ANTIBIOTICS &

ANALGESICS

By R.Hemalatha1st year

Department of Pedodontics and Preventive Dentistry

INTRODUCTIONDEFINATION OF ANTIBIOTICSCLASSIFICATION OF ANTIBIOTICSMECHANISM OF ACTIONPRINICIPLE OF ANTIBIOTIC ADMINSTRATIONAVOIDING RESISITENCE TO ANTIBIOTICSTHERAPEUTIC USE OF ANTIBIOTICS IN OMFPROPHYLACTIC ANTIBIOTICSPHARMACODYNAMIC RESPONSE OF ANTIBIOTICS IN CHILDRENANTIBIOTIC RESISTANCEALLERGY TESTINGTRIPLE ANTIBIOTIC PASTE

CONTENTS

ANALGESICSCLASSIFICATION OF ANALGESICS•Non opioid analgesics (NSAIDS)•Opioid analgesicsOTHER DRUGS WITH ANALGESIC EFFECT•Corticosteroids•Local anestheticsPAIN MANAGEMENT STRATEGIESREVIEW OF LITERATUREPRESCRIPTION WRITINGCONCLUSIONREFERENCES

CONTENTS

•Prescribe mainly orofacial infections. ( originate from odontogenic infections).

•prescribing it is a important aspect of dental practice.

•7% and 11% of all common antibiotics (betalactams, macrolides, tetracyclines,clindamycin,metronidazole).

•National Center for Disease Control and Prevention estimate that approximately one-third of all outpatient antibiotic prescriptions are unnecessary

Introduction

term 'antibiosis', - Jean Paul Vuillemin 1877 renamed antibiotics - Selman Waksman,1942.1928  Alexander Fleming - penicillin, -chemotherapy. Gerhard Domaqk in 1932 in Germany- first sulfonamide & received  Noble Prize the 1939.penicillin was commercilly available-1941 golden age of antibioticsFlorey and Chain purifying penicillin,in 1942,Chemical structure of penicillin -  Dorothy Crowfoot Hodgkin in 1945. Chlortetracycline- introduced in 1948 [for rickettsial infections]

HISTORY

What is an Antibiotic?Antibiotic is a chemical substance produced by a microorganism that inhibits the growth of or kills other microorganisms.

Antimicrobial agent is a chemical substancederived from a biological source or producedby chemical synthesis that kills or inhibits thegrowth of microorganisms.

CLASSIFICATION BASED ON SUSCEPTIBILITY OF ORGANISMS

I. Antibiotics effective against : 1) Gr +ve bacteria Eg: penicillin , erythromycin2) Gr -ve bacteria Eg: aminoglycosides,cephalosporins3) Gr +ve & Gr –ve bacteria Eg: ampicillin, amoxycillin, tetracycline, chloramphinicol,cephalsporins4) Acid fast bacilli

Eg : Streptomycin5) Fungi Eg : Nystatin

CLASSIFICATION OF ANTIBIOTICS

II) Based on mechanism of action 1. Inhibitors of cell wall synthesis -Eg: Penicillin,

cephalosporins, vancomycin,bacitracin.

2. Inhibitors of protein synthesis➢Affect the function of 30s or 50s (reversable inhibition

of protien synthesis)-Eg: Chloramphenicol,

erythromycin,tetracyclin, clindamycin.[static drugs]➢Bind to 30s and alter protein synthesis- Eg:

Aminoglycosides

[Cidal drug]

3. Inhibitors of membrane function

Eg:nystatin,ampohoteresin-B [polyene antifungals]

4. Anti-metabolites

5. Inhibitors of nucleic acid synthesis

MECHANISM OF ACTION

Tetracyclinschloramphinicolaminoglycosidesclindamycin

Penicillinscephalosporinspolymyxinbacitracinpolyenes

Intracellular Extracellular

1. Inhibitors of Cell Wall synthesisBeta-lactams•Penicillins•Cephalosporins•Monobactams•CarbapenemsGlycopeptidesFosfomycins

•initial empirical management of odontogenic infections thiazolidine ring fused with a beta lactum ring.

•6 amino-penicilanic acid- essential for the antibacterial activity

•60% bound to plasma albumin.[ inactive form]•bactericidal -bind to peptidoglycan•Narrow spectrum, •absorbed- from duodenum.•Food interferes absorption - oral 30 min before or 2-3 hr after food.•Parenteral administration- longer compaired to plasma.•High conc and eliminated -kidney

PENICILLIN

I) Natural penicillins : Penicillin G (Benzyl penicillin),procain penicillin-g, benzathine

penicillin. II) Semisynthetic penicillin- 1.Acid resistant penicillins :

Phenoxymethyl penicillin (penicillin V) 2 . Penicillinase – resistant penicillins :

Acid labile : Methicillin, nafillin, cloxacillin, dicloxacillin Acic resistant: flucloxacillin.3. Extended spectrum penicillins : a.Carboxypenicillins : Carbenicillin, ticarcillin, b. Aminopenicillin : Amipicillin, amoxicilllin. c. Ureidopenicillin : Mezlocillin, piperacillin.4. Beta lactamase inhibitors : Clavulanic acid, Sulbactum.

