lipoprotein (VLDL) occurs. A rise inHDL-CH by 5–15% is also noted. Statins are notuseful when TG alone is markedly raised.

Hypolipidaemic Drugs 271


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Table 17.3: Mechanism of action and pattern of lipid lowering effect of important hypolipidaemic drugs

Drug (daily dose) Mechanism of action Effect on lipids (%)

HMG-CoA reductase inhibitorsLovastatin (10–80 mg) ↓ CH synthesis by inhibition of rate LDL ↓ 20–55Simvastatin (5–40 mg) limiting HMG-CoA reductase HDL ↑ 5–15Atorvastatin (10–80 mg) TG ↓ 10–35Rosuvastatin (5–20 mg)

Bile acid sequestrantsCholestyramine (4–16 g) ↓ bile acid absorption, ↑ hepatic LDL ↓ 15–30Colestipol (5–30 g) conversion of CH to bile acids, HDL ↑ 3–5

↑ LDL receptors on hepatocytes TG not affected, may ↑ in some

Fibric acid derivativesGemfibrozil (1,200 mg) ↑ Activity of lipoprotein lipase, LDL ↓ 5–20Bezafibrate (600 mg) ↓ release of fatty acids from adipose may ↑ LDL when TG is highFenofibrate (200 mg) tissue HDL ↑ 10–20

TG ↓ 20–50

Nicotinic acid (2–6 g) ↓ Production of VLDL, ↓ lipolysis LDL ↓ 15–25in adipocytes HDL↑ 20–35

TG ↓ 20–50

All statins are remarkably well tolerated;overall incidence of side effects not differing fromplacebo.• Headache, nausea, bowel upset, rashes, sleep

disturbances.• Rise in serum transaminase can occur, but liver

damage is rare.• Muscle tenderness and rise in CPK levels

occurs infrequently. Myopathy is the onlyserious reaction, but is rare.

Statins are the first choice drugs for primaryhyperlipidaemias with raised LDL and totalCH levels, with or without raised TG levels, aswell as for secondary hypercholesterolaemias.Efficacy of statins in reducing raised LDL-CHassociated mortality and morbidity is now wellestablished.

Improvement in endothelial function, reduc-tion in LDL oxidation and an antiinflammatoryeffect are proposed as additional mechanisms bywhich statins may exert antiatheroscleroticaction.

Bile acid sequestrants (Resins)Cholestyramine and Colestipol are basic ion exchangeresins supplied in the chloride form. They bind bile acids

in the intestine interrupting their enterohepatic circulation.Faecal excretion of bile salts and CH (which is absorbedwith the help of bile salts) is increased. This indirectlyleads to enhanced hepatic metabolism of CH to bile acids.More LDL receptors are expressed on liver cells: clearanceof plasma IDL, LDL and indirectly that of VLDL isincreased.

Resins can retard atherosclerosis but are not popularclinically because they are unpalatable, inconvenient, causeflatulence and other g.i. symptoms, interfere with absorp-tion of many drugs, and have poor patient acceptability.

Fibric acid derivativesThe fibrates (isobutyric acid derivatives)primarily activate lipoprotein lipase which is akey enzyme in the degradation of VLDL resultingin lowering of circulating TGs. This effect appearsto be exerted through paroxisome proliferator-activated receptor α (PPARα) which enhanceslipoprotein lipase synthesis and fatty acidoxidation. PPARα may also mediate enhancedLDL receptor expression in liver. Fibratesdecrease hepatic TG synthesis as well. Drugs inthis class primarily lower TG levels by 20–50%generally accompanied by 10–15% decrease inLDL-CH and a 10–15% increase in HDL-CH.

Fibrates are the hypolipidaemic drugs ofchoice for patients with raised TG levels, whether

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or not CH levels are also raised. They may be usedas adjuvants to statins in hypercholesterolaemia.Reduction in coronary events and slowing ofatherosclerotic process has been noted in post-MI subjects. Their main side effects are g.i. upset,rashes, bodyache, rarely myopathy (particularlywhen combined with statins).

Nicotinic acid

It is a B group vitamin which in much higherdoses reduces plasma lipids. This action isunrelated to its vitamin activity and not presentin nicotinamide. When nicotinic acid is given,TGs and VLDL decrease rapidly, followed by amodest fall in LDL-CH and total CH. A 20–50%reduction in plasma TGs and 15–25% reductionin CH levels has been recorded. It is the mosteffective drug to raise HDL-CH; a 20–30%increase is generally obtained.

Nicotinic acid reduces production of VLDLin liver by inhibiting TG synthesis. It inhibitslipolysis in adipose tissue and increases activityof lipoprotein lipase that clears TGs.

Adverse effects The large doses needed forhypolipidaemic action are poorly tolerated. Onlyabout half of the patients are able to take the fulldoses. Marked flushing, heat and itching(especially in the blush area) occur after everydose. Aspirin taken daily largely prevents thereaction (PGs may be involved).

Dyspepsia is very common; vomiting anddiarrhoea occur when full doses are given. Pepticulcer may be activated.Dryness and hyperpigmentation of skin can betroublesome. Other long-term effects are: liverdysfunction and jaundice, hyperglycaemia,precipitation of diabetes.Risk of myopathy due to lovastatin is increased.

Use Nicotinic acid is highly efficacious inhypertriglyceridaemia whether associated withraised CH level or not. It is mostly used to lowerVLDL and raise HDL levels, and as an adjunctivedrug to statins/fibrates.

However, because of marked side effects, useof nicotinic acid is restricted to high-risk casesonly.

Ezetimibe

This novel drug interferes with a specific CHtransport protein NPC1C1 in the intestinalmucosa and thus reduces absorption of bothdietary and biliary CH by a mechanism differentfrom that of resins. The LDL-CH level is loweredby 15–20%. Used alone, ezetimibe is a weakhypocholesterolemic drug, but it synergises withstatins. The combination of ezetimibe + low dosestatin causes as much LDH-CH lowering as highdose of statin alone. Ezetimibe is generally welltolerated.

Hypolipidaemic Drugs 273

DRUGS FOR PEPTIC ULCER

Peptic ulcer occurs in that part of the gastrointes-tinal tract (g.i.t.) which is exposed to gastric acidand pepsin, i.e., the stomach and duodenum. Theetiology of peptic ulcer is not clearly known. Itresults probably due to an imbalance between theaggressive (acid, pepsin and H. pylori) and thedefensive (gastric mucus and bicarbonate secre-tion, prostaglandins, nitric oxide, innate resistanceof the mucosal cells) factors. A variety of psychoso-matic, humoral and vascular derangements havebeen implicated and the importance of Helico-bacter pylori infection as a contributor to ulcerformation and recurrence has been recognized.

In gastric ulcer, generally acid secretion isnormal or low. In duodenal ulcer, acid secretion ishigh in nearly half of the patients but normal inthe rest. Notwithstanding whether production ofacid is normal or high, it does contribute toulceration as an aggressive factor, reduction ofwhich is the main approach to ulcer treatment.

Regulation of gastric acid secretion The mechanismsoperating at the gastric parietal cells are summarized inFig. 18.1. The terminal enzyme H+K+ATPase (protonpump) which secretes H+ ions in the apical canaliculi ofparietal cells can be activated by histamine, ACh andgastrin acting via their own receptors located on thebasolateral membrane of these cells. Out of the threephysiological secretagogues, histamine, acting through H2

receptors, plays the dominant role, because the other two,gastrin and ACh act partly directly and partly indirectlyby releasing histamine from paracrine enterochromaffin-

like cells called “histaminocytes” located in the oxynticglands.

Approaches for the treatment of peptic ulcer are:

1. Reduction of gastric acid secretion(a) H2 antihistamines: Cimetidine, Ranitidine,

Famotidine, Roxatidine, Loxatidine(b) Proton pump inhibitors: Omeprazole,

Lansoprazole, Pantoprazole, Rabeprazole,Dexrabeprazole, Esomeprazole

(c) Anticholinergics: Pirenzepine, Propanthe-line, Oxyphenonium

(d) Prostaglandin analogues: Misoprostol.

2. Neutralization of gastric acid (Antacids)(a) Systemic: Sodium bicarbonate, Sod.

citrate(b) Nonsystemic: Magnesium hydroxide,

Mag. trisilicate, Aluminium hydroxide gel,Magaldrate, Calcium carbonate.

3. Ulcer protectives: Sucralfate, Colloidalbismuth subcitrate (CBS).

4. Anti-H. pylori drugs: Amoxicillin, Clarithromy-cin, Metronidazole, Tinidazole, Tetracycline.

H2 ANTAGONISTS

These are the first class of highly effective drugsfor acid-peptic disease. Cimetidine was the firstH2 blocker to be introduced clinically and isdescribed as the prototype.

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Fig. 18.1: Secretion of HCl by gastric parietal cell and its regulationC.Ase.—Carbonic anhydrase; Hist.—Histamine; ACh.—Acetylcholine; G—Gastrin/cholecystokinin(CCK2)receptor; M.—Muscarinic receptor; N—Nicotinic receptor; H2—Histamine H2 receptor; EP3—Prostaglandinreceptor; + = Stimulation; — = Inhibition.


1. H2 blockade Cimetidine and all other H2

antagonists block histamine-induced gastricsecretion, cardiac stimulation (prominent inisolated preparations, especially in guinea pig),uterine relaxation (in rat) and bronchial relaxa-tion. They attenuate fall in BP due to histamine,especially the late phase response seen with highdoses. They are highly selective: have no effect onH1 mediated responses or on action of othertransmitters/autacoids.

2. Gastric secretion The only significant in vivoaction of H2 blockers is marked inhibition ofgastric secretion. All phases (basal, psychic,neurogenic, gastric) of secretion are suppresseddose-dependently. Secretory responses to not onlyhistamine but also all other stimuli (ACh, gas-trin, insulin, alcohol, food) are attenuated. Thisreflects the permissive role of histamine inamplifying responses to other secretagogues.

The usual ulcer healing doses produce60–70% inhibition of 24-hour acid output. The

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276 Drugs for Gastrointestinal DisordersS

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H2 blockers have antiulcerogenic effect. Gastriculceration due to stress and drugs (NSAIDs) isprevented. They do not have any direct effect ongastric or esophageal motility or on loweresophageal sphincter (LES) tone.

Pharmacokinetics Cimetidine is adequatelyabsorbed orally, though bioavailability is 60–80%due to first pass hepatic metabolism. About2/3rd of a dose is excreted unchanged in urineand bile, the rest as oxidized metabolites. Theelimination t½ is 2–3 hr.

Adverse effects Cimetidine is well tolerated bymost patients: adverse effects occur in ~5%. Theseare generally mild.• Headache, dizziness, bowel upset, dry mouth,

rashes.• CNS effects like confusional state, restlessness,

hallucinations can occur with high dose.• Cimetidine (but not other H2 blockers) has

antiandrogenic action; increases plasmaprolactin and inhibits degradation of estradiolby liver. High doses given for long periods haveproduced gynaecomastia, loss of libido, impo-tence and temporary decrease in sperm count.

Interactions Cimetidine inhibits cytochromeP-450 and reduces hepatic blood flow. It inhibitsthe metabolism of many drugs so that they canaccumulate to toxic levels, e.g. metronidazole, theo-phylline, phenytoin, phenobarbitone, sulfonyl-ureas, warfarin, imipramine, lidocaine, quinidine.

Antacids reduce absorption of all H2 blockers.Ketoconazole absorption is decreased by

cimetidine (probably by other H2 blockers also).

Ranitidine It has several desirable features com-pared to cimetidine:• About 5 times more potent than cimetidine.• No antiandrogenic action, does not increase

prolactin secretion or spare estradiol fromhepatic metabolism—no effect on male sexualfunction or gynaecomastia.

• Lesser permeability into the brain: lowerpropensity to cause CNS effects.

• Does not significantly inhibit hepatic meta-bolism of other drugs; drug interactions mostlyhave no clinical relevance.

• Overall incidence of side effects is lower.

Famotidine It is 5–8 times more potent thanranitidine and has no antiandrogenic action.Because of low affinity for cytochrome P450 andthe low dose, drug metabolism modifyingpropensity is minimal.

Uses The H2 blockers are widely used inconditions in which it is profitable to suppressgastric acid secretion. Used in appropriate doses,all available agents have similar efficacy.1. Duodenal ulcer H2 blockers produce rapidand marked pain relief (within 2–3 days). Theyheal 60–85% ulcers at 4 weeks and 70–95% ulcersat 8 weeks.

Maintenance therapy reduces ulcer relapse.

2. Gastric ulcer Healing rates obtained ingastric ulcer are somewhat lower (50–75% at 8weeks). H2 blockers can heal NSAID associatedulcers, but are less effective than proton pumpinhibitors (PPIs) or misoprostol.3. Stress ulcers and gastritis Acutely stressfulsituations like severe burns and trauma,prolonged surgery, etc. are associated with gastricerosions and bleeding. Intravenous infusion of aa H2 blocker prevents the gastric lesions andhaemorrhage.4. Zollinger-Ellison syndrome It is a gastrichypersecretory state due to a rare tumour secre-ting gastrin. H2 blockers in high doses controlhyperacidity and symptoms in many patients, butPPIs are the drugs of choice.5. Gastroesophageal reflux disease (GERD) H2

blockers afford symptomatic relief and facilitatehealing of esophageal erosions by reducing acidityof gastric contents that are refluxed. However, theyare less effective in this condition than PPIs.6. Prophylaxis of aspiration pneumonia H2 bloc-kers given preoperatively (preferably eveningbefore also) reduce the risk of aspiration of acidicgastric contents during anaesthesia and surgery.

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PROTON PUMP INHIBITORS (PPIs)

Omeprazole It is the prototype member of sub-stituted benzimidazoles which inhibit the finalcommon step in gastric acid secretion. The PPIshave overtaken H2 blockers for acid-pepticdisorders. The only significant pharmacologicalaction of omeprazole is dose-dependent suppres-sion of gastric acid secretion; without anticholi-nergic or H2 blocking action. It is a powerfulinhibitor of gastric acid: can totally abolish HClsecretion, both resting as well as that stimulatedby any of the secretagogues, without much effecton pepsin, intrinsic factor, juice volume andgastric motility.

Omeprazole is inactive at neutral pH, but atpH < 5 rearranges to two charged cationic formsthat react covalently with SH groups of theH+K+ATPase enzyme and inactivate it irrever-sibly, especially when two molecules ofomeprazole react with one molecule of theenzyme. After diffusing into the parietal cell fromblood, it gets concentrated in the acidic pH of thecanaliculi because the charged forms generatedthere at the acidic pH are unable to diffuse back.Moreover, it gets tightly bound to the enzyme.These features and the specific localization ofH+K+ATPase to the apical membrane of parietalcells confer high degree of selectivity of action toomeprazole. Acid secretion resumes only whennew H+K+ATPase molecules are synthesized.

The oral absorption of omeprazole is ~50%,because of instability at acidic pH. As the gastricpH rises, a higher fraction (up to 3/4) may beabsorbed. PPIs should be administered in emptystomach, one hour before food. It is highlyplasma protein bound, rapidly metabolised inliver by CYP2C19 and CYP3A4 (plasma t½ ~1hr) and metabolites are excreted in urine.Inhibition of HCl secretion occurs within 1 hr,reaches maximum at 2 hr, is still half maximalat 24 hr and lasts for 3 days.

Uses

1. Peptic ulcer Omeprazole is equally or moreeffective than H2 blockers. Relief of pain is rapid

and excellent; some duodenal ulcers heal evenat 2 weeks and the remaining at 4 weeks. Gastriculcer generally requires 4–8 weeks. Continuedtreatment can prevent relapse. PPIs are anintegral component of anti-H. pylori therapy.PPIs are the drugs of choice for NSAID inducedgastric/duodenal ulcers.

PPIs may help control bleeding from pepticulcer; i.v. pantoprazole is preferred.

2. Gastroesophageal reflux disease (GERD)Omeprazole produces rapid symptom relief andis more effective than H2 blockers in promotinghealing of esophageal lesions. PPIs are the drugsof choice for patients with frequent or chronicsymptoms and/or esophagitis/erosions; i.e.stage-2 or stage-3 GERD.

3. Zollinger-Ellison syndrome Omeprazole ismore effective than H2 blockers.Adverse effects These are minimal: nausea,loose stools, headache, abdominal pain, muscleand joint pain, dizziness are complained by3–5%. Rashes, leucopenia and hepatic dys-function are infrequent.Interactions Omeprazole inhibits oxidation ofcertain drugs: diazepam, phenytoin andwarfarin levels may be increased.Lansoprazole, pantoprazole and rabeprazole are otherPPIs with only minor differences from omepra-zole. Esomeprazole and Dexrabeprazole are singleactive enantiomers respectively of omeprazoleand rabeprazole.

ANTICHOLINERGICS (See Ch.7)

Atropinic drugs reduce gastric secretion and can helphealing of peptic ulcer, but frequently produceantimuscarinic side effects. Availability of H2 blockersand PPIs has sent them into oblivion.

Pirenzepine is a selective M1 anticholinergic that hasbeen used in Europe for peptic ulcer. Gastric secretion isreduced without producing intolerable side effects.

PROSTAGLANDIN ANALOGUES

PGE2 and PGI2 are produced in the gastricmucosa and appear to serve a protective role byinhibiting acid secretion and promoting mucus



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+ HCO3̄ secretion. In addition, PGs inhibit gas-trin production, increase mucosal blood flow andprobably have an ill-defined “cytoprotective”action.

Natural PGs have very short t½. Misoprostol,a stable PG analogue, has been used in pepticulcer and healing rates comparable to cimetidinehave been obtained in 4–8 weeks. However,misoprostol is poorer in relieving ulcer pain.Some patients may even complain of increasedpain during the first week of therapy.

Major problems in the use of PG analoguesare—diarrhoea, abdominal cramps, uterinebleeding, abortion, and need for multiple dailydoses. Patient acceptability is poor. Misoprostolis occasionally used for prevention and treatmentof NSAID associated gastrointestinal injury andblood loss, though PPIs are the preferred drugsnow.

In ulcer patients, dentists should take care not toprescribe aspirin or other NSAIDs; instead chooseparacetamol/codeine/selective COX-2 inhibitor forpain relief.

ANTACIDS

These are basic substances which neutralizegastric acid and raise pH of gastric contents.Peptic activity is indirectly reduced if the pHrises above 4.

Antacids do not decrease acid production;rather, agents that raise the antral pH to > 4evoke reflex gastrin release → more acid issecreted, especially in patients with hyperacidityand duodenal ulcer; “acid rebound” occurs andgastric motility is increased.

The potency of an antacid is generallyexpressed in terms of its acid neutralizing capacity(ANC), which is defined as number of mEq of1N HCl that are brought to pH 3.5 in 15 min (or60 min in some tests) by a unit dose of theantacid preparation.

SYSTEMIC ANTACIDS

Sodium bicarbonate It is water soluble, acts instan-taneously, but the duration of action is short. It is a potent

neutralizer (1 g → 12 mEq HCl), pH may rise above 7.However, it has several demerits:(a) Absorbed systemically: large doses will induce

alkalosis.(b) Produces CO2 in stomach → distention, discomfort,

belching, risk of ulcer perforation.(c) Acid rebound occurs, but is usually short lasting.(d) Increases Na+ load: may worsen edema and CHF.

Use of sod. bicarbonate is restricted to casual treat-ment of heart burn: provides quick symptomatic relief.Other uses are to alkalinize urine and to treat acidosis.

Sodium citrate Properties similar to sod. bicarbonate;1 g neutralizes 10 mEq HCl; CO2 is not evolved.

NONSYSTEMIC ANTACIDS

These are insoluble and poorly absorbed basiccompounds that react in stomach to form the corres-ponding chloride salt. The chloride salt again reacts withthe intestinal bicarbonate so that HCO3̄ is not sparedfor absorption—no acid-base disturbance occurs.

Mag. hydroxide has low water solubility but reacts withHCl promptly and is an efficacious antacid (1 g → 30mEq HCl).

Magnesium trisilicate has low solubility and reactivity;clinically neutralizes only about 1 mEq acid per gramdue to slow action. All Mg salts have a laxative action—by generating osmotically active MgCl2 in the stomachand through Mg2+ ion induced cholecystokinin release.

Aluminium hydroxide gel It is a bland, weak and slowlyreacting antacid. On keeping it slowly polymerizes tovariable extents into still less reactive forms. Thus, theANC of a preparation gradually declines on storage. ANCusually varies from 1–2.5 mEq/g. Thus, 5 ml of itssuspension may neutralize just 1 mEq HCl.

The Al3+ ions relax smooth muscle. Thus, it delaysgastric emptying. Alum. hydrox. frequently causesconstipation due to its smooth muscle relaxant andmucosal astringent action.

Magaldrate It is a hydrated complex of hydroxy-magnesium aluminate that initially reacts rapidly withacid and releases alum. hydrox. which then reacts moreslowly. Thus, magaldrate cannot be equated to a physicalmixture of mag. and alum. hydroxides. It is a good antacidwith prompt and sustained neutralizing action.

Antacid combinations A combination of two ormore antacids is frequently used. These may besuperior to any single agent on the followingaccounts:(a) Fast (Mag. hydrox.) and slow (Alum. hydrox.)acting components yield prompt as well assustained effect.

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(b) Mag. salts are laxative, while Alum. salts areconstipating: combination may annul eachother’s action and bowel movement may be leastaffected.(c) Dose of individual components is reduced;systemic toxicity (dependent on fractionalabsorption) is minimized.

Drug interactions By raising gastric pH and byforming complexes, the non-absorbable antacidsdecrease the absorption of many drugs,especially tetracyclines, iron salts, fluoroquinolo-nes, ketoconazole, H2 blockers, diazepam, phe-nothiazines, indomethacin, phenytoin, isoniazid,ethambutol and nitrofurantoin. Stagger theiradministration by 2 hours. The efficacy of nitro-furantoin is also reduced by alkalinization ofurine.

Uses Antacids are no longer used for healingpeptic ulcer because they are needed in largeand frequent doses, are inconvenient, can causeacid rebound and bowel upset, afford littlenocturnal protection and have poor patientacceptability. They are now employed only forintercurrent pain relief and acidity, mostly self-prescribed by the patients. They continue to beused for nonulcer dyspepsia and minor episodesof heartburn, acid eructation.

ULCER PROTECTIVES

Sucralfate It is a basic aluminium salt of sulfatedsucrose; a drug of its own kind. Sucralfate polymerizesat pH < 4 by cross linking of molecules, assuming asticky gel-like consistency. It preferentially and stronglyadheres to ulcer base, especially duodenal ulcer and actsas a physical barrier preventing acid, pepsin and bile fromcoming in contact with the ulcer base. Dietary proteinsget deposited on this coat, forming another layer.

Sucralfate has no acid neutralizing action, but mayaugment gastric mucosal PG synthesis. It is minimallyabsorbed after oral administration. Though, it promoteshealing of both duodenal and gastric ulcers, it isinfrequently used now because of need for 4 large well-timed daily doses and the availability of simpler H2

blockers/PPIs. As a suspension in glycerol, sucralfate hasbeen tried in stomatitis.

Side effects are few; constipation is reported by 2%patients.

Interactions Sucralfate adsorbs many drugs and inter-feres with the absorption of tetracyclines, fluoroquinolones,cimetidine, phenytoin and digoxin. Antacids given concur-rently reduce the efficacy of sucralfate.

Colloidal bismuth subcitrate (CBS;Tripotassium dicitratobismuthate)

It is a colloidal bismuth compound; water soluble butprecipitates at pH < 5. It is not an antacid, but heals60% ulcers at 4 weeks and 80–90% at 8 weeks. Themechanism of action of CBS is not clear; probabilitiesare:

(i) Stimulation of mucosal PGE2 production.(ii) Creating a diffusion barrier by coating the ulcer.

(iii) Anti-H.pylori action.

Gastritis and nonulcer dyspepsia associated with H.pylori are also improved by CBS. Patient acceptance ofCBS is compromised by blackening of tongue, denturesand stools; by variable and delayed symptom controland inconvenience of dosing schedule. Presently, it is usedoccasionally as a component of triple drug anti-H.pyloriregimen.

ANTI-HELICOBACTER PYLORI DRUGS

H. pylori is a gram-negative bacillus uniquelyadapted to survival in the hostile environmentof stomach. It attaches to the surface epitheliumbeneath the mucus, has high urease activity—produces ammonia which maintains a neutralmicroenvironment around the bacteria, andpromotes back diffusion of H+ ions. It has beenfound as a commensal in 20–70% normal indi-viduals, and is now accepted as an importantcontributor to the causation of chronic gastritis,dyspepsia, peptic ulcer, gastric lymphoma andgastric carcinoma. Up to 90% patients ofduodenal and gastric ulcer have tested positivefor H. pylori.

Eradication of H. pylori concurrently with H2

blocker/PPI therapy of peptic ulcer has beenassociated with faster ulcer healing and lowerrelapse rate. Anti-H. pylori therapy is, therefore,now recommended in all ulcer patients who testpositive for H. pylori. In the absence of suchtesting, all cases with failed conventional ulcertherapy and relapse cases may be given thebenefit of H. pylori eradication.



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Antimicrobials that have been found clinicallyeffective against H. pylori are: amoxicillin,clarithromycin, tetracycline and metronidazole/tinidazole. However, any single drug is relativelyineffective. Resistance develops rapidly, espe-cially to metronidazole/tinidazole. Since bismuth(CBS) is active against H. pylori and resistancedoes not develop to it, early combination regimensincluded bismuth, but had poor patientacceptability; are infrequently used now. In themeantime, it was observed that omeprazolemonotherapy reduces the population of H. pyloriin the gastric antrum, probably by altering theacid environment as well as direct inhibitoryeffect. A number of 2-drug and 3-drug regimensof 1 or 2 weeks duration have been tested reporting60–96% eradication rates, but the optimumregimen is difficult to proclaim.

The US-FDA approved regimen is: lanso-prazole 30 mg + amoxicillin 1000 mg +clarithromycin 500 mg all given twice daily for2 weeks. It has achieved 86–92% eradication rate.

All regimens are complex and expensive, sideeffects are frequent and compliance is poor. Long-term benefits of H. pylori eradication therapyinclude lowering of ulcer disease prevalence andprevention of gastric carcinoma/lymphoma; butbenefits in nonulcer dyspepsia are equivocal.

ANTIEMETICS

These are drugs used to prevent or suppressvomiting (emesis).

Emesis Vomiting occurs due to stimulation of theemetic (vomiting) centre situated in the medulla oblongata.Multiple pathways can elicit vomiting (Fig. 18.2). Thechemoreceptor trigger zone (CTZ) located in the areapostrema and the nucleus tractus solitarius (NTS) are themost important relay areas for afferent impulses arisingin the g.i.t, throat and other viscera. The CTZ is alsoaccessible to blood-borne drugs, mediators, hormones,toxins, etc., because it is unprotected by the blood-brainbarrier. Cytotoxic drugs, radiation and other g.i. irritantsrelease 5-HT from enterochromaffin cells in the gut →acts on 5-HT3 receptors present on vagal afferents andsends impulses to NTS and CTZ. However, 5-HT is notthe only mediator of such signals: many peptides andother messengers are also involved.

The CTZ and NTS express a variety of receptors, e.g.histamine H1, dopamine D2, serotonin 5-HT3, cholinergicM and opioid μ through which the emetic signals are relayedand which could be targets of antiemetic drug action.

The vestibular apparatus generates impulses whenbody is rotated or equilibrium is disturbed or whenototoxic drugs act. These impulses reach the vomitingcentre mainly relayed from the cerebellum and utilizemuscarinic as well as H1 receptors.

CLASSIFICATION

1. Anticholinergics Hyoscine, Dicyclomine2. H1 antihistaminics Promethazine,

Diphenhydramine,Dimenhydrinate,Doxylamine.Cyclizine, Meclozine,Cinnarizine

3. Neuroleptics Chlorpromazine,Prochlorperazine,Haloperidol, etc.

4. Prokinetic drugs Metoclopramide,DomperidoneCisapride, MosaprideTegaserod

5. 5-HT3 antagonists Ondansetron,Granisetron

6. Adjuvant Dexamethasone,antiemetics Benzodiazepines,

Cannabinoids.

ANTICHOLINERGICS (See Ch. 5)

Hyoscine is the most effective drug for motionsickness. However, it has a brief duration ofaction; produces sedation and other anticho-linergic side effects and is suitable only for shortbrisk journies. It acts probably by blocking con-duction of nerve impulses across a cholinergiclink in the pathway leading from the vestibularapparatus to the vomiting centre. It is noteffective in vomiting of other etiologies.

Dicyclomine has been used for prophylaxis ofmotion sickness and for morning sickness.

H1 ANTIHISTAMINICS (See Ch. 7)

Some antihistaminics are antiemetic. They areuseful mainly in motion sickness and to a lesser

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Fig. 18.2: Major central and visceral structures involved in emesis and the neurohumoral receptors mediatingthe emetic response. NTS: Nucleus tractus solitarius; VC: vomiting centre; CTZ: chemoreceptor triggerzone; 5-HT3 R: 5HT3 receptor

extent in morning sickness, postoperative andsome other forms of vomiting. Their antiemeticeffect appears to be based on anticholinergic,antihistaminic and sedative properties.

Promethazine, diphenhydramine, dimenhydrinateafford protection from motion sickness for 4–6hours, but produce sedation and dryness ofmouth.

Cyclizine, meclozine (meclizine) are less sedativeand less anticholinergic. Meclozine is longacting, protects against sea sickness for nearly24 hours.

Doxylamine This H1 antihistaminic has promi-nent sedative and anticholinergic properties. Incombination with pyridoxine, it is specificallypromoted for morning sickness.Cinnarizine is an antivertigo drug, and is alsoprotective for motion sickness. It probably actsby inhibiting influx of Ca2+ from endolymph intothe vestibular sensory cells.

All antimotion sickness drugs are more effec-tive when taken ½–1 hour before commencingjourney. Once sickness has started, it is moredifficult to control; higher doses/parenteraladministration may be needed.

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NEUROLEPTICS (see Ch. 10)

These are potent antiemetics; act by blockingD2 receptors in the CTZ. They have broad-spectrum antiemetic action in:(a) Drug induced and postanaesthetic nausea

and vomiting.(b) Disease induced vomiting: gastroenteritis,

uraemia, liver disease, migraine, etc.(c) Malignancy associated and cancer chemothe-

rapy (mildly emetogenic) induced vomiting.(d) Radiation sickness vomiting (less effective).(e) Morning sickness: should not be used except

in hyperemesis gravidarum.They are not effective in motion sickness: thevestibular pathway probably does not involvedopaminergic link.

Most of these drugs produce significantdegree of sedation. Acute muscle dystonia mayoccur after a single dose, especially in childrenand girls. The antiemetic dose is generally muchlower than antipsychotic doses.

Prochlorperazine This phenothiazine is a laby-rinthine suppressant, has selective antivertigoand antiemetic actions. It is highly effectivewhen given by injection in vertigo associatedwith vomiting and is not used as antipsychotic.

PROKINETIC DRUGS

These are drugs which promote gastrointestinaltransit and speed gastric emptying.

Metoclopramide

Introduced in early 1970s as a ‘gastric hurrying’agent, metoclopramide is now a widely usedantiemetic.

Metoclopramide increases gastric peristalsiswhile relaxing the pylorus and the first part ofduodenum → speeds gastric emptying, espe-cially if it was slow.

Lower esophageal sphincter (LES) tone isincreased and gastroesophageal reflux isopposed. It also increases intestinal peristalsisto some extent, but has no significant action oncolonic motility and gastric secretion.

Metoclopramide is an effective antiemetic;by blocking D2 receptors in CTZ. The gastro-kinetic action may contribute to the antiemeticeffect.

Other manifestations of D2 receptor blockadeare chlorpromazine like extrapyramidal sideeffects and hyperprolactinaemia, but no anti-psychotic effect is exerted. The gastric hurryingand LES tonic effects are mainly due to activationof 5-HT4 receptors on myenteric interneurones,which enhance ACh release from primary motorneurone innervating the gastric and LES smoothmuscles. Because dopamine acts as an inhibitorytransmitter in the g.i.t., the D2 receptor blockingaction also contributes to the gastrokinetic effects.At high concentrations, metoclopramide canblock 5-HT3 receptors present peripherally oninhibitory myenteric interneurones and centrallyin the NTS/CTZ. The peripheral action canaugment ACh release in the gut, but appears to beminor. The central action appears to be significantonly when large doses are used to controlchemotherapy induced vomiting.

Pharmacokinetics Metoclopramide is rapidlyabsorbed orally, enters brain, crosses placentaand is secreted in milk. It is partly conjugated inliver and excreted in urine within 24 hours; t½is 3–6 hours. Orally, it acts in ½–1 hr, but within10 min after i.m. and 2 min after i.v. injection.Action lasts for 4–6 hours.

Interactions It hastens the absorption of manydrugs, e.g. aspirin, diazepam, etc. by facilitatinggastric emptying. It reduces the extent of absorp-tion of digoxin by allowing less time for it.

By blocking DA receptors in basal ganglia, itabolishes the therapeutic effect of levodopa.

Adverse effects Metoclopramide is generallywell tolerated.Sedation, dizziness, diarrhoea, muscle dystonias(especially in children) are the main side effects.Long-term use can cause parkinsonism, galactor-rhoea and gynaecomastia.

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antagonism. Effects of cisapride on gastric moti-lity resemble metoclopramide—gastric emptyingis accelerated, LES tone is improved and eso-phageal peristalsis is augmented. It restores andfacilitates motility throughout the g.i.t., includingcolon. Cisapride often produces loose stools. Itsprokinetic action is exerted mainly through 5-HT4 agonism which promotes ACh release frommyenteric neurones, aided by 5-HT3 antagonismwhich suppresses inhibitory transmission inmyenteric plexus. Cisapride is devoid of actionon CTZ and does not produce extrapyramidalsymptoms or hyperprolactinaemia. Cisapride isa prokinetic drug without antidopaminergic sideeffects, but abdominal cramps and diarrhoea canoccur.

Oral bioavailability of cisapride is ~33%. Itis primarily inactivated by hepatic metabolismby CYP3A4 with a t½ of ~10 hours. The CYP 3A4inhibitors like ketoconazole, erythromycin, HIVprotease inhibitors and some antidepressantsinhibit the metabolism of cisapride and preci-pitate serious ventricular arrhythmias liketorsades de pointes, because high concentrationsof cisapride block cardiac K+ channels andprolong Q-Tc interval. This interaction hasrestricted the use of cisapride, and it has beenwithdrawn in many countries like USA.

Indications of cisapride are –as adjuvant toPPIs in GERD and for impaired gastric emptying.

Mosapride A newer congener of cisapride withsimilar gastrokinetic and LES tonic action dueto 5-HT4 agonistic (major) and 5-HT3 anta-gonistic (minor) action in the myenteric plexus,but has not caused Q-Tc prolongation orarrhythmias. Like cisapride, it has no clinicallyuseful antiemetic action and does not produceextrapyramidal / hyperprolactinaemic sideeffects. Indications and side effects are similar tocisapride.

Tegaserod (see p. 287) This new 5-HT4 receptor partialagonist increases propulsive activity in the stomach andileum as well (in addition to major action in colon). Assuch, use as gastrokinetic is also suggested.

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Uses

1. Antiemetic: Metoclopramide is an effective andpopular drug for many types of vomiting—postoperative, drug induced, disease associated(especially migraine), radiation sickness, etc. butis less effective in motion sickness. Thoughondansetron is being preferred, metoclopramidecontinues to be used for prophylaxis andtreatment of vomiting induced by highly emeticanticancer drugs.

2. Gastrokinetic: to accelerate gastric emptying:(a) When emergency general anaesthesia has

to be given and the patient has taken foodless than 4 hours before.

(b) To relieve postvagotomy or diabetesassociated gastric stasis.

(c) To facilitate duodenal intubation.

3. Dyspepsia and other functional g.i. dis-orders.

4. Gastroesophageal reflux disease (GERD) Meto-clopramide may afford symptomatic relief inmilder cases of GERD, but is much less effectivethan PPIs/H2 blockers, and does not aid healingof esophagitis.

Domperidone It is a D2 antagonist, chemicallyrelated to haloperidol, but pharmacologicallyrelated to metoclopramide. It has a lower ceilingantiemetic and prokinetic actions. Unlike meto-clopramide, its prokinetic action is not blockedby atropine and is based only on D2 receptorblockade in upper g.i.t. Domperidone crossesblood-brain barrier poorly. Accordingly, extra-pyramidal side effects are rare, but hyperpro-lactinaemia can occur. However, it does act onCTZ which is not protected by blood-brainbarrier, though antiemetic efficacy is lower thanmetoclopramide.

Side effects of domperidone are much less thanwith metoclopramide: dry mouth, loose stools,headache, rashes, galactorrhoea.

Cisapride It is a prokinetic drug with littleantiemetic property, because it lacs D2 receptor


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5-HT3 ANTAGONISTS

Ondansetron It is the prototype of a class ofantiemetic drugs developed to control cancerchemotherapy/radiotherapy induced vomitingand later found to be highly effective in post-operative nausea and vomiting as well. It blocksthe depolarizing action of 5-HT through 5-HT3

receptors on vagal afferents in the g.i.t. as wellas in NTS and CTZ. Cytotoxic drugs/radiationproduce nausea and vomiting by causingcellular damage → release of mediators inclu-ding 5-HT from intestinal mucosa → activationof vagal afferents in the gut → emetogenicimpulses to the NTS and CTZ. Ondansetronblocks emetogenic impulses both at theirperipheral origin and their central relay.

Pharmacokinetics: Oral bioavailability of ondan-setron is 60–70% due to first pass metabolism.No clinically significant drug interactions havebeen noted. It is eliminated in urine and faeces,mostly as metabolites; t½ being 3–5 hrs, andduration of action 4–12 hr.

Other types of vomiting: Efficacy of 5-HT3 anta-gonists in prevention and treatment of post-operative nausea and vomiting is now wellestablished. Vomiting associated with drugoverdosage, uraemia, certain neurological injuriesand gastrointestinal disorders is also suppressed.

Side effects: Ondansetron is generally well tole-rated: the only common side effect is headache.Mild constipation or diarrhoea and abdominaldiscomfort occur in a few patients. Rashes andallergic reactions are possible, especially after i.v.injection.

Granisetron It is 10–15 times more potent thanondansetron and probably more effective duringthe repeat cycle of chemotherapy. It is also longeracting.

ADJUVANT ANTIEMETICS

Corticosteroids (e.g. dexamethasone 8–20 mg i.v.) canalleviate nausea and vomiting due to moderately emeto-genic chemotherapy, but are more often employed to

augment the efficacy of drugs like metoclopramide andondansetron.

Benzodiazepines Their weak antiemetic property isprimarily based on the sedative action. Used as adjuvantto metoclopramide/ondansetron, they help by relievinganxiety, anticipatory vomiting and produce amnesia forthe unpleasant procedure.

Cannabinoids Δ9 Tetrahydrocannabinol (Δ9 THC) isthe active principle of the hallucinogen Cannabis indica.It possesses antiemetic activity. Nabilone and dronabinolare less hallucinogenic and more antiemetic than Δ9 THC.Dronabinol has been used for chemotherapy inducedvomiting in patients who cannot tolerate other antiemeticsor are unresponsive to them.

Gastroesophageal reflux disease (GERD)

It is a very common problem presenting as ‘heart-burn’, acid eructation, sensation of stomachcontents coming back in the foodpipe, especiallyafter a large meal, aggravated by stooping orlying flat. Some cases have an anatomical defect(hiatus hernia) but majority are only functional(LES relaxation in the absence of swallowing).Repeated reflux of acid gastric contents intolower 1/3rd of esophagus causes esophagitis,erosions, ulcers, strictures, and increases the riskof esophageal carcinoma.

Though GERD is primarily a g.i. motilitydisorder, acidity of gastric contents is the mostimportant aggressive factor in causing symptomsand esophageal lesions. The functional abnor-mality is persistent; dietary and other lifestylemeasures (light early dinner, raising head endof bed, weight reduction and avoidance ofprecipitating factors) must be taken.

Treatment of GERD is to be individualizedaccording to severity and stage of the disorder.The site and mechanism of benefit afforded bydifferent classes of drugs in GERD is depictedin Fig. 18.3.

1. Proton pump inhibitors (PPIs) These are themost effective drugs, both for symptomatic reliefas well as for healing of esophageal lesions.Intragastric pH >4 maintained for ~18 hr/dayis considered optimal for healing of esophagitis.This level of acid suppression can be consistently

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achieved only by PPIs. Therefore, PPIs are thedrugs of choice for all stages of GERD patients,particularly severe cases. Prolonged (oftenindefinite) therapy is required in chronic casesbecause symptoms recur a few days after drugstoppage.

2. H2 blockers H2 blockers cause less completeacid suppression than PPIs—adequate symptomrelief is obtained only in mild cases; healing ofesophagitis may occur in 50–70% patients.

3. Antacids Their use in GERD is limited tooccasional or intercurrent relief of heartburn.

4. Sodium alginate It forms a thick frothy layerwhich floats on the gastric contents—mayprevent contact of acid with esophageal mucosa.It has no effect on LES tone. Combination ofalginate with antacids may be used in place ofantacids alone, but real benefit is marginal.

5. Prokinetic drugs Metoclopramide and otherprokinetic drugs may relieve regurgitation andheartburn by increasing LES tone, improvingesophageal clearance and facilitating gastricemptying, but do not affect gastric acidity orpromote healing of esophagitis. Symptom controlafforded by prokinetic drugs is inferior to thatby PPIs/H2 blockers. Prokinetic drugs areoccasionally added to PPI/H2 blocker therapy,but whether this improves outcome is not clear.

LAXATIVES(Aperients, Purgatives, Cathartics)

These are drugs that promote evacuation ofbowels. A distinction is sometimes madeaccording to the intensity of action.(a) Laxative or aperient: milder action, eliminationof soft but formed stools.(b) Purgative or cathartic: stronger action resultingin more fluid evacuation.Many drugs in low doses act as laxative and inlarger doses as purgative.

CLASSIFICATION

1. Bulk formingDietary fibre: Bran, Psyllium (Plantago)Ispaghula, Methylcellulose

2. Stool softenerDocusates (DOSS), Liquid paraffin

3. Stimulant purgatives(a) Diphenylmethanes

Phenolphthalein, Bisacodyl,Sodium picosulfate

(b) Anthraquinones (Emodins)Senna, Cascara sagrada

(c) 5-HT4 agonistTegaserod

4. Osmotic purgativesMagnesium salts: sulfate, hydroxideSodium salts: sulfate, phosphateSod. pot. tartrateLactulose.

Fig. 18.3: Sites and mechanisms of drug action ingastroesophageal reflux diseaseMetoclopramide increases lower esophageal sphincter(LES) tone and promotes gastric emptying. Proton pumpinhibitor (PPI) and H2 blocker (H2B) inhibit acid secretion,while antacids neutralize it. Alginate floats on gastriccontents and prevents contact of esophageal mucosa withgastric acid.

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MECHANISM OF ACTION

All purgatives increase the water content of thefaeces by:(a) A hydrophilic or osmotic action, retaining

water and electrolytes in the intestinallumen—increase volume of colonic contentand make it easily propelled.

(b) Acting on intestinal mucosa to decrease netabsorption of water and electrolyte; intestinaltransit is enhanced indirectly by the fluid bulk.

(c) Increasing propulsive activity as primaryaction—allowing less time for absorption ofsalt and water as a secondary effect.

Bulk purgatives

Dietary fibre (bran) consists of unabsorbable cellwall and other constituents of vegetable food—cellulose, pectins, glycoproteins and otherpolysaccharides. Psyllium and ispaghula huskcontain natural colloidal mucilage which absorbswater, swells and forms a gelatinous mass. Thisincreases water content of faeces—softens it andfacilitates colonic transit.

Bulk forming laxatives are the most appro-priate method for prevention and treatment offunctional constipation. It is the first line approachfor most patients of simple constipation. Full effectrequires daily administration for at least 3–4 days.

Generous amounts of water must be takenwith all bulk forming agents.

Stool softener

Docusates (Dioctyl sodium sulfosuccinate: DOSS) isan anionic detergent; softens the stools by netwater accumulation in the lumen due to an actionon the intestinal mucosa. It emulsifies the coloniccontents and increases penetration of water intothe faeces. It is a mild laxative; especially indicatedwhen straining at stools must be avoided. Sideeffects are cramps and abdominal pain.

Liquid paraffin is a viscous liquid; a mixture ofpetroleum hydrocarbons. It is pharmacologicallyinert. Taken for 2–3 days, it softens stools and issaid to lubricate hard scybali by coating them.

However, it is unpleasant to swallow and hasmany drawbacks such as interference withabsorption of fat-soluble vitamins, likelihood ofleakage past the anus, lipid pneumonia if ittrickles into the airway, or foreign body granu-lomas in mesenteric lymph nodes if it is absorbed.

Stimulant purgatives

They are powerful purgatives: often producegriping. Though some of them do primarilyincrease motility by acting on myenteric plexuses,the more important mechanism of action isaccumulation of water and electrolytes in thelumen by altering absorptive and secretory activityof the mucosal cell. They inhibit Na+K+ATPase atthe basolateral membrane of villous cells—transport of Na+ and accompanying water into theinterstitium is reduced. Secretion is enhanced byactivation of cAMP in crypt cells and by increasedPG synthesis.

Larger doses of stimulant purgatives cancause excess purgation → fluid and electrolyteimbalance. Hypokalaemia can occur on regularuse. Routine and long-term use must be discou-raged; produces colonic atony.

Phenolphthalein and bisacodyl are syntheticdiphenylmethanes which primarily act in thecolon and at optimum doses produce one or twosemiformed motions after 6–8 hours. However,the same dose may be ineffective in some, butcause fluid evacuations and cramps in otherindividuals. Bisacodyl can also be used assuppository.

Sodium picosulfate is another diphenylmethanewhich is hydrolysed by the colonic bacteria torelease the active form that activates the myentericneurones. Bowel movement generally occurs after6–12 hours.

Senna and Cascara sagrada are plant productscontaining anthraquinone glycosides (also calledemodins). Unabsorbed in the small intestine, theyare passed to the colon where bacteria liberatethe active anthrol form, which either acts locallyor is absorbed into circulation—excreted in bileto act on small intestine. Thus, they take 6–8 hoursto produce action.

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Taken at bedtime—a single, soft but formedevacuation generally occurs in the morning.Cramps and excessive purging occur in somecases. The active principle is believed to act onthe myenteric plexus to increase peristalsis anddecrease segmentation. They also inhibit salt andwater absorption in the colon.

Skin rashes, fixed drug eruption are seenoccasionally with both anthraquinones anddiphenyl methanes.

Tegaserod is a new selective 5-HT4 receptorpartial agonist which promotes peristaltic reflex(most prominently in the colon) and colonicsecretion (by enhancing Cl¯ efflux). Stoolfrequency is increased and partial symptomaticrelief is obtained in constipation-predominantirritable bowel syndrome which is its primaryindication. It is also approved for the treatment ofchronic constipation, and may be useful as agastrokinetic.

Osmotic purgatives

Solutes that are not absorbed in the intestineretain water osmotically and distend the bowel—increasing peristalsis indirectly. Magnesium ionsrelease cholecystokinin which may contribute tothe purgative action of Mag. salts. All inorganicsalts used as osmotic (saline) purgatives havesimilar action—produce 1–2 fluid evacuationswithin 1–3 hours with mild cramping; causenearly complete emptying of bowels. Smallerdoses may have a milder laxative action.

They are not used for the treatment ofconstipation, because after-constipation is quitecommon. However, they may be preferred forpreparation of bowel before surgery andcolonoscopy; in food/drug poisoning and asafter-purge in the treatment of tapeworminfestation.

Lactulose It is a semisynthetic disaccharide offructose and lactose which is neither digested norabsorbed in the small intestine—retains water.Further, it is broken down in the colon by bacteriato osmotically more active products. In a dose of10 g BD taken with plenty of water, it produces

soft formed stools in 1–3 days. Flatulence iscommon, cramps occur in few. Some patients feelnauseated by its peculiar sweet taste. It is not afavoured purgative for treatment of constipation.

Lactulose is also used to lower blood NH3 inhepatic encephalopathy, because its acidicbreakdown products generated in the colon reactwith NH3 to form ionized NH4 salts that are notabsorbed.

USES OF PURGATIVES

Laxatives are as important for their harmfulnessas they are for their value in medicine.Valid indications of laxatives are:

1. Functional constipation Constipation isinfrequent production of hard stools requiringstraining to pass, or a sense of incompleteevacuation.

Constipation may be spastic or atonic.

(i) Spastic constipation (irritable bowel): The stoolsare hard, rounded, stone like and difficult to pass.The first choice laxative is dietary fibre or any ofthe bulk forming agents taken over weeks/months: Tegaserod is a new option available now.Stimulant purgatives are contraindicated.

(ii) Atonic constipation (sluggish bowel): Non-drug measures like plenty of fluids, exercise,regular habits and reassurance should be tried.In resistant cases a bulk forming agent should beprescribed. In case of poor compliance or if thepatient is not satisfied—bisacodyl or senna maybe given once or twice a week for as short a periodas possible.

2. Bedridden patients (myocardial infarction,stroke, fractures, postoperative).To prevent constipation: Give bulk forming agentson a regular schedule; docusates is an alternative.To treat constipation: Enema (soap-water/glycerine) is preferred; bisacodyl or senna may beused otherwise.3. To avoid straining at stools (hernia, cardio-vascular disease, eye surgery) and in perianal

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to be dissolvedin 1 L of water

afflictions (piles, fissure, anal surgery) use ade-quate dose of a bulk forming agent, lactulose ordocusates.4. Preparation of bowel for surgery, colonoscopy,abdominal X-ray The bowel needs to be emptiedof the contents including gas. Saline purgative,bisacodyl or senna may be used.5. After certain anthelmintics (especially fortape-worm) Saline purgative or senna may be usedto flush out the worm and the anthelmintic drug.

The choice of a purgative depends on thelatency of action and type of stools desired. Thisis given in Table 18.1.

Table 18.1: Type of stools and latency of action ofpurgatives employed in usually recommended doses

Soft, formed faeces Semifluid stools Watery evacuation(take 1–3 days) (take 6–8 hr) (within 1–3 hr)

Bulk forming Phenolphthalein Saline purgativesDocusates BisacodylLiquid paraffin Sod. picosulfateLactulose Senna

TREATMENT OF DIARRHOEAS

Diarrhoea is too frequent, often too precipitatepassage of poorly formed stools. In pathologicalterms, it occurs due to passage of excess water inthe faeces.

Diarrhoeal diseases constitute a major causeof morbidity and mortality worldwide; especiallyin developing countries. More than 5 millionchildren under the age of 5 years die every year ofdiarrhoea. Even mild diarrhoea, and that inadults, is a disabling symptom and aninconvenience.

Principles of management

Rational management of diarrhoea depends onestablishing the underlying cause and institutingspecific therapy only if necessary, since mostdiarrhoeas are self-limiting. Majority of entero-pathogens are taken care of by motility and otherdefence mechanisms of the gut. Therapeuticmeasures may be grouped into:

(a) Treatment of fluid depletion and acidosis.(b) Antimicrobial drugs.(c) Nonspecific antidiarrhoeal drugs.

ORAL REHYDRATION

In majority of cases this is the only measureneeded, especially if the fluid loss is mild (5–7%BW) or moderate (7.5–10% BW).

Oral rehydration is possible if glucose isadded with salt. It capitalizes on the intactnessof glucose coupled Na+ absorption, even whenother mechanisms have failed or when intestinalsecretion is excessive—the secreted fluid lacksglucose and cannot be reabsorbed. The generalprinciples governing composition of oralrehydration solution (ORS) are:(a) It should be isotonic or somewhat hypotonic,i.e. total osmolarity 200–310 mOsm/L (diarrhoeafluids are approximately isotonic with plasma).(b) The molar ratio of glucose should be equalto or somewhat higher than Na+, but not exceed110 mM.(c) Enough K+ (15–25 mM) and bicarbonate/citrate (8–12 mM) should be provided to makeup the losses in stool.The WHO recommended a standard formula:NaCl 60 mM = 3.5 gKCl 20 mM = 1.5 gTrisod. citrate 30 mM = 2.9 gGlucose 110 mM = 20 g

This provides Na+ 90 mM, K+ 20 mM, Cl¯ 80 mM,citrate (base) 10 mM, glucose 110 mM and has atotal osmolarity of 310 mOsm/L. It is based onthe composition of cholera stools, particularly inchildren.

New formula WHO-ORS In 2002, a new formulalow Na+ low glucose ORS has been released bythe WHO based on studies carried out in severaldeveloping countries among children and adultssuffering from diarrhoeas.

The WHO and UNICEF have recommendedreplacement of standard (310 mOsm/L) ORSformula by the new (245 mOsm/L) formula.

Oral rehydration therapy (ORT) is notdesigned to stop diarrhoea, but to restore and

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maintain hydration, electrolyte and pH balanceuntil diarrhoea ceases, mostly spontaneously.

ANTIMICROBIALS

One or more antimicrobial agent is almost routi-nely prescribed to every patient of diarrhoea.However, such drugs have a limited role in theoverall treatment of diarrhoeal patients; thereasons are:

(i) Bacterial pathogen is responsible for only afraction of cases.

(ii) Even in bacterial diarrhoea, antimicrobialsalter the course of illness only in selectedcases.

(iii) Antimicrobials may prolong the carrier state.

A. Antimicrobials are of no value In diar-rhoea due to noninfective causes, such as irritablebowel syndrome, coeliac disease, pancreaticenzyme deficiency, tropical sprue (except whenthere is secondary infection), thyrotoxicosis aswell as in infective diarrhoea due to rotavirus orSalmonella food poisoning.

B. Antimicrobials are useful only in severedisease (but not in mild cases) in case of:

(i) Travellers’ diarrhoea: mostly due to entero-toxigenic E.coli (ETEC), Campylobacter or viruses:cotrimoxazole, norfloxacin, doxycycline anderythromycin reduce the duration of diarrhoeaand total fluid needed only in severe cases.

(ii) Enteropathogenic E. coli (EPEC): is lesscommon, but causes Shigella-like invasive illness.Cotrimoxazole, colistin, nalidixic acid ornorfloxacin may be used.

(iii) Shigella enteritis: only when associated withblood and mucus in stools may be treated withciprofloxacin, norfloxacin or nalidixic acid.

(iv) Salmonella typhimurium enteritis is ofteninvasive; severe cases may be treated with afluoroquinolone, cotrimoxazole or ampicillin.

(v) Yersinia enterocolitica: common in colder places,not in tropics. Cotrimoxazole is the most suitabledrug in severe cases; ciprofloxacin is analternative.

C. Antimicrobials are regularly useful in:

(i) Cholera: Though not life saving, tetracyclinesreduce stool volume to nearly ½. Cotrimoxazole ,norfloxacin, ciprofloxacin and erythromycin arethe alternatives, especially in children.

(ii) Campylobacter jejuni: Norfloxacin and otherfluoroquinolones control diarrhoea. Erythro-mycin is fairly effective.

(iii) Clostridium difficile: produces antibioticassociated psuedo-membranous enterocolitis.The drug of choice for it is metronidazole.

(iv)Amoebiasis metronidazole, diloxanide furoate(v) Giardiasis are effective drugs.

NONSPECIFIC ANTIDIARRHOEAL AGENTS

1. Antisecretory drugsSulfasalazine (Salicylazosulfapyridine) It is acompound of 5-aminosalicylic acid (5-ASA) withsulfapyridine linked through an azo bond.

The azo bond is split by colonic bacteria to release5-ASA and sulfapyridine. The former exerts a localantiinflammatory effect and is useful in ulcerativecolitis and related inflammatory bowel diseases.It is also used as a disease modifying drug inrheumatoid arthritis.

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New formula WHO-ORS

Content Concentrations

NaCl : 2.6 g Na+ — 75 mMKCl : 1.5 g K+ — 20 mMTrisod. citrate : 2.9 g Cl¯ — 65 mMGlucose : 13.5 g Citrate — 10 mMWater : 1 L Glucose — 75 mM

Total osmolarity 245 mOsm/L


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Mesalazine (Mesalamine) These are the officialnames given to 5-ASA. Realizing that 5-ASA isthe active moiety in ulcerative colitis, it has beenformulated as delayed release preparations bycoating with acrylic polymer. Such preparationsappear to be reliable for delivering 5-ASA to thedistal small bowel and colon: are as effective assulfasalazine in inflammatory bowel diseaseand produce less side effects. 5-ASA is alsoavailable as retention enema for the treatment ofdistal ulcerative colitis.

Drug interactions Coated mesalazine mayenhance the gastric toxicity of glucocorticoids andhypoglycaemic action of sulfonylureas. Inter-action with coumarins, furosemide, spironolac-tone, methotrexate and rifampicin are possible.

Corticosteroids Prednisolone (40 mg/day) orequivalent are highly effective in controllingsymptoms/inducing remission in both ulcerativecolitis and Crohn’s disease.

Racecadotril It is a recently introduced prodrugwhich after conversion to the active form in thebody inhibits the enzyme enkephalinase.Degradation of enkephalins, which are mainly δopioid receptor agonists, is prevented—resultingin attenuation of intestinal hypersecretion. Itaffords symptomatic relief in secretory diarrhoes.In contrast to loperamide, it can be given to youngchildren as well.

2. Antimotility drugs

These are opioid drugs which increase smallbowel tone and segmenting activity, reducepropulsive movements and diminish intestinalsecretions while enhancing absorption. The majoraction appears to be mediated through μ opioidreceptors located on enteric neuronal network,but direct action on intestinal smooth muscle andsecretory/absorptive epithelium has also beendemonstrated.

Codeine has prominent constipating actionwhile its dependence producing liability is low.Side effects are nausea, vomiting and dizziness.It should be used only for short periods andavoided in children.

Diphenoxylate is a synthetic opioid usedexclusively as constipating agent; action is similarto codeine. Because it is absorbed systemicallyand crosses blood-brain barrier—CNS effects dooccur. Atropine is added in subpharmacologicaldose to discourage abuse. It has caused respiratorydepression, paralytic ileus and toxic megacolonin children—contraindicated below 6 years of age.

Loperamide is an opiate analogue with majorperipheral μ opioid and additional weak anti-cholinergic property. As a constipating agent, itis much more potent than codeine. Because ofpoor water solubility—little is absorbed from theintestines. Entry into brain is negligible—CNSeffects are rare, no abuse liability.

In addition to its opiate like action on motility,loperamide also inhibits secretion: directlyinteracts with calmodulin—this may beresponsible for the antidiarrhoeal action.

Abdominal cramps and rashes are the mostcommon side effects. Paralytic ileus, toxicmegacolon with abdominal distension is a seriouscomplication in young children—contraindicatedin children < 4 years.

The utility of antimotility drugs in diarrhoeais limited to noninfective diarrhoea, mildtravellers’ diarrhoea and when diarrhoea isexhausting or idiopathic diarrhoea in AIDSpatients. Their use is a short-term measure only.

Antimotility drugs are contraindicated inacute infective diarrhoeas because they delayclearance of the pathogen from the intestine. Ifinvasive organisms (Shigella, EPEC, EH, etc.) arepresent, antimotility drugs can be disastrous.

Antimotility drugs can be used to inducedeliberate short-term constipation, e.g. after analsurgery.

DRUGS FOR COUGH

Cough is a protective reflex, its purpose beingexpulsion of respiratory secretions or foreignparticles from air passages. It occurs due tostimulation of mechano- or chemoreceptors inthroat, respiratory passages or stretch receptorsin the lungs. Cough may be useful or useless.Useless (nonproductive) cough should be sup-pressed. Useful (productive) cough serves to drainthe airway, its suppression is not desirable, mayeven be harmful. Apart from specific remedies(antibiotics, etc.), cough may be treated as asymptom (nonspecific therapy) with:

1. Pharyngeal demulcents Lozenges, coughdrops, linctuses containing syrup, glycerine,liquorice.

2. Expectorants (Mucokinetics)(a) Bronchial secretion enhancers Sodium orPotassium citrate, Potassium iodide, Guaiphe-nesin (Glyceryl guaiacolate), balsum of Tolu,Vasaka, Ammonium chloride.(b) Mucolytics Bromhexine, Ambroxol, Acetylcysteine, Carbocisteine

3. Antitussives (Cough centre suppressants)(a) Opioids Codeine, Pholcodeine.(b) Nonopioids Noscapine, Dextromethorphan,

Chlophedianol.(c) Antihistamines Chlorpheniramine, Diphen-

hydramine, Promethazine.

4. Adjuvant antitussivesBronchodilators Salbutamol, Terbutalin.

Pharyngeal demulcents sooth the throat andreduce afferent impulses from the inflamed/irritated pharyngeal mucosa, thus provide symp-tomatic relief in dry cough arising from throat.

Expectorants (Mucokinetics) are drugsbelieved to increase bronchial secretion or reduceits viscosity, facilitating its removal by coughing.

Sodium and potassium citrate are consideredto increase bronchial secretion by salt action.Potassium iodide is secreted by bronchial glandsand can irritate the airway mucosa. Prolongeduse can affect thyroid function and cause iodism;rarely used now. Guaiphenesin, vasaka, tolubalsum are plant products which are supposedto enhance bronchial secretion and mucociliaryfunction while being secreted by tracheobronchialglands. Ammonium salts are nauseating—reflexly increase respiratory secretions. A varietyof expectorant formulations containing anassortment of the above ingredients, often incombination with antitussives/antihistaminicsare marketed and briskly promoted, but objectiveevidence of efficacy of these is non-conclusive.

Bromhexine A derivative of the alkaloid vasi-cine, obtained from vasaka, is a potent mucolyticand mucokinetic capable of inducing thincopious bronchial secretion. It depolymerisesmucopolysaccharides directly as well as by

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292 Drugs for Respiratory DisordersS

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liberating lysosomal enzymes. It is particularlyuseful if mucus plugs are present.Side effects are rhinorrhoea, lacrimation, gastricirritation, hypersensitivity.

Ambroxol A metabolite of bromhexine havingsimilar mucolytic action, uses and side effects.Carbocisteine It liquefies viscid sputum byopening disulfide bonds in mucoproteins.Some patients of chronic bronchitis have beenshown to benefit. Side effects are g.i. irritation andrashes.

ANTITUSSIVES

These are drugs that act in the CNS to raise thethreshold of cough centre or act peripherally inthe respiratory tract to reduce tussal impulses, orboth these actions. Because they aim to controlrather than eliminate cough, antitussives shouldbe used only for dry unproductive cough or if it isunduly tiring, disturbs sleep or is hazardous(hernia, piles, cardiac disease, ocular surgery).

Codeine (see Ch. 24) An opium alkaloid, quali-tatively similar to but less potent than morphine.It is more selective for cough centre and is treatedas the standard antitussive; suppresses cough forabout 6 hours. The antitussive action is blockedby naloxone indicating that it is exerted throughopioid receptors in the brain. Abuse liability islow, but present; constipation is the chief draw-back. Like morphine, it is contraindicated inasthmatics and in patients with diminishedrespiratory reserve.

Pholcodeine It has practically no analgesic oraddicting property, but is similar in efficacy asantitussive to codeine and is longer acting—actsfor 12 hours.

Noscapine (Narcotine) An opium alkaloid of thebenzoisoquinoline series. It depresses cough buthas no narcotic, analgesic or dependence indu-cing properties. It is nearly equipotent antitussiveas codeine, especially useful in spasmodic cough.Headache and nausea occur occasionally as sideeffect. It can release histamine and producebronchoconstriction in asthmatics.

Dextromethorphan A synthetic compound: thed-isomer has selective antitussive action (raisesthreshold of cough centre). As effective as codeine,does not depress mucociliary function of theairway mucosa and is practically devoid ofconstipating and addicting actions. Its antitussiveaction is not blocked by naloxone, therefore, notexerted through opioid receptors.Side effect: Dizziness, nausea, drowsiness, ataxia.

Chlophedianol It is a centrally acting antitussivewith slow onset and longer duration of antitussiveaction.Side effect: Dryness of mouth, vertigo, irritability.

Antihistamines Many H1 antihistamines havebeen conventionally added to antitussive/expectorant formulations. They afford relief incough due to their sedative and anticholinergicactions, but lack selectivity for the cough centre.They have no expectorant property, may evenreduce secretions by anticholinergic action. Theyhave been specially promoted for cough inrespiratory allergic states. The second generationantihistamines like loratadine and fexofenadineare ineffective.

Bronchodilators Bronchospasm can induce oraggravate cough. Stimulation of pulmonaryreceptors can trigger both cough and broncho-constriction, especially in individuals with bron-chial hyperreactivity. Bronchodilators relievecough in such individuals and improve theeffectiveness of cough in clearing secretions byincreasing surface velocity of airflow duringcough. They should be used only when anelement of bronchoconstriction is present and notroutinely.

DRUGS FOR BRONCHIAL ASTHMA

Bronchial asthma is characterised by hyperres-ponsiveness of tracheobronchial smooth muscleto a variety of stimuli, resulting in narrowing ofair tubes, often accompanied by increased secre-tion, mucosal edema and mucus plugging.

Asthma is now recognized to be a primarilyinflammatory condition: inflammation under-

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lying hyperreactivity. An allergic basis can bedemonstrated in many adult, and higher per-centage of pediatric patients. In others, a varietyof trigger factors (infection, irritants, pollution,exercise, exposure to cold air, psychogenic) maybe involved:Extrinsic asthma: It is mostly episodic, less proneto status asthmaticus.Intrinsic asthma: It tends to be perennial, statusasthmaticus is more common.

Mast cells (present in lungs) and inflammatorycells recruited as a result of the initial reactionproduce a multitude of mediators: histamine,TNFα, PGs, LTs, PAF, interleukins, etc. whichconstrict bronchial smooth muscle, causemucosal edema, hyperemia and produce viscidsecretions, all resulting in reversible airwayobstruction. The inflammation perpetuates itselfby cell-to-cell communication and recruitment ofmore and more inflammatory cells. Bronchialsmooth muscle hypertrophy occurs over time anddamage to bronchial epithelium accentuates thehyperreactivity. Vagal discharge to bronchialmuscle is enhanced reflexly. Airway remodelingprogressively worsens the disease.Chronic obstructive pulmonary disease (COPD) is aprogressive disease with emphysema (alveolar destruction)and bronchiolar fibrosis in variable proportions. Theexpiratory airflow limitation does not fluctuate markedlyover long periods of time, but there are exacerbationsprecipitated by respiratory infections, pollutants, etc. It isclearly related to smoking and characteristically starts afterthe age of 40. Patients derive < 15% improvement in forcedexpiratory volume in 1 sec (FEV1) following inhalation ofa β agonist bronchodilator: airway obstruction is largelyirreversible.

CLASSIFICATION

I. BronchodilatorsA. Sympathomimetics: Salbutamol, Terbutaline,

Bambuterol, Salmeterol, Formoterol.B. Methylxanthines: Theophylline, Amino-

phylline, DoxophyllineC. Anticholinergics: Ipratropium bromide,

Tiotropium bromide.

II. Leukotriene antagonistsMontelukast, Zafirlukast.

III. Mast cell stabilizersSodium cromoglycate, Ketotifen.

IV. CorticosteroidsA. Systemic: Hydrocortisone, Prednisolone.B. Inhalational: Beclomethasone dipropionate,

Budesonide, Fluticasone propionate, Fluniso-lide, Ciclesonide

SYMPATHOMIMETICS (see Ch. 6)

Adrenergic drugs cause bronchodilatationthrough β2 receptor stimulation → increasedcAMP formation in bronchial muscle cell → rela-xation. In addition, increased cAMP in mastcells and other inflammatory cells decreasesmediator release. Adrenergic drugs are themainstay of treatment of reversible airwayobstruction but should be cautiously used inhypertensives, heart patients and in thosereceiving digitalis. They are the fastest actingbronchodilators when inhaled.

The highly selective β2 agonists like salbutamoland terbutaline are used in asthma to minimizecardiac side effects. Selectivity is further increasedby inhaling the drug. Inhaled salbutamolproduces bronchodilatation within 5 min and theaction lasts for 2 to 4 hours. It is, therefore, used toabort and terminate attacks of asthma but is notsuitable for round-the-clock prophylaxis. Muscletremors are the dose-related side effect. Palpita-tion, restlessness, nervousness, throat irritationand ankle edema can also occur. Oral salbutamolacts for 4–6 hours, is longer acting and safer thanisoprenaline, but similar in efficacy.

Because of more frequent side effects, oral β2

agonist therapy is reserved for patients whocannot correctly use inhalers or during severeasthma exacerbations.

However, β2 agonists do not reduce bronchialhyperreactivity: may even worsen it—this maybe responsible for the diminished responsivenessseen after long-term use. Regular use also down-regulates bronchial β2 receptors. It is felt thatpatients requiring regular β2 agonists should betreated with inhaled steroids and use of β2 agonist

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inhalers should be restricted to symptomatic reliefof wheezing.Salmeterol is the first long-acting selective β2

agonist with a slow onset of action; used byinhalation on a twice daily schedule formaintenance therapy and for nocturnal asthma,but not for acute symptoms. Concern of asthmaworsening due to regular use of inhaled β2 ago-nists applies to salmeterol also. However, clinicalstudies have shown sustained improvement inasthma symptoms and lung function. Concurrentuse of inhaled glucocorticoid with salmeterol isadvocated for patients with persistent asthma.

Long-acting β2 agonists are superior to short-acting ones in COPD.Formoterol is another long-acting selective β2

agonist which has a faster onset of action within10 min. Therefore, it can be used for rapid reversalof bronchoconstriction as well as on a regularmorning-evening schedule for round-the-clockbronchodilatation.Bambuterol is a long acting prodrug of terbutalinesuitable only for oral use.

METHYLXANTHINES

Theophylline and its compounds have beenextensively used in asthma, but are not consideredfirst line drugs any more; used more often inCOPD. Theophylline is one of the three naturallyoccurring methylated xanthine alkaloids caffeine,theophylline and theobromine. The chemicalrelation between the three is depicted below:

They are consumed as beverages. The sources andaverage alkaloid contents of the beverages, as theyare usually prepared are given below:

Source Alkaloid content in beverage

1. Thea sinensis Caffeine 50 mg in an average(Tea leaves) Theophylline 1 mg cup of tea

2. Coffea arabica Caffeine 75 mg in an average(Coffee seeds) cup of coffee

3. Theobroma cacao Theobromine 200 mg in an average(Cocoa, chocolate) Caffeine 4 mg cup of cocoa

4. Cola acuminata Caffeine 30 mg in 200 ml bottle(Guru nuts) of cola drink


1. CNS Caffeine and theophylline are CNSstimulants, primarily affect the higher centres.Caffeine produces a sense of wellbeing, alertness,beats boredom, allays fatigue, thinking becomesclearer. It tends to improve performance andincrease motor activity. Higher doses causenervousness, restlessness, panic, insomnia andexcitement. Still higher doses produce tremors,delirium and convulsions. Theophylline hasgreater propensity to produce these adverseeffects at higher doses and is definitely more toxicthan caffeine.

They also stimulate medullary vagal, respira-tory and vasomotor centres. Vomiting at highdoses is due both to gastric irritation and CTZstimulation.

2. CVS Methylxanthines directly stimulate theheart and increase force of myocardial contrac-tions. They tend to increase heart rate by directaction, but decrease it by causing vagal stimu-lation—net effect is variable. Tachycardia is morecommon with theophylline. Cardiac output andcardiac work are increased. At high doses, cardiacarrhythmias may be produced.

Methylxanthines, especially theophylline,dilate systemic blood vessels, including corona-ries, by direct action: peripheral resistance is redu-ced. However, cranial vessels are constricted,especially by caffeine: this is one of the basis of itsuse in migraine.

Effect on BP is variable and unpredictable.

3. Smooth muscles All smooth muscles arerelaxed, most prominent effect is exerted on

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bronchi, especially in asthmatics. Theophyllineis more potent: slow but sustained dose-relatedbronchodilatation is produced—vital capacity isincreased. Biliary spasm is relieved, but effect onintestines and urinary tract is negligible. Caffeinehas minimal actions.

4. Kidney They are mild diuretics; act by inhi-biting tubular reabsorption of Na+ and water.

5. Skeletal muscles Caffeine enhances contrac-tile power of skeletal muscles. Enhanceddiaphragmatic contractility probably contributesto beneficial effects of theophylline in dyspnoea.

6. Stomach Methylxanthines stimulate secre-tion of acid and pepsin in stomach. They are alsogastric irritants.

7. Metabolism Caffeine and to a smaller extenttheophylline increase BMR.

8. Mast cells and inflammatory cells Theo-phylline decreases the release of histamine andother mediators from mast cells and activatedinflammatory cells. This may contribute to itstherapeutic effect in bronchial asthma.

Mechanism of action Three distinct cellularactions of methylxanthines have been defined—(a) Release of Ca2+ from sarcoplasmic reticulum,especially in skeletal and cardiac muscle.(b) Inhibition of phosphodiesterase (PDE) whichdegrades cyclic nucleotides intracellularly.

ATP adenylylcyclase cAMP phosphodiesterase 5-AMPor or or

GTP guanylylcyclase cGMP INHIBITED BY 5-GMPTHEOPHYLLINE

Thus, the concentration of cyclic nucleotides isincreased. Bronchodilatation, cardiac stimulationand vasodilatation occur when cAMP level risesin the concerned cells.(c) Blockade of adenosine receptors: adenosineacts as a local mediator in CNS, CVS and otherorgans—contracts smooth muscles, especiallybronchial; dilates cerebral blood vessels, depres-ses cardiac pacemaker and inhibits gastric secre-tion. Methylxanthines produce opposite effects.

Action (c) is exerted at concentrations in thetherapeutic range and may be more important.There is some evidence indicating contribution ofraised cAMP levels (action ‘b’) in bronchial smoothmuscle to the therapeutic response.

Pharmacokinetics Theophylline is well absor-bed orally. It is distributed in all tissues andextensively metabolized in liver by demethylationand oxidation. Only 10% is excreted unchangedin urine. At therapeutic concentrations, the t½ inadults is 7–12 hours. Children eliminate it muchfaster and elderly more slowly.

Theophylline metabolizing enzymes aresaturable, t½ is prolonged with higher doses askinetics changes from first to zero order: plasmaconcentrations, therefore, increase dispropor-tionately.

Adverse effects Theophylline has a narrowmargin of safety. Adverse effects are primarilyreferable to g.i.t., CNS and CVS, viz dyspepsia,vomiting, nervousness, tremor, delirium, hypo-tension, arrhythmias and convulsions.

Interactions

1. Agents which induce theophylline metabo-lism and decrease its plasma level are smoking,phenytoin, rifampicin, phenobarbitone, charcoalbroiled meat meal.2. Drugs which inhibit theophylline metabolismand increase its plasma level are—erythromycin,ciprofloxacin, cimetidine, oral contraceptives,allopurinol; dose should be reduced to 2/3rd.3. Theophylline enhances the effects of—furose-mide, sympathomimetics, digitalis, oral anti-coagulants, hypoglycaemics.

Uses

1. Bronchial asthma and COPD: Theophyllinebenefits by causing bronchodilatation as well aspresumably by decreasing release of inflamma-tory mediators, improved mucociliary clearance,stimulation of respiratory drive and by aug-menting diaphragmatic contractility. However,



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because of narrow margin of safety and limitedefficacy, its use has declined. Oral theophyllinecan be used in mild-to-moderately severe asthma,as a 3rd line drug or alternative adjuvant drug. Itis more useful in COPD.

Use of intravenous aminophylline (theo-phylline-ethylenediamine, a water-soluble doublesalt) in status asthmaticus is outmoded.

2. Apnoea in premature infant: Theophyllinereduces the frequency and duration of episodesof apnoea that occur in some preterm infants.

ANTICHOLINERGICS (see Ch. 5)

Atropinic drugs cause bronchodilatation byblocking cholinergic constrictor tone; act pri-marily in the larger airways (Fig. 19.1).

Inhaled ipratropium bromide is less effica-cious than inhaled sympathomimetics, but canadd to their response. Patients of asthmatic bron-chitis, COPD and psychogenic asthma respondbetter to anticholinergics. Inhaled ipratropium/

tiotropium are the bronchodilators of choice inCOPD. They produce slower response thaninhaled sympathomimetics and are better suitedfor regular prophylactic use than for quick reliefof breathlessness. Nebulized ipratropium mixedwith salbutamol is employed in refractoryasthma.

LEUKOTRIENE ANTAGONISTS

Since it was realized that cystenyl leukotrienes(LT-C4/D4) are important mediators of bron-chial asthma, efforts were made to develop theirantagonists and synthesis inhibitors. Two cysLT1

receptor antagonists montelukast and zafirlukastare now available.

Montelukast and Zafirlukast Both have similaractions and clinical utility. They competitivelyantagonise cysLT1 receptor mediated broncho-constriction, increased vascular permeability andrecruitment of eosinophils. Bronchodilatation,reduced sputum eosinophil count, suppressionof bronchial inflammation and hyperreactivityare noted in asthma patients. Parameters of lungfunction show variable but definite improvement.

Montelukast and zafirlukast are indicated forprophylactic therapy of mild-to-moderate asthmaas alternatives to inhaled glucocorticoids. Thoughoverall efficacy is lower than inhaled steroids,they may obviate need for the latter. In severeasthma, they may permit reduction in steroid dose.However, they are not to be used for terminatingasthma episodes.

Both montelukast and zafirlukast are verysafe drugs; produce few side effects like headacheand rashes. Eosinophilia and neuropathy areinfrequent.

They are well absorbed orally. The plasma t½of montelukast is 3 to 6 hours, while that ofzafirlukast is 8 to 12 hours.

MAST CELL STABILIZERS

Sodium cromoglycate (Cromolyn sod.)

It is a synthetic chromone derivative which inhi-bits degranulation of mast cells by trigger stimuli.

Fig. 19.1: Primary sites of bronchodilator action of inhaledadrenergic β2 agonists and inhaled anticholinergics.Salbutamol mainly relaxes bronchiolar smooth muscle;Ipratropium blocks bronchoconstriction mainly in the largerairways

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Release of mediators of asthma like histamine,LTs, PAF, interleukins, etc. from mast cells as wellas other inflammatory cells is attenuated. Long-term treatment decreases the cellular inflamma-tory response: bronchial hyperreactivity is redu-ced to variable extents: bronchospasm inducedby allergens, irritants, cold air and exercise maybe reduced. However, AG:AB reaction is notinterfered with. It is also not a bronchodilator anddoes not antagonise the constrictor action ofhistamine, ACh, LTs, etc. Therefore, it is ineffectiveif given during an asthmatic attack.

Sod. cromoglycate is not absorbed orally. It isadministered as an aerosol through metered doseinhaler.

Uses

1. Bronchial asthma: Sod. cromoglycate isoccasionally used as a long-term prophylactic inmild to moderate asthma. Therapeutic benefit ismore likely in extrinsic (atopic) and exerciseinduced asthma. Its popularity has declinedbecause of less complete and less consistentresponse than inhaled steroids.

2. Allergic rhinitis: Cromoglycate is not a nasaldecongestant, but regular prophylactic use as anasal spray produces symptomatic improvementin some patients.

3. Allergic conjunctivitis: Regular use as eye dropsis beneficial in some chronic cases.

Adverse effects Bronchospasm, throat irritationand cough occurs in some patients. Rarelyheadache, dizziness, and arthralgia have beenreported.

Ketotifen It is an antihistaminic (H1) with somecromoglycate like action; stimulation of immuno-genic and inflammatory cells (mast cells,macrophages, eosinophils, lymphocytes, neutro-phils) and mediator release are decreased. It isnot a bronchodilator but produces sedation.

After 6–12 weeks of use, it reduces respiratorysymptoms in 50–70% patients of bronchialasthma, but improvement in lung function is

marginal. It also produces symptomatic relief insome patients with atopic dermatitis, perennialrhinitis, conjunctivitis, urticaria and food allergy.

CORTICOSTEROIDS

Glucocorticoids are not bronchodilators. Theybenefit asthma by reducing bronchial hyper-reactivity, mucosal edema and by suppressinginflammatory response to AG:AB reaction or othertrigger stimuli. Their mechanism of action isdetailed in Ch. 14.

The realization that asthma is primarily aninflammatory disorder which, if not controlled,accentuates with time, and the availability ofinhaled steroids that produce few adverse effectshas led to early introduction and more extensiveuse of glucocorticoids in asthma. Corticosteroidsafford more complete and sustained symptomaticrelief than bronchodilators or cromoglycate,suppress bronchial hyperreactivity, and mayinfluence airway remodeling, retarding diseaseprogression. However, long-term systemic steroidtherapy has its own adverse effects which may beworse than asthma itself.

Systemic steroid therapy It is resorted to inasthma under the following two situations:

(i) Severe chronic asthma: not controlled bybronchodilators and inhaled steroids, or whenthere are frequent recurrences of increasingseverity. After good control, try shifting the patientonto an inhaled steroid. Few patients require long-term oral steroids—in them dose should be keptat minimum.

(ii) Status asthmaticus/acute asthma exacerba-tion: asthma attack not respnding to intensivebronchodilator therapy: start with high dose of arapidly acting i.v. glucocorticoid which generallyacts in 6–24 hours—shift to oral therapy for 5 to 7days and then discontinue abruptly or taperrapidly.

Inhaled steroids These glucocorticoids havehigh topical and low systemic activity (due topoor absorption and/or marked first pass



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metabolism). Beclomethasone dipropionate, budeso-nide and fluticasone have similar properties.Ciclesonide is a new addition. Because airwayinflammation is present in early mild disease aswell, and bronchial remodeling starts developingfrom the beginning, it has been suggested thatinhaled steroids should be the ‘step one’ for allasthma patients. However, currently inhaledsteroids are not considered necessary for patientswith mild and episodic asthma. They areindicated when inhaled β2 agonists are requiredalmost daily or the disease is not only episodic.

Inhaled steroids suppress bronchial inflam-mation, increase peak expiratory flow rate, reduceneed for rescue β2-agonist inhalations and preventepisodes of acute asthma. However, they have norole during an acute attack or in status asth-maticus. Long-term experience has shown thatefficacy of inhaled steroids is maintained andreinstitution of oral steroids is seldom needed.Short courses of oral steroids may be added duringperiods of exacerbation.

COPD: High dose inhaled steroids are beneficialonly in advanced COPD with frequent exacerba-tions; should not be used in early/mild cases.

Hoarseness of voice, dysphonia, sore throat,asymptomatic or symptomatic oropharyngealcandidiasis are the most common side effects.These can be minimized by use of a spacer,gargling after every dose and prevented as wellas treated by topical nystatin.

Choice of treatment

A stepwise guideline to the treatment of asthmaas per needs of the patient has been recommended:

1. Mild episodic asthma (symptoms less thanonce daily, normal in between attacks): Inhaledshort-acting β2 agonist at onset of each episode.No regular prophylactic therapy (Step 1).

2. Seasonal asthma Start regular inhaledcromoglycate/low dose inhaled steroid (200–400μg/day) 3–4 weeks before anticipated seasonalattacks and continue till 3–4 weeks after the season

is over. Treat individual episodes with inhaledshort-acting β2 agonist.

3. Mild chronic asthma with occasional exacerba-tions (symptoms once daily or so) Regular low-dose inhaled steroid (Step 2). Alternatively, inhaledcromoglycate. Episode treatment with inhaledshort-acting β2 agonist.

4. Moderate asthma with frequent exacerbations(attacks affect activity, occur > 1 per day or mildbaseline symptoms) increasing doses of inhaledsteroid (up to 800 μg/day) + inhaled long-actingβ2 agonist (Step 3). Leukotriene antagonists may betried in patients not accepting inhaled steroids andthose not well controlled. Episode treatment withinhaled short-acting β2 agonist.

5. Severe asthma (continuous symptoms;frequent exacerbations/hospitalization) Regularinhaled steroid (800–2,000 μg/day) through a largevolume spacer device + inhaled long-actingβ2 agonist (salmeterol) twice daily. Additionaltreatment with one or more of the following(Step 4).

Sustained release oral theophylline/inhaledipratropium bromide/leukotriene antagonist/oral β2 agonist.

In patients not adequately controlled or thoseneeding frequent emergency care—institute oralsteroid therapy (Step 5). Periodically attemptwithdrawing oral steroids.

6. Status asthmaticus/Refractory asthma(i) Hydrocortisone hemisuccinate 100 mg

i.v. stat followed by 100 mg/8 hr infusion.(ii) Nebulized salbutamol + ipratropium bro-

mide intermittent inhalations.(iii) Intermittent humidified oxygen inhalation.(iv) Salbutamol/terbutaline 0.4 mg i.m./s.c.

may be added since inhaled drug may notreach smaller bronchi due to severe nar-rowing/plugging.

(v) Treat chest infection with intensive anti-biotic therapy.

(vi) Correct dehydration and acidosis withsaline + sod. bicarbonate/lactate infusion.

Vitamins are nonenergy yielding organic com-pounds, essential for normal human metabolism,that must be supplied in small quantities in thediet. This definition excludes the inorganicessential trace minerals and essential amino acidsand fatty acids which are required in much largerquantities.

The importance of vitamins as drugs is pri-marily in the prevention and treatment ofdeficiency diseases. Deficiency of many vitaminsproduces oro-dental manifestations, i.e.• Stomatitis/glossitis/sore mouth/ oral ulcers

in riboflavin, niacin, pyridoxine or vit Adeficiency.

• Spongy and bleeding gums/gingivitis/looseand deformed teeth in vit C deficiency.As such, dentists have the responsibility to

recognise and treat these deficiencies.Some vitamins do have other empirical uses

in pharmacological doses. Vitamins, as a class,are overpromoted, over- prescribed and overused.Myths like ‘they energise the body’, ‘any physicalillness is accompanied by vitamin deficiency’,‘vitamin intake in normal diet is precariouslymarginal’, ‘they are harmless’ are rampant.

Vitamins are traditionally divided into twogroups:

(a) Fat soluble (A, D, E, K): These (except vit K)are stored in the body for prolonged periods andare liable to cause cumulative toxicity after regularingestion of large amounts. Some interact withspecific cellular receptors analogous to hormones.

Table 20.1: Chemical forms, stability and daily allowanceof vitamins

Vitamin Chemical forms Thermostability Daily allowance(adult males)

Fat-soluble vitamins

Retinol (A1) Stable in 1000 μgA Dehydroretinol (A2) absence of air (4,000 IU)

β-Carotene (provit.)

Calciferol (D2) Stable 5 μgD Cholecalciferol (D3) (200 IU)

Calcitriol 1 μg

E α-Tocopherol Stable; air & UV 10 mglight decompose

Phytonadione (K1) Stable, 50–100 μg(Phylloquinone) decomposed

K Menaquinones (K2) by lightMenadione (K3)Acetomenaphthone

Water-soluble vitamins

B1 Thiamine Relatively labile 1.5 mg

B2 Riboflavin Relatively stable 1.7 mg

Nicotinic acidB3 Nicotinamide Niacin Stable 20 mg

Tryptophan (provit.)

Pyridoxine Stable in 2 mgB6 Pyridoxal absence of air

Pyridoxamine

Pantothenic acid Labile 4–7 mg

Biotin Stable 0.1–0.2 mg

Folic acid Labile 0.2 mgFolinic acid

B12 Cyanocobalamin Stable 2 μgHydroxocobalaminMethylcobalamin

C Ascorbic acid Labile in 60 mgsolution

}

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(b) Water soluble (B complex, C): These are mea-gerly stored: excess is excreted with little chanceof toxicity. They act as cofactors for specificenzymes of intermediary metabolism.

Vitamin D (Ch. 16), vit K, folic acid and B12

(Ch. 17) have already been considered. Somerelevant information is tabulated in Table 20.1.

FAT-SOLUBLE VITAMINS

VITAMIN A

Vitamin A occurs in nature in several forms, viz.retinol, retinal, dehydroretinal in fish liver oils,egg, milk, butter. The plant pigment β carotene isa provitamin found in carrot, turnip, spinach, etc.

Retinol is absorbed from the intestines by acarrier-mediated transport. Absorption is aidedby bile and is normally complete. Retinol estercirculates in chylomicrons and is stored in livercells. Free retinol released by hepatocytescombines with retinol binding protein (RBP aplasma globulin) and is transported to the targetcells. On entering them, it gets bound to the cellularretinol binding protein (CRBP). Small amount isconjugated with glucuronic acid, excreted in bile,undergoes enterohepatic circulation.

In contrast to retinol, only 30% of dietary βcarotene is absorbed. It is split into two moleculesof retinal in the intestinal wall; only half of this isreduced to retinol and utilized.

Physiological role and actions

(a) Visual cycle Retinal generated by reversibleoxidation of retinol is a component of the lightsensitive pigment Rhodopsin which is synthesizedby rods during dark adaptation. This pigment getsbleached and split into its components by dimlight and in the process generates a nerve impulse.Retinal so released is reutilized. In vit. A deficiencyrods are affected more than cones; irreversiblestructural changes with permanent nightblindness occur if the deprivation is long term.

(b) Epithelial tissue Vit A promotes differentia-tion and maintains structural integrity of epithelia

all over the body. It also promotes mucussecretion, inhibits keratinization and improvesresistance to infection. It appears to have theability to retard development of malignancies ofepithelial structures. Vit A is also required forbone growth.

(c) Reproduction Retinol is needed for mainte-nance of spermatogenesis and foetal development.

(d) Immunity Increased susceptibility to infec-tion occurs in vit A deficiency. Physiologicalamount of vit A appears to be required for properantibody response, normal lymphocyte prolife-ration and killer cell function.

Deficiency and use Vit A deficiency is quiteprevalent, especially among infants and childrenin developing countries. Manifestations are:• Xerosis (dryness) of eye, ‘Bitot’s spots’, kerato-

malacia (softening of cornea), corneal opacities,night blindness (nyctalopia) progressing tototal blindness.

• Dry and rough skin with papules (phryno-derma), hyperkeratinization, atrophy of sweatglands.

• Keratinization of bronchopulmonary epithe-lium, increased susceptibility to infection.

• Unhealthy gastrointestinal mucosa, diarrhoea.• Increased tendency to urinary stone formation

due to shedding of ureteric epithelial lining.• Sterility due to faulty spermatogenesis,

abortions, foetal malformations.

Fig. 20.1: The role of vit A in visual cycle

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• Growth retardation, impairment of specialsenses.Vit A is used for prophylaxis (3,000–5,000 IU/

day) and treatment (50,000–100,000 IU for 1–3days) of vit A deficiency. Retinoic acid and 2nd or3rd generation retinoids are used for acne, psoriasis.

Hypervitaminosis A Regular ingestion of gross excess ofretinol (100,000 IU daily for months) has producedtoxicity—nausea, vomiting, itching, erythema, dermatitis,exfoliation, hair loss, bone and joint pains, loss of appetite,irritability, bleeding, increased intracranial tension andchronic liver disease. Excess retinol is also teratogenic in ani-mals and man. Daily intake should not exceed 20,000 IU.

Acute poisoning has been described after consumptionof polar bear liver which contains 30,000 IU/g vit A.

Retinoic acid (vit A acid) Retinoic acid has vitA activity in epithelial tissues and promotesgrowth, but is inactive in eye and reproductiveorgans. All-trans retinoic acid (Tretinoin) is usedtopically, while 13–cis retinoic acid (Isotretinoin)is given orally for acne.

Retinoid receptors Retinol and retinoic acidact through nuclear retinoid receptors whichfunction in a manner analogous to the steroidreceptors: activation results in modulation ofprotein synthesis. Two distinct families of retinoidreceptors, viz. Retinoic acid receptors (RARs) andRetinoid X receptors (RXRs) have been identifiedwith differing affinities for different retinoids.

VITAMIN E

A number of tocopherols, of which α tocopherolis the most abundant and potent, have vit Eactivity. Wheat germ oil is the richest source,others are cereals, nuts, spinach and egg yolk.

Vit E is absorbed from intestine through lymphwith the help of bile; it circulates in plasma inassociation with β-lipoprotein, is stored in tissuesand excreted slowly in bile and urine asmetabolites.

Physiological role and actions Vit E acts asantioxidant, protecting unsaturated lipids in cellmembranes, coenzyme Q, etc. from free radicaloxidation damage and curbing generation of toxic

peroxidation products. However, vit E might behaving some more specific action or a structuralrole in biological membranes.

Deficiency Experimental vit E deficiency inanimals produces recurrent abortion, degenera-tive changes in spinal cord, skeletal muscles andheart, and haemolytic anaemia. No clear-cut vit Edeficiency syndrome has been described inhumans, but vit E deficiency has been implicatedin certain neuromuscular diseases in children,neurological defects in hepatobiliary disease andsome cases of haemolytic anaemia.

Supplemental doses of vit E have been givenprophylactically to patients with hepatobiliarydisease, haemolytic anaemia, to premature infantsand subjects with G-6-PD deficiency oracanthocytosis.

Large doses (400–600 mg/day) have beenreported to afford symptomatic improvement inintermittent claudication, fibrocystic breastdisease and nocturnal muscle cramps.

For its antioxidant property, vit E has beenpromoted for recurrent abortion, sterility, meno-pausal syndrome, toxaemia of pregnancy,atherosclerosis, ischaemic heart disease, cancerprevention, several skin diseases, prevention ofneurodegenerative disorders, and many otherconditions, but without convincing evidence ofbenefit.

Toxicity Even large doses of vit E for long periodshave not produced any significant toxicity, butcreatinuria and impaired wound healing havebeen reported; abdominal cramps, loose motionsand lethargy have been described as side effectsof vit E.

Vit E can interfere with iron therapy.

WATER-SOLUBLE VITAMINS

THE VITAMIN B COMPLEX GROUP

Thiamine (Aneurine, B1)

Thiamine is a pyrimidine compound present inthe outer layers of cereals (rice polishing), pulses,nuts, green vegetables, yeasts, egg and meat.

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Physiological amounts are absorbed by activetransport. When large doses are given orally, somepassive diffusion also occurs. Limited amountsare stored in tissues; excess is rapidly excreted inurine.

Physiological role After conversion in the bodyto Thiamine pyrophosphate, it acts as a coenzymein carbohydrate metabolism: decarboxylation ofketoacids and hexose monophosphate shunt.Requirement is dependent upon carbohydrateintake. It also appears to play some role inneuromuscular transmission.

Deficiency symptoms The syndrome of thiaminedeficiency beriberi is seen in dry and wet forms:

Dry Beriberi: Neurological symptoms are promi-nent—polyneuritis with numbness, tingling,hyperesthesia, muscular weakness and atrophyresulting in ‘wrist drop’, ‘foot drop’, mentalchanges, sluggishness, poor memory, loss ofappetite and constipation.

Wet Beriberi: Cardiovascular system is primarilyaffected—palpitation, breathlessness, high out-put cardiac failure and ECG changes. Proteindeficiency is commonly associated and adds tothe generalised anasarka due to CHF.

Therapeutic uses

1. Prophylactically (2–10 mg daily) in infants,pregnant women, chronic diarrhoeas, patients onparenteral alimentation.2. Beriberi—100 mg/day i.m. or i.v.3. Chronic alcoholics: Most neurological symp-toms are due to thiamine deficiency.4. In neurological and cardiovascular disorders,hyperemesis gravidarum, chronic anorexia andobstinate constipation—symptoms improvedramatically if thiamine deficiency has beencausative.

Thiamine is nontoxic.

Riboflavin (B2)

Riboflavin is a yellow flavone compound foundin milk, egg, liver, green leafy vegetables, grains.

It is well absorbed by active transport andphosphorylated in the intestine. Riboflavinphosphate (Flavin mononucleotide: FMN) isformed in other tissues as well. Body does notsignificantly store riboflavin; larger doses areexcreted unchanged in urine.

Actions and physiological role Flavin adeninedinucleotide (FAD) and flavin mononucleotide(FMN) are coenzymes for flavoproteins involvedin many oxidation-reduction reactions.

Deficiency symptoms Riboflavin deficiencygenerally occurs in association with otherdeficiencies. Characteristic lesions are angularstomatitis; sore and raw tongue, lips, throat, ulcersin mouth; vascularization of cornea. Dry scalyskin, loss of hair; anaemia and neuropathydevelop later.

Riboflavin is used only to prevent and treatariboflavinosis.

Niacin (B3)

Niacin refers to Nicotinic acid as well asNicotinamide—pyridine compounds found inliver, fish, meat, cereal husk, nuts and pulses. Theamino acid tryptophan (mainly from animalprotein) can be regarded as a provitamin, as it ispartially converted in the body to nicotinic acid.

Niacin is completely absorbed from gastro-intestinal tract. Physiological amounts aremetabolized in the body, while large doses areexcreted unchanged in urine. Modest amountsare stored in liver.