CLASSIFICATION OF PENICILLIN

ON DURATION OF ACTION

• Short acting-Procain benzyl penicillin[1-3hr]• Intermediate acting-Fortified Benzyl penicillin [12-24

hr]• Long acting- Benzathine penicillin [12- 15 days]Penicillin V – •potassium phenoxyethyl penicilllin, azidocillin - penicillinase resistent acid labile form• Potassium salt form• More rapidly absorbed• Less active than benzyl penicillin• Not used in management of severe infection.

Pencillin spectrum of activity

METHICILLIN-• penicillinase producing organism• S. aureus are sensitive.• Methicillin resistant staphyococci are resistant

to all betalactum antibiotics

NAFICILLIN - more active than methicillin • but less active than benzyl penicillin• 87%is plasma protein bound• excreted by the liver

CLOXACILLIN-5-10 times more active than methicillin

• 90- 95 / is plasma protien bound• diclozacilln-blood level is twice as that of

cloxacillin

Flucloxacillin-simillar to dicloxacillin,Less protein bound

• Staphyloccal resistant - production of a new PBP

Ampicilin- • antibacterial activity is simillar to benzyl

penicillin• More active against gram negative micro-

organisms• It is water soluble and acid resistant• Food do not interfere absorption, but

incompletely absorbed excreated by kidney• In infants and children excretion is delayed• Parenteral solution deteriorates fast

Talampicillin-•is a carboxylic ester of ampicillin•Rapidly absorbed from gut•Hydrolysed by tissue esterase in to active form.Amoxacillin- •it is amio-p- hydroxy-benzyl penicillin•Broad spectrum of activity similar to ampicillin•Orally effective, and blood levels are twice as that of ampicillin•Absorption not affected by food•Less protein bound •excreate faster than ampicillin •incidence of diarrhea is less than ampicillin.Amoxacillin spectrum of activity

Carbenicillin- •weaker antibacterial spectrum than• Advantage - against all strains of proteus, pseudomonas aeruginosa.•It is penicillinase susceptable.•It’s acid labile and must be given parentarilly.

Ticarcillin- •it is thienyle analogue of carbenicillin.•antimicrobial activity is twice that of carbenicillin.

Piperacilllin-• it is betalactamase sensitive. •broad spectrum activity against gram negative•it is acid labile. Clavulanic acid –•it is well absorbed on oral administration.•weak antibacterial activity. •potent and irreversible inhibitor of many betalactamase• protect betalactum antibiotic from inactivation.•Used in combination with amoxacillin and ticarcillin.

CephalosporinsFirst generation-More active

Second generation-

Third generation Forth generation

More active against gram positive organism

more selective against gram positive and gram negative organisms

Highly active against gram negative otganisms

simillar antibacterial activity as that 0f third generation but highly resistent to beta lactamases

Parenteral-CephalothinCefazolinCephaloridineOral-CephalexinCephadineCefadroxil

ParenteralCefuroximCefoxitinOral CefaclorCefuroxim axetal

Parenteral-CefotaximCeftizoximeCeftraxoneCefoperazoneOral-cefexim

Parenteral-CefepimeCefiperome

Cephazolin-•more active against klebicella, E.coli.•Susceptable to staphylococcal beta lactamases.preffered for surgical prophylaxis. T ½ - 2 hr. •cephalexin- orally effective first generation cephalosporin.•Has simillar spectrum of activity.T1/2- 1hr.

Cephadroxilhas good tissue penetration.•Has sustained action at the site of infection.

Cefoxitin, cefuroxime produced by actinomycete.•Highly resistant to beta lactamases (gram negative organisms)•treatment of anaerobic infection, surgical infection. • T ½- 2 hr.

Cefuroxim axetil- orally effective.Cefotaxime- 3rd generation•anaerobic & somegram positive bacteria•meningitis (gram negative bacilli),• life threatning /hospital aquired infections.•septicaemias and infections in• immunocompromised patients.

Cefpirome- serious and resistant hospital acquired•effective on all gram negative bacterias .