Physiological role and actions Nicotinic acid isreadily converted to its amide which is a compo-nent of the coenzyme Nicotinamide-adenine-dinucleotide (NAD) and its phosphate (NADP)involved in oxidation-reduction reactions. Thesepyridine nucleotides act as hydrogen acceptorsin the electron transport chain in tissue respira-tion, glycolysis and fat synthesis.

Nicotinic acid (but not nicotinamide) in largedoses is a vasodilator, particularly of cutaneousvessels. It also lowers plasma lipids.

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Deficiency symptoms Niacin deficiency produ-ces ‘Pellagra’, cardinal manifestations of whichare: Dermatitis—sun burn like dermal rash onhands, legs and face, Diarrhoea—with enteritis,stomatitis, glossitis, and Dementia—withhallucinations preceded by headache, insomnia,poor memory, motor and sensory disturbances.

Anaemia and hypoproteinaemia are commonin pellagra. Chronic alcoholics are particularlyat risk of developing pellagra.

Therapeutic uses

1. Prophylaxis and treatment of pellagra.Nicotinamide is preferred because it does notcause flushing and other side effects seen withnicotinic acid.2. Hartnup’s disease: in which tryptophantransport is impaired.3. Nicotinic acid (not nicotinamide) has beenused in peripheral vascular disease and ashypolipidaemic drug (Ch. 17).

Adverse effects Nicotinic acid, in pharmacolo-gical doses, has many side effects and toxicities(p. 273). Nicotinamide is innocuous.

Pyridoxine (B6)

Pyridoxine, Pyriodoxal and Pyridoxamine arerelated naturally occurring pyridine compoundsthat have vit B6 activity. Dietary sources are—liver,meat, egg, soybean, vegetables and whole grain.All three forms of the vitamin are well absorbedfrom the intestine. They are oxidized in the bodyand excreted as pyridoxic acid. Little is stored.

Physiological role and actions Pyridoxine andpyridoxamine are readily oxidized to pyridoxalwhich is then phosphorylated to pyridoxalphosphate—the coenzyme form. Pyridoxal depen-dent enzymes include transaminases and decar-boxylases involved in synthesis and metabolismof amino acids, formation of 5-HT, dopamine,histamine, GABA and aminolevulinic acid (firststep in synthesis of haeme). High protein dietincreases pyridoxine requirement.

Prolonged intake of large doses of pyridoxinecan suppress lactation, give rise to dependence,and has been linked with sensory neuropathy.Otherwise, pyridoxine is free from pharma-cological actions and side effects.

Drug interactions

1. Isoniazid reacts with pyridoxal to form ahydrazone, and thus inhibits generation ofpyridoxal phosphate. Isoniazid also combineswith pyridoxal phosphate to interfere with itscoenzyme function. Due to formation ofhydrazones, the renal excretion of pyridoxinecompounds is increased. Thus, isoniazid therapyproduces a pyridoxine deficiency state.2. Hydralazine, cycloserine and penicillaminealso interfere with pyridoxine utilization andaction.3. Pyridoxine, by promoting formation ofdopamine from levodopa in peripheral tissues,reduces its availability in the brain, abolishingthe therapeutic effect in parkinsonism.

Deficiency symptoms Deficiency of vit B6

usually occurs in association with that of other Bvitamins. Symptoms ascribed to pyridoxinedeficiency are—seborrheic dermatitis, glossitis,growth retardation, mental confusion, loweredseizure threshold or convulsions, peripheralneuritis and anaemia.

Therapeutic uses

1. Prophylactically (2–5 mg daily) in alcoholicsand patients with deficiency of other B vitamins.2. To prevent and treat (10–50 mg/day)isoniazid, hydralazine and cycloserine inducedneurological disturbances.3. Pyridoxine responsive anaemia (due todefective haeme synthesis) and homocystinuriaare rare genetic disorders that are benefited bylarge doses of pyridoxine.

VITAMIN C (ASCORBIC ACID)

Ascorbic acid is a 6 carbon organic acid withstructural similarity to glucose. It is a potent

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reducing agent and the l-form is biologicallyactive. Citrus fruits (lemons, oranges) and blackcurrants are the richest sources; others are tomato,potato, green chilies, cabbage and othervegetables.

Ascorbic acid is nearly completely absorbedfrom g.i.t. and widely distributed extra-andintracellularly. Increasing proportions are excre-ted in urine with higher intakes and body is notable to store more than 2.5 g. It is partly oxidizedto active (dehydroascorbic acid) and inactive(oxalic acid) metabolites.

Physiological role and actions Vit C plays arole in many oxidative and other metabolicreactions, e.g. hydroxylation of proline and lysineresidues of protocollagen—essential for forma-tion and stabilization of collagen; conversion offolic acid to folinic acid, biosynthesis of adrenalsteroids, catecholamines, oxytocin and ADH aswell as metabolism of cyclic nucleotides andprostaglandins.

Deficiency symptoms Severe vit C deficiencyScurvy, once prevalent among sailors is now seenonly in malnourished infants, children, elderly,alcoholics and drug addicts. Symptoms stemprimarily from connective tissue defect: increa-sed capillary fragility—swollen and bleeding

gums, petechial and subperiosteal haemorrhages,deformed teeth, brittle bones, impaired woundhealing, anaemia and growth retardation.

Therapeutic uses

1. Prevention of ascorbic acid deficiency inindividuals at risk (see above) and in infants:50–100 mg/ day.2. Treatment of scurvy—0.5–1.5 g/day.3. Postoperatively (500 mg daily): though vit Cdoes not enhance normal healing, suboptimalhealing can be guarded against.4. Anaemia: Ascorbic acid enhances ironabsorption and is frequently combined withferrous salts. Anaemia of scurvy is corrected byascorbic acid.5. To acidify urine (1 g TDS-QID) in urinary tractinfections.6. Large doses (2–6 g/day) of ascorbic acid havebeen tried for a variety of purposes (common coldto cancer) with inconsistent results. Severity ofcommon cold symptoms may be somewhatreduced, but not the duration of illness or itsincidence.

Adverse effects Ascorbic acid is well toleratedin usual doses. Mega doses given for long periodscan cause ‘rebound scurvy’ on stoppage. The riskof urinary oxalate stones may be increased.

ANTICANCER DRUGS

The anticancer drugs either kill cancer cells ormodify their growth. However, selectivity ofmajority of drugs is limited and they are one ofthe most toxic drugs used in therapy. Cancerchemotherapy is now of established value and ahighly specialized field; only the generalprinciples and an outline will be presented here.

In addition to their prominent role in leukae-mias and lymphomas, drugs are used in con-junction with surgery, radiotherapy andimmunotherapy in the combined modality approachfor many solid tumours, especially metastatic.

Cancer chemotherapy is employed for:1. Cure or prolonged remission: as the primary

treatment modality.2. Palliation: Shrinkage of the tumour, allevia-

tion of symptoms and/or prolongation of life.3. Adjuvant chemotherapy: to mop up any

residual malignant cells after surgery orradiotherapy.

CLASSIFICATION

A. Drugs acting directly on cells(Cytotoxic drugs)

1. Alkylating agents MechlorethamineNitrogen mustards Cyclophosphamide

IfosfamideChlorambucilMelphalan

Alkyl sulfonate BusulfanNitrosoureas Lomustine (CCNU)Triazine Dacarbazine (DTIC)

2. AntimetabolitesFolate antagonist Methotrexate (Mtx)Purine 6-Mercaptopurine (6-MP)antagonist 6-Thioguanine (6-TG)

Azathioprine, FludarabinePyrimidine 5-Fluorouracil (5-FU)antagonist Cytarabine

3. Vinca alkaloids Vincristine (Oncovin)Vinblastine

4. Taxanes Paclitaxel, Docetaxel5. Epipodophyllo- Etoposide

toxin6. Camptothecin Topotecan,

analogues Irinotecan7. Antibiotics Actinomycin D

DoxorubicinDaunorubicinBleomycins

8. Miscellaneous HydroxyureaProcarbazineL-AsparaginaseCisplatin, CarboplatinImatinib

B. Drugs altering hormonal milieu

1. Glucocorticoids Prednisolone and others2. Estrogens Ethinylestradiol

Fosfestrol

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3. Selective estrogen Tamoxifen, Toremifenereceptor modulators

4. Selective estrogen Fulvestrantreceptordown regulator

5. Aromatase Letrozoleinhibitors Anastrozole

6. Antiandrogen Flutamide, Bicalutamide7. 5-α reductase Finasteride

inhibitor Dutasteride8. GnRH Nafarelin, Triptorelin

analogues9. Progestins Hydroxyprogesterone

acetate, etc.

General toxicity of cytotoxic drugs

Majority of the cytotoxic drugs have moreprofound effect on rapidly multiplying cells,because the most important target of action arethe nucleic acids and their precursors; rapidnucleic acid synthesis occurs during cell division.Many cancers (especially large solid tumours)have a lower growth fraction (lower percentageof cells are in division) than normal bonemarrow, epithelial linings, reticuloendothelial(RE) system and gonads. These tissues areparticularly affected in a dose-dependentmanner by majority of drugs; though there aredifferences in susceptibility to individualmembers.

1. Bone marrow Depression of bone marrowresults in granulocytopenia, agranulocytosis,thrombocytopenia, aplastic anaemia. This is themost serious toxicity; often limits the dose thatcan be employed. Infections and bleeding are theusual complications.

2. Lymphoreticular tissue Lymphocytopeniaand inhibition of lymphocyte function results insuppression of cell mediated as well as humoralimmunity.

Because of action (1) and (2) + damage toepithelial surfaces, the host defence mechanisms(specific as well as nonspecific) are broken down→ susceptibility to all infections is increased. Of

particular importance are the opportunisticinfections due to low pathogenicity organisms,e.g. Candida, Pneumocystis carinii and other fungi,Herpes zoster, cytomegalovirus, Toxoplasma.

3. GIT Stomatitis, diarrhoea, shedding ofmucosa, haemorrhages occur due to decrease inthe rate of renewal of the mucous lining. Drugsthat frequently cause mucositis are—bleomycin,actinomycin D, daunorubicin, doxorubicin,fluorouracil and methotrexate.

Nausea and vomiting are prominent withmany cytotoxic drugs. This is due to direct stimu-lation of CTZ by the drug as well as generationof emetic impulses/mediators from the upperg.i.t. and other areas.

The emetogenic potential of cytotoxic drugs maybe graded as:

High Moderate Mild

Cisplatin Carboplatin BleomycinMustine Cytarabine ChlorambucilCyclophosphamide Procarbazine BusulfanActinomycin D Vinblastine FluorouracilDacarbazine Doxorubicin 6-ThioguanineLomustine Daunorubicin Hydroxyurea

6-Mercapto- Vincristinepurine Methotrexate

Etoposidel-Asparaginase

4. Skin Alopecia occurs due to damage to thecells in hair follicles. Dermatitis is anothercomplication.

5. Gonads Inhibition of gonadal cells causesoligozoospermia and impotence in males;inhibition of ovulation and amenorrhoea arecommon in females.

6. Foetus Practically all cytotoxic drugs givento pregnant women profoundly damage thedeveloping foetus → abortion, foetal death,teratogenesis.

7. Carcinogenicity Secondary cancers, espe-cially leukaemias, lymphomas and histocytictumours appear with greater frequency manyyears after the use of cytotoxic drugs. This may

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be due to depression of cell mediated andhumoral blocking factors against neoplasia.

8. Hyperuricaemia This is secondary tomassive cell destruction (uric acid is a productof purine metabolism). Gout and urate stones inthe urinary tract may develop. Allopurinol isprotective by decreasing uric acid synthesis.

In addition to these general toxicities,individual drugs may produce specific adverseeffects, e.g. neuropathy by vincristine, cardio-myopathy by doxorubicin, cystitis and alopeciaby cyclophosphamide.

Oral complications of cancer chemotherapy

The oral mucosa is particularly susceptible tocytotoxic drugs because of high epithelial cellturnover. Many chemotherapeutic drugs pro-duce oral lesions. Oral mucositis is often an earlymanifestation of toxicity. The gingival tissue andoral mucosa are regularly subjected to minortrauma during chewing, and breaches arecommon. Oral microbial flora is large and canbe the source of local (e.g. periodontal abscess)as well as blood-borne infection. Neutropeniaand depression of immunity caused by the drugindirectly increase the chances of oral infections,particularly those caused by low grade patho-gens such as Candida, Serratia, Pseudomonas, etc.Thrombocytopenia due to bone marrow depres-sion may cause gingival or mucosal bleeding.Antifibrinolytic drugs like epsilon aminocaproicacid or tranexaemic acid may help check thebleeding. Platelet transfusion is required if theplatelet count is very low. Xerostomia (causingrapid progression of dental caries) and angularcheilitis are the other problems associated withchemotherapy. Administered to children duringtooth development, cancer chemotherapy maycause hypoplasia of tooth, blunting of roots andeven tooth agenesis.

Many of the oral/dental complications ofchemotherapy can be minimized by a thoroughdental check-up before starting the regimen. Anycarious cavities, periodontal lesions, impactedlast molars and other potential sources of

infection should be appropriately treated. Allsharp cusps or dentures should be smoothenedto avoid injury. Good oral hygiene should bemaintained throughout the course. Topical useof fluoride can retard caries development.

Stomatitis and oral ulcers can be treatedwith chlorhexidine mouthwash. Nystatin orclotrimazole lotion may be used for Candidainfection. As mucositis progresses, oral lesionsbecome increasingly painful and may interferewith eating. Topical application of sucralfate andmesoprostol may afford some relief. Benzocainelozenges or lidocaine gel can reduce pain butmay interfere with taste and increase the risk ofinjury to oral mucosa. Opioid analgesics mayhave to be prescribed. Chemotherapy candamage taste buds and cause loss of tastesensation. Systemic antibiotics to coverorganisms like Pseudomonas, Klebsiella, E.coli areoften needed in addition to those for gram-positive cocci and anaerobes in case ofchemotherapy related oral infections.

In a patient receiving chemotherapy, anydental procedure should be undertaken onlyafter giving due regard to his/her immune andhaemostatic status and in consultation with thepatient’s physician. Appropriate prophylacticantibiotic to eliminate the risk of infection isimportant, since infections can easily set in orget disseminated in subjects compromised by thechemotherapy.

NOTES ON DRUGS

Alkylating agents

These compounds produce highly reactivecarbonium ion intermediates which transferalkyl groups to cellular macromolecules byforming covalent bonds. The position 7 ofguanine residues in DNA is specially susceptible,but other molecular sites are also involved. Thisresults in cross linking/abnormal base pairing/scission of DNA strand. Cross linking of nucleicacids with proteins can also take place.

Alkylating agents have cytotoxic and radio-mimetic (like ionizing radiation) actions. Many

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are cell cycle non-specific, i.e. act on dividing aswell as resting cells. Some have CNS stimulantand cholinergic properties.

Cyclophosphamide is the most commonly usedalkylating agent, effective in a wide range oftumours, and has prominent immunosuppres-sant action. Chloramphenicol increases its toxi-city by inhibiting its metabolism. Chlorambucil isselective for lymphoid tissue and is used formaintenance therapy in chronic lymphocyticleukaemia and Hodgkin’s disease. Busulfan isselective for myeloid elements and the drug ofchoice for chronic myeloid leukaemia. Melphalanis very effective in multiple myeloma. Lomustineis highly lipid soluble and especially valuablefor brain tumours and meningeal leukaemia. Themost important indication of dacarbazine ismalignant melanoma; also useful in Hodgkin’sdisease.

Antimetabolites

These are analogues related to the normalcomponents of DNA or of coenzymes involvedin nucleic acid synthesis. They competitivelyinhibit utilization of normal substrate or getthemselves incorporated forming dysfunctionalmacromolecules.

1. Folate antagonistMethotrexate (Mtx) is one of the oldest and highlyefficacious antineoplastic drugs; inhibits dihy-drofolate reductase (DHFRase)—blocking theconversion of dihydrofolic acid (DHFA) totetrahydrofolic acid (THFA) which is an essentialcoenzyme required for one carbon transferreactions in de novo purine synthesis and aminoacid interconversions. The inhibition is pseudo-irreversible because Mtx has 50,000 times higheraffinity for the enzyme than the normalsubstrate.

Methotrexate has cell cycle specific action—kills cells in S phase; primarily inhibits DNAsynthesis, but also affects RNA and proteinsynthesis. It exerts major toxicity on bonemarrow.

Aspirin and sulfonamides decrease its renaltubular secretion—enhancing its toxicity.

The toxicity of Mtx cannot be overcome byfolic acid, because it will not be converted to theactive coenzyme form. However, Folinic acid (N5formyl THFA, cirtrovorum factor) rapidlyreverses the effects. High dose Mtx with ‘folinicacid rescue’ has been employed in manydifficult-to-treat neoplasms. Mtx is used inchoriocarcinoma, acute leukaemia, carcinoma oftongue/pharynx/lung, etc. and as immuno-suppressant in rheumatoid arthritis, psoriasis,organ transplantation.

2. Purine antagonists

Mercaptopurine (6-MP) and thioguanine (6-TG) arehighly effective antineoplastic drugs. They areconverted in the body to the correspondingmonoribonucleotides which inhibit purinesynthesis and utilization of purine nucleotides.

They are specially useful in childhood acuteleukaemia, choriocarcinoma and in some solidtumours.

Azathioprine has marked effect on T-lympho-cytes, suppresses cell-mediated immunity (CMI)and is used primarily as immunosuppressant inorgan transplantation, rheumatoid arthritis, etc.

Azathioprine and 6-MP are metabolized byxanthine oxidase; their metabolism is inhibitedby allopurinol; dose has to be reduced to ¼–½ ifallopurinol is given concurrently. Thioguanineis not a substrate for xanthine oxidase; its doseneed not be reduced if allopurinol is given.

The main toxicity of antipurines is bonemarrow depression. Jaundice and hyperuricae-mia are also prominent.

3. Pyrimidine antagonists

Fluorouracil (5-FU) is converted in the body tothe corresponding nucleotide which blocks theconversion of deoxyuridilic acid to deoxythymi-dylic acid. Selective failure of DNA synthesisoccurs due to non-availability of thymidylate:thymidine can partially reverse its toxicity.Fluorouracil itself gets incorporated into nucleicacids and this may contribute to its toxicity.

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It has been particularly used for many solidtumours—breast, colon, urinary bladder, liver,etc. Topical application in cutaneous basal cellcarcinoma has yielded gratifying results.

Cytarabine is phosphorylated in the body tothe corresponding nucleotide which inhibitsDNA synthesis by DNA polymerase. It is cellcycle specific and acts primarily during S phase.Its main use is to induce remission in acuteleukaemia in children, also in adults. Other usesare—Hodgkin’s disease and non-Hodgkinlymphoma.

Vinca alkaloids

These are mitotic inhibitors, bind to microtubularprotein—‘tubulin’, prevent its polymerizationand assembly of microtubules, cause disruptionof mitotic spindle and interfere with cytoskeletalfunction. The chromosomes fail to move apartduring mitosis: metaphase arrest occurs. Theyare cell cycle specific and act in the mitotic phase.

Vincristine (oncovin) is very useful for indu-cing remission in childhood acute leukaemia.Other indications are lymphosarcoma, Hodgkin’sdisease, Wilms’ tumour, Ewing’s sarcoma andcarcinoma lung. Prominent adverse effects areperipheral neuropathy and alopecia. Bonemarrow depression is minimal.

Vinblastine is primarily employed with otherdrugs in Hodgkin’s disease and testicularcarcinoma. Bone marrow depression is moreprominent, while neurotoxicity and alopecia areless marked than with vincristine.

Taxanes

Paclitaxel is obtained from bark of the Westernyew tree, which exerts cytotoxic action by a novelmechanism. It enhances polymerization oftubulin: a mechanism opposite to that of vincaalkaloids. This results in inhibition of normaldynamic reorganization of the microtubulenetwork that is essential for vital interphase andmitotic functions.

The indications of paclitaxel are metastaticovarian and breast carcinoma after failure of first

line chemotherapy and relapse cases. It has alsoshown efficacy in advanced cases of head andneck cancer, small cell lung cancer, esophagealadenocarcinoma, etc.

The major toxicity is reversible myelosup-pression and ‘stocking and glove’ neuropathy.Chest pain, arthralgia, myalgia, mucositis andedema can be troublesome.

Docetaxel is a more potent congener ofpaclitaxel found effective in breast and ovariancancer refractory to first line drugs. Small cellcancer lung, pancreatic, gastric and head/neckcarcinomas are the other indications. Majortoxicity is neutropenia, but neuropathy is lessfrequent.

Epipodophyllotoxins

Etoposide is a semisynthetic derivative ofpodophyllotoxin, a plant glycoside. It is not amitotic inhibitor, but arrests cells in the G2 phaseand causes DNA breaks by affecting DNA topoi-somerase II function. It has been primarily usedin testicular tumours, lung cancer, Hodgkin’sand other lymphomas, carcinoma bladder.

Camptothecin analogues

Topotecan and Irinotecan are two semisyntheticanalogues of camptothecin, an antitumourprinciple obtained from a Chinese tree. They actin a manner similar to etoposide, but interactwith a different enzyme DNA topoisomerase I.

Topotecan is used in metastatic carcinoma ofovary and small cell lung cancer after primarychemotherapy has failed. The major toxicity isbone marrow depression, especially neutropenia.

Irinotecan is a prodrug which is indicated inmetastatic/advanced colorectal carcinoma,cancer lung/cervix/ovary, etc. Dose limitingtoxicity is diarrhoea.

Antibiotics

These are products obtained from microorga-nisms and have prominent antitumour activity.Practically, all of them intercalate between DNAstrands and interfere with its template function.



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Actinomycin D (Dactinomycin) is highlyefficacious in Wilms’ tumour and rhabdomyo-sarcoma and has produced good results in a fewother malignancies. Prominent adverse effectsare vomiting, stomatitis, diarrhoea, erythemaand desquamation of skin, alopecia and bonemarrow depression.

Daunorubicin (Rubidomycin) and Doxorubicinare antitumour antibiotics with quite similarchemical structures. However, utility of dauno-rubicin is limited to acute leukaemia while doxo-rubicin, in addition, is effective in many solidtumours. They are capable of causing breaks inDNA strands by activating topoisomerase II andgenerating quinone-type free radicals. They havemutagenic and carcinogenic potential.

Both these antibiotics produce cardiotoxicity(arrhythmias, cardiomyopathy—heart failure) asa unique adverse effect. Marrow depression, alo-pecia, stomatitis are the other toxic effects.

Bleomycin chelates copper or iron, producessuperoxide ions and intercalates between DNAstrands—causes chain scission and inhibitsrepair. It is highly effective in testicular tumourand squamous cell carcinoma of skin, oral cavity,head and neck, and esophagus; also useful inHodgkin’s lymphoma.

Mucocutaneous toxicity and pulmonaryfibrosis, but little myelosuppression are thespecial features.

Miscellaneous cytotoxic drugs

Hydroxyurea blocks the conversion of ribonuc-leotides to deoxyribonucleotides—thus inter-feres with DNA synthesis; exerts S-phase specificaction. Its primary therapeutic value is in chronicmyeloid leukaemia, psoriasis, polycythaemiavera and in some solid tumours. Myelosup-pression is the major toxicity.

Procarbazine After metabolic activation (it isinactive as such), procarbazine depolymerizesDNA and causes chromosomal damage. It is acomponent of the popular MOPP regimen forHodgkin’s disease. It is also useful in non-

Hodgkin lymphomas and oat cell carcinoma oflung.

Procarbazine is a weak MAO inhibitor,produces some CNS effects and interacts withfoods and drugs. Alcohol causes hot flushing anda disulfiram like reaction in patients receivingprocarbazine.

L-Asparaginase is selectively toxic to childhoodlymphoblastic leukaemia cells, because they aredeficient in L-asparagine synthetase and thusdependent on supply of L-asparagine from themedium. However, clinical response to L-aspara-ginase is short lasting. It can cause liver damageand allergic reactions, but mucositis, bonemarrow depression and alopecia do not occur.

Cisplatin is a platinum coordination complex thatis hydrolysed intracellularly to produce a highlyreactive moiety which causes cross linking ofDNA. It can also react with –SH groups inproteins and has radiomimetic property.

Cisplatin is very effective in metastatic testi-cular and ovarian carcinoma. It has found usein many other solid tumours as well.

Cisplatin is a highly emetic drug. The mostimportant toxicity is renal impairment. Tinnitus,deafness, neuropathy and hyperuricaemia areother problems. A shock like state sometimesoccurs during i.v. infusion.

Carboplatin is a less reactive second generationplatinum compound that is better tolerated andhas a toxicity profile different from cisplatin.Nephrotoxicity, ototoxicity and neurotoxicity arelow. Nausea and vomiting is milder. The doselimiting toxicity is thrombocytopenia and lessoften leucopenia. It is primarily indicated inovarian carcinoma, and has shown promise insquamous carcinoma of head and neck, smallcell lung cancer and seminoma.

Imatinib It is a novel antineoplastic drug whichacts by inhibiting certain protein kinases,especially that found in chronic myeloidleukaemia (CML) cells. Remarkable efficacy hasbeen noted in CML and in some gastrointestinalstromal tumours.

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HORMONES

They are not cytotoxic, but modify the growthof hormone-dependent tumours. All hormonesare only palliative.

Glucocorticoids have marked lympholyticaction—are primarily used in acute childhoodleukaemia and lymphomas. They induceremission rapidly but relapses inevitably occurafter variable intervals and gradually the respon-siveness is lost. Considerable palliative effectsare obtained in Hodgkin’s disease and they havea secondary role in some hormone responsivebreast cancers.

Corticosteroids are also valuable for thecontrol of complications like hypercalcaemia,haemolysis and bleeding due to thrombocyto-penia. Moreover, they afford symptomatic reliefby antipyretic and mood elevating action andpotentiate the antiemetic action of ondansetron/metoclopramide.

Estrogens produce symptomatic relief in carci-noma prostate, which is an androgen-dependenttumour. However, relapses eventually occur, butlife is prolonged. Estrogens have now beensuperseeded by GnRH agonists used with anantiandrogen.

Many breast cancers have estrogen receptorsin their cells. These respond to estrogens/antiestrogens.

Selective estrogen receptor modulators (tamoxifen),Selective estrogen receptor down regulator(fulvestrant) and Aromatase inhibitors (letrozole,etc.) are the sheet anchor of adjuvant andpalliative therapy of carcinoma breast, as wellas for prevention of breast cancer. These drugsare described in Ch. 15.

Antiandrogen Flutamide and bicalutamide (Ch.15) antagonise androgen action on prostatecarcinoma and have palliative effect inadvanced/metastatic cases. Because theyincrease androgen levels, combination withorchidectomy or GnRH analogues is required toproduce full therapeutic effect.

5-α reductase inhibitor Finasteride and dutas-teride (Ch. 15) inhibit conversion of testosteroneto dihydrotestosterone in prostate and havebeen occasionally used for palliative effect inadvanced carcinoma prostate.

GnRH agonists (see p. 218) They indirectlyinhibit estrogen/androgen secretion by suppres-sing FSH and LH release from pituitary and haveadjuvant/palliative effect in advanced estrogen/androgen dependent carcinoma breast/prostate.

Progestins bring about temporary remission insome cases of advanced, recurrent (aftersurgery/radiotherapy) and metastatic endo-metrial carcinoma.

GENERAL PRINCIPLES INCHEMOTHERAPY OF CANCER

1. In cancer chemotherapy selectivity of drugsfor the tumour cells is limited: toxicity is high.As such, measures to enhance selectivity needto be employed. Immunological defence againstmalignant cells is minimal or absent.2. A single clonogenic malignant cell is capableof producing progeny that can kill the host.Survival time is related to the number of cellsthat escape chemotherapeutic attack.3. In any cancer, subpopulations of cells differin their rate of proliferation and susceptibilityto cytotoxic drugs. These drugs kill cancer cellsby first order kinetics, i.e. a certain fraction ofcells present are killed by one treatment.4. Drug regimens or treatment cycles which caneffectively palliate large tumour burdens maybe curative when applied to minute residualtumour cell population after surgery and/orirradiation. This is the basis of the combinedmodality approach (see Fig. 21.1).5. Whenever possible, complete remissionshould be the goal of cancer chemotherapy: drugsare often used at maximum tolerated doses.Intensive regimens used at an early stage in thedisease yield better results.



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Fig. 21.1: Illustration of cancer cell dynamics with three chemotherapeutic approaches. The shaded area depicts symptoms,before which the cancer remains subclinical. The broken purple line indicates no treatment.A. A rationally designed combination of 2–5 chemotherapeutic drugs (red bar) is given cyclically. Each cycle kills 99%tumour cells, reducing the tumour cell mass by 2 log units each time. Some regrowth occurs during the rest interval, but therate of cell kill is more than regrowth and resistance does not develop. If the cycles are continued well beyond all symptomsdisappear, cure may be achieved. Radiation may be used to supplement chemotherapy.B. The cancer (in case of solid tumours) is resected surgically and the small number of residual cancer cells (at the primarysite or in metastasis) are killed by relatively few cycles of adjuvant combination chemotherapy (blue bar). This may besupplemented by radiation (in case of radiosensitive tumours).C. The chemotherapy is begun relatively late with a single but effective drug given continuously (green bar). It causesslower tumour cell kill, but symptom relief may occur. Resistance soon develops, and the tumour starts regrowing even withcontinued chemotherapy. Symptoms reappear and increase in severity. Ultimately failure of therapy and death occur.

6. Generally a combination of 2–5 drugs is givenin intermittent pulses to achieve total tumour cellkill, giving time in between for normal cells torecover (see Fig. 21.1).

Synergistic combinations and rationalsequences are devised by utilizing:

(a) Drugs which are effective when used alone.(b) Drugs with different mechanisms of action.(c) Drugs with differing toxicities.

(d) Empirically by trial and error; optimalschedules are mostly developed by thisprocedure.

(e) Kinetic scheduling: on the basis of cell cyclespecificity/nonspecificity of drugs and thephase of cell cycle at which a drug exertsits toxicity.

Proliferating cells enter the cell cycle, phasesof which are depicted in the box.

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Cytotoxic drugs are either cell cycle specificor cell cycle nonspecific.

(a) Cell cycle nonspecific Kill resting as well asdividing cells, e.g. mechlorethamine, cyclophos-phamide, chlorambucil, carmustine, dacarba-zine, L-asparaginase, cisplatin, procarbazine,actinomycin D.

(b) Cell cycle specific Kill only actively dividingcells. Their toxicity is generally expressed inS phase. However, these drugs may show consi-derable phase selectivity.

The growth fraction of solid tumours is oftenlow: it is logical to use cell cycle specific drugs inshort courses (pulses) of treatment. This allowsnoncycling cells (which are generally lesssusceptible to drugs) to re-enter the cyclebetween drug courses.7. Tumours often become resistant to the drugused repeatedly due to selection of lessresponsive cells.8. Measures employed to ameliorate the toxicityof anticancer drugs are:• Use of biological response modifiers like recombinant

granulocyte colony stimulating factor (G-CSF) andgranulocyte-macrophage colony stimulating factor (GM-CSF) viz. molgramostim, filgrastim, sargramostim hastenrecovery of neutrophil count following myelosup-pressant chemotherapy.

• Amifostine affords free thiol radical and reduces renaltoxicity of cisplatin.

• Folinic acid rescue can reduce methotrexate toxicity.• Cystitis caused by cyclophosphamide can be blocked

by mesna administered along with it.• Ondansetron ± dexamethasone, lorazepam protect

against cisplatin (and other emetic drugs) inducedvomiting

• Hyperuricaemia due to destruction of bulky tumourscan be reduced by allopurinol.

IMMUNOSUPPRESSANT DRUGS

These are drugs which inhibit cellular/humoralor both immune response and have their majoruse in organ transplantation and autoimmunediseases. The drugs are:

1. Calcineurin inhibitors (Specific T-cell inhibitors)

Cyclosporine, (Ciclosporin), Tacrolimus

2. Antiproliferative drugs (Cytotoxic drugs)Azathioprine, Cyclophosphamide,Methotrexate, Chlorambucil,Mycophenolate mofetil (MMF)Sirolimus

3. GlucocorticoidsPrednisolone and others

4. AntibodiesMuromonab CD3, Antithymocyte globulin(ATG).

The development of immune response and thesites of action of different immunosuppressantdrugs is summarized in Fig. 21.2.

Calcineurin inhibitors(Specific T-cell inhibitors)

Cyclosporine It is a cyclic polypeptide with11 amino acids, obtained from a fungus andintroduced in 1977 as a highly selective immuno-suppressant which has markedly improved thesuccess of organ transplantations. It profoundlyand selectively inhibits T lymphocyte proli-feration, IL-2 and other cytokine production andresponse of inducer T cells to IL-1 without anyeffect on suppressor T-cells.

Phases of cell cycle

Pre (nucleic acid) synthesis interval.

Synthesis of DNA occurs.

Post synthetic interval.

Mitosis occurs—two G1 cells areproduced, which either directly re-enter next cycle or pass into thenonproliferative (G0) phase.

Nonproliferating cells; a fraction ofthese are clonogenic—may remainquiescent for variable periods, butcan be recruited in cell cycle ifstimulated later.

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Fig. 21.2: Generation of humoral and cell-mediated immune response and sites of action of immunosuppressantdrugs

The antigen (Ag) is processed by macrophages or other antigen presenting cells (APC), coupled withclass II major histocompatibility complex (MHC) and presented to the CD4 helper cell which are activated byinterleukin-I (IL-1), proliferate and secrete cytokines—these in turn promote proliferation and differentiationof antigen activated B cells into antibody (Ab) secreting plasma cells. Antibodies finally bind and inactivatethe antigen.

In cell-mediated immunity—-foreign antigen is processed and presented to CD4 helper T cell whichelaborate IL-2 and other cytokines that in turn stimulate proliferation and maturation of precursor cytotoxiclymphocytes (CTL) that have been activated by antigen presented with class I MHC. The mature CTL (Killercells) recognize cells carrying the antigen and lyse them.1. Glucocorticoids inhibit MHC expression and IL-1, IL-2, IL-6 production so that helper T-cells are notactivated.2. Cytotoxic drugs block proliferation and differentiation of T and B cells.3. Cyclosporine and tacrolimus inhibit antigen stimulated activation and proliferation of helper T cells aswell as expression of IL-2 and other cytokines by them.4. Antibodies like muromonab CD3, antithymocyte globulin specifically bind to helper T cells, prevent theirresponse and deplete them

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Cyclosporine enters target cells and binds toa protein called cyclophilin. The complex thenbinds to and inactivates the enzyme calcineurinwhich is involved in transcription of cytokinegenes in the antigen activated helper T-cells. Asa result, response of the helper T cell to antigenicstimulation fails. T cell proliferation andproduction of killer lymphocytes is attenuated.

Cyclosporine selectively suppresses cell-mediated immunity, prevents graft rejection andyet leaves the recipient with enough immuneactivity to combat bacterial infection. Unlikecytotoxic immunosuppressants, it is free of toxiceffects on bone marrow and RE system. Humoralimmunity remains intact. However, it is nephro-toxic—the major limitation, and impairs liverfunction. Of particular concern to dentists is thatcyclosporine causes gum hyperplasia in about1/3rd recipients. This can be minimized by goodoral hygiene and plaque control. Other adverseeffects are sustained rise in BP, precipitation ofdiabetes, hyperkalaemia, opportunistic infec-tions, hirsutism, tremor and seizures.

Cyclosporine is the most effective drug forprevention and treatment of graft rejection reac-tion. It is routinely used in renal, bone marrowand other transplantations.

Cyclosporine is a second line drug in auto-immune diseases like severe rheumatoidarthritis, uveitis, dermatomyositis, etc. and inpsoriasis.

Drug interactions with a large number ofdrugs occur. All nephrotoxic drugs like amino-glycosides, vancomycin, amphotericin B andNSAIDs enhance its toxicity. By depressing renalfunction, it can reduce excretion of many drugs.Phenytoin, phenobarbitone, rifampin and otherenzyme inducers lower its blood levels (trans-plant rejection may result). On the other hand,CYP3A4 inhibitors erythromycin, ketoconazoleand related drugs inhibit its metabolism to causetoxicity. K+ supplements and K+ sparing diureticscan produce marked hyperkalaemia in patientson cyclosporine.

Tacrolimus (FK506) It is a newer immunosup-pressant chemically different from cyclosporinebut having the same mechanism of action and is~100 times more potent.

Antiproliferative drugs(Cytotoxic immunosuppressants)

Certain cytotoxic drugs used in cancer chemo-therapy exhibit prominent immunosuppressantaction, mainly by preventing clonal expansionof T and B lymphocytes (see Fig. 21.2).

Azathioprine (see p. 308) It is a purine antime-tabolite which has more marked immuno-suppressant than antitumour action. The basisfor this difference is not clear, but may be due toits selective uptake into immune cells and intra-cellular conversion to the active metabolite6-mercaptopurine. It selectively affects differen-tiation and function of T cells and inhibitscytolylic lymphocytes; cell-mediated immunityis primarily depressed.

The most important application of azathio-prine is prevention of renal and other graftrejection, but is less effective than cyclosporine;generally combined with it or used in patientsdeveloping cyclosporine toxicity. It has also beenused in progressive rheumatoid arthritis andsome other autoimmune diseases.

Cyclophosphamide This cytotoxic drug hasmore marked effect on B cells and humoralimmunity compared to that on T cells and cell-mediated immunity. It has been particularlyutilized in bone marrow transplantation. Lowdoses are occasionally used for maintenancetherapy in pemphigus, systemic lupus erythema-tosus and idiopathic thrombocytopenic purpura.

Methotrexate This folate antagonist is a potentimmunosuppressant which markedly depressescytokine production and cellular immunity, andhas antiinflammatory property. It has been usedas a first line drug in many autoimmune diseaseslike rapidly progressing rheumatoid arthritis (seep. 317), severe psoriasis, pemphigus, myastheniagravis, uveitis, chronic active hepatitis. Low dose

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proliferation of T lymphocytes. Accordingly,they have a more marked effect on CMI.

Corticosteroids are widely employed as com-panion drug to cyclosporine in various organtransplants. They are used in practically all casesof severe autoimmune diseases, especiallyduring exacerbation. Long-term complicationsare the greatest limitations of steroid use.

Immunosuppressant antibodies

Muromonab CD3 It is a murine monoclonal antibodyagainst the CD3 glycoprotein located near to the T cellreceptor on helper T cells. It inhibits participation of T cellsin the immune response. T cells rapidly disappear fromcirculation leading to an immune blocked state.

Muromonab CD3 has been used as induction therapytogether with corticosteroids and azathioprine for organtransplantation.

Antithymocyte globulin (ATG) It is a poly-clonal antibody purified from horse or rabbitimmunized with human thymic lymphocytes.It binds to T lymphocytes and depletes them,serving as a potent immunosuppressant. It hasbeen used primarily to suppress acute allograftrejection episodes, but can also be used ininduction regimens.

Adverse effects The two general untowardeffects of immunosuppressant therapy are:(a) Increased risk of bacterial, fungal, viral (espe-

cially CMV) as well as opportunisticinfections.

(b) Development of lymphomas and relatedmalignancies after a long latency.

Mtx maintenance therapy is relatively welltolerated.

Chlorambucil It has relatively weak immuno-suppressant action which is sometimes utilizedin autoimmune diseases and transplant main-tenance regimens.

Mycophenolate mofetil (MMF) It is a prodrugof mycophenolic acid which selectively inhibitsinosine monophosphate dehydrogenase, anenzyme essential for de novo synthesis ofguanosine nucleotides in the T and B cells (thesecells, unlike others, do not have the purinesalvage pathway). Lymphocyte proliferation,antibody production and cell-mediatedimmunity are inhibited. As ‘add on’ drug tocyclosporine + glucocorticoid in renal trans-plantation, it has been found as good or evensuperior to azathioprine. Vomiting, diarrhoea,leucopenia and g.i. bleeds are the prominentadverse effects.

Sirolimus It is an antiproliferative immuno-suppressant which acts by inhibiting a specificprotein kinase (mTOR) thereby arresting theprogression of cell cycle in activated T cells. It isused mainly as a component of antirejectionregimen in organ transplantation.

Glucocorticoids (see Ch. 14)

Glucocorticoids have potent immunosuppres-sant and antiinflammatory action, inhibit severalcomponents of the immune response. Theyparticularly inhibit MHC expression and

ANTIRHEUMATOID DRUGS

These are drugs which (except corticosteroids),can suppress the rheumatoid process and bringabout a remission, but do not have nonspecificantiinflammatory or analgesic action. They areused in rheumatoid arthritis (RA) in addition toNSAIDs and are also referred to as diseasemodifying antirheumatic drugs (DMARDs) or slowacting antirheumatic drugs (SAARDs). The onset ofbenefit with DMARDs takes a few months ofregular treatment and relapses occur a few monthsafter cessation of therapy. Recently, some biologicresponse modifiers (BRMs) have been added forresistant cases.

Rheumatoid arthritis (RA) is an autoimmunedisease in which there is joint inflammation,synovial proliferation and destruction of articularcartilage. Immune complexes composed of IgMactivate complement and release cytokines(mainly TNFα and IL-1) which are chemotacticfor neutrophils. These inflammatory cells secretelysosomal enzymes which damage cartilage anderode bone, while PGs produced in the processcause vasodilatation and pain. RA is a chronicprogressive, crippling disorder with a waxingand waning course. NSAIDs are the first linedrugs and afford symptomatic relief in pain,swelling, morning stiffness, immobility, but donot arrest the disease process.

Though mild/early cases are still mostlytreated only with NSAIDs, the current recom-

mendation is to add DMARDs as soon as thediagnosis of RA is confirmed.

CLASSIFICATION

A. Disease modifying antirheumatic drugs(DMARDs)

1. Immunosuppressants: Methotrexate,Azathioprine, Cyclosporine

2. Sulfasalazine3. Chloroquine or Hydroxychloroquine4. Leflunomide5. Gold sod. thiomalate, Auranofin6. d-Penicillamine

B. Biologic response modifiers (BRMs)

1. TNFα inhibitors: Etanercept, Infliximab,Adalimumab

2. IL-1 antagonist: Anakinra

C. Adjuvant drugs

Corticosteroids: Prednisolone and others

1. Immunosuppressants (see Ch. 21)

Methotrexate (Mtx) This dihydrofolate reductaseinhibitor has prominent immunosuppressantand antiinflammatory property. Beneficial effectsin RA are probably related to inhibition of cyto-kine production, chemotaxis and cell-mediatedimmune reaction. Induction of oral low-dose

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Antirheumatoid and Antigout Drugs

318 Antirheumatoid and Antigout DrugsS

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(7.5–15 mg) weekly Mtx regimen has improvedacceptability of this drug in RA. Mtx is now theDMARD of first choice and the standardtreatment for most patients. Response is morepredictable and sustained over long-term.

Probenecid and aspirin increase Mtx levelsand toxicity. Trimethoprim can add to inhibitionof dihydrofolate reductase and depress bonemarrow. Oral ulceration and g.i. upset are themajor side effects of low dose Mtx regimen.

Azathioprine This purine antimetabolite actsafter getting converted to 6-mercaptopurine bythe enzyme thiopurine methyl transferase(TPMT). It is a potent suppressant of cell-mediatedimmunity; appears to selectively affect differentia-tion and function of T-cells and natural killer cells.It also suppresses inflammation. However, remis-sion is induced in smaller percentage of RApatients. Given along with corticosteroids, it hasa steroid sparing effect, for which it is primarilyused now.

Other immunosuppressants like cyclosporine are rarelyused in RA.

2. Sulfasalazine (see Ch. 18)

It is a compound of sulfapyridine and 5-aminosalicylic acid (5-ASA); has antiinflammatoryactivity and is primarily used in ulcerative colitis.In addition, it suppresses the disease in significantnumber of RA patients. The mechanism of actionis not known. Sulfapyridine split off in the colonby bacterial action and absorbed systemicallyappears to be the active moiety (contrast ulcerativecolitis, in which 5-ASA acting locally in thecolon is the active component). Efficacy ofsulfasalazine in RA is modest and side effects arefew. It is used as a second line drug for mildercases.

3. Chloroquine and hydroxychloroquine(see Ch. 33)

These are antimalarial drugs found to induceremission in upto 50% patients of RA, but take3–6 months. Their advantage is relatively low

toxicity, but efficacy is also low; bony erosionsare not prevented. Their mechanism of action isnot known. However, they may be inhibiting Blymphocytes and antigen processing. Lysosomalstabilization and free radical scavenging are theother proposed mechanisms.

For RA, these drugs have to be given for longperiods: accumulate in tissues and producetoxicity, most disturbing of which is retinaldamage and corneal opacity.

Chloroquine/hydroxychloroquine are emplo-yed in milder nonerosive disease, or they arecombined with Mtx/sulfasalazine.

4. Leflunomide

This immunomodulator inhibits proliferation ofactivated lymphocytes in patients with active RA.Arthritic symptoms are suppressed andradiological progression of disease is retarded.Its efficacy has been rated comparable to Mtx andonset of benefit is as fast (4 weeks).

Leflunomide is rapidly converted in the bodyto an active metabolite which inhibits dihydro-orotate dehydrogenase and pyrimidine synthesisin actively dividing cells. Antibody productionby B-cells may be depressed. The active metabolitehas a long t½ of 2 weeks.

Adverse effects of leflunomide are diarrhoea,headache, nausea, rashes, loss of hair, thrombo-cytopenia and leucopenia. Leflunomide is analternative to Mtx or can be added to it, but thecombination is more hepatotoxic.

5. Gold

Gold is the oldest and considered to be the most effectivedrug for arresting the rheumatoid process as well as forpreventing involvement of additional joints. It reduceschemotaxis, phagocytosis, macrophage and lysosomalactivity. By an effect on synovial membrane and collagen,it prevents joint destruction.

Toxicity of parenteral gold salt (hypotension, derma-titis, stomatitis, kidney and liver damage, bone marrowdepression) is high. It is rarely used now.

Auranofin is an orally active gold compound. Plasmagold levels and efficacy are lower than with injected goldsod. thiomalate, but it is less toxic as well. Auranofin isused infrequently.

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226. d-Penicillamine

It is a copper chelating agent with a gold-like action in RA,but less efficacious; bony erosions do not heal. It is notfavoured now because it does not offer any advantage interms of toxicity, which is similar to that of gold. Loss oftaste, systemic lupus and myasthenia gravis are the otheradverse effects.

7. Biologic response modifiers

Recently, several recombinant proteins/monoclonalantibodies that bind and inhibit cytokines, especially TNFαor IL-1 have been produced and found to afford substantialbenefit in autoimmune diseases like RA, inflammatorybowel diseases, psoriasis, scleroderma, etc.

TNFααααα inhibitorsBecause TNFα plays a key role in the inflammatory cascadeof RA by activating membrane bound receptors (TNFR1

and TNFR2) on the surface of T-cells, macrophages, etc.,exogenously administered soluble TNF-receptor proteinor antibody can neutralize it and interrupt the reaction.

Etanercept is a fusion protein of TNF-receptor and Fc portionof human IgG1; Infliximab is a chimeral monoclonal antibodywhich binds and neutralizes TNFα; while Adalimumab is arecombinant monoclonal anti-TNF antibody. All of thesecause regression of inflammatory changes in the joint andslow down new erosions. Quicker response than DMARDshas been obtained. They are generally added to Mtx whenresponse to the latter is not adequate and in rapidlyprogressing cases. All are very expensive.

IL-1 antagonistAnakinra: It is a recombinant human IL-1 receptorantagonist. Clinically, it is less effective than TNFinhibitors.

8. Corticosteroids (see Ch. 14)

They have potent immunosuppressant and anti-inflammatory activity: can be inducted almost atany stage in RA along with first or second linedrugs, if potent antiinflammatory action isrequired while continuing the NSAID ± DMARD.Symptomatic releif is prompt, but they do notarrest the rheumatoid process, though jointdestruction may be slowed and bony erosionsdelayed.

Long-term use of corticosteroids carriesserious disadvantages. Therefore, either low dosesare used to supplement NSAIDs , or high dosesare employed over short periods in cases withsevere systemic manifestations .

DRUGS USED IN GOUT

Gout It is a metabolic disorder characterized byhyperuricaemia (normal plasma urate 2-7 mg/dL). Uric acid, a product of purine metabolism,has low water solubility, especially at low pH.When blood levels are high, it precipitates anddeposits in joints, kidney and subcutaneous tissue(tophy).

Secondary hyperuricaemia occurs in:

(a) Leukaemias, lymphomas, polycythaemia—especially when treated with chemotherapy orradiation: due to enhanced nucleic acid meta-bolism and uric acid production.(b) Drug induced—thiazides, furosemide, pyra-zinamide, ethambutol, levodopa, reduce uric acidexcretion by kidney.Drugs used are:

For acute goutNSAIDs

ColchicineCorticosteroids

For chronic gout / hyperuricaemiaUricosurics Synthesis inhibitorProbenecid AllopurinolSulfinpyrazone

ACUTE GOUT

Acute gout manifests as sudden onset of severeinflammation in a small joint (commonest ismetatarso-phalangeal joint of great toe) due toprecipitation of urate crystals in the joint space.The joint becomes red, swollen and extremelypainful: requires immediate treatment.

1. NSAIDs

One of the strong antiinflammatory drugs, e.g.indomethacin, naproxen, piroxicam, diclofenac oretoricoxib is given in relatively high and quicklyrepeated doses. They are quite effective interminating the attack, but may take 12–24 hours,i.e. response is somewhat slower than withcolchicine, but they are generally better tolerated.


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After the attack is over, they may be continued atlower doses for 3–4 weeks while drugs to controlhyperuricaemia take effect.

The NSAIDs have also substituted colchicinefor covering up the period of initiation ofallopurinol/ probenecid therapy in chronic gout.

2. Colchicine

It is an alkaloid from Colchicum autumnale whichis neither analgesic nor antiinflammatory, but itspecifically suppresses gouty inflammation. Itdoes not inhibit the synthesis or promote theexcretion of uric acid. Thus, it has no effect onblood uric acid levels.

An acute attack of gout is started by theprecipitation of urate crystals in the synovial fluidwhich induce an inflammatory response→granulocyte migration into the joint. Granulocytesphagocytose urate crystals and release aglycoprotein which aggravates the inflammation.

Colchicine inhibits release of the glycopro-tein and the subsequent events. By binding tofibrillar protein tubulin, it inhibits granulocytemigration into the inflamed joint and thusinterrupts the vicious cycle. Other actions ofcolchicine are:(a) Antimitotic: causes metaphase arrest by

binding to microtubules of mitotic spindle.(b) Increases gut motility through neural mecha-

nisms.

Toxicity is high and dose related.Nausea, vomiting, watery or bloody diarrhoea andabdominal cramps occur as dose limiting adverseeffects. In overdose, colchicine produces kidneydamage, CNS depression, intestinal bleeding;death is due to muscular paralysis and respiratoryfailure.

Use

Colchicine is the fastest acting drug to control anattack of acute gout. The response is dramatic;may be considered diagnostic. However, becauseof its higher toxicity, most physicians prefer usinga NSAID. Small doses of colchicine can abort an

attack of acute gout if taken at the first symptom.Maintenance doses of colchicine can be employedover short periods for prophylaxis of acute gout.

3. Corticosteroids

Intra-articular injection of a soluble steroidsuppresses symptoms of acute gout. It is indicatedin refractory cases and those not toleratingNSAIDs/colchicine.

Systemic steroids are rarely needed. They are veryeffective and produce as rapid a response ascolchicine, but are reserved for cases not respon-ding to or not tolerating NSAIDs.

CHRONIC GOUT

When pain and stiffness persist in a joint betweenattacks, gout has become chronic. Other cardinalfeatures are hyperuricaemia, tophi (chalk-likestones under the skin) and urate stones in thekidney. Chronic gouty arthritis may causeprogressive disability and permanent deformities.

1. Probenecid

It is a highly lipid-soluble organic acid developedin 1951 to inhibit renal tubular secretion ofpenicillin so that its duration of action could beprolonged. It competitively blocks active transportof organic acids by OATP in renal tubules. Thistransport is bidirectional: net effect depends onwhether secretion or reabsorption of the particularorganic acid is quantitatively more important, e.g.:(a) Penicillin is predominantly secreted by theproximal tubules, its reabsorption is minimal. Neteffect of probenecid is inhibition of excretion; moresustained blood levels are achieved.(b) Uric acid is largely reabsorbed by activetransport, while less of it is secreted; only 1/10thof filtered load is excreted in urine. Probenecid,therefore, promotes its excretion and reduces itsblood level.

Probenecid does not have any other significantpharmacological action; it is neither analgesic norantiinflammatory.

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Interactions

1. In addition to penicillins, it inhibits the uri-nary excretion of cephalosporins, sulfonamides,methotrexate and indomethacin.2. It inhibits biliary excretion of rifampicin.Pyrazinamide and ethambutol may interfere withuricosuric action of probenecid.3. Probenecid inhibits tubular secretion ofnitrofurantoin which may not attain antibacterialconcentration in urine.4. Salicylates block uricosuric action of pro-benecid.

Pharmacokinetics Probenecid is completelyabsorbed orally; 90% plasma protein bound:partly conjugated in liver and excreted by thekidney; plasma t½ is 8–10 hours.

Adverse effects Probenecid is generally welltolerated.Dispepsia is the most common side effect. Rashesand other hypersensitivity phenomena are rare.

Uses Probenecid is a second line/adjuvantdrug to allopurinol for treating chronic gout andhyperuricaemia. It gradually lowers blood uratelevel; arthritis, tophi and other lesions may takemonths to resolve. Colchicine/NSAID cover isadvised concurrently during the initial 1–2months to avoid precipitation of acute gout.

Probenecid is also used to prolong penicillinor ampicillin action by enhancing and sustainingtheir blood levels, e.g. in gonorrhoea, SABE.

2. Sulfinpyrazone

It is a pyrazolone derivative related to phenyl-butazone having uricosuric action, but is neitheranalgesic nor antiinflammatory. At the usualtherapeutic doses, it inhibits tubular reabsorptionof uric acid, but smaller doses can decrease urateexcretion. It inhibits platelet aggregation.

Sulfinpyrazone is well absorbed orally; 98%plasma protein bound. Excretion is fairly rapid,mainly by active secretion in proximal tubule.Uricosuric action of a single dose lasts for 6–10hours.

Gastric irritation is the most common sideeffect—contraindicated in patients with pepticulcer. Rashes and other hypersensitivity reactionsare uncommon. The only indication ofsulfinpyrazone is hyperuricaemia and chronicgout as an alternative to probenecid.

3. Allopurinol

This hypoxanthine analogue was synthesized asa purine antimetabolite for cancer chemotherapy.However, it had no antineoplastic activity but wasa substrate as well as inhibitor of xanthine oxidase,the enzyme responsible for uric acid synthesis(Fig. 22.1).

Allopurinol itself is a short-acting (t½ 2 hr)competitive inhibitor of xanthine oxidase, but itsmajor metabolite alloxanthine (oxypurine) is longacting (t½ 24 hr) and noncompetitive inhibitor—primarily responsible for uric acid synthesisinhibition in vivo. During allopurinol adminis-tration, plasma concentration of uric acid isreduced and that of hypoxanthine and xanthineis somewhat increased. In place of uric acid alone,all 3 oxipurines are excreted in urine. Sincexanthine and hypoxanthine are more soluble,have a higher renal clearance than that of uricacid and each has its individual solubility,precipitation and crystallization in tissues andurine does not occur.

Because of raised levels of xanthine and hypo-xanthine, some feedback inhibition of de novopurine synthesis and reutilization of meta-bolically derived purine also occurs.Pharmacokinetics About 80% of orally adminis-tered allopurinol is absorbed. It is not bound toplasma proteins; metabolized largely to alloxan-thine. During chronic medication, it inhibits itsown metabolism and about 1/3rd is excretedunchanged, the rest as alloxanthine.

Interactions(a) It inhibits the degradation of 6-mercapto-purine and azathioprine: their doses should bereduced to 1/3rd but not that of thioguanine,because it follows a different metabolic path(S-methylation).


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Fig. 22.1: Uric acid synthesis and the action of allopurinol

(b) Probenecid given with allopurinol hascomplex interaction; while probenecid shortenst½ of alloxanthine, allopurinol prolongs t½ ofprobenecid.(c) It can potentiate warfarin and theophyllineby inhibiting their metabolism.(d) A higher incidence of skin rashes has beenreported when ampicillin is given to patients onallopurinol.

Adverse effects These are uncommon.Hypersensitivity reaction consisting of rashes,fever, malaise and muscle pain is the mostfrequent.Gastric irritation, headache, nausea and dizzi-

ness are infrequent; do not need withdrawal.Liver damage is rare.

Uses Allopurinol is the first choice drug inchronic gout. Probenecid can be combined with itwhen the body load of urate is large. With long-term allopurinol therapy, tophi graduallydisappear and nephropathy is halted, evenreversed.

Secondary hyperuricaemia due to cancer chemo-therapy/radiation/thiazides or other drugs: canbe controlled by allopurinol.

Allopurinol has also been used to potentiate6-mercaptopurine or azathioprine, and as anadjuvant drug in kala-azar.

23

Pain (algesia) is an ill-defined, unpleasantsensation, usually evoked by an external orinternal noxious stimulus. It is a warning signaland primarily protective in nature, but causesdiscomfort and suffering; may even be unbearable.Dental pain is usually acute in nature and is the mostimportant symptom for which the patient comesto the dentist.

Analgesic is a drug that selectively relieves painby acting in the CNS or on peripheral painmechanisms, without significantly alteringconsciousness. Analgesics relieve pain as asymptom without affecting its cause. They areused when the noxious stimulus (evoking pain)cannot be removed, or as an adjuvant to moreetiologic approach to pain, such as antibiotictreatment of apical tooth abscess.

Analgesics are divided into two groups, viz.A. Opioid/narcotic/morphine like analgesics.B. Nonopioid/non-narcotic/antipyretic/

aspirin-like analgesics or nonsteroidalantiinflammatory drugs (NSAIDs).The antipyretic-analgesics and NSAIDs are

more commonly employed for dental pain becausetissue injury and inflammation due to toothabscess, caries, tooth extraction, etc. is the majorcause of acute dental pain.

The NSAIDs and antipyretic-analgesics are aclass of drugs that have analgesic, antipyretic andantiinflammatory actions in different measures.

In contrast to morphine, they do not depress CNS,do not produce physical dependence, have noabuse liability and are particularly effective ininflammatory pain. They act primarily onperipheral pain mechanisms but also in the CNSto raise pain threshold.

CLASSIFICATION

A. Nonselective COX inhibitors (traditionalNSAIDs)

1. Salicylates: Aspirin.2. Propionic acid derivatives: Ibuprofen, Napro-

xen, Ketoprofen, Flurbiprofen.3. Anthranilic acid derivative: Mephenamic

acid.4. Aryl-acetic acid derivatives: Diclofenac,

Aceclofenac5. Oxicam derivatives: Piroxicam, Tenoxicam.6. Pyrrolo-pyrrole derivative: Ketorolac.7. Indole derivative: Indomethacin.8. Pyrazolone derivatives: Phenylbutazone,

Oxyphenbutazone.

B. Preferential COX-2 inhibitorsNimesulide, Meloxicam, Nabumetone

C. Selective COX-2 inhibitorsCelecoxib, Etoricoxib, Parecoxib

D. Analgesic- antipyretics with poorantiinflammatory action

1. Paraaminophenol derivative: Paracetamol(Acetaminophen).

Nonsteroidal Antiinflammatory Drugsand Antipyretic-Analgesics

326 NSAIDs and Antipyretic-AnalgesicsS

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2. Pyrazolone derivatives: Metamizol (Dipy-rone), Propiphenazone.

3. Benzoxazocine derivative: Nefopam.

NSAIDs and prostaglandin (PG) synthesisinhibition

In 1971, Vane and coworkers made the landmarkobservation that aspirin and some NSAIDsblocked prostaglandin (PG) generation. This isnow considered to be the major mechanism ofaction of NSAIDs. Prostaglandins, prostacyclin(PG I2) and thromboxane A2 (TXA2) are producedfrom arachidonic acid by the enzyme cyclooxy-genase (see p. 110) which exists in a constitutive(COX-1) and an inducible (COX-2) isoforms; theformer serves physiological ‘house keeping’functions; while the latter, normally present inminute quantities, is induced by cytokines andother signal molecules at the site of inflammation→ generation of PGs locally which mediate manyof the inflammatory changes. However, COX-2 isconstitutively present at some sites in the brainand in juxtaglomerular cells: may servephysiological role at these sites. Most NSAIDsinhibit COX-1 and COX-2 nonselectively, but nowsome selective COX-2 inhibitors have been pro-duced. Features of nonselective COX-1/COX-2inhibitors (traditional NSAIDs) and selectiveCOX-2 inhibitors are compared in Table 23.1

Aspirin inhibits COX irreversibly by acety-lating one of its serine residues; return of COXactivity depends on synthesis of fresh enzyme.

Beneficial actions due to PG synthesisinhibition

• Analgesia: prevention of pain nerveending sensitization

• Antipyresis• Antiinflammatory• Antithrombotic• Closure of ductus arteriosus in newborn

Other NSAIDs are competitive and reversibleinhibitors of COX, return of activity depends ontheir dissociation from the enzyme which in turn

is governed by the pharmacokinetic characteris-tics of the compound.

Analgesia PGs induce hyperalgesia (see p. 114)by affecting the transducing property of freenerve endings—stimuli that normally do not elicitpain are able to do so. NSAIDs do not affect thetenderness induced by direct application ofPGs, but block the pain sensitizing mechanisminduced by bradykinin, TNFα, interleukins (ILs)and other algesic substances. They are, therefore,more effective against inflammation associatedpain, including acute dental/postextraction pain.

Antipyresis NSAIDs reduce body temperaturein fever, but do not cause hypothermia in normo-thermic individuals. Fever during infection isproduced through the generation of pyrogen, ILs,TNFα, interferons which induce PG productionin hypothalamus—raise its temperature set point.NSAIDs block the action of pyrogens but not thatof PGE2 injected into the hypothalamus. Theisoform present at this site appears to be COX-2(possibly COX-3 also: a splice variant of COX-1that is inhibited by paracetamol). However, fevercan occur through non-PG mediated mechanismsas well.

Shared toxicities due to PG synthesisinhibition• Gastric mucosal damage• Bleeding: inhibition of platelet function• Limitation of renal blood flow : Na+ and

water retention• Delay/prolongation of labour• Asthma and anaphylactoid reactions in

susceptible individuals

Antiinflammatory The most important mecha-nism of antiinflammatory action of NSAIDs isconsidered to be inhibition of PG synthesis at thesite of injury. The antiinflammatory potency ofdifferent compounds roughly corresponds withtheir potency to inhibit COX. However, nime-sulide is a potent antiinflammatory but relativelyweak COX inhibitor. PGs are only one of themediators of inflammation; inhibition of COX

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does not depress the production of other media-tors like LTs, PAF, cytokines, etc. Inflammation isthe result of concerted participation of a largenumber of vasoactive, chemotactic and prolifera-tive factors at different stages, and there are manytargets for antiinflammatory action.

Activated endothelial cells express adhesionmolecules (ECAM-1, ICAM-1) on their surfaceand play a key role in directing circulating leuko-cytes to the site of inflammation. Similarly,inflammatory cells express selectins and integrins.Certain NSAIDs may act by additional mecha-nisms including inhibition of expression/activityof some of these molecules and generation ofsuperoxide/other free radicals. Growth factorslike GM-CSF, IL-6 and lymphocyte transformationfactors may also be affected. Stabilization ofleucocyte lysosomal membrane and antagonismof certain actions of kinins may be contributing toNSAID action.

Table 23.1: Features of nonselective COX inhibitorsand selective COX-2 inhibitors

Action COX-1/COX-2 COX-2inhibitors inhibitors

1. Analgesic + +

2. Antipyretic + +

3. Antiinflammatory + +

4. Antiplatelet aggregatory + –

5. Gastric mucosal damage + –

6. Renal salt/water retention + +

7. Delay/prolongation of labour + +

8. Ductus arteriosus closure + ?

9. Aspirin sensitive asthmaprecipitation + –

Dysmenorrhoea Involvement of PGs in dysme-norrhoea has been clearly demonstrated: level ofPGs in menstrual flow, endometrial biopsy andthat of PGF2α metabolite in circulation are raisedin dysmenorrhoeic women. NSAIDs lower uterinePG levels—afford excellent relief in 60–70% andpartial relief in the remaining.

Antiplatelet aggregatory NSAIDs inhibit syn-thesis of both proaggregatory (TXA2) and anti-

aggregatory (PGI2) prostanoids, but effect onplatelet TXA2 predominates → therapeutic dosesof most NSAIDs inhibit platelet aggregation:bleeding time is prolonged. Aspirin is highlyactive; acetylates platelet COX irreversibly inportal circulation before it is deacetylated byfirst pass metabolism in liver. Small doses are,therefore, able to exert antithrombotic effect forseveral days. Risk of postextraction bleeding isenhanced.

Ductus arteriosus closure During foetal circu-lation, ductus arteriosus is kept patent by localelaboration of PGE2 and PGI2. Unknownmechanisms switch off this synthesis at birth andthe ductus closes. When this fails to occur, smalldoses of indomethacin or aspirin bring aboutclosure in majority of cases within a few hours byinhibiting PG production. Administration ofNSAIDs in late pregnancy has been found topromote premature closure of ductus in somecases. Dentists should avoid prescribing NSAIDs nearterm.

Parturition Sudden spurt of PG synthesis byuterus probably triggers labour and facilitates itsprogression. Accordingly, NSAIDs have thepotential to delay and retard labour. However,labour can occur in the absence of PGs.

Gastric mucosal damage Gastric pain, mucosalerosion/ulceration and blood loss are producedby all NSAIDs to varying extents: relative gastrictoxicity is a major consideration in the choice ofNSAIDs. Inhibition of synthesis of gastropro-tective PGs (PGE2, PGI2) is clearly involved,though local action inducing back diffusion ofH+ ions in gastric mucosa also plays a role.Deficiency of PGs reduces mucus and HCO3¯secrection, tends to enhance acid secretion andmay promote mucosal ischaemia. Thus, NSAIDsenhance aggressive factors and contain defensivefactors in gastric mucosa—are ulcerogenic.Paracetamol, a very weak inhibitor of COX, ispractically free of gastric toxicity and selectiveCOX-2 inhibitors are safer. Stable PG analogues(misoprostol) administered concurrently withNSAIDs counteract their gastric toxicity.

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Adverse effects of NSAIDs

GastrointestinalGastric irritation, erosions, peptic ulceration,gastric bleeding/perforation, esophagitis

RenalNa+ and water retention, chronic renalfailure, interstitial nephritis, papillarynecrosis (rare)

HepaticRaised transaminases, hepatic failure (rare)

CNSHeadache, mental confusion, behaviouraldisturbances, seizure precipitation

HaematologicalBleeding, thrombocytopenia, haemolyticanaemia, agranulocytosis

OthersAsthma exacerbation, nasal polyposis,skin rashes, pruritus, angioedema

Renal effects Conditions leading to hypovo-laemia, decreased renal perfusion and Na+ lossinduce renal PG synthesis which brings aboutintrarenal adjustments by promoting vasodila-tation, inhibiting tubular Cl¯ reabsorption (Na+

and water accompany) and opposing ADHaction.NSAIDs produce renal effects by at least 3mechanisms:• COX-1 dependent impairment of renal blood

flow and reduction of g.f.r. → can worsen renalinsufficiency.

• Juxtaglomerular COX-2 (probably COX-1 also)dependent Na+ and water retention.

• Ability to cause papillary necrosis on habitualintake.

Renal effects of NSAIDs are not marked in normalindividuals but become significant in those withCHF, hypovolaemia, hepatic cirrhosis, renaldisease and in patients receiving diuretics orantihypertensives: Na+ retention and edema canoccur; diuretic and antihypertensive drug effectsare blunted.

Anaphylactoid reactions Aspirin precipitatesasthma, angioneurotic swellings, urticaria orrhinitis in certain susceptible individuals. Thesesubjects react similarly to chemically diverseNSAIDs, ruling out immunological basis for thereaction. Inhibition of COX with consequentdiversion of arachidonic acid to LTs and otherproducts of lipoxygenase pathway may beinvolved, but there is no proof.

SALICYLATES

AspirinAspirin is acetylsalicylic acid. It is rapidlyconverted in the body to salicylic acid which isresponsible for most of the actions. Other actionsare the result of acetylation of certain macromole-cules including COX. Aspirin is one of the oldestanalgesic-antiinflammatory drugs and is stillwidely used.


1. Analgesic, antipyretic, antiinflammatoryactions Aspirin is a weaker analgesic thanmorphine type drugs: aspirin 600 mg ~ codeine60 mg, but it effectively relieves inflammatory,tissue injury related, connective tissue andintegumental pain. It is relatively ineffective insevere visceral and ischaemic pain. The analgesicaction is mainly due to obtunding of peripheralpain receptors and prevention of PG-mediatedsensitization of nerve endings. A centralsubcortical action raising threshold to painperception also contributes, but the morphine-likeaction on psychic processing or reactioncomponent of the pain is missing. No sedation,subjective effects, tolerance or physicaldependence is produced.

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Aspirin resets the hypothalamic thermostatand rapidly reduces fever by promoting heat loss(sweating, cutaneous vasodilatation), but does notdecrease heat production.

Antiinflammatory action is exerted at highdoses (3–5 g/day or 100 mg/kg/ day). Signs ofinflammation like pain, tenderness, swelling,vasodilatation and leucocyte infiltration are sup-pressed. However, progression of the underlyingdisease in rheumatoid arthritis, rheumatic feverand osteoarthritis, etc. is not affected.

2. Metabolic effects These are significant onlyat antiinflammatory doses. Cellular metabolismis increased, especially in skeletal muscles, dueto uncoupling of oxidative phosphorylation →increased heat production. There is increasedutilization of glucose → blood sugar may dec-rease (especially in diabetics) and liver glycogenis depleted. However, hyperglycaemia is oftenseen at toxic doses: this is due to centralsympathetic stimulation → release of Adr andcorticosteroids.

3. Respiration The effects are dose dependent.At antiinflammatory doses, respiration isstimulated by peripheral (increased CO2 produc-tion) and central (increased sensitivity of respira-tory centre to CO2) actions. Hyperventilation isprominent in salicylate poisoning. Further rise insalicylate level causes respiratory depression;death is due to respiratory failure.

4. Acid-base and electrolyte balance Usualanalgesic doses (0.3-1.5 g) have no effect. Anti-inflammatory doses produce significant changesin the acid-base and electrolyte composition ofbody fluids. Initially, respiratory stimulationpredominates and tends to wash out CO2 despiteincreased production → respiratory alkalosis,which is compensated by increased renal excre-tion of HCO3̄ (with accompanying Na+, K+ andwater). Most adults treated with 4–6 g/day ofaspirin stay in a state of compensated respiratoryalkalosis.

Still higher doses cause respiratory depres-sion with CO2 retention, while excess CO2 pro-

duction continues → respiratory acidosis. To thisare added dissociated salicylic acid as well asmetabolic acids (lactic, pyruvic, acetoacetic)which are produced in excess + metabolicallyderived sulfuric and phosphoric acid which areretained due to depression of renal function. Allthese combine to cause uncompensated metabolicacidosis since plasma HCO3¯ is already low. Mostchildren manifest this phase during salicylatepoisoning; while in adults, it is seen in late stagesof poisoning only.

Dehydration occurs in poisoning due to increa-sed water loss in urine (to accompany Na+, K+

and HCO3̄ ), increased sweating and hyperventi-lation.

5. CVS Aspirin has no direct effect in thera-peutic doses. Larger doses increase cardiac outputto meet increased peripheral O2 demand and causedirect vasodilatation. Toxic doses depressvasomotor centre: BP may fall. Because ofincreased cardiac work as well as Na+ and waterretention, CHF may be precipitated in patientswith low cardiac reserve.

6. GIT Aspirin and released salicylic acid irri-tate gastric mucosa → cause epigastric distress,nausea and vomiting. At high doses it stimulatesCTZ as well: vomiting has a central componentalso.

Aspirin (pKa 3.5) remains unionized anddiffusible in the acid gastric juice; but on enteringthe mucosal cell (pH 7.1), it ionizes and becomesindiffusible. This ‘ion trapping’ in the gastricmucosal cell enhances gastric toxicity. Further,aspirin particle coming in contact with gastricmucosa promotes local back diffusion of acid →focal necrosis of mucosal cells and capillaries →acute ulcers, erosive gastritis, congestion andmicroscopic haemorrhages. The occult blood lossin stools is increased by even a single tablet ofaspirin. It averages 5 ml/day at antiinflammatorydoses. Haematemesis occurs occasionally: maybe an idiosyncratic reaction.

Soluble aspirin tablets containing calciumcarbonate + citric acid and other buffered prepa-rations are less liable to cause gastric ulceration.

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7. Urate excretion Dose-related effect is seen:< 2 g/day—urate retention and antagonismof all other uricosuric drugs.2–5 g/day—variable effects, often no change.> 5 g/day—increased urate excretion.

Aspirin is not suitable for use in chronic gout.

8. Blood Aspirin, even in small doses, irrever-sibly inhibits TXA2 synthesis by platelets. Thus,it interferes with platelet aggregation and blee-ding time is prolonged to nearly twice the normalvalue. This effect lasts for about a week (turnovertime of platelets).

Long-term intake of large doses decrease syn-thesis of clotting factors in liver and predisposesto bleeding; can be prevented by prophylactic vitK therapy.

PHARMACOKINETICS

Aspirin is absorbed from stomach and smallintestines. Its poor water solubility is the limitingfactor in absorption: microfining the drug-particles and inclusion of an alkali (solubility ismore at higher pH) enhances absorption.However, higher pH also favours ionization, thusdecreasing the diffusible form.

Aspirin is rapidly deacetylated in the gut wall,liver, plasma and other tissues to release salicylicacid which is the major circulating and activeform. It is ~80% bound to plasma proteins andhas a volume of distribution ~0.17 L/kg. It slowlyenters brain but freely crosses placenta. Bothaspirin and salicylic acid are conjugated in liverwith glycine → salicyluric acid (major pathway);and with glucuronic acid. Few other minormetabolites are also produced. The metabolitesare excreted by glomerular filtration as well astubular secretion. Normally, only 1/10th isexcreted as free salicylic acid, but this can beincreased by alkalinization.

The plasma t½ of aspirin as such is 15–20min, but taken together with that of releasedsalicylic acid, it is 3–5 hours. However, metabolicprocesses get saturated over the therapeutic range;t½ of antiinflammatory doses may be 8–12 hours,

while that during poisoning may be up to 30hours. Thus, elimination is dose dependent.

ADVERSE EFFECTS

(a) Side effects that occur at analgesic dose(0.3–1.5 g/day) are nausea, vomiting, epigastricdistress, increased occult blood loss in stools. Themost important adverse effect of aspirin is gastricmucosal damage and peptic ulceration.

(b) Hypersensitivity and idiosyncrasy Thoughinfrequent, these can be serious. Reactions includerashes, fixed drug eruption, urticaria, rhinor-rhoea, angioedema, asthma and anaphylactoidreaction. Profuse gastric bleeding occurs in rareinstances.

(c) Antiinflammatory doses (3–5 g/day) producethe syndrome called salicylism—dizziness, tinni-tus, vertigo, reversible impairment of hearing andvision, excitement and mental confusion, hyper-ventilation and electrolyte imbalance. The dosehas to be titrated to one which is just below thatproducing these symptoms; tinnitus is a goodguide.

Aspirin therapy in children with rheumatoidarthritis has been found to raise serum transami-nases, indicating liver damage. An associationbetween salicylate therapy and ‘Reye’ssyndrome’, a rare form of hepatic encephalopathyseen in children having viral (varicella, influenza)infection, has been noted. In adults also, long-term therapy with high dose aspirin can causeinsidious onset hepatic injury. Salt and waterretention occurs in a dose-related manner.

(d) Acute salicylate poisoning It is more com-mon in children. Fatal dose in adults is estimatedto be 15–30 g, but is considerably lower in chil-dren. Serious toxicity is seen at serum salicylatelevels > 50 mg/dl. Manifestations are:

Vomiting, dehydration, electrolyte imbalance,acidotic breathing, hyper/hypoglycaemia,petechial haemorrhages, restlessness, deli-rium, hallucinations, hyperpyrexia, convul-sions, coma and death due to respiratoryfailure + cardiovascular collapse.

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Treatment is symptomatic and supportive. Mostimportant is external cooling and i.v. fluid withNa+, K+, HCO3̄ and glucose: according to needdetermined by repeated monitoring. Gastric lav-age to remove unabsorbed drug and haemo-dialysis to remove absorbed drug is indicated insevere cases. Blood transfusion and vit K shouldbe given if bleeding occurs.

Precautions and contraindications

• Aspirin is contraindicated in patients who aresensitive to it and in peptic ulcer, bleedingtendencies, in children suffering from chicken-pox or influenza. Due to risk of Reye’ssyndrome, pediatric formulations of aspirinare prohibited in India and the UK.

• In chronic liver disease: cases of hepaticnecrosis have been reported.

• Aspirin should be avoided in diabetics, in thosewith low cardiac reserve or frank CHF and injuvenile rheumatoid arthritis.

• Aspirin should be stopped 1 week before electivesurgery, dental extraction. In case this is notpossible, adequate haemostasis must beensured by packing the socket and use of localhaemostatics if needed.

• Given during pregnancy, it may be responsiblefor low birth weight babies. Delayed or pro-longed labour, greater postpartum blood lossand premature closure of ductus arteriosus arepossible if aspirin is taken at or near term.

• It should be avoided by breastfeeding mothers.• Avoid high doses in G-6-PD deficient

individuals—haemolysis can occur.

Interactions1. Aspirin displaces warfarin, naproxen,sulfonylureas, phenytoin and methotrexate frombinding sites on plasma proteins: toxicity of thesedrugs may occur. Its antiplatelet action increasesthe risk of bleeding in patients on oral anticoagu-lants.2. It inhibits tubular secretion of uric acid (atanalgesic doses) and antagonizes uricosuricaction of probenecid. Tubular secretion ofmethotrexate is also interfered.

3. It blunts diuretic action of furosemide orthiazides and reduces K+ conserving action ofspironolactone. Competition between canrenone(active metabolite of spironolactone) and aspirinfor active transport in proximal tubules has beendemonstrated.

USES

1. As analgesic For headache, toothache,backache, myalgia, joint pain, pulled muscle,neuralgias and dysmenorrhoea; it is effective inlow doses (0.3–0.6 g) and analgesic effect ismaximal at ~ 1000 mg. Majority of painful dentalconditions respond very well to these doses of aspirinrepeated 6–8 hourly.

2. As antipyretic It is effective in fever of anyorigin; dose is same as for analgesia. However,paracetamol, being safer, is generally preferred.

3. Acute rheumatic fever Aspirin is the firstdrug to be used in all cases; other drugs are addedor substituted only when it fails or in severe cases(corticosteroids act faster).

4. Rheumatoid arthritis Aspirin in a dose of3–5 g/day is effective in most cases. Since largedoses of aspirin are poorly tolerated for longperiods, the newer NSAIDs are preferred by most.

5. Osteoarthritis It affords symptomatic reliefonly; may be used on ‘as and when required’basis, but paracetamol is the first choice analgesicfor most cases.

6. Postmyocardial infarction and poststrokepatients By inhibiting platelet aggregation,aspirin lowers the incidence of reinfarction.Aspirin in low doses (60-150 mg/day) is nowroutinely prescribed to post-infarct patients.Aspirin reduces ‘transient ischaemic attacks’ andlowers incidence of stroke in such patients.

7. Other less well established uses of aspirin are:(a) Pregnancy-induced hypertension and pre-eclampsia.(b) Patent ductus arteriosus in newborn.(c) Familial colonic polyposis.

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Table 23.2: Dosage and preparations of propionic acid derivatives

Drug Plasma t½ Dosage Preparations

1. Ibuprofen 2 hr 400–600 mg BRUFEN, EMFLAM, IBUSYNTH 200, 400, 600 mg(5-10 mg/kg) TDS tab, IBUGESIC also 100 mg/5 ml susp.

2. Naproxen 12–16 hr 250 mg BD– NAPROSYN, NAXID, ARTAGEN, XENOBIDTDS 250 mg tab., NAPROSYN also 500 mg tab.

3. Ketoprofen 2–3 hr 50-100 mg KETOFEN 50, 100 mg tab; OSTOFEN 50 mg cap.BD–TDS RHOFENID 100 mg tab, 200 mg SR tab;

100 mg/2 ml amp.

4. Flurbiprofen 4–6 hr 50 mg BD–QID ARFLUR 50, 100 mg tab, 200 mg SR tab,FLUROFEN 100 mg tab.

(d) Prevention of colon cancer.(e) To prevent flushing attending nicotinic acidingestion.

ASPIRIN 350 mg tab, COLSPRIN 100, 325, 650 mg tabs,ECOSPRIN 75, 150, 325 mg tabs, DISPRIN 350 mg tab,LOPRIN 75, 162.5 mg tabs.An injectable preparation has been made available recently;BIOSPIRIN: Lysine acetylsalicylate 900 mg + glycine 100mg/vial for dissolving in 5 ml water and i.v. injection.

Other salicylates (salicylamide, benorylate,diflunisal) are not in use now.

PROPIONIC ACID DERIVATIVES

Ibuprofen was the first member of this class to beintroduced in 1969 as a better tolerated alternativeto aspirin. Many others have followed. All havesimilar pharmacodynamic properties, but differconsiderably in potency and to some extent induration of action (Table 23.2).

The antiinflammatory efficacy is rated some-what lower than high dose of aspirin. All inhibitPG synthesis, naproxen being the most potent;but their in vitro potency for this action does notclosely parallel in vivo antiinflammatory potency.They inhibit platelet aggregation reversibly andcause short lasting prolongation of bleeding time.

Adverse effects Ibuprofen and all its congenersare better tolerated than aspirin. Side effects aremilder and their incidence is lower.Gastric discomfort, nausea and vomiting, thoughless than aspirin or indomethacin, are still themost common side effects. Gastric erosion andoccult blood loss are rare.

CNS side effects include headache, dizziness,blurring of vision, tinnitus and depression.Rashes, itching and other hypersensitivity phe-nomena are infrequent. However, these drugsprecipitate aspirin-induced asthma.Fluid retention is less marked than that withphenylbutazone.They are not to be prescribed to pregnant womenand should be avoided in peptic ulcer patient.

Pharmacokinetics and interactions All are wellabsorbed orally, highly bound to plasma proteins(90–99%), but displacement interactions are notclinically significant—dose of oral anticoagulantsand oral hypoglycaemics need not be altered.Because they inhibit platelet function, use withanticoagulants should, nevertheless, be avoided.Similar to other NSAIDs, they are likely todecrease diuretic and antihypertensive action ofthiazides, furosemide and β blockers.

All propionic acid derivatives enter brain,synovial fluid and cross placenta. They are largelymetabolized in liver by hydroxylation and glucu-ronide conjugation and excreted in urine as wellas bile.

Uses1. Ibuprofen, available as an ‘over-the-counter’drug, is used as a simple analgesic and antipyreticin the same way as low dose of aspirin.2. Ibuprofen and its congeners are widely usedin rheumatoid arthritis, osteoarthritis and othermusculoskeletal disorders, especially where painis more prominent than inflammation.

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3. They are indicated in soft tissue injuries,tooth extraction, fractures, vasectomy, postpartumand postoperatively: suppress swelling andinflammation and are very popular in dentistry.Ibuprofen (400 mg) has been found equally ormore efficacious than a combination of aspirin(650 mg) + codeine (60 mg) in relieving dentalsurgery pain.

Choice among different members is difficult;naproxen is probably more efficacious and bettertolerated in antiinflammatory doses. It is longeracting and has the advantage of twice dailydosing. However, individuals vary in their pre-ference for different members.

ANTHRANILIC ACID DERIVATIVE (FENAMATE)

Mephenamic acid An analgesic, antipyreticand antiinflammatory drug, which inhibits COXas well as antagonises certain actions of PGs.Mephenamic acid exerts peripheral as well ascentral analgesic action.

Adverse effects Diarrhoea is the most impor-tant dose-related side effect. Epigastric distressis complained, but gut bleeding is not significant.Haemolytic anaemia is a rare but seriouscomplication.

Pharmacokinetics Oral absorption is slow butalmost complete. It is highly bound to plasmaproteins—displacement interactions can occur;partly metabolized and excreted in urine as wellas bile. Plasma t½ is 2–4 hours.

Uses Mephenamic acid is indicated primarilyas analgesic in muscle, joint and soft tissue painwhere strong antiinflammatory action is notneeded. It is quite effective in dysmenorrhoea. Itmay be used in dental pain, but has no distinctadvantage.Dose: 250–500 mg TDS; MEDOL 250, 500 mg cap;MEFTAL, 250, 500 mg tab, 100 mg/5 ml susp.PONSTAN 125, 250, 500 mg tab, 50 mg/ml syrup.

ARYL-ACETIC ACID DERIVATIVES

Diclofenac sodium An analgesic-antipyretic-antiinflammatory drug, similar in efficacy tonaproxen. It inhibits PG synthesis reversibly andis somewhat COX-2 selective. The antiplateletaction is short-lasting. Neutrophil chemotaxisand superoxide production at the inflammatorysite are reduced.

It is well absorbed orally, 99% protein bound,metabolized and excreted both in urine and bile.The plasma t½ is ~2 hours. Because of good tissuepenetrability, concentration in joints and othersites of inflammation is maintained for longerperiod extending the therapeutic effect.

Adverse effects of diclofenac are generally mild:epigastric pain, nausea, headache, dizziness,rashes. Gastric ulceration and bleeding are lesscommon. Reversible elevation of serum amino-transferases can occur; kidney damage is rare.

Diclofenac is among the most extensively usedNSAID; employed in toothache, rheumatoid andosteoarthritis, bursitis, ankylosing spondylitis,

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Drug interactions with NSAIDs

Pharmacokinetic

Oral anticoagulants MetabolismSulfonylureas inhibited;Phenytoin CompetitionValproate for plasma protein binding

Digoxin ↓ RenalLithium excretion ofAminoglycosides interacting drugMethotrexate

PharmacodynamicDiuretics : ↓ diuresisβ blocker : ↓ antihypertensive effectACE inhibitors : ↓ antihypertensive effectAnticoagulants : ↑ risk of g.i. bleedSulfonylureas : ↑ risk of hypoglycaemiaAlcohol : ↑ risk of g.i. bleedCyclosporine : ↑ nephrotoxicityCorticosteroids : ↑ risk of g.i. bleed


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dysmenorrhoea, post-traumatic and postopera-tive inflammatory conditions—affords quick reliefof pain and wound edema.Dose: 50 mg TDS, then BD oral, 75 mg deep i.m.VOVERAN, DICLONAC, MOVONAC 50 mg entericcoated tab, 100 mg S.R. tab, 25 mg/ml in 3 ml amp. fori.m. inj. DICLOMAX 25, 50 mg tab, 75 mg/3ml inj.Diclofenac potassium: VOLTAFLAM 25, 50 mg tab,ULTRA-K 50 mg tab; VOVERAN 1% topical gel.

Aceclofenac A relatively COX-2 selectivecongener of diclofenac having similar properties.Dose: 100 mg BD;ACECLO, DOLOKIND 100 mg tab, 200 mg SR tab.

OXICAM DERIVATIVES

Piroxicam It is a long-acting NSAID with potentantiinflammatory and good analgesic-antipyreticactions. It is a reversible inhibitor of COX; lowersPG concentration in synovial fluid and inhibitsplatelet aggregation—prolonging bleeding time.In addition, it decreases the production of IgMrheumatoid factor and reduces leucocytechemotaxis. Thus, it can inhibit inflammation indiverse ways.

Pharmacokinetics Piroxicam is rapidly andcompletely absorbed: 99% plasma protein bound;largely metabolized in liver by hydroxylation andglucuronide conjugation; excreted in urine andbile; enterohepatic cycling occurs. Plasma t½ islong—nearly 2 days. Steady-state concentrationsare achieved in a week. Single daily adminis-tration is sufficient.

Adverse effects Common side effects are heartburn, nausea and anorexia, but it is better

tolerated and less ulcerogenic than indomethacinor phenylbutazone; causes less faecal blood lossthan aspirin. Rashes and pruritus are seen in< 1% patients. Edema and reversible azotaemiahave been observed.

Uses Piroxicam is suitable for use as short-termanalgesic as well as long-term antiinflammatorydrug in rheumatoid and osteoarthritis, ankylosingspondylitis, acute gout, musculoskeletal injuriesand in dentistry.Dose: 20 mg BD for two days followed by 20 mg OD:DOLONEX, PIROX 10, 20 mg cap, 20 mg dispersible tab,20 mg/ml inj in 1 and 2 ml amps; PIRICAM 10, 20 mgcap.

Tenoxicam A congener of piroxicam withsimilar properties and uses.TOBITIL 20 mg tab; dose 20 mg OD.

PYRROLO-PYRROLE DERIVATIVE

Ketorolac A novel NSAID with potent analgesicand modest antiinflammatory activity. In postope-rative pain it has equalled the efficacy of morp-hine, but does not interact with opioid receptorsand is free of opioid side effects. Like otherNSAIDs, it inhibits PG synthesis and relieves painby a peripheral mechanism. In short-lasting pain,it has compared favourably with aspirin.

Ketorolac is rapidly absorbed after oral andi.m. administration. It is highly plasma proteinbound and 60% excreted unchanged in urine.Major metabolic pathway is glucuronidation;plasma t½ is 5–7 hours.

Adverse effects Nausea, abdominal pain, dys-pepsia, ulceration, loose stools, drowsiness, painat injection site, rise in serum transaminase andfluid retention have been noted.

Use Ketorolac is frequently used in postopera-tive, dental and acute musculoskeletal pain: 15–30 mg i.m. or i.v. is comparable to 10–12 mgmorphine, and can be repeated every 4–6 hours(max. 90 mg/day). It can also be used for renalcolic, migraine and pain due to bony metastasis.

Orally it is used in a dose of 10–20 mg 6 hourlyfor short-term management of moderate pain. In

Comorbid conditions aggravated by NSAIDs

• Peptic ulcer• Hypertension• Congestive heart failure• Renal insufficiency• Haemostatic disorders

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postoperative dental pain ketorolac has been ratedsuperior to aspirin 650 mg, paracetamol 600 mgand equivalent to ibuprofen 400 mg. Continuoususe for more than 5 days is not recommended.KETOROL, ZOROVON, KETANOV, TOROLAC 10 mgtab, 30 mg in 1 ml amp.

INDOLE DERIVATIVE

Indomethacin It is a potent antiinflammatorydrug with prompt antipyretic action. Indometha-cin relieves only inflammatory or tissue injuryrelated pain. It is a highly potent inhibitor ofPG synthesis and suppresses neutrophil motility.In toxic doses it uncouples oxidative phos-phorylation (like aspirin).

Pharmacokinetics Indomethacin is well absor-bed orally, rectal absorption is slow but depen-dable. It is 90% bound to plasma proteins, partlymetabolized in liver to inactive products andexcreted by kidney. Plasma t½ is 2–5 hours.

Adverse effects A high incidence (up to 50%)of gastrointestinal and CNS side effects is pro-duced.Gastric irritation, nausea, anorexia, gastricbleeding and diarrhoea are prominent.Frontal headache (very common), dizziness,ataxia, mental confusion, hallucination, depres-sion and psychosis can occur.Leukopenia, rashes and other hypersensitivityreactions are also reported.Increased risk of bleeding due to decreasedplatelet aggregability.It is contraindicated in machinery operators,drivers, psychiatric patients, epileptics, kidneydisease, pregnant women and in children.Dose: 25–50 mg BD-QID. Those not tolerating the drugorally may be given nightly suppository.IDICIN, INDOCAP 25 mg cap, 75 mg SR cap, ARTICID25, 50 mg cap, INDOFLAM 25, 75 mg caps, 1% eye drop.RECTICIN 50 mg suppository.

Uses Because of prominent adverse effects,indomethacin is used as a reserve drug inconditions requiring potent antiinflammatoryaction like ankylosing spondylitis, acute exacer-bations of destructive arthropathies, psoriatic

arthritis and acute gout that are not respondingto better tolerated NSAIDs. Use for dental pain israrely justified.

Malignancy associated fever refractory to otherantipyretics may respond to indomethacin. It hasbeen the most common drug used for medicalclosure of patent ductus arteriosus. Bartter’ssyndrome responds dramatically, as it does toother PG synthesis inhibitors.

PYRAZOLONES

Antipyrine (phenazone) and amidopyrine (aminopyrine)were introduced in 1884 as antipyretic and analgesic. Theiruse was associated with high incidence of agranulocytosis:are banned in many countries, including India. Phenylbuta-zone was introduced in 1949 and soon its active metaboliteoxyphenbutazone was also marketed. These two are potentantiinflammatory drugs, inhibit COX, but have slow onset,weak analgesic and antipyretic action. Their gastric toxicityis high; edema due to Na+ and water retention is frequentand CNS side effects, hypersensitivity reactions, hypothy-roidism are reported. They are banned in many countriesand rarely used in others due to residual risk of bonemarrow depression and other toxicity. Two other pyrazo-lones available in India—metamizol and propiphenazone areprimarily used as analgesic and antipyretic.

Metamizol (Dipyrone) In contrast to phenyl-butazone, this derivative of amidopyrine is apotent and promptly acting analgesic andantipyretic but poor antiinflammatory and noturicosuric. It can be given orally, i.m. as well asi.v, but gastric irritation and pain at injection siteoccurs. Occasionally, i.v. injection producesprecipitous fall in BP.

Few cases of agranulocytosis were reportedand metamizol was banned in the USA and someEuropean countries. However, it has beenextensively used in India and other Europeancountries. Adverse reaction data collected overfour decades shows that risk of serious toxicitywith this drug is lower than with aspirin ormany other NSAIDs. However, its fixed dosecombination with antispasmodics is banned inIndia.Dose: 0.5–1.5 g oral/i.m./i.v.; ANALGIN 0.5 g tab;NOVALGIN, BARALGAN 0.5 g tab, 0.5 g/ml in 2 mland 5 ml amps; ULTRAGIN 0.5 g/ml inj in 2 ml amp and30 ml vial.

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Propiphenazone Another pyrazolone, similar inproperties to metamizol; claimed to be bettertolerated. Agranulocytosis has not been reported.Dose: 300–600 mg TDS; marketed only in combination inseveral ‘over-the-counter’, preparations—in SARIDON,ANAFEBRIN: propiphenazone 150 mg + paracetamol250 mg tab.DART: propiphenazone 150 mg + paracetamol 300 mg +caffeine 50 mg tab.

PREFERENTIAL COX-2 INHIBITORS

Nimesulide This NSAID is a relatively weakinhibitor of PG synthesis and there is someevidence to indicate relative COX-2 selectivity.Antiinflammatory action may be exerted by othermechanisms as well, e.g. reduced generation ofsuperoxide by neutrophils, inhibition of PAFsynthesis and TNFα release, free radicalscavanging, inhibition of metalloproteinase acti-vity in cartilage. The analgesic, antipyretic andantiinflammatory activity of nimesulide has beenrated comparable to other NSAIDs. It has beenused primarily for short-lasting painful inflam-matory conditions like sports injuries, sinusitisand other ear-nose-throat disorders, dentalsurgery, bursitis, low backache, dysmenorrhoea,postoperative pain, osteoarthritis and for fever.

Nimesulide is almost completely absorbedorally, 99% plasma protein bound, extensivelymetabolized and excreted mainly in urine with at½ of 2–5 hours.

Adverse effects of nimesulide are gastrointes-tinal (epigastralgia, heart burn, nausea, loosemotions), dermatological (rash, pruritus) andcentral (somnolence, dizziness). Gastric tolera-bility of nimesulide is claimed to be better, butulcer complications may be as prevalent as withother NSAIDs. Recently, several instances offulminant hepatic failure have been associatedwith nimesulide and it has been withdrawn inseveral countries. Considering that it has not beenmarketed in the UK, USA, Australia and Canada,the overall safety of this drug, especially inchildren, has been questioned. However, mostasthmatics and those who develop bronchospasm

or intolerance to aspirin do not cross react withnimesulide. Its specific usefulness appears to beonly in such patients.Dose: 100 mg BD; NIMULID, NIMEGESIC, NIMODOL100 mg tab, 50 mg/5 ml susp.

Meloxicam This newer congener of piroxicamhas a COX-2 : COX-1 selectivity ratio of about 10.Since measurable inhibition of platelet TXA2

production (a COX-1 function) occurs at thera-peutic doses of meloxicam, it has been labelled‘preferential COX-2 inhibitor’. Efficacy ofmeloxicam in osteo- and rheumatoid arthritis iscomparable to piroxicam. Gastric side effects ofmeloxicam are milder, but ulcer complications(bleeding, perforation) have been reported onlong-term use. Thus, there is no convincingevidence that meloxicam is safer than otherNSAIDs.Dose: 7.5-15 mg OD; MELFLAM, MEL-OD, MUVIK, M-CAM 7.5 mg, 15 mg tabs.

Nabumetone It is a prodrug—generates anactive metabolite (6-MNA) which is a relativelymore potent COX-2 than COX-1 inhibitor. Itpossesses analgesic, antipyretic and anti-inflammatory activities; effective in the treatmentof rheumatoid and osteoarthritis as well as softtissue injury. Nabumetone has caused a lowerincidence of gastric erosions, ulcers and bleeding,probably because the active COX inhibitor isproduced in tissues after absorption. However,confirmatory evidence of its superiority is lacking.NABUFLAM 500 mg tab; 1 tab OD.

SELECTIVE COX-2 INHIBITORS (Coxibs)

Because of the theoretical advantage of inhibitingCOX-2 without affecting COX-1 function, somehighly selective COX-2 inhibitors have beenintroduced over the past 2 decades. They causelittle gastric mucosal damage; occurrence of pepticulcer and ulcer bleeds is clearly lower than withtraditional NSAIDs. They do not depress TXA2

production by platelets (COX-I dependent); do notinhibit platelet aggregation or prolong bleedingtime, but reduce PGI2 production by vascularendothelium.

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Currently, 3 selective COX-2 inhibitors (alsocalled coxibs) Celecoxib, Etoricoxib and Parecoxibare available in India; Lumiracoxib is marketed inEurope, while Rofecoxib and Valdecoxib have beenwithdrawn for increasing cardiovascular (CV)risk.

Selective COX-2 inhibitors and cardiovascular risk

COX-2 inhibitors reduce endothelial PGI2 productionwithout affecting platelet TXA2 synthesis. This appearsto exert prothrombotic influence and enhance CV risk.• VIGOR (VIOXX gastrointestinal outcomes research)

study in over 8000 patients found 4-fold higherincidence of myocardial infarction (MI) in rofecoxib(VIOXX) recipients compared to those on naproxen.

• APPROVE (adenomatous polyp prevention onVIOXX) a placebo controlled trial among subjectswith history of colorectal adenomas was stoppedprematurely at 3 years because it confirmed higherrisk of heart attack and stroke: rofecoxib waswithdrawn globally in 2004.

• A metaanalysis of 18 trials with rofecoxib formusculoskeletal disorders has also inferred that itincreases incidence of MI.

• Valdecoxib increased occurrence of MI in patientsundergoing coronary bypass surgery. There werereports of severe skin reactions as well. It waswithdrawn in 2005.

• Though CLASS (celecoxib long-term safety study)did not find any increase in CV events, the APC(adenoma prevention with celecoxib) trial has beenterminated prematurely due to 2.5 fold higher riskof the same.

• There is no clear evidence as yet that etoricoxib andlumiracoxib also increase CV risk.

• A joint committee in USA (2005) has concluded thatenough evidence to withdraw all selective COX-2inhibitors is lacking, but that their labelling shouldinclude a warning of CV risk.

It has been concluded that selective COX-2inhibitors should be used only in patients at highrisk of peptic ulcer, perforation or bleeds. Ifselected, they should be administered in the lowestdose for the shortest period of time. Moreover, theyshould be avoided in patients with history ofischaemic heart disease/hypertension/cardiacfailure/cerebrovascular disease, who are pre-disposed to CV events.

Concerns, other than cardiovascular, havealso been expressed about selective COX-2 inhi-bitors.

Other concerns with selective COX-2 inhibitors

• COX-1 generated PGs may also play a role ininflammation: COX-2 inhibitors may not have asbroad range of efficacy as traditional NSAIDs.

• Ulcer injury and H. pylori induce COX-2 in gastricmucosa, which may contribute to gastroprotectivePG synthesis; COX-2 inhibition may delay ulcerhealing.

• Juxtaglomerular COX-2 is constitutive; its inhibitioncan cause salt and water retention; pedal edema,precipitation of CHF and rise in BP can occur withall coxibs.

Celecoxib The COX-2 selectivity of celecoxib ismodest (6–20 fold). It exerts antiinflammatory,analgesic and antipyretic actions with lowulcerogenic potential. Platelet aggregation inresponse to collagen exposure remained intact incelecoxib recipients and serum TXB2 levels werenot reduced. Though tolerability of celecoxib isbetter than traditional NSAIDs, still abdominalpain, dyspepsia and mild diarrhoea are thecommon side effects. Rashes, edema and a smallrise in BP have also been noted.

Celecoxib is slowly absorbed, 97% plasmaprotein bound and metabolized primarily byCYP2C9 with a t½ of ~10 hours. It is approvedfor use in osteo- and rheumatoid arthritis in adose of 100–200 mg BD.CELACT, REVIBRA, COLCIBRA 100, 200 mg caps.

Etoricoxib This newer COX-2 inhibitor has thehighest COX-2 selectivity. It is suitable for once-a-day treatment of osteo/rheumatoid/acute goutyarthritis, dysmenorrhoea, acute dental surgerypain and similar conditions, without affectingplatelet function or damaging gastric mucosa.The t½ is ~ 24 hours. Side effects are dry mouth,aphthous ulcers, taste disturbance and paresthesias.Dose: 60–120 mg OD; ETODY, TOROCOXIA, ETOXIB,NUCOXIA 60, 90, 120 mg tabs.

Parecoxib It is a prodrug of valdecoxib suitablefor injection, and to be used in postoperative orsimilar short-term pain, with efficacy similar toketorolac.Dose: 40 mg oral/i.m./i.v., repeated after 6–12 hours.REVALDO, VALTO-P 40 mg/vial inj, PAROXIB 40 mg tab.

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PARA-AMINO PHENOL DERIVATIVES

Phenacetin introduced in 1887 was extensivelyused as analgesic-antipyretic but is now bannedbecause it was implicated in analgesic abusenephropathy.

Paracetamol (acetaminophen) the deethylated activemetabolite of phenacetin, was also introduced inthe last century but has come into common useonly since 1950.

Actions The central analgesic action of paraceta-mol is like aspirin, i.e. it raises pain threshold,but has weak peripheral antiinflammatorycomponent. Analgesic action of aspirin andparacetamol is additive. Paracetamol is a goodand promptly acting antipyretic.

Paracetamol has negligible antiinflammatoryaction. It is a poor inhibitor of PG synthesis inperipheral tissues, but more active on COX inbrain. One explanation offered for the discrepancybetween its analgesic-antipyretic and antiinflam-matory actions is its poor ability to inhibit COXin the presence of peroxides which are generatedat sites of inflammation but are not present inbrain. The ability of paracetamol to inhibitCOX-3 could also account for its analgesic-antipyretic action.

In contrast to aspirin, paracetamol does notstimulate respiration or affect acid-base balance;does not increase cellular metabolism. It has noeffect on CVS. Gastric irritation is insignificant—mucosal erosion and bleeding occur rarely onlyin overdose. It does not affect platelet function orclotting factors and is not uricosuric.

Pharmacokinetics Paracetamol is well absorbedorally, only about 1/4th is protein bound inplasma and distribution in the body is quiteuniform. It is conjugated with glucuronic acid and

sulfate and is excreted rapidly in urine. Plasmat½ is 2–3 hours. Effects after an oral dose last for3–5 hours.

Adverse effects In isolated antipyretic dosesparacetamol is safe and well tolerated. Nauseaand rashes occur occasionally, leukopenia is rare.

Analgesic nephropathy occurs after years of heavy ingestionof analgesics; such individuals probably have somepersonality defect. Pathological lesions are papillarynecrosis, tubular atrophy followed by renal fibrosis. Urineconcentrating ability is lost and the kidneys shrink. Becausephenacetin was commonly abused, it was primarilyimplicated and went into disrepute, though other analgesicsare also liable to produce similar effects.

Acute paracetamol poisoning It occurs speciallyin small children who have low hepatic glucu-ronide conjugating ability. If a large dose (> 150mg/kg or > 10 g in an adult) is taken, serioustoxicity can occur. Fatality is common with > 250mg/kg.

Early manifestations are just nausea, vomi-ting, abdominal pain and liver tenderness withno impairment of consciousness. After 12–18hours centrilobular hepatic necrosis occurswhich may be accompanied by renal tubularnecrosis and hypoglycaemia that may progressto coma. Jaundice starts after 2 days. Further coursedepends on the dose taken. Fulminating hepaticfailure and death are likely if the plasma levelsare high. If the levels are lower —recovery withsupportive treatment is the rule.

Mechanism of toxicity N-acetyl-p-benzoqui-noneimine (NABQI) is a highly reactive arylatingminor metabolite of paracetamol which isdetoxified by conjugation with glutathione. Whena very large dose of paracetamol is taken,glucuronidation capacity is saturated, more ofminor metabolite is formed—hepatic glutathioneis depleted and this metabolite binds covalentlyto proteins in liver cells (and renal tubules)causing necrosis. Toxicity thus shows a thresholdeffect manifesting only when glutathione isdepleted to a critical point.

In chronic alcoholics even 5–6 g/day takenfor a few days can result in hepatotoxicity because

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alcoholism induces CYP2E1 that metabolisesparacetamol to NABQI.

Treatment If the patient is brought early, vomi-ting should be induced or gastric lavage done.Activated charcoal is given to prevent furtherabsorption. Other supportive measures, asneeded, should be taken.

N-acetylcysteine infused i.v. or given orally isthe specific antidote. It replenishes hepaticglutathione and prevents binding of the toxicmetabolite to other cellular constituents. It ispractically ineffective if started 12–16 hours afterparacetamol ingestion.

Uses Paracetamol is one of the most commonlyused ‘over-the-counter’ analgesic for headache,musculoskeletal pain, toothache, dysmenorrhoea,etc. where antiinflammatory action is not required.It is relatively ineffective when inflammation isprominent. It is one of the best drugs to be used asantipyretic.

Dose to dose it is equally efficacious as aspirinfor noninflammatory conditions. Clinical studieshave found paracetamol and aspirin to be equieffectivein relieving pain after the extraction of third molars.However, paracetamol is much safer than aspirinin terms of gastric irritation, ulceration andbleeding (can be given to ulcer patients). Becauseit does not prolong bleeding time, risk of toothextraction haemorrhage is not accentuated.Paracetamol can be used in all age groups (infantsto elderly), pregnant/lactating women, inpresence of other disease states and in patients inwhom aspirin is contraindicated. It does nothave significant drug interactions. Thus, it maybe preferred over aspirin for most minorconditions.Dose: 0.5–1 g TDS; infants 50 mg; children 1–3 years 80–160 mg, 4–8 years 240–320 mg, 9–12 years 300–600 mg.CROCIN 0.5, 1.0 g tabs; METACIN, PARACIN 500 mgtab, 125 mg/5 ml syrup, 150 mg/ml paed. drops,ULTRAGIN, PYRIGESIC, CALPOL 500 mg tab, 125 mg/5ml syrup, NEOMOL, FEVASTIN, FEBRINIL 300 mg/2ml inj. CROCIN PAIN RELIEF: Paracetamol 650 mg +Caffeine 50 mg tab.

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BENZOXAZOCINE DERIVATIVE

Nefopam It is a nonopioid analgesic which does notinhibit PG synthesis, but relieves traumatic, dental,postoperative and short-lasting musculoskeletal pain.

Nefopam produces anticholinergic (dry mouth, urinaryretention, blurred vision) and sympathomimetic (tachy-cardia, nervousness) side effects. Nausea is often doselimiting. It is contraindicated in epileptics.Dose: 30–60 mg TDS oral, 20 mg i.m. 6 hourly.NEFOMAX 30 mg tab, 20 mg in 1 ml amp.

Analgesic/NSAIDs in dentistry

The antipyretic-analgesics/NSAIDs are themainstay for management of acute dental pain.While pain during an invasive dental procedureis allayed by local anaesthetic, that before andafter it is treated mostly with analgesics andNSAIDs. There is ample evidence of their efficacyin most types of pain encountered in dentistry.The cause and nature of pain (mild, moderate orsevere; acute or chronic; ratio of pain: inflam-mation) along with consideration of the riskfactors in the patient govern selection of theanalgesic. Also to be considered are the pastexperience of the patient, acceptability andindividual preference. Though NSAIDs have acommon spectrum of adverse effects, they differquantitatively among themselves in producingvarious side effects. Moreover, patients differ intheir analgesic response to different NSAIDs. Ifone NSAID is unsatisfactory in a patient, it doesnot mean that other NSAIDs will also beunsatisfactory. Some subjects ‘feel better’ on aparticular drug, but not on a closely related one.Thus, no single drug is superior to all others forevery patient. It is in this context that availabilityof such a wide range of NSAIDs may be welcome.Some guidelines are:1. Mild-to-moderate pain with little inflam-

mation: paracetamol or low-dose ibuprofen.2. Postextraction or similar acute but short-

lasting pain: ketorolac, a propionic acidderivative, diclofenac, nimesulide or aspirin.

3. Gastric intolerance to conventional NSAIDsor predisposed patients: etoricoxib or para-cetamol.


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4. Patients with history of asthma or anaphy-lactoid reaction to aspirin/other NSAIDs:nimesulide, COX-2 inhibitor.

5. Paediatric patients: only paracetamol, aspirin,ibuprofen and naproxen have been ade-quately evaluated in children — should bepreferred in them. Due to risk of Reye’ssyndrome, aspirin should be avoided unlessviral infection can be ruled out.

6. Pregnancy: paracetamol is the safest; low-doseaspirin is probably the second best.

7. Hypertensive, diabetic, ischaemic heartdisease, epileptic and other patients receivinglong-term regular medication: possibility ofdrug interaction with NSAIDs should beconsidered and the physician consulted.

Analgesic combinations

Combination of aspirin and paracetamol is

additive (not supra-additive) and a ceilinganalgesic effect is obtained when the total amountof aspirin + paracetamol is ~ 1000 mg. The sameis true of combinations of paracetamol with otherNSAIDs like ibuprofen, diclofenac, etc. There isno convincing evidence that such combinationsare superior to single agents either in efficacy orin safety. If at all used, such combinations shouldbe limited to short periods.

Combination of codeine (an opioid analgesic)with aspirin or paracetamol is also additive, butin this case combination provides additionalanalgesia beyond the ceiling effect of aspirin/paracetamol. The mechanisms of pain relief bythese two classes of drugs are different. Suchcombination can be considered rational forproviding greater analgesia. Adequate clinicaldata supports use of such combination for painrefractory to single agent.

OPIOID ANALGESICS

Opium The dark brown, resinous materialobtained from poppy (Papaver somniferum) cap-sule is called ‘Opium’. It contains two types ofalkaloids.

Phenanthrene derivativesMorphine (10% in opium)Codeine (0.5% in opium)Thebaine (0.2% in opium), (Nonanalgesic)

Benzoisoquinoline derivativesPapaverine (1%) NonanalgesicNoscapine (6%)

Opium has been known from the earliest times.Galen (2nd century AD) introduced tincture ofopium. Serturner, a pharmacist, isolated theactive principle of opium in 1806 and named it‘morphine’ after the Greek god of dreams Morpheus.In the last century a large number of semisyntheticand synthetic compounds have been developedwith morphine-like, antagonistic and mixedagonistic-antagonistic properties.

MORPHINE

Morphine is the principal alkaloid in opium andstill widely used, therefore, described as proto-type.


1. CNS Morphine has site specific depressantand stimulant actions in the CNS produced pri-marily through interaction with μ opioid receptoras a full agonist. The depressant effects are:

(a) Analgesia Morphine is a strong analgesic.Though dull, poorly localized visceral pain isrelieved better than sharply defined somatic pain;higher doses can mitigate even severe pain—degree of analgesia increasing with dose. Noci-ceptive pain arising from stimulation of peripheralpain receptors is relieved better than neuretic pain(such as trigeminal neuralgia) due to inflam-mation of or damage to neural structures. Theassociated reactions to intense pain (appre-hension, fear, autonomic effects) are alsodampened. Suppression of pain perception isselective, without affecting other sensations orproducing proportionate generalized CNSdepression (contrast general anaesthetics).

Perception of pain and its emotional orsuffering component are both altered so that painis no longer as unpleasant or distressing, i.e. thepatient tolerates pain better. The analgesic actionof morphine has spinal and supraspinalcomponents. Intrathecal injection has been shownto cause segmental analgesia without affectingother modalities. It acts in the substantia

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gelatinosa of dorsal horn to inhibit release ofexcitatory transmitters from primary afferentscarrying pain impulses. The action appears to beexerted through interneurones which areinvolved in the ‘gating’ of pain impulses. Releaseof glutamate from primary pain afferents in thespinal cord and its postsynaptic action on dorsalhorn neurones is inhibited by morphine. Actionat supraspinal sites in medulla, midbrain, limbicand cortical areas may alter processing andinterpretation of pain impulses as well as sendinhibitory impulses through descendingpathways to the spinal cord. Several aminergicand other neuronal systems appear to be involvedin the action of morphine and simultaneousaction at spinal and supraspinal sites greatlyamplifies the analgesic action.

(b) Sedation which is different from thatproduced by hypnotics is seen. Drowsiness andindifference to surroundings as well as to ownbody occurs without motor incoordination, ataxiaor apparent excitement (contrast alcohol). Higherdoses progressively produce sleep and coma. Ithas no anticonvulsant action, rather, fits may beprecipitated.

(c) Mood and subjective effects These are pro-minent. Morphine has a calming effect; there isloss of apprehension, feeling of detachment, lackof initiative, limbs feel heavy and body warm,mental clouding and inability to concentrateoccurs. In the absence of pain or apprehension,these are generally appreciated as unpleasant bynormal people. However, patients in pain oranxiety and especially addicts, perceive it aspleasurable: refer it as ‘high’. Rapid i.v. injectionby addicts gives them a ‘kick’ or ‘rush’ which isintensely pleasurable—akin to orgasm. Thus, onehas to learn to perceive the euphoric effect ofmorphine.

(d) Respiratory centre Morphine depresses res-piratory centre in a dose-dependent manner; rateand tidal volume are both decreased: death inpoisoning is due to respiratory failure. Neuro-genic, hypercapnoeic and later hypoxic drives to

respiratory centre are suppressed in succession.In addition, there is indifference to breathing:apnoeic patient may breath if commanded.

(e) Cough centre It is depressed; more sensitiveto morphine than respiratory centre.

(f) Temperature regulating centre It is depres-sed; hypothermia occurs in cold surroundings.

(g) Vasomotor centre It is depressed at higherdoses and contributes to the fall in BP.

Morphine stimulates:

(a) CTZ Nausea and vomiting occur as sideeffects, especially if stomach is full and the patientstands or moves about. Thus, morphine appearsto sensitize the CTZ to vestibular and otherimpulses. Larger doses depress vomiting centredirectly: emetics should not be tried in morphinepoisoning.

(b) Edinger Westphal nucleus of III nerve is sti-mulated producing miosis. This is a central action;no miosis occurs on topical application ofmorphine to the eye.

(c) Vagal centre It is stimulated—can cause bra-dycardia.

(d) Certain cortical areas and hippocampal cellsare stimulated. Excitation is seen in an occasionalindividual. Muscular rigidity and immobility isconsistently manifested at high doses: resemblescatalepsy seen in rats and mice. Convulsions mayoccur in morphine poisoning. The proconvulsantaction has been ascribed to inhibition of GABArelease by hippocampal interneurones. Specieslike the cat, lion, horse, sheep and cow areuniformly excited and show hyperthermia.

2. Neuro-endocrine Morphine weakenshypothalamic influence on pituitary. As a resultACTH, FSH and LH levels tend to fall, while GHand prolactin release tends to increase. However,effect on sex hormone levels are clinicallyinsignificant, except in some chronic abusers, whomay suffer from infertility. It enhances ADHrelease and can reduce urine volume. Morphine

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also causes central sympathetic stimulationresulting in mild hyperglycaemia.

3. CVS Morphine causes vasodilatation due to:(a) histamine release.(b) depression of vasomotor centre.(c) direct action decreasing tone of blood vessels.There is a shift of blood from pulmonary tosystemic circuit due to greater vasodilatation inthe latter. Therapeutic doses cause little changein BP of recumbent normovolaemic patient.Postural hypotension and fainting can occur dueto impairment of vascular reflexes. Morphine haslittle direct effect on heart; rate generally decreasesdue to stimulation of vagal centre, but mayincrease if BP falls. Cardiac work is consistentlyreduced due to decrease in peripheral resis-tance. Intracranial tension tends to rise as aconsequence of CO2 retention leading to cerebralvasodilatation.

4. GIT Constipation is a prominent feature ofmorphine action. Several factors contribute:(a) Action directly on intestines and in CNSincreases tone and segmentation but decreasespropulsive movements. Tone of duodenum andcolon may be increased to the level of spasm.(b) Spasm of pyloric, ileocaecal and analsphincters.(c) Decrease in all gastrointestinal secretions.(d) Central action causing inattention todefecation reflex.No tolerance develops to this action: addictsremain chronically constipated.

5. Other smooth muscles

(a) Biliary tract Morphine causes spasm ofsphincter of Oddi → intrabiliary pressure isincreased → may cause biliary colic.

(b) Urinary bladder Tone of both detrusor andsphincter is increased → urinary urgency anddifficulty in micturition.

(c) Bronchi Morphine releases histamine whichcan cause bronchoconstriction. This is of noconsequence in normal individuals, but can bedangerous in asthmatics.

PHARMACOKINETICS

The oral absorption of morphine is unreliablebecause of high and variable first pass meta-bolism; oral bioavailability is 1/6 to 1/4th ofparenterally administered drug. About 30% isbound to plasma proteins. Only a small fractionenters brain rather slowly. Morphine freelycrosses placenta and can affect the foetus morethan the mother. It is primarily metabolized inliver by glucuronide conjugation. Morphine-6-glucuronide is an active metabolite (inherentlymore potent than morphine) which accumulatesduring chronic dosing and contributes to anal-gesia, despite its restricted passage across blood-brain barrier. Plasma t½ of morphine averages2–3 hours. Effect of a parenteral dose lasts 4–6hours. Elimination is almost complete in 24 hoursand morphine is noncumulative. Small amountsmay persist due to enterohepatic circulation.

ADVERSE EFFECTS

Side effects of morphine are sedation, mentalclouding, lethargy and other subjective effectswhich may even be dysphoric in some subjects;vomiting is occasional in recumbent patients;constipation is common. Respiratory depression,blurring of vision, urinary retention (especiallyin elderly males) are the other side effects. BP mayfall, especially in hypovolaemic patient and if he/she walks about.

Urticaria, itch, swelling of lips may occur dueto histamine release.

Acute morphine poisoning It is accidental,suicidal or seen in drug abusers. In the non-tolerant adult, 50 mg of morphine i.m. producesserious toxicity. Manifestations are extensions ofpharmacological action: stupor or coma,flaccidity, shallow and occasional breathing,cyanosis, pinpoint pupil, fall in BP and shock,convulsions may be seen in few, pulmonaryedema occurs at terminal stages, death is due torespiratory failure.

Treatment: Consists of respiratory support andmaintenance of BP (i.v. fluids, vasoconstrictors).

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Gastric lavage should be done with pot. perman-ganate to remove unabsorbed drug.

Naloxone 0.4–0.8 mg i.v. repeated every 2–3minutes till respiration picks up, is the specificantidote. It has a short duration of action. Injectionshould be repeated every 1–4 hours later on,according to response.

Tolerance and dependence High degree oftolerance can be developed to morphine andrelated opioids if the drug is used repeatedly. It ispartly pharmacokinetic (enhanced rate ofmetabolism) but mainly pharmacodynamic(cellular tolerance). Addicts tolerate morphine ingrams: lethal dose is markedly increased. Crosstolerance among opioids is of high degree.Morphine tolerant subjects are partially crosstolerant to other CNS depressants as well.

Morphine produces pronounced psycholo-gical and physical dependence, its abuse liabilityis rated high. Concern about abuse has been amajor limitation in the use of morphine, butappropriate medical use of morphine seldomprogresses to dependence and abuse.

Withdrawal of morphine is associated withmarked drug seeking behaviour. Physical mani-festations are—lacrimation, sweating, yawning,anxiety, fear, restlessness, gooseflesh, mydriasis,tremor, insomnia, abdominal colic, diarrhoea,dehydration, rise in BP, palpitation and rapidweight loss. Delirium and convulsions are seenonly occasionally.

Treatment: consists of withdrawal of morphineand substitution with oral methadone (longacting, orally effective) followed by gradual with-drawal of methadone. However, relapse rateamong postaddicts is high. Long-term methadonemaintenance and other techniques using agonist-antagonistic drugs are also employed.

PRECAUTIONS AND CONTRAINDICATIONS

Morphine is a drug of emergency, but due carehas to be taken in its use.1. Infants and the elderly are more susceptibleto the respiratory depressant action of morphine.

2. It is dangerous in patients with respiratoryinsufficiency (emphysema, pulmonary fibrosis,cor pulmonale), sudden deaths have occurred.3. Bronchial asthma: Morphine can precipitatean attack by its histamine releasing action.4. Head injury: morphine is contraindicated inpatients with head injury. Reasons are—(a) By retaining CO2, it increases intracranialtension which will add to that caused by headinjury itself.(b) Even therapeutic doses can cause markedrespiratory depression in these patients.(c) Vomiting, miosis and altered mentationproduced by morphine interfere with assessmentof progress in head injury cases.5. Hypotensive states and hypovolaemia exag-gerate fall in BP due to morphine.6. Undiagnosed acute abdominal pain: mor-phine can aggravate certain conditions, e.g.diverticulitis, biliary colic, pancreatitis. Inflamedappendix may rupture.7. Elderly male: chances of urinary retention arehigh.8. Hypothyroidism, liver and kidney diseasepatients are more sensitive to morphine.9. Unstable personalities: are liable to continuewith its use and become addicted.

Interactions

Phenothiazines, tricyclic antidepressants, MAOinhibitors, amphetamine and neostigmine poten-tiate morphine and other opioids, either by retar-ding its metabolism or by a pharmacodynamicinteraction at the level of central neurotrans-mitters.

Morphine retards absorption of many orallyadministered drugs by delaying gastric emptying.Dose 10–50 mg oral, 10–15 mg i.m. or s.c. or 2–6 mg i.v.;2–3 mg epidural/intrathecal; children 0.1–0.2 mg/kg.MORPHINE SULPHATE 10 mg/ml inj; MORCONTIN10, 30, 60, 100 mg continuous release tabs; 30–100 mgBD; RILIMORF 10,20 mg tabs, 60 mg SR tab.

CLASSIFICATION OF OPIOIDS

1. Natural opium alkaloids: Morphine, Codeine

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2. Semisynthetic opiates: Diacetylmorphine(Heroin), Pholcodeine.

3. Synthetic opioids: Pethidine (Meperidine),Fentanyl, Methadone, Dextropropoxyphene,Tramadol.

1. Codeine It is methyl-morphine, occursnaturally in opium, and is partly converted in thebody to morphine. It is less potent than morphine(1/10th as analgesic), also less efficacious; apartial agonist at μ opioid receptor with lowceiling effect. The degree of analgesia iscomparable to aspirin (60 mg codeine ~ 600 mgaspirin); can relieve mild-to-moderate pain only.

However, it is more selective cough suppres-sant (1/3rd as potent as morphine); subanalgesicdoses (10–30 mg) suppress cough. Codeine hasvery low affinity for opioid receptors. Theanalgesic action has been ascribed to morphinegenerated by its demethylation by CYP2D6.

Codeine has good activity by oral route (oral:parenteral ratio 1:2). A single oral dose acts for4–6 hours. Constipation is a prominent side effect,but others are mild. It has been used to controldiarrhoea. The abuse liability of codeine is low.Though codeine phosphate is water soluble andcan be injected, parenteral preparation is notavailable.

2. Pholcodeine It has codeine-like properties and hasbeen used mainly as antitussive; claimed to be less consti-pating.

3. Heroin (Diamorphine, Diacetylmorphine) It is about3 times more potent than morphine; more lipid soluble:enters brain more rapidly but duration of action is similar.It is considered to be more euphorient (especially on i.v.injection) and highly addicting. However, it has no out-standing therapeutic advantage over morphine and hasbeen banned in most countries except the UK.

4. Pethidine (Meperidine)Pethidine was synthesized as an atropinesubstitute in 1939, and has some actions like it.Though chemically unrelated to morphine, itinteracts with opioid receptors (primarily μ) andits actions are blocked by naloxone. Importantdifferences in comparison to morphine are:1. Dose to dose 1/10th in analgesic potency;however, analgesic efficacy approaches near tomorphine and is more than codeine.2. After i.m. injection, the onset of action is morerapid but duration is shorter (3–4 hours).3. It does not effectively suppress cough.4. Spasmodic action on smooth muscles is lessmarked—miosis, constipation and urinaryretention are less prominent.

Pethidine is believed to induce less biliary spasm thanmorphine; traditionally preferred in cholecystitis/biliarycolic. However, there is no objective evidence to supportthis belief. One study* in patients undergoing cholecys-tectomy found pethidine to raise common bile ductpressure 14% more than equianalgesic dose of morphine.

5. It is equally sedative and euphoriant, hassimilar abuse potential. The degree of respiratorydepression seen at equianalgesic doses isequivalent to morphine.6. Tachycardia (due to antimuscarinic action)occurs instead of bradycardia.7. It causes less histamine release and is safer inasthmatics.8. It has local anaesthetic action: corneal anaes-thesia is seen after systemic doses.9. It is well absorbed, oral: parenteral activityratio is high (1/3–1/2). Pethidine is nearlycompletely metabolized in liver. The plasma t½of pethidine is 2–3 hours. Acidification of urineincreases excretion of unchanged pethidine.

Side effects These are similar to morphineexcept those mentioned above. Some atropiniceffects (dry mouth, blurred vision, tachycardia)may be noted in addition.* See Lee F and Cundiff D; Arch Intern. Med. 158, (1998), 2399.

Hydrolysis Meperidinic acid Conjugated(major metabolite) with glucuronic

Pethidine acid and excre-Demethylation Norpethidine ted in urine

(minor metabolite)

⎫⎬⎭

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Overdose of pethidine produces many excita-tory effects—tremors, mydriasis, hyperreflexia,delirium, myoclonus and convulsions. This isdue to accumulation of norpethidine which hasexcitant effects. Renal failure patients givenrepeated doses of pethidine may also experiencesimilar effects.

Nonselective MAO inhibitors interfere withhydrolysis but not with demethylation ofpethidine—norpethidine is produced in excessand excitement occurs.

Use Pethidine is primarily used as an analgesic(substitute of morphine) and in preanaestheticmedication, but not for cough or diarrhoea.Potential adverse effects due to accumulation ofnorpethidine limit its utility in patients whorequire repeated dosing.Dose: 50–100 mg i.m., s.c. (may cause irritation, localfibrosis on repeated injection), occasionally given orally ori.v.PETHIDINE HCL 100 mg/2 ml inj; 50, 100 mg tab.

5. Fentanyl A pethidine congener, 80–100 timesmore potent than morphine, both in analgesia andrespiratory depression. In analgesic doses itproduces few cardiovascular effects; has littlepropensity to release histamine. Because of highlipid solubility, it enters brain rapidly andproduces peak analgesia in 5 min after i.v.injection. The duration of action is short: startswearing off after 30–40 min due to redistribution,while elimination t½ is ~4 hr. In the injectableform it is almost exclusively used in anaesthesia(see p. 124). Transdermal fentanyl has becomeavailable for use in cancer or other types of chronicpain for patients requiring opioid analgesia.DUROGESIC transdermal patch delivering 25 μg/hr, 50μg/hr or 75 μg per hour; the patch is changed every 2 to 3days.

6. Methadone A synthetic opioid, chemicallydissimilar but pharmacologically very similar tomorphine—has analgesic, respiratory depres-sant, emetic, antitussive, constipating and biliaryactions similar to morphine.

The most important feature of methadone ishigh oral: parenteral activity ratio (1 : 2) and its

firm binding to tissue proteins. In single doses itis only slightly more potent than morphine andhas comparable duration of action (4–6 hours oni.m. injection), but it cumulates in tissues onrepeated administration—duration of action isprogressively lengthened due to gradual releasefrom these sites; plasma t½ on chronic use is24–36 hours. Plasma protein binding is 90% andit is metabolized in liver, primarily by demethy-lation and cyclization—metabolites are excretedin urine. Rifampin and phenytoin can cause with-drawal symptoms to appear in methadone-dependent subjects by inducing its metabolism.

Because of slow and persistent nature of action,sedative and subjective effects are less intense. Itis probably incapable of giving a ‘kick’. The abusepotential is rated somewhat lower than morphine.Tolerance develops more slowly. Withdrawalsyndrome is of gradual onset, taking 1–2 daysafter discontinuation, is prolonged and lesssevere.

Methadone has been used primarily as sub-stitution therapy of opioid dependence: 1 mg oforal methadone can be substituted for 4 mg ofmorphine, 2 mg of heroin and 20 mg of pethidine.Another technique is methadone maintenancetherapy in opioid addicts—sufficient dose ofmethadone is given orally to produce high degreeof tolerance so that pleasurable effects of i.v. dosesof morphine or heroin are not perceived and thesubject gives up the habit.

It can also be used as an analgesic for the sameconditions as morphine; dose 2.5–10 mg oral ori.m. but not s.c.PHYSEPTONE 10 mg inj, 2 mg/5 ml linctus.

7. Dextropropoxyphene It is similar inanalgesic action and in side effects to codeine,except that it is poor antitussive and probablyless constipating. It is nearly ½ as potent ascodeine and has a lower oral: parenteral activityratio. Marketed only in combination withparacetamol for relief of mild-to-moderate pain,the contribution of dextropropoxyphene to theanalgesic effect is questionable. The demethylatedmetabolite of dextropropoxyphene is cardiotoxic.

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Its overdose can produce rapid onset respiratorydepression, delirium and convulsions. However,the abuse potential of dextropropoxyphene isnegligible because of low potency and unpleasantside effects at higher doses.PARVODEX 60 mg cap: PARVON, PROXYVON,WALAGESIC: dextropropoxyphene 65 mg + paraceta-mol 400 mg cap; WYGESIC, SUDHINOL 65 mg +paracetamol 650 mg cap.

8. Tramadol This centrally acting analgesic isan atypical opioid which relieves pain by opioidas well as additional mechanisms. Its affinity forμ opioid receptor is modest while that for κ and δis weak. Unlike other opioids, it inhibits reuptakeof NA and 5-HT, and thus activates mono-aminergic spinal inhibition of pain. Its analgesicaction is only partially reversed by opioidantagonist naloxone.

Injected i.v. 100 mg tramadol is equianalgesicto 10 mg i.m. morphine; oral bioavailability is good(oral: parenteral dose ratio 1.2 : 1). The t½ is 3–5hours and effects last for 4–6 hrs. Tramadol causesless respiratory depression, sedation, constipa-tion, urinary retention and rise in intrabiliarypressure than morphine. It is well tolerated; sideeffects are dizziness, nausea, sleepiness, drymouth and sweating. Haemodynamic effects areminimal.

Tramadol is indicated for mild-to-mediumintensity short-lasting pain due to diagnosticprocedures, injury, surgery, dentistry, etc. as wellas for chronic pain including cancer pain, but isnot effective in severe pain. Little tendency to doseescalation is seen and abuse potential is low.Dose: 50–100 oral/i.m./slow i.v. infusion (children 1–2mg/kg) 4–6 hourly.CONTRAMAL, DOMADOL, TRAMAZAC 50 mg cap,100 mg SR tab; 50 mg/ml inj in 1 and 2 ml amps.

USES (of morphine and its congeners)

1. As analgesic Opioid analgesics are indicatedin severe pain of any type. However, their use indentistry is very limited. They only providesymptomatic relief without affecting the cause.

Morphine and its parenteral congeners areindicated in traumatic, visceral, ischaemic

(myocardial infarction), postoperative, burn,cancer pain and the like. It should be givenpromptly in myocardial infarction to allay appre-hension and reflex sympathetic stimulation.Patient controlled analgesia is an attractivetechnique of postoperative pain control in whichthe patient himself regulates the rate of i.v.fentanyl infusion according to intensity of painfelt. Opioids, especially pethidine, have beenextensively used for obstetric analgesia.

Adequate use of morphine (even i.v.) is indi-cated in an emergency. It may prevent neurogenicshock and other autonomic effects of excrucia-ting pain such as that of crush injuries, fracturemandible/maxilla, etc. Neuropathic pain res-ponds less predictably to opioid analgesics.

Transdermal fentanyl is a suitable option forchronic cancer and other terminal illness pain.

For milder pain, e.g. toothache, headache,neuralgias, etc., aspirin-like analgesics arepreferred. When they are not effective alone,codeine may be added. The combination enhancesthe ceiling analgesia. For more severe and longerlasting pain, it has been advised to combine aNSAID with the opioid.

2. Preanaesthetic medication Morphine andpethidine are used in selected patients.

3. Balanced anaesthesia and surgical anal-gesia Fentanyl, morphine or pethidine are animportant component of anaesthetic techniques(see p. 124).

4. Relief of anxiety and apprehension Speciallyin myocardial infarction, internal bleeding(haematemesis, threatened abortion, etc.) morp-hine or pethidine have been employed.

5. Acute left ventricular failure (cardiac asthma)Morphine (i.v.) affords dramatic relief by:(a) Reducing preload on heart due to vaso-dilatation and peripheral pooling of blood.(b) Tending to shift blood from pulmonary tosystemic circuit; relieves pulmonary congestionand edema.(c) Allays air hunger by depressing respiratorycentre.

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Table 24.1: Actions ascribed to different types of opioid receptors

μ (mu) κ (kappa) δ (delta)

Analgesia Analgesia (spinal κ1) Analgesia (Spinal + Affective

(supraspinal μ1 + spinal μ

2) (Supraspinal-κ

3) component of supraspinal)

Respiratory depression (μ2) Respiratory depression (lower ceiling) Respiratory depression

Sedation Dysphoria, hallucinations Affective behaviourEuphoria Miosis (lower ceiling) Reinforcing actionsMiosis Sedation Reduced g.i. motilityReduced g.i. motility (μ

2) Physical dependence (nalorphine type)

Physical dependence (morphine type)

Table 24.2: Nature of interaction of opioid ligands with the three major types ofopioid receptors, and equivalent analgesic doses

Ligand μ (mu) κ (kappa) δ (delta) Analgesic*dose (mg)

1. Morphine Ago. (St) Ago. (W) Ago. (W) 10

2. Nalorphine Anta. (St) Ago. (M) (?) —

3. Pentazocine P.Ago., Anta. (W) Ago. (M) — 30–60

4. Buprenorphine P.Ago Anta. (M) — 0.3–0.4

5. Butorphanol P.Ago (W) Ago. (St) — 1–3

6. Naloxone Anta. (St) Anta. (M) Anta. (W) —

7. Met/Leu Enkephalin Ago. (M) — Ago. (St) —

8. β-Endorphin Ago. (St) — Ago. (St) —

9. Dynorphin A, B Ago. (W) Ago. (St) Ago. (W) —

* Equivalent single parenteral analgesic dose.P. Ago—Partial agonist: have lower efficacy, though affinity (potency) may be high.St—Strong action; M—Moderate action; W—Weak action (low affinity).

(d) Cuts down sympathetic stimulation bycalming the patient, reduces cardiac work.

6. Cough Codeine or its substitutes are widelyused for suppressing dry, irritating cough (seeCh. 19).

7. Diarrhoea The constipating action of codeinehas been used to check diarrhoea and to increasethe consistency of stools in colostomy. Syntheticopioids exclusively used as antidiarrhoeals arediphenoxylate and loperamide (see Ch. 18).

OPIOID RECEPTORS

Morphine and other opioids exert their actionsby interacting with specific receptors present onneurones in the CNS and in peripheral tissues.Chemical modification of morphine structure hasyielded a number of compounds which have a

complex pattern of morphine-like and otheragonistic and antagonistic actions that cannot beexplained on the basis of a single opioid receptor.Radioligand binding studies have divided theopioid receptors into three types (μ, κ, δ); whichhave been cloned. Each has a specific pharma-cological profile and pattern of anatomicaldistribution in brain, spinal cord and peripheraltissues. Subtypes of μ and κ receptor have beenidentified. The proposed functional role of the 3types of opioid receptors is listed in Table 24.1.

Opioid ligands can interact with differentopioid receptors as agonists, partial agonists orcompetitive antagonists. The overall pattern ofeffect of a particular agent depends not only onthe nature of its interaction with different opioidreceptors but also on its relative affinity for these,e.g. morphine is an agonist on μ, κ and δ receptors,

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but its affinity for μ receptors is much higher thanthat for the other two. The effects, therefore, areprimarily the result of μ receptor activation.

The nature and intensity of action of complexaction opioids and antagonists are summarizedin Table 24.2.

µ receptor The μ receptor is characterized by itshigh affinity for morphine. It is the major receptormediating actions of morphine and its congeners.Endogenous ligands for μ receptor—peptidescalled Endomorphins 1 and 2—have only recentlybeen found in mammalian brain—producebiological effects ascribed to this receptor. Highdensity of μ receptors has been detected inperiaqueductal grey, thalamus, nucleus tractussolitarious, nucleus ambiguus and area postrema.

κκκκκ receptor This receptor is defined by its highaffinity for ketocyclazocine and dynorphin A; thelatter is considered to be its endogenous ligand.Analgesia caused by κ agonists is primarilyspinal, but lower ceiling supraspinal analgesiais also produced.

δδδδδ receptor This receptor has high affinityfor Leu/Met enkephalins which are itsendogenous ligands. The δ mediated analgesia isagain mainly spinal (δ receptors are present indorsal horn of spinal cord), but the affectivecomponent of supraspinal analgesia appears toinvolve δ receptors because these receptors arepresent in limbic areas—also responsible fordependence and reinforcing actions. Myentericplexus neurones express high density of δreceptors—mediate reduced g.i. motility.

Opioid receptor transducer mechanisms All 3types of opioid receptors (μ, κ, δ) have been cloned;all are G-protein coupled receptors situated mostlyon prejunctional neurones. They generallyexercise inhibitory modulation by decreasingrelease of the junctional transmitter (Fig. 24.1). Assuch, various monoaminergic (NA, DA, 5-HT),GABA, glutamate (NMDA) pathways areintricately involved in opioid actions.

Opioid receptor activation reduces intra-cellular cAMP formation and opens K+ channels(mainly through μ and δ receptors) or suppresses

Fig. 24.1: Opioid receptor transducer mechanismsAC-Adenylyl cyclase; Gi-coupling protein; cAMP-Cyclic AMP

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voltage gated N type Ca2+ channels (mainly κreceptor). These actions result in neuronalhyperpolarization and reduced availability ofintracellular Ca2+ → decreased neurotransmitterrelease by CNS and myenteric neurones (e.g.glutamate from primary nociceptive neurones).

COMPLEX ACTION OPIOIDS AND OPIOIDANTAGONISTS

1. Agonist-antagonists (κ analgesics)Nalorphine, Pentazocine, Butorphanol

2. Partial/weak µ agonist + κ antagonistBuprenorphine

3. Pure antagonistsNaloxone, NaltrexoneClinically, the agonist-antagonist (agonist at

one opioid receptor, antagonist at another) andpartial/weak agonist (low intrinsic activity)opioids are analgesics of efficacy comparable tolow doses of morphine, but with a limited doserange. They cause low ceiling respiratory depres-sion and have lower abuse potential. However,in only few situations they have proven to beadvantageous over the full μ agonists.

1. Nalorphine It is a κ agonist and μ antagonist; hasanalgesic action, but not used clinically because ofdysphoric and psychotomimetic effects. Naloxone hasreplaced it as a morphine antidote.

2. Pentazocine It is the first agonist-antagonistto be used as an analgesic. The μ antagonisticaction is weak while κ agonistic action is moremarked. Important differences from morphineare:

(a) Analgesia caused by pentazocine is primarilyspinal (κ1) and has a different character than thatcaused by morphine. Parenterally 30 mgpentazocine = 10 mg morphine; but ceiling effectis lower, i.e. at higher doses proportionate increasein analgesia does not occur.(b) Sedation and respiratory depression is 1/3 to1/2 of morphine at lower doses, and has a lowerceiling, does not increase much beyond 60 mgdose.

(c) Tachycardia and rise in BP are produced dueto sympathetic stimulation. This increases cardiacwork; better avoided in coronary ischaemia andmyocardial infarction.(d) Biliary spasm and constipation are less severe.(e) Vomiting is less frequent. Other side effectsare sweating and lightheadedness.(f) Subjective effects are pleasurable (morphinelike) at lower doses: recognised by post-addictsas an opiate. However, as dose is increased, thesebecome unpleasant (nalorphine like at > 60 mgi.m.) and psychotomimetic effects (κ, σ mediated)appear.

Tolerance, psychological and physical depen-dence to pentazocine develops on repeated use.Withdrawal syndrome has features of bothmorphine and nalorphine abstinence, but ismilder in intensity. ‘Drug seeking’ occurs. Abuseliability is rated lower than morphine.

Injected in morphine dependent subjects, itprecipitates withdrawal. Antagonistic action is1/5th as potent as nalorphine: not enough to beuseful in morphine poisoning.

Pharmacokinetics and use Pentazocine is effec-tive orally, though considerable first passmetabolism occurs; oral: parenteral ratio is 1 : 3.It is oxidized and glucuronide conjugated in liverand excreted in urine. Plasma t½ is 3–4 hours,duration of action of a single dose is 4–6 hours.Oral dose: 50–100 mg, efficacy like codeine.Parenteral dose: 30–60 mg i.m., s.c., may cause localfibrosis on repeated injection due to irritant property.FORTWIN 25 mg tab., 30 mg/ml inj., PENTAWIN,SUSEVIN 30 mg/ml inj.

Pentazocine is indicated for postoperativeand moderately severe pain in burns, trauma,fracture, cancer, etc. Though abuse liability is low,frequent side effects and potential for dysphoric/psychotomimetic effect limits its utility.

3. Butorphanol It is a κ analgesic, similar tobut more potent than pentazocine (butorphanol2 mg = pentazocine 30 mg). Sedation, nausea,cardiac stimulation and other side effects aresimilar to pentazocine, but subjective effects areless dysphoric and less psychotomimetic (it is a

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weaker σ agonist at higher doses). BP is notincreased.

The abuse potential of butorphanol is low. Themost outstanding feature is that butorphanol canneither substitute for nor antagonize morphine.This shows its very weak interaction with μreceptors.

It has been used in a dose of 1–4 mg i.m. or i.v.for postoperative and other short-lasting painfulconditions, but should be avoided in patients withcardiac ischaemia.BUTRUM 1 mg/ml, 2 mg/ml inj.

4. Buprenorphine It is a synthetic thebainecongener, highly lipid-soluble μ analgesic that is25 times more potent than morphine. It has aslower onset and longer duration of action. Aftera single dose, analgesia lasts for 6–8 hours; butwith repeated use, duration of action increases to~24 hours.

Sedation, vomiting, miosis, subjective andcardiovascular effects are similar to morphine,but constipation is less marked. Postural hypo-tension is prominent. Respiratory depression (andanalgesia) exhibit ceiling effect. It substitutes formorphine at low levels of dependence butprecipitates withdrawal in highly dependentsubjects, reflecting its partial agonistic action at μreceptors. Antagonistic action on κ receptor hasalso been described.

Lower degree of tolerance and physical as wellas psychological dependence develops withbuprenorphine on chronic use. Its withdrawalsyndrome resembles that of morphine but isdelayed for several days, is milder and longerlasting. ‘Drug seeking’ is present. Abuse liabilityis rated lower than morphine.

Even naloxone (at high dose) only partiallyreverses buprenorphine effects and does notprecipitate its withdrawal; probably because ofmore tight binding of buprenorphine to opioidreceptors.

Buprenorphine has good efficacy by sublin-gual route, is highly plasma protein bound andremains in tissues for several days; t½ is 40 hours.It is mostly excreted unchanged in bile and findsits way out of the body in faeces.

Dose: 0.3–0.6 mg i.m., s.c. or slow i.v., also sublingual0.2–0.4 mg 6–8 hourly.NORPHIN, TIDIGESIC 0.3 mg/ml inj. 1 and 2 ml amps.0.2 mg sublingual tab; BUPRIGESIC, PENTOREL 0.3 mg/ml inj in 1, 2 ml amp.

Use: Buprenorphine is indicated for long-lasting painful conditions requiring an opioidanalgesic, e.g. cancer pain. It has also beenrecommended for premedication, postoperativepain and in myocardial infarction, but seldom usedfor dental pain.

PURE OPIOID ANTAGONISTS

1. Naloxone It is N-alylnor-oxymorphone anda competitive antagonist for all types of opioidreceptors. However, it blocks μ receptors at muchlower doses than those needed to block κ or δreceptors. It is devoid of any kind of agonisticactivity even at high doses (20 times μ blockingdose). No subjective or autonomic effects areproduced in individuals who have not receivedan opioid. No physical/psychological depen-dence or abstinence syndrome has been observed.

Injected intravenously (0.4–0.8 mg) it promp-tly antagonizes all actions of morphine: analgesiais gone, respiration is not only normalized buteven stimulated—probably due to sudden sensiti-zation of respiratory centre to the retained CO2, orit is a manifestation of acute withdrawal, pupilsdilate. However, sedation is less completelyreversed.

At 4–10 mg dose, it also antagonizes theagonistic actions of nalorphine, pentazocine, etc.

Actions of buprenorphine are prevented butnot effectively reversed by naloxone, because itfails to displace buprenorphine that has alreadybound to the opioid receptors.

Naloxone 0.4 mg i.v. precipitates morphinewithdrawal in dependent subjects: the syndromelasts for 2–3 hours.

It also blocks placebo, acupuncture and stress-induced analgesia: showing involvement ofendogenous opioid peptides in these.

Naloxone is inactive orally because of highfirst pass metabolism in liver. Injected i.v. it acts

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in 2–3 min. The primary pathway of metabolismis glucuronidation. Plasma t½ is 1 hour in adultsand 3 hours in newborns.NARCOTAN 0.4 mg in 1 ml (adult) and 0.04 mg in 2 ml(infant) amps; NALOX, NEX 0.4 mg inj.

Use Naloxone is the drug of choice for morphinepoisoning (0.4–0.8 mg i.v. every 2–3 min: max 10mg) and for reversing neonatal asphyxia due toopioid use during labour. It is also used to treatoverdose with other opioids and agonist-antagonists (except buprenorphine).

2. Naltrexone It is chemically related to nalo-xone and is another pure opioid antagonistdevoid of subjective and other agonistic effects.Naltrexone differs from naloxone in being orallyactive, more potent and having a long duration ofaction (1–2 days) which makes it suitable for‘opioid blockade’ therapy of postaddicts: 50 mg/day is given orally so that if the subject takes his/her usual shot of the opioid, no subjective effectsare produced and the craving subsides. Alcoholcraving is also reduced by naltrexone; it is beingused to prevent relapse of heavy drinking. Sideeffects are nausea and headache; high doses cancause hepatotoxicity.NALTIMA, NALTROX 50 mg tab.

ENDOGENOUS OPIOID PEPTIDES

In the mid 1970s, with herculean efforts, a numberof peptides having morphine-like actions wereisolated from mammalian brain, pituitary, spinalcord and g.i.t. These are active in very smallamounts, their actions are blocked by naloxone,and they bind with high affinity to the opioidreceptors. There are 3 distinct families of opioidpeptides. Each is derived from a specific largeprecursor polypeptide.

1. Endorphins β-endorphin (β-END) having31 amino acids is the most important of the endor-phins. It is derived from Pro-opio-melanocortin(POMC) which also gives rise to γ-MSH, ACTHand two lipotropins. β-END is primarily μ agonistbut also has δ action.

2. Enkephalins Methionine-enkephalin(met-ENK) and leucine-enkephalin (leu-ENK) arethe most important. Both are pentapeptides. Thelarge precursor peptide proenkephalin has 4 met-ENK and 1 leu-ENK residues. The two ENKs havea slightly different spectrum of activity; while met-ENK has equal affinity for μ and δ sites, leu-ENKprefers δ receptors.

3. Dynorphins Dynorphin A and B (DYN-A,DYN-B) are 8–17 amino acid peptides derivedfrom prodynorphin which contains 3 leu-ENKresidues also. DYNs are more potent on κreceptors, but also activate μ and δ receptors.

The opioid peptides constitute an endogenousopioid system which normally modulates painperception, mood, hedonic (pleasure related) andmotor behaviour, emesis, pituitary hormonerelease and g.i.t. motility, etc.

β-END injected directly into brain is 20–40times more potent analgesic than morphine. Itsprimary localization in hypothalamus and pitui-tary and its long t½ ascribes it a neurohormonefunction which modulates the release of otherhormones. It decreases LH, FSH release andincreases GH and prolactin release. Naloxone hasopposite effects on the levels of these hormones—suggesting that the system is constitutively active.

The wide distribution of ENKs and DYNs andtheir short t½ suggests function as neuromodulatoror neurotransmitter. They appear to regulate painresponsiveness at spinal and supraspinal levels.Naloxone blocks placebo, acupuncture and stress-induced analgesias, suggesting the involvementof opioid peptides in these responses. Opioidpeptides also appear to participate in regulationof affective behaviour and autonomic function.

Morphine and other opioids act as exogenousagonists on some of the receptors for these peptides.This has given an explanation for the existence ofspecific receptors in the body for exogenoussubstances like morphine.

Opioids in dental pain

Dental pain is mostly either due to or associatedwith inflammation. As such, the antiinflammatoryanalgesics or NSAIDs are more effective and more

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suitable than opioid analgesics. The latter areoccasionally employed as additional drugs withaspirin, paracetamol, ibuprofen or the like to boosttheir analgesic effect. When an opioid has to begiven, an oral drug like codeine is most suited,because dental patients are mostly ambulatoryand suffer from dull, continuous, short-lastingpain. Oral pentazocine or tramadol are thealternatives. Risk of producing dependence isnegligible with such use. Efficacy of dextro-propoxyphene in enhancing analgesic action ofNSAIDs is doubtful. Role of injected opioids like

morphine, pethidine or fentanyl in dentistry islimited to occasional intraoperative or periope-rative use to supplement the local anaesthetic andallay apprehension.

Clearly, the place of analgesics in dental painis secondary to treatment of the cause of pain byappropriate local (antiseptics, cavity filling, rootcanal therapy, etc.) and systemic (antibiotics)measures. Short-term use of opioids, as is madein dentistry, has no significant drug interactionsand does not require modification of otherconcurrent medication.

Opioids in Dental Pain 353

Local anaesthetics (LAs) are drugs which upontopical application or local injection cause rever-sible loss of sensory perception, especially of pain,in a restricted area of the body. They block gene-ration and conduction of nerve impulse at all partsof the neurone where they come in contact, withoutcausing any structural damage. Thus, not onlysensory but also motor impulses are interruptedwhen a LA is applied to a mixed nerve, resultingin muscular paralysis and loss of autonomiccontrol as well.

Local anaesthetics are employed routinely bydentists; so much so that current practice of den-tistry is inconceivable without local anaesthesia.Important differences between general and localanaesthesia are listed in Table 25.1.

Table 25.1: Comparative features of general andlocal anaesthesia

General Localanaesthesia anaesthesia

1. Site of action CNS Peripheral nerves 2. Area of body involved Whole body Restricted area 3. Consciousness Lost Unaltered 4. Care of vital functions Essential Usually not

needed 5. Physiological trespass High Low 6. Poor health patient Risky Safer 7. Use in non-cooperative Possible Not possible

patient 8. Major surgery Preferred Cannot be used 9. Minor surgery Not Preferred

preferred

CLASSIFICATION

Injectable

Low potency, short durationProcaine, Chloroprocaine

Intermediate potency and durationLidocaine (Lignocaine)Prilocaine

High potency, long durationTetracaine (Amethocaine)BupivacaineRopivacaineDibucaine (Cinchocaine)

Surface Anaesthetic

Soluble InsolubleCocaine BenzocaineLidocaine ButylaminobenzoateTetracaine (Butamben)Benoxinate Oxethazaine

Mepivacaine, Etidocaine, Articaine, Dyclonine are otherlocal anaesthetics occasionally used in some countries.

Some other drugs, e.g. propranolol, chlorpromazine,H1 antihistaminics, quinine have significant LA activity,but are not used for this purpose because of local irritancyor other prominent systemic activity. Local anaesthesiacan be produced by cooling as well, e.g. application of ice,CO2 snow, ethylchloride spray.

CHEMISTRY

The clinically useful LAs are weak bases withamphiphilic property. A hydrophilic secondary

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or tertiary amine on one side and a lipophilicaromatic residue on the other are joined by analkyl chain through an ester or amide linkage.

Ester linked LAs Cocaine, procaine, chloropro-caine, tetracaine, benzocaine.

Amide linked LAs Lidocaine, bupivacaine, dibu-caine, prilocaine, ropivacaine.

Features of amide LAs(compared to ester LAs)

• Produce more intense and longer lastinganaesthesia

• Bind to α1 acid glycoprotein in plasma• Not hydrolysed by plasma esterases• Rarely cause hypersensitivity reactions; no

cross sensitivity with ester LAs

Because of their short duration, less intenseanalgesia and higher risk of hypersensitivity, theester linked LAs are rarely used for infiltration ornerve block, but are still used topically on mucousmembranes.

MECHANISM OF ACTION

The LAs block nerve conduction by decreasingthe entry of Na+ ions during upstroke of actionpotential (AP). As the concentration of the LA isincreased, the rate of rise of AP and maximumdepolarization decreases (Fig. 25.1) causingslowing of conduction. Finally, local depolari-zation fails to reach the threshold potential andconduction block ensues.

The LAs interact with a receptor situatedwithin the voltage sensitive Na+ channel and raisethe threshold of channel opening: Na+ permea-bility fails to increase in response to an impulseor stimulus. The details are explained in Fig. 25.2.At physiological pH, the LA molecule is partlyionized. The equilibrium between the unionizedbase form (B) and the ionized cationic form (BH+)depends on the pKa of the LA.

The predominant active species (cationic formof LA) is able to approach its receptor only whenthe channel is open at the inner face and it bindsmore avidly to the inactivated state of the channel.Thus, a resting nerve is rather resistant toblockade. Blockade develops rapidly when thenerve is stimulated repeatedly. The degree ofblockade is frequency dependent: greaterblockade at higher frequency of stimulation.Blockade of conduction by LA is not due to hyper-polarization; in fact, resting membrane potentialis unaltered because K+ channels are blocked onlyat higher concentrations of LA.

The onset time of blockade is related prima-rily to the pKa of the LA. Those with lower pKa(7.6–7.8), e.g. lidocaine, mepivacaine are fastacting, because 30–40% LA is in the undissociatedbase form at pH 7.4 and it is this form which

Fig. 25.1: Effect of progressively increasing concentrations(b, c, d) of a local anaesthetic on the generation of an actionpotential in a nerve fibre, (a) Untreated nerve fibre

Mechanism of Local Anaesthetic Action 355

356 Local AnaestheticsS

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Fig. 25.2: A model of the axonal Na+channel depicting the site and mechanism of action of localanaestheticsThe Na+ channel has an activation gate (‘m’) near its extracellular mouth and an inactivation gate (‘h’)at the intracellular mouth. In the resting state the activation gate is closed. Threshold depolarization ofthe membrane opens the activation gate allowing Na+ ions to flow in along the concentration gradient.Within a few msec, the inactivation gate closes and ion flow ceases. The channel recovers to the restingstate in a time-dependent manner.

The local anaesthetic (LA) receptor is located within the channel in its intracellular half. The LAtraverses the membrane in its lipophilic form (B), reionizes in the axoplasm and approaches the LAreceptor through the intracellular mouth of the channel. It is the cationic form (BH+) of the LA whichprimarily binds to the receptor. The receptor has higher affinity or is more accessible to the LA in theactivated state compared to resting state. Binding of LA to its receptor stabilizes the channel in theinactivated state and thus reduces the probability of channel opening.

The neuronal Na+ channel is a 300 KD glycoprotein composed of a large (α) and two small (β1, β2)subunits. The α subunit encloses the Na+ selective pore within its 4 homologous domains (I to IV), eachdomain has 6 membrane spanning helical segments (S1 to S6) connected alternately by intracellularand extracellular loops. The wall of the pore is formed by all four S5-S6 segments, while the short nonhelicalloops connecting S5-S6 on the extracellular surface fold into the pore and serve as the activation gate.Voltage sensors located in the S4 segments move vertically on depolarization and open the activationgate by allosteric conformational change. A few msec later, the short intracellular loop connecting domainsIII and IV folds into the inner mouth of the pore inactivating the channel. The LA receptor is located inS6 segment of domain IV. Channel activation either transforms the LA receptor to a higher affinity confor-mation or exposes it on the wall of the pore, and this persists during the subsequent inactivation phase.

penetrates the axon. Procaine, tetracaine, bupi-vacaine have higher pKa (8.1–8.9), only 15% orless is unionized at pH 7.4; these are slow acting.Chloroprocaine is an exception, having rapidonset despite high pKa (9.1).

LOCAL ACTIONS

The clinically used LAs have no/minimal localirritant action and block sensory nerve endings,nerve trunks, neuromuscular junction, ganglio-nic synapse and receptors (non-selectively),i.e. those structures which function through

increased Na+ permeability. They also reducerelease of acetylcholine from motor nerve endings.Injected around a mixed nerve they causeanaesthesia of skin and paralysis of voluntarymuscle supplied by that nerve.

Sensory and motor fibres are inherentlyequally sensitive, but some LAs exhibit unequalability to block them, e.g. bupivacaine producessensory block at much lower concentration thanthat needed for motor block. Sensitivity to LA isdetermined by diameter of the fibres as well as byfibre type. In general smaller fibres are more

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sensitive than larger fibres. Diameter remainingthe same, myelinated nerves are blocked earlierthan nonmyelinated. Fibres differ in the criticallength of the axon that must be exposed to the LAfor effective blockade. Smaller fibres tend to haveshorter critical lengths because in them voltagechanges propagate passively for shorter distances.Also, more slender axons have shorter internodaldistances and LAs easily enter the axon at thenodes of Ranvier. The density of Na+ channel ismuch higher at these nodes. Moreover, frequencydependence of blockade makes smaller sensoryfibres more vulnerable since they generate highfrequency longer lasting action potentials thanthe motor fibres.

Autonomic fibres are generally more suscep-tible than somatic fibres. Among the somatic affe-rents order of blockade is : pain—temperaturesense—touch—deep pressure sense. Since painis generally carried by smaller diameter fibresthan those carrying other sensations or motorimpulses, pain is the first modality to be affectedby LAs. Applied to the tongue, bitter taste is lostfirst followed by sweet and sour, and salty tastelast of all.

In general, fibres that are more susceptible toL A are the first to be blocked and the last torecover. Also, location of the fibre within a nervetrunk determines the latency, duration and oftenthe depth of local anaesthesia. Nerve sheathsrestrict diffusion of the LA into the nerve trunk sothat fibres in the outer layers are blocked earlierthan the inner or core fibres. As a result, the moreproximal areas supplied by a nerve are affectedearlier because axons supplying them are locatedmore peripherally in the nerve than those sup-plying distal areas. The differential arrangementof various types of sensory and motor fibres in amixed nerve may partly account for the differentialblockade.

The LA often fails to afford adequate pain controlin inflamed tissues (like infected tooth). The likelyreasons are:a. Inflammation lowers pH of the tissue—greater

fraction of the LA is in the ionized formhindering diffusion into the axolemma.

b. Blood flow to the inflamed area is increased— the LA is removed more rapidly from thesite.

c. Effectiveness of Adr injected with the LA isreduced at the inflamed site.

d. Inflammatory products may oppose LAaction.

Addition of a vasoconstrictor, e.g. adrenaline(1:50,000 to 1:200,000):• prolongs duration of action of LAs by

decreasing their rate of removal from the localsite into the circulation.

• enhances the intensity of nerve block.• reduces systemic toxicity of LAs: rate of

absorption is reduced and metabolism keepsthe plasma concentration lower.

• provides a more bloodless field for surgery.• increases the chances of subsequent local

tissue edema and necrosis as well as delayswound healing by reducing oxygen supplyand enhancing oxygen consumption in theaffected area.

• may raise BP and promote arrhythmia insusceptible individuals.

SYSTEMIC ACTIONS

Any LA injected or applied locally is ultimatelyabsorbed and can produce systemic effectsdepending on the concentration attained in theplasma and tissues.

C.N.S.

All LAs are capable of producing a sequence ofstimulation followed by depression. Cocaine is apowerful CNS stimulant causing in sequenceeuphoria—excitement—mental confusion—rest-lessness—tremor and twitching of muscles—convulsions—unconsciousness—respiratorydepression—death, in a dose-dependent manner.

Procaine and other synthetic LAs are much lesspotent in this regard. At safe clinical doses, theyproduce little apparent CNS effects. Higher doseor accidental i.v. injection produces CNS stimu-lation followed by depression.

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Lidocaine, on the contrary, can initially causedrowsiness and lethargy, but higher dosesproduce excitation followed by depression likeothers.

The basic action of all LAs is neuronal inhibi-tion; the apparent stimulation seen initially is dueto inhibition of inhibitory neurones. At high doses,all neurones are inhibited and flattening of wavesin the EEG is seen.

CVS

Heart LAs are cardiac depressants, but nosignificant effects are observed at conventionaldoses. At high doses or on inadvertent i.v.injection, they decrease automaticity, excitability,contractility, conductivity and prolong refractoryperiod (RP). They have a quinidine-like antiarrhy-thmic action. Procaine is not used as antiarrhy-thmic because of short duration of action andpropensity to cause CNS effects, but its amidederivative procainamide is a classical antiarrhy-thmic. At high plasma concentrations, electro-physiological properties of heart may be markedlyaltered, QTc interval is prolonged and LAs canthemselves induce cardiac arrhythmias.Bupivacaine is relatively more cardiotoxic and hasproduced ventricular tachycardia or fibrillation.Lidocaine has little effect on contractility andconductivity; it abbreviates RP and is used as anantiarrhythmic (see Ch. 12).

Blood vessels LAs tend to produce fall in BP.This is primarily due to sympathetic blockade,but high concentrations, as attained locally at thesite of injection, do cause direct relaxation ofarteriolar smooth muscle. Bupivacaine is morevasodilatory than lidocaine, while prilocaine isthe least vasodilatory. Toxic doses of LAsproduce cardiovascular collapse. Cocaine hassympathomimetic property; causes local vaso-constriction, marked rise in BP and tachycardia.

Procaine and related drugs have weak anticholinergic,antihistaminic, ganglion blocking, neuromuscular blockingand smooth muscle relaxant properties, but these areclinically insignificant.

PHARMACOKINETICS

Soluble surface anaesthetics (lidocaine, tetra-caine) are rapidly absorbed from mucousmembranes and abraded areas, but absorptionfrom intact skin is poor. Procaine does notsignificantly penetrate mucous membranes. Rateof absorption depends on the blood flow to thearea of application or injection; faster absorptionoccurring from more vascular tissues. Thus, intra-oral injection results in quicker and higher bloodlevels than s.c. injection on limbs or trunk. Theentry into blood after injection into an alveolarbone (maxilla) is very rapid. Once absorbed, theLA being lipophilic rapidly enters highly perfusedorgans, viz brain, heart, liver and kidney.

Procaine is negligibly bound to plasma pro-teins, but amide LAs are bound to plasma α1 acidglycoprotein. LAs are rapidly but briefly boundto tissues, especially nerves, at the site of injection.Ester linked LAs (procaine, etc.) are rapidlyhydrolysed by plasma pseudocholinesterase andthe remaining by esterases in the liver. Amidelinked LAs ( lidocaine, etc.) are degraded only inthe liver microsomes by dealkylation andhydrolysis. Metabolism of lidocaine is hepaticblood flow dependent. The maximal safe dose ofLAs is lower in patients with hepatic disease andin the elderly who have decreased liver function.

After oral ingestion, both procaine andlidocaine have high first pass metabolism in theliver. Thus, they are not active orally for anti-arrhythmic purposes.

ADVERSE EFFECTS

Systemic toxicity on rapid i.v. injection is relatedto the intrinsic anaesthetic potency of the LA.However, toxicity after topical application orregional injection is influenced by the relativerates of absorption and metabolism; those rapidlyabsorbed but slowly metabolized are more toxic.1. CNS effects are light-headedness, dizziness,auditory and visual disturbances, mental con-fusion, disorientation, shivering, twitchings,involuntary movements, finally convulsions andrespiratory arrest. This can be prevented andtreated by diazepam.

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2. Cardiovascular toxicity of LAs is manifestedas bradycardia, hypotension, cardiac arrhyth-mias and vascular collapse.3. Injection of LAs may be painful, but localtissue toxicity of LAs is low. However, woundhealing may be sometimes delayed. Addition ofvasoconstrictors enhances the local tissuedamage; rarely localized mucosal sloughing andnecrosis result. Vasoconstrictors should not beadded for ring block of hands, feet, fingers, toes,penis and in pinna. Bupivacaine has the highestlocal tissue irritancy.4. Hypersensitivity reactions like rashes, angio-edema, dermatitis, contact sensitivity, asthma andrarely anaphylaxis occur. These are more commonwith ester linked LAs, but rare with lidocaine orits congeners. Cross reactivity is frequent amongester compounds, but not with amide linked LAs.Often, methylparaben added as a preservative incertain LA solutions is responsible for the allergicreaction.

Precautions and interactions

1. Before injecting the LA, aspirate lightly toavoid intravascular injection.2. Inject the LA slowly and take care not to exceedthe maximum safe dose, especially in children.3. Propranolol (probably other β blockers also)may reduce metabolism of lidocaine and otheramide LAs by reducing hepatic blood flow.

4. Vasoconstrictor (adrenaline) containing LAshould be avoided for patients with ischaemicheart disease, cardiac arrhythmia, thyrotoxicosis,uncontrolled hypertension, and those receivingβ blockers (rise in BP due to unopposed α action)or tricyclic antidepressants (uptake blockade ofAdr).

INDIVIDUAL COMPOUNDS

Important properties of local anaesthetics arecompared in Table 25.2.

Cocaine It is a natural alkaloid from leaves of Erythroxyloncoca, a south American plant growing on the foothills of theAndes. The natives of Peru and Bolivia habitually chewthese leaves. Cocaine is a good surface anaesthetic and israpidly absorbed from buccal mucous membrane. It wasfirst used for ocular anaesthesia in 1884. Cocaine shouldnever be injected; it is a protoplasmic poison and causestissue necrosis. Cocaine produces prominent CNSstimulation with marked effect on mood and behaviour. Itinduces a sense of wellbeing, delays fatigue and increasespower of endurance. In susceptible individuals it producesa state referred to as ‘high’ leading to strong psychologicalbut little physical dependence. Cocaine is unique amongdrugs of abuse in not producing significant tolerance onrepeated use; sometimes reverse tolerance is seen (beha-vioural effects are experienced at lower doses).

In the periphery, it blocks uptake of NA and Adr intoadrenergic nerve endings, resulting in higher concentrationof the transmitter around the receptors—sympathomi-metic effect, potentiation of directly acting sympathomi-metics and suppression of indirectly acting sympathomi-metics. Local vasoconstriction, tachycardia, rise in BP andmydriasis are the reflection of its sympathomimetic action.

Because of these central and peripheral effects as wellas local tissue toxicity, cocaine is not used clinically.

Table 25.2: Comparative properties of important local anaesthetics

Potency Concn. Safe max Metabolism inused dose* (for inj.) Onset Duration of

surface injection toxic (%) plasma liver nerve block Total mg (mg/kg) (min)

Cocaine 1 1 1 – not injected fast – + –

Procaine 1/10 1/2 1/6 1–2% 400 6 slow + + 30–60

Lidocaine 1 2 1/6 0.5–2% 300 4.5 fast – + 60–120

Tetracaine 4 10 2 0.25–0.5% 80 1.2 slow + + 180–480

Bupivacaine – 10 2 0.25–0.5% 100 1.5 interm. – + 180–360

Dibucaine 6 15 3 0.25–0.5% 50 – slow – + 180–600

* Without adrenaline; addition of adrenaline may increase safe limit by upto 50%

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Procaine It is the first synthetic local anaestheticintroduced in 1905. Its popularity declined after theintroduction of lignocaine: practically not used now. It isnot a surface anaesthetic. Paraaminobenzoic acid (PABA)is released on hydrolysis of procaine which can antagonisethe antibacterial action of sulfonamides given to treatinfections.

Procaine forms poorly soluble salt with benzylpenicillin; procaine penicillin injected i.m. acts for 24 hoursdue to slow absorption from the site of injection.

Lidocaine (Lignocaine) Introduced in 1948, itis currently the most widely used LA. It is aversatile LA, good both for surface application aswell as injection and is available in a variety offorms. Injected around a nerve, it blocks con-duction within 3 min, whereas procaine may take15 min; also anaesthesia is more intense andlonger lasting. Vasodilatation occurs in theinjected area. It is used for surface application,infiltration, nerve block, epidural and spinalanaesthesia. Cross sensitivity with ester LAs isnot seen. In contrast to other LAs, early centraleffects of lidocaine are depressant, i.e. drowsiness,mental clouding, altered taste and tinnitus.Overdose causes muscle twitching, convulsions,cardiac arrhythmias, fall in BP, coma andrespiratory arrest like other LAs. Lidocaine is apopular antiarrhythmic (see Ch. 12).XYLOCAINE, GESICAIN 4% topical solution, 2% jelly,2% viscous, 5% ointment, 1% and 2% injection (with orwithout adrenaline), 5% heavy (for spinal anaesthesia);100 mg/ml spray (10 mg per puff).

For dental anaesthesia: 2 ml cartridge or prefilledsyringe containing lidocaine 2% with or without adrenaline1:80000. The solution in cartridge is preservative free. Thisformulation is particularly indicated in patients who areallergic to the preservative and not to lidocaine.

Prilocaine It is similar to lidocaine but does not causevasodilatation at the site of infiltration and has lowerCNS toxicity due to larger volume of distribution.

Eutectic lidocaine/prilocaine This is a uniquepreparation which can anaesthetise intact skinafter surface application. Eutectic mixture refersto lowering of melting point of two solids whenthey are mixed. This happens when lidocaine andprilocaine are mixed in equal proportion at 25°C.The resulting oily liquid is emulsified into waterto form a cream that is applied under occlusivedressing for 1 hr before i.v. cannulation, split skin

graft harvesting and other superficial procedures.Anaesthesia up to a depth of 5 mm lasts for 1–2hr after removal. It has been used as an alternativeto lidocaine infiltration.PRILOX 5% cream.

In dentistry, it has been tried for obtundingpain of intrapalatal injection and as alternativeto infiltration anaesthesia for some procedures.

Tetracaine (Amethocaine) A highly lipid-soluble PABA ester, more potent and more toxicdue to slow hydrolysis by plasma pseudocholi-nesterase. It is both surface and conduction blockanaesthetic, but its use is restricted to topicalapplication to the eye, nose, throat, tracheo-bronchial tree and rarely for spinal or caudalanaesthesia of long duration. Though it is slowacting, absorption from tracheobronchial sprayis very fast and blood concentrations approachthose attained after i.v. injection. Because of rapidmucosal absorption and high systemic toxicity,its use for surface anaesthesia in the mouth isrestricted.ANETHANE powder for solution, 1% ointment.

Bupivacaine A potent and long-acting highlylipid soluble amide linked LA: used forinfiltration, nerve block, epidural and spinalanaesthesia of long duration. A 0.25–0.5%solution injected epidurally produces adequateanalgesia without significant motor blockade. Asa result, it has become very popular in obstetrics(mother can actively cooperate in vaginal delivery)and for postoperative pain relief by continuousepidural infusion. Because of high lipid solubilityit distributes more in tissues than in blood afterspinal/epidural injection—less likely to reach thefoetus (when used during labour) to produceneonatal depression. Bupivacaine is more proneto prolong QTc interval and induce ventriculartachycardia or cardiac depression.MARCAIN 0.5%, 1% (hyperbaric for spinal anaesthesia).SENSORCAINE 0.25%, 0.5% inj, 0.5% heavy inj.Levobupivacaine is the S(–) enantiomer of bupivacaine;equally potent LA, but less cardiotoxic and less prone tocause seizures in overdose.

Ropivacaine A newer bupivacaine congener, equally longacting but less cardiotoxic. It blocks A δ and C fibres more

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completely (involved in pain transmission) than A β fibreswhich control motor function. Continuous epiduralropivacaine is being used for relief of postoperative andlabour pain. It can also be employed for nerve blocks.

Dibucaine (Cinchocaine) It is the most potent, mosttoxic and longest acting LA. It is used as a surfaceanaesthetic on less delicate mucous membranes (analcanal) and occasionally for spinal anaesthesia of longduration.NUPERCAINE 0.5% inj., NUPERCAINAL 1% ointment,in OTOGESIC 1% ear drops.

Benoxinate It is a good surface anaestheticfor the eye; has little irritancy. A 0.4% solutionrapidly produces corneal anaesthesia sufficientfor tonometry without causing mydriasis orcorneal damage.BENDZON 0.4% eyedrops.

Benzocaine and Butylaminobenzoate (Butam-ben) Because of very low aqueous solubility,these LAs are not significantly absorbed frommucous membranes or abraded skin. They pro-duce long-lasting anaesthesia without systemictoxicity. They are used as lozenges for stomatitis,sore throat; as dusting powder/ointment onwounds/ulcerated surfaces and as suppositoryfor anorectal lesions. Both are PABA derivative—can antagonise sulfonamides locally.PROCTOSEDYL-M: Butylaminobenzoate 1% oint withframycetin and hydrocortisone acetate: for piles.PROCTOQUINOL 5% ointment of benzocaine.ZOKEN 20% gel.

Oxethazaine A potent topical anaesthetic, unique inionizing to a very small extent even at low pH values. Itis, therefore, effective in anaesthetising gastric mucosadespite acidity of the medium. Swallowed along withantacids it affords symptomatic relief in gastritis, druginduced gastric irritation, gastroesophageal reflux andheartburn.MUCAINE 0.2% in alumina gel + magnesium hydroxidesuspension; 5-10 ml orally.

USES AND TECHNIQUES OFLOCAL ANAESTHESIA

1. Surface anaesthesia It is produced by topi-cal application of surface anaesthetics to mucousmembranes and abraded skin. Only the super-ficial layer is anaesthetised. Onset and durationdepends on the site, the drug, its concentration

and form, e.g. lidocaine sprayed in the mouth orthroat acts in 2–5 min and produces anaesthesiafor 30–45 min. Addition of Adr does not affectduration of topical anaesthesia. Absorption ofsoluble LAs from mucous membranes is rapid;blood concentrations of lidocaine and tetracainesprayed in throat/tracheobronchial tree approachthose attained on i.v. injection—toxicity can occur.Except for eutectic lidocaine/prilocaine, no otherLA is capable of anaesthetizing intact skin.Surface anaesthesia is extensively used in the eye,throat, urethra, and anal canal. Topical LA isoccasionally applied in the mouth for stomatitis/ulcers, and in nose/ear for painful lesions.

2. Infiltration anaesthesia Dilute solution ofLA is infiltrated under the skin in the area ofoperation—blocks sensory nerve endings. Onsetof action is almost immediate and duration isshorter than that after nerve block, e.g. lidocaine30–60 min, bupivacaine 120–180 min. Infiltrationis used for minor operations, e.g. incisions,excisions, some dental procedures, hydrocele,herniorrhaphy, etc. when the area to beanaesthetized is small. Relatively larger amountof LA is required compared to the area anaes-thetised, but motor function is not affected.

3. Conduction block The LA is injectedaround nerve trunks so that the area distal toinjection is anaesthetised and paralysed.

(a) Field block It is produced by injecting theLA subcutaneously in a manner that all nervescoming to a particular field are blocked—as isdone for dental procedures, herniorrhaphy,appendicectomy, scalp stitching, operations onforearms and legs, etc. Larger area can beanaesthetised with lesser drug compared toinfiltration. The same concentration of LA as forinfiltration is used for field block.

(b) Nerve block It is produced by injection ofthe LA around the appropriate nerve trunks orplexuses. The area of resulting anaesthesia islarger compared to the amount of drug used.Muscles supplied by injected nerve/plexus areparalysed. The latency of anaesthesia depends

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on the drug and the area to be covered by diffusion,e.g. lidocaine anaesthetises intercostal nerveswithin 3 min, but brachial plexus block may take15 min. For plexus block a ‘flooding’ technique isused and larger volumes are needed. Nerve blocklasts longer than field block or infiltrationanaesthesia. Frequently performed nerve blocksare—lingual, intercostal, ulnar, sciatic, femoral,brachial plexus, trigeminal, facial, phrenic, etc.—used for many dental procedures including toothextraction, operations on eye, limbs, abdominalwall, fracture setting, trauma to ribs, neuralgias,persistent hiccup, etc.

4. Spinal anaesthesia The LA is injected inthe subarachnoid space between L2–3 or L3–4,i.e. below the lower end of spinal cord. The primarysite of action is the nerve roots in the cauda equinarather than the spinal cord. Lower abdomen andhind limbs are anaesthetised and paralysed. Thelevel of anaesthesia depends on volume andspeed of injection, specific gravity of drug solutionand posture of the patient. The drug solutioncould be hyperbaric (in 10% glucose) or isobaricwith CSF.

Nerve roots rapidly take up and retain the LA.Since autonomic preganglionic fibres are moresensitive and somatic motor fibres less sensitivethan somatic sensory fibres, the level ofsympathetic block is about 2 segments higherand the level of motor paralysis about 2 segmentslower than the level of cutaneous analgesia.

The duration of spinal anaesthesia dependson the drug used and its concentration. Additionof 0.2–0.4 mg of adrenaline to the LA prolongsspinal anaesthesia by about 1/3rd.

Spinal anaesthesia is used for operations onthe lower limbs, pelvis, lower abdomen, prosta-tectomy, fracture setting, obstetric procedures,caesarean section, etc.

Possible complications of spinal anaesthesiaare fall in BP, respiratory paralysis, headachenausea/vomiting, cauda equina syndrome (lossof control over bladder and bowel sphincter) andrarely meningitis.

5. Epidural anaesthesia The spinal duralspace is filled with semiliquid fat through whichnerve roots travel. The LA injected in this space—acts primarily on nerve roots (in the epidural aswell as subarachnoid spaces to which it diffuses)and small amount permeates through interverte-bral foramina to produce multiple paravertebralblocks. Epidural injection can be made in thethoracic, lumbar or sacral region according to thearea of desired anaesthesia.

Lidocaine and bupivacaine are popular drugsfor epidural anaesthesia. Duration of anaesthesiais longer with bupivacaine and action of both thedrugs is prolonged by addition of adrenaline.Cardiovascular complications are similar to thatafter spinal anaesthesia, but headache andneurological complications are less becauseintrathecal space is not entered. Zone ofdifferential sympathetic blockade is not evidentafter epidural injection but motor paralysis is 4–5segments caudal. Continuous epidural anaes-thesia can be instituted by inserting a catheterand making repeated injections.

Local anaesthesia in dentistry

In the practice of dentistry LAs are mainly usedby nerve block (for branches of lingual nerve) orby infiltration/regional block techniques to carryout various restorative/operative procedures.Less commonly, they are applied topically topainful oral ulcers and other superficial lesions.

The total amount of LA injected for dentalanaesthesia is generally much smaller (e.g. 20 –80 mg of lidocaine) than that used for otherpurposes like brachial plexus block, multiplenerve blocks or epidural anaesthesia. As such,systemic toxicity of dental anaesthesia is usuallynot a major concern. Reports of serious adverseeffects are rare. Many side effects that have beendescribed (like palpitation, pallor, sweating,uneasiness, giddiness, fainting, nausea, tremor)in fact have their origin in the apprehension ofthe patient to the injection given in the mouth.However, because the volume of LA needed fordental anaesthesia in children is only marginally

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less than that in adults, a higher per kg dose isinjected and the safety margin is reduced;systemic toxicity is more likely. It is, therefore,desirable to use vasoconstrictor containing LA inchildren, though the longer duration of resultingsoft tissue anaesthesia is apprehended to causemore postoperative biting injuries.

Because of greater vascularity in the upperjaw, soft tissue anaesthesia after maxillaryinfiltration of the LA is shorter lasting than thesame drug injected into the lower jaw. Thisdifference in duration of action is more markedfor plain LA solutions than for those containinga vasoconstrictor. After nerve block, the durationof dental pulp anaesthesia is generally 1/5th to1/3rd that of soft tissue anaesthesia. The plainsolution may be preferred when a shorter durationof soft tissue anaesthesia without complete pulpalanaesthesia is required, when operative haemor-rhage is not a concern, and when a vasocons-trictor is contraindicated. Plain LA has beenconsidered appropriate for short maxillary archprocedures.

Lidocaine (2%) with adrenaline (1:80,000) isthe standard LA preparation used in dentalpractice. It produces good soft tissue as well aspulpal anaesthesia and reduces postextractionbleeding. After injection, pulpal anaesthesia isobtained in 2–3 min and lasts for 40–60 min,whereas soft tissues remain anaesthetised for2–3 hours. However, complete pain relief may not

be achieved in few patients with very sensitiveteeth or marked inflammation. In comparison,plain lidocaine (2%) provides soft tissue anaes-thesia for 45–90 min, while pulpal anaesthesia isbrief (10–20 min) and unreliable. Moreover,haemorrhage control is poor due to vasodilatoryaction of lidocaine. Its use in dentistry is limitedto superficial and brief procedures or when avasoconstrictor is contraindicated. After intraoralinjection, systemic absorption of lidocaine isrelatively rapid due to high lipid solubility.

Topically, lidocaine may be applied on painfuloral ulcers and prior to intraoral injection of theLA in apprehensive patients. The 10% sprayformulation produces widespread oral mucosalanaesthesia which may be utilized before takingimpressions or dental X-ray in fussy patients.

Bupivacaine (0.5%) with adrenaline (1:200,000)is less frequently used in dentistry. Because ofvery high lipid solubility, it is largely taken up byperidontal soft tissues while penetration into boneis poorer. The onset of pulpal anaesthesia isslower, may take > 5 min to start, is less intenseand relatively short-lasting (<2 hr), while softtissues may remain anaesthetized for up to 8hours. Long-lasting oral surgery or procedureswhich require extended postoperative paincontrol such as removal of impacted third molarsare the indications for use of bupivacaine.

Ropivacaine is occasionally used in dentistry,and there is no specific indication for it.

Local Anaesthesia in Dentistry 363

Antimicrobial drugs are the greatest contributionof the 20th century to therapeutics. Their adventchanged the outlook of the physician about thepower drugs can have on diseases. They are oneof the few drugs which can cure rather than justpalliate diseases. As a class, they are one of themost frequently used as well as misused drugs.Apart from analgesics, they are the commonestdrugs that dentists routinely prescribe themselves.

Drugs in this class differ from all others inthat they are designed to inhibit/kill the infectingorganism and to have no/minimal effect on therecipient. This type of therapy is generally calledchemotherapy which has come to mean ‘treatmentof systemic infections with specific drugs thatselectively suppress the infecting microorganismwithout significantly affecting the host.’ Thebasis of selective microbial toxicity is the actionof the drug on a component of the microbe (e.g.bacterial cell wall) or metabolic process (e.g.folate synthesis) that is not found in the host, ora high affinity for certain microbial biomolecules.Due to analogy between the malignant cell andthe pathogenic microbes, treatment of neoplasticdiseases with drugs is also called chemotherapy.

Antibiotics These are substances produced bymicroorganisms, which selectively suppress thegrowth of or kill other microorganisms at verylow concentrations. This definition excludesother natural substances which also inhibit

microorganisms but are produced by higherforms (e.g. antibodies) or even those produced bymicrobes but are needed in high concentrations(ethanol, lactic acid, H2O2).

Initially, the term ‘chemotherapeutic agent’was restricted to synthetic compounds, but nowsince many antibiotics and their analogues havebeen synthesized, this criterion has becomeirrelevant; both synthetic and microbiologicallyproduced drugs need to be included together.However, it would be more meaningful to use theterm antimicrobial agent (AMA) to designatesynthetic as well as naturally obtained drugs thatattenuate microorganisms.

The history of chemotherapy may be divided into 3phases.(a) The period of empirical use: of ‘mouldy curd’ byChinese on boils, chaulmoogra oil by the Hindus inleprosy, chenopodium by Aztecs for intestinal worms,mercury by Paracelsus (16th century AD) for syphilis,cinchona bark (17th century AD) for fevers.

(b) Ehrlich’s phase of dyes and organometallic com-pounds (1890–1935): With the discovery of microbes inthe later half of the 19th century and that they are thecause of many diseases: Ehrlich toyed with the idea thatif certain dyes could selectively stain microbes, they couldalso be selectively toxic to these organisms, and tried met-hylene blue, trypan red, etc. He developed the arsenicals—atoxyl for sleeping sickness, arsphenamine in 1906 andneoarsphenamine in 1909 for syphilis. He coined the term‘chemotherapy’ because he used drugs of known chemicalstructure (that of most other drugs in use at that timewas not known) and showed that selective attenuationof infecting parasite was a practical proposition.

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(c) The modern era of chemotherapy was ushered byDomagk in 1935 by demonstrating the therapeutic effectof Prontosil, a sulfonamide dye, in pyogenic infection. Itwas soon realized that the active moiety was paraaminobenzene sulfonamide, and the dye part was not essential.Sulfapyridine (M & B 693) was the first sulfonamide tobe marketed in 1938.

The phenomenon of antibiosis was demonstrated byPasteur in 1877: growth of anthrax bacilli in urine wasinhibited by air-borne bacteria. Fleming (1929) found thata diffusible substance was elaborated by Penicilliummould which could destroy Staphylococcus on the cultureplate. He named this substance penicillin but could notpurify it. Chain and Florey followed up this observationin 1939 which culminated in the clinical use of penicillinin 1941. Because of the great potential of this discoveryin treating war wounds, commercial manufacture ofpenicillin soon started.

In the 1940s, Waksman and his colleagues undertooka systematic search of Actinomycetes as source ofantibiotics and discovered streptomycin in 1944. Thisgroup of soil microbes proved to be a treasure-house ofantibiotics and soon tetracyclines, chloramphenicol,erythromycin and many others followed. All three groupsof scientists Domagk, Fleming-Chain-Florey andWaksman received the Nobel Prize for their discoveries.

In the past 50 years emphasis has shifted fromsearching new antibiotic producing organisms todeveloping semisynthetic derivatives of older antibioticswith more desirable properties or differing spectrum ofactivity. Few novel synthetic AMAs (e.g. fluoroquino-lones, oxazolidinones) have also been produced.

CLASSIFICATION

Antimicrobial drugs can be classified in manyways:

A. Chemical structure

1. Sulfonamides and related drugs:Sulfadiazine and others, Sulfones—Dapsone (DDS), Paraaminosalicylic acid(PAS).

2. Diaminopyrimidines: Trimethoprim,Pyrimethamine.

3. Quinolones: Nalidixic acid, Norfloxacin,Ciprofloxacin, etc.

4. β-lactam antibiotics: Penicillins,Cephalosporins, Monobactams,Carbapenems.

5. Tetracyclines: Oxytetracycline,Doxycycline, etc.

6. Nitrobenzene derivative: Chloramphenicol.7. Aminoglycosides: Streptomycin,

Gentamicin, Neomycin, etc.8. Macrolide antibiotics: Erythromycin,

Clarithromycin, Azithromycin, etc.9. Lincosamide antibiotics: Lincomycin,

Clindamycin.10. Polypeptide antibiotics: Polymyxin-B,

Colistin, Bacitracin, Tyrothricin.11. Glycopeptides: Vancomycin, Teicoplanin12. Oxazolidinone: Linezolid.13. Nitrofuran derivatives: Nitrofurantoin,

Furazolidone.14. Nitroimidazoles: Metronidazole, Tinidazole.15. Nicotinic acid derivatives: Isoniazid,

Pyrazinamide, Ethionamide.16. Polyene antibiotics: Nystatin,

Amphotericin-B, Hamycin.17. Azole derivatives: Miconazole,

Clotrimazole, Ketoconazole, Fluconazole.18. Others: Rifampin, Spectinomycin,

Sod. fusidate, Cycloserine, Viomycin,Ethambutol, Thiacetazone, Clofazimine,Griseofulvin.

B. Mechanism of action

1. Inhibit cell wall synthesis: Penicillins,Cephalosporins, Cycloserine, Vancomycin,Bacitracin.

2. Cause leakage from cell membranes:Polypeptides—Polymyxins, Colistin,Bacitracin. Polyenes—Amphotericin B,Nystatin, Hamycin.

3. Inhibit protein synthesis: Tetracyclines,Chloramphenicol, Erythromycin,Clindamycin, Linezolid.

4. Cause misreading of m-RNA code and affectpermeability: Aminoglycosides—Streptomycin, Gentamicin, etc.

5. Inhibit DNA gyrase: Fluoroquinolones—Ciprofloxacin.

6. Interfere with DNA function: Rifampin,Metronidazole.

7. Interfere with DNA synthesis: Acyclovir,Zidovudine.

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366 Antimicrobial Drugs: General Considerations

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Sulfonamides, Sulfones, PAS, Trimetho-prim, Pyrimethamine, Ethambutol.

C. Type of organisms against whichprimarily active

1. Antibacterial: Penicillins, Aminoglycosides,Erythromycin, etc.

2. Antifungal: Griseofulvin, Amphotericin B,Ketoconazole, etc.

3. Antiviral: Acyclovir, Amantadine,Zidovudine, etc.

4. Antiprotozoal: Chloroquine, Pyrimetha-mine, Metronidazole, Diloxanide, etc.

5. Anthelmintic: Mebendazole, Pyrantel, Nic-losamide, Diethyl carbamazine, etc.

D. Spectrum of activity

Narrow spectrum Broad spectrumPenicillin G TetracyclinesStreptomycin ChloramphenicolErythromycin

The initial distinction between narrow andbroad-spectrum antibiotics is no longer clearcut.Drugs with all ranges of intermediate band width,e.g. extended spectrum penicillins, newer cepha-losporins, aminoglycosides, fluoroquinolones arenow available. However, the terms ‘narrowspectrum’ and ‘broad spectrum’ are still applied.

E. Type of action

Primarily bacteriostaticSulfonamides ErythromycinTetracyclines EthambutolChloramphenicol Clindamycin

Linezolid

Primarily bactericidalPenicillins CephalosporinsAminoglycosides VancomycinPolypeptides CiprofloxacinRifampin MetronidazoleCotrimoxazole

Some primarily static drugs may become cidalat higher concentrations (as attained in the

urinary tract), e.g. sulfonamides, erythromycin,nitrofurantoin. On the other hand, some cidaldrugs, e.g. cotrimoxazole, streptomycin may onlybe static under certain circumstances.

F. Antibiotics are obtained from:

FungiPenicillin GriseofulvinCephalosporin

BacteriaPolymyxin B TyrothricinColistin AztreonamBacitracin

ActinomycetesAminoglycosides MacrolidesTetracyclines PolyenesChloramphenicol

PROBLEMS THAT ARISE WITHTHE USE OF AMAs

1. Toxicity

(a) Local irritancy: This is exerted at the site ofadministration. Gastric irritation, pain andabscess formation at the site of i.m. injection,thromboflebitis of the injected vein are thecomplications. Practically all AMAs, especiallyerythromycin, tetracyclines, certain cephalo-sporins and chloramphenicol are irritants.

(b) Systemic toxicity: Practically all AMAs pro-duce dose related and predictable organ toxi-cities. Characteristic toxicities are exhibited bydifferent AMAs.Some have a high therapeutic index—doses up to100-fold range may be given without apparentdamage to host cells. These include penicillins,some cephalosporins and erythromycin.Others have a lower therapeutic index—doses haveto be individualized and toxicity watched for,e.g.:

Aminoglycosides : 8th cranial nerve andkidney toxicity.

Tetracyclines : liver and kidney dam-age, antianabolic effect.

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Chloramphenicol : bone marrow depres-sion.

Still others have a very low therapeutic index—useis highly restricted to conditions where nosuitable alternative is available, e.g. :

Polymyxin B : neurological and renaltoxicity.

Vancomycin : hearing loss, kidneydamage.

Amphotericin B : kidney, bone marrowand neurological toxi-city.

2. Hypersensitivity reactions

Practically all AMAs are capable of causinghypersensitivity reactions. These are unpredic-table and unrelated to dose. The whole range ofreactions from rashes to anaphylactic shock canbe produced. The more commonly involvedAMAs are—penicillins, cephalosporins, sulfona-mides, fluoroquinolones.

3. Drug resistance

It refers to unresponsiveness of a microorganismto an AMA and is akin to the phenomenon oftolerance seen in higher organisms.