Monobactams- inhibits gram negative bacilli .•It is resistant to gram negative beta-lactemases . •hospital acquired infections.• T1/2 1.8 hrs

Imipenem - it is extremely potent and most broad spectrum beta-lactam antibiotic

Imipenem spectrum of activity

2. Inhibitors of Protein Synthesis

•Aminoglycosides•MLSK (Macrolides, Lincosamides, Streptogramins, Ketolides)•Tetracyclines•Glycylcyclines•Phenicols•Oxazolidinones•Ansamycins

USES•Gram-positives, except Streptococus and Enterococcus. •combine with aminoglycoside (Gentamicin or Streptomycin) & penicillin, ampicillin or vancomycin for severe enterococcal infections (Synergy)• In serious infection, with beta-lactams or fluoroquinolones•Gram-negative nosocomial infections •severe systemic infections

•Broad spectrum of action•Rapid bactericidal effect• Inhibitors of Protein Synthesis• Related in structure and function• Drugs differ based on location of radical groups attached to the 3 ring basic structure

Kanamycin •develops resistance quickly•Hospital use only• Nephrotoxic and toxic for ears•Drug Dosage Adjustment:•Monitoring mandatory. •Control the serum level for peak -ensure the bactericidal effect and avoid side effects

AMINOGLYCOSIDES

Broad spectrum antibiotics- Tetracycline

Group I- • Chlortetracycline -Cl• Tetracycline - OH,-H• Oxytetracycline Group II-• Demeclocycline- OH,-H,-Cl• LymicylineGrope III-• Doxycycline – OH,-H,-CH3,-H• Minocycline - -H, -H,- N(CH3)2

Broad spectrum antibiotic.Low absorption through git.Rapid renal excretion,Low phototoxicMarked alteration of intestinal bacteria.

Demiclocycline-Intermediate potency.High plasma binding capacity.Slower renal excretion.Highest phototoxic.

Doxicycline-High potency.Complete absorbtion from intestine.High plasma binding.T1/2- 18-24 hr.Leaast alteration of intestinal flora.Low toxixcity &metabolised in liver.

Tetracycline

•anti bacterial spectrum – similar penicillin.•against penicilin resistant staphylococci.•small intestine.•partially destroyed by gastric juice, (enteric coated tablets)

•Various preparation- enteric coated tablets Estolate form (most resistant by gastric acid) Sterate Ethylsuccinate [parenteral] Glucoheptonate[parenteral ]•drugs belonging to this group- olindomycin, Spiramycin (Anti microbial -higher than erythromycin)New macrolids- roxithromycin, clarithromycin• Simillar spectrum of erythromycin• More resistant to acid hydrolysis.• Better tissue level are achieved.

Erythromycin (Macrolides )

• Chemically differ from the macrolide group -lactone ring contains a nitrogen atom.

• simillar activity that of erythromycin.• better tissue penetration.• longer half life than erythromycin.

Clarithromycin-• Differ from erythromycin only in methylation of

hydroxyl group.• Rapidly absorbed from gut.• Has longer half life and better tissue penetration.

Azithromycin(Newer macrolides [azalids] )

Is a lincosamide

•Widely distributed in tissue fluids and tissues, including bone. •Avoid in the routine odontogenic infection•An excellent alternative drug in penicillin-resistant anaerobic infections•Used in Osteomyelitis of the jaws •Antimicrobial activity in colon is for 5days.

Clindamycin

CHLORAMPHENICOL

Uses-•for extra-intestinal•severe salmonella infection.• Empiric treatment of meningitis,• crosses BBB well.Toxicity:•bone marrow aplasia •Hematological abnormalities.

•Relatively small molecule, easily enters Gram-positive and Gram-negative Bacteria•Spectrum of Action:Gram-positive and Gram-negative bacteria, Chlamydia, Mycoplasma and Rickettsiae.•Target is Ribosome•Binds to 50S subunit -inhibits elongation step of protein synthesis

3. Inhibitors of Membrane Functions•Polymixins•Cyclic lipopeptides

Uses •Gram-negative UTI, blood, CSF and eye infections.•used in combination against very resistant Pseudomonas, KPC.• High toxicity – neurotoxic and nephrotoxic

•Target =Membrane phospholipids, LPS) & lipoproteins• Outer and Cytoplasmic Membrane Effect•More permeable membrane. leakage of cellular molecules, inhibition of respiration and increased water uptake leading to cell death.•Gram-positives are naturally resistant (too thick to permit access)

Lipopeptides: PolymyxinsPolymyxin B

4. Anti - Metabolites•Sulphonomaides•Trimethoprim

USES-•UTI’s• otitis media in children, chronic bronchitis in adults,• enteritis •Travelers’ Diarrhea.

• Natural Resistance• Enterococcus –poorly expressed• S. pneumoniae• Ps. aeruginosa (impermeability)

Anti-Metabolitessulphonomides

Trimethoprim/Sulfamethoxazole:

5. Inhibitors of Nucleic Acid Synthesis

•Quinolines•Furanes

• Small and hydrophilic• easily diffuse n reach Target = Topoisomerases• Rapid bactericidal activity

• 1st Generation Quinolones: Gram-negatives, UTI high concentrations -infection.

• Fluoroquinolones: GarenoxacinGram-negative and Gram-positive ( Anaerobes, Atypicals, S.pneumoniae and Pseudomonas)

• Ciprofloxacin, Levofloxacin, Norfloxacin, Ofloxacin - More effective (lower MIC values).Spectrum -Staphylococci, Streptococci and Pneumococci (sparfloxacin). More widespread tissue distribution .