Natural resistance Some microbes have alwaysbeen resistant to certain AMAs. They lack themetabolic process or the target site which isaffected by the particular drug. This is generallya group or species characteristic, e.g. gram-nega-tive bacilli are normally unaffected by penicillinG, or M. tuberculosis is insensitive to tetracyclines.This type of resistance does not pose a significantclinical problem.

Acquired resistance It is the development ofresistance by an organism (which was sensitiveearlier) due to the use of an AMA over a periodof time. This can happen with any microbe andis a major clinical problem. However, develop-ment of resistance is dependent on the micro-organism as well as the drug. Some bacteria arenotorious for rapid acquisition of resistance, e.g.

staphylococci, coliforms, tubercle bacilli. Otherslike Strep. pyogenes and spirochetes have notdeveloped significant resistance to penicillindespite its widespread use for > 50 years.Gonococci quickly developed resistance tosulfonamides, but only slowly and low-graderesistance to penicillin. However, in the past 30years, highly penicillin-resistant gonococciproducing penicillinase have appeared.

Resistance may be developed by mutation orgene transfer.

Mutation It is a stable and heritable geneticchange that occurs spontaneously and randomlyamong microorganisms. It is not induced by theAMA. Any sensitive population of a microbecontains a few mutant cells which require higherconcentration of the AMA for inhibition. Theseare selectively preserved and get a chance to pro-liferate when the sensitive cells are eliminatedby the AMA. Thus, in time it would appear thata sensitive strain has been replaced by a resistantone, e.g. when an antitubercular drug is usedalone. Mutation and resistance may be:

(i) Single step: A single gene mutation may confer highdegree of resistance; emerges rapidly, e.g. enterococci tostreptomycin, E. coli and Staphylococci to rifampin.

(ii) Multistep: A number of gene modifications areinvolved; sensitivity decreases gradually in a stepwisemanner. Resistance to erythromycin, tetracyclines andchloramphenicol is developed by many organisms in thismanner.

Sometimes mutational acquisition of resistance isaccompanied by decrease in virulence, e.g. certainrifampin-resistant staphylococci and low-grade penicillin-resistant gonococci have decreased virulence.

Gene transfer (infectious resistance) from oneorganism to another can occur by:

(i) Conjugation Sexual contact through the for-mation of a bridge or sex pilus is common amonggram-negative bacilli of the same or anotherspecies. This may involve chromosomal or extra-chromosomal (plasmid) DNA. The gene carryingthe ‘resistance’ or ‘R’ factor is transferred onlyif another ‘resistance transfer factor’ (RTF) is alsopresent. Conjugation frequently occurs in the

Drug Resistance 367


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IIIcolon where a large variety of gram-negativebacilli come in close contact. Even nonpatho-genic organisms may transfer R factor to patho-genic organisms, which may become widespreadby contamination of food or water. Chloramphe-nicol resistance of typhoid bacilli, streptomycinresistance of E. coli, penicillin resistance ofHaemophilus and gonococci and many othershave been traced to this mechanism. Concomi-tant acquisition of multidrug resistance hasoccurred by conjugation. Thus, this is a veryimportant mechanism of resistance acquisition.

(ii) Transduction It is the transfer of gene carryingresistance through the agency of a bacteriophage. The Rfactor is taken up by the phage and delivered to anotherbacterium which it infects. Certain instances of penicillin,erythromycin and chloramphenicol resistance have beenfound to be phage mediated.

(iii) Transformation A resistant bacterium may releasethe resistance carrying DNA into the medium and thismay be imbibed by another sensitive organism—becomingunresponsive to the drug. This mechanism is probablynot clinically significant except isolated instances ofpneumococcal resistance to penicillin G due to alteredpenicillin binding protein, and some other cases.

Resistance once acquired by any of the abovemechanisms becomes prevalent due to theselection pressure of a widely used AMA, i.e.presence of the AMA provides opportunity forthe resistant subpopulation to thrive in prefe-rence to the sensitive population.

Resistant organisms can be drug tolerant ordrug destroying or drug impermeable.

(a) Drug tolerant There is loss of affinity of thetarget biomolecule of the microorganism for aparticular AMA, e.g. resistant Staph. aureus andE. coli develop a RNA polymerase that does notbind rifampin, certain penicillin-resistantpneumococcal strains have altered penicillinbinding proteins; and trimethoprim resistanceresults from plasmid-mediated synthesis of adihydrofolate reductase that has low affinity fortrimethoprim. Another mechnism is acquisitionof an alternative metabolic pathway, e.g. certainsulfonamide-resistant bacteria switch over toutilizing preformed folic acid in place of synthe-sizing it from PABA taken up from the medium.

(b) Drug destroying The resistant microbe ela-borates an enzyme which inactivates the drug,e.g.(i) β-lactamases are produced by staphylococci,Haemophilus, gonococci, etc. which inactivatepenicillin G. The β-lactamases may be present inlow quantity but strategically located peri-plasmically (as in gram-negative bacteria) so thatthe drug is inactivated soon after entry, or maybe elaborated in large quantities (by gram-positive bacteria) to diffuse into the medium anddestroy the drug before entry.(ii) Chloramphenicol acetyl transferase is acqui-red by resistant E. coli, H. influenzae and S.typhi.(iii) Some of the aminoglycoside-resistantcoliforms produce enzymes which adenylate/acetylate/phosphorylate specific aminoglyco-side antibiotics.

(c) Drug impermeable Many hydrophilic anti-biotics gain access into the bacterial cell throughspecific channels formed by proteins called‘porins’, or need specific transport mechanisms.These may be lost by the resistant strains, e.g.concentration of some aminoglycosides and tet-racyclines in the resistant gram-negative bacterialstrains has been found to be much lower thanthat in their sensitive counterparts when bothwere exposed to equal concentrations of thedrugs. Similarly, the low degree penicillin-resis-tant gonococci are less permeable to penicillinG; chloroquine-resistant P. falciparum accumu-lates less chloroquine. The bacteria may alsoacquire plasmid directed inducible energydependent efflux proteins in their cell membranewhich pump out tetracyclines. Active efflux-based resistance has been detected forerythromycin and fluoroquinolones as well.

Cross resistance Acquisition of resistance toone AMA conferring resistance to another AMA,to which the organism has not been exposed, iscalled cross resistance. This is more commonlyseen between chemically or mechanisticallyrelated drugs, e.g. resistance to one sulfonamidemeans resistance to all others, and resistance to

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one tetracycline means insensitivity to all others.Such cross resistance is often complete. However,resistance to one aminoglycoside may not extendto another, e.g. gentamicin-resistant strains mayrespond to amikacin. Sometimes unrelated drugsshow partial cross resistance, e.g. between tetra-cyclines and chloramphenicol, between erythro-mycin and lincomycin.

Cross resistance may be two-way, e.g. bet-ween erythromycin and clindamycin and viceversa or one-way, e.g. development of neomycinresistance by Enterobacteriaceae makes theminsensitive to streptomycin, but many strepto-mycin-resistant organisms remain susceptible toneomycin.

Prevention of drug resistance It is of utmostclinical importance to curb development of drugresistance. Measures are:(a) No indiscriminate and inadequate or undulyprolonged use of AMAs should be made. Thiswould minimize the selection pressure and resis-tant strains will get less chance to preferentiallypropagate. For acute localized infections in other-wise healthy patients, symptom determinedshorter courses of AMAs are advocated.(b) Prefer rapidly acting and selective (narrowspectrum) AMAs whenever possible; broad-spec-trum drugs should be used only when a specificone cannot be determined or is not suitable.(c) Use combination of AMAs whenever pro-longed therapy is undertaken, e.g. tuberculosis,SABE.(d) Infection by organisms notorious for develop-ing resistance, e.g. Staph. aureus, E. coli, M. tuber-culosis, Proteus, etc. must be treated intensively.

4. Superinfection (Suprainfection)

This refers to the appearance of a new infectionas a result of antimicrobial therapy.

Use of most AMAs causes some alteration inthe normal microbial flora of the body. The nor-mal flora contributes to host defence by elabo-rating substances called bacteriocins which inhibitpathogenic organisms. Further, ordinarily, the

pathogen has to compete with the normal florafor nutrients, etc. to establish itself. Lack ofcompetition may allow even a normally non-pathogenic component of the flora, which is notinhibited by the drug (e.g. Candida), to predomi-nate and invade. More complete the suppressionof body flora, greater are the chances of deve-loping superinfection. Thus, it is commonly asso-ciated with the use of broad/extended spectrumantibiotics, such as tetracyclines, chlorampheni-col, ampicillin, newer cephalosporins; especiallywhen combinations of these are employed.Tetracyclines are more prone than chloram-phenicol and ampicillin is more prone thanamoxicillin to cause superinfection diarrhoeasbecause of incomplete absorption—higheramounts reach the lower bowel and causegreater suppression of colonic bacteria.

Superinfections are more common when hostdefence is compromised.

Superinfection 369

Sites involved in superinfection are those thatnormally harbour commensals, i.e. oropharynx:intestinal, respiratory and genitourinary tracts;occasionally skin.

Superinfections are generally more difficultto treat. The organisms frequently involved,manifestations and drugs for treating super-infections are:(a) Candida albicans: thrush, monilial diarrhoea,vulvovaginitis; treat with nystatin or clotrima-zole.(b) Resistant staphylococci: enteritis; treat withcloxacillin/vancomycin/linezolid.

Conditions predisposing to superinfections

• Corticosteroid therapy• Leukaemias and other malignancies, especially

when treated with anticancer drugs (these arealso immunosuppressants and decrease WBCcount)

• Acquired immunodeficiency syndrome (AIDS)• Agranulocytosis• Diabetes, disseminated lupus erythematosus


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(c) Clostridium difficile: pseudomembranous ente-rocolitis associated with the use of clindamycin,tetracyclines, aminoglycosides, ampicillin, cotri-moxazole; more common after colorectal surgery;the organism produces an enterotoxin whichdamages gut mucosa forming plaques; metroni-dazole and vancomycin are the drugs of choice.

(d) Proteus: Urinary tract infection, enteritis; treatwith a cephalosporin or gentamicin.

(e) Pseudomonas: Urinary tract infection, enteritis;treat with carbenicillin, piperacillin, ceftazidime,cefoperazone or gentamicin.To minimize superinfections:

(i) Use specific (narrow-spectrum) AMAwhenever possible.

(ii) Do not use antimicrobials to treat trivial,self-limiting or untreatable (viral) infec-tions.

(iii) Do not unnecessarily prolong antimicro-bial therapy.

5. Nutritional deficiencies

Some of the B complex group of vitamins and vitK synthesized by the intestinal flora is utilizedby man. Prolonged use of antimicrobials whichalter this flora may result in vitamin deficiencies.

Neomycin causes morphological abnorma-lities in the intestinal mucosa—steatorrhoea andmalabsorption syndrome can occur.

6. Masking of an infection

A short course of an AMA may be sufficient totreat one infection but only briefly suppressanother one contacted concurrently. The otherinfection will be masked initially, only tomanifest later in a severe form. Examples are:

(i) Syphilis masked by the use of a single doseof penicillin which is sufficient to curegonorrhoea.

(ii) Tuberculosis masked by a short course ofstreptomycin given for trivial respiratoryinfection.

CHOICE OF AN ANTIMICROBIAL AGENT

After having established the need for using asystemic AMA in a patient by ascertaining thatthe condition is due to a treatable (mostlybacterial) infection, and that it is not likely toresolve by itself or by the use of local measures(antiseptics, drainage of pus, etc.), one has tochoose a suitable drug from the large number avai-lable. The choice depends on the peculiarities ofthe patient, the infecting organism and the drug.

Patient factors

1. Age may affect kinetics of many AMAs.Conjugation and excretion of chloramphenicolis inefficient in the newborn: larger doses pro-duce gray baby syndrome. Sulfonamides displacebilirubin from protein binding sites—can causekernicterus in the neonate because their blood-brain barrier is more permeable. The t½ ofaminoglycosides is prolonged in the elderly andthey are more prone to develop VIII nerve toxi-city. Tetracyclines accumulate in the developingteeth and bone —discolour and weaken them—are contraindicated below the age of 6 years.

2. Renal and hepatic function Cautious useand modification of the dose of an AMA (withlow safety margin) becomes necessary when theorgan of its disposal is defective (see box).

Antimicrobials needing dose reduction/avoidance in renal failure

Reduce dose even in mild failureAminoglycosides Amphotericin BCephalosporins EthambutolVancomycin Flucytosine

Reduce dose only in moderate-severe failureMetronidazole CarbenicillinCotrimoxazole FluoroquinolonesAztreonam ClarithromycinMeropenem Imipenem

Drugs to be avoidedCephalothin TalampicillinNalidixic acid TetracyclinesNitrofurantoin (except doxycycline)

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Antimicrobials to be avoided or used at lowerdose in liver disease are:

caused allergic reaction—it has to be avoided inthat patient, e.g. erythromycin or clindamycin arethe alternative drugs for dental infection inpatients allergic to penicillin. β-lactams, sulfona-mides, fluoroquinolones and nitrofurantoinfrequently cause allergy.

5. Impaired host defence Integrity of hostdefence plays a crucial role in overcoming aninfection. Pyogenic infections occur readily inneutropenic patients; while if cell-mediatedimmunity is impaired (e.g. AIDS), infections bylow-grade pathogens and intracellular orga-nisms abound. In an individual with normalhost defence, a bacteriostatic AMA may achievecure; while intensive therapy with cidal drugsis imperative in those with impaired hostdefence (see box on p. 369) or when the orga-nisms are protected by a barrier, e.g. intraosseousinfections, SABE. Even then complete eradicationof the organism may not occur.

6. Pregnancy All AMAs should be avoided inthe pregnant because of risk to the foetus.Penicillins, many cephalosporins and erythromy-cin are safe, while safety data on most others is notavailable. Therefore, manufacturers label ‘con-traindicated during pregnancy’. Tetracyclinescarry risk of acute yellow atrophy of liver,pancreatitis and kidney damage in the mother.They also cause teeth and bone deformities in theoffspring. Aminoglycosides can cause foetal eardamage. Animal studies indicate increased risk tothe foetus especially with fluoroquinolones,cotrimoxazole, chloramphenicol, sulfonamidesand nitrofurantoin. Though metronidazole has notbeen found to be teratogenic, its mutagenic poten-tial warrants caution in use during pregnancy.

7. Genetic factors Primaquine, nitrofurantoin,sulfonamides, chloramphenicol and fluoro-quinolones are likely to produce haemolysis inG-6PD deficient patient.

Organism-related considerations

Each AMA has a specific effect on a limitednumber of microbes. Successful chemotherapy

Choice of Antimicrobial Agent 371

Antimicrobials in liver disease

Drugs to be avoidedErythromycin estolate TetracyclinesPyrazinamide Nalidixic acidTalampicillin Pefloxacin

Dose reduction neededChloramphenicol IsoniazidMetronidazole RifampinClindamycin

3. Local factors The conditions prevailing at thesite of infection greatly affect the action of AMAs.(a) Presence of pus and secretions decrease theefficacy of most AMAs, especially sulfonamidesand aminoglycosides. Antibiotics cannot cureperiodontal or periapical abscesses, unless thepus is surgically drained. Drainage of the abscessreduces the population of causative bacteria,suppresses anaerobic bacteria by exposure tooxygen, and improves diffusion of the antibioticinto the abscess cavity. Adequate drainage of pusand exudates is very important for the cure oforofacial infections.(b) Presence of necrotic material or foreign bodymakes eradication of infection practically impos-sible.(c) Haematomas foster bacterial growth; tetracyc-lines, penicillins and cephalosporins get boundto the degraded haemoglobin in the haematoma.(d) Lowering of pH at site of infection reducesactivity of macrolide and aminoglycoside anti-biotics.(e) Anaerobic environment in the centre of anabscess impairs bacterial transport processeswhich concentrate aminoglycosides in thebacterial cell, rendering them less susceptible.(f) Penetration barriers may hamper the accessof the AMA to the site of infection in subacutebacterial endocarditis (SABE), endophthalmitis,prostatitis, etc.

4. Drug allergy History of previous exposureto an AMA should be obtained. If a drug has


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IIImust be rational and demands a diagnosis. Aclinical diagnosis should first be made, at leasttentatively, and the likely pathogen guessed.

Ideally, the identity and antimicrobial sensi-tivity of the infecting bacteria should be deter-mined before instituting systemic antibacterialtherapy. However, being time consuming (at least48 hours) and expensive, this is impractical formost dental infections which are acute in natureand treatment cannot be delayed. Moreover, it isnot always possible to obtain appropriate samplesof the infected material for bacteriological testing.Nevertheless, a good guess can generally be madefrom the clinical features and local experience.The causative organisms of common orodentalinfections like alveolar abscesses, periodontalabscesses, dental pulp infections, chronic perio-dontitis, acute necrotizing ulcerative gingivitis(ANUG), etc. are usually Bacteroides and otheranaerobes like Fusobacterium, Porphyromonas,Prevotella, Veillonella, Peptostreptococci (mostlygram-negative and a few gram-positive), aerobicgram-positive cocci chiefly viridans groupStreptococci and spirochetes. The anaerobespredominate, more so in abscesses than in cellulitis.

Orodental infections are often mixed bacterialinfections. Therefore, the drugs mostly selectedare from penicillin/amoxicillin (with or withoutclavulanic acid)/some cephalosporins likecefuroxime or cefaclor which are active on anae-robes, erythromycin, azithromycin, clindamycin,vancomycin, doxycycline, ofloxacin andmetronidazole/tinidazole. Most dentists initiateempirical therapy with amoxicillin +metronidazole. Further therapy is modified on thebasis of clinical response, but hasty and arbitrarychanges in antibiotic therapy are not advisable. Ifpossible (especially in serious infections),specimen for bacteriological examination shouldbe collected before initiating empirical therapy,so that in case of failure of the first choice drug,alternative AMA could be selected in the light ofbacteriological findings.

In a few situations like ANUG, oral thrush,the clinical diagnosis itself indicates the infecting

organism and directs the choice of drug (peni-cillin/doxycycline+metronidazole for ANUG;nystatin/clotrimazole for thrush).

Bacteriological sensitivity testing This is generallydone by disk-agar diffusion method using standardizedconcentrations of antibiotics based on clinically attainedplasma concentrations of these. As such, they serve onlyas guides and cannot be blindly extrapolated to theclinical situation in every patient and for every organism.Broth cultures with break-point concentration (concentra-tion that demarcates between sensitive and resistantbacteria) of antibiotics probably yield more reliableresults. Break-point concentrations are based on clinicallyattainable serum concentrations of the antibiotic.

Minimum inhibitory concentration (MIC), i.e. the lowestconcentration of an antibiotic which prevents visiblegrowth of a bacterium determined in microwell cultureplates using serial dilutions of the antibiotic is moreinformative, but not estimated routinely.

Minimum bactericidal concentration (MBC) of the anti-biotic is determined by subculturing from tubes with novisible growth. If the organism is killed, no growth willoccur; but if it was only inhibited in the parent culture—it will grow on subculturing in antibiotic-free medium.MBC is the concentration of the antibiotic which kills99.9% of the bacteria. A small difference between MICand MBC indicates that the antibiotic is primarilybactericidal, while a large difference indicatesbacteriostatic action. MBC is not used to guide selectionof antibiotics in clinical practice.

Postantibiotic effect (PAE) After a brief exposure ifthe organism is placed in antibiotic-free medium, it startsmultiplying again, but after a lag period which dependson the antibiotic as well as the organism. This lag periodin growth resumption is known as ‘postantibiotic effect’.A long postantibiotic effect has been noted with fluoro-quinolones, aminoglycosides and to some extent with β-lactam antibiotics.

Drug factors

When any one of a number of AMAs could beused to treat an infection, choice among them isbased upon specific properties of these AMAs:1. Spectrum of activity: For definitive therapy,a narrow spectrum drug which selectively affectsthe concerned organism is preferred, because itis generally more effective than a broad-spectrumAMA and is less likely to disturb the normalmicrobial flora. However, for empirical therapy,often a broad-spectrum drug has to be used tocover all likely pathogens.

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2. Type of activity: A bactericidal antibiotic maybe preferred over bacteriostatic because it directlyreduces the number of bacteria at the site ofinfection, while bacteriostatic drug only preventsincrease in their number. This is speciallyimportant while treating patients with impairedhost defence, life-threatening infections, infec-tions at less accessible sites (SABE, osteomyelitis)or when carrier state is possible (typhoid).Further, acute infections generally resolve fasterwith bactericidal than with bacteriostatic drugs,and most bactericidal drugs exert prolongedpostantibiotic effect, so that maintenance of druglevel continuously above MIC is not essential.With bacteriostatic AMAs, the bacteria startmultiplying again when drug level falls belowMIC, which may result in relapse of infection.3. Sensitivity of the organism: Assessed on thebasis of MIC values (seldom determined fordental infections) and consideration of post-antibiotic effect.4. Relative toxicity: Obviously, a less toxic anti-biotic is preferred, e.g. a β-lactam over an amino-glycoside or erythromycin over clindamycin.5. Pharmacokinetic profile: For optimum action,the antibiotic has to be present at the site ofinfection in sufficient concentration for anadequate length of time. This depends on theirpharmacokinetic characteristics. Most antibioticsare given at 2–4 half-life intervals—thusattaining therapeutic concentrations only inter-mittently. For many organisms, aminoglycosides,fluoroquinolones and metronidazole produce‘concentration-dependent inhibition’—inhibitoryeffect depends on the ratio of peak concentrationto the MIC; the same daily dose of gentamicinproduces better action when given as a singledose than if it is divided into 2–3 portions. Onthe other hand, β-lactams, vancomycin andmacrolides produce ‘time-dependent inhibi-tion’—antimicrobial action depends on thelength of time the concentration remains aboveMIC; division of daily dose has better effect.However, the doses should be so spaced that thesurviving organisms again start multiplying anda cidal action is exerted.

Penetration to the site of infection alsodepends on the pharmacokinetic properties of thedrug. A drug, which penetrates better and attainshigher concentration, is likely to be more effective.Penetration of AMAs into bone is generally poor,but clindamycin penetrates very well and is agood choice for purulent osteitis and certain othertooth infections. The fluoroquinolones haveexcellent tissue penetration—attain high concen-trations in soft tissues, lungs, prostate, joints, etc.Ciprofloxacin and rifampin have very goodintracellular penetration. Cefuroxime, ceftria-xone, chloramphenicol, ciprofloxacin attain highCSF concentration. On the other hand, penicil-lins and aminoglycosides penetrate poorly intoCSF unless meninges are inflamed. Ampicillin,cephalosporins and erythromycin attain highbiliary concentration.6. Route of administration: Many AMAs can begiven orally as well as parenterally, but amino-glycosides, penicillin G, carbenicillin, manycephalosporins, vancomycin, etc. have to begiven by injection only. For less severe infections,an oral antibiotic is preferable; but for seriousinfections, e.g. spreading cellulitis, meningitis,septicaemias, a parenteral antibiotic may bechosen.7. Evidence of clinical efficacy: Relative valueof different AMAs in treating an infection isdecided on the basis of comparative clinical trials.Optimum dosage regimens and duration of treat-ment are also determined on the basis of suchtrials. Reliable clinical trial data, if available, isthe final guide for choice of the antibiotic.8. Cost: Less expensive drugs are to be preferred.

COMBINED USE OF ANTIMICROBIALS

More than one AMAs are frequently used con-currently. This should be done only with aspecific purpose and not blindly in the hope thatif one is good, two should be better and threeshould cure almost any infection. The objectivesof using antimicrobial combinations are:

1. To achieve synergism Every AMA has aspecific effect on selected microorganisms.

Combined Use of Antimicrobials 373


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IIIDepending on the drug pair as well as the orga-nism involved, either synergism (supra-additiveeffect), additive action, indifference or antago-nism may be observed when two AMAsbelonging to different classes are used together.

Synergism may manifest in terms of decreasein the MIC of one AMA in the presence of another,or the MICs of both may be lowered. If the MICof each AMA is reduced to 25% or less, the pairis considered synergistic, 25–50% of each isconsidered additive and more than 50% of eachindicates antagonism. Thus, a synergistic drugsensitizes the organisms to the action of the othermember of the pair. This may also manifest asa more rapid lethal action of the combinationthan either of the individual members.Synergistic prolongation of postantibiotic effecthas also been demonstrated for combinations ofβ-lactams with aminoglycoside and by additionof rifampin to a variety of antibiotics.

Every combination is unique; the same drugsmay be synergistic for one organism but anta-gonistic for another. However, general guidelinesare:(a) Two bacteriostatic agents are often additive,but rarely synergistic, i.e. combination of tetra-cyclines, chloramphenicol, erythromycin, etc. Asulfonamide used with trimethoprim is a specialcase where supra-additive effect is obtainedbecause of sequential block in folate metabolismof certain bacteria (Ch. 27). The combination oftenexerts cidal action which is curative in someinfections while the individual components areonly static or ineffective in these.

Another special example is the combinationof a β-lactamase inhibitor clavulanic acid orsulbactam with amoxicillin or ampicillin for β-lactamase producing H. influenzae, N. gonorrhoeaeand other organisms.

(b) Two bactericidal drugs are frequently addi-tive and sometimes synergistic if the organismis sensitive to both, e.g.:• Penicillin/ampicillin + streptomycin/genta-

micin for enterococcal SABE

• Carbenicillin/ticarcillin + gentamicin for Pseu-domonas infection, especially in neutropenicpatients.

• Rifampin + isoniazid in tuberculosis.In the above cases, the combination producesfaster cure and reduces the chances of relapseby more complete eradication of the pathogen.

(c) Combination of a bactericidal with a bacte-riostatic drug may be synergistic or antagonisticdepending on the organism. In general (i) If theorganism is highly sensitive to the cidal drug—response to the combination is equal to the staticdrug given alone (apparent antagonism), becausecidal drugs act primarily on rapidly multiplyingbacteria, while the static drug retards multipli-cation. This has been seen with penicillin +tetracycline/chloramphenicol on pneumococciwhich are highly sensitive to penicillin.Penicillin + erythromycin for group A strepto-cocci and nalidixic acid + nitrofurantoin for E.coli have also shown antagonism.(ii) If the organism has low sensitivity to thecidal drug—synergism may be seen, e.g.:• Penicillin + sulfonamide for actinomycosis• Streptomycin + chloramphenicol for K. pneu-

moniae infection• Rifampin + dapsone in leprosyThus, wherever possible, synergistic combina-tions may be used to treat infections that arenormally difficult to cure. Full doses ofindividual drugs are given for this purpose.

2. To reduce severity or incidence of adverseeffects This is possible only if the combinationis synergistic so that the doses can be reduced.This is needed for AMAs with low safety margin,which when used alone in effective doses,produce unacceptable toxicity, e.g. Streptomycin+ penicillin G for SABE due to Strep. faecalis.

However, in most instances, the individualdoses of a synergistic pair should not be reduced.

3. To prevent emergence of resistance Muta-tion conferring resistance to one AMA is inde-pendent of that conferring resistance to another.

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If the incidence of resistant mutants of a bacillusinfecting an individual for drug P is 10–5 and fordrug Q is 10–7, then only one out of 1012 bacilliwill be resistant to both. The chances of itssurviving host defence and causing a relapsewould be meagre.

This principle of using two or more AMAstogether is valid primarily for chronic infectionsneeding prolonged therapy; has been widelyemployed in tuberculosis, leprosy and nowadopted for H. pylori, HIV as well. It is of littlevalue in most acute and short-lived infections.However, rifampin given with ciprofloxacinprevents Staph. aureus resistance to the latter.

4. To broaden the spectrum of antimicrobialaction This is needed in:

(a) Treatment of mixed infection Bronchiectasis,peritonitis, certain urinary tract infections, brainabscesses, diabetic foot infection, bedsores,gynaecological infections and many orodentalinfections are mixed infections. Often, aerobic andanaerobic organisms sensitive to different drugsare involved. Obviously, two or more AMAshave to be used to cover the pathogens. Drugsshould be chosen on the basis of bacteriologicaldiagnosis and sensitivity pattern, and shouldbe employed in full doses. Clindamycin ormetronidazole are generally included to coveranaerobes. It may sometimes be possible to finda single agent effective against all the causativeorganisms.

(b) Initial treatment of severe infections Wherebacterial diagnosis is not known; drugs coveringgram-positive and gram-negative (in certainsituations anaerobes as well), e.g. ampicillin +gentamicin; cephalosporin or erythromycin + anaminoglycoside ± metronidazole or clindamycin,may be given together. Rational combinationsincrease the certainty of curing the infection inthe first attempt, but should be continued onlytill bacteriological data become available. Whenthe organism and its sensitivity has beendetermined, severity of infection is in itself notan indication for combination therapy.

Combinations should not be used as a substitutefor accurate diagnosis.

(c) Topically Generally, AMAs which are notused systemically, are poorly absorbed from thelocal site and cover a broad range of gram-positive and gram-negative bacteria are combi-ned for topical application, e.g. bacitracin,neomycin, polymyxin B.

Disadvantages of antimicrobial combinations

1. They foster a casual rather than rational out-look in the diagnosis of infections and choiceof AMA.

2. Increased incidence and variety of adverseeffects. Toxicity of one agent may be enhancedby another, e.g. vancomycin + tobramycinand gentamicin + cephalothin produceexaggerated kidney failure.

3. Increased chances of superinfections.4. If inadequate doses of nonsynergistic drugs

are used — emergence of resistance may bepromoted.

5. Higher cost of therapy.

PROPHYLACTIC USE OF ANTIMICROBIALS

This refers to the use of AMAs for preventing thesetting in of an infection or suppressingcontacted infection before it becomes clinicallymanifest. AMAs are frequently given prophylac-tically; but in a number of circumstances, this isat best wasteful if not harmful. The differencebetween treating and preventing infections isthat treatment is directed against a specificorganism infecting an individual patient, whileprophylaxis is often against all organismscapable of causing infection.

Antimicrobial prophylaxis is highly success-ful when it is directed against specific organisms,e.g. use of benzathine penicillin to preventstreptococcal infection responsible for rheumaticfever; isoniazid ± rifampicin to prevent tuber–culosis in contacts, or mefloquine/doxycyclineto prevent malaria in travellers to endemic areas.On the other hand, when it is intended to prevent

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IIIinfection in general, antibiotic prophylaxis oftenserves no purpose, may even be deleterious byincreasing the likelihood of resistant infections.It is not possible to prevent all infections at alltimes in all individuals. Use of antibiotics in viralupper respiratory infections to prevent secondarybacterial invasion; to cover clean elective surgeryor normal labour; to prevent chest infection inunconscious patients falls in this category.

Though the merit of antibiotic prophylaxis incertain high-risk situations has been questioned,it is frequently given in case of:(a) Dirty contaminated wounds (e.g. fromroadside accidents).(b) Catheterization/instrumentation of urinarytract, endoscopies.(c) Chronic obstructive lung disease: to preventacute exacerbation.(d) Immunocompromised patients.(e) Surgical wound infection.

Antimicrobial prophylaxis in dentistry

This is warranted for two distinct purposes viz.(a) prevention of local wound infection, and(b) prevention of distant infection (e.g. bacterialendocarditis) in predisposed patients followingdental procedures.

Prophylaxis of dental wound infection

Wound infection occurs due to microbial contami-nation of the surgical site. It is important for thedental surgeon to see that the wound left aftertooth extraction, etc. does not get infected. Use ofsterile instruments, cross-infection controlmeasures (antiseptic/disinfectant, etc.) and goodsurgical technique to minimise tissue damage,haematoma and devascularization are theprimary, and often the only measures needed. Inaddition, systemic antimicrobial prophylaxis isadvocated in selected situations.

Prophylaxis should be employed only whenthere is a clear risk of wound infection thatoutweighs the possible drawbacks of antibioticuse. In general, antibiotic prophylaxis is notrequired for routine dental surgery, except in

patients at special risk. Simple extractions andminor periodontal procedures in otherwisehealthy subjects are associated with very low riskof wound infection. Incidence of postoperativeinfection is quite low even after difficult surgerysuch as removal of impacted third molar, andantimicrobial prophylaxis is not required.However, it may be given when surgery involvesextensive instrumentation, bone cutting or isprolonged. It has been found that the incidence ofpostoperative infection is higher when oralsurgery had lasted 2 hours or more. Prophylaxisshould also be given for procedures in which aprosthesis is inserted into the bone or soft tissue,such as dental implants. Extensive reconstructivesurgery of upper or lower jaw also warrantsantibiotic prophylaxis.

All orodental procedures which disturb/damage mucosa including extractions, scaling,etc. need to be covered by prophylaxis in diabetics,corticosteroid recipients and other immuno-compromised subjects.

The selection of drug, dose, timing andduration of prophylactic medication is crucial. Itis important that the antibiotic is not startedprematurely and is not continued beyond the timewhen bacteria have access to the surgical wound.Administration of the AMA has to be so timedthat peak blood levels occur when the clot isforming in the surgical wound. Thus, most of theoral drugs are given 1 hour before tooth extractionor other short procedures, while i.v. or i.m. drugsare given just prior to it. Most of the AMAs do notpenetrate the clot once it is formed and is olderthan 3 hours. Thus, late and prolonged presenceof the antibiotic in circulation serves no purpose,but can foster resistant organisms. However,when the sugery has been performed in thepresence of local infection, continuation of theprophylactic AMA beyond 4 hours after thedental procedure may be justified. In case ofprolonged dental surgery, the antibiotic may berepeated i.v. during the procedure.

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blood levels several times higher than MIC for thecommon oral pathogens. Because the resident oralflora is generally the source of the infectingorganism for dental surgery wounds, theprophylactic AMA should be active against gram-positive cocci and oral anaerobes. Beingbactericidal and safe, amoxicillin is generally thefirst choice drug. The commonly employedantibiotics for prevention of wound infection indentistry are listed in the box.

procedures are covered with antibioticprophylaxis in susceptible individuals.

Though prophylaxis has also been advocatedby some for subjects with hip/knee jointreplacement and other orthopedic prosthesis, thisis considered unnecessary by others because oflack of evidence that prosthetic joint gets infectedfollowing dental procedures. However, due toserious nature of infection at these sites,prophylaxis may be given to patients at specialrisk such as recent joint replacement, past historyof prosthetic joint infection and patients withrheumatoid arthritis.

The same antibiotics and regimens describedabove for prevention of dental wound infectioncan be employed for prophylaxis of distantinfections. However, since patients withprosthetic heart valves, those with history ofbacterial endocarditis in the past and those to beoperated under general anaesthesia areconsidered to be at greater risk and have a poorerprognosis if they develop bacterial endocarditis,it has been advocated that gentamicin 120 mg(2 mg/kg) i.m./i.v. may be given just before thedental procedure in addition to amoxicillin (orits substitute) and another dose of amoxicillin500 mg (12.5 mg/kg) be repeated 6 hours after theprocedure.

Another regimen used in patients allergic topenicillin is vancomycin 1 g (20 mg/kg) i.v. over2 hours + gentamicin 120 mg (2 mg/kg) i.m./i.v.just before the procedure.

Antiseptic rinse with chlorhexidine (0.2%)held in the mouth for 1 minute just before dentaltreatment has been advocated as an adjuvantmeasure because it has been shown to reduce theseverity of bacteraemia following dentalextraction.

FAILURE OF ANTIMICROBIAL THERAPY

Antimicrobials may fail to cure an infection/fever, or there may be relapses. This is rare whenantimicrobial therapy was begun, in the firstplace, on sound clinical and/or bacteriologicalbasis. When a real or apparent failure of the

Antimicrobial Prophylaxis in Dentistry 377

For patientsallergic topenicillin

Oral (single dose given 1 hour beforeprocedure)

1. Amoxicillin 2 g (50 mg/kg)2. Cephalexin 2 g (50 mg/kg)3. Cefadroxil 2 g (50 mg/kg)4. Clindamycin 600 mg

(20 mg/kg)5. Azithromycin 500 mg

(15 mg/kg)

Parenteral (single injection just beforeprocedure)

1. Ampicillin 2 g (50 mg/kg) i.m/i.v2. Cefazolin 1 g (25 mg/kg) i.v.3. Clindamycin 600 mg (20 mg/kg) i.v. for

penicillin allergic patients

⎫⎬⎭

Prophylaxis of distant infection

Injury to a mucosa that is laden with bacteriaintroduces some of these into the bloodstream.Transient bacteraemia occurs regularly duringdental extraction, scaling, intraligamentary localanaesthetic injection, root canal treatment,placement of dental implant or any otherprocedure in which the gingival margin ismanipulated. The blood-borne bacteria can causelife-threatening endocarditis in subjects withpostrheumatic or congenital endocardial abnor-malities such as mitral stenosis and othervalvular defects, artificial heart valves or previoushistory of bacterial endocarditis. As such, it isimperative that the above-mentioned orodental


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antimicrobial regimen occurs, the diagnosis andtherapy should be reviewed. One of the followingcauses will usually be identified:1. Improper selection of drug, dose, route orduration of treatment.2. Treatment begun too late.3. Failure to take necessary adjuvant measures,e.g. drainage of abscesses, empyema, etc.;

removal of renal stones, other foreign bodies;cavity closure; control of diabetes, etc.4. Poor host defence—as in leukaemias, neutro-penia and other causes; especially if bacterio-static AMA is used.5. Infecting organism present behind barriers,such as vegetation on heart valves (in SABE),inside the eyeball, blood-brain barrier.

SULFONAMIDES

Sulfonamides were the first antimicrobial agents(AMAs) effective against pyogenic bacterialinfections. Sulfonamido-chrysoidine (ProntosilRed) was one of the dyes included by Domagkto treat experimental streptococcal infection inmice and found it to be highly effective. Hesubsequently cured his daughter of streptococcalsepticaemia (which was 100% fatal at that time)by prontosil. By 1937, it became clear thatprontosil was broken down in the body to releasesulfanilamide which was the active antibacterialagent. A large number of sulfonamides wereproduced and used extensively, but because ofrapid emergence of bacterial resistance and theavailability of many safer and more effectiveantibiotics, their current utility is limited, exceptin combination with trimethoprim (ascotrimoxazole) or pyrimethamine (for malaria).

potency and pharmacokinetic property. A free amino groupin the para position (N4) is required for antibacterial activity.

Sulfonamides that are still of clinical interestare:1. Short acting (4–8 hr):

Sulfadiazine2. Intermediate acting (8–12 hr):

Sulfamethoxazole3. Long acting (~7 days):

Sulfadoxine, Sulfamethopyrazine4. Special purpose sulfonamides:

Sulfacetamide sod., Sulfasalazine, Mafenide,Silver sulfadiazine

Antibacterial spectrumSulfonamides are primarily bacteriostatic againstmany gram-positive and gram-negative bacteria.However, bactericidal concentrations may beattained in urine. Sensitivity patterns amongmicroorganisms have changed from time to timeand place to place. Those still sensitive are:many Strepto. pyogenes, Haemophilus influenzae,H. ducreyi, Calymmatobacterium granulomatis,Vibrio cholerae. Only a few gonococci, meningo-cocci, pneumococci, Escherichia coli, and Shigellarespond, but majority are resistant. Anaerobicbacteria are not susceptible.Chlamydiae: trachoma, lymphogranuloma vene-reum, inclusion conjunctivitis.Actinomyces, Nocardia and Toxoplasma.

27

Sulfonamides, Cotrimoxazole, Quinolonesand Nitroimidazoles

Chemistry All sulfonamides may be considered to bederivatives of sulfanilamide (p-aminobenzene sulfo-namide). Individual members differ in the nature of N1

(Sulfonamido N) substitution, which governs solubility,

380 Sulfonamides, Cotrimoxazole, Quinolones and NitroimidazolesS

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Mechanism of action Many bacteria synthe-size their own folic acid (FA) of whichp-aminobenzoic acid (PABA) is a constituent,and is taken up from the medium. Sulfonamidesbeing structural analogues of PABA, inhibitbacterial folate synthase → FA is not formed anda number of essential metabolic reactions suffer.Sulfonamides competitively inhibit the union ofPABA with pteridine residue to form dihydro-pteroic acid which conjugates with glutamicacid to produce dihydrofolic acid. Also, beingchemically similar to PABA, the sulfonamidemay itself get incorporated to form an alteredfolate which is metabolically injurious.

Human cells also require FA, but they utilizepreformed FA supplied in diet and areunaffected by sulfonamides. Evidences in favourof this mechanism of action of sulfonamides are:(a) PABA, in small quantities, antagonizes the

antibacterial action of sulfonamides.(b) Only those microbes which synthesize their

own FA, and cannot take it from the mediumare susceptible to sulfonamides.Pus and tissue extracts contain purines and

thymidine which decrease bacterial requirementfor FA and antagonize sulfonamide action. Pusis also rich in PABA.

Resistance to sulfonamides Most bacteria arecapable of developing resistance to sulfona-mides. Prominent among these are gonococci,pneumococci, Staph. aureus, meningococci, E. coli,Shigella and some Strep. pyogenes, Strep. viridansand anaerobes. The resistant mutants either:(a) produce increased amounts of PABA, or(b) their folate synthase enzyme has low affinity

for sulfonamides, or(c) adopt an alternative pathway in folate

metabolism.When an organism is resistant to onesulfonamide, it is resistant to them all. No crossresistance between sulfonamides and other classof AMAs has been noted. Development of resis-tance has markedly limited the clinical useful-ness of this class of compounds.

Pharmacokinetics Sulfonamides are nearlycompletely absorbed from g.i.t. Extent of plasmaprotein binding differs considerably (10–95%)among different members. The highly proteinbound members are longer acting. Sulfonamidesare widely distributed in the body. The free formof sulfadiazine attains the same concentration inCSF as in plasma. They cross placenta freely.

The primary pathway of metabolism ofsulfonamides is acetylation at N4 by nonmicro-somal N-acetyl transferase, primarily in liver.There are slow and fast acetylators, but thedifference is mostly insufficient to be clinicallysignificant. The acetylated derivative is inactive,but can contribute to the adverse effects. It isgenerally less soluble in acidic urine — mayprecipitate and cause crystalluria.

Sulfonamides are excreted mainly by thekidney. The more lipid-soluble members arehighly reabsorbed in the tubule, therefore arelonger acting.

Sulfadiazine It is the prototype of the general purposesulfonamides which is rapidly absorbed orally and rapidlyexcreted in urine. It has good penetrability in brain andCSF—was the preferred compound for meningitis.Dose: 0.5 g QID to 2 g TDS; SULFADIAZINE 0.5 g tab.

Sulfamethoxazole It has slower oral absorption andurinary excretion—intermediate duration of action, t½ inadults averages 10 hours. It is the preferred compoundfor combining with trimethoprim because the t½ of bothis similar. However, a high fraction is acetylated, whichis relatively insoluble—crystalluria can occur.Dose: 1 g BD for 2 days, then 0.5 g BD.GANTANOL 0.5 g tab.

Sulfadoxine, Sulfamethopyrazine These are ultralongacting compounds, action lasting > 1 week because ofhigh plasma protein binding and slow renal excretion (t½5–9 days). They attain low plasma concentration (of freeform) and are not suitable for treatment of acutepyogenic infections. They are used in combination withpyrimethamine in the treatment of malaria, Pneumocystisjiroveci pneumonia in AIDS patients and in toxoplasmo-sis. They have caused serious cutaneous reactions.

Sulfacetamide sod. It is a highly soluble compoundyielding neutral solution which is only mildly irritatingto the eye in concentrations up to 30%. It is used topicallyfor ocular infections due to susceptible bacteria andchlamydia.LOCULA, ALBUCID 10%, 20%, 30% eye drops, 6% eye oint.

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Sulfasalazine (see p. 289, 318) used in ulcerative colitisand rheumatoid arthritis.

Mafenide It is not a typical sulfonamide, because a —CH2—bridge separates the benzene ring and the aminogroup. It is used only topically. In contrast to typicalsulfonamides, it is active in the presence of pus andagainst Pseudomonas, clostridia which are not inhibitedby typical sulfonamides. It has been mainly employedfor burn dressing to prevent infection, but not to treatalready infected cases.

Silver sulfadiazine Used topically as 1% cream, it isactive against a large number of bacteria and fungi, eventhose resistant to other sulfonamides, e.g. Pseudomonas.It slowly releases silver ions which appear to be largelyresponsible for the antimicrobial action. It is consideredto be one of the most effective drugs for preventing infectionof burnt surfaces and chronic ulcers.

Adverse effects

Adverse effects to sulfonamides are relativelycommon. These are:• Nausea, vomiting and epigastric pain.• Crystalluria is dose related but infrequent

now. Precipitation in urine can be minimizedby taking plenty of fluids and by alkalinizingthe urine in which sulfonamides and theiracetylated derivatives are more soluble.

• Hypersensitivity reactions occur in 2–5%patients. These are mostly in the form ofrashes, urticaria and drug fever. Photosensiti-zation is reported. Stevens-Johnson syndromeand exfoliative dermatitis are more commonwith long-acting agents.

• Hepatitis, unrelated to dose, occurs in 0.1%patients.

• Topical use of sulfonamides is not recommen-ded because of risk of contact sensitization.However, ocular use is permitted.

• Sulfonamides cause haemolysis in a dose-dependent manner in individuals with G-6-PD deficiency.

Interactions Sulfonamides inhibit the metabo-lism (possibly displace from protein bindingalso) of phenytoin, tolbutamide and warfarin—enhance their action.They displace methotrexate from binding anddecrease its renal excretion—toxicity can occur.

Uses

Systemic use of sulfonamides alone (not combinedwith trimethoprim or pyrimethamine) is rare now.

Ocular sulfacetamide sod. (10–30%) is a cheapalternative in trachoma/inclusion conjunctivitis.Topical silver sulfadiazine or mafenide are usedfor preventing infection on burn surfaces.

COTRIMOXAZOLE

The fixed dose combination of trimethoprimand sulfamethoxazole is called cotrimoxazole.Trimethoprim is a diaminopyrimidine related tothe antimalarial drug pyrimethamine whichselectively inhibits bacterial dihydrofolate reduc-tase (DHFRase). Cotrimoxazole introduced in1969 causes sequential block of folate metabolismas depicted in Fig. 27.1. Trimethoprim is >50,000times more active against bacterial DHFRasethan against the mammalian enzyme. Thus,human folate metabolism is not interfered atantibacterial concentrations of trimethoprim.Individually, both sulfonamide and trimetho-prim are bacteriostatic, but the combinationbecomes cidal against many organisms. Maxi-mum synergism is seen when the organism issensitive to both the components, but even whenit is moderately resistant to one component, theaction of the other may be enhanced.

Sulfamethoxazole was selected for combi-ning with trimethoprim because both have nearlythe same t½ (~ 10 hr). Optimal synergy in caseof most organisms is exhibited at a concentrationratio of sulfamethoxazole 20 : trimethoprim 1, theMIC of each component may be reduced by3–6 times. This ratio is obtained in the plasmawhen the two are given in a dose ratio of 5 : 1,because trimethoprim enters many tissues, hasa larger volume of distribution than sulfa-methoxazole and attains lower plasma concen-tration. However, the concentration ratio in manytissues is less than 20 : 1. Trimethoprimadequately crosses blood-brain barrier andplacenta, while sulfamethoxazole has a poorerentry. Moreover, trimethoprim is more rapidlyabsorbed than sulfamethoxazole—concentration

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ratios may vary with time. Trimethoprim is 40%plasma protein bound, while sulfamethoxazoleis 65% bound. Trimethoprim is partly metabo-lized in liver and excreted in urine.

Spectrum of action Antibacterial spectra oftrimethoprim and sulfonamides overlap consi-derably. Additional organisms covered by thecombination are—Salmonella typhi, Serratia,Klebsiella, Enterobacter, Yersinia enterocolitica,Pneumocystis jiroveci and many sulfonamide-resistant strains of Staph. aureus, Strep. pyogenes,Shigella, enteropathogenic E. coli, H.influenzae,gonococci and meningococci.

Resistance Bacteria are capable of acquiringresistance to trimethoprim mostly throughmutational or plasmid mediated acquisition ofa DHFRase having lower affinity for theinhibitor. However, resistance to the combinationhas been slow to develop compared to eitherdrug alone. Widespread use of the combinationhas resulted in reduced responsiveness of manyoriginally sensitive strains.

Adverse effects All adverse effects seen withsulfonamides can be produced by cotrimoxazole.• Nausea, vomiting, stomatitis, headache and

rashes are the usual manifestations.• Folate deficiency (megaloblastic anaemia) is

infrequent, occurs only in patients withmarginal folate levels.

• Blood dyscrasias occur rarely.It should not be given during pregnancy: trimet-hoprim being an antifolate, there is theoretical

teratogenic risk. Neonatal haemolysis andmethaemoglobinaemia can occur if it is givennear term.• Patients with renal disease may develop

uraemia. Dose should be reduced in modera-tely severe renal impairment.

• Diuretics given with cotrimoxazole have pro-duced a higher incidence of thrombocytopenia.

Preparations SEPTRAN, SEPMAX, BACTRIM, CIPLIN,ORIPRIM, SUPRISTOL, FORTRIMTrimethoprim Sulfamethoxazole

80 mg + 400 mg tab: 2 BD for 2 days then 1 BD.160 mg + 800 mg tab: double strength (DS); 1 BD.20 mg + 100 mg pediatric tab.40 mg + 200 mg per 5 ml susp; infant 2.5 ml (not

to be used in newborns), children 1–5yr 5 ml, 6–12 year 10 ml (all BD).

160 mg + 800 mg per 3 ml for i.m. injection12 hourly. (CIPLIN, ORIPRIM-IM)

8 0 mg + 400 mg per 5 ml for i.v. injection(WK-TRIM, ORIPRIM-IV) 10–15 ml BD.

Cotrimazine It is a combination of trimethoprim withsulfadiazine. Its utility is similar to that of cotrimoxazole.Trimethoprim Sulfadiazine

90 mg + 410 mg: AUBRIL; 2 tab BD for 2 days,then 1 BD.

180 mg + 820 mg: TRIGLOBE FORTE tab.

Uses

The popularity of cotrimoxazole for treatment ofsystemic infections has declined. It is still usefulin tonsillitis, pharyngitis, sinusitis, otitis media,chronic bronchitis, etc. but is only occasionallyemployed for orodental infections, especially in patientsallergic to β-lactam antibiotics. Urinary tractinfections, both acute as well as recurrent casesand those with prostatitis are its major indicationsnow. Many cases of bacterial diarrhoeas anddysentery respond to cotrimoxazole. Cotrimoxa-zole is an alternative drug for chancroid andgranuloma inguinale. Used in high doses, it is afirst line drug for Pneumocystis jiroveci pneumoniain AIDS patients.

QUINOLONES

These are synthetic antimicrobials having aquinolone structure and are active primarily

Fig. 27.1: Sequential block in bacterial folate metabolism

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against gram-negative bacteria, though newerfluorinated compounds also inhibit gram-positive ones. The first member Nalidixic acidintroduced in mid-1960s had usefulness limitedto urinary and g.i. tract infections because of lowpotency, modest blood and tissue levels, res-tricted spectrum and high frequency of bacterialresistance. A breakthrough was achieved in theearly 1980s by fluorination of the quinolonestructure at position 6 and introduction of apiperazine substitution at position 7 resulting inderivatives called fluoroquinolones with highpotency, expanded spectrum, slow developmentof resistance, better tissue penetration and goodtolerability.

Nalidixic acid

It is active against gram-negative bacteria, especiallycoliforms: E. coli, Proteus, Klebsiella, Enterobacter, Shigellabut not Pseudomonas. It acts by inhibiting bacterial DNAgyrase and is bactericidal. Resistance to nalidixic aciddevelops rather rapidly.

Nalidixic acid is absorbed orally, highly plasma proteinbound and partly metabolized in liver: one of themetabolites is active. It is excreted in urine with a plasmat½ ~8 hrs. Concentration of the free drug in plasma andmost tissues attained with the usual doses is non-therapeutic for systemic infections. However, high con-centration attained in urine (20–50 times than in plasma)is lethal to the common urinary pathogens.

Adverse effects These are relatively infrequent, consistmostly of g.i. upset and rashes.Most important toxicity is neurological—headache,drowsiness, vertigo, visual disturbances, occasionallyseizures (especially in children).

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Phototoxicity is rare. Individuals with G-6-PD deficiencymay develop haemolysis.Dose: 0.5–1 g TDS or QID; GRAMONEG, WINTOMYLON,URODIC, 0.5 g tab, 0.3 g/5 ml syrup.

Use: Nalidixic acid has poor activity against oralpathogens and has practically no utility in dentistry. It isprimarily used as a urinary antiseptic. Nitrofurantoinshould not be given concurrently—antagonism occurs.

It has also been employed in diarrhoea caused byProteus, E. coli, Shigella or Salmonella.

FLUOROQUINOLONES

These are quinolone antimicrobials having oneor more fluorine substitutions. The ‘firstgeneration’ fluoroquinolones (FQs) introduced in1980s have one fluoro substitution. In the 1990s,compounds with additional fluoro and othersubstitutions have been developed—furtherextending antimicrobial activity to gram-positivecocci and anaerobes, and/or confering metabolicstability (longer t½). These are referred to as‘second generation’ FQs. The latest memberslabelled ‘third generation’ FQs have stillenhanced activity and a spectrum covering mostgram positive respiratory pathogens as well.

First generation fluoroquinolones

Norfloxacin OfloxacinCiprofloxacin Pefloxacin

Second generation fluoroquinolones

Lomefloxacin LevofloxacinSparfloxacin Gatifloxacin

MoxifloxacinThird generation fluoroquinolones

Gemifloxacin Prulifloxacin

Mechanism of action The FQs inhibit theenzyme bacterial DNA gyrase which nicksdouble-stranded DNA, introduces negativesupercoils and then reseals the nicked ends. Thisis necessary to prevent excessive positivesupercoiling of the strands when they separateto permit replication or transcription. The DNAgyrase consists of two A and two B subunits; the


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A subunit carries out nicking of DNA, B subunitintroduces negative supercoils and then Asubunit reseals the strands. FQs bind to Asubunit with high affinity and interfere with itsstrand cutting and resealing function. In gram-positive bacteria the major target of FQ action isa similar enzyme topoisomerase IV which nicksand separates daughter DNA strands after DNAreplication. Greater affinity for topoisomerase IVmay confer higher potency against gram-positivebacteria. The bactericidal action probably resultsfrom digestion of DNA by exonucleases whoseproduction is signalled by the damaged DNA.

In place of DNA gyrase or topoisomerase IV,the mammalian cells possess an enzymetopoisomerase II (that also removes positivesupercoils) which has very low affinity for FQs—hence the low toxicity to host cells.

Mechanism of resistance Because of theunique mechanism of action, plasmid mediatedtransferable resistance probably does not occur.Resistance noted so far is due to chromosomalmutation producing a DNA gyrase or topo-isomerase IV with reduced affinity for FQs, ordue to reduced permeability/increased efflux ofthese drugs across bacterial membranes. Incontrast to nalidixic acid, which selects singlestep resistant mutants at high frequency, FQ-resistant mutants are not easily selected.Therefore, resistance to FQs has been slow todevelop. However, increasing resistance hasbeen reported among Salmonella, Pseudomonas,staphylococci, gonococci and pneumococci.

Ciprofloxacin (prototype)

It is the most potent first generation FQ activeagainst a broad range of bacteria, the mostsusceptible ones are the aerobic gram-negativebacilli, especially the Enterobacteriaceae andNeisseria. The MIC of ciprofloxacin against theseis usually < 0.1 μg/ml, while gram-positivebacteria are inhibited at relatively higher concen-trations. The spectrum of action is summarizedbelow:

Highly susceptible

E. coli Neisseria gonorrhoeaeK. pneumoniae N. meningitidisEnterobacter H. influenzaeSalmonella typhi H. ducreyiOther Salmonella Campylobacter jejuniShigella Yersinia enterocoliticaProteus Vibrio cholerae

Moderately susceptible

Pseudomonas aeruginosa LegionellaStaph. aureus Brucella

(including MRSA) ListeriaStaph. epidermidis Bacillus anthracisBranhamella catarrhalis Mycobact. tuberculosis

Organisms which have shown low/variablesusceptibility are: Strep. pyogenes, Strep. faecalis,Strep. pneumoniae, Mycoplasma, Chlamydia,Mycobact. kansasii, Mycobact. avium.

Notable resistant bacteria are: Bacteroidesfragilis, Clostridia, anaerobic cocci. As such,majority of oral pathogens are not covered byciprofloxacin (and other FQs).The remarkable microbiological features of cipro-floxacin (also other FQs) are:• Rapidly bactericidal activity and high

potency.• Relatively long postantibiotic effect on Ente-

robacteriaceae, Pseudomonas and Staph.• Low frequency of mutational resistance.• Low propensity to select plasmid type resis-

tant mutants.• Protective intestinal streptococci and anae-

robes are spared.• Active against many β-lactam and amino-

glycoside resistant bacteria.• Less active at acidic pH.

Pharmacokinetics Ciprofloxacin is rapidlyabsorbed orally, but food delays absorption, andfirst pass metabolism occurs. The pharmaco-kinetic characteristics are given in Table 27.1.The most prominent feature of ciprofloxacin(and other FQs) is high tissue penetrability:concentration in lung, sputum, muscle, bone,

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Table 27.1: Pharmacokinetic characteristics and doses of fluoroquinolones

CIPROFL NORFL PEFL OFL LEVOFL LOME SPAR GATI

1. Oral bioavailability (%) 60–80 35–45 90–100 85–95 ~100 > 90 90 96

2. Plasma protein binding (%) 20–35 15 20–30 25 25 10 40 20

3. Vol. of distribution (L/kg) 3–4 2 2 1.5 1.3 1.7–2.5 3.6 –

4. Percent metabolized 20 25 85 5–10 5 20 60 < 5

5. Elimination t½ (hr) 3–5 4–6 8–14 5–8 8 6–9 15–20 8

6. Routes of administration oral, i.v. oral oral, i.v. oral, i.v. oral, i.v. oral oral oral, i.v.

7. Dose (mg) : oral 250–750 400 400 200–400 500 400 200–400 200–400(BD) (BD) (BD) (BD) (OD) (OD) (OD) (OD)

: i.v. 100–200 — 400 200 500 — — 200-400

Quinolones 385

prostate and phagocytes exceeds that in plasma,but CSF and aqueous levels are lower. It isexcreted primarily in urine, both by glomerularfiltration and tubular secretion. Urinary andbiliary concentrations are 10–50-fold higher thanplasma.

Adverse effects Ciprofloxacin has good safetyrecord: side effects occur in ~10% patients, butare generally mild; withdrawal is needed onlyin 1.5%.• Gastrointestinal: nausea, vomiting, bad taste,

anorexia. Because gut anaerobes are not affec-ted—diarrhoea is infrequent.

• CNS: dizziness, headache, restlessness, anxiety,insomnia, impairment of concentration, tremor.Seizures are rare, occur only at high doses.

• Skin/hypersensitivity: rash, pruritus, photo-sensitivity, urticaria, swelling of lips, etc.

• Tendonitis and tendon rupture: few cases arereported.

Ciprofloxacin and other FQs are contraindicatedduring pregnancy. Use in children requirescaution due to fear of damage to weight bearingjoints.

Interactions

• Plasma concentration of theophylline andwarfarin are increased by ciprofloxacin (alsoby norfloxacin and pefloxacin) due to inhi-bition of metabolism: toxicity of these drugscan occur.

• NSAIDs may enhance the CNS toxicity of FQs;seizures are reported.

• Antacids, sucralfate and iron salts given con-currently reduce absorption of FQs.

CIFRAN, CIPLOX, CIPROBID, QUINTOR, CIPROLET250, 500, 750 mg tab, 200 mg/100 ml i.v. infusion, 3mg/ml eye drops.

Uses Ciprofloxacin is effective in a broad rangeof infections including some difficult to treat ones.Because of wide spectrum bactericidal activity,oral efficacy and good tolerability, it is beingextensively employed for blind therapy of anyinfection, but should not be used for minor casesor where gram-positive organisms and/oranaerobes are primarily causative. As such, it isnot a suitable drug for majority of orodental infections.The only specific indication is infection causedby susceptible Pseudomonas which is rare in dentalpractice. Because ofloxacin, gatifloxacin andmoxifloxacin are more active against gram-positive bacteria and anaerobes, they have morepotential utility in dentistry. Ciprofloxacin may becombined with metronidazole for some refractorymixed infections like periodontitis.

Ciprofloxacin is a very popular drug for manysystemic infections, viz. urinary tract infection,bacterial gastroenteritis, typhoid fever, gonor-rhoea caused by penicillinase producing aswell as nonpenicillinase producing gonococci,chancroid, skin and soft tissue infections, woundand gynaecological infections, skeletal infections,etc. It is not a primary drug for respiratory tract


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infections. In combination with other antibiotics,ciprofloxacin has been used for serious infectionslike gram-negative septicaemias, meningitis, etc.It is a frequent component of combination chemo-therapy for multidrug resistant tuberculosis.

Norfloxacin It is less potent than ciprofloxacin.Many Pseudomonas and gram-positive organismsare not inhibited at clinically attained concen-trations. Moreover, it attains lower concentrationin tissues. It is metabolized as well as excretedunchanged in urine.

Norfloxacin is primarily used for urinary andgenital tract infections. It is also good forbacterial diarrhoeas.NORBACTIN, NORFLOX 200, 400, 800 mg tab, 3 mg/ml eye drops; UROFLOX, NORILET 200, 400 mg tab.

Pefloxacin It is the methyl derivative of norflo-xacin; more lipid soluble, completely absorbedorally, penetrates tissues better and attainshigher plasma concentrations. It is highly meta-bolized—partly to norfloxacin which contributesto its activity. Pefloxacin has longer t½:cumulates on repeated dosing achieving plasmaconcentrations twice as high as after a singledose. Because of this, it is effective in manysystemic infections in addition to those of theurinary and g.i. tract.PELOX, 200, 400 mg tab, to be taken with meals; 400mg/5 ml inj (to be diluted in 100–250 ml of glucosesolution but not saline since it precipitates in presenceof Cl¯ ions), PERTI, 400 mg tab.

Ofloxacin This FQ is intermediate betweenciprofloxacin and norfloxacin in activity againstgram-negative bacteria, but is comparable to ormore potent than ciprofloxacin for gram-positiveorganisms and certain anaerobes; better suitedfor orodental infections. It also inhibits M. tuber-culosis; can be used in place of ciprofloxacin. Itis highly active against M. leprae: is being usedin alternative multidrug therapy regimens.

Ofloxacin is relatively lipid soluble; oralbioavailability is high: attains higher plasmaconcentrations. It is excreted largely unchangedin urine; dose needs to be reduced in renalfailure.

Ofloxacin is comparable to ciprofloxacin inthe therapy of systemic and mixed infections. Itis particularly suitable for chronic bronchitis andother respiratory or ENT infections. Inhibition oftheophylline metabolism is less marked.

Gonorrhoea has been treated with a single200 mg dose. It is also useful in nongonococcalurethritis.ZANOCIN, TARIVID 100, 200, 400 mg tab; 200 mg/100 ml i.v. infusion, ZENFLOX also 50 mg/5 ml susp.

Levofloxacin It is the levoisomer of ofloxacinhaving improved activity against Strep. pneumo-niae and some other gram-positive and gram-negative bacteria. Anaerobes are moderatelysusceptible. Oral bioavailability of levofloxacinis nearly 100%; oral and i.v. doses are similar.It is mainly excreted unchanged and a singledaily dose is sufficient.

Theophylline, warfarin, cyclosporine andzidovudine pharmacokinetics has been found toremain unchanged during levofloxacin treat-ment. The primary indication of levofloxacin iscommunity-acquired pneumonia and exacerba-tions of chronic bronchitis. High cure rates havebeen noted in sinusitis, pyelonephritis and skin/soft tissue infections as well.TAVANIC, GLEVO 500 mg tab, 500 mg/100 ml inj.

Lomefloxacin It is a second generation difluo-rinated quinolone more active against somegram-negative bacteria and Chlamydia. Becauseof longer t½ and persistence in tissues, it issuitable for single daily administration. It isprimarily excreted unchanged in urine; doseneeds to be reduced in renal insufficiency.LOMEF-400, LOMEDON, LOMADAY 400 mg tab.

Sparfloxacin This second generation difluori-nated quinolone has enhanced activity againstgram-positive bacteria (especially Strep. pneu-moniae, Staphylococcus, Enterococcus), Bacteroidesfragilis, other anaerobes and mycobacteria. Itsmajor indications include pneumonias, exacer-bations of chronic bronchitis, sinusitis and otherENT infections, but does not have any specificutility in dentistry. Reports suggest good efficacy

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in tuberculosis, Mycobacterium avium infection inAIDS patients and in leprosy. A higher incidenceof phototoxic reactions is reported: recipientsshould be cautioned not to go out in the sun.Slight prolongation of QTc interval has beennoted; should be avoided in patients takingcisapride, tricyclic antidepressants, phenothia-zines, class IA and class III antiarrhythmics, etc.Because of longer t½, it is suitable for single dailydosing.TOROSPAR 200, 400 mg tab; SPARTA, SPARQUIN,SPARDAC 100, 200 mg tab.

Gatifloxacin Another 2nd generation FQ thathas excellent activity against Strep. pneumoniae,many atypical respiratory pathogens includingChlamydia pneumoniae and certain anaerobes. Agreater affinity for topoisomerase IV may beresponsible for improved activity against gram-positive cocci. The major indication of gatifloxa-cin is community-acquired pneumonia, exacer-bation of chronic bronchitis, and other upper/lower respiratory tract infections. Significantactivity against gram-positive cocci and anae-robes has prompted its use in dental infectionsas well.Dose: 400 mg on 1st day, followed by 200–400 mg OD,oral or i.v. MYGAT 200,400 mg tab, 400 mg/200 ml inj;GATIQIN 200, 400 mg tab, GAITY 200, 400 mg tab,400 mg/40 ml inj.

Gatifloxacin has the potential to cause tachy-cardia and prolong QTc interval; contraindicatedin hypokalaemia and with other drugs that canprolong QT. Phototoxicity, CNS effects andswelling over face are the other side effects.

Moxifloxacin It is also a long-acting 2ndgeneration FQ having high activity against Str.pneumoniae, other gram-positive bacteriaincluding β-lactam/macrolide resistant ones andsome anaerobes. Bacterial topoisomerase IV is themajor target of action. Moxifloxacin is primarilyused for pneumonias, bronchitis, sinusitis, otitismedia, etc. and has been tried in orodentalinfections as an alternative drug. Side effects aresimilar to other FQs. It should not be given topatients predisposed to seizures and to those

receiving proarrhythmic drugs. Phototoxicityoccurs only rarely.Dose: 400 mg OD; MOXIF 400 mg tab.

Gemifloxacin This potent third generation FQhas enhanced activity against gram positivebacteria and certain anaerobes. It is primarilyindicated in pneumonia and exacerbations ofchronic bronchitis. A higher incidence of skinrashes has been reported.Dose: 320 mg OD for 5-7 days.GAMETOP, GEMBAX, TOPGEM 320 mg tab.

Prulifloxacin It is the prodrug of ulifloxacin, andis a broad spectrum FQ active against many gramnegative and some gram positive bacteria,including Staph. aureus and Strep. pneumoniae. Asingle daily dose of 600 mg is effective in urinarytract and respiratory tract infections. Tolerabilityprofile is similar to ciprofloxacin.ALPRULI, PRULIFACT 600 mg tab.

NITROIMIDAZOLES

MetronidazoleMetronidazole, the prototype member of this classwas introduced in 1959 for trichomonas vaginitisand later found to be a broad-spectrum anti-protozoal drug against Entamoeba histolytica andGiardia lamblia. Its efficacy in anaerobic bacterialinfection was a chance discovery, and it is nowextensively used to treat oral and other anaerobicinfections. Several congeners of metronidazolehave been subsequently produced, of whichTinidazole, Secnidazole, Ornidazole and Satranida-zole are in clinical use.

Many anaerobic bacteria, such as Bact. fragilis,Bact. melaninogenicus, Fusobacterium, Clostridiumperfringens, Cl. difficile, Peptococcus, Peptostrepto-coccus, Prevotella, Veillonella, Campylobacter,Helicobacter pylori and spirochetes are susceptibleto metronidazole. Though it does not directlyinhibit the helminth Dracunculus medinensis,extraction of the worm from under the skin isfacilitated. It does not affect aerobic bacteria.Clinically significant resistance has not developedamong E. histolytica, but decreased responsive-ness of T. vaginalis has been observed in some

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areas. Anaerobic bacteria can also developmetronidazole resistance, but this is not a clinicalproblem except in case of H. pylori.

Metronidazole is selectively toxic to anaerobicmicroorganisms. After entering the cell by diffu-sion, its nitro group is reduced by certain redoxproteins operative only in anaerobic microbes toa highly reactive nitro radical which exertscytotoxicity. The nitro radical of metronidazoleacts as an electron sink which competes with thebiological electron acceptors of the anaerobicorganism for the electrons generated by thepyruvate: ferredoxin oxidoreductase (PFOR)enzyme pathway of pyruvate oxidation. Theenergy metabolism of anaerobes is, thus,disrupted. Aerobic environment attenuatescytotoxicity of metronidazole by inhibiting itsreductive activation. Anaerobes which developmetronidazole resistance have been founddeficient in the mechanism that generates thereactive nitro radical from it.

Metronidazole, in addition, has been foundto inhibit cell-mediated immunity, to inducemutagenesis and to cause radiosensitization.

Pharmacokinetics Metronidazole is almostcompletely absorbed from the small intestines:little unabsorbed drug reaches the colon. It iswidely distributed in the body, attaining thera-peutic concentration in vaginal secretion, semen,saliva and CSF. It is metabolized in liver prima-rily by oxidation and glucuronide conjugation,and excreted in urine. Plasma t½ is 8 hrs.

Adverse effects Side effects of metronidazoleare relatively frequent and unpleasant, but mostlynonserious.• Anorexia, nausea, bitter or metallic taste and

abdominal cramps are the most common.Looseness of stool is occasional.

• Less frequent side effects are—headache,glossitis, dryness of mouth, dizziness, rashesand transient neutropenia.

• Prolonged administration may cause peri-pheral neuropathy and CNS effects. Seizureshave followed very high doses.

• On i.v. injection, thromboflebitis of injected veinoccurs if the solution is not well diluted.

Metronidazole is contraindicated in neurologicaldisease, blood dyscrasias, first trimester ofpregnancy (though no teratogenic effect has yetbeen demonstrated, its mutagenic potentialwarrants caution) and chronic alcoholism.

Interactions A disulfiram-like intolerance toalcohol occurs among some patients takingmetronidazole; they should be instructed to avoiddrinking.Enzyme inducers (phenobarbitone, rifampin) mayreduce its therapeutic effect.Cimetidine can reduce metronidazole metabolism:its dose may need to be decreased.Metronidazole enhances warfarin action byinhibiting its metabolism; prothrombin time ofpatients taking warfarin should be monitoredwhen metronidazole is prescribed. It can decreaserenal elimination of lithium.

PreparationsFLAGYL, METROGYL, METRON, ARISTOGYLALDEZOLE 200, 400 mg tab, 200 mg/5 ml susp. (as benzoylmetronidazole: tasteless); 500 mg/100 ml i.v. infusion;UNIMEZOL 200, 400 mg tabs, 200 mg/5 ml susp.

Uses

Metronidazole in a dose of 200–400 mg TDS(15–30 mg/kg/day) is extensively used to treatorodental infections, because anaerobic bacteriaare frequently involved. Certain oral anaerobesnot inhibited by penicillin/amoxicillin aresusceptible to metronidazole. It is the drug ofchoice for ANUG in which it is often combinedwith either penicillin V, amoxicillin, erythromycinor tetracycline. The response is rapid withdisappearance of the causative spirochete-fusobacterium complex from the lesions andresolution of pain, bleeding, ulceration and badbreath within 2 to 3 days. A 5-day course is oftensufficient. Periodontitis, pericoronitis, acuteapical infections and some endodontic infectionsalso respond well to metronidazole given for 5–7days. Because it is not active against aerobic andfacultative bacteria, metronidazole is mostly

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combined with a penicillin, cephalosporin ormacrolide antibiotic.

Metronidazole is an effective drug foranaerobic bacterial infections that occur at othersites as well, e.g. following colorectal/pelvicsurgery, appendicectomy, brain abscesses,endocarditis, etc. Because these are serious andoften mixed infections, metronidazole is generallygiven i.v. (15 mg/kg over 1 hr) and combined withgentamicin or a 2nd/3rd generation cephalo-sporin. Oral metronidazole is the drug of choicefor antibiotic associated pseudomembranousenterocolitis caused by Cl. difficile. Used alongwith clarithromycin/amoxicillin and a protonpump inhibitor, metronidazole is a component oftriple drug therapy for eradication of H. pylori inpatients with peptic ulcer/nonulcer dyspepsia.

The most important clinical use ofmetronidazole is to treat protozoal infections. Itis the drug of choice for all forms of amoebicinfection, including acute dysentery, chronicintestinal amoebiasis and liver abscess. It is alsoa first line drug for intestinal giardiasis andtrichomonas vaginitis. Nonspecific bacterialvaginosis also responds to oral metronidazole.

Tinidazole It is an equally efficacious congenerof metronidazole, similar to it in every way except:• Metabolism is slower; t½ is ~12 hours; duration

of action is longer; thus, it is more suited forsingle dose or once daily therapy ofamoebiasis, giardiasis and trichomoniasis.

• Some comparative trails in amoebiasis havereported higher cure rates.

• It is claimed to be better tolerated; the incidenceof side effects is lower: metallic taste (2%),nausea (1%), rash (0.2%).

TINIBA 300, 500, 1000 mg tabs; 800 mg/400 ml i.v.infusion; TRIDAZOLE, 300, 500 mg tab; FASIGYN 0.5 gand 1 g tab.

For orodental infections, tinidazole has been usedin a dose of 0.5 g (10 mg/kg) BD for 5 days. Inother serious anaerobic infections the recom-mended dose is 2 g orally followed by 0.5 g BD for5 days. In case oral treatment is not possible, 800mg can be infused slowly i.v. daily till oral therapyis instituted. A single 2 g (oral) or 0.8 g (i.v.) doseis given for prophylaxis of anaerobic infectionbefore colorectal surgery.

Secnidazole A congener of metronidazole withthe same spectrum of activity and potency.Absorption after oral administration is rapid andcomplete, but metabolism is slower resulting ina plasma t½ of 17–29 hours. In intestinalamoebiasis, a single 2 g dose has been found toyield cure rates equal to multiple doses ofmetronidazole and tinidazole. Side effect profileis similar to metronidazole and reported incidenceis 2–10%. It has not been used in dentistry to anysignificant extent.SECNIL, SECZOL 0.5, 1.0 g tabs; NOAMEBA-DS 1.0 gtab.

Ornidazole Activity similar to metronidazole,but it is slowly metabolized—has longer t½(12–14 hr). Dose and duration of regimens foramoebiasis, giardiasis, trichomoniasis, anaerobicinfections and bacterial vaginosis resemblethose for tinidazole. Side effect profile is alsosimilar.DAZOLIC 500 mg tab, 500 mg/100 ml vial for i.v. infusion.ORNIDA 500 mg tab, 125 mg/5 ml susp.

Satranidazole Another nitroimidazole havinglonger t½ (14 hr) and greater potency. Advantagesclaimed are: better tolerability—no nausea,vomiting or metallic taste, absence of neurologicaland disulfiram-like reactions and that it does notproduce the acetamide metabolite which is a weakcarcinogen. Its role in dental infections has notbeen defined.SATROGYL 300 mg tab.

Nitroimidazoles 389

These are antibiotics having a β-lactam ring. Thetwo major groups are penicillins and cephalospo-rins. These are the most commonly used antibio-tics in dentistry. Monobactams and carbapenemsare the newer additions.

PENICILLINS

Penicillin was the first antibiotic to be usedclinically in 1941. It is a miracle that the leasttoxic drug of its kind was the first to be discovered.It was originally obtained from the fungusPenicillium notatum, but the present source is ahigh yielding mutant of P. chrysogenum.

Chemistry and properties The penicillin nuc-leus consists of fused thiazolidine and β-lactamrings to which side chains are attached throughan amide linkage (Fig. 28.1). Penicillin G (PnG),

having a benzyl side chain (at R), is the originalpenicillin used clinically.

The side chain of natural penicillin can besplit off by an amidase to produce 6-amino-penicillanic acid. Other side chains can then beattached to it resulting in different semisyntheticpenicillins with unique antibacterial activitiesand different pharmacokinetic profiles.

At the carboxyl group attached to thethiazolidine ring, salt formation occurs with Na+

and K+; these salts are more stable than the parentacid. Sod. PnG is highly water soluble. It is stablein the dry state, but solution deteriorates rapidlyat room temperature, though remains stable at4°C for 3 days. Therefore, PnG solutions arealways prepared freshly. PnG is also thermolabileand acid labile.

Unitage 1 U of crystalline sod. benzyl penicillin= 0.6 μg of the standard preparation. Thus 1 g =1.6 million units or 1 MU = 0.6 g.

Mechanism of action

All β-lactam antibiotics interfere with the synthe-sis of bacterial cell wall. The bacteria synthesizeUDP-N-acetyl muramic acid pentapeptide, called‘Park nucleotide’ (because Park in 1957 found itto accumulate when susceptible Staphylococcuswas grown in the presence of penicillin) andUDP-N-acetyl glucosamine. The peptidoglycan

Fig. 28.1: Chemical structure of penicillins. (1) Thiazolidinering; (2) Beta-lactam ring; (X) Bond which is broken bypenicillinase

28

Beta-Lactam Antibiotics

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residues are linked together forming long strandsand UDP is split off. The final step is cleavage ofthe terminal D-alanine of the peptide chains bytranspeptidases; the energy so released is utilizedfor establishment of cross linkages between pep-tide chains of the neighbouring strands (Fig. 28.2).This cross linking provides stability and rigidityto the cell wall.

The β-lactam antibiotics inhibit the transpepti-dases so that cross linking (which maintains theclose knit structure of the cell wall) does not takeplace. These enzymes and related proteins consti-tute the penicillin binding proteins (PBPs) whichhave been located in the bacterial cell membrane.Each organism has several PBPs and PBPsobtained from different species differ in theiraffinity towards different β-lactam antibiotics.This fact probably explains their differingsensitivity to the various β-lactam antibiotics.

When bacteria divide in the presence of aβ-lactam antibiotic—cell wall deficient (CWD)forms are produced. Because the interior of thebacterium is hyperosmotic, the CWD forms swelland burst → bacterial lysis. This is how β-lactamantibiotics exert bactericidal action. Under cer-tain conditions and in case of certain organisms,bizarre shaped or filamentous forms, which areincapable of multiplying, result. Grown inhyperosmotic medium, globular ‘giant’ forms orprotoplasts are produced. Lytic effect of theseantibiotics may also be due to derepression ofsome bacterial autolysins which normally func-tion during cell division.

Rapid cell wall synthesis occurs when theorganisms are actively multiplying; β-lactamantibiotics are more lethal in this phase.

The peptidoglycan cell wall is unique tobacteria. No such substance is synthesized (parti-cularly, D-alanine is not utilized) by higher ani-mals. This is why penicillin is practically nontoxicto man.

In gram-positive bacteria, the cell wall isalmost entirely made of peptidoglycan, which is>50 layers thick and extensively cross linked,so that it may be regarded as a single giant

Penicillins 391

Fig. 28.2: Key features of bacterial cell wall synthesis andcell wall structure, depicting the site of action of β-lactamantibiotics and vancomycinA. Cross linking of peptidoglycan residues of neighbouring

strands by cleavage of terminal D-alanine (D-Ala) andtranspeptidation with the chain of 5 glycine (Gly5)residues. The β-lactam antibiotics (β-L) block cleavageof terminal D-Ala and transpeptidation. The peptidogly-can units are synthesized within the bacterial cell andare transported across the cell membrane byattachment to a bactoprenol lipid carrier for assemblyinto strands. Vancomycin (V) binds tightly to the terminalD-Ala-D-Ala sequence and prevents its release fromthe carrier, so that further transpeptidation cannot takeplace.

B. The highly cross linked peptidoglycan strands inbacterial cell wall

NAM—N-acetyl muramic acid;NAG—N-acetylglucosamine; L-Ala—L-alanine; D-Glu—D-glutamic acid; L-Lys—L-Lysine

392 Beta-Lactam AntibioticsS

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mucopeptide molecule. In gram-negative bacteria,it consists of alternating layers of lipoprotein andpeptidoglycan (each layer 1–2 molecule thick withlittle cross linking). This may be the reason forhigher susceptibility of the gram-positive bacteriato PnG.

Blood, pus, and tissue fluids do not interferewith the antibacterial action of β-lactam antibiotics.

PENICILLIN-G (BENZYL PENICILLIN)

Antibacterial spectrum PnG is a narrowspectrum antibiotic; activity is limited primarilyto gram-positive bacteria and few others.

Cocci: Streptococci (except viridans, group D orenterococci) are highly sensitive, so are manypneumococci. Staph. aureus, though originally verysensitive, has acquired resistance to such an extentthat it must be counted out of PnG spectrum. Gram-negative cocci—Neisseria gonorrhoeae and N.meningitidis are susceptible to PnG, thoughincreasing number of gonococci have developedpartial and others high degree resistance.

Bacilli: Gram-positive bacilli—majority of B.anthracis, Corynebacterium diphtheriae, and practi-cally all Clostridia (tetani and others), Listeria arehighly sensitive, so are spirochetes (Treponemapallidum and others), but Bacteroides fragilis islargely resistant, though Bact. melaninogenicus issusceptible. Other anaerobes involved inorodental infections and responsive to PnG arefusobacteria, peptostreptococci, Eubacterium,Campylobacter, Prevotella and Porphyromonas.

Actinomyces israelii is only moderately sensitive.Majority of aerobic gram-negative bacilli (excepta few E. coli, Proteus), Mycobacterium tuberculosis,rickettsiae, chlamydiae, protozoa, fungi andviruses are totally insensitive to PnG.

Bacterial resistance Many bacteria are inhe-rently insensitive to PnG because in them thetarget enzymes and PBPs are located deeperunder lipoprotein barrier where PnG is unable topenetrate or have low affinity for PnG. Theprimary mechanism of acquired resistance isproduction of penicillinase.

Penicillinase It is a narrow spectrum β-lacta-mase which opens the β-lactam ring and inacti-vates PnG and some closely related congeners.Majority of Staphylococci and some strains of gono-cocci, B. subtilis, E. coli, H. influenzae and few otherbacteria produce penicillinase. The gram-positivepenicillinase producers elaborate large quantitiesof the enzyme which diffuses into the sur-roundings and can protect other inherentlysensitive bacteria. In gram-negative bacteria,penicillinase is found in small quantity, but isstrategically located inbetween the lipoproteinand peptidoglycan layers of the cell wall. Staphy-lococcal penicillinase is inducible, and methi-cillin is an important inducer; while in gram-negative organisms, it is mostly a constitutiveenzyme.

Some resistant bacteria become penicillintolerant and not penicillin destroying. Their targetenzymes are altered to have low affinity forpenicillin, e.g. highly resistant pneumococciisolated in some areas have altered PBPs. Themethicillin-resistant Staph. aureus (MRSA) haveacquired a PBP which has very low affinity forβ-lactam antibiotics. The low level penicillin-resistant gonococci are less permeable to the drug,while high degree resistant ones producepenicillinase, as do highly resistant H. influenzae.Both these appear to have acquired the penicilli-nase plasmid by conjugation or transduction andthen propagated by selection.

The gram-negative bacteria have ‘porin’channels formed by specific proteins located intheir outer membrane. Permeability of various β-lactam antibiotics through these channels differs:ampicillin and other members which are activeagainst gram-negative bacteria cross the porinchannels much better than PnG. Some gram-negative bacteria become resistant by loss of porinchannels or their alteration.

Pharmacokinetics

Penicillin G is acid labile—destroyed by gastricacid. As such, less than 1/3rd of an oral dose isabsorbed in the active form. A larger fraction is

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absorbed by infants and the elderly because oflower gastric acidity. Absorption of sod. PnG fromi.m. site is rapid and complete; peak plasma levelis attained in 30 min. It is distributed mainlyextracellularly; reaches most body fluids, butpenetration in serous cavities and CSF is poor.However, in the presence of inflammation(sinovitis, meningitis, etc.) adequate amounts mayreach these sites. About 60% is plasma proteinbound. It is little metabolized because of rapidexcretion.

The pharmacokinetics of PnG is dominatedby very rapid renal excretion; about 10% by glo-merular filtration and the rest by tubular secretion.The plasma t½ of PnG in healthy adult is 30 min.Neonates have incompletely developed tubularsecretion—t½ of PnG is longer; it approachesadult value at 3 months and then is even shorterduring childhood. Aged and those with renalfailure excrete penicillin slowly. Tubular secretionof PnG can be blocked by probenecid—higher andlonger lasting plasma concentrations areachieved. Probenecid has also been shown todecrease the volume of distribution of penicillins.

Preparations and dose

1. Sod. penicillin G (crystalline penicillin) injection: 0.5–5MU i.m./i.v. 6–12 hourly. It is available as dry powder invials to be dissolved in sterile water at the time of injection.BENZYL PEN 0.5, 1 MU inj.

Repository penicillin G injections These are insoluble saltsof PnG which must be given by deep i.m. (never i.v.)injection. They release PnG slowly at the site of injection,which then meets the same fate as soluble PnG.

1. Procaine penicillin G inj. 0.5–1 MU i.m. 12–24 hourlyas aqueous suspension. Plasma concentrations attainedare lower, but are sustained for 1–2 days; PROCAINEPENICILLIN-G 0.5, 1 MU dry powder in vial.

Fortified procaine penicillin G inj: contains 3 lac U procainepenicillin and 1 lac U sod. penicillin G to provide rapid aswell as sustained blood levels. FORTIFIED P.P. INJ 3+1lac U vial.

2. Benzathine penicillin G 0.6–2.4 MU i.m. every 2–4 weeksas aqueous suspension. It releases penicillin extremelyslowly—plasma concentrations are very low but remaineffective for prophylactic purposes for up to 4 weeks.PENIDURE-LA (long acting), LONGACILLIN, PENCOM,0.6, 1.2, 2.4 MU as dry powder in vial.

Adverse effectsPenicillinG is one of the most nontoxic antibiotics;up to 100 MU (60 g) has been injected in a daywithout any direct toxicity.

Local irritancy and direct toxicity Pain at i.m.injection site, nausea on oral ingestion andthrombophlebitis of injected vein are dose-relatedexpressions of irritancy.

Toxicity to the brain may be manifested asmental confusion, muscular twitchings, convul-sions and coma, when very large doses (> 20 MU)are injected i.v.; especially in patients with renalinsufficiency. Bleeding has also occurred withsuch high doses due to interference with plateletfunction.

Accidental i.v. injection of procaine penicillinproduces CNS stimulation, hallucinations andconvulsions due to procaine. Being insoluble, itmay also cause microembolism.

Hypersensitivity These reactions are the majorproblem in the use of penicillins. An incidence of1–10% is reported. Individuals with an allergicdiathesis are more prone to develop penicillinreactions. PnG is the most common drugimplicated in drug allergy. This scare haseliminated it from general use.

Frequent manifestations of penicillin allergyare—rash, itching, urticaria and fever. Wheezing,angioneurotic edema, serum sickness and exfo-liative dermatitis are less common. Anaphylaxisis rare (1 to 4 per 10,000 patients) but may be fatal.Fear of causing anaphylactic shock has severelyrestricted the use of injected PnG.

All forms of natural and semisynthetic peni-cillins can cause allergy, but it is more commonlyseen after parenteral than oral administration.Incidence is highest with procaine penicillin:procaine is itself allergenic. The course ofpenicillin hypersensitivity is unpredictable, i.e.an individual who tolerated penicillin earlier mayshow allergy on subsequent administration andvice versa.

There is partial cross sensitivity betweendifferent types of penicillins; an individual whohas exhibited immediate type of hypersensiti-

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vity—urticaria, angioedema, bronchospasm, ana-phylaxis or serum sickness with one penicillinshould not be given any other type of penicillin.However, if the earlier reaction had been only arash, penicillin may be given cautiously—oftenno untoward effect is seen. History of penicillinallergy must be elicited before injecting it. Ascratch test or intradermal test (with 2–10 U) maybe performed first. On occasions, this itself hascaused fatal anaphylaxis. Testing with benzyl-penicilloyl-polylysine is safer. However, anegative intradermal test does not rule out delayedhypersensitivity. It should also be realised thatpresence of antibodies to penicillin does not meanallergy to it, because practically everyone whoreceives penicillin develops antibodies to it.

For the development of antibodies, penicillinor a product of it (mostly penicilloyl moiety—major determinant) acts as a hapten. There aremany minor determinants as well.

Topical use of penicillin is highly sensitizing(contact dermatitis and other reactions). There-fore, all topical preparations of penicillin havebeen banned, except for use in eye as solution incase of gonococcal ophthalmia.

If a patient is allergic to penicillin, it is best touse an alternative antibiotic. Hyposensitizationby the injection of increasing amounts of penicillinintradermally at hourly intervals may be tried ifthere is no other choice.

Superinfections These are rare with PnG because of itsnarrow spectrum; though bowel, respiratory andcutaneous microflora does undergo changes.

Jarisch-Herxheimer reaction Penicillin injected in asyphilitic patient (particularly secondary syphilis) mayproduce shivering, fever, myalgia, exacerbation of lesions,even vascular collapse. This is due to sudden release ofspirochetal lytic products and lasts for 12–72 hours. Itdoes not recur and does not need interruption of therapy.Aspirin and sedation afford relief of symptoms.

Uses

Penicillin G is the drug of choice for infectionscaused by organisms susceptible to it, unless thepatient is allergic to this antibiotic. However, usehas declined very much due to fear of causinganaphylaxis.

1. Dental infections Parenteral PnG remainseffective in majority of common infectionsencountered in dentistry, particularly thosearising as a sequelae of carious lesions and arecaused by both aerobic and anaerobic bacteriasuch as Streptococci, Peptostreptococci, Eubacterium,Prevotella, Porphyromonas, Fusobacterium. Atordinary doses {0.5 – 2 MU i.m. 6 hourly (sod.PnG) or 12–24 hourly (procaine PnG)} it can beused for periodontal abscess, periapical abscess,pericoronitis, acute suppurative pulpitis, ANUG,oral cellulitis, etc. Penicillin G can also beemployed prophylactically to cover dental proce-dures in predisposed patients. However, manyoriginally susceptible oral pathogens haveacquired penicillin resistance and dental (as wellas medical) practitioners are too scared to injectPnG unless there is no other choice. Therefore, indental practice, use of PnG is very much restrictednow.

2. General medical uses Other medical condi-tions treated with PnG are:a. Streptococcal infections: pharyngitis, tonsilli-tis, otitis media, scarlet fever, rheumatic fever, etc.For bacterial endocarditis caused by viridansstreptococci, high doses (20–40 MU/day) arerequired in combination with gentamicin.b. Pneumococcal infections (pneumonia, menin-gitis) only if the infecting strain is found to besensitive to PnG.c. Meningococcal meningitis and other infec-tions.d. Gonorrhoea caused by nonpenicillinaseproducing N. gonorrhoeae that are still sensitive toPnG.e. Syphilis: benzathine penicillin is the drug ofchoice for all stages because T. pallidum has notdeveloped penicillin resistance.f. Diphtheria , tetanus and other rare infectionslike gas gangrene, anthrax, actinomycosis.

Prophylactic uses of PnG are:• To prevent recurrence of rheumatic fever:

benzathine penicillin is the preparation ofchoice.

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• Surgical prophylaxis (in combination withgentamicin).

• To protect agranulocytosis patients (anaminoglycoside may be given in combination).

SEMISYNTHETIC PENICILLINS

Semisynthetic penicillins are produced by che-mically combining specific side chains (in placeof benzyl side chain of PnG) or by incorporatingspecific precursors in the mould cultures. Thus,procaine penicillin and benzathine penicillin aresalts of PnG and not semisynthetic penicillins.The aim of producing semisynthetic penicillinshas been to overcome the shortcomings of PnG,which are:

1. Poor oral efficacy.2. Susceptibility to penicillinase.3. Narrow spectrum of activity.4. Hypersensitivity reactions (this has not

been overcome in any preparation).In addition, some β-lactamase inhibitors have

been developed which themselves are not anti-bacterial but augment the activity of penicillinsagainst β-lactamase producing organisms.

CLASSIFICATION

1. Acid-resistant alternative to penicillin GPhenoxymethyl penicillin (Penicillin V).

2. Penicillinase-resistant penicillins Methicillin,Cloxacillin.

3. Extended spectrum penicillins(a) Aminopenicillins: Ampicillin, Bacampicillin,

Amoxicillin.(b) Carboxypenicillins: Carbenicillin, Ticarcillin.(c) Ureidopenicillins: Piperacillin, Mezlocillin.

β-lactamase inhibitors Clavulanic acid,Sulbactam Tazobactam.

ACID-RESISTANT ALTERNATIVE TOPENICILLIN-G

Phenoxymethyl penicillin (Penicillin V)It differs from PnG only in that it is acid stable;oral absorption is better; peak blood level isreached in 1 hour and plasma t½ is 30–60 min.

The antibacterial spectrum of penicillin V isidentical to that of PnG, but it is about 1/5 asactive against Neisseria, other gram-negativebacteria and anaerobes. Oral penicillinV is asuitable drug to treat many nonserious dentalinfections and trench mouth, but it cannot bedepended upon for more serious infections. Otherconditions treated with penicillin V arestreptococcal pharyngitis, sinusitis, otitis mediaand minor pneumococcal infections. It can beemployed for prophylaxis of rheumatic feverwhen an oral drug has to be selected.Dose: 250–500 mg, children 125–250 mg; given 6 hourly(250 mg = 4 lac U). CRYSTAPEN-V, KAYPEN, 125, 250mg tab, 125 mg/5 ml dry syr—for reconstitution.,PENIVORAL 65, 130 mg tab.

PENICILLINASE-RESISTANT PENICILLINS

These congeners have side chains that protect theβ-lactam ring from attack by staphylococcalpenicillinase. However, this also partiallyprotects the bacteria from the β-lactam ring:nonpenicillinase producing organisms are lesssensitive to these drugs than to PnG. Their onlyindication is infections caused by penicillinaseproducing Staphylococci for which they are thedrugs of choice except in areas where methicillin-resistant Staph. aureus (MRSA) has becomeprevalent. They are not resistant to gram-negativeβ-lactamases.

Methicillin It is highly penicillinase resistant but not acidresistant—must be injected. It has been largely replacedby cloxacillin.

Methicillin-resistant Staph. aureus (MRSA) haveemerged in many areas. These are insensitive to cloxacillinand to other β-lactams as well as to erythromycin,aminoglycosides and tetracyclines. The MRSA have alteredPBPs which do not bind penicillins. The drug of choice forthese organisms is vancomycin/linezolid, but ciprofloxacincan also be used.

Cloxacillin It has an isoxazolyl side chain andis highly penicillinase as well as acid resistant. Itis less active against PnG sensitive organisms:should not be used as its substitute. It is moreactive than methicillin against penicillinaseproducing Staph, but not against MRSA. Because

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staphylococcal infections are rare in the oralcavity, cloxacillin is infrequently used in dentistry.

Cloxacillin is incompletely but dependablyabsorbed from oral route, especially if taken inempty stomach. It is > 90% plasma protein bound.Elimination occurs primarily by kidney, alsopartly by liver. Plasma t½ is about 1 hour.Dose: 0.25–0.5 g orally every 6 hours; for severe infections0.25–1 g may be injected i.m. or i.v.—higher blood levelsare produced.KLOX 0.25, 0.5 g cap, 125 mg/3 g dry syr, 0.25, 0.5 g inj;BIOCLOX, CLOCILIN 0.25, 0.5 g cap; 0.25, 0.5 g/vial inj.

Oxacillin, Dicloxacillin, Flucloxacillin (Floxacillin) areother isoxazolyl penicillins, similar to cloxacillin.

EXTENDED SPECTRUM PENICILLINS

These semisynthetic penicillins are active againsta variety of gram-negative bacilli as well. Theycan be grouped according to their spectrum ofactivity.

1. Aminopenicillins

This group, led by ampicillin, has an aminosubstitution in the side chain. Some are prodrugsand all have quite similar antibacterial spectra.None is resistant to penicillinase or to otherβ-lactamases.

Ampicillin It is active against all organismssensitive to PnG; in addition, many gram-negativebacilli, e.g. H. influenzae, E. coli, Proteus, Salmonellaand Shigella are inhibited. However, due to wide-spread use, many of these have developedresistance; usefulness of this antibiotic hasdecreased considerably.