Ciprofloxacin and Ofloxacin -systemic infections.• Sparfloxacin, Gatifloxacin, MoxifloxacinTrovafloxacin (removed cardiac arrhythmias, liver destruction, phototoxicity.)

•Gatifloxacin (Tequin®) removed from market 05/01/06 - diabetes.

Quinolones

PencillinsBetalactums inhibit final stage of peptidoglycan sysnthesis

Pencillin binds to proteins and inhibit PBP activity•Weekens the cell wall•vulnerable to damage

by solutes in surrounding

Glycopeptide [vancomycin, teicoplanin]•Inhibits cell wall

synthesis in bacteria- binding with D-alanyl-D-alanine terminus of cell wall.

•Inhibits release of the bulding block unit from the carrier

•pervents peptidoglycans synthesis

Polyene [amphotericin-B, nystatin, hamycin, natamycin]

high affinity for ergosterol •form a micropore in

the fungal wall

•Cell permiability is through pores ions, aminoacids, water soluble substances leak out.

Tetracyclins [streptomyces aureofaciens]•passive diffusion porin

proteins

•energy-dependent system –(inner cytoplasmic membrane).

•Bind to 30s•Prevent access to

aminoacyl t RNA to the acceptor site on the mRNA-ribosome complex

•Inhibition of protein synthesis

Chloramphinicol [streptomyces venezuela]•facilitated

diffusion.•prevent the

binding of the amino-acid-containing end of the aminoacyl tRNAto the accepor site on the 50s ribosome

•peptide bond formation is inhibited

•interruption of protein synthesis

Macrolides [streptomyces erythreus] •passive

diffusion.•Binds to 50s

ribosomes.•inhibits

translocaation -btwn synthesised peptidyl tRNA molecule moves from the acceptor site on the ribosomes.

•Interruption of protein synthesis.

Clindamycin-•Binds to 50s

ribosomes, has simillar binding site as that of erythromycin.

Aminoglycosides [actinomyces sp]•Diffuse by porin protiens.

•Crsses cytoplasmic membrane by ETC blocked by reduction of ph, hyperosmolarity.

•bind to polysome and interfears with protein synthesis

•misreading and premature termination of translation of mRNA.

•aberrant protiens .•altered permibility and further drug transport.

III) Classification based on spectrum of activity ➢Narrow spectrum ➢Eg: Penicillin G➢Broad spectrum ➢Eg: Tetracyclines,chloramphenicol

" Imipenem

" Metranidazole

" Chloramphenicol " Vancomycin

" Clindamycin " Aminoglycosides

" Erythromycin " Cephalosporin(s)

" Tetracyclines " Penicillin(s) " Bacteriostatic antibiotics " Bactericidal antibiotics

➢IV) Based on type of action

V) Based on the source of antibiotics ➢Fungi : Penicillin, Cephalosporin.➢Bacteria : Polymyxin B, Bacitracin ➢Actinomycetes : Aminoglycosides, Tetracyclines Chlorampheniol, Macrolides,polyenes VI)Sources of Antibacterial Agents• Natural - mainly fungal sources• Semi-synthetic - chemically-altered natural compound• Synthetic - chemically designed in the labVII)Against anaerobes •Chlormaphenicol•Teicoplanin,Vancomycin ,Telavancin•Metronidazole•Thiamphenicol

Anti-fungal antibiotics

• A. polyenes-• Amphotricine B, nystatin, hamycin,natamycin• B. heyerocyclic benzofuran-• Griseofulvin

• Natamycin- 15mg/kg 12 hourly, infants- [8-30 days older] 15 mg/kg 8 hourly, children-10mg/kg 6 hourly, adult- 125- 250mg/kg 6 hourly.

• pseudomembranus colitis- orally• Effective alternative for the treatment of endocarditis, in

penicillin allergic patients.

• Teicoplanin- used in osteomyelitis, endocarditis, methicillin resistant strains infections.

• Can be given I.M

• Bacitracin- active against gram positive bacteria.• Only topically used• Used in opthalmical infection, infected ulcers, and in dressing

of wound after debridemant. British journal of surgery 1980, vol 67

Nystatin- highly toxic • Used for topically application.• Not absorbed on oral administraton, can be

used in monilial diarrhoea [super infection]

Vancomycin- primarily active against gram positive bacteria.

• bacteriostatic drug, in combination with gentamycin or tobramycin - bacteriocidal.

• Poorly absorbed after oral absorption, always given I.V.

• Half life 6 hr. Peak concentration is 60 micrograms/ml, higher concentratio causes ototoxicity.

• Is not a first -line of antibiotic• Causes potential toxicity- aplastic

anemia,gray baby syndrome.• Indicated for life thratning conditions-

bacterial meningitis, rickettsial infections.

Chloramphinicol

Metronidazole• Nitroimidazole antibiotic •anerobic bacteria and protozoa•antibiotic, amebicide, and antiprotozoal.[

•DOC-mild-to-moderate  Cl.difficle infection

•MOA-taken up by diffusion, is selectively absorbed by anerobic bacteria & protoza. •non-enzymatically reduced by reacting with reduced ferredoxin, which is generated by pyruvate oxido-reductase.