Ampicillin is more active than PnG for Strep.viridans and enterococci (therefore better suitedfor dental infections), equally active for pneu-mococci, gonococci and meningococci (penicillin-resistant strains are resistant to ampicillin aswell); but less active against other gram-positivecocci. Penicillinase producing Staph. are notaffected, as are other gram-negative bacilli, suchas Pseudomonas, Klebsiella, indole positive Proteusand anaerobes like Bacteroides fragilis.

Pharmacokinetics Ampicillin is not degradedby gastric acid; oral absorption is incomplete butadequate. Food interferes with absorption. It ispartly excreted in bile and reabsorbed—entero-hepatic circulation occurs. However, primarychannel of excretion is kidney, but tubular secretionis slower than for PnG; plasma t½ is 1 hour.Dose: 0.5–2 g oral/i.m./i.v. depending on severity ofinfection, every 6 hours; children 25–50 mg/kg/day.AMPILIN, ROSCILLIN, BIOCILIN 250, 500 mg cap; 125,250 mg/5 ml dry syr; 100 mg/ml pediatric drops; 250,500 mg and 1.0 g per vial inj.

Uses

Because of their broader spectrum of actioncovering both gram-positive and gram-negativeaerobic as well as anaerobic bacteria that aremostly causative agents of dental infections,aminopenicillins are one of the commonest antibioticsused in dentistry. Amoxicillin is generally preferredover ampicillin because it produces higher andmore sustained blood levels as well as a lowerincidence of diarrhoea, but ampicillin can be usedfor the same indications.

The general medical indications of ampicillinare:1. Urinary tract infections: response rate has

declined now due to emergence of resistantstrains.

2. Respiratory tract infections: bronchitis,sinusitis, otitis media, etc.

3. Meningitis: not as dependable now due toresistance.

4. Gonorrhoea caused by nonpenicillinaseproducing N. gonorrhoeae can be treated witha single oral dose 3.5 g + 1 g probenecid.

5. Bacillary dysentery due to Shigella: fewercases respond now.

6. Typhoid fever: infrequently used now due towidespread resistance.

7. Cholecystitis: responds well.8. Subacute bacterial endocarditis: preferred over

PnG.9. Septicaemias: combined with gentamicin or

3rd generation cephalosporin.

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Adverse effects Diarrhoea is frequent after oraladministration of ampicillin. It is incompletelyabsorbed—the unabsorbed drug irritates thelower intestines as well as causes markedalteration of bacterial flora.

It produces a high incidence (up to 10%) ofrashes, especially in patients with AIDS, EB virusinfections or lymphatic leukaemia. Concurrentadministration of allopurinol also increases theincidence of rashes. Sometimes, the rashes maynot be allergic but toxic in nature.

Patients with a history of immediate type ofhypersensitivity to PnG should not be givenampicillin as well.

Interactions Hydrocortisone inactivates ampi-cillin if mixed in the i.v. solution.By inhibiting colonic flora, it may interfere withdeconjugation and enterohepatic cycling of oralcontraceptives → failure of oral contraception.Probenecid retards renal excretion of ampicillin.

Bacampicillin It is an ester of ampicillin whichis nearly completely absorbed from the g.i.t. It is aprodrug and is largely hydrolysed during absorp-tion. Thus, higher plasma levels are attained.Tissue penetration is also claimed to be better. Itdoes not markedly disturb intestinal ecology—incidence of diarrhoea is claimed to be lower.Dose: 400–800 mg BD; PENGLOBE 200, 400 mg tab.

Note: A fixed dose combination of ampicillin + cloxacillin(AMPILOX and others) containing 250 mg of each per capor per vial inj. is vigorously promoted for postoperative, skinand soft tissue, respiratory, urinary and other infections.This combination is not synergistic since cloxacillin is notactive against gram-negative bacteria and does not inhibitgram-negative β-lactamases, while ampicillin is not activeagainst staphylococci. Thus, for any given infection, one ofthe components is useless but adds to the cost and adverseeffects. Since the amount of the drug which is actually goingto act in any individual patient is halved (when thecombination is used), efficacy is reduced and chances ofselecting resistant strains is increased. Both drugs areineffective against MRSA. As such, this combination isneeded only when mixed staphylococcal and gram-negativeinfection is proven, which is very infrequent. Blind therapywith this combination is irrational and harmful.

Amoxicillin It is a close congener of ampicillin(but not a prodrug); similar to it in all respectsexcept:

• Oral absorption is better; food does not interferewith absorption; higher and more sustainedblood levels are produced.

• Incidence of diarrhoea is lower.• It is less active against Shigella and H. influenzae.Many physicians now prefer it over ampicillinfor bronchitis, urinary infections, SABE andgonorrhoea. Amoxicillin is one of the most frequentlyused antibiotics for treatment of dental infections sincemajority of cases resolve with 250–500 mg TDSgiven for 5 days. It is also the first choice drug forprophylaxis of local wound infection as well asdistant infection (endocarditis) following dentalsurgery in susceptible patients (see p. 377).Dose: 0.25–1 g TDS oral/i.m.; AMOXYLIN, NOVAMOX,SYNAMOX 250, 500 mg cap, 125 mg/5 ml dry syr.AMOXIL, MOX 250, 500 mg caps; 125 mg/5 ml dry syr;250, 500 mg/vial inj. MOXYLONG: Amoxicillin 250 mg +probenecid 500 mg tab (also 500 mg + 500 mg DS tab).

2. Carboxy penicillins

Carbenicillin The special feature of this peni-cillin congener is its activity against Pseudomonasaeruginosa and indole positive Proteus which arenot inhibited by PnG or aminopenicillins. It is lessactive against Salmonella, E. coli and Enterobacter,while Klebsiella and gram-positive cocci areunaffected by it. Pseudomonas strains less sensitiveto carbenicillin have developed in some areas,especially when inadequate doses have been used.

Carbenicillin is neither penicillinase resistantnor acid resistant. It is inactive orally and isexcreted rapidly in urine (t½ 1 hr). It is used assodium salt in a dose of 1–2 g i.m. or 1–5 g i.v.every 4–6 hours. At the higher doses, enough Namay be administered to cause fluid retention andCHF in patients with borderline renal or cardiacfunction.

High doses have also caused bleeding byinterferring with platelet function. This appearsto result from perturbation of agonist receptorson platelet surface.PYOPEN, CARBELIN 1 g, 5 g, per vial inj.

The indications for carbenicillin are—seriousinfections caused by Pseudomonas or Proteus, e.g.burns, urinary tract infection, septicaemia, but

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piperacillin is now preferred. It is often usedtogether with gentamicin. Orodental infectionsare rarely caused by Pseudomonas; if at all theyoccur in immunocompromised patients. Thesemay be treated with carbenicillin or piperacillin.

Ticarcillin It is more potent than carbenicillin againstPseudomonas, but other properties are similar to it.

3. Ureidopenicillins

Piperacillin This antipseudomonal penicillinis about 8 times more active than carbenicillin. Ithas good activity against Klebsiella and is usedmainly in neutropenic/immunocompromisedpatients having serious gram-negative infectionsand in burns. Elimination t½ is 1 hour. Concurrentuse of gentamicin or tobramycin is advised.Dose: 100–150 mg/kg/day in 3 divided doses (max 16 g/day) i.m. or i.v. The i.v. route is preferred when > 2 g is tobe injected.PIPRAPEN 1 g, 2 g vials; PIPRACIL 2 g, 4 g vials for inj;contains 2 mEq Na+ per g.

Mezlocillin It has activity similar to ticarcillin againstPseudomonas and inhibits Klebsiella as well. It is given paren-terally primarily for infections caused by enteric bacilli.

BETA-LACTAMASE INHIBITORS

β-lactamases are a family of enzymes producedby many gram-positive and gram-negativebacteria that inactivate β-lactam antibiotics byopening the β-lactam ring. Different β-lactamasesdiffer in their substrate affinities. The inhibitorsof this enzyme clavulanic acid, sulbactam andtazobactam are available for clinical use.

Clavulanic acid Obtained from Streptomycesclavuligerus, it has a β-lactam ring but noantibacterial activity of its own. It inhibits a widevariety (class II to class V) of β-lactamases (butnot class I cephalosporinase) produced by bothgram-positive and gram-negative bacteria.

Clavulanic acid is a ‘progressive’ inhibitor:binding with β-lactamase is reversible initially,but becomes covalent later—inhibition increas-ing with time. Called a ‘suicide’ inhibitor, it getsinactivated after binding to the enzyme. Itpermeates the outer layers of the cell wall of gram-

negative bacteria and inhibits the periplasmicallylocated β-lactamase.

Pharmacokinetics Clavulanic acid has rapidoral absorption and a bioavailability of 60%; canalso be injected. Its elimination t½ of 1 hr andtissue distribution matches amoxicillin withwhich it is used (called coamoxiclav). However,it is eliminated mainly by glomerular filtrationand its excretion is not affected by probenecid.Also, it is largely hydrolysed and decarboxylatedbefore excretion, while amoxicillin is primarilyexcreted unchanged by tubular secretion.

Uses Addition of clavulanic acid re-establishesthe activity of amoxicillin against β-lactamaseproducing resistant Staph. aureus (but not MRSAthat have altered PBPs), Peptococcus, H. influenzae,N. gonorrhoeae, E. coli, Proteus, Klebsiella, Salmonella,Shigella and Bact. fragilis. Addition of clavulanicacid makes no difference to amoxicillin alone incase the infecting strain is amoxicillin sensitive.Coamoxiclav is indicated for:• Skin and soft tissue infections, intra-abdominal

and gynaecological sepsis, urinary, biliary andrespiratory tract infections: especially whenempiric antibiotic therapy is to be given forhospital-acquired infections.

• Dental infections caused by β-lactamase producingbacteria.

• Gonorrhoea (including PPNG), single doseamoxicillin 3 g + clavulanic acid 0.5 g +probenecid 1 g is highly curative.

AUGMENTIN, ENHANCIN, AMONATE: Amoxicillin250 mg + clavulanic acid 125 mg tab; 1–2 tab TDS, severeinfections 4 tabs 6 hourly.Also AUGMENTIN: Amoxicillin 1 g + clavulanic acid 0.2g vial and 0.5 g + 0.1 g vial; inject 1 vial deep i.m. or i.v. 6–8 hourly for severe infections.It is more expensive than amoxicillin alone.

Adverse effects are the same as for amoxicillinalone; g.i. tolerance is poorer—especially inchildren. Other side effects are Candida stomati-tis/vaginitis and rashes. Some cases of hepaticinjury have been reported with the combination.

Sulbactam It is a semisynthetic β-lactamaseinhibitor, related chemically as well as in activity

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to clavulanic acid. It is also a progressive inhibitor,highly active against class II to V but poorly activeagainst class I β-lactamase. On weight basis, it is2–3 times less potent than clavulanic acid for mosttypes of the enzyme, but the same level of inhibi-tion can be obtained at the higher concentrationsachieved clinically. Sulbactam does not inducechromosomal β-lactamases, while clavulanic acidcan induce some of them.

Oral absorption of sulbactam is inconsistent.Therefore, it is preferably given parenterally. Ithas been combined with ampicillin for use againstβ-lactamase producing resistant strains.Absorption of its complex salt with ampicillin—sultamicillin tosylate is better, which is given orally.Indications are:• PPNG gonorrhoea; sulbactam per se inhibits

N. gonorrhoeae.• Mixed aerobic-anaerobic infections, tooth

abscess, intra-abdominal, gynaecological,surgical and skin/ soft tissue infections,especially those acquired in the hospital.

SULBACIN, AMPITUM: Ampicillin 1 g + sulbactam 0.5g per vial inj; 1–2 vial deep i.m. or i.v. injection 6–8 hourly.Sultamicillin tosylate: BETAMPORAL, SULBACIN 375 mgtab.

Pain at site of injection, thrombophlebitis ofinjected vein, rash and diarrhoea are the mainadverse effects.

Tazobactam is another β-lactamase inhibitorsimilar to sulbactam. Its pharmacokineticsmatches with piperacillin with which it has beencombined for use in severe infections likeperitonitis, pelvic/urinary/respiratory infectionscaused by β-lactamase producing bacilli.However, the combination is not active againstpiperacillin-resistant Pseudomonas, and againstPseudomonas that develop resistance by losingpermeability to piperacillin.Dose: 0.5 g combined with piperacillin 4 g injected i.v. over30 min 8 hourly.PYBACTUM, TAZACT, TAZOBID, ZOSYN 4 g + 0.5 gvial for inj.

CEPHALOSPORINSThese are a group of semisynthetic antibioticsderived from ‘cephalosporin-C’ obtained from a

fungus Cephalosporium. They are chemicallyrelated to penicillins; the nucleus consists of aβ-lactam ring fused to a dihydrothiazine ring,(7-aminocephalosporanic acid). By addition ofdifferent side chains at position 7 of β-lactam ring(altering spectrum of activity) and at position 3 ofdihydrothiazine ring (affecting pharmacokine-tics), a large number of semisynthetic compoundshave been produced. These have been conven-tionally divided into 4 generations. This divisionhas a chronological sequence of development,but more importantly, takes into considerationthe overall antibacterial spectrum as well aspotency.

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First generation cephalosporins

Parenteral OralCefazolin Cephalexin

CephradineCefadroxil

Second generation cephalosporins

Parenteral OralCefuroxime Cefaclor

Cefuroxime axetil

Third generation cephalosporins

Parenteral OralCefotaxime CefiximeCeftizoxime Cefpodoxime proxetilCeftriaxone CefdinirCeftazidime CeftibutenCefoperazone Ceftamet pivoxil

Fourth generation cephalosporins

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All cephalosporins are bactericidal and have thesame mechanism of action as penicillin, i.e.inhibition of bacterial cell wall synthesis. However,they bind to different proteins than those whichbind penicillins. This may explain differences inspectrum, potency and lack of cross resistance.

Acquired resistance to cephalosporins couldhave the same basis as for penicillins, i.e.:

(a) alteration in target proteins (PBPs) reducingaffinity for the antibiotic.

(b) impermeability to the antibiotic so that itdoes not reach its site of action.

(c) elaboration of β-lactamases which destroyspecific cephalosporins (cephalospori-nases).

Though the incidence is low, resistance has beendeveloped by some organisms, even against thethird generation compounds. Individual cepha-losporins differ in their:

(a) Antibacterial spectrum and relative potencyagainst specific organisms.

(b) Susceptibility to β-lactamases from differentorganisms.

(c) Pharmacokinetic properties—many have tobe injected, some are oral; majority are notmetabolized but are excreted rapidly by thekidney and have short t½s, probenecidinhibits their tubular secretion.

FIRST GENERATION CEPHALOSPORINS

These were developed in the 1960s , have highactivity against gram-positive but weaker againstgram-negative bacteria.

Cefazolin It is active against most PnG sensitiveorganisms, i.e. streptococci (pyogenes as wellviridans), gonococci, meningococci, C. diphtheriae,H.influenzae, clostridia, and Actinomyces. It is moreactive against Klebsiella and E. coli but quitesusceptible to staphylococcal β-lactamase. It canbe given i.m. (less painful) as well as i.v. and hasa longer t½ (2 hours) due to slower tubularsecretion; attains higher concentration in plasmaand in bile. It is the preferred parenteral firstgeneration cephalosporin, especially for surgicalprophylaxis.

Dose: 0.25 g 8 hourly (mild cases), 1 g 6 hourly (severecases) i.m. or i.v.ALCIZON, ORIZOLIN 0.25 g, 0.5 g, 1 g per vial inj.

Cephalexin It is an orally effective firstgeneration cephalosporin, similar in spectrum tocefazolin, but less active against H. influenzae. Itis little bound to plasma proteins, attains highconcentration in bile and is excreted unchangedin urine; t½ ~60 min. It is one of the commonlyused cephalosporins; finds place in dentistry as analternative to amoxicillin.Dose: 0.25–1 g 6–8 hourly (children 25–100 mg/kg/day).CEPHACILLIN 250, 500 mg cap; SPORIDEX,ALCEPHIN, CEPHAXIN 250, 500 mg cap, 125 mg/5 mldry syr., 100 mg/ml pediatric drops.ALCEPHIN-LA: Cephalexin + probenecid (250 + 250 mgand 500 + 500 mg) tabs.

Cephradine Another orally active drug, almostidentical to cephalexin, but less active againstsome organisms. Oral administration has causeddiarrhoea as side effect. It is available forparenteral use also.Dose: 0.25–1 g 6–12 hourly oral/i.m/i.v.CEFLAD 0.25, 0.5, 1 g per vial inj.

Cefadroxil A close congener of cephalexin; hasgood tissue penetration including that in alveolarbone (tooth socket); exerts more sustained actionat the site of infection; can be given 12 hourlydespite a t½ of 1 hr. It is excreted unchanged inurine, but dose needs to be reduced only ifcreatinine clearance is < 50 ml/min. Theantibacterial activity of cefadroxil and indicationsare similar to those of cephalexin; frequentlyselected for dental infections.Dose: 0.5–1 g BD. DROXYL 0.5, 1 g tab, 250 mg/5 ml syr;CEFADROX 0.5 g cap, 125 mg/5 ml syr and 250 mg kidtab; KEFLOXIN 0.5 g cap, 0.25 g Distab, 125 mg/5 mlsusp.

SECOND GENERATION CEPHALOSPORINS

These were developed subsequent to the firstgeneration compounds and are more activeagainst gram-negative organisms, with somemembers active against anaerobes.

Cefuroxime It is resistant to gram-negativeβ-lactamases: has high activity against organisms

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producing these enzymes including PPNG andampicillin-resistant H. influenzae, while retainingsignificant activity on gram-positive cocci andcertain anaerobes. It is well tolerated by i.m. routeand attains relatively higher CSF levels. It hasbeen used in some mixed infections and for singledose i.m. therapy of gonorrhoea due to PPNG.CEFOGEN, SUPACEF, FUROXIL 250 mg and 750 mg/vial inj; 0.75–1.5 g i.m. or i.v. 8 hourly, children 30–100mg/kg/day.

Cefuroxime axetil This ester of cefuroxime iseffective orally, though absorption is incomplete.The activity depends on in vivo hydrolysis andrelease of cefuroxime. Because of activity on anae-robes, it is frequently chosen for dental infections.Dose: 250–500 mg BD, children half-dose; CEFTUM,SPIZEF 125, 250, 500 mg cap, tab and 125 mg/5 ml susp.

Cefaclor It retains significant activity by the oralroute and is more active than the first generationcompounds against H. influenzae, E. coli, Pr.mirabilis and anaerobes found in oral cavity.KEFLOR, VERCEF, DISTACLOR 250 mg cap, 125 and250 mg distab, 125 mg/5 ml dry syr, 50 mg/ml ped.drops.

THIRD GENERATION CEPHALOSPORINS

These compounds introduced in the 1980s havehighly augmented activity against gram-negativeEnterobacteriaceae; some inhibit Pseudomonas aswell. All are highly resistant to β-lactamases fromgram-negative bacteria. However, they are lessactive on gram-positive cocci and anaerobes. Assuch, they are seldom used in dentistry.

Cefotaxime It is the prototype of the thirdgeneration cephalosporins; exerts potent actionon aerobic gram-negative as well as some gram-positive bacteria, but is not so active on anaerobes(particularly Bact. fragilis), Staph. aureus and Ps.aeruginosa. Prominent indications are meningitiscaused by gram-negative bacilli (attains relativelyhigh CSF levels), life-threatening resistant/hospital-acquired infections, septicaemias andinfections in immunocompromised patients; dose1–2 g i.m. or i.v. 6–12 hourly (children 50–100mg/kg/day).

Cefotaxime is deacetylated in the body; themetabolite exerts weaker but synergistic actionwith the parent drug. The plasma t½ of cefota-xime is 1 hr, but is longer for the deacetylatedmetabolite—permitting 12 hourly doses in manysituations.OMNATAX, ORITAXIM, CLAFORAN 0.25, 0.5, 1.0 gper vial inj.

Ceftizoxime It is similar in antibacterial activityand indications to cefotaxime, but is not meta-bolized—excreted by the kidney at a slower rate;t½ 1.5–2 hr.Dose 0.5–1 g i.m./i.v. 8 or 12 hourly.CEFIZOX, EPOCELIN 0.5 and 1 g per vial inj.

Ceftriaxone The distinguishing feature of thiscephalosporin is its longer duration of action (t½8 hr), permitting once or at the most twice dailydosing. Penetration into CSF is good, and it iseliminated equally in urine and bile.

Ceftriaxone has shown high efficacy in a widerange of serious infections including bacterialmeningitis, multiresistant typhoid fever,abdominal sepsis and septicaemias. A singledose of 250 mg i.m. has proven curative ingonorrhoea including PPNG and in chancroid.

Hypoprothrombinaemia and bleeding arespecific adverse effects. Haemolysis is reported.OFRAMAX, MONOCEF, MONOTAX 0.25, 0.5, 1.0 g pervial inj;1–2 g i.v. or i.m./day.Meningitis: 4 g followed by 2 g i.v. (children 75–100 mg/kg) once daily for 7–10 days.Typhoid: 4 g i.v. daily × 2 days followed by 2 g/day(children 75 mg/kg) till 2 days after fever subsides.

Ceftazidime The most prominent feature of thisthird generation cephalosporin is its high activityagainst Pseudomonas. It has been specifically usedin febrile neutropenic patients with haematolo-gical malignancies, burn, etc. Its activity againstEnterobacteriaceae is similar to that of cefotaxime,but it is less active on Staph. aureus, other gram-positive cocci and anaerobes like Bact. fragilis. Itsplasma t½ is 1.5–1.8 hr.

Neutropenia, thrombocytopenia, rise in plasmatransaminases and blood urea have been reported.Dose: 0.5–2 g i.m. or i.v. every 8 hr, children 30 mg/kg/day. Resistant typhoid 30 mg/kg/day.FORTUM, CEFAZID, ORZID 0.25, 0.5 and 1 g per vial inj.

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Cefoperazone Like ceftazidime, it differs fromother third generation compounds in havingstronger activity on Pseudomonas and weakeractivity on other organisms. It is good for S. typhiand B. fragilis also, but more susceptible toβ-lactamases. The indications are—severe urinary,biliary, respiratory, skin-soft tissue infections,meningitis and septicaemias. It is primarilyexcreted in bile; t½ is 2 hr. It has hypoprothrom-binaemic action but does not affect platelet function.A disulfiram-like reaction with alcohol has beenreported.MAGNAMYCIN 0.25 g, 1, 2 g inj; CEFOMYCIN,NEGAPLUS 1 g inj; 1-2 g i.m./i.v. 12 hourly.

Cefixime It is an orally active third generationcephalosporin highly active against Enterobacte-riaceae, H. influenzae, Strep. pyogenes, Strep.pneumoniae and is resistant to many β-lactamases.However, it is not active on Staph. aureus andPseudomonas. It is longer acting (t½ 3 hr) and hasbeen used in a dose of 200–400 mg BD forrespiratory, urinary and biliary infections. Stoolchanges and diarrhoea are the most prominentside effects.TOPCEF, ORFIX 100, 200 mg tab/cap, CEFSPAN 100mg cap, 100 mg/5 ml syr.

Cefpodoxime proxetil It is the orally activeester prodrug of 3rd generation cephalosporincefpodoxime. In addition to being highly activeagainst Enterobacteriaceae and streptococci, itinhibits Staph. aureus. It is used mainly for respi-ratory, urinary, skin and soft tissue infections.Dose: 200 mg BD (max 800 mg/day)CEFOPROX 100, 200 mg tab, 100 mg/5 ml dry syr;CEPODEM 100, 200 mg tab, 50 mg/5 ml susp.

Cefdinir This orally active 3rd generationcephalosporin has good activity against manyβ-lactamase producing organisms. Most res-piratory pathogens including gram-positive cocciare susceptible. Its indications are pneumonia,acute exacerbations of chronic bronchitis, ENTand skin infections.Dose: 300 mg BDSEFDIN, ADCEF 300 mg cap, 125 mg/5 ml susp.

Ceftibuten Another oral 3rd generationcephalosporin, active against both gram-positive

and gram-negative bacteria, and stable toβ-lactamases. It is indicated in respiratory, urinaryand gastrointestinal infections.Dose: 200 mg BD or 400 mg OD.PROCADAX 400 mg cap, 90 mg/5 ml powder for oralsuspension.

FOURTH GENERATION CEPHALOSPORINS

Cefepime Developed in 1990s, this 4th genera-tion cephalosporin has antibacterial spectrumsimilar to that of 3rd generation compounds, butis highly resistant to β-lactamases, hence activeagainst many bacteria resistant to the earlierdrugs. Ps. aeruginosa and Staph. aureus are alsoinhibited. Due to high potency and extendedspectrum, it is effective in many serious infectionslike hospital-acquired pneumonia, febrile neutro-penia, bacteraemia, septicaemia, etc.Dose: 1–2 g i.v. 8–12 hourly; KEFAGE 0.5, 1.0 g inj.

Cefpirome This 4th generation cephalosporinhas become available for the treatment of seriousand resistant hospital-acquired infectionsincluding septicaemias, lower respiratory tractinfections, etc. Its zwitterion character permitsbetter penetration through porin channels ofgram-negative bacteria. It is resistant to manyβ-lactamases and is more potent; than the 3rdgeneration compounds.Dose: 1–2 g i.m./i.v. 12 hourly;CEFROM, CEFORTH 1 g inj.

Adverse effects

Cephalosporins are generally well tolerated butare more toxic than penicillin.1. Pain after i.m. injection occurs with manycephalosporins. Thrombophlebitis can occur oni.v. injection.2. Diarrhoea due to alteration of gut ecology orirritative effect is more common with oralcephradine and parenteral cefoperazone whichis significantly excreted in bile.3. Hypersensitivity reactions caused by cephalo-sporins are similar to penicillin, but incidence islower. Rashes are the most frequent manifestation,

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but anaphylaxis, angioedema, asthma andurticaria have also occurred. About 10% patientsallergic to penicillin show cross reactivitywith cephalosporins. Those with a history ofimmediate type of reactions to penicillin shouldbetter not be given a cephalosporin. Skin tests forsensitivity to cephalosporins are unreliable.

A positive Coombs’ test occurs in many buthaemolysis is rare.4. Nephrotoxicity Cephalothin and a few othershave low-grade nephrotoxicity which may beaccentuated by pre-existing renal disease,concurrent administration of an aminoglycosideor loop diuretic.5. Bleeding occurs with cephalosporins havinga methylthiotetrazole or similar substitution atposition 3 (cefoperazone, ceftriaxone). This is dueto hypoprothrombinaemia caused by the samemechanism as warfarin and is more common inpatients with cancer, intra-abdominal infectionor renal failure.6. Neutropenia and thrombocytopenia are rareadverse effects reported with ceftazidime andsome others.7. A disulfiram-like interaction with alcohol hasbeen reported with cefoperazone.

Uses

A. Dental infections: There are no compellingindications for cephalosporins in dentistry exceptas alternative to penicillin/amoxicillin, especiallyin patients who develop rashes or other milderallergic reactions (but not immediate type ofhypersensitivity), and in cases with penicillin/amoxicillin-resistant infection. As such, they areused to a lesser extent than penicillins. Only oralantibiotics are routinely employed in dentistry,while parenteral ones are reserved for serious andfulminating infections. Therefore, the orally active1st and 2nd generation cephalosporins are mainlyprescribed for orodental infections. The firstgeneration agents like cephalexin or cephadroxilare used because of their high activity againstgram-positive aerobic bacteria and their good

penetration into alveolar bone (like tooth socket).Though they do not directly kill anaerobes,removal of aerobic organisms improves oxygenavailability at the local site, especially in alveolarbone, and indirectly checks growth of anaerobes.

The 2nd generation compounds like cefuro-xime axetil and cefaclor are the only ones withgood activity against oral anaerobes, and are thepreferred cephalosporins for dental indications.Cephalosporins are especially valuable fororodental infections caused by Klebsiella, whichthough rare, may occur in neutropenic patients.Anaerobes are less prominent in acute gingivalcellulitis which often responds rapidly tocephalosporins. Cephalexin and cephadroxil arealternatives to amoxicillin for prophylaxis of localwound infection as well as of bacterial endo-carditis following dental surgery in predisposedpatients.

B. General medical uses: Cephalosporins arenow extensively used in medicine.1. As alternatives to PnG in allergic patients(other than immediate hypersensitivity), one ofthe first generation compounds may be used.2. Respiratory, urinary and soft tissue infectionscaused by gram-negative organisms, especiallyKlebsiella, Proteus, Enterobacter, Serratia.3. Penicillinase producing staphylococcalinfections.4. Septicaemias caused by gram-negativeorganisms: an aminoglycoside may be combinedwith a cephalosporin.5. Surgical prophylaxis: Cefazolin is employedfor most types of surgeries.6. Meningitis caused by H. influenzae, Enterobac-teriaceae: cefuroxime, cefotaxime and ceftriaxonehave been specially used. Ceftazidime + gentami-cin is the most effective therapy for Pseudomonasmeningitis.7. Gonorrhoea caused by penicillinase pro-ducing organisms: ceftriaxone is a first choicedrug for single dose therapy. Cefuroxime andcefotaxime have also been used for this purpose.For chancroid also, a single dose is as effective ascotrimoxazole or erythromycin given for 7 days.

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8. Typhoid: ceftriaxone and cefoperazone are thefastest acting drugs.9. Mixed aerobic-anaerobic infections seen incancer patients, those undergoing colorectalsurgery, obstetric complications: cefuroxime,cefaclor or one of the third generation compoundsis used.10. Hospital-acquired infections resistant tocommonly used antibiotics: cefotaxime, ceftizo-xime or a fourth generation drug may work.11. Prophylaxis and treatment of infections inneutropenic patients: ceftazidime or another thirdgeneration compound, alone or in combinationwith an aminoglycoside.

MONOBACTAMS

Aztreonam It is a novel β-lactam antibiotic inwhich the other ring is missing (hence mono-bactam). It inhibits gram-negative enteric bacilliand H. influenzae at very low concentrations andPseudomonas at moderate concentrations, but doesnot inhibit gram-positive cocci or faecal anaerobes.It is resistant to gram-negative β-lactamases. Themain indications of aztreonam are hospital-acquired infections originating from urinary,biliary, gastrointestinal and female genital tracts.

Lack of cross sensitivity with other β-lactamantibiotics appears to be the most promisingfeature of aztreonam: permiting its use in patientsallergic to penicillins or cephalosporins. There isno specific indication of aztreonam in dentistry.It is eliminated in urine with a t½ of 1.8 hours.Dose: 0.5–2 g i.m. or i.v. 6–12 hourly.AZENAM, TREZAM 0.5 g, 1 g, 2 g per vial inj.

CARBAPENEMS

Imipenem It is an extremely potent and very broadspectrum β-lactam antibiotic whose range of activityincludes gram-positive cocci, Enterobacteriaceae, Ps.aeruginosa, Listeria as well as anaerobes like Bact. fragilisand Cl. difficile. It is resistant to most β-lactamases andinhibits penicillinase producing staphylococci.

A limiting feature of imipenem is its rapid hydrolysisby the enzyme dehydropeptidase I located on the brushborder of renal tubular cells. An innovative solution tothis problem is its combination with cilastatin, a reversibleinhibitor of dehydropeptidase I, which has matchedpharmacokinetics with imipenem (t½ of both is 1 hr) andprotects it.

Imipenem-cilastatin 0.5 g i.v. 6 hourly (max 4 g/day)has proved effective in a wide range of serious hospital-acquired infections including those in neutropenic, cancerand AIDS patients, but has been overtaken by meropenemnow.

Imipenem has propensity to induce seizures at higherdoses and in predisposed patients. Diarrhoea, vomitingand rashes are the other side effects. IMINEM, LASTINEM250 mg + 250 mg/vial and 500 mg + 500 mg/vial inj.

Meropenem This newer carbapenem is nothydrolysed by renal peptidase; does not need tobe protected by cilastatin. Like imipenem, it isactive against both gram-positive and gram-negative bacteria, aerobes as well as anaerobesand is not destroyed by many β-lactamases.

Meropenem is a reserve drug for the treatmentof serious nosocomial infections like septicaemia,febrile neutropenia, intraabdominal and pelvicinfections, etc. caused by cephalosporin-resistantbacteria. It can also be employed for serious/difficult to treat orodental infections. The adverseeffects of meropenem are similar to imipenem, butit is less likely to cause seizures.Dose: 0.5-2.0 g (10-40 mg/kg) by slow i.v. injection 8hourly.MERONAM, MENEN, UBPENEM 0.5, 1.0 g/vial inj.

Faropenem Another carbapenem β-lactamantibiotic that is orally active against many gram-positive as well as gram-negative bacteria,including some anaerobes. Strep. pneumoniae, H.influenzae and Moraxella catarrhalis are highlysusceptible. It has been mainly used in respiratory,ENT and genitourinary infections. Usual sideeffects are diarrhoea, abdominal pain, nausea andrashes.Dose: 200-300 mg oral TDS; FARONEM 100, 200 mg tab.

TETRACYCLINES

These are a class of antibiotics having a nucleusof four cyclic rings.

All are obtained from soil actinomycetes. The first to beintroduced was chlortetracycline in 1948. It contrastedmarkedly from penicillin and streptomycin (the other twoantibiotics generally available at that time) in being activeorally and in affecting a wide range of microorganisms—hence called ‘broad-spectrum antibiotic’. Oxytetracyclinesoon followed; others were produced later, either frommutant strains or semisynthetically.

All tetracyclines are slightly bitter solids whichare slightly water soluble, but their hydrochloridesare more soluble. Aqueous solutions are unstable.All have practically the same antimicrobial activity(with minor differences). The subsequentlydeveloped members have high lipid solubility,greater potency and some other differences. Thetetracyclines still available in India for clinical useare:

Tetracycline DemeclocyclineOxytetracycline Doxycycline

Minocycline

Mechanism of action The tetracyclines areprimarily bacteriostatic; inhibit protein synthesisby binding to 30S ribosomes in susceptible orga-nism. Subsequent to such binding, attachmentof aminoacyl-t-RNA to the mRNA-ribosomecomplex is interferred with (Fig. 29.1). As a result,the peptide chain fails to grow.

The sensitive organisms have an energydependent active transport process whichconcentrates tetracyclines intracellularly. Ingram-negative bacteria tetracyclines diffusethrough the porin channels as well. The morelipid-soluble members (doxycycline, minocycline)enter by passive diffusion also (this is partlyresponsible for their higher potency). The carrierinvolved in active transport of tetracyclines isabsent in the host cells. Moreover, proteinsynthesizing apparatus of host cells is lesssusceptible to tetracyclines. These two factors areresponsible for the selective toxicity oftetracyclines for the microbes.

Antimicrobial spectrum When originally intro-duced, tetracyclines inhibited practically all typesof pathogenic microorganisms except fungi andviruses; hence the name ‘broad-spectrumantibiotic’. However, promiscous and oftenindiscriminate use has gradually narrowed thefield of their usefulness.

29

Tetracyclines, Chloramphenicol andAminoglycoside Antibiotics

406 Tetracyclines, Chloramphenicol and Aminoglycoside AntibioticsS

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Fig. 29.1: Bacterial protein synthesis and the site of action of antibiotics

The messenger RNA (mRNA) attaches to the 30S ribosome. The initiation complex of mRNA starts protein synthesis andpolysome formation. The nacent peptide chain is attached to the peptidyl (P) site of the 50S ribosome. The next amino acid(a) is transported to the acceptor (A) site of the ribosome by its specific tRNA which is complementary to the basesequence of the next mRNA codon (C). The nacent peptide chain is transferred to the newly attached amino acid bypeptide bond formation. The elongated peptide chain is shifted back from the ‘A’ to the ‘P’ site and the ribosome movesalong the mRNA to expose the next codon for amino acid attachment. Finally, the process is terminated by the terminationcomplex and the protein is released.(1) Aminoglycosides bind to several sites at 30S and 50S subunits as well as to their interface—freeze initiation, interferewith polysome formation and cause misreading of mRNA code. (2) Tetracyclines bind to 30S ribosome and inhibitaminoacyl tRNA attachment to the ‘A’ site. (3) Chloramphenicol binds to 50S subunit—interferes with peptide bondformation and transfer of peptide chain from ‘P’ site. (4) Erythromycin and clindamycin also bind to 50S ribosome andhinder translocation of the elongated peptide chain back from ‘A’ site to ‘P’ site and the ribosome does not move along themRNA to expose the next codon. Peptide synthesis may be prematurely terminated.

1. Cocci: All gram-positive and gram-negativecocci were originally sensitive, but nowmany Strep. pyogenes, Staph. aureus and enterococcihave become resistant. Responsiveness of Strep.pneumoniae has decreased somewhat. Tetra-cyclines (especially minocycline) are now activeagainst only few N. gonorrhoeae and N.meningitidis.2. Most gram-positive bacilli, e.g. Clostridia andother anaerobes, Listeria, Corynebacteria,Propionibacterium acnes, B. anthracis are inhibitedbut not Mycobacteria, except some atypical ones.3. Sensitive gram-negative bacilli are—H.ducreyi, Calymmatobacterium granulomatis, V. cho-lerae, Yersinia pestis, Y. enterocolitica, Campylobacter,Helicobacter pylori, Brucella, Pasteurella multocida,

F. tularensis and many anaerobes; some H.influenzae have become insensitive.

Enterobacteriaceae are now largely resistant.Notable bacilli that are not inhibited are Pseudo-monas aeruginosa, Proteus, Klebsiella, Salmonellatyphi and many Bact. fragilis. MIC againstanaerobes is relatively higher.4. Spirochetes, including T. pallidum and Borreliaare quite sensitive.5. All rickettsiae (typhus, etc.) and chlamydiaeare highly sensitive.6. Mycoplasma and Actinomyces are moderatelysensitive.7. Entamoeba histolytica and Plasmodia areinhibited at high concentrations.

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Resistance Resistance to tetracyclines developsslowly in a graded manner. In such bacteria,usually the tetracycline concentrating mechanismbecomes less efficient or the bacteria acquirecapacity to pump it out. Another mechanism isplasmid mediated synthesis of a ‘protection’protein which protects the ribosomal binding sitefrom the tetracycline. Elaboration of tetracyclineinactivating enzymes is an unimportant mecha-nism of tetracycline resistance. Due to wide-spread use, tetracycline resistance has becomecommon among gram-positive cocci, E. coli,Enterobacter and many others. Nearly completecross resistance is seen among different membersof the tetracycline group. However, some orga-nisms not responding to other tetracyclines maybe inhibited by therapeutically attained concen-trations of minocycline (the most potent agent).

Partial cross resistance between tetracyclinesand chloramphenicol has been noted.

Pharmacokinetics

The pharmacokinetic differences between indi-vidual tetracyclines are included in Table 29.1.The older tetracyclines are incompletely absorbedfrom g.i.t.; absorption is better if taken in emptystomach. Doxycycline and minocycline arecompletely absorbed irrespective of food. Tetra-cyclines have chelating property—form insolubleand unabsorbable complexes with calcium andother metals. Milk, iron preparations, nonsystemicantacids and sucralfate reduce their absorption.Administration of these substances andtetracyclines should be staggered, if they cannotbe avoided altogether.

Table 29.1: Comparative features of tetracyclines

Tetracycline (T) Demeclocycline (Deme) Doxycycline (Doxy)Oxytetracycline (OxyT) Minocycline (Mino)

1. Source Oxy T: S. rimosus S. aureofaciens Doxy: semisyntheticT: semisynthetic (mutant) Mino: semisynthetic

2. Potency Low Intermediate High (Doxy < Mino)

3. Intestinal absorption T: moderate Moderate Complete,Oxy T: moderate No interference by food

4. Plasma protein OxyT: Low High Highbinding T: Intermediate

5. Elimination T: Rapid renal Partial metabolism, Doxy: Primarily excreted inOxy T excretion slower renal excretion faeces as conjugate

Mino: Primarily metabolized,excreted in urine and bile

6. Plasma t½ 6–10 hr. 16–18 hr. 18–24 hr.

7. Dosage 250–500 mg QID 300 mg BD 200 mg initially,or TDS then 100–200 mg OD

8. Alteration of Marked Moderate Leastintestinal flora

9. Incidence of High Intermediate Lowdiarrhoea

10. Phototoxicity Low Highest Doxy: High

11. Specific toxicity OxyT: less tooth Deme: more phototoxic, Doxy: low renal toxicity.discolouration diabetes insipidus Mino: Vestibular toxicity,

less superinfections

⎫⎬⎭

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Tetracyclines are widely distributed in thebody (volume of distribution > 1 L/kg). Variabledegree of protein binding is exhibited by differentmembers. They are concentrated in liver, spleen,gingival tissue and bind to the connective tissue inbone and teeth. Intracellularly, they bind tomitochondria. Minocycline accumulates in bodyfat. The CSF concentration of most tetracyclinesis about 1/4th of plasma concentration, whethermeninges are inflamed or not.

Most tetracyclines are primarily excreted inurine by glomerular filtration; dose has to bereduced in renal failure; doxycycline is anexception to this. They are partly metabolized andsignificant amounts enter bile—some degree ofenterohepatic circulation occurs. They aresecreted in milk in amounts sufficient to affect thesuckling infant.

Enzyme inducers like phenobarbitone andphenytoin enhance metabolism and shorten thet½ of doxycycline.

Administration Oral capsule is the dosage formin which tetracyclines are most commonlyadministered. The capsule should be taken ½ hrbefore or 2 hr after food.

Tetracyclines are not recommended by i.m.route because it is painful and absorption fromthe injection site is poor. Slow i.v. injection maybe given in severe cases, but is rarely requirednow.

A variety of topical preparations (ointment,cream, etc.) are available, but should not be used,because there is high risk of sensitization. How-ever, ocular application is not contraindicated.

Preparations

1. Oxytetracycline: TERRAMYCIN 250, 500 mg cap, 50mg/ml in 10 ml vials inj; 3% skin oint, 1% eye/ear oint.

2. Tetracycline: ACHROMYCIN, HOSTACYCLINE,RESTECLIN 250, 500 mg cap. 3% skin oint, 1% eye/ear drops and oint.

3. Demeclocycline (Demethylchlortetracycline):LEDERMYCIN 150, 300 mg cap/tab.

4. Doxycycline: TETRADOX, BIODOXI, DOXT,NOVADOX, 100 mg cap.

5. Minocycline: CYANOMYCIN 50, 100 mg caps.

Adverse effects

Irritative effects Tetracyclines have irritantproperty: can cause epigastric pain, nausea,vomiting and diarrhoea. The irritative diarrhoeais to be distinguished from that due to superinfec-tion. Esophageal ulceration has occurred byrelease of the material from capsules in the eso-phagus during swallowing, especially with doxy-cycline. Intramuscular injection of tetracyclinesis very painful; thrombophlebitis of the injectedvein can occur, especially on repeated use.

Dose-related toxicity

1. Liver damage Fatty infiltration of liver andjaundice occurs occasionally. Oxytetracyclineand tetracycline are safer in this regard.Tetracyclines are risky in pregnant women, canprecipitate acute hepatic necrosis which may befatal.

2. Kidney damage It is a risk only in thepresence of existing kidney disease. All tetracyc-lines, except doxycycline, accumulate andenhance renal failure. A reversible Fanconysyndrome like condition is produced by outdatedtetracyclines. This is caused by degradedproducts—epitetracycline, anhydrotetracyclineand epianhydrotetracycline which damageproximal renal tubules. Exposure to acidic pH,moisture and heat favours such degradation.

3. Phototoxicity A sun burn-like or other severeskin reaction on exposed parts is seen in someindividuals. A higher incidence has been notedwith demeclocycline and doxycycline. Distortionof nails occurs occasionally.

4. Teeth and bones Tetracyclines have chela-ting property. Calcium-tetracycline chelate getsdeposited in developing teeth and bone. Givenfrom midpregnancy to 5 months of extrauterinelife, the deciduous teeth are affected: browndiscolouration, ill-formed teeth, more susceptibleto caries. Tetracyclines given between 3 monthsand 6 years of age affect the crown of permanentanterior dentition. Repeated courses are moredamaging.

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Given during late pregnancy or childhood,tetracyclines can cause temporary suppressionof bone growth. The ultimate effect on stature ismostly insignificant, but deformities and reduc-tion in height are a possibility with prolongeduse.

5. Antianabolic effect Tetracyclines reduceprotein synthesis and have an overall cataboliceffect. They induce negative nitrogen balance andcan increase blood urea.

6. Increased intracranial pressure is noted insome infants.

7. Diabetes insipidus Demeclocycline antago-nizes ADH action and reduces urine concentra-ting ability of the kidney. It has been tried inpatients with inappropriate ADH secretion.

8. Vestibular toxicity Minocycline can causeataxia, vertigo and nystagmus which subsidewhen the drug is discontinued.

Hypersensitivity This is infrequent with tetra-cyclines. Skin rashes, urticaria, glossitis, pruritusani and vulvae, even exfoliative dermatitis havebeen reported. Angioedema and anaphylaxis areextremely rare. Complete cross sensitization isexhibited by different tetracyclines.

Superinfection Tetracyclines are the most com-mon antibiotics responsible for superinfections,because they cause marked suppression of theresident flora.

Though mouth, skin or vagina may be invol-ved, intestinal superinfection by Candida albicansis most prominent; pseudomembranous entero-colitis is rare but serious. Higher doses suppressthe flora more completely—greater chance ofsuperinfection: doses on the lower side of therange should be used whenever possible. Thetetracycline should be discontinued at the firstsign of superinfection and appropriate therapyinstituted.

Doxycycline and minocycline are less liableto cause diarrhoea, because only small amountsreach the lower bowel in the active form.

Precautions

1. Tetracyclines should not be used duringpregnancy, lactation and in children.

2. They should be avoided in patients ondiuretics: blood urea may rise in such patients.

3. They should be used cautiously in renal orhepatic insufficiency.

4. Preparations should never be used beyondtheir expiry date.

5. Do not mix injectable tetracyclines withpenicillin—inactivation occurs.

Uses

Orodental conditions Tetracyclines are of limitedusefulness in treating acute dental infections andare infrequently selected for this purpose.However, they benefit certain forms of periodontaldisease by virtue of their broad-spectrumantimicrobial action as well as by suppressingthe activity of matrix metalloproteinases derivedfrom neutrophils and fibroblasts that contributeto the gingival inflammation. These enzymes areCa2+ dependent and tetracyclines chelate Ca2+. Inaddition, tetracyclines may benefit periodontalinflammation by scavenging free (oxygen)radicals.

Tetracyclines have an important adjuvant rolein the management of chronic periodontitisrefractory to conventional therapy with localhygienic and surgical measures, and in juvenileperiodontitis. In refractory periodontal disease2-week tetracycline (1 g/day) or doxycycline(0.1–0.2 g/day) therapy controls gingival inflam-mation and helps to normalise the periodontalmicroflora from a mixture of anaerobic gram-negative bacilli + spirochetes to the usual one inwhich gram-positive bacteria predominate.Tetracyclines are highly active against theActinobacillus sp. that is held responsible fordestruction of gums and bone loss in juvenileperiodontitis. Appropriate surgical treatmentcombined with 2 to 4-week tetracycline therapyhalts progression of this disease.

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General medical uses Although tetracyclinesare broad-spectrum antibiotics, they areemployed only for those infections for which amore selective and less toxic AMA is not available.Clinical use of tetracyclines has very muchdeclined due to availability of fluoroquinolonesand other efficacious AMAs.

1. Tetracyclines are often employed when thenature and sensitivity of the infecting organismcannot be reasonably guessed. However, they arenot dependable for empirical treatment ofserious/life-threatening infections. They may alsobe used for initial treatment of mixed infections.

2. Tetracyclines are still the drug of first choicein:(a) Venereal diseases: Lymphogranuloma vene-reum, granuloma inguinale, nonspecific urethritiscaused by Chlamydia trachomatis.(b) Atypical pneumonia due to Mycoplasmapneumoniae and psittacosis.(c) Cholera: Tetracyclines have adjuvant valueby reducing stool volume and limiting the durationof diarrhoea.(d) Brucellosis: Tetracyclines are combined withgentamicin or rifampin.(e) Plague: Tetracyclines are preferred for blind/mass treatment of suspected cases during anepidemic, though streptomycin often acts faster.(f) Relapsing fever due to Borrelia recurrentis.(g) Rickettsial infections: typhus, rocky mountainspotted fever, Q fever, etc.

3. Tetracyclines are second choice drugs:(a) To penicillin/ampicillin for tetanus, anthrax,actinomycosis and Listeria infections.(b) To ciprofloxacin or ceftriaxone for gonorrhoeain patients allergic to penicillin.(c) To ceftriaxone for syphilis in patients allergicto penicillin.(d) To azithromycin for trachoma due to Ch.trachomatis and pneumonia due to Ch. pneumoniae.

4. Other situations in which tetracyclines maybe used are:(a) Urinary tract infections.

(b) Community-acquired pneumonia.(c) Amoebiasis: along with other amoebicides forchronic intestinal amoebiasis.(d) As adjuvant to quinine or sulfadoxine-pyrimethamine for chloroquine-resistant P.falciparum malaria.(e) Acne: prolonged therapy with low doses maybe used in severe cases.(f) Chronic obstructive lung disease: prophylac-tic use may reduce the frequency of exacerbations.

CHLORAMPHENICOL

Chloramphenicol was initially obtained fromStreptomyces venezuelae in 1947. It was soonsynthesized chemically and the commercialproduct now is all synthetic.

It is a yellowish white crystalline solid,aqueous solution is quite stable, stands boiling,but needs protection from light. It has anitrobenzene substitution, which is probablyresponsible for the antibacterial activity and itsintensely bitter taste.

Mechanism of action Chloramphenicol inhibitsbacterial protein synthesis by interferring with‘transfer’ of the elongating peptide chain to thenewly attached aminoacyl-tRNA at the ribosome-mRNA complex. It specifically attaches to the 50Sribosome and thus may hinder the access ofaminoacyl-tRNA to the acceptor site for aminoacidincorporation (see Fig. 29.1). Probably, by actingas a peptide analogue, it prevents formation ofpeptide bonds.

At high doses, it can inhibit mammalianmitochondrial protein synthesis as well. Bonemarrow cells are specially susceptible.

Antimicrobial spectrum Chloramphenicol isprimarily bacteriostatic, though high concentra-tions have been shown to exert cidal effect on some

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bacteria, e.g. H. influenzae. It is a broad-spectrumantibiotic, active against the same range oforganisms (gram-positive and negative bacteria,rickettsiae, chlamydia, mycoplasma) as tetra-cyclines. Notable differences between these twoare:(a) Chloramphenicol is highly active againstSalmonella including S. typhi, but resistant strainsare now rampant.(b) It is more active than tetracyclines against H.influenzae (though many have now developedresistance), B. pertussis, Klebsiella and anaerobesincluding Bact. fragilis.(c) It is less active against gram-positive cocci,spirochetes, certain Enterobacteriaceae andChlamydia. Entamoeba and Plasmodiac are notinhibited.

Like tetracyclines, it is ineffective againstMycobacteria, Pseudomonas, many Proteus, virusesand fungi.

Resistance Most bacteria are capable ofdeveloping resistance to chloramphenicol, whichgenerally emerges in a graded manner, as withtetracyclines. Being orally active, broad spectrumand relatively cheap, chloramphenicol wasextensively and often indiscriminately used,especially in developing countries, resulting inhigh incidence of resistance among many gram-positive and gram-negative bacteria.

In many areas, highly chloramphenicol resis-tant S. typhi have emerged due to transfer of Rfactor by conjugation. Resistance among gram-negative bacteria is generally due to acquisitionof R plasmid encoded for an acetyl transferase—an enzyme which inactivates chloramphenicol.Acetyl-chloramphenicol does not bind to thebacterial ribosome. In many cases, this plasmidhas also carried resistance to ampicillin andtetracycline. Multidrug-resistant S. typhi havearisen.

Decreased permeability into the resistantbacterial cells (chloramphenicol appears to enterbacterial cell both by passive as well as facilitateddiffusion) and lowered affinity of bacterial ribo-some for chloramphenicol are other mechanisms

of resistance. Partial cross resistance betweenchloramphenicol and erythromycin/clindamycinhas been noted, because all these antibiotics bindto 50S ribosome at adjacent sites. Some crossresistance with tetracyclines also occurs, thoughthe latter binds to 30S ribosome.

Pharmacokinetics

Chloramphenicol is rapidly and completelyabsorbed after oral ingestion. It is 50–60% boundto plasma proteins and very widely distributed:volume of distribution 1 L/kg. It freely penetratesserous cavities and blood-brain barrier: CSFconcentration is nearly equal to that of unbounddrug in plasma. It crosses placenta and is secretedin bile and milk.

Chloramphenicol is primarily conjugatedwith glucuronic acid in the liver and little is excre-ted unchanged in urine. Cirrhotics and neonates,who have low conjugating ability, require lowerdoses. The metabolite is excreted mainly in urine.Plasma t½ of chloramphenicol is 3–5 hours inadults. It is increased only marginally in renalfailure: dose need not be modified.

Administration The commonest route ofadministration of chloramphenicol is oral—ascapsules; 250–500 mg 6 hourly (max. total dose28 g), children 25–50 mg/kg/day. It is alsoavailable for application to eye/ear, but topicaluse at other sites is not recommended.CHLOROMYCETIN, ENTEROMYCETIN, PARAXIN,250 mg, 500 mg cap, 1% eye oint, 0.5% eye drops, 5% eardrops, 1% applicaps.

Chloramphenicol palmitate (CHLOROMYCE-TIN PALMITATE, ENTEROMYCETIN, PARAXIN 125mg/5 ml oral susp) is an insoluble tasteless esterof chloramphenicol, which is inactive as such.It is nearly completely hydrolysed in the intestineby pancreatic lipase and absorbed as freechloramphenicol, but produces lower plasmaconcentration.

Chloramphenicol succinate (ENTEROMYCETIN,CHLOROMYCETIN SUCCINATE, KEMICETINE 1 g/vial inj, PHENIMYCIN 0.25, 0.5, 1.0 g inj. is the solublebut inactive ester which is used in the parenteral

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preparations. Intramuscular injection is painfuland produces lower blood levels. It is hydrolysedin tissues to the free active form. However,bioavailability even on i.v. injection is only 70%due to renal excretion of the ester before hydrolysis.

Adverse effects

1. Bone marrow depression Of all drugs, chlo-ramphenicol is the most important cause ofaplastic anaemia, agranulocytosis, thrombocyto-penia or pancytopenia. Two forms are recognized:(a) Non-dose related idiosyncratic reaction: Thisis rare (1 in 40,000), unpredictable, but serious,often fatal, probably has a genetic basis and ismore common after repeated courses. Aplasticanaemia is the most common manifestation. Manyvictims, even if they survive, develop leukaemiaslater.(b) Dose and duration of therapy related myelo-suppression: a direct toxic effect, predictable andprobably due to inhibition of mitochondrialenzyme synthesis. This is often reversible with-out long-term sequelae. Liver and kidney diseasepredisposes to such toxicity.

2. Hypersensitivity reactions Rashes, fever,atrophic glossitis, angioedema are infrequent.

3. Irritative effects Nausea, vomiting, diar-rhoea, pain on injection.

4. Superinfections These are similar to tetra-cyclines, but less common.

5. Gray baby syndrome It occurred when highdoses (~100 mg/kg) were given prophylacticallyto neonates, especially premature. The baby stop-ped feeding, vomited, became hypotonic andrespiration became irregular; an ashen graycyanosis developed, followed by cardiovascularcollapse and death.

It occurs because of inability of the newbornto adequately metabolize and excrete chloram-phenicol.

Interactions Chloramphenicol inhibits tolbuta-mide, chlorpropamide, warfarin, cyclophos-phamide and phenytoin metabolism. Toxicity can

occur if dose adjustments are not done. Pheno-barbitone, phenytoin, rifampin enhance chloram-phenicol metabolism → reduce its concentration→ failure of therapy may occur.

Erythromycin, clindamycin and chloramp-henicol can exhibit mutual antagonism ofantibacterial action; probably, due to proximityof their binding sites on bacterial 50S ribosome.

Uses

Because of serious (though rare) bone marrowtoxicity:(a) Never use chloramphenicol for minor infec-tions or those of undefined etiology.(b) Do not use chloramphenicol for infectionstreatable by other safer antimicrobials.(c) Avoid repeated courses.(d) Daily dose not to exceed 2–3 g; duration oftherapy to be < 2–3 weeks, total dose in a course< 28 g.(e) Regular blood counts (especially reticulocytecount) may detect dose-related bone marrowtoxicity but not the idiosyncratic type.

In view of the above limitations, there is noindication in dentistry that warrants use ofchloramphenicol despite its broad-spectrumantimicrobial action. In general medicine alsosystemic use of chloramphenicol is restricted to afew conditions.

1. Enteric fever Till recently chloramphenicolwas the drug of choice for typhoid fever. However,emergence of resistant strains of S. typhi hasmarkedly reduced response rate.

Chloramphenicol does not prevent or curetyphoid carrier state. It is only static while cidalaction is required to eradicate carrier state.

2. H. influenzae meningitis Chloramphenicol ishighly efficacious; it has excellent penetrabilityinto CSF. However, the 3rd generation cephalo-sporins are being increasingly used now.

3. Anaerobic infections caused by Bact. fragilisand others (wound infections, pelvic and brain

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abscesses, etc.) respond well to chloramphenicol.However, clindamycin or metronidazole arepreferred for these. Penicillin/cephalosporin isgenerally combined since most are mixedinfections.

4. Intraocular infections Chloramphenicol givensystemically attains high concentration in ocularfluid. It is the preferred drug for endophthalmitiscaused by sensitive organisms.

5. As second choice drug(a) to tetracyclines for brucellosis, cholera,rickettsial and chlamydial infections.(b) to erythromycin for whooping cough.(c) to penicillin for meningococcal or pneumo-coccal meningitis, e.g. in patients allergic topenicillin.(d) to cotrimoxazole for Shigella dysentery enteritis.(e) to fluoroquinolones in urinary tract infections.

6. Topically In conjunctivitis, external earinfections—it is highly effective. Topical use onskin or other areas is not recommended becauseof risk of sensitization.

AMINOGLYCOSIDE ANTIBIOTICS

These are a group of natural and semisynthe-tic antibiotics having polybasic amino groupslinked glycosidically to two or more aminosugarresidues. While they are extensively used to treatmedical, surgical, gynaecological and othersystemic infections, they are seldom employed indentistry.

Unlike penicillin, which was a chance disco-very, aminoglycosides are products of deliberatesearch for drugs effective against gram-negativebacteria. Streptomycin was the first memberdiscovered in 1944 by Waksman and hiscolleagues. It assumed great importance becauseit was active against tubercle bacilli. Others havebeen produced later; now aminoglycosides are asizable family. All aminoglycosides are producedby soil actinomycetes and have many commonproperties.

Systemic aminoglycosidesStreptomycin AmikacinGentamicin SisomicinKanamycin NetilmicinTobramycin

Topical aminoglycosidesNeomycin Framycetin

MECHANISM OF ACTION

The aminoglycosides are bactericidal antibiotics,all having the same general pattern of actionwhich may be described in two main steps:(a) Transport of the aminoglycoside through thebacterial cell wall and cytoplasmic membrane.(b) Binding to ribosomes resulting in inhibitionof protein synthesis.

Transport of aminoglycoside into the bacterialcell is a multistep process. They diffuse acrossthe outer coat of gram-negative bacteria throughporin channels. Entry from the periplasmic spaceacross the cytoplasmic membrane is carriermediated which is linked to the electron transportchain. Thus, penetration is dependent uponmaintenance of a polarized membrane and onoxygen dependent active processes. These areinactivated under anaerobic conditions; anaero-bes are not sensitive and facultative anaerobes

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Common properties of aminoglycoside antibiotics

1. All are used as sulfate salts, which are highly watersoluble; solutions are stable for months.

2. They ionize in solution; are not absorbed orally;distribute only extracellularly; do not penetrate brainor CSF.

3. All are excreted unchanged in urine by glomerularfiltration.

4. All are bactericidal and more active at alkaline pH.5. They act by interferring with bacterial protein

synthesis.6. All are active primarily against aerobic gram-

negative bacilli and do not inhibit anaerobes.7. There is only partial cross resistance among them.8. They have relatively narrow margin of safety.9. All exhibit ototoxicity and nephrotoxicity.


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are more resistant when O2 supply is deficient,e.g. inside big abscesses. Penetration is alsofavoured by high pH; aminoglycosides are ~20times more active in alkaline than in acidicmedium.

Once inside the bacterial cell, streptomycinbinds to 30S ribosomes, but other aminoglyco-sides bind to additional sites on 50S subunit aswell as to 30S-50S interface. They freeze initiationof protein synthesis (see Fig. 29.1), prevent poly-some formation and promote their disaggregationto monosomes so that only one ribosome isattached to each strand of mRNA. Binding ofaminoglycoside to 30S-50S juncture causesdistortion of mRNA codon recognition resultingin misreading of the code: one or more wrongamino acids are entered in the peptide chain and/or peptides of abnormal lengths are produced.Different aminoglycosides cause misreading atdifferent levels depending upon their selectiveaffinity for specific ribosomal proteins.

The cidal action of these drugs appears to bebased on secondary changes in the integrity ofbacterial cell membrane, because other antibio-tics which inhibit protein synthesis (tetracyclines,chloramphenicol, erythromycin) are only static.After exposure to aminoglycosides, sensitive bac-teria become more permeable; ions, amino acidsand even proteins leak out followed by cell death.This probably results from incorporation of thedefective proteins into the cell membrane. One ofthe consequences of aminoglycoside inducedalteration of cell membrane is augmentation ofthe carrier-mediated entry of the antibiotic. Thisreinforces the lethal action.

The cidal action of aminoglycosides isconcentration dependent, i.e. rate of bacterial cellkilling is directly related to the ratio of the peakantibiotic concentration to the MIC value. Theyalso exert a long and concentration dependent‘postantibiotic effect’. It has, therefore, beenargued that despite their short t½ (2–4 hr), singleinjection of the total daily dose of aminoglycosidemay be more effective and possibly less toxic thanits conventional division into 2–3 doses.

MECHANISM OF RESISTANCE

Resistance to aminoglycosides is acquired by oneof the following mechanisms:(a) Acquisition of cell membrane bound inactiva-ting enzymes which phosphorylate/adenylate oracetylate the antibiotic. The conjugated amino-glycosides do not bind to the target ribosomesand are incapable of enhancing active transportlike the unaltered drug. These enzymes areacquired mainly by conjugation and transfer ofplasmids. Nosocomial microbes have become richin such plasmids, some of which encode formultidrug resistance. This is the most importantmechanism of development of resistance toaminoglycosides. Susceptibility of differentaminoglycosides to these enzymes differs. Thus,cross resistance among different members ispartial or absent.(b) Mutation decreasing the affinity of ribosomalproteins that normally bind the aminoglycoside:this mechanism can confer high degree resistance,but operates to a limited extent, e.g. E. coli thatdevelop streptomycin resistance by single stepmutation do not bind the antibiotic on thepolyribosome. Only a few other instances areknown, and this type of resistance is specific for aparticular aminoglycoside.(c) Decreased efficiency of the aminoglycosidetransporting mechanism: either the pores in theouter coat become less permeable or the activetransport is interfered. This again is not frequentlyencountered in the clinical setting. In somePseudomonas which develop resistance, theantibiotic induced 2nd phase active transport hasbeen found to be deficient.

SHARED TOXICITIES

The aminoglycosides produce toxic effects whichare common to all members, but the relativepropensity differs (Table 29.2).

1. Ototoxicity This is the most important doseand duration of treatment related adverse effect.The vestibular or the cochlear part may be prima-rily affected by a particular aminoglycoside. These

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drugs are concentrated in the labyrinthine fluidand are slowly removed from it when the plasmaconcentration falls. Ototoxicity is greater whenplasma concentration of the drug is persistentlyhigh and above a threshold value. The vestibular/cochlear sensory cells and hairs undergoconcentration dependent destructive changes.Aminoglycoside ear drops also can causeototoxicity when instilled in patients withperforated eardrum; contraindicated in them.

Cochlear damage It starts from the base andspreads to the apex; hearing loss affects the highfrequency sound first, then progressively encom-passes the lower frequencies. No regeneration ofthe sensory cells occurs; auditory nerve fibresdegenerate in retrograde manner—deafness ispermanent. Older patients and those with pre-existing hearing defect are more susceptible.Initially, the cochlear toxicity is asymptomatic;can be detected only by audiometry. Tinnitus thenappears, followed by progressive hearing loss.On stopping the drug, tinnitus disappears in4–10 days, but frequency loss persists.

Vestibular damage Headache is usually first toappear, followed by nausea, vomiting, dizziness,nystagmus, vertigo and ataxia. When the drug isstopped at this stage, it passes into a chronic phaselasting 6 to 10 weeks in which the patient isasymptomatic while in bed and has difficulty onlyduring walking. Compensation by visual andproprioceptive positioning and recovery (often

partial) occurs over 1–2 years. Permanency ofchanges depends on the extent of initial damageand the age of the patient (elderly have poorrecovery).

2. Nephrotoxicity It manifests as tubulardamage resulting in loss of urinary concentratingpower, low g.f.r., nitrogen retention, albuminuriaand casts. Aminoglycoside toxicity is related tothe total amount of the drug received by thepatient. It is more in the elderly and in those withpre-existing kidney disease. Provided the drug ispromptly discontinued, renal damage causedby aminoglycosides is totally reversible. Animportant implication of aminoglycoside inducednephrotoxicity is reduced clearance of theantibiotic → higher blood levels → enhancedototoxicity.

3. Neuromuscular blockade All aminogly-cosides reduce ACh release from the motor nerveendings. Effect of this action is not manifestedordinarily in the clinical use of these drugs.However, apnoea and fatalities have occurredwhen these antibiotics were put into peritonial orpleural cavities after an operation, especially if acurare-like muscle relaxant had been used duringsurgery. Rapid absorption from the peritoneum/pleura produces high blood levels and adds tothe residual action of the neuromuscular blocker.

Neomycin and streptomycin have higherpropensity while tobramycin is least likely toproduce this effect.

Myasthenic weakness is accentuated by thesedrugs. Neuromuscular blockers should be usedcautiously in patients receiving aminoglycosides.

PRECAUTIONS AND INTERACTIONS

1. Avoid during pregnancy: risk of foetalototoxicity.

2. Avoid concurrent use of other ototoxic drugs,e.g. high ceiling diuretics, minocycline.

3. Avoid concurrent use of other nephrotoxicdrugs, e.g. amphotericin B, vancomycin,cyclosporine and cisplatin.


Table 29.2: Comparative toxicity of aminoglycosideantibiotics (tentative)

Systemically used Ototoxicity Nephrotoxicityaminoglycoside vestibular cochlear

1. Streptomycin ++ ± +2. Gentamicin ++ + ++3. Kanamycin + ++ ++4. Tobramycin +± + +5. Amikacin + ++ ++6. Sisomicin ++ + ++7. Netilmicin + + ++


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4. Cautious use in patients past middle age andin those with kidney damage.

5. Cautious use of muscle relaxants in patientsreceiving an aminoglycoside.

6. Do not mix aminoglycoside with any drug inthe same syringe/infusion bottle.

Streptomycin

It is the oldest aminoglycoside antibiotic obtai-ned from Streptomyces griseus; used extensivelyin the past, but now practically restricted totreatment of tuberculosis. The antimicrobialspectrum of streptomycin is relatively narrow:active primarily against aerobic gram-negativebacilli, and potency is low. Sensitive organismsare —H. ducreyi, Brucella, Yersinia pestis, Francisellatularensis, Nocardia, Calym. granulomatis, M.tuberculosis. Only few strains of E. coli, H. influenzae,V. cholerae, Shigella, Klebsiella, enterococci andsome gram-positive cocci are now inhibited, thattoo at higher concentrations. All other organismsare unaffected.

Resistance Many organisms develop rapidresistance to streptomycin, either by one-stepmutation or by acquisition of plasmid whichcodes for inactivating enzymes. In the intestinaland urinary tracts, resistant organisms mayemerge within 2 days of therapy. E. coli., H.influenzae, Str. pneumoniae, Str. pyogenes, Staph.aureus have become largely resistant. If it is usedalone, M. tuberculosis also become resistant.

Streptomycin dependence Certain mutants grown in thepresence of streptomycin become dependent on it andgrow faster in its presence. This occurs when the antibioticinduced misreading of the genetic code becomes a normalfeature for the organism.

Cross resistance Only partial and often unidirec-tional cross resistance occurs between strepto-mycin and other aminoglycosides.

Pharmacokinetics Streptomycin is highly ioni-zed. It is neither absorbed nor destroyed in theg.i.t. However, absorption from injection site inmuscles is rapid. It is distributed onlyextracellularly: volume of distribution (0.3 L/kg)

is nearly equal to the extracellular fluid volume.It attains low concentrations in serous fluids likesynovial, pleural, etc. Concentrations in CSF andaqueous humour are often non-therapeutic, evenin the presence of inflammation. Plasma proteinbinding is clinically insignificant.

Streptomycin is not metabolized—excretedunchanged in urine. Glomerular filtration is themain channel: tubular secretion and reabsorptionare negligible. The plasma t½ is 2–4 hours, butthe drug persists longer in tissues. Renal clearanceof streptomycin parallels creatinine clearance andis approximately 2/3rd of it. Half-life is prolongedand accumulation occurs in patients with renalinsufficiency, in the elderly as well as in neonateswho have low g.f.r. Reduction in dose or increasein dose interval is essential in these situations.

These pharmacokinetic features apply to allsystemically administered aminoglycosides.

Adverse effects About 1/5th patients givenstreptomycin 1 g BD i.m. experience vestibulardisturbances. Auditory disturbances are lesscommon.

Streptomycin has the lowest nephrotoxicityamong aminoglycosides. Hypersensitivity reac-tions are rare; rashes, eosinophilia, fever andexfoliative dermatitis have been noted. Anaphy-laxis is very rare. Topical use is contraindicatedfor fear of contact sensitization.

Superinfections are not significant. Pain atinjection site is common. Paraesthesias andscotoma are occasional.AMBISTRYN-S 0.75, 1 g dry powder per vial for inj.Acute infections: 1 g (0.75 g in those above 50 yr age) i.m.BD for 7–10 days.Tuberculosis: 1 g or 0.75 g i.m. OD or twice weekly for30–60 days.

Uses

Streptomycin is not used in dentistry. Other usesare:1. Tuberculosis: see Ch. 31.2. Subacute bacterial endocarditis (SABE): Streptomycin(now mostly gentamicin) is given in conjunction withpenicillin. A 4–6 weeks of treatment is needed.

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3. Plague: It effects rapid cure, may be employed inconfirmed cases, but tetracyclines have been morecommonly used.4. Tularaemia: Streptomycin is the drug of choice forthis rare disease.

In most other situations, e.g. urinary tractinfection, peritonitis, septicaemias, etc. wherestreptomycin was used earlier, gentamicin or oneof the newer aminoglycosides is now preferreddue to widespread resistance to streptomycin andits low potency.

Gentamicin

It was obtained from Micromonospora purpurea in1964; has become the most commonly usedaminoglycoside for acute infections. The pro-perties of gentamicin including plasma t½ of 2–4hours after i.m. injection are the same as describedabove for streptomycin, but there are followingdifferences:(a) It is more potent (MIC for most organisms is4–8 times lower.)(b) It has a broader spectrum of action: effectiveagainst Ps. aeruginosa and most strains of Proteus,E. coli, Klebsiella, Enterobacter, Serratia.(c) It is ineffective against M. tuberculosis, Strep.pyogenes and Strep. pneumoniae, but inhibits manyStrep. faecalis and some Staph. aureus.(d) It is relatively more nephrotoxic.

Dose: The dose of gentamicin must be preciselycalculated according to body weight and level ofrenal function. For an average adult with normalrenal function (creatinine clearance > 100 ml/min), 3–5 mg/kg/day i.m. either as single dose ordivided in three 8 hourly doses is recommended.

The daily dose of gentamicin (and otheraminoglycosides) should be reduced in patients

with impaired renal function according to themeasured creatinine clearance. A general guide-line is given in the box.GARAMYCIN, GENTASPORIN, GENTICYN 20, 60, 80,240 mg per vial inj; also 0.3% eye/ear drops, 0.1% skincream.

Use in dentistry Because of its predominantlygram-negative spectrum of activity, inefficacyagainst anaerobes and need for parenteraladministration, gentamicin (and other amino-glycosides) is not employed to treat dentalinfections. The only application in dentistry is togive gentamicin 2 mg/kg i.m./i.v. (single dose) tosupplement amoxicillin or vancomycin forprophylaxis of bacterial endocarditis followingdental surgery in patients with prosthetic heartvalves or in those having past history of bacterialendocarditis or those to be operated under generalanaesthesia.

General medical uses Gentamicin is thecheapest (other than streptomycin) and the firstline aminoglycoside antibiotic. However, becauseof low therapeutic index, its use should berestricted to serious gram-negative bacillaryinfections.1. Gentamicin is very valuable for preventingand treating respiratory infections in critically illpatients; in those with impaired host defence(receiving anticancer drugs or high-dosecorticosteroids; AIDS; neutropenic), patients inresuscitation wards, with tracheostomy or onrespirators; postoperative pneumonias; patientswith implants and in intensive care units. It isoften combined with a penicillin/cephalosporinor another antibiotic in these situations. However,resistant strains have emerged in many hospitalsand nosocomial infections are less amenable togentamicin now. Another aminoglycoside(tobramycin, amikacin, sisomicin, netilmicin) isthen selected on the basis of the sensitivity pattern.2. Pseudomonas, Proteus or Klebsiella infections:burns, urinary tract infection, pneumonia, lungabscesses, osteomyelitis, middle ear infection,septicaemia, etc. are an important area of use of


Guideline for dose adjustment of gentamicin inrenal insufficiency

CLcr (ml/min) % of daily dose

70 70% daily50 50% daily30 30% daily10–30 60% alternate day<10 40% alternate day


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gentamicin. It may be combined with piperacillinor a third generation cephalosporin for seriousinfections. Topical use on infected burns and inconjunctivitis is permissible.3. Meningitis caused by gram-negative bacilli.Because this is a serious condition, drug combina-tions including an aminoglycoside are often used.4. SABE: gentamicin is more commonly used inplace of streptomycin to accompany penicillin.

Kanamycin

Obtained from S. kanamyceticus (in 1957), it was the secondsystemically used aminoglycoside to be developed afterstreptomycin. It is similar to streptomycin in all respectsincluding lack of activity against Pseudomonas. However,it is more toxic, both to the cochlea and to kidney. Hearingloss is more common than vestibular disturbance.

Because of toxicity and narrow spectrum of activity,it has been largely replaced by other aminoglycosides. It isoccasionally used as a second line drug in resistanttuberculosis.Dose: 0.5 g i.m. BD-TDS: KANAMYCIN, KANCIN,KANAMAC 0.5, 1 g inj.

Tobramycin

It was obtained from S. tenebrarius in the 1970s.The antibacterial and pharmacokinetic proper-ties, as well as dosage are almost identical togentamicin, but it is 2–4 times more active againstPseudomonas and Proteus, including those resis-tant to gentamicin. However, it is not useful forcombining with penicillin in the treatment ofenterococcal endocarditis. It should be used onlyas a reserve alternative to gentamicin. Seriousinfections caused by Pseudomonas and Proteus areits only current indications. Ototoxicity andnephrotoxicity is probably lower than gentamicin.Dose: 3–5 mg/kg day in 1–3 doses.TOBACIN 20, 60, 80 mg in 2 ml inj. 0.3% eye drops.TOBRANEG 20, 40, 80 mg per 2 ml inj.

AmikacinIt is a semisynthetic derivative of kanamycin towhich it resembles in pharmacokinetics, dose andtoxicity. The outstanding feature of amikacin isits resistance to bacterial aminoglycoside inacti-vating enzymes. Thus, it has the widest spectrumof activity, including many organisms resistant

to other aminoglycosides. However, relativelyhigher doses are needed for Pseudomonas, Proteusand Staph. infections.

The range of conditions in which amikacincan be used is the same as for gentamicin. It isrecommended as a reserve drug for hospitalacquired gram-negative bacillary infections. It iseffective in tuberculosis, but rarely used for thispurpose. More hearing loss than vestibulardisturbance occurs in toxicity.Dose: 15 mg/kg/day in 1–3 doses; urinary tract infection7.5 mg/kg/day.AMICIN, MIKACIN, MIKAJECT 100 mg, 250 mg, 500mg in 2 ml inj.

Sisomicin

Introduced in 1980s, it is a natural aminogly-coside from Micromonospora inyoensis that ischemically and pharmacokinetically similar togentamicin, but somewhat more potent onPseudomonas, a few other gram-negative bacilliand β-haemolytic Streptococci. It is moderatelyactive on faecal Streptococci—can be combinedwith penicillin for SABE. However, it is susceptibleto aminoglycoside inactivating enzymes andoffers no advantage in terms of ototoxicity andnephrotoxicity. It can be used interchangeablywith gentamicin for the same purposes in the samedoses.ENSAMYCIN, SISOPTIN 50 mg, 10 mg (pediatric) perml in 1 ml amps.

Netilmicin

This semisynthetic derivative of sisomicin has abroader spectrum of activity than gentamicin. Itis relatively resistant to aminoglycoside inacti-vating enzymes and thus effective against manygentamicin-resistant strains. It is more activeagainst Klebsiella, Enterobacter and Staphylococci,but less active against Ps. aeruginosa.

Pharmacokinetic characteristics and dosageof netilmicin are similar to gentamicin. Experi-mental studies have shown it to be less ototoxic,but clinical evidence is inconclusive: hearing lossoccurs, though fewer cases of vestibular damagehave been reported.

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Dose: 4–6 mg/kg/day in 1–3 doses; NETROMYCIN10, 25, 50 mg in 1 ml, 200 mg in 2 ml and 300 mg in 3ml inj.

Neomycin

Obtained from S. fradiae, it is a wide spectrumaminoglycoside, active against most gram-negative bacilli and some gram-positive cocci.However, Pseudomonas and Strep. pyogenes are notsensitive. Neomycin is highly toxic to the internalear (mainly auditory) and to kidney. It is, there-fore, not used systemically. It is poorly absorbedfrom the g.i.t. Oral and topical administration doesnot ordinarily cause systemic toxicity.Dose: 0.25–1 g QID oral, 0.3–0.5% topical.NEOMYCIN SULPHATE 350, 500 mg tab, 0.3% skin oint,0.5% skin cream, eye oint.NEBASULF: Neomycin sulph. 5 mg, bacitracin 250 U,sulfacetamide 60 mg/g oint. and powder for surfaceapplication.POLYBIOTIC CREAM: Neomycin sulph. 5 mg, polymyxin5,000 IU, gramicidin 0.25 mg/g cream.

Uses

1. Topically (often in combination with poly-myxin, bacitracin, etc.) for infected wound, ulcers,burn, external ear infections, conjunctivitis.

2. Orally for:(a) Preparation of bowel before surgery: mayreduce postoperative infections.(b) Hepatic coma: Neomycin, by suppressingintestinal flora, diminishes NH3 production inthe colon which on absorption causes encephalo-pathy. However, because of the toxic potential, itis infrequently used for this purpose.

Adverse effects Applied topically neomycinhas low sensitizing potential, however, rashesdo occur.Oral neomycin has a damaging effect on intestinalvilli—prolonged treatment can induce malabsor-ption syndrome with diarrhoea and steatorrhoea.Superinfection by Candida can also occur.

Applied to serous cavities (peritoneum), it cancause apnoea due to the muscle paralysing action.

Framycetin

Obtained from S. lavendulae, it is very similar toneomycin. It is too toxic for systemic adminis-tration and is used topically on skin, eye, ear inthe same manner as neomycin.SOFRAMYCIN, FRAMYGEN 1% skin cream, 0.5% eyedrops or oint.


MACROLIDE ANTIBIOTICS

These are antibiotics having a macrocycliclactone ring with attached sugars. Erythromycinhas been in use from the 1950s, Roxithromycin,Clarithromycin and Azithromycin are the lateradditions.

ERYTHROMYCIN

It was isolated from Streptomyces erythreus in 1952and is widely employed, mainly as an alternativeto penicillin. It is quite frequently prescribed indentistry. Water solubility of erythromycin islimited, and the solution remains stable onlywhen kept in cold.

Mechanism of action Erythromycin is bacte-riostatic at low but cidal at high concentrations.Cidal action also depends on the organismconcerned and its rate of multiplication. Sensitivegram-positive bacteria accumulate erythromycinintracellularly by active transport which isresponsible for their high susceptibility to thisantibiotic. It is several fold more active in alkalinemedium, because the nonionized (penetrable)form of the drug is favoured at higher pH.

Erythromycin acts by inhibiting bacterialprotein synthesis. It combines with 50S ribosomesubunit and interferes with ‘translocation’ (seeFig. 29.1). After peptide bond formation betweenthe newly attached amino acid and the nacent

peptide chain at the acceptor (A) site the elongatedpeptide is translocated back to the peptidyl (P)site, making the A site available for nextaminoacyl tRNA attachment. This is preventedby erythromycin and the ribosome fails to movealong the mRNA to expose the next codon. As anindirect consequence, peptide chain may beprematurely terminated: synthesis of largerproteins is specifically suppressed.

Antimicrobial spectrum It is narrow, includesmostly gram-positive and a few gram-negativeorganisms, and overlaps considerably with thatof penicillin G. Erythromycin is highly activeagainst Str. pyogenes and Str. pneumoniae, N.gonorrhoeae, Clostridia, C. diphtheriae, Listeria. Mostpenicillin-resistant Staphylococci and Streptococciwere initially sensitive, but have now becomeresistant to erythromycin as well.

In addition, Campylobacter, Legionella, Branha-mella catarrhalis, Gardnerella vaginalis andMycoplasma that are not affected by penicillin arehighly sensitive to erythromycin. Few othersincluding oral anaerobes, H. influenzae, H. ducreyi,B. pertussis, Chlamydia trachomatis, Str. viridans, N.meningitidis and Rickettsiae are moderatelysensitive. Enterobacteriaceae, other gram-negativebacilli and B. fragilis are not inhibited.

Resistance All cocci readily develop resistanceto erythromycin, mostly by mechanisms which

30

Macrolide and OtherAntibacterial Antibiotics

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render them less permeable to erythromycin oracquire the capacity to pump it out. ResistantEnterobacteriaceae have been found to producean erythromycin esterase. Alteration in theribosomal binding site for erythromycin byplasmid encoded methylase enzyme is yet anothermechanism of resistance. All the above types ofresistance are plasmid mediated, while changein the 50S ribosome by chromosomal mutationhas also been found.

Cross resistance with other macrolides,clindamycin and chloramphenicol occurs becausethe ribosomal binding sites for all these areproximal to each other.

Pharmacokinetics Erythromycin base is acidlabile. To protect it from gastric acid, it is given asenteric coated tablets, from which absorption isincomplete and food delays absorption byretarding gastric emptying. Its acid stable estersare better absorbed.

Erythromycin is widely distributed in thebody, enters into abscesses, crosses serousmembranes and placenta but not blood-brainbarrier. It is 70–80% plasma protein bound, partlymetabolized and excreted primarily in bile in theactive form. Renal excretion is minor; dose neednot be altered in renal failure. The plasma t½ is1.5 hours, but erythromycin persists longer intissues.

Preparations and dose

Dose: 250–500 mg 6 hourly (max. 4 g/day), children 30–60 mg/kg/day.1. Erythromycin (base): ERYSAFE 250, mg tabs,EROMED 333 mg tab, 125 mg/5 ml susp.2. Erythromycin stearate: blood levels produced aresimilar to those after erythromycin base. ERYTHROCIN250, 500 mg tab, 100 mg/5 ml susp., 100 mg/ml ped.drops. ETROCIN, ERYSTER 250 mg tab, 100 mg/5 mldry syr, EMTHRO 250 mg tab, 125 mg/5 ml susp.3. Erythromycin estolate (lauryl sulfate): it is relativelyacid stable and better absorbed after oral administration.However, concentration of free and active drug in plasmamay be the same as after administration of erythromycinbase. Certain organisms hydrolyse it to liberate the freeform intracellularly and are more susceptible to it.ALTHROCIN 250, 500 mg tab, 125 mg kid tab, 125 mg/5 ml and 250 mg/5 ml dry syr, 100 mg/ml ped. drops,

E-MYCIN 100, 250 mg tab, 100 mg/5 ml dry syr;ERYC-S 250 mg tab, 125 mg/5 ml dry syr.4. Erythromycin ethylsuccinate: well absorbed orally;ERYNATE 100 mg/5 ml dry syr, ERYTHROCIN 100 mg/ml drops, 125 mg/5 ml syr.

Adverse effects Erythromycin base is a remar-kably safe drugs, but side effects do occur.

1. Gastrointestinal Mild-to-severe epigastricpain is experienced by many patients, especiallychildren, on oral therapy. Diarrhoea is occasional.Erythromycin stimulates motilin receptors in the g.i.t.—thereby induces gastric contractions, hastens gastricemptying and promotes intestinal motility. However,contribution of this action to the g.i. side effects is notknown.

2. Very high doses of erythromycin have causedreversible hearing impairment.

3. Hypersensitivity Rashes and fever are infre-quent. Other allergic manifestations are rare witherythromycin base or esters other than estolate.

Hepatitis with cholestatic jaundice resemb-ling viral hepatitis or extrahepatic biliary obs-truction occurs with the estolate ester (rarely withethyl succinate or stearate ester) after 1–3 weeks.Incidence is higher in pregnant women. It clearson discontinuation of the drug, and is probablydue to hypersensitivity to the estolate ester;erythromycin base or other esters can be given tothese patients without recurrence. Though theestolate is acid stable, tasteless and betterabsorbed, it has been banned in some countries(but not in India).

Interaction Erythromycin inhibits hepatic oxi-dation of many drugs. The clinically significantinteractions are—rise in plasma levels of theo-phylline, carbamazepine, valproate, warfarin,terfenadine, astemizole and cisapride.

Several cases of Q-T prolongation, seriousventricular arrhythmias and death have beenreported due to inhibition of CYP3A4 byerythromycin/clarithromycin resulting in highblood levels of concurrently administeredterfenadine/astemizole/cisapride (see p. 103 and283).

Macrolide Antibiotics 421

422 Macrolide and Other Antibacterial AntibioticsS

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Uses

Dental infections Because erythromycin is orallyadministered, safe and active against both aerobicand anaerobic gram-positive bacteria commonlyinfecting dental structures and mouth, it is thesecond choice drug to penicillins for periodontal/periapical abscesses, necrotizing ulcerativegingivitis, postextraction infections, gingivalcellulitis, etc. It is particularly valuable for patientsallergic to penicillins, or those with penicillin-resistant infections. However, it is not activeagainst gram negative anaerobes involved inpolymicrobial orodental infections. Further, beingbacteriostatic, it is less effective than penicillinsin eradicating dental infections caused by penicil-lin-sensitive bacteria. It is a good alternative topenicillin for prophylactic uses in dentistry.

General medical uses The most commonindications of erythromycin are as a substitutefor penicillins in allergic patients for pharyngitis,tonsillitis and other respiratory/ENT infectionsas well as for prophylaxis of rheumatic fever. It isone of the first choice drugs for atypicalpneumonia caused by Mycoplasma pneumoniae,diphtheria (antitoxin therapy is the primarymeasure), early stages of whooping cough andchancroid. It is a second choice drug forLegionnaires’ pneumonia, Campylobacter enteri-tis, chlamydial urogenital infections and someskin/soft tissue infections caused by penicillinresistant Staph. aureus, but not MRSA.

NEWER MACROLIDES

In an attempt to overcome the limitations oferythromycin like narrow spectrum, gastricintolerance, gastric acid lability, low oralbioavailability, moderate tissue penetration andshort half-life, a number of semisyntheticmacrolides have been produced, of whichroxithromycin, clarithromycin and azithromycinare available.

Roxithromycin It is a semisynthetic longer-acting acid-stable macrolide whose antimicrobialspectrum resembles closely with that of

erythromycin. It is more potent against Branh.catarrhalis, Gard. vaginalis and Legionella but lesspotent against B. pertussis. Improved enteralabsorption and tissue penetration, an averageplasma t½ of 12 hours making it suitable for twicedaily dosing, as well as better gastric tolerabilityare its desirable features.

Though its affinity for cytochrome P450 islower, drug interactions with terfenadine,cisapride and others are not ruled out. Thus, it isan alternative to erythromycin for respiratory,ENT, orodental, skin and soft tissue and genitaltract infections with similar efficacy.Dose: 150–300 mg BD 30 min before meals, children2.5–5 mg/kg BD;ROXID, ROXIBID, RULIDE 150, 300 mg tab, 50 mg kidtab, 50 mg /5 ml liquid; ROXEM 50 mg kid tab, 150 mg tab.

Clarithromycin The antimicrobial spectrum ofclarithromycin is similar to erythromycin; in addi-tion, it includes Mycobact. avium complex (MAC),other atypical mycobacteria and Mycobact. leprae.It is more active against sensitive strains ofgram-positive cocci, many oral anaerobes likeBact. melaninogenicus, Peptococcus as well asCl. perfringens (but not Bact. fragilis), Moraxella,Legionella, Mycoplasma pneumoniae and Helicobacterpylori. However, bacteria that have developedresistance to erythromycin are resistant toclarithromycin also.

Clarithromycin is more acid stable thanerythromycin, and is rapidly absorbed; oral bio-availability is ~50% due to first pass metabolism;food delays absorption. It has slightly greatertissue distribution than erythromycin and ismetabolized by saturation kinetics—t½ isprolonged from 3–6 hours at lower doses to 6–9hours at higher doses. An active metabolite isproduced. About 1/3rd of oral dose is excretedunchanged in urine, but no dose modification isneeded in liver disease or in mild-to-moderatekidney failure.

Clarithromycin is indicated in upper andlower respiratory tract infections, orodentalinfections, sinusitis, otitis media, atypicalpneumonia, skin and skin structure infectionsmostly due to Strep. pyogenes and some Staph.

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aureus. Used as a component of triple drugregimen (see p. 280) it eradicates H. pylori in 1–2weeks. It is a first line drug in combinationregimens for MAC infection in AIDS patients anda second line drug for other atypical mycobacterialdiseases as well as leprosy.Dose: 250 mg BD for 7 days; severe cases 500 mg BD up to14 days.CLARIBID 250, 500 mg tab, 250 mg/5 ml dry syr;CLARIMAC 250, 500 mg tabs; SYNCLAR 250 mg tab,125 mg/5 ml dry syr.

Side effects of clarithromycin are similar toerythromycin, but gastric tolerance is better.High doses can cause reversible hearing loss.Few cases of pseudomembranous enterocolitis,hepatic dysfunction or rhabdomyolysis arereported. Its safety in pregnancy and lactation isnot known. The drug interaction potential is alsosimilar to erythromycin.

Azithromycin This azalide congener of ery-thromycin has an expanded spectrum, improvedpharmacokinetics, better tolerability and druginteraction profiles. It is more active than othermacrolides against H. influenzae, and certainanaerobes like Peptostreptococcus, few Clostridia,but less active against gram-positive cocci. Highactivity is exerted on respiratory pathogens—Mycoplasma, Chlamydia pneumoniae, Legionella,Moraxella and on others like Campylobacter, Ch.trachomatis, N. gonorrhoeae. However, it is notactive against erythromycin-resistant bacteria.Penicillinase producing Staph. aureus areinhibited but not methicillin-resistant ones. Goodactivity is noted against MAC.

The remarkable pharmacokinetic propertiesare acid stability, rapid oral absorption, markedtissue distribution and intracellular penetration.However, absorption is decreased by food.Concentration in most tissues exceeds that inplasma. Particularly high concentrations areattained inside macrophages and fibroblasts:volume of distribution is ~30 L/kg. Slow releasefrom the intracellular sites contributes to its longterminal t½ of >50 hr. It is largely excretedunchanged in bile, renal excretion is < 10%.

Azithromycin can be used in orodentalinfections in place of erythromycin, particularlyin patients not tolerating the latter. It has betteractivity against oral spirochetes and gramnegative anaerobes causing dental infections.Azithromycin is an alternative for prophylaxis ofpostdental surgery wound infection/endocarditisin predisposed patients. Because of higherefficacy, better gastric tolerance and convenientonce a day dosing, azithromycin is now preferredover erythromycin as first choice drug forinfections such as:(a) Legionnaires’ pneumonia.(b) Chlamydia trachomatis: nonspecific urethritisand genital infections in both men and women. Itis also the drug of choice for chlamydial pneu-monia and is being preferred over tetracycline fortrachoma in the eye.

The other indications of azithromycin arepharyngitis, tonsillitis, sinusitis, otitis media,pneumonias, acute exacerbations of chronicbronchitis, streptococcal and some staphylococcalskin and soft tissue infections, and gonorrhoea. Incombination with at least one other drug it iseffective in the prophylaxis and treatment of MACin AIDS patients.Dose: 500 mg once daily 1 hour before or 2 hours afterfood, (children above 6 months 10 mg/kg) for 3 days issufficient for most infections.AZITHRAL 250, 500 mg cap and 250 mg per 5 ml drysyr; AZIWOK 250 mg cap, 100 mg kid tab, 100 mg/5 mland 200 mg/5 ml susp. AZIWIN 100, 250, 500 mg tab,200 mg/5 ml liq. Also AZITHRAL 500 mg inj.

Side effects are mild gastric upset, abdominalpain (less than erythromycin), headache anddizziness. Azithromycin has been found not tointeract with hepatic CYP3A4 enzyme.Interaction with theophylline, carbamazepine,warfarin, terfenadine and cisapride is not likely,but cannot be totally ruled out.

MISCELLANEOUS ANTIBIOTICS

Clindamycin

It is a lincosamide antibiotic similar in mechanismof action (inhibits protein synthesis by binding

Macrolide Antibiotics 423


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to 50S ribosome) and spectrum of activity toerythromycin with which it exhibits partial crossresistance. It inhibits most gram-positive cocci(including penicillinase producing Staph., but notMRSA), C. diphtheriae, Nocardia, Actinomyces,Toxoplasma, but the distinctive feature is its highactivity against a variety of anaerobes, especiallyBact. fragilis. Aerobic gram-negative bacilli,spirochetes, Chlamydia, Mycoplasma and Rickettsiaare not affected.

Oral absorption of clindamycin is good. Itpenetrates into most skeletal and soft tissues,but not brain and CSF; accumulates in neutro-phils and macrophages. It is largely metabolizedand metabolites are excreted in urine and bile. Thet½ is 3 hr.

Side effects are rashes, urticaria, abdominalpain, but the major problem is diarrhoea andpseudomembranous enterocolitis due to Clostri-dium difficile superinfection which is potentiallyfatal. The drug should be promptly stopped andmetronidazole (alternatively vancomycin) givento treat it.

Because of the potential toxicity, use of clin-damycin is restricted to anaerobic and mixedinfections, especially by Bact. fragilis causingabdominal, pelvic and lung abscesses. It isgenerally combined with an aminoglycoside orcephalosporin. Anaerobic streptococcal and Cl.perfringens infections and those involving boneand joints respond well. It has also been employedto prevent surgical site infection in colorectal/pelvic surgery. Topically it can be used for infectedacne vulgaris.

In the treatment of dental infections, clinda-mycin is frequently used as a reserve drug forthose caused by anaerobic bacteria in patientswho cannot be given a penicillin or a macrolideor for cases not responding to these antibiotics.Because of good penetration into bone, clinda-mycin is particularly suited for dentoalveolarabscesses and other bone infections caused byStaphylococci or Bacteroides. It is an alternativeantibiotic for prophylaxis of endocarditis due topostextraction bacteraemia in patients with

damaged heart valves or other risk factors.Because only a single dose is needed for thispurpose, there is little risk of pseudomembranousenterocolitis which otherwise is the mostimportant limitation of clindamycin.

Clindamycin, erythromycin and chloramphe-nicol can exhibit mutual antagonism, probablybecause their ribosomal binding sites are proximal;binding of one hinders access of the other to itstarget site. Clindamycin potentiates neuro-muscular blockers.Dose: 150–300 mg QID oral; 200–600 mg i.v. 8 hourly;DALCAP 150 mg cap; CLINCIN 150, 300 mg cap;DALCIN, 150, 300 mg cap, 300 mg/2 ml and 600 mg/4ml inj.

Lincomycin

It is the forerunner of clindamycin; has similar antibacterialand toxic properties, but is less potent and produces ahigher incidence of diarrhoea and colitis—deaths haveoccurred. Thus, it has been largely replaced by clindamycin.Dose: 500 mg TDS-QID oral; 600 mg i.m. or by i.v. infusion6–12 hourly.LINCOCIN 500 mg cap, 600 mg/2 ml inj; LYNX 250, 500mg cap, 125 mg/5 ml syr, 300 mg/ml inj in 1, 2 ml amp.