•sulfinamides and thioether linkages with cysteine enzymes deactivate these critical enzymes.

USES-

•anaerobes in intra-abdominal abscess, (B.fragilis, spp, Fusobacterium spp, Clostridium spp, Peptostreptococcus spp, Prevotella spp ) 

• bone and joint infections, septicemia, 

•endometritis, or endocarditis.

•Pseudomembranous colitis due to Clostridium difficile

•Helicobacter pylori eradication therapy,

•MDR -peptic ulcer disease

•periapical abscess, periodontal abscess, acute pericoronitis of impacted or partially erupted teeth; often used in conjunction with Amoxicillin

Adverse Effects •Nausea, diarrhea, metallic taste•IV adminstration- Thrombophlebitis

•Infrequent adverse effects include: Hypersensitivity reactions (rash, itch, flushing, fever), headache, dizziness, vomiting, glossitis, stomatitis, dark urine, and/or paresthesia.•High doses and/or long-term systemic •Leukopenia, neutropenia, peripheral neuropathy•CNS toxicity.• National Toxiology Program (NTP) -human carcinogen

Quantitative Measure• MIC = lowest concentration of antibiotic that inhibits growth(measured visually)• Interpretation of quantitative susceptibility tests is based on: relationship of the MIC to the achievable concentration of antibiotic in body fluids with the dosage given•For treatment purposes, the dosage of antibiotic given shouldyield a peak body fluid concentration 3-5 times higher than the MIC orMIC x 4 = dosage to obtain peak achievable concentration

MIC-MINIMAL INHIBITORY CONCENTRATION

Quantitative Measure• MBC = lowest concentration of antibiotic that kills bacteria

MBC – Minimum Bacterial Concentration

PRINCIPLES FOR CHOOSING THE APPROPRIATE ANTIBIOTIC

•Identify the causative organism •Empirical therapy •70% infections- mixed flora•5% aerobes•25% anaerobes

Indications for obtaining cultures ✓Patient who has received treatment for three

days without improvement✓postoperative wound infection✓recurrent infection✓actinomycosis is suspected✓Osteomyelitis is present

➢Broth dilution susceptability test using a micro dilution plate-

determine quantitative result.

➢Disc diffusion method -qualitative susceptability result.

➢Gradient diffusion test [ E- test]- qualitative susceptability result.

DETERMINATION OF ANTIBIOTIC

SENSITIVITY

1) Proper dose ➢MIC➢Over dosing ➢Underdosing

2) Selection of antibiotic-➢Disc diffusion method is employed.➢Use of specific narrow spectrum antibiotic ➢Use of least toxic antibiotic.

3) Proper time interval ➢Plasma half-life (T ½)➢Elimination and frequency of dosing➢4) Proper route of administration • Oral route• Parenteral routes

III) PRINCIPLES OF ANTIBIOTIC

ADMINISTRATION

BACTERICIDAL RATHER THAN A BACTERIOSTATIC

DRUG

•Bactericidal - immunocompromosed conditions.

•Bacteriostatic- less chance of superinfection

USE OF SPECIFIC, NARROW-SPECTRUM ANTIBIOTIC

➢Decreases resistance, decreases superinfections

MINIMAL INHIBITORY CONCENTRATION (MIC) Penicillin G Penicillin V Oxacillin Cefazolin Cephalexin

Streptococcus 0.005 0.015 0.02 0.2 1.0

Staphylococcus (non-penicillinase) 0.03 0.03 0.3 0.6 6.0

Staphylococcus (penicillinase) R R 0.4 0.6 6.0

Penicillin G Erythromycin Clindamycin Metronidazole

Bacteroides oralis 1.6 0.1 0.1 2.8

Bacteroides melaninogenicus 1.0 0.4 0.01 3.0

Bacteroides fragilis R 2.0 0.2 3.1

Cefazolin Cephalexin Gentamicin

Escherichia coli 0.8 12.0 2.0

Proteus mirabilis 3.0 20.0 1.0

Klebsiella pneumoniae 3.0 20.0 1.5

Pseudomonas aeruginosa

> 400.0 > 100.0 1.5

Pediatric dose = Child's BSA in M2

1.73M2x Adult Dosage

Pediatric = dose

child's age in months 

150x Adult DoseFried's Rule

Pediatric  =dose

child's age in yearschild's age in years + 12 years

x Adult DoseYoung's Rule

Clarks Rule Pediatric= dose 

child's weight (x)= x 150 lbs 150 x Adult Dose

Fluid Requirements = TBSA burned (%) x Weight (kg) x 4 mL (RL)1 kg

Parkland's Formula:

Nomogram Method

Pediatric Dosage formulas

MAXIMUM DOSAGE FOR LIFE-THREATENING INFECTIONS

6 2 g Vancomycin 8 3-6 mg/kg Tobramycin 6 2 g Tetracycline 4 10-12 x 106 U Penicillin G

4-6 8-12 g Oxacillin 8 21 mg/kg Metronidazole

6 2-4 g Erythromycin 8 3-6 mg/kg Gentamicin

6 2-5 g Clindamycin 6 50 mg/kg Chloramphenicol 4 8-12 g Cephalothin 4 6-12 g Cefoxitin 6 4-8 g Cefazolin

4 6-12 g Cefamandole 4 24-40 g Carbenicillin 4 12 g/day Ampicillin 8 15-25 mg/kg Amikacin

" Dosage interval (hr) Total daily dosage Antibiotic

PEDIATRIC DOSAGES OF COMMONLY USED ANTIBIOTICS Drug Daily dosage

Amoxicillin 20-25 mg/kg/day PO in 3 doses Ampicillin 25-50 mg/kg/day PO, IM or Iv in 4 doses Cephalothin 80-160 mg/kg/day PO, IM or IV in 6 doses Cephalexin 25-50 mg/kg/day PO in 4 doses Chloramphenicol 75-100 mg/kg/day IV in 4 doses Clindamycin 10-20 mg/kg/day PO, IM, or IV in 3-4 doses Cloxacillin 50-100 mg/kg/day PO in doses Dicloxacillin 12.5-50 mg/kg/day PO in 2 doses Doxycycline 5.0 mg/kg/day PO in 2 doses Erythromycin 30-50 mg/kg/day PO in 4 doses Gentamicin 6.0 mg/kg/day IM in 3 doses Metronidazole 30-40 mg/kg/day PO Minocycline 4.0 mg ist day, then 4.0 mg/kg/day in 2 doses Penicillin G 100,000 U/kg day IM or IV in 3 doses Penicillin V 50 mg/kg/day PO in 3-4 doses Streptomycin 20-40 mg/kg/day IM in 3 doses Tobramycin 3-5 mg/kg/day IM in 3 doses Vancomycin 50 mg/kg/day IV in 4 doses

TOXIC EFFECTS OF ANTIBIOTIC Some antibiotic kill / injure human cells

Penicillin Amphotericin B

Cephaloridine Aminoglycosides

Renal urinary system Erythromycin Pseudomembranous colitis

Diarrhea Clindamycin Hepatitis Tetracycline

Gastrointestinal system Vertigo Vancomycin Myoclonic seizures Penicillin and cephalosporin VertigoGentamicin Deafness Tobramycin

Nervous system

Carbenicillin (and ticarcillin) Aplastic anemia,Leukoplakia Chloramphenicol

Hematologic " PROBLEM " ANTIBIOTIC

tubular necrosis

Decreased platelet aggregation

Antibiotic-associated colitis (AAC) •Clindamycin, ampicilin-amoxicillin•Cephalosporins•Clinical features

➢Watery diarrhea➢Cramping abdominal pain, fever and leukocytosis➢Treatment :To discontinue the causative antibiotic, restore

fluid and electrolyte balance and administer anti-clostridia antibiotics like the usual choice is oral vancomycin, metronidazole

Superinfection :•Eg: overgrowth of Candida in the oral cavity•broad-spectrum antibiotics results in decreased normal host flora•Seen in the form of bacteremia, U T I, pneumonia owing to the over growth of resistent micro-organisms- Klebicella, Aerobacter, Pseudomonas, Candida.•Oral signs- stomatitis, glossitis, black hairy tongue.[staphylococci, streptococci, bacteroids, candida] .•More common In compromised host-Leukemias,AIDS,Agranulocytosis ,Uncontrolled diabeties, corticosteroid therapy

UNFAVORABLE DRUG INTERACTIONS

Antibiotic Other drug Effect Aminglycoside Ethacrynic acid Increased ototoxicity

Cephaloridine Ethacrynic acid Nephrotoxicity

Furosemide

Tetracycline Coumarin Increased anticoagulation

Tetracycline Antacids Absorption inhibited

Bactericidal antibiotic Bacteriostatic antibiotic Decreased effectiveness

ampicillin

Estrogen-containing birth control pills

Decreased effectiveness of birth control pills

Drugs to avoided in liver disorders-

• Erythromycin estolate• Tetracyclin• Taiampicillin• Dose reduction-• Chloramphinicol• Metronidazole• Clindamycin

PREGNANCY AND ANTIBIOTICS

Safe antibioticspenicillinscephalosporinserythromycin

Drugs contraindicated in children- Chloramphinicol Tetracycline

MONITORING THE PATIENT

➢Adjunctive surgery

➢Fluid balance

➢Response to treatment :

➢The response begins by the second day, and initially it is a

subjective sense of feeling better.