VancomycinIt is a glycopeptide antibiotic discovered in 1956as a penicillin substitute that has assumed spe-cial significance due to efficacy against MRSA,Strep. viridans, Enterococcus and Cl. difficile. It isbactericidal to gram-positive cocci, Neisseria,Clostridia, oral cavity anaerobes and diphthe-roids. However, in hospitals where it has beenextensively used for surgical prophylaxis, etc.,vancomycin-resistant Staph. aureus (VRSA),Enterococcus faecium and E. faecalis have emerged.These nosocomial bacteria are resistant tomethicillin and most other antibiotics as well.

Vancomycin acts by inhibiting bacterial cellwall synthesis. It binds to the terminal dipeptide‘D-ala-D-ala’ sequence of peptidoglycan units—prevents its release from the bactoprenol lipidcarrier so that assembly of the units at the cellmembrane and their cross linking to form the cellwall cannot take place. Enterococcal resistanceto vancomycin is due to a plasmid mediated

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alteration of the dipeptide target reducing itsaffinity for vancomycin.

Vancomycin is not absorbed orally. After i.v.administration, it is widely distributed, penetratesserous cavities, inflamed meninges and isexcreted mainly unchanged by glomerularfiltration with a t½ of 6 hours. Dose reduction isneeded in renal insufficiency.

Toxicity: Systemic toxicity of vancomycin is high.It can cause plasma concentration dependentnerve deafness which may be permanent. Kidneydamage is also dose related. Other oto andnephrotoxic drugs like aminoglycosides must bevery carefully administered when vancomycin isbeing used. Skin allergy and fall in BP during i.v.injection due to histamine release are the otherproblems. Rapid i.v. injection has caused chills,fever, urticaria and intense flushing—called ‘Redman syndrome’.

Uses: Given orally (125–500 mg 6 hourly), it isthe second choice drug to metronidazole forantibiotic associated pseudomembranous entero-colitis caused by C. difficile.

Systemic use (500 mg 6 hourly or 1 g 12 hourlyinfused i.v. over 1 hr) is restricted to serious MRSAinfections for which it is the most effective drug,and as a penicillin substitute (in allergic patients)for enterococcal endocarditis along with genta-micin. It is also used in dialysis patients and thoseundergoing cancer chemotherapy. Penicillin-resistant pneumococcal infections and infectioncaused by diphtheroids respond very well tovancomycin.VANCOCIN-CP 150 mg tab, 500 mg/vial inj;VANCOGEN, VANCORID-CP 500 mg/vial inj;VANCOLED 0.5, 1.0 g inj.

Use of vancomycin in dental infections ishighly restricted to the few cases that do notrespond to other safer antibiotics and arehypersensitive to penicillin. In penicillin allergicpatients vancomycin 1 g (20 mg/kg) i.v. infusionis an alternative to amoxicillin for combining withgentamicin for prophylaxis of endocarditis inhigh-risk patients undergoing dental surgery.

Teicoplanin It is a recently developed glyco-peptide antibiotic which in fact is a mixture of 6similar compounds. It is active against gram-positive bacteria only; mechanism of action andspectrum of activity is similar to vancomycin.Notable features are:• It is more active than vancomycin against

enterococci, and equally active against MRSA.• Some vancomycin-resistant enterococci (VRE)

but not Staph. aureus (VRSA) are susceptible toteicoplanin.

• It can be injected i.m. as well; is excreted bykidney; dose needs to be reduced in renalinsufficiency; has a very long t½ (3–4 days).

• Toxicity is less than vancomycin; adverseeffects are rashes, fever, granulocytopenia andrarely hearing loss. Reactions due to histaminerelease are very rare (1 in 2500).

Teicoplanin is indicated in enterococcalendocarditis (along with gentamicin); MRSA andpenicillin-resistant streptococcal infections inplace of vancomycin.Dose: 400 mg first day—then 200 mg daily i.v. or i.m.;severe infection 400 mg × 3 doses 12 hourly—then 400 mgdaily.TARGOCID, TECOCIN, TECOPLAN 200, 400 mg pervial inj. for reconstitution.

OXAZOLIDINONE

Linezolid This is the first member of a new classof synthetic AMAs ‘Oxazolidinones,’ which hasbecome available for the treatment of resistantgram-positive coccal (aerobic and anaerobic) andbacillary infections. It is active against MRSAand some VRSA, VRE, penicillin-resistant Strep.pyogenes, Strep. viridans and Strep. pneumoniae,Corynebacterium, Listeria, Clostridia and Bact.fragilis. It is primarily bacteriostatic, but can exertcidal action against some streptococci, pneumo-cocci and B. fragilis. Gram-negative bacteria arenot affected.

Linezolid inhibits bacterial protein synthesisby acting at an early step and a site different fromthat of other AMAs. It binds to the 23S fraction ofthe 50S ribosome and interferes with formation ofthe initiation complex. Binding of linezolid stops

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protein synthesis before it starts. As such, there isno cross resistance with any other class of AMAs.

Linezolid is rapidly and completely absorbedorally, partly metabolized nonenzymatically andexcreted in urine. Plasma t½ is 5 hrs.

Linezolid has been used for skin and softtissue infections, community-and hospital-acquired pneumonias, bacteraemias and otherdrug-resistant gram-positive infections. Given byoral or i.v. routes, it has achieved high cure rates.However, to prevent emergence of resistance tothis valuable drug, use should be restricted toserious hospital-acquired pneumonias, febrileneutropenia, wound infections and others causedby multidrug-resistant gram-positive bacteriasuch as VRE, vancomycin-resistant-MRSA, multi-resistant S. pneumoniae, etc. Being bacteriostatic,it is not suitable for treatment of enterococcalendocarditis. There are no indications in dentistryfor linezolid.Dose: 600 mg BD, oral/ i.v.; LIZOLID 600 mg tab; LINOX600 mg tab, 200 mg/100 ml i.v. infusion.

Side effects to linezolid have been few;mostly mild abdominal pain and bowel upset.Occasionally, rash, pruritus, headache, oral/vaginal candidiasis have been reported. Becauselinezolid is a MAO inhibitor, interactions withadrenergic/serotonergic drugs and excessdietary tyramine are expected. No cytochromeP450 enzyme related interactions seem likely.

Fusidic acidIt is a narrow spectrum steroidal antibiotic, that is activeagainst penicillinase producing Staphylococci and few othergram-positive bacteria. It acts by inhibiting bacterialprotein synthesis and is used only topically for boils,folliculitis, sycosis barbae and other cutaneous infections.FUCIDIN-L, FUCIBACT, FUSIDERM; 2% oint. and cream.

POLYPEPTIDE ANTIBIOTICS

These are low molecular weight cationic polypeptideantibiotics. All are powerful bactericidal agents, but notused systemically due to toxicity. All are produced bybacteria. Clinically used ones are:

Polymyxin B BacitracinColistin Tyrothricin

Polymyxin B and Colistin Polymyxin and colistin wereobtained in the late 1940s from Bacillus polymyxa and

B. colistinus respectively. They are active against gram-negative bacteria only; all except Proteus, Serratia andNeisseria are inhibited. Both have very similar range ofactivity, but colistin is more potent on Pseudomonas,Salmonella and Shigella.

Mechanism of action They are rapidly acting bactericidalagents; have a detergent-like action on the cell membrane.They have high affinity for phospholipids: the peptidemolecules (or their aggregates) of the antibiotic orientbetween the phospholipid and protein films in gram-negative bacterial cell membrane causing membranedistortion or pseudopore formation. As a result, ions,amino acids, etc. leak out. Sensitive bacteria take up moreof the antibiotic.

They exhibit synergism with many other AMAs byimproving their penetration into the bacterial cell.

Resistance Resistance to these antibiotics has never beena problem. There is no cross resistance with any otherAMA.

Adverse effects Little or no absorption occurs from oralroute or even from denuded skin (burn, ulcers). Appliedtopically, they are safe—no systemic effect or sensitizationoccurs. A rash is rare.• Given orally, side effects are limited to the g.i.t.—

occasional nausea, vomiting, diarrhoea.• Systemic toxicity of these drugs (when injected) is high:

flushing and paresthesias (due to liberation of histaminefrom mast cells), marked kidney damage, neurologicaldisturbances, neuromuscular blockade.

Preparation and dose

Polymyxin B: (1 mg = 10,000 U)NEOSPORIN POWDER: 5,000 U with neomycin sulf.3,400 U and bacitracin 400 U per g.NEOSPORIN EYE DROPS: 5,000 U with neomycin sulf.1,700 U and gramicidin 0.25 mg per ml.NEOSPORIN-H EAR DROPS: 10,000 U with neomycinsulf. 3,400 U and hydrocortisone 10 mg per ml.

Colistin sulfate: 25–100 mg TDS oral; WALAMYCIN 12.5mg (25,000 i.u.) per 5 ml dry syr, COLISTOP 12.5 mg/5ml and 25 mg/5 ml dry syr.

Uses

(a) Topically Usually in combination with otherantimicrobials for skin infections, burns, otitis externa,conjunctivitis, corneal ulcer—caused by gram-negativebacteria including Pseudomonas.

(b) Orally Gram-negative bacillary (E. coli, Salmonella,Shigella) diarrhoeas, especially in infants and children;Pseudomonas superinfection enteritis.

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Bacitracin It is one of the earliest discovered antibioticsfrom a strain of Bacillus subtilis. In contrast to polymyxin,it is active mainly against gram-positive organisms (bothcocci and bacilli). Neisseria, H. influenzae and few othergram-negative bacteria are also affected.

It acts by inhibiting cell wall synthesis at a step earlierthan that inhibited by penicillin. Subsequently, it increasesthe efflux of ions by binding to cell membrane. It isbactericidal.

Bacitracin is not absorbed orally. It is not usedparenterally because of high toxicity, especially to thekidney. Use is restricted to topical application for infectedwounds, ulcers, eye infections—generally in combinationwith neomycin, polymyxin, etc.In NEBASULF 250 U/g powder, skin oint, eye oint; inNEOSPORIN 400 U/g powder. (1 U = 26 μg).It does not penetrate intact skin, therefore, of little value infurunculosis, boils, carbuncles, etc.

Tyrothricin It is a mixture of gramicidin and tyrocidin,obtained from Bacillus bravis. It is active against gram-positive and a few gram-negative bacteria. It acts on cellmembrane causing leakage and uncouples oxidativephosphorylation in the bacteria.

Tyrothricin is not absorbed orally and is too toxic forsystemic use; causes haemolysis. Used only topically; doesnot cause sensitization.TYRODERM: 0.5 mg/g skin cream; PROTHRICIN 0.2mg/ml topical solution.TYOTOCIN: 0.05% otic solution with benzocaine 1.25%,antipyrine 5%, hexylresorcinol 0.1%.

URINARY ANTISEPTICS

Some AMAs, in orally tolerated doses, attain antibacterialconcentration only in the urinary tract. Like many otherdrugs, they are concentrated in the kidney tubules, andare used only for urinary tract infection. They have beencalled urinary antiseptics because this may be consideredas a form of local therapy. Nitrofurantoin andmethenamine are two such agents; infrequently used now.

Nitrofurantoin

It is a primarily bacteriostatic compound, but may becidal at higher concentrations and in acidic urine: its activityis enhanced at lower pH. It inhibits many gram-negativebacteria, but due to development of resistance, activity is

now restricted largely to E. coli. Resistance to nitrofurantoindevelops slowly and no cross resistance with any otherAMA is known. It antagonizes the action of nalidixic acid.Susceptible bacteria appear to enzymatically reducenitrofurantoin to generate reactive intermediates whichdamage DNA.

Pharmacokinetics It is well absorbed orally; rapidlymetabolized in liver and other tissues; less than half isexcreted unchanged in urine; plasma t½ is 30–60 min.Antibacterial concentrations are not attained in blood ortissues.

Adverse effects Commonest is gastrointestinalintolerance—nausea, epigastric pain and diarrhoea.An acute reaction with chills, fever and leucopenia occursoccasionally.

Peripheral neuritis, haemolytic anaemia and apulmonary reaction with fibrosis on chronic use areinfrequent events.

Use The only indication for nitrofurantoin is urinary tractinfection, but it is infrequently used now. It can be employedfor prophylaxis of urinary tract infection aftercatheterization.FURADANTIN 50, 100 mg tab, URINIF 100 mg tab.

Methenamine (Hexamine)

It is hexamethylene-tetramine; inactive as such;decomposes slowly in acidic urine to release formaldehydewhich inhibits all bacteria. This drug exerts no antimicrobialactivity in blood and tissues, including kidney parenchyma.Acidic urine is essential for its action; urinary pH must bekept below 5.5 by administering some organic acid whichis excreted as such, e.g. mandelic acid or ascorbic acid.

Methenamine is administered in enteric coated tabletsto protect it from decomposing in gastric juice.

MANDELAMINE 0.5 g, 1 g tab: 1 g TDS or QID withfluid restriction to ensure adequate concentration offormaldehyde in urine.

Its use is restricted to chronic, resistant type of urinarytract infections, not involving kidney substance.

Adverse effects Gastritis can occur due to release offormaldehyde in stomach.Chemical cystitis and haematuria may develop with highdoses given for long periods.

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ANTITUBERCULAR DRUGS

Tuberculosis is a chronic granulomatous diseaseand a major health problem in developingcountries. About 1/3rd of the world’s populationis infected with Mycobact. tuberculosis. As perWHO estimate, 9 million people globally developactive TB and 1.7 million die of it annually. InIndia, it is estimated that nearly 2 million peopledevelop active disease every year and about 0.5million die from it.

A new dimension got added in the 1980s dueto spread of HIV with high prevalence oftuberculosis and Mycobact. avium complex(MAC) infection among these patients.Emergence of ‘multidrug resistant’ (MDR) TB ofwhich over 0.4 million cases are occurringglobally every year, is threatening the wholefuture of current antitubercular chemotherapy.

Remarkable progress has been made in thelast 60 years since the introduction of Streptomy-cin in 1947 for the treatment of tuberculosis.Besides adding a number of effective drugs,strategies in the management of TB have beenimproved based on the understanding of biologyof this infection, and clear-cut treatmentguidelines have been formulated. While dentistsare not called upon to treat tuberculosis, theyshould be familiar with important features ofantitubercular drugs and the current therapeutic

regimens. According to their clinical utility, theanti-TB drugs can be divided into:

First line: These drugs have high antitubercularefficacy as well as low toxicity; are usedroutinely.

Second line: These drugs have either lowantitubercular efficacy or high toxicity or both;are used in special circumstances only.

First line drugs

1. Isoniazid (H) 4. Ethambutol (E)2. Rifampin (R) 5. Streptomycin (S)3. Pyrazinamide (Z)

Second line drugs

1. Thiacetazone (Tzn) Newer drugs2. Para-aminosalicylic 1. Ciprofloxacin

acid (PAS) 2. Ofloxacin3. Ethionamide (Etm) 3. Clarithromycin4. Cycloserine (Cys) 4. Azithromycin5. Kanamycin (Kmc) 5. Rifabutin6. Amikacin (Am)7. Capreomycin (Cpr)

Isoniazid (Isonicotinic acid hydrazide, H)

Isonicotinic acid hydrazide (INH, isoniazid) isthe antitubercular drug parexcellence, and an

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Adverse effects INH is well tolerated by mostpatients. Peripheral neuritis and a variety ofneurological manifestations (paresthesias, num-bness, mental disturbances, rarely convulsions)are the most important dose-dependent toxiceffects. These are due to interference with utiliza-tion of pyridoxine and its increased excretion inurine. Pyridoxine given prophylactically (10 mg/day) prevents neurotoxicity. INH neurotoxicityis treated by pyridoxine 100 mg/day.

Hepatitis, a major adverse effect of INH, isdue to dose-related damage to liver cells and isreversible on stopping the drug. Other side effectsare rashes, fever, acne and arthralgia.ISONEX 100, 300 mg tabs, ISOKIN 100 mg tab, 100 mgper 5 ml liq.

Rifampin (Rifampicin, R)

It is a semisynthetic derivative of rifamycin Bobtained from Streptomyces mediterranei. Rifampinis bactericidal to M. tuberculosis and manyother gram-positive and gram-negative bacterialike Staph. aureus, N. meningitidis, H. influenzae,E. coli, Klebsiella, Pseudomonas, Proteus andLegionella. Against TB bacilli, it is as efficaciousas INH and better than all other drugs. It actsbest on slowly or intermittently (spurters)dividing M. tub. as well as on many atypicalmycobacteria. Both extra- and intracellularorganisms are affected. It has good sterilizingand resistance preventing actions.

Rifampin inhibits DNA-dependent RNAsynthesis. The probable basis of selective toxicityis that mammalian RNA polymerase does notavidly bind rifampin.

Mycobacteria and other organisms developresistance to rifampin rather rapidly. Rifampinresistance is nearly always due to mutation in therepoB gene (the target of rifampin action) reducingits affinity for the drug. No cross resistance withany other antitubercular drug has been noted.

Pharmacokinetics It is well absorbed orally,widely distributed in the body: penetratescavities, caseous masses, placenta and meninges.It is metabolized in liver to an active deacetylated

Antitubercular Drugs 429

essential component of all antitubercular regi-mens, unless the patient is not able to tolerate itor bacilli are resistant. It is primarily tuberculo-cidal. Fast multiplying organisms are rapidlykilled, but quiescent ones are only inhibited. Itacts on extracellular as well as on intracellularTB (bacilli present within macrophages); isequally active in acidic and alkaline medium. Itis one of the cheapest antitubercular drugs.However, most atypical mycobacteria are notinhibited by INH.

The most plausible mechanism of action ofINH is inhibition of synthesis of mycolic acidswhich are unique fatty acid component ofmycobacterial cell wall. This may explain thehigh selectivity of INH for mycobacteria (it is notactive against any other microorganism). A genelabelled inh A which encodes for a fatty acidsynthase enzyme is the likely target of INHaction. The sensitive mycobacteria concentrateINH and convert it by a catalase-peroxidaseenzyme into an active metabolite that appears tointeract with the inh A gene.

About 1 in 106 tubercle bacilli is inherentlyresistant to clinically attained INH concentra-tions. If INH is given alone, such bacilliproliferate selectively and after 2–3 months(sometimes even earlier) an apparently resistantinfection emerges. The most common mechanismof INH resistance is by mutation of the catalase-peroxidase gene so that the bacilli do notgenerate the active metabolite of INH. Resistancemay also involve mutation in the target inh Agene. Other resistant TB bacilli lose the activeINH concentrating process.

Pharmacokinetics INH is completely absorbedorally and penetrates all body tissues, tubercularcavities, placenta and meninges. It is extensivelymetabolized in liver; most important pathwaybeing acetylation—metabolites are excreted inurine. The rate of INH acetylation shows geneticvariation: there are slow and fast acetylators.

INH induced peripheral neuritis appears tobe more common in slow acetylators.

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metabolite which is excreted mainly in bile; somein urine also. The t½ of rifampin is variable(2–5 hours).

Interactions Rifampin is a microsomal enzymeinducer increasing CYP3A4,CYP2D6, CYP1A2,etc; enhances its own metabolism as well as thatof many drugs including warfarin, oral contra-ceptives, corticosteroids, sulfonylureas, steroids,HIV protease inhibitors, ketoconazole, etc.Contraceptive failures have occurred.

Adverse effects The incidence of adverse effectsis similar to INH.

Hepatitis, a major adverse effect, generallyoccurs in patients with pre-existing liver diseaseand is dose related. Other serious but rarereactions are:• ‘Respiratory syndrome’: breathlessness which

may be associated with shock and collapse.• Purpura, haemolysis, shock and renal failure.Minor reactions are:• ‘Cutaneous syndrome’: flushing, pruritus +

rash, redness and watering of eyes.• ‘Flu syndrome’: with chills, fever, headache,

malaise and bone pain.• ‘Abdominal syndrome’: nausea, vomiting,

abdominal cramps with or without diarrhoea.Urine and secretions may become orange-red—but this is harmless.

Other uses of rifampin are:

(i) Leprosy.(ii) Prophylaxis of Meningococcal and H.

influenzae meningitis and carrier state.(iii) Second/third choice drug for MRSA,

diphtheroids and Legionella infections.(iv) Combination of doxycycline and rifampin

is the first line therapy of brucellosis.RCIN 150, 300, 450, 600 mg caps, 100 mg/5 ml susp.RIMACTANE, RIMPIN 150, 300, 450 mg caps, 100 mg/5 ml syr.; RIFAMYCIN 450 mg cap, ZUCOX 300,450,600 mg tabs. To be taken 1 hr. before or 2 hr. after food.

Pyrazinamide (Z)

Chemically similar to INH, pyrazinamide (Z) wasdeveloped parallel to it in 1952. It is weakly

tuberculocidal and more active in acidic medium.It is highly lethal to intracellularly located bacillias well as to those at sites showing an inflamma-tory response (pH is acidic at both these locations).It has good sterilizing activity and is highlyeffective during the first 2 months of therapy wheninflammatory changes are present. Its use hasenabled regimens to be shortened and risk ofrelapse to be reduced. Mechanism of antimyco-bacterial action of Z resembles INH. Resistance toZ develops rapidly if it is used alone, and is due tomutation in the gene which encodes for the enzymegenerating the active metabolite of Z.

Pyrazinamide is absorbed orally, widelydistributed, has good penetration in CSF, exten-sively metabolized in liver and excreted in urine;plasma t½ 6–10 hours.

Hepatotoxicity is the most important dose-related adverse effect, but it appears to be lesscommon in the Indian population than inWestern countries.Hyperuricaemia is due to inhibition of uric acidsecretion in kidney: gout can occur.Other adverse effects are arthralgia, flushing,rashes, fever and loss of diabetes control.PYZINA 0.5, 0.75, 1.0 g tabs, 0.3 g kid tab; PZA-CIBA0.5, 0.75 g tabs, 250 mg/5 ml syr; RIZAP 0.75, 1.0 gtabs

Ethambutol (E)

Ethambutol is selectively tuberculostatic andclinically as active as S. Fast multiplying bacilliare more susceptible as are many atypical myco-bacteria. Added to the triple drug regimen ofRHZ, it has been found to hasten the rate ofsputum conversion and to prevent developmentof resistance.

The mechanism of action of E is not fullyunderstood, but it has been found to inhibitarabinogalactan synthesis and to interfere withmycolic acid incorporation in mycobacterial cellwall. Resistance to E develops slowly; in manycases it is due to alteration in the target gene. Nocross resistance with any other antituberculardrug has been noted.

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About 3/4th of an oral dose of E is absorbed.It is distributed widely but penetrates meningesincompletely and is temporarily stored in RBCs.Less than ½ of E is metabolized. It is excreted inurine by glomerular filtration and tubularsecretion; plasma t½ is ~4 hrs.

Patient acceptability of E is very good andside effects are few. Loss of visual acuity/colourvision, field defects due to optic neuritis is themost important dose and duration of therapydependent toxicity. Ethambutol produces fewother symptoms: nausea, rashes, fever, neuro-logical changes are infrequent.MYCOBUTOL, MYAMBUTOL, COMBUTOL 0.2, 0.4,0.6, 0.8, 1.0 g tabs.

Streptomycin (S)

The pharmacology of streptomycin is describedin Ch. 29. It was the first clinically usefulantitubercular drug. It is tuberculocidal, but lesseffective than INH or rifampin; acts only onextracellular bacilli (because of poor penetrationinto cells). It penetrates tubercular cavities, butdoes not cross to the CSF, and has poor actionin acidic medium.

Resistance develops rapidly to streptomycin.In case of S resistant infection, it must be stoppedat the earliest due to the risk of producing Sdependent bacilli. Most atypical mycobacteriaare unaffected by S.

Popularity of S in the treatment of tubercu-losis has declined due to need for i.m. injectionsand lower margin of safety because ofototoxicity.

Thiacetazone (Tzn, Amithiozone)

Thiacetazone is a tuberculostatic, low efficacy drug; doesnot add to the therapeutic effect of H, S or E, but delaysresistance to these drugs. It is orally active, and primarilyexcreted unchanged in urine with a t½ of 12 hr. The majoradverse effects of Tzn are hepatitis, exfoliative dermatitis,Stevens-Johnson syndrome and rarely bone marrowdepression. The common side effects are anorexia,abdominal discomfort, loose motions and minor rashes.A mild anaemia persists till Tzn is given. Tzn is a reserveantitubercular drug, sometimes added to INH inalternative regimens.

Dose: 150 mg OD in adults, 2.5 mg/kg in children, ascombined tablet with isoniazid.

Para-amino salicylic acid (PAS)

It is related to sulfonamides—chemically as well as inmechanism of action, but is not active against otherbacteria: selectivity may be due to difference in the affinityof folate synthase of TB and other bacteria for PAS.

PAS is tuberculostatic and one of the least activedrugs: does not add to the efficacy of more active drugsthat are given with it; only delays development ofresistance. Resistance to PAS is slow to develop.

It is absorbed completely by the oral route anddistributed all over except in CSF. About 50% PAS isacetylated; competes with acetylation of INH—prolongsits t½. It is excreted rapidly by glomerular filtration andtubular secretion; t½ is short, ~1 hour.

Patient acceptability of PAS is poor because offrequent anorexia, nausea and epigastric pain.

Ethionamide (Etm)

It is a tuberculostatic drug of moderate efficacy that actson both extra- and intracellular organisms. Atypicalmycobacteria are sensitive. Resistance to Etm developsrapidly. It is absorbed orally, distributes all over includingCSF, completely metabolized and has a short duration ofaction (t½ 2–3 hr).

Anorexia, nausea, vomiting and abdominal upset arecommon. Other side effects are aches and pains, rashes,hepatitis, peripheral or optic neuritis, mental disturbancesand impotence.

Cycloserine (Cys)

It is an antibiotic obtained from S. orchidaceus, and is achemical analogue of D-alanine: inhibits bacterial cell wallsynthesis by inactivating the enzymes which recemize L-alanine and link two D-alanine residues. Cys istuberculostatic and inhibits some other gram-positivebacteria, E. coli, Chlamydia also.

It is absorbed orally, diffuses all over, CSFconcentration is equal to that in plasma. About 1/3 of adose is metabolized, rest is excreted unchanged by kidney.The CNS toxicity of Cys is high—sleepiness, headache,tremor and psychosis. It is rarely used.

Kanamycin, Amikacin and Capreomycin are moretoxic antibiotics used as reserve drugs in rare casesnot responding to the usual therapy, or infection byatypical mycobacteria. All exhibit similar ototoxicity andnephrotoxicity.

NEWER DRUGS

Ciprofloxacin, Ofloxacin (see Ch. 27 for des-cription) The fluoroquinolones are a useful new

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addition to the antitubercular drugs. Ciproflo-xacin, ofloxacin, moxifloxacin and sparfloxacinare active against M. tuberculosis as well asM. avium complex (MAC) and M. fortuitum. Theypenetrate cells and kill mycobacteria lodged inmacrophages also. Because of their goodtolerability, ciprofloxacin and ofloxacin are beingincreasingly included in combination regimensagainst MDR tuberculosis and MAC infection inHIV patients. They are also being used tosupplement ethambutol + streptomycin in caseswhen H, R, Z have been stopped due to hepato-toxicity. However, neither ciprofloxacin norofloxacin have enhanced the sterilizing abilityof long-term regimens containing H and R.

Clarithromycin, Azithromycin (See Ch. 30)These newer macrolide antibiotics are activeagainst most nontubercular mycobacteriaincluding MAC, M. fortuitum, M. Kansasii and M.marinum. Clarithromycin has been used to agreater extent because its MIC values are lower,but azithromycin may be equally efficacious dueto its higher tissue and intracellular levels. InAIDS patients, life-long therapy is required—maycause ototoxicity.

Rifabutin It is related to rifampin in structure andmechanism of action; but less active against M.tuberculosis and more active against MAC. Only partialcross resistance occurs between the two. Rifabutin is usedfor prophylaxis of MAC infection in AIDS patients. Forthe treatment of established MAC infection, it has beenadded to ethambutol + clarithromycin/azithromycin.

TREATMENT OF TUBERCULOSIS

The therapy of tuberculosis has undergoneremarkable change. The conventional 12–18-month treatment has been replaced by moreeffective and less toxic 6-month treatment whichalso yields higher completion rates.The goals of antitubercular chemotherapy are:(a) Kill dividing bacilli Drugs with early bacteri-cidal action rapidly reduce bacillary load in thepatient and achieve quick sputum negativity sothat the patient is non-contagious to the

community: transmission of TB is interrupted.This also affords quick symptom relief.

(b) Kill persisting bacilli To effect cure and pre-vent relapse. This depends on sterilizingcapacity of the drug.

(c) Prevent emergence of resistance So that thebacilli remain susceptible to the drugs.

The relative activity of the first line drugs inachieving these goals differs, e.g. H and R arethe most potent bactericidal drugs active againstall populations of TB bacilli, while Z acts beston intracellular bacilli and those at inflamedsites—has very good sterilizing activity. On theother hand, S is active only against rapidlymultiplying extracellular bacilli. E is bacterio-static—mainly serves to prevent resistance andmay hasten sputum conversion. The generalprinciples of antitubercular chemotherapy are:• Use of any single drug in tuberculosis results

in the emergence of resistant organisms andrelapse in almost 3/4th patients. A combi-nation of two or more drugs must be used.

• Isoniazid and R are the most efficaciousdrugs; their combination is definitelysynergistic—duration of therapy is shortenedfrom > 12 months to 9-months. Addition of Zfor the initial 2 months further reducesduration of treatment to 6 months.

• A single daily dose of all first line anti-tubercular drugs is preferred. The ‘directlyobserved treatment short course’ (DOTS) wasrecommended by the WHO in 1995.

• The response is fast in the first few weeks asthe fast dividing bacilli are eliminatedrapidly. Symptomatic relief is evident within2–4 weeks. The rate of bacteriological, radio-logical and clinical improvement declinessubsequently. Bacteriological cure takes muchlonger.

SHORT COURSE CHEMOTHERAPY (SCC)

These are regimens of 6–9 month duration whichhave been found to be highly efficacious. Afterseveral years of experience a WHO expert group

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has framed clear-cut treatment guidelines* (1997)for different categories of TB patients. The doseof first line anti-TB drugs has been standardizedon body weight basis and is applicable to bothadults and children (Table 31.1).

All regimens have an initial intensive phaselasting for 2–3 months aimed to rapidly kill theTB bacilli, bring about sputum conversion andafford symptomatic relief. This is followed by acontinuation phase lasting for 4–6 months duringwhich the remaining bacilli are eliminated sothat relapse does not occur. Treatment of TB iscategorized into 4 categories by site and severityof disease, sputum smear positivity/negativityand history of previous treatment. The category-wise treatment regimens are summarized inTable 31.2.

Category I This category includes:• New (untreated) smear positive pulmonary

TB.• New smear negative pulmonary TB with

extensive parenchymal involvement.• New cases of severe forms of extrapulmonary

TB, viz. meningitis, miliary, pericarditis,peritonitis, bilateral or extensive pleuraleffusion, spinal, intestinal, genitourinary TB.

Initial phase Four drugs HRZ + E or S are givendaily or thrice weekly for 2 months. The RevisedNational Tuberculosis Control Programme

(RNTCP) has been launched in India in 1997,which is implementing DOTS. Out of the WHOrecommended regimens, the RNTCP has decidedto follow thrice weekly regimen, since it isequally effective, saves drugs and effort, and ismore practical.

Continuation phase Two drugs HR for 4 monthsor HE for 6 months are given. When both H and Rare used, thrice weekly regimen is permissible.Under the RNTCP, thrice weekly treatment with Hand R is given for 4 months. This phase is extendedto 6–7 months (total duration 8–9 months) for TBmeningitis, miliary and spinal disease.

Table 31.1: Recommended doses of antitubercular drugs@

Daily dose 3 � per week dose

Drug mg/kg For > 50 kg mg/kg For > 50 kg

Isoniazid (H) 5 (4–6) 300 mg 10 (8–12) 600 mg

Rifampin (R) 10 (8–12) 600 mg 10 (8–12) 600 mg

Pyrazinamide (Z) 25 (20–30) 1500 mg 35 (30–40) 2000 mg

Ethambutol (E) 15 (15–20) 1000 mg 30 (25–35) 1600 mg

Streptomycin (S) 15 (12–18) 1000 mg£ 15 (12–18) 1000 mg

@ The WHO guidelines also describe a twice weekly dosage schedule, but do not recommend it.£ Dose to be reduced to 750 mg above 50 yr age and to 500 mg above 65 yr age; also in patientswith renal impairment.

Table 31.2: Category-wise alternative treatmentregimens for tuberculosis (WHO 1997)

TB Initial phase Continuation Totalcategory (daily/ 3�per week) phase duration

I 2 HRZE (S) 4 HR/4 H3R3 6or 6 HE 8

II 2 HRZES + 5 HRE or 81 HRZE 5 H3R3E3 8

III 2 HRZ 4 HR/4 H3R3 6or 6 HE 8

IV Chronic case: See text

Explanation of standard code• Each anti-TB drug has a standard abbreviation (H, R, Z,

E, S).• The numeral before a phase is the duration of that phase

in months.• The numeral in subscript (e.g. H3 R3) is number of doses

of that drug per week. If there is no subscript numeral,then the drug is given daily.

Chemotherapy of Tuberculosis 433

* Treatment of tuberculosis: Guidelines for NationalProgrammes, Second Edition (1997), WHO, Geneva.


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Category II These are smear positive failure,relapse and interrupted treatment cases. Thesepatients may have resistant bacilli and are atgreater risk of developing MDR-TB.

Initial phase All 5 first line drugs are given for2 months followed by 4 drugs (HRZE) foranother month. Continuation phase is started ifsputum is negative, but 4 drug treatment iscontinued for another month if sputum ispositive at 3 months.

Continuation phase Three drugs (HRE) aregiven for 5 months either daily or thrice weekly(only thrice weekly under the RNTCP).

Category III These are new cases of smear nega-tive pulmonary TB with limited parenchymalinvolvement or less severe forms of extrapulmo-nary TB, viz, lymph node TB, unilateral pleuraleffusion, bone (excluding spine), peripheral jointor skin TB.

Initial phase Three drugs (HRE) given for 2months are enough because the bacillary load issmaller.

Continuation phase This is similar to categoryI, i.e. 4 months daily/thrice weekly HR or 6months daily HE therapy. Under the RNTCP,only thrice weekly HR regimen is followed.

Category IV These are chronic cases who haveremained or have become smear positive aftercompleting fully supervised retreatment (Cate-gory II) regimen. These are most likely MDRcases.

Multidrug resistant (MDR) TB is defined asresistance to both H and R and may be anynumber of other anti-TB drugs. MDR-TB has amore rapid course (some die in 4–16 weeks).Treatment of these cases is difficult because thesecond line drugs are less efficacious, less conve-nient, more toxic and more expensive.

Choice of therapy depends on drugs used inthe earlier regimen, dosage and regularity withwhich they were taken, presence of associateddisease like AIDS/diabetes/leukaemia/silicosis,

and whether sensitivity of the pathogen tovarious drugs is known (by in vitro testing) orunknown.

The actual regimen is devised according tothe features of the individual patient.

Extensively drug resistant (XDR) TB Recently,the WHO and CDC (USA) have identified TB casesthat are ‘extensively drug resistant’. This term hasbeen applied to bacilli that are resistant to at least4 most effective cidal drugs, i.e. cases resistant toH, R, a FQ, one of Kmc/Am/Cpr with or withoutany number of other drugs. The XDR-TB isvirtually untreatable; mortality is high,particularly among HIV positive patients.

Tuberculosis in pregnant / breastfeedingwomen The WHO considers HRZ to be safe tothe foetus and recommends that standard 6-month regimen 2 HRZ + 4 HR should be given.E can be added during late but not earlypregnancy. In india it is advised to treat pregnantTB patients with 2HRE+7HR (total 9 months).Treatment of TB should not be withheld ordelayed because of pregnancy. All anti-TB drugsare compatible with breastfeeding.

Chemoprophylaxis This is indicated in:(a) Contacts of open cases who show recentMantoux conversion.(b) Children with positive Mantoux and a TBpatient in the family.(c) Neonate of tubercular mother.(d) Patients of leukaemia, diabetes, silicosis, orthose who are HIV positive and show a positiveMantoux.

The standard drug for chemoprophylaxis ofTB is H 300 mg (10 mg/kg in children) dailyfor 6–12 months. Now because of high incidenceof H resistance, a combination of H (5 mg/kg)and R (10 mg/kg) given daily for 6 months ispreferred.

Tuberculosis in AIDS patients The associa-tion of HIV and TB infection is a serious problem.HIV positive cases have more severe and moreinfectious TB. HIV infection is the strongest riskfactor for making latent TB overt.

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ANTILEPROTIC DRUGS

Leprosy, caused by Mycobacterium leprae, has beenconsidered incurable since ages and bears a socialstigma. However, due to development of effectiveantileprotic drugs, it is entirely curable now, butdeformities/defects already incurred may notreverse. Though certain forms of leprosy produceoral/dental lesions, chemotherapy of leprosy isnot managed by dentists. Only a brief account ofthe antileprotic drugs is therefore relevant. Theantileprotic drugs are:1. Sulfone Dapsone (DDS)2. Phenazine derivative Clofazimine3. Antitubercular drugs Rifampin

Ethionamide4. Other antibiotics Ofloxacin

MinocyclineClarithromycin

Dapsone (DDS)

It is diamino diphenyl sulfone (DDS), the simplest,oldest, cheapest, most active and most commonlyused member of its class.

Dapsone is chemically related to sulfonamidesand has the same mechanism of action, i.e.inhibition of PABA incorporation into folic acid;its antibacterial action is antagonized by PABA.It is leprostatic at very low concentrations.Specificity for M.leprae may be due to differencein the affinity of its folate synthase.

Dapsone resistance among M. leprae was firstnoted in 1964. It has increased and has necessi-tated use of multidrug therapy (MDT). However,the peak serum concentration of dapsone after100 mg/day dose exceeds MIC for M. leprae bynearly 500 times; it continues to be active againstlow to moderately resistant bacilli.

Dapsone is completely absorbed after oraladministration and is widely distributed in thebody. It is concentrated in skin (especiallylepromatous skin), muscle, liver and kidney.

Dapsone is acetylated as well as glucuronideand sulfate conjugated in liver. The plasma t½ ofdapsone is variable, though often > 24 hrs. Thedrug is cumulative due to retention in tissues andenterohepatic circulation. Elimination takes 1–2weeks or longer.

Dapsone is generally well tolerated at doses100 mg/day or less.Mild haemolytic anaemia is common. It is a dose-related toxicity—reflects oxidising property of thedrug. Patients with G-6-PD deficiency are moresusceptible.Gastric intolerance—nausea and anorexia arefrequent.Other side effects are methaemoglobinaemia,headache, paresthesias, mental symptoms anddrug fever.Cutaneous reactions include allergic rashes,hypermelanosis, phototoxicity.Lepra reaction.

Other use In combination with pyrimethaminedapsone can be used for chloroquine-resistantmalaria.

Clofazimine (Clo)

It is a dye with leprostatic and antiinflammatoryproperties; acts probably by interfering withtemplate function of DNA. When used alone,resistance to clofazimine develops in 1–3 years.

Clofazimine is orally active. It accumulates inmany tissues, especially in fat and in crystallineform. The t½ is 70 days so that intermittent therapyis possible.

In case of M. tuberculosis infection, drugs usedare the same as in non-HIV cases. Short coursechemotherapy must be immediately started ondiagnosis of TB. The initial 2 HRZE phase isfollowed by a continuation phase of HR for 7months (total 9 months). Alternatively, 3 drugsHRE are used for 4 months in the continuationphase.Mycobacterium avium complex (MAC): infectionis particularly common in HIV patients. Themost effective regimen is clarithromycin +ethambutol + rifabutin ± one FQ. Azithromycinmay be substituted in place of clarithromycin.

Antileprotic Drugs 435


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It has been used as a component of multidrugtherapy of leprosy. Because of its antiinflammatoryproperty, it is valuable in lepra reaction.

In the doses employed for multidrug therapy(MDT) clofazimine is well tolerated. The majordisadvantage is reddish-black discolouration ofskin, especially on exposed parts. Discolourationof hair and body secretions may also occur.Dryness of skin and itching is often troublesome.Conjunctival pigmentation may create cosmeticproblem.

Enteritis with intermittent loose stools,nausea, abdominal pain, anorexia and weightloss can occur.

Rifampin (R)

It is an important antitubercular drug; alsobactericidal to M. leprae; rapidly renders leprosypatients noncontagious. Up to 99.99% M. lepraeare killed in 3–7 days. However, it is notsatisfactory if used alone—some bacilli persisteven after prolonged treatment—resistancedevelops. It has been included in the multidrugtherapy of leprosy and shortens duration oftreatment. The 600 mg monthly dose used inleprosy is relatively nontoxic and does not inducemetabolism of other drugs. It should not be givento patients with hepatic or renal dysfunction.

Ethionamide This antitubercular drug has significantantileprotic activity, but causes hepatotoxicity in ~ 10%patients. It has been used as an alternative to clofazimine.

Ofloxacin Used as a component of MDT,ofloxacin has been found to hasten thebacteriological and clinical response in leprosy.However, it is not included in the standardtreatment protocols, but can be used in alternativeregimens in case rifampin cannot be used, or toshorten the duration of treatment.

Minocycline Because of high lipophilicity, thistetracycline is active against M. leprae. A dose of100 mg/day produces peak blood levels thatexceed MIC against M. leprae by 10–20 times. It isbeing tried in alternative MDT regimens.

Clarithromycin It is the only macrolide anti-biotic with significant activity against M. leprae.However, it is less bactericidal than rifampin. Itis being included in alternative MDT regimens.

TREATMENT OF LEPROSY

Leprosy is a chronic granulomatous infectioncaused by Mycobacterium leprae; primarily affec-ting skin, mucous membranes and nerves. TheNational Leprosy Control Programme waslaunched in India in 1955, and has been changedto National Leprosy Eradication Programme(NLEP) in 1982. India achieved elimination ofleprosy as a public health problem (prevalencerate < 1 case per 10,000 population) in Dec. 2005,but some states still have > 1 case per 10,000.

Two polar types—lepromatous (LL) andtuberculoid (TT) with 4 intermediate forms—borderline (BB), borderline lepromatous (BL),borderline tuberculoid (BT) and indeterminate (I)of the disease are recognized.

For operational purposes, leprosy has beendivided into:

Paucibacillary leprosy (PBL) (Non-infectious):This includes TT, BT, I and polyneuritic.

Multibacillary leprosy (MBL) (Infectious): Thisincludes LL, BL and BB.

Multidrug therapy (MDT) of leprosy

Multidrug therapy with rifampin, dapsone andclofazimine was introduced by the WHO in 1981.This was implemented under the NLEP. The MDTis the regimen of choice for all cases of leprosy. Itsadvantages are:• Effective even in cases with primary dapsone

resistance.• Prevents emergence of dapsone resistance.• Affords quick symptom relief and renders MBL

cases noncontagious.• Reduces total duration of therapy.

Initially under standard MDT, the PBL caseswere treated with dapsone + rifampin for 6months, while the MBL cases were treated with

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dapsone + rifampin + clofazimine for 2 years, ortill disease inactivity was achieved.

Encouraged by the very low relapse ratesobtained with 2-year MDT for MBL cases, theWHO has recommended shortening the durationto 1 year for the mass programme, and this hasbeen implimented in India under NLEP.

Multidrug therapy of leprosy

Multibacillary Paucibacillaryleprosy leprosy

Rifampin 600 mg once a 600 mg once a monthmonth supervised supervised

Dapsone 100 mg daily self- 100 mg daily self-administered administered

Clofazimine 300 mg once a —month supervised +50 mg daily self- —administered

Duration 12 months 6 months

On the other hand, some patients do notachieve disease inactivity after 1 year or even after2-year MDT. Independent leprologists, therefore,prefer to keep the duration of therapy flexible tilldisease inactivity/skin smear negativity isachieved both in MBL and in PBL.

It may be concluded that, where feasible,treatment till cure of individual patient should beensured both in MBL and in PBL.

Alternative regimens Many alternative regimens incor-porating newer antileprotic drugs have been investigated.However, these are used only in case of rifampin resistanceor when it is impossible/inadvisable to employ thestandard MDT regimen. Some of these are:

• Cloflazimine 50 mg + any two of ofloxacin 400 mg/minocycline 100 mg/clarithromycin 500 mg daily for6 month followed by clofazimine 50 mg + any one ofofloxacin 400 mg/minocycline 100 mg daily foradditional 18 months.

• In case of refusal to accept clofazimine: ofloxacin 400mg or minocycline 100 mg daily can be substituted forit in the standard MDT.

• A multicentric trial has shown that PBL cases havingfew bacteria in the body and only one skin lesion can betreated with a single dose of rifampin 600 mg +ofloxacin 400 mg + minocycline 100 mg (ROM regimen).This regimen has been recommended by the WHO forpatients with solitary lesion PBL.

• Four drug regimen of rifampin 600 mg + sparfloxacin200 mg + clarithromycin 500 mg + minocycline 100mg daily for 12 weeks.

Reactions in leprosy

Lepra reaction These occur in LL, usually with institutionof chemotherapy and/or intercurrent infection. It is a JarishHerxheimer (Arthus) type of reaction due to release ofantigens from the killed bacilli. It may be mild, severe orlife- threatening (erythema nodosum leprosum).

Lepra reaction is of abrupt onset; existing lesionsenlarge, become red, swollen and painful; several newlesions may appear. Malaise, fever and other constitutionalsymptoms may be present and marked.

Clofazimine (200 mg daily) is highly effective incontrolling the reaction (except the most severe one) pro-bably because of its antiinflammatory property.

Other drugs used are—analgesics, antipyretics,antibiotics, etc. according to need. Corticosteroids shouldbe used only in severe cases.

Reversal reaction This is seen in TT—is a manifestationof delayed hypersensitivity to M. leprae antigens. Cutaneousulceration, multiple nerve involvement with pain andtenderness occur suddenly even after completion oftherapy. It is treated with clofazimine or corticosteroids.

Chemotherapy of Leprosy 437

ANTIFUNGAL DRUGS

These are drugs used for superficial and deep(systemic) fungal infections.

A disquietening trend after 1950s has beenthe emergence of more sinister type of fungalinfections which are, to a large extent, iatrogenic.These are associated with the introduction anduse of anticancer/immunosuppressant drugs,corticosteroids, broad-spectrum antibiotics,dentures, indwelling catheters and implants andemergence of AIDS. As a result of breakdown ofhost defence mechanisms by the above agents,saprophytic fungi easily invade living tissue.Candida albicans is normally resident in the oralcavity. It invades to cause infection when hostdefence is impaired or the oral flora is disturbed.

Many topical antifungals have been availablesince the antiseptic era. Two important antibio-tics, viz, amphotericin B and griseofulvin as wellas a number of imidazoles and triazoles have beendeveloped for topical and/or systemic use since1960s. Some novel antifungals, e.g. terbinafinehave been added lately.

CLASSIFICATION

1. AntibioticsA. Polyenes: Amphotericin B (AMB), Nystatin,

Hamycin, Natamycin (Pimaricin)B. Heterocyclic benzofuran: Griseofulvin

2. Antimetabolite Flucytosine (5-FC)3. Azoles

A. Imidazoles (topical): Clotrimazole,Econazole, Miconazole

(systemic) : KetoconazoleB. Triazoles (systemic): Fluconazole,

Itraconazole, Voriconazole4. Allylamine Terbinafine5. Other topical agentsTolnaftate, Undecylenic acid, Benzoic acid,Quiniodochlor, Ciclopirox olamine, Butenafine,Sod. thiosulfate.

POLYENE ANTIBIOTICS

The name polyene is derived from their highlydouble-bonded structure.

Amphotericin B (AMB)

It is obtained from Streptomyces nodosus.

The polyenes possess a macrocyclic ring, one sideof which has several conjugated double bondsand is highly lipophilic, while the other side ishydrophilic with many OH groups. They are allinsoluble in water and unstable in aqueousmedium.

The polyenes have high affinity for ergosterolpresent in fungal cell membrane: combine with it,get inserted into the membrane and severalmolecules together orient themselves in such a

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way as to form a ‘micropore’ through which ions,amino acids and other water-soluble substancesmove out. Thus, cell permeability is markedlyincreased.

Cholesterol, present in host cell membranes,closely resembles ergosterol; the polyenes bind toit as well, though with lesser affinity. Thus, theselectivity of action of polyenes is low, and AMBis one of the most toxic systemically usedantibiotics. Bacteria do not have sterols and areunaffected by polyenes.

AMB is active against a wide range of yeastsand fungi—Candida albicans, Histoplasmacapsulatum, Cryptococcus neoformans, Blastomycesdermatitidis, Coccidioides immitis, Torulopsis,Rhodotorula, Aspergillus, Sporothrix, etc. Dermato-phytes are inhibited in vitro, but concentrationsof AMB attained in infected skin are low andineffective. It is fungicidal at high and static atlow concentrations.

Resistance to AMB is not a problem in theclinical use of the drug. AMB is also active onvarious species of Leishmania.

AMB is not absorbed orally, but is active inthe gut lumen and topically. Administered i.v. asa suspension made with the help of deoxycholate(DOC), it gets widely distributed in the body, butpenetration in CSF is poor. It binds to sterols intissues and to lipoproteins in plasma and staysin the body for long periods. The terminalelimination t½ is 15 days. About 60% of AMB ismetabolized in the liver. Excretion occurs slowlyboth in urine and bile.

Administration and dose Amphotericin B can beadministered orally (50–100 mg QID) for intestinalmoniliasis; also topically for vaginitis, otomycosis, etc.:FUNGIZONE OTIC 3% ear drops.

For systemic mycosis, it is available as dry powderalong with DOC for extemporaneous dispersion beforeuse: FUNGIZONE INTRAVENOUS, MYCOL 50 mg vial.It is diluted to 500 ml with glucose solution and 0.3 mg/kg is infused over 4–8 hours.

New amphotericin B formulations In an attempt toimprove tolerability of i.v. infusion of AMB, reduce itstoxicity and achieve targeted delivery, 3 new lipidformulations of AMB have been produced.

(a) Amphotericin B lipid complex (ABLC): Contains 35%AMB incorporated in ribbon-like particles of dimyristoylphospholipids.

(b) Amphotericin B colloidal dispersion (ABCD): Disc shapedparticles containing 50% each of AMB and cholesterylsulfate are prepared as aqueous dispersion.

(c) Liposomal amphotericin B (small unilamellar vesicles;SUV): Consists of 10% AMB incorporated in uniform sized(60-80 nM) unilamellar liposomes made up of lecithinand other biodegradable phospholipids.

The liposomal - AMB produces equivalent blood levels,has similar clinical efficacy with less acute reaction andrenal toxicity. It thus appears more satisfactory, can beinfused at higher rates (3-5 mg/kg/day), but is manytimes costlier than conventional AMB. Its specificindications are—as empirical therapy in febrile neutropenicpatients not responding to antibacterial antibiotics,critically ill deep mycosis cases and in kala azar.FUNGISOME (liposomal AMB) 10 mg, 25 mg, 50 mg pervial inj.

Adverse effects The toxicity of AMB is high.

(a) Acute reaction This occurs with each infusionand consists of chills, fever, aches and pain allover, nausea, vomiting and dyspnoea lasting for2–5 hours probably due to release of cytokines(IL, TNFα).

Thrombophlebitis of the injected vein can occur.

(b) Long-term toxicity Nephrotoxicity is the mostimportant. It occurs fairly uniformly and is doserelated: manifestations are—azotaemia, reducedg.f.r., acidosis, hypokalaemia and inability toconcentrate urine.

Most patients develop slowly progressinganaemia due to bone marrow depression.

Uses Amphotericin B can be used topically fororal, vaginal and cutaneous candidiasis andotomycosis.

It is the most effective drug for various typesof systemic mycoses and is the gold standard ofantifungal therapy. However, because of highertoxicity of AMB, the azole antifungals are nowpreferred in conditions where their efficacyapproaches that of AMB (see Table 32.1).

Leishmaniasis: AMB is the most effective drug forresistant cases of kala azar.

Antifungal Drugs 439

440 Antifungal and Antiviral DrugsS

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Interactions Rifampin and minocycline, thoughnot antifungal in their own right, potentiate AMBaction.

Aminoglycosides, vancomycin, cyclosporineand other nephrotoxic drugs enhance the renalimpairment caused by AMB.

Nystatin

Obtained from S. noursei, it is similar to AMB inantifungal action and other properties. However,because of higher systemic toxicity, it is used onlylocally.

In dentistry, topically applied nystatin is the2nd choice drug to clotrimazole for oral thrush,denture stomatitis, antibiotic associated stomatitis,corticosteroid associated oral candidiasis and muco-cutaneous candidiasis of lips, etc. The 1 lac U (1 mg= 2,000 U) tablet is placed in the mouth to dissolveslowly 4 times a day, or it can be crushed andsuspended in glycerine for application on thelesions. A bitter foul taste and nausea are the sideeffects.

Given orally, it is not absorbed; can be usedfor monilial diarrhoea. It is effective (but less thanazoles) in monilial vaginitis—1 lac U tab insertedtwice daily. Similarly, it is used for corneal,

conjunctival and cutaneous candidiasis in theform of an ointment. No irritation or other sideeffect is ordinarily seen.

Candidal resistance to nystatin is not a clinicalproblem. It is ineffective in dermatophytosis.MYCOSTATIN 5 lac U tab, 1 lac U vaginal tab, 1 lac U/g oint, NYSTIN EYE 1 lac U/g ophthalmic oint.

Hamycin It was isolated from S. pimprina and developedby Hindustan Antibiotics at Pimpri. It is similar to nystatin,but more water soluble. Use is restricted to topicalapplication for oral thrush, cutaneous candidiasis, monilialand trichomonas vaginitis and otomycosis by Aspergillus.HAMYCIN, IMPRIMA 5 lac U/g oint, 2 lac U/ ml suspfor topical use, 4 lac U vaginal ovules.

Natamycin (Pimaricin) It is similar to nystatin; is non-irritating to the eye and has been used particularly inFusarium solani keratitis. Both monilial and trichomonasvaginitis are amenable to natamycin.NATAMYCIN 2% cream, 25 mg vaginal tab, PIMAFUSINVAGINAL 100 mg vaginal tab.

HETEROCYCLIC BENZOFURAN

Griseofulvin

This antibiotic obtained from Penicillium griseo-fulvum is active against most dermatophytes,including Epidermophyton, Trichophyton, Micro-sporum, etc., but not against Candida and other

Table 32.1: Choice of drugs for systemic mycoses

Disease Drugs

1st choice 2nd choice

1. Candidiasisoral/vaginal/cutaneous FLU/NYS/CLO ITRdisseminated AMB/VORI FLU

2. Cryptococcosis AMB ± 5-FC FLU

3. Histoplasmosis ITR/AMB FLU

4. Coccidioidomycosis AMB/FLU ITR/KTZ

5. Blastomycosis ITR/AMB KTZ/FLU

6. Sporotrichosis (disseminated) AMB ITR

7. Paracoccidioidomycosis ITR AMB/VORI

8. Aspergillosis AMB/VORI ITR

9. Mucormycosis AMB —

10. Chromomycosis ITR KTZ/5-FC

AMB—Amphotericin B; 5-FC—Flucytosine; KTZ—Ketoconazole; FLU—Fluconazole;ITR—Itraconazole; NYS—Nystatin; CLO—Clotrimazole; VORI-Voriconazole

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fungi causing deep mycosis. Bacteria are alsoinsensitive. Griseofulvin interferes with mitosis—multinucleated and stunted fungal hyphae resultfrom its action. It also causes abnormal metaphaseconfigurations.

Adverse effects Toxicity of griseofulvin is lowand usually not serious. Headache is the com-monest complaint, followed by g.i.t. disturbances.CNS symptoms and peripheral neuritis areoccasional.

Use Griseofulvin is used orally only fordermatophytosis. As such, it has no utility indentisry. It is ineffective topically. Systemic azolesand terbenafine are equally or more efficacious;preferred now for dermatophytosis and tinea ofnails as well.GRISOVIN-FP, DERMONORM 250, 500 mg tabs.

Interactions Griseofulvin induces warfarin meta-bolism and reduces efficacy of oral contraceptives.Phenobarbitone reduces the oral absorption andinduces the metabolism of griseofulvin.Griseofulvin can cause intolerance to alcohol.

FLUCYTOSINE (5-FC)

It is a pyrimidine antimetabolite which is inactive as such.It is taken up by fungal cells and converted into 5-fluoro-deoxyuridylic acid which is an inhibitor of thymidylatesynthesis. Thymidylic acid is a component of DNA.

It is a narrow spectrum fungistatic, active againstCryptococcus neoformans, Torula, Chromoblastomyces; and afew strains of Candida. Other fungi and bacteria areinsensitive. Flucytosine is not employed as the sole therapy,but only to potentiate AMB.

IMIDAZOLES AND TRIAZOLES

These are presently the most extensively usedantifungal drugs.

Three imidazoles are entirely topical, whileketoconazole is used both orally and topically.The triazoles fluconazole, itraconazole andvoriconazole have largely replaced ketoconazolefor systemic mycosis because of greater efficacyas well as fewer side effects and drug interactions.

The imidazoles and triazoles have broad-spectrum antifungal activity covering dermato-

phytes, Candida, other fungi involved in deepmycosis, Nocardia, some gram-positive and anae-robic bacteria, e.g. Staph. aureus, Strep. faecalis, Bac.fragilis and Leishmania.

The mechanism of action of imidazoles andtriazoles is the same. They inhibit the fungal cyto-chrome P450 enzyme lanosterol 14-demethylaseand thus impair ergosterol synthesis leading to acascade of membrane abnormalities in the fungus.The lower host toxicity of triazoles compared toimidazoles has correlated with their lower affinityfor mammalian CYP450 enzyme and lesserpropensity to inhibit mammalian sterol synthesis.However, because they are active against certainbacteria as well (which do not have ergosterol),other mechanisms of action also appear to beinvolved.

Development of fungal resistance to azoles hasnot so far posed any significant clinical problem.

Clotrimazole It is effective in the topicaltreatment of tinea infections like ringworm.Athlete’s foot, otomycosis and oral, cutaneous,vaginal candidiasis have responded in >80%cases. It is the most commonly used drug fororopharyngeal candidiasis; 10 mg troche ofclotrimazole is allowed to dissolve in the mouth3 to 4 times a day or the lotion/gel is applied/swirled in the mouth for as long as possible. Fordenture stomatitis, patients are advised to applyclotrimazole lotion/gel to the fitting surface ofthe denture before wearing it. Also, the dentureshould be kept overnight in sod. hypochlorite/benzalkonium/cetrimide solution, and it shouldbe worn only when needed. Topical clotrimazolecan be used to treat angular cheilitis that often isa mixed candidal, streptococcal, staphylococcalinfection.

Clotrimazole is well tolerated by most patients.Local irritation with stinging and burningsensation occurs in some. No systemic toxicity isseen after topical use.SURFAZ, CLODERM 1% lotion, cream, powder; 100 mgvaginal tab. CANDID 1% cream, gel, lotion, powder.

Econazole It is similar to clotrimazole; and ishighly effective in dermatophytosis, otomycosis,



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oral thrush, but is somewhat inferior to clotri-mazole in vaginitis. No adverse effects, exceptlocal irritation in few is reported.ECONAZOLE 1% oint, 150 mg vaginal tab; ECODERM1% cream.

Miconazole It is an alternative drug to clotri-mazole for tinea, pityriasis versicolor, otomycosis,oral, cutaneous and vulvovaginal candidiasis;single application on skin acts for a few days.

Irritation after cutaneous application isinfrequent, no systemic adverse effects are seen.DAKTARIN 2% gel, 2% powder and solution;GYNODAKTARIN 2% vaginal gel; ZOLE 2% oint, lotion,dusting powder and spray, 1% ear drops, 100 mg vaginalovules.

Ketoconazole (KTZ)

It is the first orally effective broad-spectrumantifungal drug, useful in dermatophytosis,superficial candidiasis as well as in deep mycosis.The oral absorption of KTZ is facilitated by gastricacidity because it is more soluble at lower pH. Inthe blood it is largely bound to albumin and RBCs.Hepatic metabolism is extensive; metabolites areexcreted in urine and faeces. Elimination of KTZis dose dependent: t½ varies from 1½ to 6 hours.Penetration in CSF is poor. In spite of relativelyshort t½, a single daily dose is satisfactory in lesssevere cases. The usual dose is 200 mg OD or BD.FUNGICIDE, NIZRAL, FUNAZOLE, KETOVATE 200mg tab.FUNGINOC, NIZRAL 2% oint, 2% shampoo (fordandruff), KETOVATE 2% cream.

Adverse effects Ketoconazole is much less toxicthan AMB, but more side effects occur than withitraconazole or fluconazole that have largelyreplaced it for systemic use.

The most common side effects are nausea andvomiting; can be reduced by giving the drug withmeals. Others are—loss of appetite, headache,paresthesia, rashes and hair loss.

Ketoconazole decreases androgen productionfrom testes and it displaces testosterone fromprotein binding sites. Gynaecomastia, loss of hairand libido, and oligozoospermia may be themanifestations. Menstrual irregularities occur in

some women due to suppression of estradiolsynthesis. Hepatotoxicity is infrequent.

Interactions H2 blockers, proton pump inhibi-tors and antacids decrease the oral absorption ofKTZ by reducing gastric acidity.

Rifampin, phenobarbitone, carbamazepineand phenytoin induce KTZ metabolism andreduce its efficacy.

Ketoconazole inhibits cytochrome P450,especially CYP3A4, and raises the blood level ofseveral drugs including warfarin, sulfonylureas,phenytoin, cyclosporine, diazepam, nifedipine,indinavir. A dangerous interaction with terfe-nadine, astemizole and cisapride has been noted:polymorphic ventricular tachycardia and fatalventricular fibrillation have occurred due toexcessive rise in plasma levels of these drugs.

Use Ketoconazole is rarely used in dentalpractice. Topically, it has been employed for tineaand other forms of dermal mycosis. Dandruffoften responds to KTZ applied as a shampoo. OralKTZ is effective in several forms of systemicmycosis, but fluconazole and itraconazole havelargely replaced it for these indications due totheir higher efficacy, fewer side effects and druginteractions.

Ketoconazole is occasionally used in dermalleishmaniasis and in kala azar. High-dose KTZhas been used in Cushing’s syndrome to decreasecorticosteroid production.

Fluconazole

It is a water- soluble triazole having a wider rangeof activity than KTZ; indications includecryptococcal meningitis, systemic and mucosalcandidiasis in both normal and immunocom-promised patients, coccidioidal meningitis andhistoplasmosis.

Fluconazole is 94% absorbed; oral bioavai-lability is not affected by food or gastric pH. It isprimarily excreted unchanged in urine with a t½of 25–30 hours. Fungicidal concentrations areachieved in nails, vagina and saliva; penetration

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into brain and CSF is good. Dose reduction isneeded in renal impairment.

Adverse effects Fluconazole produces few sideeffects: mostly nausea, vomiting, abdominal pain,rash and headache.Selectivity for fungal cytochrome P450 is higher;unlike KTZ, it does not inhibit steroid synthesisin man: antiandrogenic and other endocrine sideeffects have not occurred.It is not recommended in pregnant and lactatingmothers.

Interactions Though fluconazole affects hepaticdrug metabolism to a lesser extent than KTZ,increased plasma levels of phenytoin, astemizole,cisapride, cyclosporine, warfarin, zidovudine andsulfonylureas have been observed. A few cases ofventricular tachycardia have been reported whenfluconazole was given with cisapride. The samecaution as with KTZ or itraconazole needs to beapplied in coadministering other drugs.

Use Fluconazole can be administered orally aswell as i.v. (in severe infections).

Oral fluconazole 150 mg/day for 2 weeks ishighly effective in Candida infections of the mouth,but should be given only to patients notresponding to topical treatment. A single 150 mgoral dose can cure vaginal candidiasis.

Most tinea infections and cutaneous candi-diasis can be treated with 150 mg weekly for4 weeks.

For disseminated candidiasis, cryptococcal/coccidioidal meningitis and other systemic fungalinfections the dose is 200–400 mg/day for 4–12weeks or longer.

An eye drop is useful in fungal keratitis.SYSCAN, ZOCON, FORCAN, FLUZON 50, 100, 150,200 mg caps, 200 mg/100 ml i.v. infusion.SYSCAN 0.3% eye drops.

Itraconazole

This orally active triazole antifungal has a broaderspectrum of activity than KTZ or fluconazole;includes some moulds like Aspergillus. It is

fungistatic, but effective in immunocompromisedpatients. Steroid hormone synthesis inhibitionand serious hepatotoxicity are absent initraconazole.

Oral absorption of itraconazole is variable. Itis enhanced by food and gastric acid. Itraconazoleis highly protein bound, accumulates in vaginalmucosa, skin and nails, but penetration into CSFis poor. It is largely metabolized in liver byCYP3A4; an active metabolite is produced whichis excreted in faeces; t½ varies from 30–64 hours.

Itraconazole is well tolerated in doses below200 mg/day. Gastric intolerance is significant at> 400 mg/day. Dizziness, pruritus, headache andhypokalaemia are the other common side effects.Unsteadiness and impotence are infrequent.Antiandrogenic and other hormonal adverseeffects are not seen.

Drug interactions Oral absorption of itracona-zole is reduced by antacids, H2 blockers andproton pump inhibitors.Rifampin, phenobarbitone, phenytoin and carba-mazepine induce itraconazole metabolism andreduce its efficacy.Itraconazole inhibits CYP3A4; drug interactionprofile is similar to KTZ; ventricular arrhythmiashave occurred with terfenadine, astemizole,cisapride and class III antiarrhythmics. Phenytoin,digoxin, sulfonylurea, protease inhibitors, war-farin and cyclosporine levels are also increased.

Uses Itraconazole is the preferred azole for mostsystemic mycosis (see Table 32.1) that are notassociated with meningitis. It also affords somerelief in aspergillosis. It is highly effective invaginal candidiasis, dermatophytosis and ony-chomycosis, but use is restricted to cases notamenable to topical therapy. It is seldom used indentistry for oral candidiasis.Dose: 100 mg OD—200 mg BD oral; 200 mg infused i.v.over 1 hour OD or BD.SPORANOX, CANDITRAL, FLUCOVER 100 mg cap,ITASPOR 100 mg cap, 200 mg/20 ml vial.

Voriconazole

It is a second generation broad-spectrum triazoleintroduced lately for difficult to treat fungal



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infections like invasive aspergillosis, dissemina-ted infections caused by fluconazole resistantCandida, Fusarium infections, and febrile neutro-penia not responding to antibacterial therapy. Thedrug interaction profile is similar to itraconazole.Rashes, visual disturbances, QTc prolongationand an acute reaction on i.v. injection are thesignificant adverse effects.Dose: 200 mg 1 hour before or 1 hour after meal orally;4-6 mg/kg/slow i.v. infusion every 12 hours.VFEND 50 mg, 200 mg tabs, 200 mg/vial for i.v. infusion;FUNGIVOR 200 mg tab.

TERBINAFINE

This orally and topically active drug againstdermatophytes and Candida belongs to a newallylamine class of antifungals. In contrast toazoles which are primarily fungistatic, terbina-fine is fungicidal: shorter courses of therapy arerequired and relapse rates are low. It acts as anoncompetitive inhibitor of ‘squalene epoxidase’,an early step enzyme in ergosterol biosynthesisby fungi. Accumulation of squalene within fungalcells appears to be responsible for the fungicidalaction. The mammalian enzyme is inhibited onlyby 1000-fold higher concentration of terbinafine.

Side effects of oral terbinafine are gastric upset,rashes, taste disturbance. Some cases of hepaticdysfunction and haematological disorder arereported. Enzyme inducers lower, and enzymeinhibitors raise its steady-state plasma levels.Terbinafine does not inhibit CYP450.

Topical terbinafine can cause erythema,itching, dryness, irritation, urticaria and rashes.

Use Terbinafine applied topically as 1% creamor orally 250 mg OD is indicated in tinea pedis/corporis/cruris/capitis and pityriasis versicolor.Onychomycosis is treated by 3–6 months oraltherapy.

It is less effective against cutaneous andmucosal candidiasis: 2–4 weeks oral therapy maybe used as an alternative to fluconazole.LAMISIL, SEBIFIN, DASKIL 250 mg tab, 1% topicalcream. EXIFINE 125, 250 mg tabs, 1% cream.

OTHER TOPICAL ANTIFUNGALS

All these drugs are used for dermatophytosis.

1. Tolnaftate It is an effective drug for tinea crurisand tinea corporis—most cases respond in 1–3 weeks.Because of poor penetrability, it is less effective in tineapedis and other hyperkeratinized lesions. For the samereason, it is ineffective in tinea capitis—involving scalpand tinea unguium—involving nails. Tolnaftate is noteffective in candidiasis or other types of superficialmycosis.

2. Ciclopirox olamine It is effective in tinea infections,pityriasis versicolor and dermal candidiasis. Also usedfor vaginal candidiasis.

3. Undecylenic acid It is fungistatic used topically,generally in combination with its zinc salt. It is inferior tothe drugs described above, but is still used for tineapedis, nappy rash and tinea cruris.

4. Benzoic acid It has antifungal and antibacterialproperty in slightly acidic medium. It is fungistatic—weaker than tolnaftate; on hyperkeratotic lesions, it is usedin combination with salicylic acid (as Whitfield’s ointment).Irritation and burning sensation is experienced by manypatients.

5. Butenafine This congener of terbinafine has the samemechanism of action, but is used only topically for tineacruris/corporis/pedis.

6. Quiniodochlor By the oral route, it is used as aluminal amoebicide. It also has weak antifungal andantibacterial activity. By external application, it has beenused for dermatophytosis, mycosis barbae, seborrhoeicdermatitis, and pityriasis versicolor.

7. Sodium thiosulfate It is a weak fungistatic, activeagainst Malassezia furfur. A 20% solution applied twicedaily for 3–4 weeks is effective in pityriasis versicolor.

ANTIVIRAL DRUGS

Viruses are the ultimate expression of para-sitism: they not only take nutrition from the hostcell but also direct its metabolic machinery tosynthesize new virus particles. Viral chemo-therapy, therefore, is difficult, as it would requireinterference with cellular metabolism in the host.However, virus directed enzymes have beenidentified in the infected cell and some viruseshave a few enzymes of their own which may havehigher affinities for some inhibitors than theregular cellular enzymes. Drugs could also target

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virus specific steps like cell penetration,uncoating, reverse transcription, virus assemblyor maturation. Another stumbling block is thatin majority of acute infections viral replicationis already at its peak when symptoms appear.To be effective, therefore, therapy has to bestarted in the incubation period, i.e. has to beprophylactic.

The application of antiviral drugs in dentistry isrestricted to treatment of oropharyngeal herpes simplexand herpes labialis that occur particularly inimmunocompromised patients.

Dentists run the risk of accidental exposure toHIV infection, and should be well informed aboutits prophylaxis.

CLASSIFICATION

1. Anti-Herpes virusIdoxuridine, Acyclovir, Valacyclovir,Famciclovir, Ganciclovir, Foscarnet

2. Anti-Retrovirus(a) Nucleoside reverse transcriptase inhibitors (NRTIs):

Zidovudine (AZT), Didanosine, Zalcitabine,Abacavir, Stavudine, Lamivudine

(b) Non-nucleoside reverse transcriptase inhibitors(NNRTIs): Nevirapine, Efavirenz

(c) Protease inhibitors: Ritonavir, Indinavir,Nelfinavir, Saquinavir, Lopinavir

3. Anti-Influenza virusAmantadine, Rimantadine, Oseltamivir,Zanamivir

4. Nonselective antiviral drugsRibavirin, Lamivudine, Interferon α

ANTI-HERPES VIRUS DRUGS

Idoxuridine

It is 5-iodo-2-deoxyuridine (IUDR); acts as a thymidineanalogue. It was the first pyrimidine antimetabolite to beused as antiviral drug. It competes with thymidine, getsincorporated in DNA so that faulty DNA is formed whichbreaks down easily. It is effective only against DNA virusesand clinical utility is limited to Herpes simplex keratitis.

Acyclovir is an equally efficacious and better toleratedalternative.

Acyclovir

This deoxiguanosine analogue antiviral drugrequires a virus specific enzyme for conversion tothe active metabolite that inhibits DNA synthesisand viral replication.

Acyclovir is preferentially taken up by thevirus infected cells. Because of selectivegeneration of the active inhibitor in the virusinfected cell and its greater inhibitory effect onviral DNA synthesis, acyclovir has low toxicityfor host cells: a several hundred-fold chemo-therapeutic index has been noted.

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Acyclovir Herpes virus specific thymidine kinase

Acyclovir monophosphate Cellular kinases

Inhibits herpes virus DNApolymerase competitively

Acyclovirtriphosphate Gets incorporated in viral DNA

and stops lengthening of DNAstrand. The terminated DNAinhibits DNA-polymeraseirreversibly.

Acyclovir is active only against herpes groupof viruses; H. simplex type I is most sensitivefollowed by H. simplex type II > varicella-zostervirus = Epstein-Barr virus, while cytomegalovirus(CMV) is practically not affected. Both H. simplexand varicella-zoster virus can develop resistanceto acyclovir during therapy.

Pharmacokinetics Only about 20% of an oraldose of acyclovir is absorbed. It is little plasmaprotein bound and is widely distributed in thebody. Acyclovir is primarily excreted unchangedin urine, plasma t½ is 2–3 hours. Renalimpairment necessitates dose reduction.ZOVIRAX 200 mg tab, 250 mg/vial for i.v. inj; CYCLOVIR200 mg tab, 5% skin cream; HERPEX 200 mg tab, 3% eyeoint, 5% skin cream; OCUVIR 200, 400, 800 mg tab, 3%eye oint, ACIVIR-DT 200, 400, 800 mg tab. ACIVIR EYE3% oint.

Use Acyclovir is effective in patients withnormal as well as deficient immune status.


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1. Mucocutaneous H. simplex is a type I virusdisease, remains localized to lips and gums anddoes not usually require specific treatment. Startedearly, 5 times daily application of acyclovir 5%cream may abort or shorten the duration ofrecurrences in herpes labialis. Prophylactic oralacyclovir 200 mg 3 times a day therapy mayprevent sun exposure related recurrences.Symptomatic improvement can occur in acuteherpetic gingivostomatitis by acyclovir 200 mg5 times daily for 10 days. The disease often getsdisseminated in immunocompromised indivi-duals and may be treated with oral or i.v. acyclovir(15 mg/kg/day) for 7 days, but recurrences arenot prevented.

2. Genital H. simplex is generally caused by typeII virus, and is treated with topical, oral orparenteral acyclovir depending upon the stageand severity of disease. Symptomatic relief isafforded, but subsequent recurrences are notprevented. Continuous oral medication is advisedto ward off recurrences, if they are frequent.

3. H. simplex encephalitis (type I virus): Acycloviris the drug of choice. Treatment is effective only ifstarted early: delay precludes salutary effect onmortality and neurological complications.

4. H. simplex (type I) keratitis: Acyclovir is nowpreferred over idoxuridine.

5. Herpes zoster: Acyclovir should be used onlyin immunodeficient individuals or in severe cases:affords symptomatic relief and faster healing oflesions, but postherpetic neuralgia is notprevented.

6. Chickenpox: in patients with immunodefi-ciency and in neonates calls for acyclovir therapy.

Adverse effects

Topical: stinging and burning sensation after eachapplication.Oral: The drug is well tolerated; headache, nausea,malaise and some CNS effects are reported.Intravenous: rashes, sweating, emesis and fall inBP occur only in few patients.

Dose dependent decrease in g.f.r. is the mostimportant toxicity; occurs especially in those withkidney disease; normalises on discontinuationof the drug. Reversible neurological manifes-tations (tremors, lethargy, disorientation, hallu-cinations, convulsions and coma) have beenascribed to higher doses.

Valacyclovir It is an ester prodrug of acyclovirwith improved oral bioavailability due to activetransport by peptide transporters in the intestine.It is completely converted into acyclovir in thebody. Orolabial herpes can be treated by singleday therapy (2 g BD). In immunocompromisedpatient 1 g BD for 5 days is recommended.VALCIVIR 0.5 g, 1.0 g tabs.

Famciclovir It is an ester prodrug of a guaninenucleoside analogue penciclovir; has good oralbioavailability and prolonged intracellular t½ ofthe active triphosphate metabolite. Like acyclovir,it needs viral thymidine kinase for generation ofthe active DNA polymerase inhibitor. It is usedas an alternative to acyclovir for orolabial orgenital herpes and herpes zoster.Dose: Orolabial herpes 500 mg TDS for 7–10 days.FAMTREX 250, 500 mg tabs.Side effects are headache, nausea, loose motions,itching, rashes and mental confusion.

Ganciclovir It is an analogue of acyclovir which is activeagainst all herpes viruses including H. simplex, H. zoster,E-B virus and cytomegalovirus (CMV). It is more activethan acyclovir against CMV. The mechanism of actionand basis of virus selectivity is similar to acyclovir.

Systemic toxicity of ganciclovir is high (bone marrowdepression, rash, fever, vomiting, neuropsychiatric distur-bances) and use is restricted to severe CMV infections.

Foscarnet It is a simple straight chain phosphonateunrelated to any nucleic acid precursor which inhibits viralDNA polymerase and reverse transcriptase. It is activeagainst H. simplex (including strains resistant to acyclovir),CMV (including ganciclovir resistant ones) and HIV.Toxicity of foscarnet is high.

ANTI-RETROVIRUS DRUGS

These are drugs active against human immuno-deficiency virus (HIV) which is a retrovirus. They

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are useful in prolonging life and postponingcomplications of acquired immunodeficiencysyndrome (AIDS) or AIDS-related complex (ARC),but do not cure the infection. The clinical efficacyof antiretrovirus drugs is monitored primarily byplasma HIV-RNA assays and CD4 lymphocytecount carried out at regular intervals.

The first antiretrovirus (ARV) drug Zidovudinewas developed in 1987. Over the past 20 oddyears > 25 drugs belonging to 3 classes have beenintroduced and a large number of others areunder development.

Nucleoside reverse transcriptaseinhibitors (NRTIs)

Zidovudine It is a thymidine analogue (azido-thymidine, AZT), the prototype NRTI. Afterphosphorylation in the host cell—zidovudinetriphosphate selectively inhibits viral reversetranscriptase (RNA-dependent DNA polymerase)in preference to cellular DNA polymerase.

Single-stranded viral RNAVirus directed reverse transcriptase(inhibited by zidovudine triphosphate)

Double-stranded viral DNA

On the template of single-stranded RNA genomeof HIV, a double-stranded DNA copy is producedby viral reverse transcriptase. This DNAtranslocates to the nucleus and is integrated withchromosomal DNA of the host cell, which thenstarts transcribing viral genomic RNA as well asmRNA. Under the direction of viral mRNA, viralregulatory and structural proteins are produced.Finally, viral particles are assembled and matu-red. Zidovudine thus prevents infection of newcells by HIV but has no effect on virus directedDNA that has already integrated into the hostchromosome. It is effective only against retro-viruses. Zidovudine itself gets incorporated intothe growing viral DNA and terminates chainelongation. Resistance to AZT occurs by pointmutations which alter reverse transcriptaseenzyme. In the past, when AZT was used alone,>50% patients became nonresponsive to AZT

within 1–2 years therapy due to growth ofresistant mutants.

Pharmacokinetics The oral absorption of AZTis rapid, but bioavailability is ~65%. It is quicklycleared by hepatic glucuronidation (t½ 1 hr); 15–20% of the unchanged drug along with themetabolite is excreted in urine.

Adverse effects Toxicity is mainly due to partialinhibition of cellular DNA polymerase. Anaemiaand neutropenia are the most important anddose-related adverse effects.Nausea, anorexia, abdominal pain, headache,insomnia and myalgia are common at the start oftherapy but diminish later.Myopathy, lactic acidosis, hepatomegaly, convul-sions and encephalopathy are infrequent.

Interactions Paracetamol increases AZT toxicity,probably by competing for glucuronidation.Azole antifungals also inhibit AZT metabolism.Stavudine and zidovudine exhibit mutualantagonism by competing for the same activationpathway.

Use Zidovudine is used in HIV- infected patientsonly in combination with at least 2 other ARVdrugs. HIV-RNA titer is reduced to undetectablelevels and CD4 count increases progressively.Immune status is improved and opportunisticinfections become less common. There is a sense ofwell-being and patients gain weight. However,beneficial effects are limited from a few months toa couple of years after which progressively non-responsiveness develops.

Didanosine It is a purine nucleoside analoguewhich after intracellular conversion to didano-sine triphosphate competes with ATP forincorporation into viral DNA, inhibits HIV reversetranscriptase and terminates proviral DNA.Antiretroviral activity of didanosine is equivalentto AZT. Mutational resistance develops, and it isused only in combination regimens.

In contrast to AZT, it does not cause myelo-suppression. The prominent dose-related toxicityis peripheral neuropathy and rarely pancreatitis.

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Diarrhoea, abdominal pain and nausea are theside effects.

Stavudine It is also a thymidine analogue whichacts in the same way as AZT. By utilizing thesame thymidine kinase for activation, AZTantagonises the effect of stavudine. Resistance tostavudine develops as for other NRTIs.

The anti-HIV efficacy of stavudine is com-parable to AZT, and it is used now in combinationregimens. The major dose-related toxicity isperipheral neuropathy; pancreatitis is rare.

Lamivudine This deoxycytidine analogue isphosphorylated intracellularly and inhibits HIVreverse transcriptase as well as hepatitis B virus(HBV) DNA polymerase. Its incorporation intoDNA results in chain termination. Most humanDNA polymerases are not affected and systemictoxicity of lamivudine is low. Point mutation inHIV-reverse transcriptase and HBV-DNA poly-merase gives rise to rapid lamivudine resistance.

Lamivudine is used in combination with otheranti-HIV drugs, and appears to be as effectiveas AZT. It is also frequently used for chronichepatitis B. HBV-DNA titre is markedly reducedand biochemical as well as histological indicesof liver function improve. However, viral titresrise again after discontinuation. Even with conti-nued medication HBV viraemia tends to returnafter 1 year due to emergence of resistant mutants.

Lamivudine is generally well tolerated. Sideeffects are headache, fatigue, nausea, anorexia,abdominal pain. Pancreatitis and neuropathy arerare.

Abacavir (ABC) This guanosine analogue is apotent ARV drug that acts after intracellularconversion to carbovir triphosphate. Resistanceto ABC develops slowly, and it exhibits little crossresistance with other NRTIs. Hypersensitivityreactios such as rashes, fever, flue-like symptomsare the major problems.

Non-nucleoside reverse transcriptaseinhibitors (NNRTIs)

Nevirapine and Efavirenz These are nucleosideunrelated compounds which directly inhibit HIV

reverse transcriptase without the need for intra-cellular phosphorylation. Their locus of actionon the enzyme is also different. They are morepotent than AZT on HIV-1, but do not inhibitHIV-2. Viral resistance to these drugs developsby point mutation and cross resistance is commonamong different NNRTIs, but not with NRTIs orPIs.

The NNRTIs are indicated in combinationregimens for HIV, and have succeeded in reducingHIV-RNA levels when an earlier regimen hasfailed. Rashes, nausea, headache are the usualside effects. Fever and rise in liver enzymes canoccur with nevirapine, while efavirenz can causea variety of neuropsychiatric symptoms.

Retroviral protease inhibitors (PIs)

An aspartic protease enzyme encoded by HIVis involved in the production of structuralproteins and enzymes (including reverse trans-criptase) of the virus. The large viral polyproteinis broken into various functional components bythis enzyme. This protease acts at a late step inHIV replication, i.e. maturation of the new virusparticles when the RNA genome acquires the coreproteins and enzymes. The protease inhibitors—ritonavir, indinavir, nelfinavir, saquinavir andlopinavir bind to the protease molecule andinterfere with its cleaving function. They are moreeffective viral inhibitors than AZT. Because theyact at a late step of viral cycle, they are effective inboth newly as well as chronically infected cells.Under their influence, HIV-infected cells produceimmature noninfectious viral progeny—henceprevent further rounds of infection.

All PIs (especially ritonavir) are inhibitors ofCYP3A4—interact with many drugs. Among thedrugs used in dentistry whose plasma levels areincreased by PIs are metronidazole, lidocaine,midazolam and carbamazepine. Nelfinavir andritonavir induce their own metabolism throughother CYP isoenzymes.

Viral resistance develops against the PIs overmonths due to selection of resistant mutants in astepwise manner. Current recommendations are

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to use a PI in combination with two NRTIs or oneNRTI + one NNRTI. Because different PIs eitherinhibit or induce specific CYP isoenzymes todifferent extents, drug interactions with them arecommon and often unpredictable. Particularly,rifampin and other enzyme inducers enhance themetabolism of PIs and render them ineffective.

The most prominent adverse effects of PIs aregastrointestinal intolerance, asthenia, headache,paresthesia, dizziness, rash, abnormal distri-bution of body fat and exacerbation of diabetes.Indinavir produces crystalluria and increases riskof urinary calculi.

TREATMENT OF HIV INFECTION

The treatment of HIV infection and its compli-cations is complex, prolonged, needs expertise,strong motivation and commitment of the patient,resources and is expensive. However, in IndiaARV drugs are provided free under the NationalAIDS control programme.

Because of rapid development of resistance tomonotherapy with any ARV drug and inevitabletherapeutic failure, it is now mandatory to treatHIV infection with a combination of 3 or moreARV drugs. This is called ‘highly activeantiretroviral therapy’ (HAART).

It has been realized that even with HAARTwhich rapidly kills > 99% virions, a small numbersurvive within the resting CD4 lymphocytes andinvariably give rise to relapse. As the diseaseprogresses in the individual (and several ARVdrugs are used), the HIV population becomesgenetically complex and diverse with respect tosusceptibility to drugs. Each failing regimen limitsfuture treatment options.

Since none of the currently available regimenscan eradicate HIV from the body of the patient,the goal of therapy is to maximally and durablyinhibit viral replication so that the patient canattain and maintain effective immune responsetowards potential microbial pathogens.

Health authorities and professional bodieshave framed elaborate guidelines for selecting

patients for anti-HIV therapy as well as fordevising suitable treatment regimens, details ofwhich are beyond the scope of this text, becausedentists do not treat HIV infection.

Briefly, treatment is recommended for allsymptomatic HIV disease patients and forasymtomatic cases with CD4 count, < 200/μl.Treatment is not recommended for asymptomaticcases with reasonable immune competence (CD4cell count > 350/μl), while decision to treatasymptomatic cases with CD4 cell count between350/μl and 200/μl depends on rate of decline inCD4 count, HIV-RNA level and other factors.

Some ARV drug combinations are given inthe box.

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Preferred and alternative ARV combinations

Preferred regimens

2 NRTI + NNRTI (PI sparing)1. Zidovudine + lamivudine + efavirenz

2 NRTI + PI1. Zidovudine + lamivudine + lopinavir/r

Alternative regimens2 NRTI + NNRTI (PI sparing)1. Zidovudine + lamivudine + nevirapine2. Lamivudine + stavudine + efavirenz3. Lamivudine + stavudine + nevirapine4. Lamivudine + abacavir + efavirenz5. Lamivudine + abacavir + nevirapine

2 NRTI + PI1. Lamivudine + zidovudine + indinavir2. Lamivudine + stavudine + ritonavir3. Lamivudine + abacavir + lopinavir/r4. Lamivudine + abacavir + nelfinavir

3 NRTI*1. Zidovudine + lamivudine + abacavir

* Only when a NNRTI or PI cannot be used; as in patientreceiving rifampin.

Treatment failures are to be anticipated andoccur within the first year or in successive yearswith nearly all regimens. Optimally, the regimenshould be changed entirely (all 3 drugs changed)to drugs that have not been administered earlier.With repeated failures, it may become moredifficult to construct an active combination.


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Prophylaxis of HIV infection

Post-exposure prophylaxis (PEP) Health careworkers including dentists and others who getaccidentally exposed to the risk of HIV infectionby needlestick or other sharp injury, contact withblood, saliva or other biological fluid of patientsor by blood transfulsion should be considered forPEP. The aim of PEP is to suppress local viralreplication prior to dissemination, so that theinfection is aborted. However, PEP is notnecessary when the contact is only with intactskin, or with mucous membrane by only a fewdrops for short duration. The National AIDSControl Organization (NACO, Inida) recom-mends 2 types of regimens (see box) for PEPdepending on the magnitude of risk of HIVtransmission.

HIV infection may not be prevented, onset of AIDsmay be delayed by the late-start PEP.

Perinatal prophylaxis Treatment of the motherwith zidovudine continued in the neonate for 6weeks substantially reduces the chances oftransmission of HIV to the offspring. Combination(2 or 3 drug) prophylaxis is more effective.

ANTI-INFLUENZA VIRUS DRUGS

Amantadine

Chemically, it is a tricyclic amine unrelated toany nucleic acid precursor, but inhibits replica-tion of influenza A virus (a myxovirus). It appearsto act at an early step (possibly uncoating) as wellas at a late step (viral assembly) in viral replication.A protein designated ‘M2’ which acts as an ionchannel has been identified as one of its targets ofaction. Resistance to amantadine develops bymutation causing amino acid substitutions in theM2 protein. Amantadine is well absorbed orallyand excreted unchanged in urine over 2–3 days(t½ 16 hr).

Adverse effects Generally well tolerated; nausea,anorexia, insomnia, dizziness, nightmares, lackof mental concentration, hallucinations andpostural hypotension have been reported. Ankleedema occurs due to local vasoconstriction.

Uses

1. Prophylaxis of influenza A2, especially in highrisk patients. It is quite virus specific: influenza Bis unaffected.2. Treatment of influenzal (A2) illness: a modesttherapeutic effect (reduction in fever, congestionand cough) occurs if the drug is given quicklyafter the symptoms appear.3. Parkinsonism (see Ch. 9).

Rimantadine It is a more potent, long-acting (t½ 30 hr)and better tolerated congener of amantadine. Dose andclinical application is similar to amantadine.

Oseltamivir (TAMIFLU) This recently developed anti-influenza virus drug has a broader-spectrum activitycovering influenza A, influenza B and avian-influenza

⎫⎬⎭

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When indicated, PEP should be started as soonas possible, preferably within 1-2 hours ofexposure. The likelihood of preventing infectiondeclines with the delay; some guidlines do notrecommend starting it beyound 72 hours ofexposure. According to others, in case of default,PEP may be started even 1-2 weeks later. Though

Post-exposure prophylaxis of HIV

Basic (2 drug) regimen (for low risk)*

Zidovudine 300 mg + Twice dailyLamivudine 150 mg for 4 weeks

Expanded (3 drug) regimen (for high risk)$

Zidovudine 300 mg + Twice dailyLamivudine 150 mg

+Indinavir 800 mg Thrice daily(or another PI) All for 4 weeks

*Low risk• When the source is HIV positive, but asymptomatic

with low HIV-RNA titre and high CD4 cell count.• Exposure is through mucous membrane, or super-

ficial scratch, or through thin and solid needle.$High risk• When the source is symptomatic AIDS patient with

high HIV-RNA titre or low CD4 count.• Exposure is through major splash or large area

contact of longer duration with mucous membraneor abraded skin or through large bore hollow needle,deep puncture, visible patient’s blood on the needle.

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(bird flu) H5N1 and other strains (swine flu). It is an esterprodrug that is rapidly and nearly completely hydrolysedduring absorption in intestine and by liver to the activeform oseltamivir carboxylate. It acts by inhibiting influenzavirus neuraminidase enzyme which is needed for releaseof progeny virions from the infected cell. Spread of thevirus in the body is thus checked.

Oseltamivir is indicated both for prophylaxis as wellas treatment of influlenza A, B, bird flu and swine flu.

Zanamivir (RELENZA) Another influenza virus (A, B,avian strains) neuraminidase inhibitor that is adminis-tered by inhalation as a powder due to very low oralbioavailability. The mechanism of action, clinical utilityand efficacy of zanamivir are similar to that of oseltamivir.

NONSELECTIVE ANTIVIRAL DRUGS

Ribavirin This purine nucleoside analogue has broad-spectrum antiviral activity, including that againstinfluenza A and B, respiratory syncytial virus and manyother DNA and double-stranded RNA viruses. Its mono-and triphosphate derivatives generated intracellularlyinhibit GTP and viral RNA synthesis and have other sitesof action as well. No viral resistance to ribavirin has yetbeen observed.

Administered orally or i.v. ribavirin has been used ininfluenza A/B and measles in immunosuppressedpatients as well as for herpes virus infections and acutehepatitis, but clinical benefits are uncertain. Nebulizedribavirin has been used for respiratory syncytial virusbronchiolitis in infants and children.

Interferon ααααα

Interferons are low molecular weight glycoproteincytokines produced by host cells in response to viralinfections and some other inducers. They have nonspecificantiviral as well as other complex effects on immunityand cell proliferation. Interferons bind to specific cell

surface receptors and affect viral replication at multiplesteps: viral penetration, synthesis of viral mRNA, assemblyof viral particles and their release, but the most widespreadeffect is direct or indirect suppression of viral proteinsynthesis, i.e. inhibition of translation. Interferon receptorsare tyrosine protein kinase receptors which on activationphosphorylate cellular proteins. These then inducetranscription of ‘interferon-induced proteins’ which exertantiviral effects.

Interferons inhibit many RNA and DNA viruses, butthey are host specific: those produced by another specieshave poor activity in man. Three types of human interferons(α, β and γ) have been produced by recombinant DNAtechnology. Only interferon α2A and α2B have antiviralactivity. Recently, more active pegylated interferons havebeen produced.

Uses

1. Chronic hepatitis B and C.2. AIDS-related Kaposi’s sarcoma (but not to treat HIVas such).3. Condyloma acuminata caused by papilloma virusrefractory to podophyllin.4. H. simplex, H. zoster and CMV infections in immuno-compromised patients.5. Rhinoviral cold: intranasal interferon is prophylactic.Interferon is not effective orally. Clinical utility of s.c. ori.m. injected interferon is limited by substantial adverseeffects.

Adverse effects

Flu-like symptoms—fatigue, aches and pains, malaise,fever, dizziness, anorexia, taste and visual disturbances:develop a few hours after each injection, but become milderlater.Neurotoxicity—numbness, neuropathy, tremor, sleepi-ness, rarely convulsions.Myelosuppression (dose limiting).

Antiviral Drugs 451

33

Antiprotozoal andAnthelmintic Drugs

ANTIMALARIAL DRUGS

These are drugs used for prophylaxis, treatmentand prevention of relapses of malaria.

Malaria, caused by 4 species of the protozoalparasite Plasmodium, is endemic in most parts ofIndia and other tropical countries. It is one of themajor health problems.

CLASSIFICATION1. 4-Aminoquinolines Chloroquine,

AmodiaquinePiperaquine

2. Quinoline-methanol Mefloquine3. Cinchona alkaloid Quinine, Quinidine4. Biguanide Proguanil

(Chloroguanide)5. Diaminopyrimidine Pyrimethamine6. 8-Aminoquinolines Primaquine7. Sulfonamides Sulfadoxine,

and sulfone Sulfamethopyrazine,Dapsone

8. Tetracyclines Tetracycline,Doxycycline

9. Sesquiterpine Artesunate, Artemether,lactones Arteether

10. Aminoalcohols Halofantrine,Lumefantrine

11. Naphthoquinone Atovaquone.

OBJECTIVES AND USE OF ANTIMALARIALS

The aims of using drugs in relation to malarialinfection are:

(i) To prevent and treat clinical attack ofmalaria.

(ii) To completely eradicate the parasite fromthe patient’s body.

(iii) To reduce the human reservoir of infection— cut down transmission to mosquito.

These are achieved by attacking the parasite at itsvarious stages of life cycle in the human host (seeFig. 33.1). Antimalarials that act on erythrocyticschizogony are called erythrocytic schizontocides,those that act on preerythrocytic as well asexoerythrocytic (P. vivax) stages in liver are calledtissue schizontocides, while those which killgametocytes in blood are called gametocides.Antimalarial drugs exhibit considerable stageselectivity of action (see Table 33.1). Antimalarialtherapy is given in the following forms.

1. Causal prophylaxis The preerythrocyticphase (in liver), which is the cause of malarialinfection and clinical attacks, is the target for thispurpose. Proguanil is a causal prophylacticprimarily for P. falciparum, but is not very effectiveagainst P. vivax. Primaquine is a causalprophylactic for all species of malaria, but hasnot been used in mass programmes because of itstoxic potential.

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Fig. 33.1: The life cycle of malarial parasite in man. Stages and forms of theparasite at which different types of antimalarial drugs act are indicated

2. Suppressive prophylaxis The schizonto-cides which suppress the erythrocytic phase andthus attacks of malarial fever can be used asprophylactics. Though the exoerythrocytic phasein case of vivax and other relapsing malariascontinues, clinical disease does not appear. Drugsused are chloroquine (300 mg base weekly); inareas with chloroquine-resistant P. falciparum:mefloquine (250 mg weekly) or doxycycline (100mg daily for not more than 6 weeks).

Chemoprophylaxis of malaria should belimited to short-term use in special risk groups,such as — nonimmune travellers, nonimmunepersons living in endemic areas for fixed periods(army units, labour forces), infants and children.For pregnant women ‘intermittent preventive

therapy’ (IPTp) with sulfadoxine 1500 mg +pyrimethamine 75 mg single dose each in 2nd and3rd trimester is recommended in areas with highP. falciparum endemicity.

3. Clinical cure The erythrocytic schizonto-cides are used to terminate an episode of malarialfever. These are:(a) Fast-acting high-efficacy drugs: Chloroquine,quinine, mefloquine, lumefantrine, atovaquone,artemisinin. They can be used singly to treatattacks of malarial fever.(b) Slow-acting low-efficacy drugs: Proguanil, pyri-methamine, sulfonamides, tetracyclines. They areused only in combination for clinical cure.

The faster acting drugs are preferred. Theexoerythrocytic phase of vivax persists which can

Antimalarial Drugs 453

454 Antiprotozoal and Anthelmintic DrugsS

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Table 33.1: Comparative properties of antimalarial drugs

Preerythro. Erythrocytic Phase Exo- Gametes Resistance Toxicityerythro. grading

Drug Fal. Viv. Activity Onset Duration Viv. Fal. Viv.

1. Chloroquine – – + Fast Long – – + Slow ±

2. Mefloquine – – + Int Long – – – Minor ++

3. Quinine – – + Int Short – – + Minor +++

4. Proguanil + ± + Slow Short – * * Rapid ±

5. Pyrimethamine – – + Slow Long – * * Minor +

6. Primaquine + + ± – – + + + Minor ++

7. Sulfonamides – – ± Slow Long – – – Minor +±

8. Tetracyclines + – + Slow Short – – – Nil +

9. Artemisinin – – + Fastest Short – + + Nil +

10. Lumefantrine – – + Int. long – – – Nil +

*Do not kill gametes but inhibit their development in mosquito.Preerythro. — Preerythrocytic stage; Exoerythro. — Exoerythrocytic stageFal. — P. falciparum; Viv — P. vivax; Int — Intermediate

cause relapses subsequently without reinfection.Thus, the above drugs are radical curatives forfalciparum but not for vivax malaria. Recrudes-cences occur in falciparum infection if the blood isnot totally cleared of the parasites by the drug.

The drugs and regimens used for uncompli-cated falciparum and vivax malaria are listed inthe box (see box on p. 455). Only oral drugs areused for uncomplicated malaria.

Severe and complicated falciparum malaria Thisincludes P. falciparum infection attended by oneor more of hyperparasitaemia, hyperpyrexia, fluidand electrolyte imbalance, hypoglycaemia,prostration, cardiovascular collapse, pulmonaryedema, jaundice, haemoglobinuria, black waterfever, renal failure and cerebral malaria.Parenteral (i.m./i.v.) drugs have to be used; oraldrugs may be substituted when the conditionimproves. Drugs employed are—artesunate/artemether/arteether or quinine.

4. Radical cure Drugs which attack the exo-erythrocytic stage (hypnozoites) given togetherwith a clinical curative achieve total eradicationof the parasite from the patient’s body. A radical

curative is needed in relapsing malaria, while infalciparum malaria — adequate treatment of cli-nical attack leaves no parasite in the body (thereis no secondary exoerythrocytic tissue phase).Drug of choice for radical cure of vivax malaria isprimaquine 15 mg daily for 2 weeks immediatelyfollowing 3 day chloroquine (or other schizonto-cide) therapy.

There is no point in antirelapse treatment inhighly endemic areas, because chances ofreinfection would be high.

5. Gametocidal This refers to the eliminationof the male and female gametes of Plasmodiaformed in the patient’s blood. Gametocidal actionis of no benefit to the patient being treated, butwill reduce the transmission to mosquito.

Primaquine is gametocidal to all species ofPlasmodia, while chloroquine and quinine areactive against vivax but not falciparum gametes.• A single 45 mg (0.75 mg/kg) dose of prima-quine is employed immediately after clinical cureof falciparum malaria.

Artemisinins, though early phase gameto-cidals, do not kill mature gametes.

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The mechanism of action of chloroquine is notcompletely known. It is actively concentrated bysensitive intraerythrocytic plasmodia. Byaccumulating in the acidic vesicles of the parasiteand because of its weakly basic nature, it raisesthe vesicular pH and thereby interferes withdegradation of haemoglobin by parasiticlysosomes. Polymerization of toxic heme tonontoxic parasite pigment hemozoin is inhibitedby formation of chloroquine-heme complex. Hemeitself or its complex with chloroquine thendamages the plasmodial membranes. Otherrelated antimalarials like quinine, mefloquine,appear to act in an analogous manner.

Chloroquine resistance among P.vivax hasbeen slow in developing. However, P. falciparumhas acquired significant resistance and resistantstrains have become prevalent, especially ineastern part of India, South-East Asia, Africa andSouth America and some of these have becomemultidrug resistant.

Resistance in P. falciparum is associated witha decreased ability of the parasite to accumulatechloroquine.

Other actions Chloroquine is active againstEntamoeba histolytica and Giardia lamblia also.It has antiinflammatory, local irritant and localanaesthetic (on injection), weak smooth musclerelaxant, antihistaminic and antiarrhythmicproperties.

Pharmacokinetics Oral absorption of chloro-quine is excellent. About 50% gets bound in theplasma. It is concentrated in spleen, kidney, lungs,liver (several hundred-fold), skin, leucocytes andsome other tissues. Its selective accumulation inretina is responsible for the ocular toxicity seenwith prolonged use.

Chloroquine is partly metabolized by liver andslowly excreted in urine. The plasma t½ variesfrom 3–10 days or more. Because of tight tissuebinding, small amounts persist in the body formonths.

Adverse effects Toxicity of chloroquine islow, but side effects are frequent and unpleasant:


Treatment of uncomplicated malaria

A. Vivax malaria

1. Chloroquine 600 mg (10 mg/kg) followed by300 mg (5 mg/kg) after 8 hours and then for next2 days (total 25 mg/kg over 3 days) +Primaquine 15 mg (0.25 mg/kg) daily × 14 days

In occasional case of chloroquine resistance2. Quinine 600 mg (10 mg/kg) 8 hourly × 7 days +

Doxycycline 100 mg daily × 7 days +Primaquine (as above)

B. Chloroquine-sensitive falciparum malaria

1. Chloroquine (as above) + Primaquine 45 mg(0.75 mg/kg) single dose (as gametocidal)

In case of intolerance to chloroquine2. Sulfadoxine 1500 mg (25 mg/kg) + Pyrimethamine

75 mg (1.25 mg/kg) single dose +Primaquine 0.75 mg/kg single dose

C. Chloroquine-resistant falciparum malaria

1.* Artesunate 100 mg BD (4 mg/kg/day) × 3 days +Sulfadoxine# 1500 mg (25 mg/kg) +Pyrimethamine 75 mg (1.25 mg/kg) single dose

or2. Artesunate 100 mg BD (4 mg/kg/day) × 3 days +

Mefloquine# 750 mg (15 mg/kg) on 2nd day and500 mg (10 mg/kg) on 3rd day.

or3. Artemether 80 mg + Lumefantrine 480 mg twice

daily × 3 days (child 25–35 kg BW ¾ dose;15–25 kg BW ½ dose; 5–15 kg BW ¼ dose)

or4.$ Quinine 600 mg (10 mg/kg) 8 hourly × 7 days +

Doxycycline 100 mg daily × 7 days.

*First line ACT under NVBDCP$Second line drug under NVBDCP#Sulfadoxine-pyrimethamine (S/P) alone and mefloquinealone are also used, but should preferably be combinedwith artesunate.

CHLOROQUINE

It is a rapidly acting erythrocytic schizontocideagainst all species of Plasmodia; controls mostclinical attacks in 1– 2 days with disappearanceof parasities from peripheral blood. However, ithas no effect on pre- and exoerythrocytic phasesof the parasite — does not prevent relapses invivax malaria.


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nausea, vomiting, anorexia, uncontrollableitching, epigastric pain, uneasiness, difficulty inaccomodation and headache. Suppressive doseshave been safely given for 3 years.• Prolonged use of high doses (as needed for

rheumatoid arthritis, DLE, etc.) may cause lossof vision due to retinal damage.

• Loss of hearing, rashes, photoallergy, mentaldisturbances, myopathy and graying of haircan occur on long-term use.

Chloroquine should not be coadministered withmefloquine, amiodarone and other antiarrhy-thmics.

Uses

1. Chloroquine is the drug of choice for clinicalcure and suppressive prophylaxis of all typesof malaria, except that caused by resistant P.falciparum.2. Extraintestinal amoebiasis.3. Rheumatoid arthritis (Ch. 22).4. Discoid lupus erythematosus—very effective;

less valuable in systemic LE.5. Lepra reactions.6. Photogenic reactions.

Amodiaquine It is almost identical to chloro-quine in properties and is less unpalatable. It canbe used as an alternative to chloroquine for clinicalcure of uncomplicated malaria, but is notrecommended for prophylaxis because of somereports of fatal hepatitis and agranulocytosisamong travelers to Africa in the 1980s.Amodiaquine appears to be active againstchloroquine resistant P. falciparum and is beingtried in combination with artesunate as ACT inareas with resistant falciparum malaria.

Side effects of amodiaquine are similar tochloroquine; itching may be less common.

Piperaquine It is a bisquinoline congener of chloroquinedeveloped in China as a long acting (t½ 2-3 weeks)erythrocytic schizontocide with a slower onset of action. Itis active against chloroquine-resistant P. falciparum and isbeing used in far-east countries for treating falciparummalaria along with dihydroartemisinin as ACT.

MEFLOQUINE

It is a drug developed to deal with the problem ofchloroquine-resistant P. falciparum. Mefloquine isa rapidly acting erythrocytic schizontocide, butslower than chloroquine or quinine; effectiveagainst chloroquine-sensitive as well as resistantplasmodia. It controls fever and eliminatescirculating parasites in infections caused by P.falciparum or P. vivax. However, like chloroquine,relapses occur subsequently in vivax malaria. Itis also an efficacious suppressive prophylacticfor multiresistant P. falciparum and other types ofmalaria. Mefloquine resistance among P.falciparum has become common in Thailand,Cambodia and Myanmar, but is not a problemyet in India. Resistance to mefloquine conferscross resistance to quinine and halofantrine.

The mechanism of action of mefloquine is notknown, but appears to be similar to that ofchloroquine.

Pharmacokinetics Oral absorption of meflo-quine is good but quite slow. Extensive meta-bolism occurs in liver and it is primarily secretedin bile. Considerable enterohepatic circulation ofmefloquine and its tissue binding accounts forthe long t½ which is 2–3 weeks.

Adverse effects Mefloquine is bitter in taste;common reaction is dizziness, nausea, vomiting,diarrhoea, abdominal pain and sinus brady-cardia. Major concern has been a variety ofneuropsychiatric reactions (disturbed sense ofbalance, ataxia, errors in operating machinery,strange dreams, anxiety, hallucinations, rarelyconvulsions) occurring in some recipients.

Interactions Halofantrine or quinidine/quininegiven to patients who have received mefloquinecause QTc lengthening—cardiac arrests arereported.

Use Mefloquine is an effective drug for multi-resistant P. falciparum. Because of its potentialtoxicity, cost and long t½, its use is being restric-ted to areas where such strains are prevalent. Tocheck the development of mefloquine resistance,current recommendation is to use it only in

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conjunction with artesunate for chloroquine/multidrug resistant falciparum malaria. It cannotbe given parenterally and is not used incomplicated/cerebral malaria.

QUININE

Quinine is the levo rotatory alkaloid obtainedfrom cinchona bark. Its d-isomer quinidine isused as an antiarrhythmic (and for malaria as wellin some countries).

Quinine is an erythrocytic schizontocide forall species of Plasmodia; less effective and moretoxic than chloroquine. Resurgence of interest inquinine is due to the fact that most chloroquineand multidrug resistant strains of P. falciparumare still sensitive to it. However, even quinineresistance has been encountered in some countriesbut not in India. There is partial cross resistancebetween quinine and mefloquine, but manymefloquine-resistant cases respond to quinine.

Quinine has no effect on preerythrocytic stageand on hypnozoites of relapsing malaria, but killsvivax gametes. Like chloroquine, it is a weak base:acts in an analogous manner.

Quinine has many other actions. It is intenselybitter and irritant: orally causes nausea, vomitingand epigastric discomfort. Gastric secretion isstimulated. Weak analgesic, antipyretic actions,impairment of hearing and vision are producedat higher doses. Cardiodepressant, antiarrhy-thmic and hypotensive actions are similar toquinidine. Quinine stimulates uterine contrac-tions, but reduces skeletal muscle contractility.Hypoglycaemia can occur on i.v. injection ofquinine.

Pharmacokinetics Quinine is rapidly andcompletely absorbed orally. A large fraction of thedose is metabolized in the liver by CYP3A4 andexcreted in urine with a t½ of 10–12 hours;noncumulative.

Adverse effects Toxicity of quinine is high anddose related; 8–10 g taken in a single dose may befatal.

Cinchonism Large single doses or higher thera-peutic doses taken for a few days produce a

syndrome called cinchonism. It consists ofringing in ears, nausea, vomiting, headache,mental confusion, vertigo, difficulty in hearingand visual defects. Diarrhoea, flushing andmarked perspiration may also appear.

Few individuals are idiosyncratic/hypersen-sitive to quinine. Purpura, rashes, itching, angio-edema of face and bronchoconstriction may alsoappear.

Uses

1. Malaria: Quinine is used orally for uncomp-licated chloroquine-resistant malaria (alone or incombination with sulfa + pyrimethamine ortetracycline), and i.v. for complicated/cerebralmalaria.

2. Nocturnal muscle cramps.

3. Spermicidal: in vaginal creams.

4. Varicose veins: injected along with urethane,it causes thrombosis and fibrosis of the varicosevein mass.

PROGUANIL (CHLOROGUANIDE)

It is a slow acting erythrocytic schizontocidewith causal prophylactic property against P.falciparum. Gametocytes exposed to proguanil arenot killed but fail to develop in the mosquito. It iscyclized in the body to a triazine derivative (cyc-loguanil) which inhibits plasmodial DHFRase inpreference to the mammalian enzyme. Resistanceto proguanil develops rapidly due to mutationalchanges in the plasmodial DHFRase enzyme.

Proguanil is slowly but adequately absorbedfrom the gut, is partly metabolized and excretedin urine; t½ is 16–20 hours; noncumulative. It isvery well tolerated; side effects are less comparedto chloroquine; mild abdominal upset, vomiting,occasional stomatitis.

Current use of proguanil is restricted toprophylaxis of malaria in combination withchloroquine in areas with low level chloroquineresistance among P. falciparum. In some countriesits combination with atovaquione is used fortreating resistant falciparum malaria.



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PYRIMETHAMINE

It is a directly acting inhibitor of DHFRase that hashigh affinity for plasmodial enzyme (~2000 timesgreater than for the mammalian enzyme). Incontrast to trimethoprim, it has very poor action onbacterial DHFRase. Under the influence ofpyrimethamine, schizogony of malarial parasitein blood gradually stops. At high doses, it inhibitsToxoplasma gondii.

Pyrimethamine is a slowly acting erythrocyticschizontocide, but not a radical curative. If usedalone, resistance develops rather rapidly bymutation in the DHFRase enzyme of the parasite.

Pharmacokinetics Absorption of pyrimethaminefrom g.i.t. is good but slow. It is metabolized andexcreted in urine with a t½ of 4 days. Prophylacticconcentrations remain in blood for 2 weeks.

Adverse effects Pyrimethamine is relativelysafe. The only side effects are occasional nauseaand rashes. Folate deficiency due to pyrimetha-mine therapy is rare. This can be treated by folinicacid.

Uses Pyrimethamine is used only in combi-nation with a sulfonamide or dapsone to treatfalciparum malaria.

SULFONAMIDE-PYRIMETHAMINE (S/P)COMBINATION

Sulfonamides/dapsone are not particularlyeffective antimalarial drugs in their own right;have some inhibitory influence on the erythro-cytic phase, especially of P. falciparum. However,they form supra-additive synergistic combinationwith pyrimethamine due to sequential block.Though both components are slow acting, thecombination acts faster, so that it can be employedas a clinical curative, particularly for P. falciparum;efficacy against P. vivax is rather low. By theaddition of sulfonamide, development of resis-tance to pyrimethamine is retarded. Resistance toS/P combination has become prevalent in South-East Asia, but is sporadic in India, restricted

mainly to northeastern states. There is no crossresistance with other groups of antimalarial drugs.

Sulfadoxine and sulfamethopyrazine areultra-long acting sulfonamides — attain low bloodconcentrations, but are able to synergise withpyrimethamine which also has long t½. Thecombination has the potential to cause seriousadverse effects (exfoliative dermatitis, Stevens-Johnson syndrome, etc.) due to the sulfonamidecomponent. Therefore, its use is restricted to singledose treatment of uncomplicated chloroquine-resistant P. falciparum malaria.

The S/P combination is the first choicetreatment for toxoplasmosis which mainly occursin immunocompromised patients.

PRIMAQUINE

In contrast to other antimalarial drugs, prima-quine is a poor erythrocytic schizontocide: hasweak action on P. vivax, but blood forms of P.falciparum are totally insensitive. Primaquinediffers from all other available antimalarials inhaving a marked effect on primary as well assecondary tissue phases of the malarial parasite.Thus, it is a causal prophylactic and radicalcurative but not a clinical curative. It is highlyactive against gametocytes and hypnozoites.

The mechanism of action of primaquine is notknown. However, it is different from that ofchloroquine.

Pharmacokinetics Primaquine is readily absor-bed after oral ingestion. It is oxidized in liver witha plasma t½ of 3–6 hours and excreted in urinewithin 24 hours. It is not a cumulative drug.

Adverse effects The usual doses of primaquineproduce only abdominal pain, g.i. upset,weakness or uneasiness in chest as side effect.

The most important toxic potential is dose-related haemolysis, methaemoglobinaemia,tachypnoea and cyanosis. These are due to theoxidant property of primaquine. In normalindividuals doses < 60 mg (base) produce littlehaemolysis. Those with G-6-PD deficiency are

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highly sensitive and haemolytic anaemia canoccur with 15–30 mg/day. The incidence of G-6-PD deficiency is low among Indians, except insome tribal people. Passage of dark urine is anindication of haemolysis.

Use The primary indication of primaquine isfor radical cure of relapsing (vivax) malaria.

Falciparum malaria: A single 45 mg dose ofprimaquine is given with the curative dose ofchloroquine to kill the gametes and cut downtransmission to mosquito.

Tetracyclines These antibiotics have slowlyacting and weak erythrocytic schizontocidalaction against all plasmodial species. In addition,preerythrocytic stage of P. falciparum is inhibited.However, they are never used alone to treatmalaria. They are used in combination withquinine or S/P for the treatment of chloroquine-resistant falciparum malaria.

Doxycycline 100 mg/day is used as a 2nd lineprophylactic for travellers to chloroquine-resistant P. falciparum areas.

ARTEMISININ DERIVATIVES

Artemisinin is the active principle of the plantArtemisia annua used in Chinese traditionalmedicine as ‘Quinghaosu’. It is a sesquiterpinelactone active against P. falciparum resistant to allother antimalarial drugs as well as sensitivestrains. Potent and rapid blood schizontocideaction is exerted eliciting quicker defervescenceand parasitaemia clearance (<48 hr) than chloro-quine or any other drug.

Artemisinin is poorly soluble in water as wellas oil. Several derivatives have been produced, ofwhich Artemether is soluble in oil, while Artesunate(sod.) is water soluble. Another compoundArteether has been developed in India. They donot kill hypnozoites but act on immaturefalciparum gametes. So far no resistance amongP. falciparum patients to artemisinin has beennoted.

Because these are short-acting drugs, monothe-rapy with them needs to be extended beyond thedisappearance of the parasites to prevent

recrudescence. Recrudescence can be totallyprevented by combining 3 day artesunate with along-acting drug.

Mechanism of action of artemisinin is notdefinitely known. The endoperoxide bridge in itsmolecule appears to interact with heme in theparasite. Iron-mediated cleavage of the bridgereleases a highly reactive free radical species thatbinds to membrane proteins, causes lipidperoxidation, damages endoplasmic reticulum,inhibits protein synthesis and ultimately resultsin lysis of the parasite.

Pharmacokinetics Both artesunate and arte-mether are prodrugs. They are rapidly absorbedand converted into the active metabolite dihydro-artemisinin. Their reported t½ are variable, butshort.

Adverse effects Artesunate/artemether pro-duce few adverse effects; most are mild: nausea,vomiting, abdominal pain, itching and drug fever.Abnormal bleeding, dark urine, S-T segmentchanges, Q-T prolongation, first degree A-V block,have been noted, but subside when the patientimproves or drug is stopped. Intravenousartesunate is much safer than i.v. quinine.

Interactions Concurrent administration of arte-misinin compounds with terfenadine, astemizole,antiarrhythmics, tricyclic antidepressants andphenothiazines may increase risk of cardiacconduction defects.

Use Oral artemisinins are to be used only fortreating acute attacks of uncomplicated falciparummalaria (both chloroquine sensitive as well asresistant). To preserve their powerful antimalarialactivity and to contain recrudescences, bothWHO and NVBDCP (India) recommend thatartemisinins should be used only in combinationwith a long acting schizontocide like mefloquine/lumefantrine or S/P. Such artemisinin-basedcombination therapy (ACT) is highly effective andhas been found to reduce the prevalence of malariaas well as to check the spread of drug-resistantstrains. The currently available ACT regimens aregiven in the box (see box on p. 460).



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Use of artemisinin derivatives for prophylaxisof malaria is irrational and not allowed.Severe and complicated falciparum malaria:Parenteral artemisinin, viz. artesunate (i.v. ori.m.)/artemether (i.m.)/arte ether (i.m.) given tillthe patient is fit to take oral medication, followedby 3 day ACT is highly effective, better toleratedand is now preferred over i.v. quinine.

Halofantrine It is a phenanthrene methanol bloodschizontocide having activity comparable to mefloquineagainst P. falciparum resistant to chloroquine and S/P.

Because of unreliable oral absorption and potential tocause cardiac toxicity, halofantrine is seldom used.

Lumefantrine is an orally effective long-acting congenerof halofantrine that has not shown cardiotoxicity. It iscombined with artemether for treatment of falciparummalaria as ACT.

Atovaquone This synthetic naphthaquinone is a rapidlyacting erythrocytic schizontocide for P. falciparum and otherplasmodia. Proguanil potentiates its antimalarial actionand prevents emergence of resistance. A fixed dose oralcombination of the two drugs is used for 3 day treatmentof uncomplicated chloroquine-resistant P. falciparummalaria in some countries.

Atovaquone is also approved as a second line drugfor opportunistic infections with P. jiroveci and T. gondii inAIDS patients. It produces few side effects—diarrhoea,vomiting, headache, rashes and fever.

ANTIAMOEBIC DRUGS

These are drugs useful in infection caused by theprotozoa Entamoeba histolytica.

Fig. 33.2: The luminal cycle and invasive forms ofamoebiasis. T—trophozoite; C—cysts

ACT regimens for uncomplicated falciparum malaria

1. Artesunate—mefloquine (AS/MQ)Artesunate 100 mg BD (4 mg/kg/day) × 3 days + Mefloquine 750 mg (15 mg/kg) on 2nd day and500 mg (10 mg/kg) on 3rd day (total 25 mg/kg).

2. Artemether—lumefantrine (1:6)Artemether (80 mg BD) + lumefantrine (480 mg BD) × 3 daysCOARTEM, LUMERAX (artemether 20 mg + lumefantrine 120 mg tab.) to be taken with fatty meal.Adult and child >35 kg 4 tab BD; child 25–35 kg 3 tab BD; 15–25 kg 2 tab BD; 5–15 kg 1 tab BD,all for 3 days; also ARTE PLUS 80 mg + 480 mg tab (for adults only).

3. Artesunate—sulfadoxine + pyrimethamine (AS/S/P)Artesunate 100 mg BD (4 mg/kg/day) × 3 days + Sulfadoxine 1500 mg (25 mg/kg) andpyrimethamine 75 mg (1.25 mg/kg) single dose.

Amoebiasis has a worldwide distribution, but it isendemic in most parts of India and other developingcountries. The disease occurs by faecal contamination offood and water. Amoebic cysts reaching the intestinetransform into trophozoites which either live on the surfaceof colonic mucosa as commensals—form cysts that passinto the stools (luminal cycle) and serve to propagate thedisease, or invade the mucosa—form amoebic ulcers (Fig.33.2) and cause acute dysentery (with blood and mucusin stools) or chronic intestinal amoebiasis (with vagueabdominal symptoms, amoeboma).

Occasionally, the trophozoites pass into the blood-stream, reach the liver via portal vein and cause amoebicliver abscess. Other organs like lung, spleen, kidney andbrain are rarely involved in extraintestinal amoebiasis. Inthe tissues, only trophozoites are present; cyst formationdoes not occur. Tissue phase is always secondary to intes-tinal amoebiasis, which may be asymptomatic. In thecolonic lumen, the Entamoebae live in symbiotic relationshipwith bacteria, and a reduction in colonic bacteria reducesthe amoebic population.

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CLASSIFICATION

1. Tissue amoebicides(a) For both intestinal and extraintestinal

amoebiasis:Nitroimidazoles: Metronidazole,Tinidazole, Secnidazole, Ornidazole,SatranidazoleAlkaloids: Emetine, Dehydroemetine

(b) For extraintestinal amoebiasis only:Chloroquine

2. Luminal amoebicides(a) Amide : Diloxanide furoate, Nitazoxanide(b) 8-Hydroxyquinolines: Quiniodochlor

(Iodochlorohydroxyquin, Clioquinol),Diiodohydroxyquin (Iodoquinol)

(c) Antibiotics: Tetracyclines

Metronidazole Metronidazole and other nitro-imidazoles are the first line drugs for all forms ofamoebiasis. They are also active against otherprotozoa (Trichomonas vaginalis, Giardia lamblia)as well as against many anaerobic bacteria, andare described in Ch. 27.

Emetine

It is an alkaloid from Cephaelis ipecacuanha. Emetine is apotent amoebicide—kills trophozoites but has no effecton cysts. It acts by inhibiting protein synthesis in amoebaeby arresting intraribosomal translocation of tRNA-aminoacid complex.

In acute dysentery the stool is rapidly cleared of thetrophozoites and symptomatic relief occurs in 1–3 days.It is highly efficacious in amoebic liver abscess also.

Emetine cannot be given orally because it will bevomited out. It is administered by s.c. or i.m. injection.Emetine is very slowly excreted in urine taking 1–2 months:can produce cumulative toxicity.

Toxicity of emetine is high, the most prominent ofwhich is nausea, vomiting, abdominal cramps, myo-carditis, ECG changes, heart failure, hypotension andmyositis. It is now rarely used for severe intestinal orhepatic amoebiasis only in patients not responding to ornot tolerating metronidazole.

Dehydroemetine is a semisynthetic derivative of emetine;equally effective but less cumulative and less toxic to theheart.

Chloroquine

Chloroquine kills trophozoites of E. histolytica andis highly concentrated in liver. Therefore, it isused in hepatic amoebiasis only. Because it iscompletely absorbed from the upper intestine andnot so highly concentrated in the intestinal wall—it is neither effective in invasive dysentery nor incontrolling the luminal cycle (cyst passers).

For amoebic liver abscess, chloroquine issometimes given along with or immediately aftera course of metronidazole to ensure completeeradication of the trophozoites in liver. A luminalamoebicide must always be given with or afterchloroquine to abolish the luminal cycle.

Diloxanide furoate

It is a highly effective luminal amoebicide: direc-tly kills trophozoites responsible for productionof cysts. The furoate ester is hydrolysed inintestine and the released diloxanide is largelyabsorbed. Diloxanide is a weaker amoebicidethan its furoate ester : no systemic antiamoebicactivity is evident despite its absorption.

Diloxanide furoate exerts no antibacterialaction. It is less effective in invasive amoebicdysentery, because of poor tissue amoebicidalaction. However, it has produced high cure ratesin mild intestinal amoebiasis and in asympto-matic cyst passers.

Diloxanide furoate is very well tolerated; theonly side effects are flatulence, occasional nausea,itching and rarely urticaria.

Nitazoxanide This congener of the antitape-worm drug niclosamide has been introduced forthe treatment of giardiasis, but is useful inamoebic dysentery and cryptosporidiasis also. Itsactive metabolite acts by inhibiting the enzymepyruvate: ferredoxin oxidoreductase (PFOR) inthe parasite.

8-Hydroxyquinolines

The 8-hydroxyquinolines were widely employedin the past. All have similar properties; are activeagainst Entamoeba, Giardia, Trichomonas, some

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fungi (dermatophytes, Candida) and some bac-teria. They kill the cyst forming trophozoites inthe intestine, but do not have tissue amoebicidalaction. Like diloxanide furoate, they are not veryeffective in acute amoebic dysentery but affordrelief in chronic intestinal amoebiasis. Theirefficacy in eradicating cysts from asymptomaticcarriers is rated lower than that of diloxanidefuroate and they are totally valueless inextraintestinal amoebiasis.

8-Hydroxyquinolines are well tolerated:produce few side effects—nausea, transient looseand green stools, pruritus, etc. Goiter has beenreported after prolonged medication.

Iodism (furunculosis, inflammation of mucousmembranes) may occur due to chronic iodineoverload. Individuals sensitive to iodine mayexperience an acute reaction with chills, fever,angioedema and cutaneous haemorrhages.

Prolonged/repeated use of relatively highdoses of quiniodochlor caused a neuropathicsyndrome called ‘subacute myelo-optic neuro-pathy’ (SMON) in Japan in an epidemic form,affecting several thousand people in 1970.However, despite widespread use in the past, onlysporadic and unconfirmed cases have beenreported from India. These drugs have beenbanned in Japan and few other countries; but inIndia, they are banned only for pediatric patients,because their use for chronic diarrhoeas inchildren has caused blindness. They may beemployed in intestinal amoebiasis as alternativeto diloxanide furoate.

Other uses are—giardiasis; local treatment ofmonilial and trichomonas vaginitis, fungal andbacterial skin infections.

Tetracyclines They directly inhibit amoebaeonly at high concentrations. The older tetra-cyclines are incompletely absorbed in the smallintestine, reach the colon in large amounts andinhibit the bacterial flora with which Entamoebaelive symbiotically. Thus, they indirectly reduceproliferation of entamoebae in the colon and arespecially valuable in chronic, difficult to treatcases with only the luminal cycle and little

mucosal invasion. Tetracyclines have an adjuvantrole, in conjunction with a directly acting luminalamoebicide. They are not good for acute dysenteryand for hepatic amoebiasis.

DRUGS FOR GIARDIASIS

Giardia lamblia is a flagellate protozoon whichmostly lives as a commensal in the intestine. Itsometimes invades the mucosa and causes diar-rhoea requiring treatment. Many drugs useful inamoebiasis are also effective in giardiasis.

Metronidazole and its congeners are the drugsof choice for giardiasis. Quiniodochlor andnitazoxanide are the alternatives. In addition,furazolidone, a nitrofuran compound activeagainst gram-negative bacilli including Salmonellaand Shigella is effective in diarrhoea caused byGiardia.

DRUGS FOR TRICHOMONIASIS

Trichomonas vaginalis is another flagellateprotozoon which causes vulvovaginitis. A largenumber and variety of drugs are effective byvaginal application, but may not entirely clearthe infection; recurrences are frequent; repeatcourses are required.

1. Drugs used orallyMetronidazole 400 mg TDS for 7 days or 2 g singledose, or Tinidazole 600 mg daily for 7 days or 2 gsingle dose or Secnidazole 2 g single dose, are thedrugs of choice. They produce >90% cure.Additional intravaginal treatment is required onlyin refractory cases. A hard core of recurrent casesmay remain. A repeat course can be given after 6weeks and additional treatment for nonspecificvaginosis often helps. In some cases recurrencesare due to reinfection from the male partner. Insuch cases, both partners should be treated con-currently to prevent cross infection of each other.

2. Drugs used intravaginally

Drugs that are effective locally in trichomonasvaginitis and are available as vaginal pessaries

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to be inserted in the vagina every night for 1 – 2weeks include antiamoebics like quiniodochlor,diiodohydroxyquin, antifungals like clotrimazole,hamycin, natamycin and antiseptic like povidoneiodine.

DRUGS FOR LEISHMANIASIS

Visceral leishmaniasis (kala-azar) caused by Leishmaniadonovani occurs in several tropical and subtropical regionsof the world. It is endemic in the eastern States of India,particularly Bihar.

Leishmaniasis is transmitted by the bite of the femalesandfly phlebotomus. In the fly the parasite exists in theflagellate extracellular (promastigote) form, while in man itis found only intracellularly within macrophages in thenonflagellate (amastigote) form.Drugs used in the treatment of leishmaniasis are:

Antimonial Sodium stibogluconate (SSG)Diamidine Pentamidine

Antifungal drugs Amphotericin B (AMB)Ketoconazole (KTZ)

Others MiltefosineParomomycinAllopurinol

Sodium stibogluconate (SSG) It is the drug of choicefor kala-azar, but no longer useful in Bihar because ofextensive resistance. It is a water-soluble pentavalentantimonial containing 1/3 antimony by weight. Themechanism of action and the basis of selective toxicity tothe leishmania amastigotes is unclear.

Sod. stibogluconate is rapidly absorbed from the siteof i.m. injection and excreted unchanged in urine within6–12 hours. A small fraction enters tissues and remainsstored for long periods. Repeated doses are cumulative.

It is available as aqueous solution; and is administeredby deep i.m. or slow i.v. injection daily for 20-30 days.However, most cases now fail to respond due todevelopment of resistance.

Nausea, vomiting, metallic taste, cough, painabdomen, pain and stiffness of injected muscle, sterileabscesses, and mental symptoms are the side effects.

Sod. stibogluconate, nevertheless, is less toxic thanamphotericin B and pentamidine.

Pentamidine The diamidines are active against L.donovani, Trypanosomes, Pneumocystis carinii, some bacteriaand fungi (Blastomyces). Their mechanism of action is notproperly understood. Pentamidine probably interacts withkinetoplast DNA and inhibits topoisomerase II, or inter-feres with aerobic glycolysis and utilization of polyamines.

Dose: 4 mg/kg deep i.m. or slow i.v. injection (over 1 hr)on alternate days for 5–25 weeks.

Toxicity of pentamidine is high. Because of its strongbasic nature, it causes histamine release which can producesharp fall in BP, cardiovascular collapse, dyspnoea,palpitation, fainting, vomiting, rigor and fever.

Other adverse effects are rashes, mental confusion,kidney and liver damage, ECG changes.

Pentamidine causes cytolysis of pancreatic β cells:insulin is released initially causing hypoglycaemia. Lateron, permanent insulin-dependent diabetes mellitus canresult in some cases.

Pentamidine is now a reserve drug only for antimonialfailure cases of kala-azar when amphotericin B cannot beused. It is also a second line drug for Pneumocystis jirovecipneumonia in AIDS patients.

Amphotericin B (AMB) Like fungi, Leishmania has highpercentage of ergosterol and is susceptible to this antifungalantibiotic. Amphotericin B is highly effective in kala-azar:up to 98% clinical and parasitological cure has beenreported in stibogluconate resistant cases. Despite itstoxicity and need for repeated slow i.v. infusions, it hasbecome the standard treatment for kala-azar in Bihar dueto high incidence of SSG resistance. It is also effective inmucocutaneous leishmaniasis.

Ketoconazole Another antifungal drug found to killLeishmania by inhibiting conversion of lanosterol to ergosterol.It is quite effective in dermal leishmaniasis but efficacy inkala-azar is lower; may be used as add-on drug.

Miltefosine It is the first effective oral drug for kala-azar, which though under study for long, has not beenmarketed. Stibogluconate resistant cases also respond tomiltefosine.

Paromomycin Introduced as an oral drug for amoebiasisin the 1960s and soon withdrawn, this aminoglycosideantibiotic has been found to be highly effective in kala-azar when injected i.m. Though, paromomycin producesototoxicity and elevated serum transaminases, it has beenapproved for use in kala-azar.

Allopurinol This hypoxanthine analogue and uric acidsynthesis inhibitor exerts selective toxic effect on amas-tigotes. The unique purine salvage pathway present inLeishmania metabolizes allopurinol into the correspondingnucleotides which interfere with protein synthesis.

Allopurinol is employed only as a companion drug toantimonials in resistant cases.

ANTHELMINTIC DRUGS

Anthelmintics are drugs that either kill (vermi-cide) or expel (vermifuge) infesting helminths.

Helminthiasis is prevalent globally (1/3rd ofthe world’s population harbours them), but ismore common in developing countries with

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Table 33.2: Choice of drugs for helminthiasis

Worm First choice drugs Alternative drugs

1. ROUNDWORM Mebendazole, Albendazole, Piperazine, Levamisole,Ascaris lumbricoides Pyrantel Ivermectin

2. HOOKWORMAncylostoma Pyrantel, Mebendazole, Levamisole

duodenale AlbendazoleNecator americanus Mebendazole, Albendazole Pyrantel

3. THREADWORM Pyrantel, Mebendazole, PiperazineEnterobius (Oxyuris) Albendazole

vermicularis

4. Strongyloides stercoralis Ivermectin Albendazole

5. WHIPWORMTrichuris trichiura Mebendazole Albendazole

6. Trichinella spiralis Albendazole Mebendazole

7. FILARIA Diethyl carbamazine, AlbendazoleWuchereria bancrofti, IvermectinBrugia malayi

8. GUINEAWORM MetronidazoleDracunculus medinensis

9. TAPEWORMSTaenia saginata Praziquantel, Niclosamide AlbendazoleTaenia solium Praziquantel Niclosamide, AlbendazoleHymenolepis nana Praziquantel NiclosamideNeurocysticercosis Albendazole Praziquantel

10. HYDATID DISEASEEchinococcus granulosus, Albendazole MebendazoleE. multilocularis Albendazole

poorer personal and environmental hygiene. Inthe human body, g.i.t. is the abode of manyhelminths, but some also live in tissues, or theirlarvae migrate into tissues. Helminthiasis is rarelyfatal, but is a major cause of ill health.

The common worm infestations and thecurrent drugs of choice for these are listed in Table33.2.

Mebendazole

This broad-spectrum anthelmintic has producednearly 100% cure rate/reduction in egg count inroundworm, hookworm (both species), Enterobiusand Trichuris infestations, but is much less activeon Strongyloides. Up to 75% cure has been reportedin tapeworms, but H. nana is relatively insensitive.

It expels Trichinella spiralis from intestines, butefficacy in killing larvae that have migrated tomuscles is uncertain. Prolonged treatment hasbeen shown to cause regression of hydatid cystsin the liver. Treatment after resection of the cystmay prevent its regrowth.

The immobilizing and lethal action of meben-dazole on worms is rather slow: takes 2–3 days todevelop. It acts probably by blocking glucoseuptake in the parasite and depletion of itsglycogen stores. The site of action of mebendazoleappears to be the microtubular protein ‘β-tubulin’of the parasite. It binds to β-tubulin of susceptibleworms with high affinity and inhibits itspolymerization.

Absorption of mebendazole from intestines isminimal.

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No preparation or postdrug fasting/ purging isrequired.• Ascaris, hookworm, Enterobius and Trichuris: a

single dose of 400 mg.• Tapeworms and strongyloidosis: 400 mg daily

for 3 consecutive days.• Trichinosis: Three-day treatment expels the

adult worm from intestine.• Neurocysticercosis: Treatment with 15 mg/kg

daily for 8-15 days has produced results betterthan praziquantel. Albendazole is the drug ofchoice now.

• Hydatid disease: 400 mg BD for 4 weeks, repeatafter 2 weeks (if required), up to 3 courses.

Pyrantel pamoate

This polyanthelmintic has high efficacy againstAscaris, Enterobius and Ancylostoma comparableto that of mebendazole. Lower cure rates (about60%) have been obtained in case of Necatorinfestation. It is less active against Strongyloidesand inactive against Trichuris or other worms.

Pyrantel causes activation of nicotiniccholinergic receptors in the worms resulting inpersistent depolarization → slowly developingcontracture and spastic paralysis. Worms are thenexpelled. Because piperazine causes hyperpolari-zation and flaccid paralysis, it antagonizes theaction of pyrantel. Cholinergic receptors inmammalian skeletal muscle have very low affinityfor pyrantel. Only 10–15% of an oral dose ofpyrantel pamoate is absorbed.

Pyrantel pamoate is remarkably free of sideeffects: occasional g.i. symptoms, headache anddizziness is reported. Abnormal migration ofworms is not provoked.

Use For Ascaris, Ancylostoma and Enterobius: asingle dose of 10 mg/kg is recommended. A 3-day course for Necator and for Strongyloides hasbeen suggested.

Piperazine

This relatively narrow spectrum anthelmintic ishighly active against Ascaris and Enterobius.


Mebendazole is well tolerated even by patientsin poor health. Diarrhoea, nausea and abdominalpain have attended its use in heavy infestation.Incidents of expulsion of Ascaris from mouth ornose have occurred.

Uses

Round wormHook wormTrichuris

Enterobius: 100 mg single dose, repeated after2–3 weeks.Trichinella spiralis: 200 mg BD for 4 days; lesseffective than albendazole.Hydatid disease: 200–400 mg BD or TDS for 3–4weeks; less effective than albendazole.

Albendazole

This congener of mebendazole: retains the broad-spectrum activity and excellent tolerability of itspredecessor, and has the advantage of single dosetreatment in many cases. One dose treatment hasproduced cure rates in ascariasis, hookworm (bothspecies) and enterobiasis which are comparableto 3-day treatment with mebendazole. Results intrichuriasis have been inferior to mebendazole.In strongyloidosis, it is more effective thanmebendazole. Three-day treatment has been foundnecessary for tapeworms including H. nana.Results in hydatid disease and hookworm havebeen superior to mebendazole.

Absorption of albendazole after oral adminis-tration is moderate but inconsistent. The fractionabsorbed is converted to its sulfoxide metabolitewhich is active. Albendazole sulfoxide is widelydistributed in the body, enters brain and is excretedin urine with a t½ of 8.5 hours. Thus, albendazoleis able to exert antihelmintic activity in tissues aswell.

Albendazole is well tolerated; only gastro-intestinal side effects have been noted. Prolongeduse as in hydatid or in cysticercosis has causedheadache, fever, alopecia, jaundice and neutro-penia.

100 mg twice a day for 3 consecutivedays. No fasting, purging or any otherpreparation of the patients is needed.

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However, it is now considered a second choicedrug even for these worms. Piperazine causeshyperpolarization of Ascaris muscle by a GABAagonistic action opening Cl¯ channels that causerelaxation and depress responsiveness tocontractile action of ACh. Flaccid paralysis occursand worms are expelled alive. No fasting orpatient preparation is required. Piperazine doesnot excite Ascaris to abnormal migration.

A considerable fraction of the oral dose ofpiperazine is absorbed. It is partly metabolizedin liver and excreted in urine.

Piperazine is safe and well tolerated. Nausea,vomiting, abdominal discomfort and urticaria areoccasional.Dizziness and excitement occur at high doses;toxic doses produce convulsions.

Levamisole, Tetramisole

Tetramisole is recemic; its levo isomer (levamisole)was found to be more active and is preferred now.Both are active against many nematodes, but useis restricted to ascariasis and ancylostomiasis,because action on other worms is poor. It stimu-lates the ganglia in worms, causes tonic paralysiswhich results in expulsion of live worms.

Uses For Ascaris infestation a single dose oflevamisole 150 mg for adults is advocated.Levamisole is a second line drug for A. duodenale;2 doses at 12-hour interval are suggested.Levamisole is an immunomodulator as well—restoresdepressed T cell function. It has been tried in aphthousulcers and recurrent herpes, but repeated doses producesevere reactions; not used now.

One or two doses used in helminthiasis are welltolerated. Incidence of side effects—nausea,abdominal pain, giddiness, fatigue, drowsinessor insomnia is low.

Diethyl carbamazine citrate (DEC)

It is the first drug for filariasis. DEC is absorbedafter oral ingestion, distributed all over the body,metabolized in liver and excreted in urine. Plasmat½ of usual clinical doses is 4–12 hours.

Diethylcarbamazine has a highly selectiveeffect on microfilariae (Mf). A dose of 2 mg/kgTDS clears Mf of W. bancrofti and B. malayi fromperipheral blood in 7 days. The most importantaction of DEC appears to be alteration of Mfmembranes so that they are readily phagocytosedby tissue fixed monocytes, but not by circulatingphagocytes. Muscular activity of the Mf and adultworms is also affected due to hyperpolarizationso that they are dislodged. Prolonged treatmentmay kill adult B. malayi and probably W. bancroftiworms as well.

DEC is active against Mf of Loa loa andOnchocerca volvulus. The adult worm of L. loa butnot O. volvulus is killed.

Uses

1. Filariasis: 2 mg/kg TDS produces rapidsymptomatic relief; Mf disappear from blood andpatient becomes noninfective to mosquitoes in 7days. A total dose of 72–126 mg/kg spread over12 to 21 days may kill adult worms and achieveradical care. Elephantiasis due to chroniclymphatic obstruction is not affected by DEC.2. Tropical eosinophilia: DEC (2–4 mg/kg TDS) for2–3 weeks produces dramatic improvement in thesigns and symptoms of eosinophilic lung ortropical eosinophilia.

Loa loa and O. volvulus infections can also betreated with DEC, but ivermectin is preferred.

Adverse effects These are common but generallynot serious. Nausea, loss of appetite, headache,weakness and dizziness are the usual complaints.

A febrile reaction with rash, pruritus, enlarge-ment of lymph nodes and fall in BP may occurdue to mass destruction of Mf and adult worms.

Ivermectin

It is an extremely potent semisynthetic derivativeof the antinematodal principle obtained fromStreptomyces avermitilis. Ivermectin is the drug ofchoice for single dose treatment of onchocerciasisand strongyloidosis, and is comparable to DEC

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for bancroftian and brugian filaria. It is alsohighly effective in cutaneous larva migrans andascariasis, while efficacy against Enterobius andTrichuris is moderate. Certain insects, notablyscabies and head lice are killed by ivermectin.

Nematodes develop tonic paralysis whenexposed to ivermectin. It acts through a specialtype of glutamate gated Cl¯ channel found onlyin invertebrates. Potentiation of GABAergictransmission in the worm has also been observed.The lack of GABA-related actions in man couldbe due to its low affinity for mammalian GABAreceptors and its exclusion from the brain,probably by P-glycoprotein mediated efflux at theblood-brain barrier.

A single 10–15 mg (0.2 mg/kg) oral dose ofivermectin, preferably with 400 mg albendazole,given annually for 5–6 years has been used forfilariasis.

Ivermectin is the only drug effective orally inscabies and pediculosis. Single 0.2 mg/kg dosecures most patients.

Ivermectin is well absorbed orally, widelydistributed in the body, sequestrated in liver andfat and has a long elimination t½ of 48–60 hours.Side effects have been mild—pruritus, giddiness,nausea, abdominal pain, constipation, lethargyand transient ECG changes, but more importantare the reactions due to degeneration products ofthe Mf.

Niclosamide

It is a highly effective drug against cestodesinfesting man—Taenia saginata, T. solium,Diphyllobothrium latum and Hymenolepis nana, aswell as threadworm. The drug appears to act byinhibiting oxidative phosphorylation inmitochondria and interfering with anaerobicgeneration of ATP by the tapeworm. Injured byniclosamide, the tapeworms are partly digestedin the intestine. In cases of T. solium, digestion ofthe dead segments can be hazardous, because theova released from them may develop into larvaein the intestine, penetrate its wall and causevisceral cysticercosis.

For tapeworm (T. saginata), two doses ofniclosamide 1 g each are given 1 hour apartfollowed by a saline purge after 2 hours to washoff the worm.

For H. nana, the 2 g dose is repeated daily for 5days. Praziquantel is now preferred due to singledose treatment.

Niclosamide is tasteless and nonirritating. Itis minimally absorbed from g.i.t.—no systemictoxicity occurs. It is well tolerated; minorabdominal symptoms are produced occasionally.

Praziquantel

This anthelmintic has wide ranging activityagainst Schistosomes, other flukes, tapeworms, andtheir larval forms, but not against nematodes(round worms). It is rapidly taken up by suscep-tible worms and appears to act by causing leakageof intracellular calcium from the membranes →contracture and paralysis: intestinal worms areexpelled. Praziquantel is active against adult aswell as juvenile and larval stages of tapeworms.

At relatively higher concentrations, it causesvacuolization of the tegument and release of thecontents of tapeworms and flukes followed bytheir destruction by the host. This action appearsto be more important in cases of schistosomes andflukes.

Pharmacokinetics Praziquantel is rapidly absor-bed from intestines and undergoes high first passmetabolism in liver which limits its systemicbioavailability. Phenytoin, carbamazepine andpossibly dexamethasone induce praziquantelmetabolism and further reduce its bioavailability.Patients of neurocysticercosis are often receivingthese drugs—may contribute to therapeuticfailure of praziquantel. It crosses blood-brainbarrier and attains therapeutic concentrations inthe brain and CSF. The plasma t½ is short(1.5 hours). Metabolites are excreted chiefly inurine.

Adverse effects Despite systemic absorption,praziquantel has exhibited no systemic toxicity.



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It tastes bitter: can produce nausea and abdo-minal pain. Other side effects are headache,dizziness and sedation. When used for schisto-somes and visceral flukes, symptoms like itching,urticaria, rashes, fever and bodyache occur as areaction to the destroyed parasites.

Uses

1. Tapeworms: Praziquantel is the drug ofchoice for all species of human tapeworms. Asingle dose achieves > 90% cure rate. Because italso kills tapeworm larvae, there is no risk of

cysticercosis in case of T. solium and of reinfectionin case of H.nana.

2. Neurocysticercosis: Higher dose of praziquantelgiven daily for 15 days kills tapeworm larvaelodged in brain and other tissues. Inflammatoryneurological reactions occur in cerebral cysti-cercosis needing steroid cover. It is now the 2ndchoice drug to albendazole. It is contraindicatedin ocular cysticercosis.3. Flukes: Praziquantel is the drug of choice forall schistosome and fluke infestations exceptFasciola hepatica.

Antiseptics, Disinfectants andOther Locally Acting Drugs

ANTISEPTICS AND DISINFECTANTS

The terms antiseptic and disinfectant connote anagent which inhibits or kills microbes on contact.Conventionally, agents used on living surfaces(patient’s mouth, dentist’s hands, etc.) are calledantiseptics while those used for inanimate objects(instruments, working surfaces, water supply,privies, etc.) are called disinfectants. There isconsiderable overlap and many agents are usedin either way. A practical distinction between thetwo on the basis of a growth inhibiting action onone hand, and a direct lethal action on the other isfutile because these are often concentrationdependent actions. The term Germicide covers bothcategory of drugs.

There, however, is difference between‘disinfection’ and ‘sterilization’. While sterili-zation means complete killing of all forms ofmicroorganisms, disinfection refers to reductionin the number of viable pathogenic microbes to alevel that they do not pose a risk to individualswith normal host defence. The terms ‘sanitization’and ‘decontamination’ also have similar connota-tion. Thus, in ordinary usage, disinfectants donot eliminate all microbes. Application of a dis-infectant to the dentists working plateform doesnot make it totally germ free.

Antiseptics and disinfectants are used indentistry to check cross infection as well as toprevent and treat some infective conditions. Many

instruments are sterilized by autoclaving, butcertain instruments, working surfaces andoperating light handles, etc. cannot be autoclaved;have to be sanitized by disinfectants.

The era of antiseptics and disinfectants was heraldedby Semmelweiss (washing of hands in chlorinated lime)and Lister (antiseptic surgery by the use of phenol) in the19th century. These germicides differ from systemicallyused antimicrobials by their low parasite selectivity—aretoo toxic for systemic use. However, many systemicantimicrobials are applied topically as well and someantibiotics (bacitracin, neomycin) are restricted to topicaluse, but are generally not enumerated with the antiseptics.A strict distinction is thus impossible.

A good antiseptic/disinfectant should be:(i) Chemically stable.

(ii) Cheap.(iii) Nonstaining with agreeable colour and

odour.(iv) Cidal and not merely static, destroying

spores as well.(v) Active against all pathogens—bacteria,

fungi, viruses, protozoa.(vi) Able to spread through organic films and

enter folds and crevices.(vii) Active even in the presence of blood, pus,

exudates and excreta.(viii) Require brief time of exposure.

A disinfectant in addition should not corrode orrust instruments and be easily washable. Anantiseptic in addition should be:

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(i) Rapid in action and afford sustainedprotection.

(ii) Nonirritating to tissues, should not delayhealing.

(iii) Nonabsorbable, produce minimum toxicityif absorbed.

(iv) Nonsensitizing (no allergy).(v) Compatible with soaps and other deter-

gents.

Spectrum of activity of majority of antiseptic-disinfectants is wide, reflecting nonselectivity ofaction. However, some are rather selective, e.g.hexachlorophene, chlorhexidine, quaternaryammonium antiseptics, gentian violet andacriflavin are more active on gram-positive thanon gram-negative bacteria; silver nitrate is highlyactive against gonococci and benzoyl peroxideagainst P. acnes.

Mechanisms of action of germicides are varied,but can be grouped into:

(a) Oxidation of bacterial protoplasm.(b) Denaturation of bacterial proteins including

enzymes.(c) Detergent like action increasing permea-

bility of bacterial membrane.

Factors which modify the activity of germicidesare:

(i) Temperature and pH.(ii) Period of contact with the microorganism.

(iii) Nature of microbe involved.(iv) Size of innoculum.(v) Presence of blood, pus or other organic

matter.

Potency of a germicide is generally expressed byits phenol coefficient or Rideal Walker coefficient,which is the ratio of the minimum concentrationof a test drug required to kill a 24 hour culture ofB. typhosa in 7.5 minute at 37.5°C to that of phenolunder similar conditions. This test has onlylimited validity, particularly in relation to anti-septics which have to be tested on living surfaces.

Therapeutic index of an antiseptic is definedby comparing the concentration at which it acts

on microorganisms with that which produceslocal irritation, tissue damage or interference withhealing.

CLASSIFICATION

1. Phenol derivatives: Phenol, Cresol, Hexylre-sorcinol, Chloroxylenol, Hexachlorophene,Triclosan.

2. Oxidizing agents: Pot. permangnate,Hydrogen peroxide, Benzoyl peroxide.

3. Halogens: Iodine, Iodophores, Chlorine,Chlorophores.

4. Biguanide: Chlorhexidine.

5. Quaternary ammonium (Cationic): Cetri-mide, Cetylpyridinium chloride, Benzal-konium chloride, Dequalinium chloride.

6. Soaps: of Sod. and Pot.

7. Alcohols: Ethanol, Isopropanol.8. Aldehydes: Formaldehyde, Glutaraldehyde.

9. Acids: Boric acid, Acetic acid.

10. Metallic salts: Silver nitrate, Mild silverprotein, Zinc sulfate, Calamine, Zinc oxide.

11. Dyes: Gentian violet, Acriflavine, Proflavine.12. Furan derivatives: Nitrofurazone.

1. PHENOLS

Phenol (Carbolic acid) It is one of the earliestused antiseptics and still the standard for com-paring other germicides. It is a relatively weakagent (static at 0.2%, cidal at >1%, poor action onbacterial spores). It is a general protoplasmic poison,injuring microbes and tissue cells alike—at higherconcentrations causes skin burns and is a caustic.It acts by denaturing bacterial proteins. Organicmatter diminishes its action slightly while alkaliesand soaps do so profoundly (carbolic soaps arenot more germicidal than soap itself). It is nowseldom employed as an antiseptic, but beingcheap, it is used to disinfect urine, faeces, pus,sputum of patients and is sometimes included inantipruritic preparations because of its mild localanaesthetic action.

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Cresol It is methyl-phenol; more active (3–10times) and less damaging to tissues. Used fordisinfection of utensils, excreta and for washinghands.LYSOL is a 50% soapy emulsion of cresol.

Hexylresorcinol It is a more potent derivativeof the phenolic compound resorcinol that isodourless and nonstaining; used as mouthwash,lozenge and as antifungal.

Triclosan It is a chlorinated bisphenol havingbroad spectrum activity against most oralbacteria. Denaturation of membrane boundenzymes is primarily responsible for itsbactericidal action. Triclosan is nonirritating, doesnot stain teeth and its sensitization potential isnegligible.

The hydroalcoholic solution of a mixture ofphenolic volatile oils thymol, menthol, eucalyptolalong with benzoic acid is a popular mouthwashLISTERINE. It is widely used for bad breath, dentalplaque and gingivitis.

Chloroxylenol It has a phenol coefficient of 70;does not coagulate proteins, is noncorrosive,nonirritating to intact skin, but efficacy is reducedby organic matter. It is poorly water soluble; thecommercial 4.8% solution (DETTOL) is preparedin 9% terpinol and 13% alcohol and is used forsurgical antisepsis. A 0.8% skin cream and soap,1.4% lubricating obstetric cream (for vaginalexamination, use on forceps, etc.) and amouthwash (DETTOLIN 1%) are also available.These preparations have very low contactsensitization potential, but lose activity if dilutedwith water and kept for some time.

Hexachlorophene This potent chlorinatedphenol acts by inhibiting bacterial enzymes and(in high concentration) causing bacterial lysis. Itis odourless, nonirritating and does not stain. Itsactivity is reduced by organic matter but not bysoap. It is commonly incorporated in soap andother cleansing antiseptics for surgical scrub.Activity against gram-positive bacteria is high,but poor against gram-negative organisms (P.acnes) and spores. The degerming action is slow

but persistent due to deposition on the skin as afine film that is not removed by rinsing with water.Incorporated in toilet products, it is a gooddeodorant.

Use of a 3% solution for baby bath markedly reducedthe incidence of staphylococcal infections, but producedbrain damage (especially in premature neonates). Around1970 several fatalities occurred in USA. Since then use ofpreparations containing > 2% hexachlorophene have beenbanned.

2. OXIDIZING AGENTS

Potassium permanganate It occurs as purplecrystals, highly water soluble, liberates oxygenwhich oxidizes bacterial protoplasm. Theavailable oxygen and germicidal capacity is usedup if much organic matter is present—the solutiongets decolourised. A 1:4000 to 1:10,000 solution(condy’s lotion) is used for gargling, douching,irrigating cavities, urethra and wounds. Theantiseptic action is rather slow. Higher concen-trations cause burns and blistering—popularitytherefore has declined.

It has also been used to disinfect water (wells,ponds) and for stomach wash in alkaloidalpoisoning. It promotes rusting and is not goodfor surgical instruments.

Hydrogen peroxide It liberates nacent oxygenwhich oxidizes necrotic matter and bacteria. A3% solution produces 10 volumes of oxygen,much of which escapes in the molecular form.Catalase present in tissues speeds decompositionresulting in foaming. This helps in loosening andremoving slough, ear wax, etc. Hydrogen peroxidehas poor penetrability and a weak, transientantiseptic action. The potency declines further onkeeping. Use therefore is much restricted.

Hydrogen peroxide mouthwash has beenemployed in acute necrotizing gingivitis becauseof predominance of anaerobic bacteria in thiscondition. Though efficacy in reducing plaqueformation is marginal, H2O2 mouthwash has beenadvocated in periodontal disease. A 20-30%solution in water or ether has also been used as ableaching agent on the teeth. Frequent use of 3%H2O2 rinse can produce oral ulcers.

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Benzoyl peroxide It is specifically activeagainst P. acnes and used on acne vulgaris.

3. HALOGENS

Iodine It is a rapidly acting, broad spectrum(bacteria, fungi, viruses) microbicidal agent; hasbeen in use for more than a century. Acts byiodinating and oxidizing microbial protoplasm.A 1 : 20,000 solution kills most vegetative formswithin 1 min. Even bacterial spores are killed withhigher concentration/longer contact. Organicmatter retards, but does not nullify its germicidalaction.

Solid iodine is corrosive, stronger solutions(> 5%) cause burning and blistering of skin.Tincture iodine (2% in alcohol) stings on abrasions.It is used on cuts, for degerming skin beforesurgery, and to treat ring worm. Mandel’s paint(1.25% iodine dissolved with the help of Pot.iodide forming soluble I3̄ -ions) is applied on sorethroat. A nonstaining iodine ointment (IODEX 4%) ispopular as antiseptic and counterirritant. Someindividuals are sensitive to iodine—rashes andsystemic manifestations occur in them.

Iodophores These are soluble complexes ofiodine with large molecular organic compoundsthat serve as carriers—release free iodine slowly.The most popular—Povidone (Polyvinyl-pyrrolidone) iodine: is nonirritating, nontoxic,nonstaining and exerts prolonged germicidalaction. Treated areas can be bandaged or occludedwithout risk of blistering. It is used on boils,furunculosis, burns, otitis externa, ulcers, tinea,monilial/trichomonal/ nonspecific vaginitis andfor surgical scrubbing, disinfection of endoscopesand instruments. In dentistry, 1% povidoneiodine oral rinse is employed for gingivitis.BETADINE 5% solution, 5% ointment, 7.5% scrub solution,200 mg vaginal pessary; PIODIN 10% solution, 10%cream, 1% mouthwash; RANVIDONE AEROSOL 5%spray with freon propellant.

Chlorine A highly reactive element and a rapidlyacting, potent germicide, 0.1–0.25 ppm kills mostpathogens (but not M. tuberculosis) in 30 sec.However, the degerming action is soon exhausted

and it lacks substantivity. It is used to disinfecturban water supplies. Organic matter bindschlorine, so that excess has to be added to obtainfree chlorine concentration of 0.2–0.4 ppm. This isknown as the ‘chlorine demand’ of water. Chlorineis more active in acidic or neutral medium.

Chlorophores These are compounds thatslowly release hypochlorous acid (HOCl).Because of ease of handling, they are used inpreference to gaseous chlorine.

(i) Chlorinated lime (bleaching powder) It isobtained by the action of chlorine on lime;resulting in a mixture of calcium chloride andcalcium hypochlorite. On exposure, it decomposesreleasing 30–35% W/W chlorine. It is used asdisinfectant for drinking water, swimming poolsand sanitizer for privies, etc. The bleaching actionis occasionally utilized for removing stains fromteeth and for their cosmetic whitening.

(ii) Sodium hypochlorite solution Contains 4–6%sodium hypochlorite. It is a powerful disinfectantused in dairies for milk cans and other equipment,infant feeding bottles, etc. It is unstable and tooirritant to be used as antiseptic, except for rootcanal therapy in dentistry. Irrigation of root canalwith 2% sod. hypochlorite solution loosens anddissolves dead tooth pulp in addition to exertingrapid antisepsis.

4. BIGUANIDE

Chlorhexidine A powerful, nonirritating,cationic antiseptic that disrupts bacterial cellmembrane. Denaturation of intracellular proteinsoccurs as a secondary action. It is relatively moreactive against gram positive bacteria. Likehexachlorophene it persists on the skin for a longtime. Present in SAVLON (see below), it isextensively used for surgical scrub, neonatal bath,mouthwash, obstetrics and as general skinantiseptic.

Chlorhexidine is the most widely employedantiseptic in dentistry, mainly in the form of oralrinse (0.12–0.2%) or toothpaste (0.5–1%). It is one

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of the most effective antiplaque and antigingivitisagents. Good results have been obtained in acutenecrotizing gingivitis. Rinsing before theprocedure, chlorhexidine solution preventsinfections following periodontal and other formsof oral surgery. Twice daily chlorhexidine rinsemarkedly reduces oral infections in immuno-compromised patients including those with AIDS.Major disadvantage of intraoral use of chlor-hexidine is brownish discolouration of teeth andtongue, an unpleasant after-taste, alteration oftaste perception and occasionally oral ulceration.CHLODIN, FLUDENT-CH, HEXIL, REXIDIN 0.2%mouthwash.

5. QUATERNARY AMMONIUM (CATIONIC) ANTISEPTICS

These are detergents; cidal to bacteria, fungi andviruses. However, many gram-negative bacteria(specially Pseudomonas) , M. tuberculosis andbacterial spores are relatively resistant. They actby altering permeability of cell membranes. Soaps,being anionic, neutralize their action, whilealcohol potentiates them. They spread throughoil and grease, have cleansing and emulgentproperties. They are nonirritating and mildlykeratolytic. However, the germicidal action israther slow and bacteria may thrive under a filmformed by them on the skin. Pus, debris andporous material like cotton, polyethylene reducetheir activity. Occasionally sensitization occurs.These disadvantages not withstanding, they arewidely used as sanitizers, antiseptic anddisinfectant for surgical instruments, gloves, etc.,but should not be considered sterilizing.

Cetrimide A soapy powder with a faint fishyodour; used as 1–3% solution, it has good clean-sing action, efficiently removing dirt, grease, tarand congealed blood from road side accidentwounds. Alone or in combination with chlorhexi-dine, it is one of the most popular hospitalantiseptic and disinfectant for surgicalinstruments, utensils, baths, etc.CETAVLON CONCENTRATE: Cetrimide 20%SAVLON LIQUID ANTISEPTIC: Chlorhexidine gluconate1.5% + Cetrimide 3%.

SAVLON/CETAVLEX CREAM: Chlorhexidine HCl 0.1%+ Cetrimide 0.5%.SAVLON HOSPITAL CONCENTRATE: Chlorhexidinegluconate 7.5% + Cetrimide 15%.

Cetylpyridinium chloride It is similar to cetri-mide, has been included in mouth washes andlozenges to reduce plaque formation. However, itleaves a bad taste and can cause oral ulceration.

Benzalkonium chloride It is highly soluble inwater and alcohol. A 1:1000 solution is used forsterile storage of instruments and 1 in 5000 to 1 in10,000 for douches, irrigation, etc.

Dequalinium chloride Has been used in gumpaints and lozenges.DEQUADIN 0.25 mg lozenges.

6. SOAPS

Soaps are anionic detergents; weak antiseptics,affect only gram positive bacteria. Their useful-ness primarily resides in their cleansing action.Washing hands and other surfaces with soap andwarm water is one of the most effective methodsof preventing transmission of infection byremoving/diluting pathogenic bacteria. Soapscan be medicated by other antiseptics.

7. ALCOHOLS

Ethanol It is an effective antiseptic and cleansingagent at 40–90% concentration. The rapidity ofaction increases with the concentration upto 70%and decreases above 90%. It acts by precipitatingbacterial proteins. A cotton swab soaked in 70%ethanol rubbed on the skin kills 90% bacteria in 2min.; has been used before hypodermic injectionand on minor cuts. It is an irritant and should notbe applied to mucous membranes or to delicateskin (scrotum), ulcers, etc. Applied to openwounds, it produces a burning sensation, injuresthe surface and forms a coagulum under whichbacteria could grow.

Usefulness of alcohol in dentistry is limited;effective concentrations cannot be applied ongums or oral mucosa. The concentration (5 – 10%)present in many mouth rinses (as solvent for

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essential oils, etc.) has no antiseptic efficacy.However, it enhances the antiseptic activity ofiodine and chlorhexidine when employed assolvent for these. Because alcohol evaporateswithout leaving any residue and has goodcleansing property, it is often employed to sanitizeworking surfaces in dentistry, but it is a poor dis-infectant for instruments—does not kill sporesand promotes rusting.

Isopropanol It is less volatile and can be usedin place of ethanol.

8. ALDEHYDES

Formaldehyde It is a pungent gas—sometimesused for fumigation. A 37% aqueous solutioncalled Formalin is diluted to 4% and used forhardening and preserving dead tissues. Itdenatures proteins and is a general protoplasmicpoison, but acts slowly. Though a broad-spectrum germicide, use as antiseptic is restrictedby its irritating nature and pungent odour. It isoccasionally employed to disinfect instrumentsand excreta. Those who handle formalin candevelop eczematoid reactions.

Glutaraldehyde It is less volatile, less pungent,less irritating and better sterilizing agent thanformalin. It exerts broad-spectrum activity againstbacteria, viruses and fungi but needs to beactivated by alkalinization of the solution.Organic matter does not inactivate it, and its 2%solution is often used in dentistry as an immersiondisinfectant for instruments that cannot beautoclaved, but prolonged contact is needed. Itshould not be used to disinfect working surfacesbecause repeated inhalation of its vapours caninduce asthma. Repeated application on skin cancause sensitization. The alkalinized solution hasa short shelf-life (2 weeks) unless stablilizingagents are added.

9. ACIDS

Boric acid It is only bacteriostatic and a veryweak antiseptic. But being nonirritating even to

delicate structures, saturated aqueous solutions(4%) have been used for irrigating eyes,mouthwash, douche, etc. Boroglycerine paint(30%) is used for stomatitis and glossitis. A 10%ointment (BOROCIDE) is available for cuts andabrasion. It is included in prickly heat powdersand ear drops. However, boric acid is notinnocuous; systemic absorption causes vomiting,abdominal pain, diarrhoea, visual disturbancesand kidney damage. Hence its use for irrigatingbladder, large wounds, as ointment on extensiveburnt areas, liberal use of powder for infants isnot recommended.

Acetic acid It is a weak antiseptic, active particularlyagainst Pseudomonas. Dressing dipped in dilute acetic acidis occasionally applied on burnt areas.

10. METALLIC SALTS

Silver compounds These are astringent andcaustic; react with SH, COOH, PO4 and NH2

groups of proteins.Silver nitrate rapidly kills microbes, action

persisting for long periods because of slow releaseof Ag+ ions from silver proteinate formed byinteraction with tissue proteins. Tissues getstained black due to deposition of reduced silver.Silver nitrate touch is used for hypertrophiedtonsillitis and aphthous ulcers. It is highly activeagainst gonococci—1% solution is used forophthalmia neonatorum.

Zinc salts They are astringent and mild anti-septics.(i) Zinc sulfate is highly water soluble, 0.1–1% isused for eye wash and in eye/ear drops (Zinc-boric acid drops— in ZINCO-SULFA 0.1% eye drop).Applied to skin, it decreases perspiration.(ii) Calamine and zinc oxide are insoluble. Inaddition to being mildly antiseptic, they arepopular dermal protectives and adsorbants.

11. DYES

Gentian violet (crystal violet) This rosanilinedye is active against staphylococci, other gram-

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positive bacteria and fungi, but gram-negativeorganisms and mycobacteria are insensitive.Aqueous or alcoholic solution (0.5–1%) is usedon furunculosis, bed sores, chronic ulcers,infected eczema, thrush, Vincent’s angina,ringworm, etc. It has become unpopular due todeep staining.

Acriflavine and Proflavine These are orange-yellow acridine dyes active against gram-positivebacteria and gonococci. Their efficacy is notreduced by organic matter and is enhanced inalkaline medium. Solutions lose efficacy onexposure to light—store in amber bottles. Theyare nonirritant and do not retard healing—parti-cularly suitable for chronic ulcers and wounds.Bandage impregnated with acriflavine-vaselineis used for burn dressing;ACRINOL 0.1% acriflavine cream.

The triple dye lotion contains gentian violet0.25% + brilliant green 0.25% + acriflavine 0.1%

(TRIPLE DY), has been used for burns and fordressing umbilical stump in neonates.

12. FURAN DERIVATIVES

Nitrofurazone It is cidal to both gram-positiveand negative, aerobic and anaerobic bacteria evenin high dilutions, but activity is reduced in thepresence of serum. Acts by inhibiting enzymesnecessary for carbohydrate metabolism inbacteria. It is highly efficacious in burns and forskin grafting. Its local toxicity is negligible—butsensitization occurs frequently.FURACIN 0.2% cream, soluble ointment, powder.

Antiseptics and disinfectants in dentistry

Antiseptics and disinfectants are used extensivelyin dentistry. The main purposes for which theyare employed along with the commonly usedagents are given in the box.

Antiseptics and Disinfectants in Dentistry 475

Use and selection of antiseptics/disinfectants in dentistry

Purposes Prefered agents

1. Cleaning and disinfection of working surfaces, Alcoholsinstrument trays, operating light handles, etc. NH4

+ antiseptics

2. Cold sterilization of certain instruments and Glutaraldehydestorage of sterilized equipment. NH4

+ antiseptics

3. Decontamination of the dentist’s and assistant’s hands. Soaps, cresolChloroxylenolNH4

+ antiseptics

4. Prevention and treatment of dental plaque and Chlorhexidineperiodontal disease. NH4

+ antiseptics

Triclosan

5. Treatment of ANUG, aphthous ulcers and other Povidone iodineinfective oral conditions. Chlorhexidine

Hydrogen peroxideBoric acidSilver nitrate

6. Root canal therapy. Hypochlorite Na+

7. Preoperative preparation of oral mucosa by reducing Chlorhexidinebacterial load so as to minimise local as well as distant Povidone iodineinfection.

8. As an ingredient of certain dentifrices. ChlorhexidineNa4

+ antiseptics, Triclosan

Na4+: Quaternary ammonium

ANUG: Acute necrotizing ulcerative gingivitis.


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LOCALLY ACTING DRUGS

A variety of drugs applied topically to the skin ormucous membranes produce therapeutic effectslocalized to the site of application. They act pri-marily by virtue of their physical/mechanical/chemical/biological attributes. Some of theserelevant to dentistry are:

Demulcents Demulcents are inert substanceswhich sooth inflamed/denuded mucosa or skinby preventing contact with air/irritants in thesurroundings. They are, in general, high mole-cular weight substances and are applied as thickcolloidal/viscid solutions in water.

Glycyrrhiza, the sweet tasting root of liquorice,is used to sooth the throat and as flavouring/sweetening agent. Glycerine is a clear, sweet,viscous liquid that is used as vehicle for gum/throat paints and as emollient on dry/crackedlips. Undiluted glycerine is dehydrating andproduces a warm sensation in the mouth. It alsohas mild antiseptic property. Methylcellulose, gumacacia and propylene glycol are other demulcents.

Emollients Emollients are bland oily sub-stances which sooth and soften skin. They form anocclusive film over the skin, preventing evapo-ration, thus restoring elasticity of cracked and dryskin. Olive oil, arachis oil, sesame oil, hard andsoft paraffin, liquid paraffin, wool fat, bees waxand spermaceti are the commonly employedemollients. They are also used as vehicles fortopically applied medicaments and as ointmentbases.

Adsorbants and protectives Adsorbants arefinely powdered, inert and insoluble solidscapable of binding to their surface (adsorbing)noxious and irritant substances. They are alsocalled protectives because they afford physicalprotection to the skin or mucosa. Other protectivesform a continuous, adherent and flexible occlusivecoating on the skin. Demulcents and emollientsalso serve as protectives.

Magnesium stearate, zinc stearate, talc,calamine, zinc oxide, starch, collodion, Aloevera gel, dimethicone and sucralfate are used asprotectives.

Sucralfate is an aluminium salt of sulfatedsucrose that has been employed as peptic ulcerprotective. It is formulated as a topical gel as wellto be applied on aphthous ulcers; serves tofacilitate healing by covering the denuded surface.The gel can be applied on burns, bedsores,excoriated skin, diabetic ulcers as well.

Astringents Astringents are substances thatprecipitate proteins, but do not penetrate cells,thus affecting the superficial layer only. They areintended to toughen the surface making itmechanically stronger and decrease exudation.

Tannic acid obtained from nutgalls andtannins found in tea, catechu, betelnut arevegetable astringents. Glycerine of tannic acid(30%) and mouthwashes/gum paints containingtannic acid (1–5%) are used to strengthen gumsand to check bleeding from them. Efficacyhowever, is dubious. Heavy metal salts haveastringent property. Zinc chloride, zinc sulfate,aluminium chloride, ferric chloride, strontiumchloride are included in several mouthwashesand dental gels to afford symptomatic relief andpromote healing of oral lesions, as well as toreduce dentine sensitivity and gum bleeding.Alcohol is a potent astringent, but is unsuitablefor use in mouth. It is rubbed on skin to preventbedsores. Other uses of astringents are in bleedingpiles and as antiperspirant/deodorant.

Caustics These are corrosive chemicals thatcause local tissue destruction and sloughing.Concentrated solutions of silver nitrate, zincchloride, phenol, trichloroacetic acid andpodophyllum resin are caustic and have beenused to remove moles, warts, papillomas andnecrotic material. They are to be applied carefullyon the lesions only so as to avoid ulceration ofnormal mucosa/skin.

The use of caustics in dentistry is very limited;occasionally applied on aphthous ulcers. Silvernitrate painted on exposed necks of teeth canreduce dentine sensitivity, but is not favouredbecause of black staining. Carefully appliedtrichloracetic acid can reduce pain of peri-coronitis.

Drugs and Aids with Specific Applicationin Dental Disorders

Most of the common problems affecting teeth,gums and oral mucosa are managed primarilyby various professionally carried out dentalprocedures, often aided by some specific drugs/agents which have little application outsidedentistry. Selected dental conditions and specificagents are briefly described in this chapter.

ANTIPLAQUE AND ANTIGINGIVITIS AGENTS

Plaque Dental plaque is a tenaciously adherentsoft deposit on the tooth surface, composedmainly of bacterial aggregates embedded in amatrix of polysaccharides and glycoproteins,that resists removal by ordinary brushing andrinsing. Plaque is the primary causative factorin both dental caries and periodontal diseases.

Dental plaque tends to develop sponta-neously unless teeth are cleaned thoroughly andregularly. The salivary glycoproteins getadsorbed on the tooth surface and form a thinmembrane-like pellicle over it within minutesafter brushing. With time, the glycoproteinmolecules cross-link and form an insolublecoating over the tooth. The resident oral bacteriaanchor on this coating and gradually developinto a plaque. The bacterial composition of theplaque is dynamic (changes with time). As theplaque grows and ages, gram negative andanaerobic bacteria predominate. Bacterialproducts like lactic acid, ammonia, hydrogen

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sulfide and other toxic metabolites generated inthe plaque irritate gingival margins and produceinflammation (gingivitis). The gums becomeedematous, swollen and develop subgingivalpockets. Mediators released by the inflam-matory reaction perpetuate the conditionproducing chronic gingivitis. Enzymes likehyaluronidase and collagenase produced by thepathogens damage the connective tissue supportto the teeth; gums become spongy andperiodontal disease develops.

Periodontal disease can be prevented as wellas treated by inhibiting plaque formation andremoving it mechanically before it producesinflammatory changes. Regular brushing of teethby correct technique is the most effective methodof inhibiting plaque. However, this may not bepractical in all individuals. Plaque on some partsof the teeth is left behind after brushing by mostpeople. Periodic professional scaling of the teethmay be required in susceptible individuals. Thismay be supplemented by use of antiplaqueagents.

Since bacteria are the major component ofplaque, antibacterial drugs are the most importantantiplaque agents.

Effective therapy of plaque requires that thedrug applied as mouth rinse, gels or toothpasteremains at the site without being washed awayto exert sustained antimicrobial effect. As such,

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the two most important properties of an anti-plaque agent are antimicrobial spectrum coveringthe relevant microbes and ‘substantivity’ whichrefers to persistence of the substance on thesurface of teeth/gums due to initial binding andsubsequent slow release.

Chlorhexidine It exerts high antiplaque activity,largely because of its substantivity in the mouth,rather than due to any unique spectrum ofactivity on oral microbes, which nevertheless areinhibited. Chlorhexidine binds electrostaticallyto the acidic groups in the surface proteinsaffording the substantivity. Though it can alsobind to hydroxyapatite of the teeth, this is lessimportant for the antiplaque activity. Theamount of chlorhexidine retained on the oralmucosa/tooth surface depends on the volumeas well as concentration of the rinse solution.Lowering the pH (acidification) of rinse solutionmarkedly decreases retention of chlorhexidineon oral mucosa. Calcium ions inhibit chlorhexi-dine binding as well as displace already bounddrug. Accordingly, toothpastes containing cal-cium salts reduce substantivity of chlorhexidineif rinsing is done within 30-60 min of brushingwith such a toothpaste. Optimum benefitsappear to be obtained by twice daily mouthrinsing for 1-3 min with 10–15 ml of 0.12–0.2%chlorhexidine solution. Such rinsing achievesmarked reduction in the number of oral bacteria(85% reduction in 24 hours and 95% reduction

after 5 days). With long-term use, bacterialcounts tend to increase again, but approximately70% reduction is maintained till rinsing iscontinued. Resistance to chlorhexidine bybacteria is not clinically significant.

Twice daily oral rinse with 0.2% chlorhexi-dine consistently reduces dental plaque andprevents onset of gingivitis. Long-term regularuse protects against periodontal diseases insusceptible individuals and improves gingivalhealth. However, it should be employed only asadjuvant to other oral hygienic measures andprofessional care. The main disadvantage ofchlorhexidine oral rinse is brown staining ofteeth and tongue. Heavy tea/coffee consump-tion intensifies the staining effect. A lingeringbitter aftertaste and occasional mucosalulceration are the other side effects.CHLODIN, CLOHEX, ORAHEX, REXIDIN, HEXIL 0.2%mouth wash.

Quaternary ammonium antiseptics such ascetrimide, cetylpyridinium chloride and benzal-konium chloride are other effective antiplaqueagents, but are inferior to chlorhexidine. Beingcationic, they also exhibit considerable sub-stantivity, but their retention on oral mucosaafter rinsing is less than that of chlorhexidine.Since they are more active against gram positivebacteria than against gram negative, they arebetter suited for prophylaxis of plaque than fortreatment of aged plaque/gingivitis. Adverseeffects are burning sensation in the mouth, badtaste, discolouration of teeth and oral ulcers.They are alternative antiplaque agents.Cetrimide: 0.1% in STOLIN gum paint.Benzalkonium chloride: 0.02% in ZYTEE gel; 0.01% inDENTOGEL gel.

Phenolic antiseptics like triclosan and LISTERINEare another class of germicides that have anti-plaque activity and are employed in mouthwashes, tooth pastes/powders and gum paints.Triclosan is active against both gram positiveand negative bacteria. The binding of triclosan assuch to gingival tissues and dental plaque isrelatively weak (has lower substantivity than

Antiplaque Agents

1. Chlorhexidine2. Quaternary ammonium antiseptics

Cetylpyridinium chlorideBenzalkonium chloride

3. PhenolsTriclosanListerine

4. Oxygenating agentsHydrogen peroxideSodium perborate

5. Zinc citrate6. Stannous fluoride7. Sanguinarine

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chlorhexidine). However, certain polyvinylcopolymers and zinc salts included with it intoothpastes and dentifrices prolong its substan-tivity to nearly 12 hours. As such, these arecommon ingredients of proprietary toothpastesand toothpowders intended to prevent and treatplaque formation and gingivitis. The nonstaining,nonirritating nature of triclosan, and that it doesnot impart bad taste or odour favours its use.Triclosan: 0.3% in REXIDIN PLUS gel; TRIGUARD,MAGDENT-KF, THERMOBEST tooth pastes.

Oxygenating agents Hydrogen peroxide (1.5-3%)and sodium perborate (3-6%) used as oral rinserelease molecular oxygen and particularly inhibitanaerobic microbes. As such, they are often usedin ANUG in which anaerobes play a major role.Though regular rinsing with H2O2 may reduceplaque scores, efficacy is limited due to itstransient action. Frequent rinsing may cause oralulceration.

Zinc citrate/chloride Included in some toothpastes and gum paints, zinc citrate (2-4%) or zincchloride (1%) have been found to decreaseplaque formation, probably due to activityagainst gram positive cocci which predominatein early stage plaque. Its mild astringent actionon gums may also help. However, it has utilityonly as an adjuvant antiplaque agent.Zinc chloride: 0.09% in DENTOMAX gel, TRIGUARD mouthwash; 1.0% in STOLIN gum paint.

Stannous fluoride Daily oral rinsing with stan-nous fluoride (0.1–0.3%) significantly reducesdental plaque. Both tin and fluoride ions appearto contribute to the antiplaque activity. Both aremildly antibacterial. Stannous ions reduce theadhesion of gram positive bacteria to the toothsurface and alter their metabolism, whilefluoride ions inhibit bacterial glycolytic enzymesand glucose transport. However, long termantiplaque efficacy of stannous fluoride is muchinferior to chlorhexidine, and staining of teethmay discourage its use. Some toothpastescontain stannous fluoride.

Sanguinarine It is an alkaloid from the blood-root plant with high in vitro activity against many

periodontal pathogens and high affinity fordental plaque. The antibacterial action has beenascribed to inhibition of sulfhydryl enzymes ofthe bacteria. Sanguinarine requires low pH(below 5.5) to transform into the active quater-nary imminium configuration. Accordingly,sanguinarine oral rinse solution and toothpasteare formulated at low pH. However, this low pHmay not be maintained in the oral fluid for long.

Though some trials have shown modest shortterm antiplaque and gingivitis reducing actionof sanguinarine, others have found marginaloverall efficacy. One explanation offered for thediscrepancy between high in vitro antibacterialactivity and poor clinical efficacy is its tightbinding to the oral tissues with minimalsubsequent release to act on the pathogens. Itproduces few side effects, but the taste is founddisagreeable by many individuals.

ANTIBIOTICS IN PERIODONTAL DISEASE

The causative role of bacterial pathogens in allforms of periodontal disease suggests that spe-cific antibiotics should have major therapeuticvalue. However, in majority of cases antibioticsare unable to afford long-term benefit or modifycourse of the disease. The reason may be thatthe causative bacteria are derived from theresident oral flora which can, at best, besuppressed by antibiotics only temporarily.Recolonization occurs once the drug is stopped,or even during long-term use due todevelopment of resistance. As such, antibioticshave only adjuvant role, and that too only incertain types of periodontal disease. Plaqueremoval supplemented by appropriate perio-dontal surgical procedures and followed by oralhygienic and plaque control measures are theprimary therapeutic interventions.

Though many antibiotics like penicillins,erythromycin, vancomycin, etc. have been tried,none is now recommended. Only tetracyclinesand metronidazole have established adjuvanttherapeutic value in severe/rapidly progressingor refractory forms of periodontitis. In such cases,

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IIItetracycline (1 g/day)/doxycycline (200 mg/day) therapy favourably alters the subgingivalflora by eliminating spirochetes and gramnegative bacilli with less effect on gram positivebacteria. Additional mechanisms of benefit oftetracyclines proposed are halting of periodontalconnective tissue breakdown by inhibition ofCa2+ dependent collagenases and free radicalscavenging (see p. 409).

Oral metronidazole when combined withconventional local measures affords clearcutadditional benefit in advanced periodontitiswith pocket formation and connective tissue loss,as well as in juvenile periodontal disease. Thebenefit is ascribed to its specific activity againstanaerobic pathogens. It has also been used bylocal application to the gums in combined gelformulation with chlorhexidine. The dramatictherapeutic effect of metronidazole in ANUG isdescribed on p. 388.REXIDIN-M, ORAHEX-M, METROHEX: Metronidazole 1%+ chlorhexidine 0.25% gel.

ANTICARIES DRUGS

Dental caries is localized loss of tooth tissue dueto bacterial action resulting in formation cavityin tooth. The cariogenic bacteria, mainlyStreptococcus mutans, Lactobacilli and otherspresent in dental plaque breakdown dietarysugars to produce lactic acid on the tooth surface.Sucrose is most easily converted into acids byplaque bacteria and is the most cariogenic sugar.The acid remaining in contact with tooth enamelfor sufficient time destroys hydroxyapatitecrystals causing demineralization and loss oftooth substance.

Anticaries drugs help only to prevent dentalcaries, since no drug can restore already formedcaries cavity. The drugs are:1. Fluoride: makes tooth more resistant to caries

and has weak antibacterial action.2. Antiplaque agents (mainly chlorhexidine and

triclosan): reduce the population of cario-genic bacteria.

Other preventive measures for caries are:(a) Restriction of sugar containing food(b) Frequent brushing of teeth(c) Prevention of xerostomia by good hydrationand other measures, since dryness of mouthpromotes caries.

Fluoride

The carioprotective role of fluoride was realizedwhen high incidence of dental caries amongchildren in certain geographical areas wasrelated to the low fluoride levels in the localwater supply. Systematic epidemiologicalstudies and the beneficial effect of fluoride sup-plementation have confirmed this relationship.

Mechanism of actionThe hardness of tooth enamel is primarily dueto its hydroxyapatite crystals; but these arereadily dissolved by the action of acid over aperiod of time. Fluoride radical being highlyreactive exchanges with hydroxyl radicalforming fluorapatite. The fluorapatite is a morecompact, harder and less acid labile substancethan hydroxyapatite. As a result teeth becomeless prone to caries.

Further, fluoride enhances remineralizationof enamel that has been attacked by acid. Freefluoride ions released from fluorapatite by theaction of acid raise the local fluoride ionconcentration and facilitate remineralization ofdamaged enamel.

Fluoride is mildly antibacterial. However,plaque bacteria bind fluoride with high affinity,so that fluoride concentration in plaque is severaltimes higher than its salivary concentration:significant intraplaque bacteriostasis may beexerted. Fluoride ions inhibit acid formingenzyme of plaque bacteria providing anothermechanism of carioprotection.

Fluoride therapy

To reduce the incidence of dental caries,particularly among children, fluoride can eitherbe administered systemically or applied locallyto the teeth.

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Systemic fluorideSystemic administration of fluoride is indicatedonly in areas with established fluoride deficientwater supply. It is considered that a concen-tration of 0.7–1.0 p.p.m. fluoride is optimum forhealth, and both low as well as high fluoridecontent of drinking water is harmful. Fluoridesupplementation is needed only to the extent thatdeficit in drinking water is made good. This canbe done in several ways.1. Fluoridation of water supply This is practical

in urban areas with common piped watersupply to the masses, but not in communitiesdrawing water from separate sources (likewells, ponds, etc). The amount of fluoride tobe added must be determined by frequentlymeasuring the content in natural water andadjusting it to achieve a final level of 0.5–1.0p.p.m. The optimum level is lower in tropicalcountries and in summer because volume ofdaily water consumption is higher. Failureto adjust the fluoride content to the optimumlevel can expose the population to the risk offluorosis.

2. Fluoridation of common salt This is anotherway of supplementing fluoride intake. InEurope, table salt has been fortified with200–350 mg/kg of salt in deficient areas.

3. Sodium fluoride tablets / lozenges / dropsInfants and children in deficient areas whereno mass fuoridation (of water or salt) is done,may be protected against high incidence ofcaries by administering sodium fluoridetablets (0.55 and 1.1 mg), lozenges (2.2 mg)or drops (0.55 and 1.1 mg per drop) daily tillthe age of 16 years. Lozenges and drops alsoprovide local application to the teeth.However, to avoid risk of fluorosis, use ofthese supplements must be guided bymeasurement of fluoride in the local drinkingwater.

Topical fluorideFluoride is effective in enhancing resistance tocaries even when applied directly to the toothsurface. Since there is little risk of systemic as

well as dental fluorosis due to topical fluoride,it can be employed without regard to the fluoridecontent of drinking water or food. The permea-tion and uptake of topically applied fluoride intothe outer layers of tooth enamel depends on thefluoride salt used, its concentration and the timefor which it remains in contact with the toothsurface. Low concentration of fluoride can beapplied by the subject himself (daily), or fluoridemay be applied at high concentration by thedentist once a while (generally every 6 months).1. Fluoride toothpastes This is the easiest and

most frequently employed method of fluorideapplication. Most of the commerciallymarketed toothpastes now contain fluoride.The commonest salt added is sodiummonofluorophosphate (MFP) at a concentrationof 0.76%. Other salts used earlier have somelimitations. Calcium salts used as abrasivesin certain dentifrices inactivate sodiumfluoride, while stannous fluoride can stainteeth. Some other compounds and co-polymers have been included in toothpastesto improve retention of fluoride on the tooth.Care must be exercised to avoid ingestion offluoridated toothpastes (especially by infantsand young children) to prevent systemictoxicity. Thorough rinsing of the mouth isadvised after brushing with fluoridatedtoothpaste.

2. Fluoride mouth rinse Sodium fluoride(0.055%) and stannous fluoride (0.1%)solution have been used as daily mouth rinseby susceptible individuals to prevent caries.The rinse solution is held in the mouth for1–3 min. and swished around. It is thendiscarded and food/drink are avoided fornext 30 min to minimise washing away offluoride that is in contact with the teeth.Though stannous fluoride is more effectivethan sodium fluoride, it can stain the teeth.

3. Professionally applied fluoride Caries pro-tective effect of fluoride can also be obtainedby providing brief intensive exposure to theteeth by the dentist at relatively long intervals.High concentrations of sodium fluoride and

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IIIstannous fluoride have disadvantages and areno longer used.(a) Acidulated phosphate fluoride (APF) This

fluoride system suitable for application tothe teeth by the dentist has beenspecifically developed to achieve highfluoride permeation into the enamel andthus afford prolonged caries protection.Formulated as a solution or gel, it contains1.23% fluoride and 0.1M orthophosphoricacid; the pH is adjusted to about 3.0. Thisacidic medium enhances fluoride diffu-sion into the enamel while orthophos-phoric acid prevents enamel dissolution.Applications are generally repeated at 6month intervals and the optimal durationof each application is 4 min. Because ofthe high fluoride concentration, it canproduce nausea, vomiting and acutefluoride toxicity if swallowed. Precautionstaken to avoid ingestion are—use of dis-posable tray applicator, upright positionduring application, instruction not toswallow the solution/gel, constantsuction of saliva during application andwiping the teeth and gums dry after theapplication.

(b) Fluoride varnishes These are non-aqueouspreparations which are not washed off bysaliva and are retained on the teeth forlonger period. A 2% sodium fluoridelacquer in resin base or a polyurethanevarnish containing 0.7% fluoride ispainted over the teeth or applied to thecavity. The efficacy of these preparationsis variable and they are less popular.

Fluoride toxicity

Chronic fluoride toxicity The condition is calledfluorosis and occurs due to excess fluoride contentof drinking water, or occasionally due toindustrial exposure or ingestion of fluoridesupplements/toothpastes, etc. over a period oftime. Low levels of excess fluoride (>2 p.p.m.)in drinking water produce dental fluorosis in

children, while higher levels (>8 p.p.m.) produceskeletal fluorosis in children as well as in adults.

Dental fluorosis It occurs in children due torelatively low excess fluoride exposure from birthto 14 years of age when teeth are developing anderupting. There is hypomineralization of enamelwhile its protein content increases. White flecksappear on the teeth. Later there is browndiscolouration, pitting, hypoplasia and deformityof dentition.

Skeletal fluorosis is a crippling disorder pro-ducing rigidity of spine, kyphosis, thoracic andpelvic deformity; limb bones become thick butbrittle, spontaneous fractures occur and liga-ments calcify.

Fluorosis can be prevented by changing thesource of drinking water or defluoridation ofwater by adsorption on activated alumina/charcoal, or by avoiding other sources of excessfluoride, as the case may be. Once fluorosis hasdeveloped, it can only be halted but not reversed.

Acute fluoride toxicity Ingestion of gross over-dose of fluoride causes acute toxicity; especiallyin children; > 5 mg/kg sodium fluoride isconsidered lethal. The toxic manifestations arenausea, vomiting, abdominal pain, gastricerosion, muscle weakness, spasms and tetanydue to hypocalcaemia, acidosis, hypotension andcardiac arrhythmia.

Treatment consists of gastric lavage, calciumgluconate infusion (i.v.) to precipitate excessfluoride and to counteract hypocalcaemia,correction of acidosis and fluid/electrolyteimbalance, and other supportive measures.

Antiplaque agents for caries

The crucial role of dental plaque in the causationof caries has already been described. As such,antiplaque measures including use of orallyapplied germicides can clearly reduce theincidence of caries and add to the protectionafforded by fluoride. The antiplaque agents havebeen considered earlier (see p. 478). The two mostcommonly used agents are:

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Chlorhexidine Used mainly as a mouth rinse orgel, it reduces the population of Streptococcusmutans and other cariogenic bacteria. The riskof caries occurrence is reduced, but regular usecauses staining of teeth.

Triclosan Because it is nonirritant, tasteless andnonstaining, it is included along with otheractive ingredients in many anticaries andantiplaque toothpastes and gels.

DESENSITIZING AGENTS

Desensitizing agents are those which applied tothe teeth mitigate dentine sensitivity (also calleddentine hypersensitivity), i.e. shooting paintriggered from sensitive tooth by thermal (hotand cold), mechanical (touch, chewing, blast ofair) or chemical (sour and sweet food) stimuli.Dentine may get exposed to external stimuli dueto enamel damage caused by chewing hardsubstances, age related tooth attrition, erosionby acidic food at the crown; or due to denudationof root as a result of gingival recession of oldage, faulty brushing, periodontal disease, etc.Dentine is traversed by numerous fine fluid-filled dentinal tubules. When these tubules areexposed, mechanical and thermal stimuli causeabnormal perturbations of the fluid in thetubules and activate the nerve endings at theirinner mouth or in the pulp, while solublechemicals (acids/sugars in food) diffuse throughthe tubules and act on the sensory nerves—allproducing sharp pain.