➢From that time onward, objective signs of improvement occur

➢Duration of antibiotic therapy 2-3 days

CAUSES OF FAILURE IN TREATMENT OF INFECTION➢Inadequate surgical treatment ➢Depressed host defenses➢Presence of foreign body➢Antibiotic problems

▪Drug not reaching infection▪Dose not adequate ▪Wrong bacterial diagnosis▪Wrong antibiotic

Combination antibiotic therapy :.Indications :•increase the antibacterial spectrum in life-threatening sepsis of unknown cause.•to increase the bactericidal effect against a specific organism.•In the prevention of the rapid emergence of resistant bacteria

• Adjunctive treatment :– Endodontic therapy or extraction– Surgical drainage– Many chronic dentoalveolar abscesses need

curettage.

• Initial stage- Aerobic bacteria invade

•Severe infection- Aerobic and anaerobic bacteria invade

Abscess

•Advanced stage- anaerobic infection

Odontogenic infection, oral and maxillofacial

implications

Pericoronitis :•Acute pericoronitis, if severe, may require antibiotic therapy.•Treatment - debridement, drainage of the site, penicillin 500 mg qid, amoxacillin 500mg qid, clindamycin 300mg qid

Dento Alveolar Abscess :Acute dentoalveolar abscess and cellulitis Penicillin is the drug of choice

Therapeutic uses of antibiotics in maxillofacial surgery

Soft tissue wounds •open for six hours or more, (considered infected,)•if primary closure is elected, a delayed primary closure is preffered•delayed technique cannot be utilized,-antibiotic support is helpful.•early primary closure -amoxicillin with clavulanic acid

Chronic inflammatory periodontal diseases-•TOPICAL MEASURES - Tetracyclins, metronidazole 250mg tid, , penicillins500mg qid, cephalosporinsANUG-Topical measures with systemic antibiotic penicillin, metronidazle400mg qid,

•Identify the causative organisms•antibiotics for a much longer period -soft tissue infections•Jaws that require special therapy•Actinomycosis ,Fungal infections

Antibiotic regimen for osteomyelitis

For hospitalalized/ when inta-venous therapy is indicated-Aqueous penicillin, 2 million Units IV Q6h, metronidazole 500mg q6h for 4 - 6 weeks ORAmpicillin/sulbactum 1.5 to 3.0 gm IV q6h for 2 days then amoxacillin/clavulanate (augmentin)875, 125.mg PO bd for 4 to 6 weeksFOR OUT PATIENT TREATMENTpenicillin V 2gm + metronidazole 500mg q8h for 2 to 4 weeks after last sequestrum removal and patient with out symptons.ORcefoxitin 1 gm q8h IV OR IMcephalexin 500mg q6h PO for 2 to 4 weeksORclindamycin 600, 900mg q6h IV then clindamycin 300, 450 mg PO.

Regimen for fracture•therapeutic doses for 10 to 14 days•should begin as early as possible after diagnosisPre-operatively• penicillin 2 million units or cefazolin 0.5 gm-1.5 gm 12 hr [25-

50 mg/kg]Post-operatively• Penicillin 500mg 6 hr [30-40 mg /kg]• Cephalexin 500mg 6 hr [25- 50 mg/kg]• In suspected intra-cranial contamination-• Pre-operatively- naficillin 2-6 gm 6hr+ gentamycin 3-5mg/kg

8 hr• Post-operatrively- cephalexin 500mg 6 hr[25-50 mg/kg]

Burke (1973) : “preventive antibiotics are indicated if there is a high probability that a patient’s natural resistance to bacterial invasion will not overcome the combined bacterial and physiological challenge of a surgical procedure”.

PROPHYLAXIS FOR WOUND INFECTION IN ORAL AND MAXILLOFACIAL

SURGERY •Patient with normal defenses may require prophylaxis for some procedures :•Long (over three hours)procedure requires the use of prophylactic. •Bone graft procedures. •implants of metal, plastic or other alloplastic material.•Immucocompromised host.•cytotoxic cancer chemotherapy.•immunosuppressive drugs such as glucocorticoids, azathioprine (Imuran), or cyclosporine.

•For intraoral procedures, the drug of choice is penicillin given parenterally, one or two million units preoperatively and an additional dose every one and a half to two hours. The last dose is given after complete recovery.

•procedure has risk of significant bacterial contamination and a high incidence of infection.•organism & antibiotic susceptibility of the causative organism must be known.•To be effective and to minimize adverse effects, the antibiotic must be in the tissue at the time of contamination (operation) and it must be continued for no more than four hours after cessation of contamination.•The drug must be given in dosages sufficient to reach four times the MIC of the causative organisms.