The desensitizing agents aim to interrupt thispain-inducing process by either creating a plugin the dentinal tubules, or by sealing their mouthat the tooth surface, or by modulating thegeneration of painful nerve impulses. Mostdesensitizing agents are self-applied by thepatient 1–3 times daily, while some are appliedby the dentist once a while. Though it is desirablethat the desensitizing agent produces rapidrelief, in reality, most agents act slowly – needregular application over several days to weeksfor optimum relief.

The commonly used desensitizing agents are:1. Potassium nitrate At a concentration of 5%,

it is the most frequently included activeingredient of desensitizing toothpastes. Thepaste is to be applied on the sensitive teethand left in place for ~ 5 minutes beforebrushing lightly and then rinsing it off. Thisis repeated 2–3 times daily. Potassium nitrateis believed to obliterate the dentinal tubulesby precipitation, as well as to dampen thepain inducing nerve impulses.Potassium nitrate 5%: in MICRODENT-K, SENSODENT-KF, AQUADENT-K, EMOFORM, TRIGUARD,MAGDENT-KF, THERMOSEAL toothpastes.

2. Strontium chloride It is an alkali-earth metalsalt that precipitates proteins in the dentinaltubular fluid and thus tends to limit/obstructthe easy displacement of fluid by the paininducing stimuli. Calcification of the bonycomponent of tooth is believed to be hastenedby strontium ions providing anothermechanism of desensitizing action. Manydesensitizing toothpastes and gels contain10% strontium chloride.Strontium chloride 10%: in SENOLIN gel; inSENSOFORM, FLODENT, STOLIN, THERMODENTtoothpastes.

3. Potassium oxalate It diffuses into thedentinal tubules, reacts with ionic calcium inthe fluid there to produce calcium oxalatewhich being insoluble deposits as crystals.These crystals hinder fluid movement in thetubules induced by external stimuli lesseningthe pain.

4. Fluoride Fluoride compounds like sodiummonofluorophosphate, sodium/stannousfluoride are included in many multi-ingredient desensitizing toothpastes. Thesemay react with calcium and produce calciumfluoride crystals in the dentinal tubules.Stannous fluoride may deposit fine layers oftin particles in the tubules creating partialobstruction. In the long term fluoride ionaccelerates secondary dentine formationwhich may reinforce the tubules and reducedentine sensitivity. However, the contribution

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IIIof the fluoride salt to the short-term desen-sitizing action of these toothpastes isuncertain.Sodium monofluorophosphate 0.7%: in MICRODENT-KF, MAGDENT-KF, SENSODENT-KF, TRIGUARD,THERMO-BEST toothpastes.Fluoride iontophoresis Quick diffusion offluoride ions into the dentinal tubules isobtained by applying electrical currentthrough 2% sodium fluoride solution. Itcauses rapid desensitization of sensitivetooth, but requires special equipment andexpert application; it is therefore expensiveand often needs several repititions.

5. Formaldehyde At a concentration of 1-1.5%,it is a weak desensitizing agent. Its mostprominent action is denaturetion andprecipitation of proteins. Such action withinthe dentinal tubules may underlie its desensi-tizing property. However, it has disagreeabletaste and smell, and is not favoured now.Formaldehyde 0.25%: in STOLIN toothpaste withstrontium chloride 10% (any contribution of this low(0.25%) concentration to the desensitizing action isuncertain).

6. Dentine bonding agents Certain acrylicbonding agents (like hydroxy ethyl metha-crylate), some resins, composites, varnishes,etc. have been developed which can beburnished on the exposed root or sensitivepart of crown to seal off the external openingsof the exposed dentinal tubules. Aftersuitable preparation of the sensitive tooth anduse of primers, the bonding agent is appliedand allowed to dry. A long lasting bondingwith dentine occurs rapidly—so that stimuliwhich induced pain earlier are blocked fromreaching the pulpal nerve endings. Thetreatment may have to be repeated at suitableintervals.

OBTUNDANTS

Obtundants are almost obsolete drugs whichwhen applied to the teeth and gums produce akind of numbness that could dampen toothache

due to cavity formation and other causes, as wellas pain of excavation. They penetrate poorly anddo not relieve deep seated or sharp pain.Obtundants act by:1. Stimulation followed by desensitization of nerve

endings: Clove oil, Thymol, Menthol,Camphor, Phenol.Majority of these are essential oils orsteroptenes which have a characteristicpleasant smell and irritate sensory nerve-endings. They have counter-irritant propertyand produce relative numbness due todesensitization of sensory nerves lasting oneto few hours. Clove oil has been used as ahousehold remedy for tooth ache, but canstain the tooth.

2. Astringent action: Stannous chloride, Zincchloride, Paraformaldehyde.They precipitate surface proteins and mayinterfere with the function of pain receptors.The pain relieving action is mild.Local anaesthetics have rendered obtundantsredundant.

MUMMIFYING AGENTS

Mummification connotes hardening of deadtissue and rendering it resistant to microbialattack and degradation. Mummifying agentsused earlier in dentistry are protoplasmicpoisons having astringent and preservativeproperties. Before the availability of modern rootcanal filling materials, they were used duringroot canal therapy to kill the tissues in tooth pulp,make it hard and dry so that it does not getinfected later. Commonly used mummifyingagents were:1. Formaldehyde or Paraformaldehyde (Paraform)

mixed with zinc oxide or zinc sulfate +creosote and made into a paste for filling inthe root canal. Paraformaldehyde releasesformaldehyde slowly which destroys allliving tissues in the pulp, hardens it andmakes it resistant to future infection. A localanaesthetic like lidocaine or benzocaine was

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included by some, especially when formal-dehyde was used, to prevent pain caused bythe filling.

2. Iodoform + Phenol made into a paste withglycerine. To improve the smell of the paste,eugenol and cinnamon oil were generallyadded. The liberated iodine as well as phenolkept the pulp uninfected.

3. Tannic acid mixed with some of the aboveadditives was also used.Apart from the possibility of systemic toxic

effects due to absorption of the mummifyingagents, the major disadvantage was that the deadtooth pulp was retained, albait in a dry and hardcondition, but chances of future infection/inflammation could not be ruled out.

The modern technique of root canal therapyis to perform pulpectomy, achieve a tissue freedry canal and obliterate it by packing with gutta-percha (a tough material made from latex) points,silver points or epoxy resin canal sealant. These areinert, impervious, nonirritant materials whichpreclude risk of reinfection and do not cause anycomplication.

BLEACHNG AGENTS

These are agents used to remove stains fromteeth or to improve their whiteness. Most of thebleaching agents act by oxidizing the stain/yellowish coating on the enamel, but fewreducing agents also have stain removing action.1. Oxygen releasing agents They release

oxygen which reacts with the organicpigment to decolourise it and loosen it fromtooth surface. It is then washed off to exposethe white enamel.Hydrogen peroxide is the primary oxygenating

agent. While the dilute (3%) mouth wash isoccasionally used as an antiseptic/antiplaqueagent (see p. 479), the concentrated solution (20–30%) in water (perhydrol) or ether (pyrozone)may be applied carefully to the stained teeth andwiped off for cosmetic whitening. However,burning sensation, erythema, inflammation and

sloughing may occur if it comes in contact withgingival/oral mucosa.

Carbamide peroxide is an equimolar complexof urea with hydrogen peroxide, which acts as acarrier and releases hydrogen peroxide onreacting with water. Some tooth whitenerscontain 10% carbamide peroxide.

Sodium peroxide is water soluble, releasesoxygen in solution and may be used forbleaching teeth. Sodium perborate is insoluble butslowly releases oxygen on coming in contact withwater. It is present in some tooth powders.2. Chlorine releasing agent Bleaching powder

(chlorinated lime) slowly releases chlorinewhich acts as an oxidizing agent anddecolourises many dyes. Addition of aceticacid to bleaching powder immediately beforeapplication accelerates its decomposition andhastens stain removal.Excessive use of any oxidizing bleaching

agent may damage the tooth enamel and evenaffect dentine. Tooth sensitivity and weakeningof crown may result. The oral microbial floramay also be disturbed.3. Reducing agent Sodium thiosulfate is a

reducing agent which is used for removingcertain stains, e.g. iodine stain. Sequentialapplication of an oxidizing agent followedby a reducing agent may be needed for silverstain.

4. Silica It is a nonabrasive adsorbant whichhas been included in some whitening tooth-pastes and tooth powders.Use of laser for whitening the teeth is

increasing.

DISCLOSING AGENTS

Dyes used to facilitate clear visualization of dentalplaque are called disclosing agents. By staining thebacterial plaque deeply, they increase the contrastbetween plaque and the gums. Dyes selected forthe purpose are those which:• have higher affinity for the bacterial plaque

than for oral mucosa/teeth.

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III• are not bad tasting, irritating or toxic.• diffuse uniformly and stain all supragingival

plaque.• are easily washed off by rinsing after plaque

removal.Dyes used as disclosing agent are:1. Erythrosine It is the most commonly used

disclosing agent. This red dye is blandtasting, nontoxic and stains plaque deeply,but the gums and oral mucosa also take lightstain. The residual stain goes after repeatedrinsing.

2. Fluorescein It is a yellow dye whichfluoresces under ultraviolet light; isselectively taken up by the bacterial plaque,but not by oral soft tissue. As such, afterrinsing with an aqueous solution offluorescein, the plaque can be demarcatedclearly, but needs ultraviolet light. However,it is nonirritating and nontoxic.

3. Two-tone dye It is used to differentiate theolder and thicker part of plaque from thethinner, newer plaque. A mixture of red andgreen dye is used; the mature plaque appearsblue while the fresh plaque appears red.The disclosing agents may be applied either

by rinsing the mouth with a dilute solution ofthe dye, or it may be painted on the teeth with abrush/cotton swab. If the dye is available intablet form, it may be chewed, swished aroundin the mouth followed by rinsing. The plaque isthen removed by scaling or other techniques.

DENTIFRICES

These are powders or pastes used as hygiene aidsfor routine dental care during brushing.Dentifrices facilitate cleaning of teeth and gums,improve their appearance and control badbreath. They may be medicated to impart specificpreventive and therapeutic properties. The usualingredients present in dentifrices may begrouped into the following.1. Abrasives Finely powdered inert and

poorly soluble solids having smooth particlesare used as dental abrasives, e.g. prepared

chalk, silicates, calcium phosphate, magnesiumcarbonate, aluminium oxide, magnesium oxide.Silica used in gel toothpastes has mildabrasive action. Sodium bicarbonate is anothermild abrasive which on reacting with slightlyacidic saliva releases some CO2 that facilitatesfoaming during brushing. It also reduces oralbacteria that thrive in the acidic medium.Coarse particles like charcoal, pumicepowder should not be used routinely becausethey may scratch and damage the enamel.Limited use may however be made carefullyfor strong abrasive action. Generally tooth-pastes are less abrasive than tooth powders.

2. Detergents These are surface acting agents(surfactants) which reduce surface tensionbetween oil and water and produce foam onbrushing. They emulsify fats and help in sus-pending fine particles. This action promotescleaning of teeth and gums and removal offood particles sticking to the teeth. The foamalso provides lubrication during brushing.Sodium lauryl sulfate has been a populardetergent in toothpastes, because it promotespenetration of fluoride into dentine, canloosen plaque and has antibacterial action.However, it can irritate oral mucosa; regularuse can produce sore mouth. It is beingreplaced by nonirritating agents like laurylsarcosinate. Other detergents present indentifrices are dioctyl sodium sulfosuccinate,ammonium lauryl sulfate, dodecyl benzenesulfonate, etc.

3. Humectants and binding agents Humectantslike glycerine (glycerol), sorbitol and propyleneglycol retain moisture and prevent drying oftoothpaste. Glycerine (~10%) is most com-monly included because it is sweet,nongreesy and adds thickness, softness andsmoothness to the paste. Binding agents likemethyl cellulose, bentonite, macilage of tragacanthswell in the presence of water and holdtogether the solid and liquid phases of thepaste. They also give thick consistency to thepaste.

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4. Sweetening agents Saccharine is an artificialsweetener, about 500 times more sweet thansugar. Small amount is added to the denti-frices to mask their blandness, improve theirtaste and make them acceptable even tochildren. It is noncariogenic as are other lesscommonly used sweeteners like sorbitol andglycerol.

5. Flavouring agents Essential (volatile) oilswith a characteristic pleasant aroma areadded to dentifrices to improve their flavourand acceptability. They also counteracthalitosis (bad breath). Menthol is verycommonly used, because it produces acooling sensation in the mouth and impartsa feeling of freshness. Other flavouringagents are thymol, eugenol, camphor, clove oil.

6. Colouring agents Many dentifrices are white,but some are brightly coloured blue, greenor cherry red to make them look attractiveby the addition of methylene blue, chlorophylland liquor rubri or other permitted colours.

7. Medicated dentifrices Certain medicationsare added to the toothpastes and toothpowders so as to empower them withprophylactic/therapeutic activity againstspecific dental conditions. These are:Fluoride: Sodium monofluorophosphate orsodium fluoride for caries prevention. Mosttoothpastes contain a fluoride.Antiseptics: Chlorhexidine, triclosan orbenzalkonium chloride for prevention andtreatment of dental plaque. A copolymer isoften included with triclosan to prolong itssubstantivity.Desensitizing agents: Potassium nitrate orstrontium chloride are mostly added to treatdentine sensitivity.Bleaching agents: Carbamide peroxide is thecommonest bleaching agent added to stain-removing dentifrices.Some dentifrices contain more than one

medicament and have broader spectrum ofutility.

Dentifrices 487

Drug interaction refers to modification ofresponse to one drug by another when they areadministered simultaneously or in quick succes-sion. The modification is mostly quantitative, i.e.the response is either increased or decreased inintensity, but sometimes it is qualitative, i.e. anabnormal or a different type of response isproduced. The possibility of drug interactionarises whenever a patient concurrently receivesmore than one drug, and the chances increasewith the number of drugs taken.

Many medical/dental conditions are treatedwith a combination of drugs. The componentsof the combination are so selected that theycomplement each other’s action, e.g. an antibioticis used along with an analgesic to treat a painfulinfective condition; adrenaline is combined withlidocaine for dental anaesthesia; mixed aerobic-anaerobic bacterial infections, including manyorodental infections, are treated with acombination of antimicrobials. More commonly,multiple drugs are used to treat a patient who issuffering from two or more diseases at the sametime. The chances of unintended/adverse druginteractions are greater in this later situationbecause an assortment of different drugs maybe administered to a patient depending on his/her diseases/symptoms.

Several drug interactions are desirable anddeliberately employed in therapeutics, e.g. thesynergistic action of ACE inhibitors + diuretics

to treat hypertension or sulfamethoxazole +trimethoprim to treat bacterial infection or furo-semide + amiloride to prevent hypokalaemia.These are well-recognized interactions and donot pose any undue risk to the patient. The focusof attention in this chapter are drug interactionswhich may interfere with the therapeuticoutcome, be responsible for adverse effects, ormay even be fatal (bleeding due to excessiveanticoagulant action).

The severity of drug interactions in mostcases is highly unpredictable. Because the dentistprescribes and administers certain drugs, he/shemust know which drugs are not to be prescribed

36

Drug Interactions

Regular medication drugs

(Likely to be involved in drug interactions)1. Antidiabetics2. Antihypertensives3. Antianginal drugs4. Antiarthritic drugs5. Antiepileptic drugs6. Antiparkinsonian drugs7. Oral contraceptives8. Anticoagulants9. Antiasthmatics

10. Psychopharmacological agents11. Antipeptic ulcer drugs12. Corticosteroids13. Antitubercular drugs14. Anti-HIV drugs

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concurrently. More importantly, a large sectionof dental patients are elderly, who are especiallylikely to be receiving one or several drugs fortheir chronic medical conditions like hyper-tension, diabetes, arthritis, etc. (see box forregular medication drug classes employedcommonly). The dentist may prescribe certaindrugs which may interact with those alreadybeing taken by the patient and result in adverseconsequences. It is, therefore, imperative for thedentist to elicit a detailed medical history of thepatient and record all the medication that he/she is currently on. The list of potential adversedrug interactions is already quite long andconstantly growing. It is practically impossiblefor anyone to know/remember all possible druginteractions. Fortunately, the clinically importantand common drug interactions that may beencountered in dental practice are relatively few.These are listed in Table 36.1. More exhaustivecompilations and documentation are availablein specialized books, monographs, reviewarticles and computer database on the subject,but these also need constant updating.

Certain types of drugs (see box) can beidentified that are most likely to be involved inclinically important drug interactions. Thedentist may take special care and pay attentionto the possibility of drug interactions when thepatient is receiving one or more of such medi-cations or when he/she intends to prescribe anyof such drugs. Consultation with the physiciantreating the medical condition is advised.

Types of drugs most likely to be involved inclinically important drug interactions

• Drugs with narrow safety margin, e.g.aminoglycoside antibiotics, digoxin, lithium

• Drugs affecting closely regulated bodyfunctions, e.g. antihypertensives, antidia-betics, anticoagulants

• Highly plasma protein bound drugs likeNSAIDs, oral anticoagulants, sulfonylureas

• Drugs metabolized by saturation kinetics,e.g. phenytoin, theophylline

MECHANISMS OF DRUG INTERACTIONSDrug interactions can be broadly divided intopharmacokinetic and pharmacodynamic interac-tions. In certain cases, however, the mechanismsare complex and may not be well understood.Few interactions take place even outside thebody when drug solutions are mixed beforeadministration.

Pharmacokinetic interactions

These interactions alter the concentration of theobject drug at its site of action (and consequentlythe intensity of response) by affecting its absorp-tion, distribution, metabolism or excretion.

Pharmacokinetic interactions

• Alteration of absorption or first-pass meta-bolism

• Displacement of plasma protein bound drug• Alteration of drug binding to tissues affecting

volume of distribution and clearance• Inhibition/induction of metabolism• Alteration of excretion

Absorption Absorption of an orally adminis-tered drug can be affected by other concurrentlyingested drugs. This is mostly due to formationof insoluble and poorly absorbed complexes inthe gut lumen, as occurs between tetracyclinesand calcium/iron salts, antacids or sucralfate.Phenytoin absorption is decreased by sucralfatedue to binding in the g.i. lumen. Such inter-actions can be minimized by administering thetwo drugs with a gap of 2–3 hours so that theydo not come in contact with each other in theg.i.t. Ketoconazole absorption is decreased by H2

blockers and proton pump inhibitors, becausegastric acidity needed for dissolution andabsorption of ketoconazole is reduced by thesedrugs. Antibiotics like ampicillin, tetracyclines,cotrimoxazole markedly reduce gut flora thatnormally deconjugates oral contraceptivesteroids secreted in the bile as glucuronides andpermits their enterohepatic circulation. Severalinstances of contraceptive failure have been

Pharmacokinetic Interactions 489

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reported with concurrent use of these antibioticsdue to lowering of the contraceptive blood levels.Alteration of gut motility by atropinic drugs,tricyclic antidepressants, opioids and prokineticdrugs like metoclopramide or cisapride can alsoaffect drug absorption.

Distribution Interactions involving drug distri-bution are primarily due to displacement of onedrug from its binding sites on plasma proteinsby another drug. Drugs highly bound to plasmaproteins that have a relatively small volume ofdistribution like oral anticoagulants, sulfonyl-ureas, certain NSAIDs and antiepileptics areparticularly liable to displacement interactions.Another requirement is that the displacing drugshould bind to the same sites on the plasmaproteins with higher affinity. Displacement ofbound drug will initially raise the concentrationof the free and active form of the drug in plasmathat may result in toxicity. However, such effectsare usually brief because the free form rapidlygets distributed, metabolized and excreted sothat steady-state levels are only marginallyelevated. The clinical outcome of displacementinteractions is generally significant only whendisplacement extends to tissue binding sites aswell or is accompanied by inhibition ofmetabolism and/or excretion. Quinidine hasbeen shown to reduce the binding of digoxin totissue proteins as well as its renal and biliaryclearance by inhibiting the efflux transporterP-glycoprotein, resulting in nearly doubling ofdigoxin blood levels and toxicity.

Metabolism Certain drugs reduce or enhancethe rate of metabolism of other drugs. They maythus affect the bioavailability (if the drug under-goes extensive first pass metabolism in liver) andthe plasma half-life of the drug (if the drug isprimarily eliminated by metabolism).Inhibitionof drug metabolism may be due to competitionfor the same CYP 450 isoenzyme or cofactor, andattains clinical significance mostly for drugs thatare metabolized by saturation kinetics. Macro-lide antibiotics, azole antifungals, chloram-

phenicol, omeprazole, cimetidine, HIV-proteaseinhibitors, ciprofloxacin and metronidazole aresome important inhibitors of metabolism ofmultiple drugs. Because lidocaine metabolismis dependent on hepatic blood flow, propranololhas been found to prolong its t½ by reducingblood flow to the liver.

A number of drugs induce microsomal drugmetabolizing enzymes and enhance biotrans-formation of several drugs (including their ownin many cases). Induction involves genemediated increased synthesis of certain CYP450isoenzymes; takes 1 – 2 weeks of medication withthe inducer to produce maximal effect (contrastinhibition of metabolism which developsquickly) and regresses gradually over 1 – 3 weeksafter discontinuation of the inducer. Barbiturates,phenytoin, carbamazepine, rifampin, cigarettesmoking, chronic alcoholism and certainpollutants are important microsomal enzymeinducers. Instances of failure of antimicrobialtherapy with metronidazole, doxycycline orchloramphenicol have occurred in patients whoare on long-term medication with an inducingdrug. Contraceptive failure and loss of thera-peutic effect of many other drugs have occurreddue to enzyme induction. On the other hand,the toxic dose of paracetamol is lower in chronicalcoholics and in those on enzyme inducingmedication because one of the metabolites ofparacetamol is responsible for its overdosehepatotoxicity.

Excretion Interaction involving excretion areimportant mostly in case of drugs activelysecreted by tubular transport mechanisms, e.g.probenecid inhibits tubular secretion ofpenicillins and cephalosporins and prolongstheir plasma t½. This is particularly utilized inthe single dose treatment of gonorrhoea. Aspirinblocks the uricosuric action of probenecid anddecreases tubular secretion of methotrexate.Change in the pH of urine can also affectexcretion of weakly acidic or weakly basic drugs.This has been utilized in the treatment of poison-ings. Diuretics and to some extent tetracyclines,ACE inhibitors and certain NSAIDs have been

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Table 36.1: Clinically important drug interactions in dentistry

Precipitant drug* Object drug£ Likely interaction and comments

1. Ampicillin Oral contraceptives Interruption of enterohepatic circulation of the estrogen →Amoxicillin failure of contraception; Advise alternative contraception

Oral anticoagulants Inhibition of gut flora → decreased vit K production ingut → risk of bleeding; Monitor INR and reduce anticoagu-lant dose if needed.

2. Probenecid Penicillin Inhibition of tubular secretion → prolongation of antibioticAmpicillin action; Desirable interaction utilized for single dose therapy.Cephalosporins

3. Allopurinol Ampicillin Increased incidence of rashes; Avoid concurrent use.4. Carbenicillin Aspirin and other Perturbation of surface receptors on platelets → additive

Ticarcillin antiplatelet drugs platelet inhibition → risk of bleeding; Avoid concurrent use5. Ceftriaxone Oral anticoagulants Additive hypoprothrombinaemia → bleeding; Monitor INR

Cefoperazone and reduce dose of anticoagulant.6. Sulfonamides Phenytoin Displacement$ + inhibition of metabolism → phenytoin

Cotrimoxazole toxicity; Avoid concurrent useWarfarin Displacement + inhibition of metabolism + decreased

production of vit K in gut → risk of bleeding; Monitor INRand reduce dose of warfarin

Sulfonylureas Displacement + inhibition of metabolism → hypoglycaemia;Avoid concurrent use

Thiazide diuretics Increased incidence of thrombocytopenia; Avoid concurrentuse

Oral contraceptives Interruption of enterohepatic circulation of the estrogen →failure of contraception; Advise alternative contraception

7. Metronidazole Alcohol Accumulation of acetaldehyde → disulfiram-like or bizarreTinidazole reactions; warn the patient not to drink alcoholCefoperazone

8. Metronidazole Lithium salts Decreased excretion → Li+ toxicity; Monitor Li+ level andTinidazole reduce lithium dose

Warfarin Inhibition of metabolism → risk of bleeding; Avoidconcurrent use

9. Ciprofloxacin Theophylline Inhibition of metabolism → toxicity of object drug; MonitorNorfloxacin Warfarin and reduce dose of object drugPefloxacin

10. Erythromycin Terfenadine Inhibition of metabolism by CYP3A4 → rise in blood levelClarithromycin Astemizole of object drug → dangerous ventricular arrhythmia;Ketoconazole Cisapride Concurrent use contraindicatedItraconazoleFluconazole PhenytoinHIV-protease Carbamazepineinhibitors Warfarin

Sulfonylureas Inhibition of metabolism by CYP3A4 → toxicity of objectDiazepam drug; Avoid concurrent use or readjust dose of object drugTheophyllineCyclosporineHIV protease inhibitorsStatins Inhibition of metabolism, higher risk of myopathy;

Avoid concurrent use.

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11. Tetracyclines Oral contraceptives Interruption of enterohepatic circulation of the estrogen →failure of contraception; Advise alternative contraception

Lithium salts Rise in plasma Li+ level due to decreased excretion; Avoiduse of tetracycline or monitor and reduce dose of lithium

12. Iron salts Tetracyclines Decreased absorption due to formation of complexes inCalcium salts Fluoroquinolones g.i.t. → failure of antibiotic therapy; stager drugAntacids administration by 2–3 hoursSucralfate

13. Furosemide Minocycline Enhanced vestibular toxicity; Avoid concurrent useAminoglycoside Additive ototoxicity and nephrotoxicity; Avoid concurrentantibiotics use

14. Diuretics Tetracycline Antianabolic effect of tetracycline increases urea productionwhich is retained by the diuretic; Avoid concurrent use

15. Tetracyclines Penicillins Bactericidal action of penicillins and cephalosporins may beChloramphenicol Cephalosporins antagonized by the bacteriostatic antibiotics; AvoidMacrolide antibiotics concurrent use, consult the physicianClindamycin

16. Clindamycin Erythromycin Mutual antagonism of antibacterial action due to proximalClarithromycin binding sites on bacterial ribosomes; Avoid concurrent useAzithromycinChloramphenicol

17. Phenobarbitone Metronidazole Induction of metabolism → failure of antimicrobial therapy;Phenytoin Doxycycline Avoid concurrent use or increase antibiotic dose withCarbamazepine Chloramphenicol monitoringRifampin

18. Chloramphenicol Warfarin Inhibition of metabolism → toxicity of the object drug;Phenytoin Avoid concurrent use or monitor and reduce dose of objectSulfonylureas drug

19. NSAIDs Ciprofloxacin and Enhanced CNS toxicity, seizures; Avoid concurrent useother fluoroquinolones

20. Aspirin and Sulfonylureas Displacement and/or reduced elimination → toxicity ofother NSAIDs Phenytoin object drug; Avoid concurrent use/substitute NSAID with

Valproate paracetamolMethotrexateWarfarin Enhanced risk of bleeding due to antiplatelet action andHeparin gastric mucosal damage; Avoid concurrent useACE inhibitors Reduced antihypertensive effect due to inhibition of renalβ blockers PG synthesis; Avoid concurrent useThiazide diureticsFurosemide Reduced diuretic action due to PG synthesis inhibition in

kidney; Avoid concurrent useAlcohol Increased risk of gastric mucosal damage and gastricCorticosteroids bleeding; Concurrent use contraindicated

21. Aspirin Spironolactone Reduced K+ conserving action due to decreased tubularsecretion of canrenone (active metabolite of spironolactone);Avoid concurrent use

22. Chronic Paracetamol Hepatotoxic dose of paracetamol is reduced; doses < 3 g/alcoholism day are safe

23. Chlorpromazine Morphine Enhanced CNS and respiratory depression; Avoid concurrentImipramine and Pethidine useother TCAs Codeine

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24. TCAs Adrenaline (added to Potentiation due to neuronal uptake inhibition → rise in BP;local anaesthetic) Use plain local anaesthetic solution

25. Promethazine Diazepam and other Additive CNS and respiratory depression, motorAlcohol benzodiazepines impairment; Avoid concurrent useOpioidsAntipsychotics

26. Cimetidine Diazepam and Inhibition of metabolism → exaggerated CNS depression;Isoniazid other benzodiazepines Avoid concurrent use or reduce benzodiazepine dose

27. Propranolol Adrenaline (injected with Rise in BP due to blockade of vasodilator action of adrenalinelocal anaesthetic) that enters systemic circulation; Avoid adrenaline containing

local anaesthetic or limit volume of injected local anaestheticsolution

Lidocaine Reduced hepatic clearance of lidocaine; amount used indental anaesthesia safe, but ceiling dose is reduced

28. Lidocaine β-blockers Enhanced bradycardia and hypotension; Avoid concurrentuse

Quinidine and other Exaggerated cardiac depression, precipitation ofantiarrhythmic drugs arrhythmias; Avoid concurrent use

NSAIDs: Nonsteroidal antiinflammatory drugsTCAs: Tricyclic antidepressants

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found to raise steady-state blood levels of lithiumby promoting its tubular reabsorption.

Pharmacodynamic interactions

These interactions derive from modification ofthe action of one drug at the target site by anotherdrug, independent of a change in its concen-tration. This may result in an enhanced response(synergism), an attenuated response (antago-nism) or an abnormal response. The phenomenaof synergism and antagonism are described inChapter 3, and are deliberately utilized intherapeutics for various purposes. Of clinicalsignificance are the in-advertent concurrentadministration of synergistic or antagonistic pairof drugs with adverse consequences. Someexamples are:1. Excessive sedation, respiratory depression,

motor incoordination due to concurrentadministration of a benzodiazepine (dia-zepam), a sedating antihistaminic (prometha-zine), a neuroleptic (chlorpromazine), anopioid (morphine) or drinking alcoholicbeverage while taking any of the above drugs.

2. Excessive fall in BP and fainting due toconcurrent administration of α1 adrenergicblockers, vasodilators, ACE inhibitors, highceiling diuretics and cardiac depressants.

3. Additive prolongation of prothrombin timeand bleeding by administration of ceftriaxoneor cefoperazone to a patient on oralanticoagulants.

4. Excessive platelet inhibition resulting inbleeding due to simultaneous use of aspirin/ticlopidine/clopidogrel and carbenicillin.

5. Additive ototoxicity due to use of an amino-glycoside antibiotic in a patient receivingfurosemide.

6. Precipitous fall in BP and myocardialischaemia due to use of sildenafil by patientsreceiving organic nitrates, because nitratesincrease generation of cGMP, while sildenafilprevents its degradation by inhibiting PDE 5.

7. Blunting of K+ conserving action of spiro-nolactone by aspirin, because it inhibits thetubular secretion of canrenone (an activemetabolite of spironolactone).

8. Antagonism of bactericidal action of β-lactamantibiotic by combining it with a bacterio-

Pharmacodynamic Interactions 493

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static drug like tetracycline, erythromycin orclindamycin.

9. Mutual antagonism of antibacterial action ofmacrolides, clindamycin and chloram-phenicol due to interference with each other’sbinding to the bacterial 50S ribosome.

10. Attenuation of antihypertensive effect ofACE inhibitors/β blockers/diuretics byNSAIDs due to inhibition of renal PGsynthesis.

11. Blockade of antiparkinsonian action of levo-dopa by neuroleptics and metoclopramidehaving antidopaminergic action.

Abnormal responses sometimes result frompharmacodynamic interaction between certaindrugs, e.g. metronidazole and cefoperazoneinhibit the enzyme aldehyde dehydrogenaseresulting in bizarre distressing symptoms if thepatient drinks alcohol. The basis of certaininteractions is not explained, e.g. ampicillin hasproduced high incidence of skin rashes inpatients treated with allopurinol.

Drug interactions before administration

Certain drugs react with each other and getinactivated if their solutions are mixed beforeadministration. In combined oral or parenteralformulations the manufacturers take care thatsuch incompatibilities do not take place. Inpractice situations these in vitro interactionsoccur when injectable drugs are mixed in the

same syringe or infusion bottle. Some examplesare:• Penicillin G or ampicillin mixed with genta-

micin or another aminoglycoside antibiotic.• Thiopentone sodium when mixed with

succinylcholine or morphine.• Heparin when mixed with penicillin/

gentamicin/hydrocortisone.• Noradrenaline when added to sodium

bicarbonate solution.In general, it is advisable to avoid mixing of anytwo or more parenteral drugs before injecting.

Comment Not all patients taking interactingdrugs experience adverse consequences, but itis advisable to take due precautions to avoidmishaps in all cases where interactions arepossible. That two drugs have the potential tointeract does not necessarily contraindicate theirconcurrent use. In many cases, knowledge of thenature and mechanism of the possibleinteraction may permit their concurrent useprovided appropriate dose adjustments aremade or other corrective measures are taken. Alist of clinically significant and common druginteractions that may be encountered in dentalpractice is given in Table 36.1, along with thesuggested corrective measure. However, it is agood practice to consider the possibility of druginteraction whenever two or more drugs areprescribed to a patient, or any drug is added towhat the patient is already taking.

Index

A

Abacavir, 445, 448Abciximab, 269, 270Abrasives, 486Absorption of drugs, 10, 14-16Acarbose, 224, 226-27Acebutolol, 93, 95 Aceclofenac, 325, 334Acenocoumarol, 264, 266Acetaminophen. See ParacetamolAcetazolamide, 205, 209Acetic acid, 470, 474Acetylation of drugs, 21-22, 429Acetylcholine (ACh), 68, 70-73Acetylcholinesterase (AChE), 71,

73Acetylcysteine, 291, 339Acetylsalicylic acid. See AspirinAcid neutralizing capacity

(ANC), 278Acidulated phosphate fluoride

(APF), 482Acriflavine, 470, 475Acromegaly, 216, 217, 218ACTH (Adrenocorticotropic

hormone), 215, 219, 228Actinomycin D, 305, 310Action potential (AP): local

anaesthetic on, 355Activation of drugs, 20, 21Active transport of drugs, 13-14Acute necrotizing ulcerative

gingivitis (ANUG), 372,388, 394, 471, 473

Acyclovir, 445, 446Adalimumab, 317, 319Addiction: to drugs, 61Adenosine, 199, 201-02Adenylyl cyclase: cAMP

pathway, 38, 39Adrenaline (Adr), 3, 59, 81, 83-

88, 90, 263, 357, 363

Adrenergicblockers, 90-97drugs, 83-90receptors, 82-83transmission, 81-83, 84, 85

Adrenocorticosteroids.See Corticosteroids

Adsorbants, 476Adverse drug effects, 56-63Affinity, 35Agonist, 34, 35, 47AIDS: drugs for, 447-50Akathisia, 159Albendazole, 464, 465, 468Alcohol,

ethyl, 139-42, 470, 473-74, 491methyl, 142-43

Alcoholism: dental implications,142

Aldehyde dehydrogenaseinhibitor, 142

Aldosterone, 196, 210, 228, 229Aldosterone antagonist, 195, 196-

97, 205, 210-11Alendronate, 255Alfa adrenergic blockers, 91-93,

180Alfacalcidol, 254Alfa tocopherol (vit E), 299, 301Alfuzosin, 91Alkylating agents, 305, 307Allergy: to drugs, 58-60Allopurinol, 321-22, 463, 491Allylestrenol, 240Alprazolam, 133, 138, 169Alteplase (rt-PA), 268Aluminium hydroxide, 274, 278Amantadine, 150, 154, 445, 450Ambroxol, 291, 292Amethocaine. See TetracaineAmikacin (Am), 413, 418, 428,

431Amiloride, 179, 205, 210, 214Amineptine, 163, 168

Aminoglycoside antibiotics, 130,413-19, 489

common properties, 413mechanism of action, 413shared toxicities, 414use in dentistry, 417

Aminopenicillins, 395, 396, 397Aminophylline, 296, also See

Theophylline5-Aminosalicylic acid (5-ASA).

See MesalazineAmiodarone, 199, 201Amitriptyline, 163-65Amlodipine, 174, 177Amodiaquine, 452, 456Amoxapine, 164, 165Amoxicillin, 274, 280, 369, 377,

388, 395, 397, 491Amphetamine, 83, 88-89Amphotericin B (AMB), 438-40,

463liposomal, 439

Ampicillin, 374, 395, 396-97, 491Amrinone, 195, 197Anabolic steroids, 236Anaemia: drugs for, 256-60Anaesthesia: general, 117-25

complications of, 124general: in dentistry, 117local vs general, 354local: in dentistry, 362-63mechanism of (general), 117-

18stages of, 118techniques of: local, 361-62

Anakinra, 317, 319Analgesic: combinations, 340

definition, 325in dentistry, 339nonopioid, 325-40opioid, 307, 340, 341-48, 352-

53Analgesic nephropathy, 338Anaphylactic reaction, 59

496 Essentials of Pharmacology for Dentistry

Anaphylactic shock: treatmentof, 59, 90

Anastrozole, 239, 306Androgens, 235-36Aneurine. See ThiamineAngina pectoris, 96, 177, 183-88Angiotensin (AII), 171-72

antagonists, 175-76, 178, 182,196

converting enzyme (ACE)inhibitors, 171, 173-75,178, 182, 195, 196

receptor, 172Anorectic drugs, 90Antacid, 274, 278-79, 285, 489, 492

combinations, 278Antagonism, 46-48Antagonist: competitive, 34, 35,

47, 48Anterior pituitary hormones,

215-18Anthelmintics, 463-68Anthraquinone purgatives, 285,

286Antiamoebic drugs, 387-89, 460-62Antiandrogens, 236, 311Antianginal drugs, 96, 177, 183-

88, 488Antianxiety drugs, 96, 168-70Antiarrhythmic drugs, 197-201Antibiotic, 364

in periodontal disease, 479Anticancer: drugs, 305-11

general principles in use of,311-12

general toxicity, 306-07, 313oral complications of, 307

Anticaries drugs, 480-83Anticholinergic drugs, 76-80,

277, 280, 293, 296Anticholinesterases, 74-76

poisoning, 75-76Anticoagulants, 264-68

and dental surgery bleeding,264

Anticonvulsants, 143-49, 162Antidepressants, 163-68

atypical,167-68Antidiabetic drugs, 219-28Antidiarrhoeal drugs, 289-90

Antidiuretic hormone (ADH),205, 212-14

Antidiuretics, 212-14Antiemetics, 280-84Antiepileptics, 143-49Antiestrogen, 238Antifibrinolytics, 269Antifungal drugs, 438-44Antigingivitis agents, 480-83Antihaemophilic factor, 262Anti-herpes virus drugs, 445-46Antihistamines, 101-04, 280-81,

292H1 blockers, 101-04, 280-81, 292H2 blockers, 126, 274-76, 285,

442second generation (H1), 103-04,

292Anti H. pylori drugs, 274, 279-80Antihypertensive drugs, 92, 96,

174, 177, 178-82combinations of, 182-83

Antileprotic drugs, 435-37Antimalarial drugs, 452-60

causal prophylactics, 452clinical curatives, 453-54, 455for chloroquine resistant

falciparum malaria, 455,456, 457, 458, 459, 460

gametocidal, 454radical curative, 454, 458, 459suppressive prophylactics, 453

Antimetabolites, 305, 308-09Antimicrobial agent, 364

antagonism among, 374choice of, 370-73combinations, 373-75failure of therapy with, 377-78in liver disease, 371in pregnancy, 371in renal insufficiency, 370mechanisms of action, 365-66prophylactic use of, 375-77prophylaxis in dentistry, 376-

77synergism among, 373-74

Antineoplastic. See AnticancerAntioxidant vitamin, 301Antiparkinsonian drugs, 79, 149-

54

Antiplaque agents, 477-79Antiplatelet drugs, 269-71Antiprogestin, 241Antipsychotic drugs, 155, 156-60Antipyretic-analgesics, 325-40Anti-retrovirus drugs, 445, 446-49Antirheumatoid drugs, 317-18Antiseptics, 469-75

definition, 469desirable properties, 469factors modifying activity of,

470in dental plaque and

periodontal disease,475, 478-79

in dentistry, 475Antithrombotic. See Antiplatelet

drugsAntithymocyte globulin (ATG),

316Antithyroid drugs, 249-50Antitubercular drugs, 428-33Antitussives, 291, 292Antiviral drugs, 444-51Anxiety, 96, 155, 160, 168-70Aphthous ulcers, 475, 476Arecoline, 72, 73Aripiprazole, 156, 157, 158Arteether, 452, 454, 459Artemether, 452, 454, 455, 459,

460Artemisinin, 459-60Artesunate, 452, 454, 455, 459,

460Ascorbic acid, 299, 303-04Aspirin, 108, 111, 112, 141, 263,

269-70, 325, 328-32, 491and dental surgery bleeding,

263, 331Astemizole, 103, 167, 421, 442Asthma: bronchial, 292-98Astringents, 476, 484

in dentistry, 484Atenolol, 93, 95, 180, 187Atorvastatin, 271, 272Atovaquone, 452, 460Atracurium, 129, 130Atrial fibrillation (AF), 194, 198,

200, 267Atrial flutter (Afl), 194, 198

Index 497

Atropine, 70, 75, 76-79Atropine methonitrate, 76Atypical antidepressants, 163,

164, 167-68Atypical antipsychotics, 156, 158Autacoids: definition, 98A-V block, 90, 198, 199, 202Azathioprine, 305, 308, 315, 318Azelastine, 102, 104Azithromycin, 377, 420, 423, 432,

492AZT (Azidothymidine). See

ZidovudineAztreonam, 370, 404

B

Bacampicillin, 397Bacitracin, 426, 427Baclofen, 131, 132Bactericidal AMAs, 366, 473Bacteriological sensitivity testing,

372Bacteriostatic AMAs, 366, 373Bambuterol, 88, 293, 294Barbiturates, 122, 133, 134-36,

144, 490Beclomethasone dipropionate,

293, 298Belladonna poisoning, 75, 79Benidipine, 176Benign hypertrophy of prostate

(BHP): drugs for, 92-93,237

Benoxinate, 354, 361Benserazide, 150, 152Benzalkonium chloride, 470, 473,

478, 487Benzathine penicillin, 393, 394Benzhexol. See TrihexyphenidylBenzocaine, 354, 361, 484Benzodiazepines (BZDs), 123-24,

126, 131, 133, 136-39,143, 147, 169

antagonist, 139receptor, 136-37

Benzoic acid, 444Benzothiadiazines. See ThiazidesBenzoyl peroxide, 472Benzthiazide, 205, also See

Thiazide diuretics

Beta adrenergic blockers, 83, 93-97,108, 109, 178, 179-80, 184,187, 195, 196, 199, 200-01

Beta carotene, 299, 300Beta-lactam antibiotics, 390-404Beta-lactamase inhibitors, 398-99Betamethasone, 232, also See

CorticosteroidsBethanechol, 72, 73Bezafibrate, 271, 272, also See

Fibric acid derivativesBicalutamide, 236-37, 306, 311Biguanide, 224, 225-26Bioavailability, 15-16Biological membrane, 10-11Biological response modifiers,

313, 317, 319Biotransformation, 20-25Biperiden, 76, 78, 150Bisacodyl, 286, 288Bishydroxycoumarin, 264, 266Bismuth: colloidal, 279Bisoprolol, 93, 196Bisphosphonates (BPNs), 255Bleaching agents, 485Bleaching powder, 472, 485Bleomycin, 305, 306, 310Blood-brain barrier, 17, 54Boric acid, 470, 474, 475Bran, 285-86Bretylium, 85, 199, 201Broad spectrum antibiotics, 366,

405-13Bromhexine, 291Bromocriptine, 107, 153, 217Bronchial asthma: drugs for, 292-

98Bronchodilators, 292, 293-96Budesonide, 293, 298Bumetanide, 205, 207Bupivacaine, 354, 359, 360, 363Buprenorphine, 348, 350, 351Bupropion, 164, 168Buspirone, 169-70Busulfan, 305, 306, 308Butamben, 354, 361Butenafine, 438, 444Butorphanol, 348, 350-51Butyrocholinesterase (BuChE). See

Pseudocholinesterase

C

Cabergoline, 218Caffeine, 294-95Calamine, 474, 476Calciferol, 253-54, 299Calcitonin, 253,Calcitriol, 253-54, 299Calcium, 250-52

carbonate, 252, 274, 329daily allowance, 252

Calcium channel blockers (CCBs),109, 176-78, 187, 245

Camphor, 484Cancer chemotherapy. See

Anticancer drugsgeneral principles in, 311-13oral compliations of, 307

Capreomycin (Cpr), 428, 431Captopril, 173-74Carbachol, 72, 73Carbamazepine, 143, 146, 148,

162, 491, 492Carbamide peroxide, 485, 487Carbapenems, 404Carbenicillin, 397-98, 491Carbidopa, 152, 154Carbimazole, 247, 248Carbocisteine, 292Carbolic acid. See PhenolCarbonic anhydrase (CAse), 203,

204inhibitors, 205, 209-10

Carbonyl iron, 257Carboplatin, 305, 310Carcinogenicity, 63Cardiac glycosides, 190-95Cardiotonic drugs. See DigitalisCarisoprodol, 131Carriers as targets of drug action,

32, 34Carrier transport, 12, 13Carvedilol, 93, 97, 180, 196Cascara sagrada, 285, 286Catecholamines (CAs), 81-83, also

See individual drugsCaustics, in dentistry, 476Cefaclor, 399, 401, 403Cefadroxil, 399, 400Cefazolin, 399, 400Cefdinir, 399, 402


Cefepime, 399, 402Cefixime, 399, 402Cefoperazone, 399, 402, 491Cefotaxime, 399, 401Cefpirome, 399, 402Cefpodoxime proxetil, 399, 402Ceftazidime, 399, 401Ceftibuten, 399, 402Ceftizoxime, 399, 401Ceftriaxone, 399, 401Cefuroxime, 399, 400Cefuroxime axetil, 399, 401, 403Celecoxib, 337Centchroman, 243Centrally acting muscle

relaxants, 130-32Cephalexin, 377, 399, 400, 403Cephalosporins, 399-404, 491, 492

in dental infections, 403Cephradine, 399, 400Cetirizine, 102, 103Cetrimide, 470, 473, 478Cetyl pyridinium chloride, 470,

473, 478Cheese reaction, 92, 163, 180, 183Chemotherapy. See

Antimicrobialdefinition, 4, 364failure of, 377-78history of, 364-65of cancer, 305-13

Child dose calculation, 50-51Chlophedianol, 292Chlorambucil, 305, 308, 316Chloramphenicol, 410-13

in dental infections, 412palmitate, 411succinate, 411

Chlordiazepoxide, 133, 136, 142,169

Chlorhexidine, 470, 472-73, 475,478, 483, 487

in caries, 483in dental plaque and

periodontal disease, 478Chlorinated lime (bleaching

powder), 472, 485Chlorine, 472, 485Chlormezanone, 131Chloroguanide. See ProguanilChlorophores, 472

Chloroprocaine, 354, 356Chloroquine, 317, 318, 452, 453,

454, 455-56, 461Chloroxylenol, 470, 471Chlorpheniramine, 102, 104, 291Chlorpromazine (CPZ), 156-60,

280, 492Chlorpropamide, 224, 225Chlorthalidone, 178, 205Chlorzoxazone, 131Cholestyramine, 271, 272Choline esters, 72-73Cholinergic

antagonists, 70, 76-80drugs, 72-73transmission, 70-72

Cholinesterase reactivators, 76Cholinesterases, 71Cholinoceptors, 71-72Cholinomimetic alkaloids, 72, 73Chronic obstructive pulmonary

disease (COPD), 78, 293,294, 295, 296, 298

Ciclesonide, 293, 298Ciclopirox olamine, 438, 444Cimetidine, 275-76, also See H2

antagonistsCinchocaine. See DibucaineCinnarizine, 102, 104, 281Ciprofloxacin, 289, 365, 383, 384-

86, 431-32, 491Cisapride, 283, 421, 491Cisplatin, 305, 306, 310Citalopram, 163, 164, also See

Selective serotoninreuptake inhibitors

Citrovorum factor. See Folinic acidClarithromycin, 280, 420, 422-23,

432, 436, 491Clavulanic acid, 398-99Clearance of drug (CL), 27Clemastine, 102Clidinium, 76, 78Clindamycin, 377, 423-24, 492

in dentistry, 377, 424Clinical pharmacology, 4Clobazam, 133, 147Clofazimine (Clo), 435-36, 437Clomiphene citrate, 238Clomipramine, 163, 164, 165, 168Clonazepam, 143,147, 148, 169

Clonidine, 85, 180-81Clopamide, 205, also See Thiazide

diureticsClopidogrel, 270Clorgyline, 163Clotrimazole, 441Clove oil, 484Cloxacillin, 395-96, 397Clozapine, 106, 157, 158Coagulants, 260-63Cobra bite, 75Cocaine, 85, 359Codeine, 290, 292, 341, 345Colchicine, 320Colestipol, 272Colistin, 289, 426Collodion, 476Colloidal bismuth subcitrate

(CBS), 274, 279Competitive: antagonism, 47, 48

enzyme inhibition, 33COMT inhibitors, 150, 154Congestive heart failure (CHF)

drugs for, 96, 175, 190-97effect on drug kinetics, 54treatment of, 195-97

Conscious sedation (indentistry), 125

Constipation: treatment of, 287Contraceptives, 241-43

emergency (postcoital), 241, 242hormonal, 241-43injectable, 242

Controlled release tablet/capsule, 30

Coronary steal, 177, 188Corticosteroids, 228-34, 284, 290,

297-98, 311, 316implications in dentistry, 234

Corticotropin. See ACTHCortisol. See HydrocortisoneCo-transmission, 70Cotrimazine, 382Cotrimoxazole, 289, 381-82Cough: drugs for, 291-92COX-I/COX-2 (cyclooxygenase)

isoenzymes, 110, 111,326-28

COX-2 (cyclooxygenase-2)inhibitors, 325, 336-38,340

Index 499

Cresol, 470, 471, 475Cretinism, 247, 249Cromoglycate sod (Cromolyn

sod), 296-97Cross resistance, 368-69Cross tolerance, 55Cumulation, 55Curare, 127, also See TubocurarineCyanide poisoning, 187Cyanocobalamin. See Vit. B12

CyclicAMP(cAMP), 3, 38, 39, 87,295

Cyclic GMP (cGMP), 40, 185, 295Cyclizine, 102, 104, 281Cyclooxygenase (COX), 110, 269

inhibitor, 111, 326-28,also See Nonsteriodalantiinflammatory drugs

isoforms, 110, 326Cyclopentolate, 76, 78Cyclophosphamide, 305, 308, 315Cycloserine (Cys), 431Cyclosporine, 313-15, 491Cyproheptadine, 102, 106Cytarabine, 305, 309Cytochrome P450 (CYP)

isoenzymes, 21Cytotoxic drugs, 305-10, 315-16

D

Dacarbazine (DTIC), 305, 308Danazol, 236Dantrolene, 130, 159Dapsone (DDS), 435, 437Daunorubicin (Rubidomycin), 310DDS. See DapsoneDecamethonium (C-10), 126, 128Deflazacort, 232Dehydroemetine, 461Demeclocycline, 407, 408Demulsants, 476

pharyngeal, 291Dental plaque; antiseptics in, 475,

478-79Dentifrices, 486-87Dentine bonding agents, 484Detine sensitivity, 483Depot preparations, 9, 15Depression (of function), 31

mental, 155, 163-68

Dequalinium chloride, 470, 473Dermojet, 9Desamino-Oxytocin, 244Desensitization, 41, 43Desensitizing agents, 483-84Desflurane, 120, 122Desipramine, 85, 163Desloratadine, 102, 103Desmopressin, 213, 214Desogestrel, 240, 242Detergents, 486Dexamethasone, 232, also See

CorticosteroidsDexchlorpheniramine, 102Dexfenfluramine, 88, 89Dexrabeprazole, 274Dextromethorphan, 292Dextropropoxyphene, 346, 347DHE (Dihydroergotamine), 91,

107, 109Diabetes

implications in dentistry, 228insipidus, 208, 212, 213mellitus, 219-20, 223, 227-28

Diarrhoea: treatment of, 288-90antimicrobials in, 289antimotility drugs in, 290antisecretory drugs in, 289-90

Diazepam, 123, 125, 126, 131,133, 136-38, 147, 149,169

Dibucaine, 359, 361Diclofenac sod., 325, 333-34Dicumarol. See

BishydroxycoumarinDicyclomine, 76, 78, 280Didanosine, 447Dietary fibre, 286Diethyl carbamazine citrate

(DEC), 466Diethylstilbestrol (Stilbestrol), 237Diffusion: of drugs, 12Diffusion hypoxia, 119, 121Digitalis, 190-95, 199-202

toxicity, 192-93Digitoxin, 190, 192Digoxin, 190-94, 195.

also See Digitalisantibodies, 193

Dihydroergotamine (DHE), 91,107, 109

Dihydroergotoxine, 91, 92, 107Dihydrofolate reductase

(DHFRase) inhibitorsbacterial, 381-82mammalian, 308protozoal, 457, 458

Dihydropyridines (DHPs), 176-78Dihydrotestosterone, 235, 237Diiodohydroxyquin, 461, 463Dilling’s formula, 50Diloxanide furoate, 461Diltiazem, 176, 177, 178, 199, 201Dimenhydrinate, 102, 280, 281Dioctyl sulfo succinate (DOSS).

See DocusatesDiphenhydramine, 101, 102,280,

281Diphenoxylate, 290Dipyridamole, 188, 270Dipyrone. See MetamizolDisclosing agents, 485-86Disease modifying

antirheumatoid drugs(DMARDs), 317-19

Disinfectants, 469-75definition, 469in dentistry, 475desirable properties of, 269-70

Disopyramide, 199, 200Dissociative anaesthesia, 120, 124Distribution of drugs, 16-20Disulfiram, 142, 388Diuretics, 178-79, 182, 195, 205-12Diuretic therapy: complications,

208-09Divalproex, 143, 147DMPA (Depot medroxy

progesterone acetate),242

Dobutamine, 88, 197Docetaxel, 309Docusates, 286Dofetilide, 199, 201Domperidone, 126, 280, 283Donepezil, 74, 75DOPA, 81Dopamine (DA), 81, 88, 150, 151,

197Dose: of drug, 28-30, 43-45, 48-49

child, 50-51for elderly, 51


loading, 29-30maintenance, 30

Dose-response relationship, 43Dothiepin, 163, 164Doxacurium, 126, 129Doxazosin, 91, 92, 180Doxepin, 163, 164Doxophylline, 293Doxorubicin, 305, 310Doxycycline, 405, 407, 408, 409,

452, 459Doxylamine, 280, 281Dronabinol, 284Drug

absorption, 10, 14-16abuse, 61action, 31, 36, 39activation, 20, 21addiction, 61adverse effects, 56-63allergy, 58-60combinations (fixed dose), 49-

50combined effect of, 45-48definition, 4dependence, 60-61diffusion, 11-12distribution, 10, 16-20dosage, 28-30, 48-49effect, 36, 39efficacy, 43-44excretion, 10, 25-26factors modifying action of,

50-55habituation, 61induced diseases, 63interactions: 45-48, 488-94

before administration, 46,494

in dentistry, 491-93mechanism of, 15, 19, 23-

24, 26, 46-48, 54-55, 489-90, 493

mechanisms of action, 31-42metabolism, 20-25nomenclature, 4-5penetration into brain, 17-18potency, 43-44resistance, 55, 367-69routes of administration, 5-9

selectivity, 44-45storage, 19-20transport, 10-14withdrawal reactions, 60, 61

Duloxetine, 163, 164Dydrogesterone, 240Dyflos, 74, also See

OrganophosphatesDynorphins, 348, 352

E

Ebastine, 102, 103Echothiophate, 74Econazole, 438, 441-42Edrophonium, 74EDRF (Endothelium dependent

relaxing factor), 72, 99Efavirenz, 445, 448-49Eicosanoids, 109-15Elimination rate constant (K), 27Emergency contraception, 241,

242Emesis, 280, 281Emetine, 461, 462Emollients, 476Enalapril, 174, also See

Angiotensin convertingenzyme inhibitors

Endogenous (major) depression:treatment, 168

Endorphins (β-END), 348, 352Enkephalins, 348, 352Entacapone, 150, 154Enzyme

induction, 23-24inhibition, 23, 32 33stimulation, 32, 33

Ephedrine, 84, 88Epidural anaesthesia, 362Epilepsies, 143

during dental procedures, 149treatment, 149

Epinephrine. See AdrenalineEplerenone, 205, 211Epsilon amino caproic acid

(EACA), 269Erogometrine (Ergonovine), 107,

243, 244Ergot alkaloids, 91, 92, 107

Ergotamine, 91, 92, 107, 108-09Ergotoxine, 91Erythrityl tetranitrate, 184, 186Erythromycin, 420-22

in dental infections, 422Erythropoietin, 260Erythrosine, 486Escitalopram, 163, 164, also See


Eserine. See PhysostigmineEsmolol, 93, 96, 183Esomeprazole, 274, 277, also See

Proton pump inhibitorsEstradiol, 237, also See EstrogensEstrogens, 237-38, 311, also See

Oral contraceptivesEtanercept, 317, 319Ethambutol (E), 428, 430-31, 433Ethamsylate, 262-63Ethanol. See Alcohol ethylEther, 120, 121Ethinyl estradiol, 237, also See

Oral contraceptivesEthinyl estranol. See LynestrenolEthionamide (Etm), 428, 431, 436Ethosuximide, 143, 146Ethyl alcohol. See Alcohol ethylEthylbiscoumacetate, 264, 266Etidronate, 255Etoposide, 309Etoricoxib, 319, 325, 337, 339Eutectic lidocaine/prilocaine,

360Excretion: of drugs, 10, 25-26Exemestane, 239Exocytosis, 69, 71, 81Expectorants, 291-92Ezetimibe, 271, 273

F

Facilitated diffusion, 12-13Factors modifying drug action,

50-55Famciclovir, 445, 446Famotidine, 276, also See H2

antagonistsFaropenem, 404Felodipine, 177, 179, 184

Index 501

Fenofibrate, 271, 272, also SeeFibric acid derivatives

Fenfluramine, 88, 89Fentanyl, 124, 125, 346, 347

transdermal, 346, 347Ferric

ammonium citrate, 257hydroxide, 257

Ferrousfumarate, 257gluconate, 257succinate, 257sulfate, 257

Fexofenadine, 102, 103Fibric acid derivatives (Fibrates),

271, 272-73Fibrin, 263Fibrinogen, 262Fibrinolytic drugs, 268-69Filtration: of drugs, 12Finasteride, 237, 311First dose effect, 92, 180First order kinetics, 28, 29First pass metabolism, 24-25Fixed dose ratio combinations,

49-50Flavoxate, 76, 78Flecainide, 199, 200Fluconazole, 438, 440, 442-43, 491

in oral candidiasis, 443Flucytosine (5-FC), 441Fludarabine, 305Flumazenil, 137, 139Flunarizine, 108, 109Fluorescein, 486Fluoride, 480-82, 483, 487Fluorosis, 482Fluoroquinolones (FQs),383-87,

431-32, 4925-Fluorouracil (5-FU), 305, 308Fluoxetine, 163, 164, also see


Flupenthixol, 156, 157Fluphenazine, 156, 157Flurazepam, 133, 138Flurbiprofen, 325, 332Flutamide, 236, 311Fluticasone propionate, 293, 298

Fluvoxamine, 163, 164, also seeSelective serotoninreuptake inhibitors

Folic acid, 259-60antagonists. See Dihydrofolate

reductase inhibitorFolinic acid (THFA), 260, 308Follicle stimulating hormone

(FSH), 215, 218Fomepizole, 143Formalin (Formaldehyde), 470,

474, 484Formoterol, 88, 89, 293, 294Foscarnet, 446Fosinopril, 173Fosphenytoin, 146, 149Framycetin, 419Frusemide. See FurosemideFulvestrant, 239, 311Furazolidone, 462Furosemide, 179, 195, 205-07,

212, 492, also See Highceiling diuretics

Fusidic acid, 426

G

GABAA-benzodiazepine receptor,136-37

Gabapentin, 143, 148Ganciclovir, 445, 446Ganglionic

blocking agents, 76, 80stimulants, 80

Gastric acid secretion: regulationof, 274, 275

Gastric hurrying agent, 282,also See Prokinetic drugs

Gastroesophageal reflux disease(GERD), 284

drugs for, 276, 277, 283, 284-85Gatifloxacin, 387Gelatin foam, 263Gemfibrozil, 271, 272, also See

Fibric acid derivativesGemifloxacin, 383, 387General anaesthetics (GA),

117-25Genetics: and drug action, 52

Gentamicin, 417-18, also SeeAminoglycosideantibiotics

in dentistry, 417Gentian violet, 470, 474Germicide, 469-70Gestodene, 240Giardiasis: drugs for, 462Glaucoma: drugs for, 73, 95, 97,

115, 212Glibenclamide, 224, 225, also See

Oral hypoglycaemicsGliclazide, 224, 225Glimepiride, 224, 225Glipizide, 224, 225Glucagon, 228Glucocorticoid receptor, 40, 42, 231Glucocorticoids, 228-33, also See

Corticosteroidsantagonist, 241

Glucuronide conjugation, 21Glutaraldehyde, 474, 475Glutathione conjugation, 22Glyburide. See GlibenclamideGlycerol (Glycerine), 476, 486, 487Glyceryl trinitrate (GTN), 184,

186, also See NitratesGlycopeptide antibiotics, 424-25Glycoprotein (GP) IIb/IIIa

antagonists, 270Glycopyrrolate, 76, 78, 126Glycyrrhiza, 476GnRH agonists, 218, 311Goiter, 249Gold, 318Gonadotropins (Gns), 218Gout: drugs for, 319-22G-proteins, 37, 38, 39Granisetron, 284Graves’ disease, 249, 250Gray baby syndrome, 412Griseofulvin, 440-41Growth hormone (GH), 216-17Guaiphenesin, 291Guanethidine, 84, 85

H

H1 antagonists, 101-04H2 antagonists, 105, 126, 274-76, 285


Habituation, 61Haematinics, 256-60Haemophilia, drugs for, 214, 262,

263-64Haemostasis in dentistry, 263-64Haemostatics: local, 263Half life (t½), 27-28Halofantrine, 460Haloperidol, 156, 157, 280Halothane, 120, 121Hamycin, 440Heart block. See A-V blockHeparan sulfate, 264, 265Heparin, 264-65, 267, 269

antagonist, 265-66low molecular weight, 265

Heroin, 345Herpes simplex: drugs for, 445-46

mucocutaneous, 446Hexachlorophene, 470, 471Hexamethonium, 70, 80Hexamine. See MethenamineHexylresorcinol, 471High-ceiling diuretics, 179, 195,

205-07Highly active antiretroviral

therapy (HAART), 449Histamine, 98-101

receptors, 99, 100HIV infection: drugs for, 446-49

postexposure prophylaxis, 450treatment guidelines, 449

HMG-CoA reductase inhibitors(Statins), 271-72

Hofmann elimination, 23, 129Homatropine,76Hormonal contraceptives, 241-43Hormone: definition, 215Hormone replacement therapy

(HRT), 238, 241Humectants, 486Hydralazine, 181, 182, 196Hydrochlorothiazide, 179, 205, also

See Thiazide diureticsHydrocortisone, 228, 231, 232,

also See CorticosteroidsHydroflumethiazide, 205, also See

Thiazide diureticsHydrogen peroxide, 470, 471,

475, 478, 479, 485

Hydrolysis: of drugs, 21Hydroxocobalamin, 258, also See

Vit B12

Hydroxychloroquine, 318Hydroxyprogesterone caproate,

2408-Hydroxyquinolines, 461-625-Hydroxytryptamine (5-HT), 98,

105-06antagonists, 106-07receptor subtypes, 105

Hydroxyurea, 310Hydroxyzine, 102, 170Hyoscine, 76, 79, 280

butyl bromide, 76, 78Hypersensitivity (allergic)

reactions, 58-60to penicillin, 393-94

Hypertension: drugs for, 92, 96,174, 177, 178-82

Hypertensive emergencies/urgencies, 183

Hyperthyroidism. SeeThyrotoxicosis

Hypervitaminosis A, 301Hypervitaminosis D, 254Hypnotics, 133-39

definition, 133Hypoglycaemic drugs, See

Antidiabetic drugsHypolipidemic drugs, 271-73Hypothyroidism, 247, 248, 249

I

Ibuprofen, 325, 332-33, 353Ibutilide, 199, 201Idiosyncrasy, 58Idoxuridine, 445Ifosfamide, 305Imatinib, 305, 310Imidapril, 173Imipenem, 404Imipramine, 163, 164-66, 492Immunosuppressants, 313-16

in rheumatoid arthritis, 317-18Implants, 9Inamrinone. See AmrinoneIndapamide, 179, 205Indinavir, 445, 448, 449

Indomethacin, 214, 319, 335Induction of drug metabolism,

23-24, 32, 33, 490Infertility: drugs for, 218, 238Infliximab, 317, 319INH. See IsoniazidInhaled steroids, 297-98Inhalation of drugs, 8Inhalational anaesthesia, 118-22Inhibition of drug metabolism,

23, 490Inodilator, 197Insulin, 220-24, 227

aspart, 222glargine, 222, 223glulisine, 222human, 222lispro, 222preparations, 222-23reactions to, 223receptor, 221-22

Insulin-like growth factors(IGFs), 222, 223

Interferon a, 451Intolerance, 58Intraarterial injection, 6Intradermal injection, 9Intramuscular injection (i.m.), 9

absorption from, 15Intravenous anaesthetics, 122-24Intravenous injection (i.v.), 9Intrinsic activity, 35Inverse agonists, 34, 35, 137Iodide. sod./pot., 249, 250, 291Iodine 249, 250, 472

radioactive (131I), 249, 250Iodochlorohydroxyquin. See

QuiniodochlorIodoform, 485Iodophores, 472Ion channels as targets of drug

action, 33-34Ipratropium bromide, 76, 78Irinotecan, 309Iron, 256-58

absorption, 256-57deficiency: oral manifestations,

256dextran, 258hydroxy polymaltose, 257sorbitol-citric acid, 258

Index 503

Irritation, 31Isoflurane, 120, 121-22Isoniazid (INH; H), 428-29, 433,

434Isoprenaline (Iso), 83, 88, 90Isopropanol, 474Isosorbide dinitrate, 186, 196Isosorbide mononitrate, 186Isoxsuprine, 88, 245Ispaghula, 285, 286Itraconazole (ITR), 440, 443, 491Ivermectin, 464, 466-67

J

Jarisch-Herxheimer reaction, 394

K

Kala-azar. See LeishmaniasisKanamycin (Kmc), 413, 418, 428,

431Ketamine, 124Ketoconazole (KTZ), 440, 442,

463, 491Ketoprofen, 325, 332Ketorolac, 325, 334-35, 339Ketotifen, 297Kidney disease and drugs, 53-54,

370Kinetics of drug elimination, 26-

30

L

Labetalol, 93, 97, 180Labour: induction/augmentation,

115, 244Labour: suppression, 245Lacidipine, 177, 184Lactulose, 287, 288Lamivudine, 445, 448, 449, 450Lamotrigine, 145, 147-48, 162Lansoprazole, 274, 277, also See

Proton pump inhibitorsL-Asparaginase, 310, 313Latanoprost, 115Laxatives, 285-88L-Dopa. See LevodopaLeflunomide, 318Leishmaniasis: drugs for, 463

Lepra reaction, 437Leprosy: drugs for, 435-37

alternative regimens for, 437multidrug therapy (MDT) in,

436-37Lercanidipine, 176Letrozole, 239, 311Leucovorin. See Folinic acidLeukotrienes (LTs), 110, 111, 114

antagonists, 296, 298Leuproreline, 218Levamisole, 464, 466Levarterenol. See NoradrenalineLevetiracetam, 144, 148Levobupivacaine, 360Levocetirizine, 102, 104Levodopa, 150-52, 494Levofloxacin, 383, 386Levonorgestrel, 240, 242Lidocaine, 199, 200, 354, 355, 358,

359, 360, 362-63Ligand, 34Lignocaine. See LidocaineLincomycin, 424Linezolid, 425-26Liothyronine. See

TriiodothyronineLiquid paraffin, 286, 476Liquorice, 291, 476Lisinopril, 174, also See

Angiotensin convertingenzyme inhibitors

Listerine, 471, 478Lithium, 160-62, 491

alternatives to, 162Liver disease and drugs, 53, 371Loading dose: of drug, 29-30Local anaesthesia, 354-63

compared to generalanaesthesia, 354

in dentistry, 360, 362-63techniques of, 361-62

Local anaesthetics (LAs), 354-63mechanism of action, 355-56with adrenaline, 90, 357, 363

Local routes of administration,5-6

Lomefloxacin, 385, 386Lomustine (CCNU), 305, 308Loperamide, 290

Lopinavir, 445, 448, 449Loratadine, 102, 103Lorazepam, 123, 147-49, 169, 313Losartan, 175, also See

Angiotensin antagonistLovastatin, 272, also See StatinsLoxapine, 156, 157Loxatidine, 274, also See H2

antagonistsLumefantrine, 454, 460Lutenizing hormone (LH), 215,

218Lypressin, 213Lynestrenol, 240

M

MAC (Mycobacterium aviumcomplex): drugs for, 435

Macrolide antibiotics, 420-23Mafenide, 381Magaldrate, 278Magnesium

hydroxide, 278, 285, 287sulfate, 245trisilicate, 278

Maintenance dose (of drug), 30Malignant hyperthermia, 121, 130Malignant neuroleptic

syndrome, 159Mania, 155, 160, 162Manic depressive illness (MDI,

Bipolar disorder), 160,162

Mannitol, 211-62Mast cell stabilizers, 293, 296-97Mebendazole, 464-65Mebhydroline, 102Mechanism of drug action, 31-42Meclozine (Meclizine), 102, 281Medroxyprogesterone acetate,

240, 242Mefloquine, 454, 455, 456, 460Meglitinide analogues, 225, 226,

227Meloxicam, 336Melphalan, 308Menadione, 261, 262

sodium bisulfite, 262sodium diphosphate, 262


Menthol, 484, 487Meperidine. See PethidineMephenamic acid, 333Mephenesin, 131Mephentermine, 88, 89Mercaptopurine (6-MP), 305, 308Meropenem, 404Mesalazine (5-ASA, Mesalamine),

290Mestranol, 237Metabolism. See

BiotransformationMetabolism: presystemic (first

pass), 24-25Metamizol, 335Metformin, 225-26, also See

BiguanidesMethacholine, 72, 73Methadone, 346Methamphetamine, 88Methandienone, 236Methanol. See Alcohol methylMethenamine, 427Methicillin, 395Methicillin resistant Staph. aureus

(MRSA), 392, 395drugs for: 395, 425-26

Methimazole, 249Methocarbamol, 131, 132Methohexitone, 120, 123Methotrexate (Mtx), 308, 313,

315-16, 317-18Methoxamine, 88, 89Methyl alcohol, 142-43Methylation of drugs, 22Methyl cellulose, 285, 476, 486Methyldopa, 181, 182Methylergometrine, 243, 244Methylprednisolone, 232Methylxanthines, 293, 294-96Methysergide, 106, 108, 109Metoclopramide, 282-83, 285Metolazone, 205Metoprolol, 93, 95Metronidazole, 289, 387-89, 461,

462in orodental infections, 388,

479-80Mexiletine, 200

Mezlocillin, 398Mianserin, 164, 167Miconazole, 442Microsomal enzymes, 22

induction, 23-24, 490Midazolam, 124, 125, 149Mifepristone, 241, 242Miglitol, 224Migraine, 96, 107-09Milk ejection reflex, 244Milk: excretion of drugs in, 25Milrinone, 197Miltefosine, 463Mineralocorticoid, 210, 229, 232Minimal alveolar concentration

(MAC), 117, 120Minimum bactericidal

concentration (MBC), 372Minimum inhibitory

concentration (MIC), 372Minocycline, 405, 407, 408, 436,

437, 492Miotic, 73, 75, 77Mirtazapine, 164, 168Misoprostol, 115, 243, 278Mivacurium, 126, 129Mizolastine, 101, 102Moclobemide, 163-64Monoamine oxidase (MAO), 82,

84, 105, 152, 163inhibitors (MAOI), 84, 85, 153,

163Monobactams, 404Montelukast, 296, also See

Leukotriene antagonistsMood stabiliser, 160-62Morning sickness, 280, 281, 282Morphine, 341-48

dependence, 344in dental pain, 353poisoning, 343-44, 352

Mosapride, 283Motion sickness: drugs for, 79,

104, 280, 281Moxifloxacin, 383, 387Muromonab CD3, 316Muscarine, 72, 73Muscarinic

actions, 72-73antagonists, 76-79receptor, 71-72

Muscle relaxants, 126-32centrally acting, 130-32

Mushroom poisoning, 73Mutagenicity of drugs, 63Myasthenia gravis, 75, 233, 315Mycophenolate mofetil, 313, 316Mydriatics, 76, 77, 79Myocardial infarction (MI):

drugs for, 96, 188-89Myxoedema, 249, also See

Hypothyroidism

N

Nabumetone, 325, 336N-acetylcysteine, 339Nafarelin, 218, 306Nalidixic acid, 383, 427Nalorphine, 350Naloxone, 344, 350, 351-52Naltrexone, 142, 350, 352Nandrolone, 236Naproxen, 319, 325, 332, 333Nasal administration of drugs, 8Nasal decongestants, 89, 90Natamycin, 438, 440Nateglinide, 224, 225, 226Nebivolol, 93, 96Nefopam, 339Nelfinavir, 445, 448Neomycin, 413, 419, 426Neostigmine, 74, 75Nerve block anaesthesia, 361-62Netilmicin, 415, 418Neurohumoral transmission,

67-70Neuroleptic drugs. See

Antipsychotic drugsNeuromuscular blocking agents,

126, 127-30Neuroses, 155Nevirapine, 448, 449Niacin (Vit B3), 299, 302-03Niclosamide, 464, 467Nicorandil, 187, 196Nicotinamide. See NiacinNicotine, 80Nicotinic acid (Vit B3) 272, 273,

299, 302-03Nicotinic actions, 73

Index 505

Nicotinic receptors, 37, 72, 127Nicoumalone. See

AcenocoumarolNifedipine, 176, 177, 183Nimesulide, 336, 339, 340Nimodipine, 177Nitazoxanide, 461Nitrates, 184-87, 196Nitrate tolerance, 186Nitrazepam, 133, 138Nitrendipine, 177, 178, 184Nitric oxide (NO), 185, 187,

also See EDRFNitrofurantoin, 427Nitrofurazone, 475Nitroglycerine. See Glyceryl

trinitrateNitroimidazoles, 387-89, 461Nitroprusside sod., 181-82, 183Nitrous oxide (N2O), 121, 125Nomegestrol, 240Nonbenzodiazepine hypnotics,

134, 139-40Noncompetitive antagonism, 47,

48Noncompetitive enzyme

inhibition, 33Nonmicrosomal enzymes, 22Nonnucleoside reverse

transcriptase inhibitors(NNRTIs), 445, 448, 449

Nonsedating antihistamines.See Antihistamines:second generation

Nonsteroidal antiinflammatorydrugs (NSAIDs), 108,111, 325-40

and dental surgery bleeding,263

and gastric mucosal damage,276, 277, 278, 327

and PG synthesis inhibition,111, 326-28

drug interactions with, 333in rheumatoid arthritis, 317,

331, 332, 333in dentistry, 263, 339-40in gout, 319-20in migraine, 108shared toxicities, 326, 327, 328

Noradrenaline (NA), 68, 81, 82,83, 84, 87, 88, 90

Norepinephrine. SeeNoradrenaline

Norethisterone. SeeNorethindrone

Norethindrone, 240enanthate (NEE), 242

Norfloxacin, 289, 383, 385, 386, 491Norgestimate, 240Nortriptyline, 163, 164Noscapine, 292, 341Nucleoside reverse transcriptase

inhibitors (NRTIs), 445,447-48, 449

Nystatin, 438, 440in oral candidiasis, 440

O

Obtundants, 484Octreotide, 216Ofloxacin, 385, 386, 431-32, 435,

436Olanzapine, 156, 157, 158Omeprazole, 277, also See Proton

pump inhibitorsOncovin. See VincristineOndansetron, 107, 126, 280, 284,

313On-off effect, 152, 153Opioid

agonist-antagonists, 350-51analgesics, 126, 188, 341-38antagonists (pure), 351-52antidiarrhoeals, 290, 348antitussives, 291, 292, 345in dental pain, 352-53in preanaesthetic medication,

126, 346peptides, 352receptors, 348-50

Opium, 341Oral

absorption of drugs, 14-15, 16anticoagulants, 264, 266-67,

268, 491contraceptives (OCs), 241-43hypoglycaemic drugs, 224-28iron preparations, 257-58

rehydration salt/solution(ORS), 288-89

route of administration, 6Organophosphates, 74, 75Organophosphate poisoning, 75-

76Ornidazole, 389Oseltamivir, 445, 450-51Osmotic diuretics, 205, 211-12Osmotic (saline) purgatives, 285,

287, 288Osteomalacia, 254-55Osteoporosis, 252, 253, 255

anabolic steroids in, 236bisphosphonates in, 252, 255calcium in, 252raloxifene in, 239vit D in, 252

Oxazepam, 20, 133, 169Oxazolidinone antimicrobial,

365, 425-26Oxcarbazepine, 143, 146Oxethazaine, 354, 361Oxidation of drugs, 20-21Oxidized cellulose, 263Oximes, 76Oxybutynin, 76, 78Oxymetazoline, 88, 89Oxymetholone, 236Oxyphenbutazone, 325, 335Oxyphenonium, 76, 78Oxytetracycline, 405, 407, 408Oxytocics, 243-45Oxytocin, 244

P

Paclitaxel, 305, 3092-PAM. See PralidoximePamidronate, 255Pancuronium, 126, 129Pantoprazole, 274, 277, also See

Proton pump inhibitorsPara aminosalicylic acid (PAS), 428Paracetamol, 3, 325, 331, 338-39,

340poisoning, 338-39

Paraffin, liquid, 476Paraformaldehyde (Paraform), 484Parasympathetic system, 67, 68


Parasympathomimetic drugs. SeeCholinergic drugs

Parathyroid hormone (PTH), 251,252-53

Parecoxib, 325, 337Parenteral routes, 8-9Parkinsonism, drugs for, 79,

149-54Paromomycin, 463Paroxetine, 163,164, also See


Paroxysmal supraventriculartachycardia (PSVT), 96,194-95, 198, 199, 201, 202

Partial agonist, 34, 35, 47Pefloxacin, 383, 385, 386Pellet implantation, 9Penfluridol, 156Penicillamine, 317, 319Penicillinase, 392Penicillins, 390-99

acid resistant, 395benzathine, 393benzyl (G), 390, 392-95extended spectrum, 395, 396-98in dental infections, 394penicillinase resistant, 395-96phenoxymethyl (V), 395procaine, 393semisynthetic, 395-98

Pentaerythritol tetranitrate, 184,186

Pentamidine, 463Pentazocine, 348, 350, 353Pentolinium, 80Peptic ulcer: drugs for, 274-80Perindopril, 173, 174, 178Periodontal disease

antibiotics in, 479-80antiseptics in, 478-79drugs for, 477-80tetracyclines in, 409, 479-80

Peripheral decarboxylaseinhibitors, 150, 152-53

Pernicious anaemia, 259Pethidine, 345-46, 347P-glycoprotein, 13, 17, 18, 25Pharmaceutics, 4Pharmacodynamics, 3, 31-55

Pharmacogenetics, 52Pharmacogenomics, 52Pharmacokinetics, 3, 10-30Pharmacology: definition, 3

relevance to dentistry, 3Pharmacotherapeutics, 4Pharmacy: definition, 4Phenindione, 264, 266Pheniramine, 101, 102Phenobarbitone, 133, 135, 144,

149, also See BarbituratesPhenol, 470, 476, 484, 485

coefficient, 470Phenolphthalein, 286, 288Phenothiazines, 156, 157Phenoxybenzamine, 48, 91-92Phenoxymethyl penicillin, 395Phentolamine, 91, 92, 180, 183Phenylbutazone, 325, 335Phenylephrine, 83, 88, 89Phenyl propanolamine, 88, 89Phenytoin, 144-46, 148, 149, 491,

492Pheochromocytoma, 92, 96Pholcodeine, 292, 345Phospholipase C-IP3-DAG

pathway, 38, 40Photosensitivity, 60Phylloquinone. See vit. KPhysical dependence, 60Physostigmine, 74, 75, 79Phytonadione (vit K1), 261-62,

267, 299Pilocarpine, 72, 73Pimozide, 156, 157, 159Pindolol, 93, 95Pinocytosis, 14Pioglitazone, 224, 225, 226Pipecuronium, 126, 129Piperacillin, 395, 398Piperaquine, 452, 456Piperazine, 464, 465-66Piroxicam, 319, 334pKa, 11, 12Placebo, 52-53Placental transfer of drugs, 18, 61Plaque (dental), 477Plasma half life (t½), 27-28Plasma protein binding, 18-19Plateau principle, 28-29

Platelet activating factor (PAF),115-16

Podophyllum resin, 476Poisoning, 57-58Polyene antibiotics, 438-40Polymyxin B, 426Polypeptide antibiotics, 426Postantibiotic effect (PAE), 372,

414Postpartum haemorrhage (PPH),

115, 244Potassium

channel openers, 184, 187iodide, 250, 291nitrate, 483, 487oxalate, 483permanganate, 471sparing diuretics, 179, 205,

210-11Potentiation, 46Povidone iodine, 472, 475Pralidoxime (2-PAM), 76Pramipexole, 153Pravastatin, 271Praziquantel, 464, 467-68Prazosin, 91, 92, 180Preanaesthetic medication, 125-

26, 346-47Prednisolone, 231, 232, also See

CorticosteroidsPreferential COX-2 inhibitors,

325, 336Pregabalin, 148Pregnancy: and drugs, 51, 61, 62

category of drugs, 62Pressor agents, 88, 89, 90Presystemic (first pass)

metabolism, 24-25Prilocaine, 354, 355, 360, 361Primaquine, 452, 454, 455, 458-59Primidone, 144, 148Prinzmetal’s angina. See Variant

anginaProbenecid, 26, 320-21, 393, 397,

491Procainamide, 199, 200Procaine, 355, 357, 359, 360, 393Procarbazine, 310Prochlorperazine, 280, 282Procyclidine, 76, 78, 150

Index 507

Prodrug, 20-21Progesterone, 218, 239-41Progestins, 239-41, 242, also See

Oral contraceptivesProguanil (Chloroguanide), 453,

454, 457Prokinetic drugs, 280, 282-83, 285Prolactin (Prl), 217Prolonging drug action, 30Promethazine, 101, 102, 126, 281,

493Propafenone, 199, 200Propantheline, 76, 78Propionic acid derivatives, 332-

33, 339Propiphenazone, 326, 336Propofol, 123, 125Propranolol, 93, 108, 109, 178,

184, 200Propylthiouracil, 249Prostacyclin (PGI2), 110, 113, 269Prostaglandins (PGs), 109-15,

245, 277-78synthesis inhibitors.

See Non-steroidalantiinflammatory drugs

Prostanoid receptors, 114-15Protamine sulfate, 265Protease inhibitors (PIs);

retroviral, 445 448-49Protectives, 476Proton pump inhibitors (PPIs),

126, 274, 277, 284-85Prulifloxacin, 383, 387Pseudocholinesterase (BuChE), 71

deficiency/atypical, 52, 128Psychological dependence, 60Psychopharmacological agents

(Psychotropic drugs),155-70

Psychoses, 155Psyllium, 285, 286Purgatives, 285-88

bulk forming, 286mechanism of action, 286stimulant, 286-87

Purine antagonists, 305, 308, 315Pyrantel pamoate, 464, 465Pyrazinamide (Z), 430, 433Pyridostigmine, 74

Pyridoxine (vit B6), 299, 303, 429Pyrimethamine, 454, 458Pyrimethamine-sulfonamide

combination, 455, 458,460

Pyrimidine antagonists, 308-09

Q

Quaternary ammoniumantiseptics, 470, 473,475, 478

Quetiapine, 156, 157, 158Quinidine, 193, 199-200, 493Quinine, 453, 454, 455, 457Quiniodochlor, 444, 461, 462Quinolones, 382-87

R

Rabeprazole, 274, also See Protonpump inhibitors

Racecadotril, 290Raloxifene, 239Ranolazine, 184, 188Ramipril, 173, 174, 178Ranitidine, 274, 276, also See H2

antagonistsReboxetine, 163Receptors, 34-42

desensitization, 41, 43enzyme linked, 40, 41functions of, 41, 43G-protein coupled, 37-39nature of, 35-36occupation theory, 35regulating gene expression,

40, 42regulation, 40-41subtypes, 36transducer mechanisms, 36-

40, 42two-state model, 35with intrinsic ion channel, 37,

39-40Rectal administration, 6Redistribution, 17‘Red man’ syndrome, 425Reduction of drugs, 21Reflux esophagitis. See

Gastroesophageal reflux

Renal excretion of drugs, 25-26Renin: Angiotensin system

(RAS), 171-73Repaglinide, 225, 226Replacement therapy, 31, 238Reserpine, 82, 85, 105Resistance: to AMAs, 55, 367-69Reteplase, 268Retinoic acid, 301Retinol, 299, 300-01Retroviral protease inhibitors

(PIs), 445, 448-49Rivastigmine, 74, 75Reversal reaction: in leprosy, 437Reverse transcriptase inhibitors,

447-48Reversible inhibitors of MAO-A

(RIMAs), 163-64Reye’s syndrome, 330, 331Rheumatic fever, 233, 331, 375, 394Rheumatoid arthritis, 233, 308,

315, 317-19Ribavirin, 451Riboflavin (vit B2), 299, 302Rickets, 254Rideal-Walker coefficient, 470Rifabutin, 428, 432, 435Rifampin (Rifampicin, R), 429-30,

433, 434, 436, 437Rimantadine, 445, 450rINN (recommended International

NonproprietaryName), 4

Risedronate, 225Risk-benefit ratio, 45Risperidone, 107, 157, 158Ritodrine, 88, 89, 245Ritonavir, 448, 449Rivastigmine, 74, 75Rizatriptan, 109Rocuronium, 129Ropinirole, 150, 153Ropivacaine, 355, 360-61, 363Rosiglitazone, 225, 226Rosuvastatin, 271, 272Routes of administration, 5-9Roxatidine, 274, also See H2

antagonistsRoxithromycin, 422


S

Salbutamol, 45, 88, 89, 293, 298Salicylates, 328-32Salicylazosulfapyridine. See

SulfasalazineSalmeterol, 88, 89, 293, 294Sanguinarine, 479Saquinavir, 445, 448Satranidazole, 389, 461Schizophrenia, 155, 160

drugs for. See Antipsychoticdrugs

Scopolamine. See HyoscineScurvy, 304Secnidazole, 389, 461, 462Secondary effects, 57Second gas effect, 119Sedative, 133-38

definition, 133Selective COX-2 inhibitors, 111,

278, 325, 327, 336-37, 340Selective estrogen receptor

modulators (SERMs),239, 311

Selective serotonin reuptakeinhibitors (SSRIs), 163,164, 166-67, 168

Selectivity of drugs, 44-45Selegiline, 150, 152, 153Senna, 286-87, 288Serotonergic receptors, 105-06Serotonin. See 5-

HydroxytryptamineSertraline, 164, also See Selective

serotonin reuptakeinhibitors

Sevoflurane, 120, 122Sex hormones, 235-42Sibutramine, 88, 89-90Side effects, 57Silver nitrate, 474, 476Silver sulfadiazine, 381Simvastatin, 271, 272, also See

StatinsSirolimus, 313, 316Sisomicin, 415, 418Sitagliptin, 224, 227Skeletal muscle relaxants, 126-32Sleep, 133, 136, 139

SMON, 52, 462Sodium

alginate, 285bicarbonate, 278, 486citrate, 278cromoglycate, 296-97, 298fluoride, 481, 483, 487hypochlorite solution, 472monofluorophosphate (MPF),

481, 487nitroprusside, 181-82, 183perborate, 479, 485peroxide, 485phosphate, 285pot. tartrate, 285stibogluconate, 463sulfate, 285thiosulfate, 444, 485valproate. See Valproic acid

Somatostatin, 216Somatrem, 216Somatropin, 216Sotalol, 93, 95, 199, 201Sparfloxacin, 383, 385, 386-87Spinal anaesthesia, 362Spironolactone, 196-97, 210-11, 212Stannous chloride, 484Stannous fluoride, 479, 481, 487Stanozolol, 236Statins (HMG-CoA reductase

inhibitors), 271-72, 273Status asthmaticus, 297, 298Status epilepticus, 148, 149Stavudine, 448, 449Stimulation, 31Stokes-Adams syndrome, 90Streptokinase, 268-69Streptomycin (S), 413, 415, 416-

17, 431, 433Strontium chhoride, 483Styptics, 263Subcutaneous injection (s.c.), 9

absorption from, 15Sublingual administration, 6Substantivity, 478Succinylcholine (SCh), 126, 127,

129, 130Sucralfate, 279, 476Sulbactam, 398-99Sulfacetamide sod., 380

Sulfadiazine, 379, 380, 382Sulfadoxine, 380, 455, 458, 460Sulfamethoxazole, 380, 381, 382,

also See CotrimoxazoleSulfamethopyrazine, 380, 458Sulfanilamide, 379Sulfasalazine, 289, 318, 381Sulfinpyrazone, 321Sulfonamides, 379-81, 454Sulfonamide-pyrimethamine

(S/P), 455, 458, 460Sulfone, 435, also See DapsoneSulfonylureas, 220, 224-25, 227,

491, 492Sultamicillin tosylate, 399Sumatriptan, 105, 108, 109Superactive GnRH agonists, 218,

311Superinfection (Suprainfection),

369-70Supersensitivity, 41, 58Surface anaesthesia, 361Suxamethonium.

See SuccinylcholineSweetening agents, 487Sympathetic nervous system, 67,

68Sympathomimetics, 81-90

directly acting, 83indirectly acting, 83

Synergism, 46among antimicrobials, 373-74

T

Tachyphylaxis, 55Tacrine, 74Tacrolimus, 315Talc, 476Tamoxifen citrate, 239, 311Tamsulosin, 91, 92, 180Tannic acid/Tannins, 476, 485Tardive dyskinesia, 159Target level strategy, 29Tazobactam, 399Teicoplanin, 425Telmisartan, 175, 176Temazepam, 138Tenectaplase, 268Tenoxicam, 334

Index 509

Teratogenicity, 61-63Terazosin, 91, 92, 180Terbinafine, 444Terbutaline, 88, 89, 293Terfenadine, 103, 421Teriparatide, 253Terlipressin, 213, 214Testosterone, 235-36Tetracaine, 359, 360Tetracyclines, 405-10, 452, 454,

459, 462in chronic periodontitis, 409,

479-80Tetramisole, 466Thalidomide, 61, 62Theophylline, 294-96, 298, 491

ethylenediamine(Aminophylline), 296

Therapeutic index, 45Thiacetazone (Tzn), 431Thiamine (vit B1), 299, 301-02Thiazide diuretics, 179, 207-08,

212Thiazolidinediones, 224, 225, 226,

2276-Thioguanine (6-TG), 308Thiopentone sod., 17, 122-23, 129Thioridazine, 156, 157, 158Thrombolytics. See Fibrinolytic

drugsThromboxane A2 (TXA2), 110,

111, 112, 113, 269, 270,326, 327

Thymol, 484Thyroid disease and drugs, 54Thyroid hormones, 246-49Thyroid inhibitors, 249-50Thyroid stimulating hormone

(TSH), 218-19, 246, 247Thyrotoxicosis

(Hyperthyroidism),249, 250

drugs for, 249-50Thyrotropin. See Thyroid

stimulating hormoneThyroxine (T4), 246-49Tianeptine, 167Tibolone, 237Ticlopidine, 270, 271Timolol, 93, 95, 97

Tinidazole, 389, 461, 462Tiotropium bromide, 76, 78Tissue plasminogen activator

(rt-PA, Alteplase), 268Tizanidine, 131, 132Tobramycin, 415, 418Tocolytics. See Uterine relaxantsTolbutamide, 224, 225Tolcapone, 152, 154Tolerance, 55Tolnaftate, 444Tolterodine, 76, 78Topical application of drugs, 5-6Topiramate, 148, 162Topotecan, 309Torasemide, 205, 207Torsades de pointes, 198, 199, 201Toxic effects, 57Toxicology: definition, 4Tramadol, 167, 347Trandolapril, 173Tranexaemic acid, 264, 269Tranquillizer, 156Transdermal therapeutic systems

(TTS), 8Transducer mechanisms, 36-40, 42Transporters (drug), 12-14, 32, 34Traveller’s diarrhoea, 289, 290Trazodone, 164, 167Triamcinolone, 232Triamterene, 211, 212Triazolam, 133, 138Trichloroacetic acid, 476Triclosan, 470, 471, 475, 478-79,

483, 487Tricyclic antidepressants (TCAs),

109, 163, 164-66, 168, 493Trifluoperazine, 157, 158Trifluperidol, 157Triflupromazine, 157, 158Trigeminal neuralgia, 146, 148Trihexyphenidyl, 76, 78, 150Triiodothyronine (T3), 246-49Trimetazidine, 188Trimethaphan camforsulfonate,

80Trimethoprim + sulfamethoxazole,

381-82, also See Cotrimoxazole

Trimipramine, 164

Tripotassium dicitratobismuthate,279, 280

Triptorelin, 218Triprolidine, 102,

also See H1 antagonistsTropicamide, 76, 78, 79Tuberculosis, 428

chemoprophylaxis, 434extensively drug resistant

(XDR), 434in AIDS patients, 434-35in breastfeeding women, 434in pregnancy, 434multidrug resistant (MDR), 434short course chemotherapy

(SCC), 432-34treatment of, 432-35

Tubocurarine (d-TC), 70, 72, 127,128, 129

Tubular reabsorption/secretionof drugs, 25, 26

Two tone dye, 486Tyramine, 83, 163Tyrothricin, 427

U

Ulcerative colitis: drugs for, 233,289, 290

Ulcer protectives, 274, 279Unstable angina, 184, 187, 267, 271Uricosuric drugs, 319, 320-21Urinary antiseptics, 427Urinary pH and excretion of

drugs, 25-26Urokinase, 268Uterine

relaxants, 245stimulants, 115, 243-45

V

Valacyclovir, 445, 446Valethamate, 76, 78Valproic acid (Sodium

valproate), 145, 146-47,148, 162

Valsartan, 175, 176Vancomycin, 424-25

in dentistry, 425Variant angina, 177, 184, 186, 187


Vasodilators, 181-82, 195-96Vasomotor reversal, 86, 91Vasopressin. See Antidiuretic

hormoneVecuronium, 126, 129Venlafaxine, 164, 168Ventricular fibrillation (VF), 198Verapamil, 176, 177, 178, 201Vigabatrin, 145, 148Vildagliptin, 224, 227Vinblastine, 309Vinca alkaloids, 309Vincristine, 309Visual cycle: vit A in, 300Vitamins, 299-304

definition, 299fat soluble, 299, 300-01vit A, 299, 300-01vit B complex, 301-03vit B12, 258-59, 299vit C, 299, 303vit D, 251, 253-55, 299

vit E, 299, 301vit K, 261, 262-63, 299water soluble, 299, 300, 301-04

Volume of distribution (V), 16-17Voriconazole, 438, 443-44

W

Warfarin sod., 266, 267, 268Withdrawal reactions, 60, 61Wool fat, 476

X

Xanthines. See MethylxanthinesXipamide, 205Xylometazoline, 88, 89

Y

Yohimbine, 91, 92Young’s formula, 50Yuzpe method, 242

Z

Zafirlukast, 115, 296Zalcitabine, 445Zaleplon, 134, 139Zanamivir, 445, 451Zero order kinetics, 28, 29Zidovudine (AZT), 445, 447, 449,

450Zinc

citrate/chloride, 479, 484oxide, 474, 476, 484stearate, 476sulfate, 474, 484

Ziprasidone, 156, 157, 158Zoledronate, 255Zollinger-EIlison syndrome, 276,

277Zolpidem, 134, 139Zonisamide, 144, 148Zopiclone, 134, 138-39

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