Principles for the use of prophylactic antibiotics

Developmental pharmacokinetics•Slower GI but faster IM absorption in infancy•More body water vs lipid in early life•Limited protein binding in infants•Larger liver/body weight ratio in infants•Immature enzymes in neonates•Larger brain/body weight ratio and higher blood–brain barrier •permeability in younger children•Immature renal function in infants

Pharmacodynamics respone of drugs in children

Adverse effects•Valproate hepatotoxicity increased in young children (with learning difficulties and receiving multiple AEDs)•Thalidomide only causes phocomelia while the limb is forming•Grey baby syndrome – chloramphenicol in young children•Tetracyclines only stain developing enamel

Terence Stephenson,British Journal of Clinical Pharmacology,2005

THE AMERICAN ACADEMY OF PEDIATRIC DENTISTRY (AAPD)

Antibiotic prophylactic regimens 2011

" Clindamycin 20mg/kg (maximum 600mg) IV or IM or cefazolin 25mg/kg (maximum 1g) IV or IM within 30 min before dental procedure

" Children allergic to penicillin and unable to take oral medications

" Clindamycin 20mg/kg (maximum 600mg) orally 1 h prior to dental procedure

" Children allergic to penicillin

Ampicillin 50mg /kg (maximum 2g)IV or IM within 30 min before dental procedure

Children not allergic to penicillin and unable to take oral medications

Amoxicillin 50mg/kg (maximum 2g) orally 1 hr prior to dental procedure

Children not allergic to penicillin

PROPHYLAXIS REGIMEN IN PATIENTS WITH PROSTHETIC VALVE

I) Standard Regimen A) Preoperatively : 30 minutes before surgery

Ampicillin 1.0-2.0 g IM or IV and Gentamicin 1.5 mg/kg IM or IV

B) Postoperatively Penicillin V 1.0 g PO 6 hours after initial dose or

Repeat preoperative regimen 8 hours after initial dose

II) Penicillin – allergic patientA) Vancomycin•Preoperatively : 1.0 g by slow IV drip (over 6 hour period). •1 hour before surgery •Postoperatively : No repeat doses

III) Pediatric dosageA) Standard regimen•Ampicillin : 50 mg/kg per dose•Gentamicin : 2.0 mg/kg per dose •Penicillin V : 500 mg per dose

B) Penicillin Allergic patient•Vancomycin 20 mg/kg per dose

Under L.A•Amoxacillin 3 gm or clindamycin 600mg 1 hr pre-

operatively and amoxacillin 1gm after 6 hrUnder G.A•Amoxacillin 0.5 gm IM after 6 hr or 3 gm 4 hr + 1 gm

probensid post-operatively. OR•Clarithromycin 500mg or azithromycin 2 gm 6 hr post-

operatively. •With previous history of infective endocarditis- Amox

1gm+ gentamycin 120mg IM and Amox 0.5 oral gm after 6 hr

OR•Vancomycin IV 1gm + gentamycin 120 mg 6 hr post-

operatively.

Surgical prophylaxis-

Antibiotic Resistence

Antibiotics in dentistry--a boon or bane? APUA Newsletter 15(1):1-5. Walton RE, Zerr M, 1997.

American Heart Association (AHA) -taking antibiotics for routine dental procedures was no longer recommended. Today antibiotics are only recommended for:1. An artificial heart valve or who have had a heart valve repaired

with artificial material.2. A history of endocarditis.3. Certain congenital heart defects.4. A heart transplant with abnormal heart valve function.dentistry is the medical discipline guilty of some of the most antibiotics abuse.•several negative consequences happen. •Overuse promotes natural mutation of common bacteria, resulting in newer resistant strains.•Antibiotics -VERY useful to treat resistant bacterial infection, but remain effective if urgent changes are made to curb the spread of antibiotic-resistant bacteria and disease.

Bacteria  already resistant•Acinetobacter•Anthrax•Gonorrhea•Group B streptococcus•Klebsiella pneumonia•Methicillin-resistant Staphlylococcus aureus (MRSA)•Neisseria meningitides•Shigella•Streptococcus pneumoniae•Tuberculosis (TB.•Typhoid fever•Vancomycin-resistant enterococci (VRE).•Vancomycin-Intermediate/Resistant Staphylococcus aureus (VISA/VRSA)http://articles.mercola.com/sites/articles/archive/2011/03/11/consequence-of-antibiotics-overuse.aspx

ANTIBIOTIC ALLERGY TESTS

•NO SINGLE TEST FOR ANTIBIOTIC ALLERGY. •Except Penicillin, immunoreactive drug metabolites rarely identified.•IgE-mediated hypersensitivity.

• SKIN TESTING -•Amoxycillin side chain–specific immune reactions warrant specific amoxycillin skin testing.

•Intradermal skin testing is difficult to do in children under 10 years of age.•Most nonpruritic maculopapular rashes will not be predicted by skin testing.

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Principle of skin testing• allergen is introduced into the skin

• contact with cutaneous mast cells

• Binding of the allergen occurs

• patient's mast cells are coated with IgE recognizing that specific allergen.

• then adjacent allergen-specific IgE -cross-linked on the mast cell surface & activated

• positive skin test, • transient "wheal-and-flare" reaction (15 to 20 min)

• central area of superficial skin edema (wheal) surrounded by erythema (flare). pruritic reaction represents the immediate phase.

•cutaneous mast cells are not activated, (no edema or erythema develo& the test is negative)

• Falsely negative skin tests such as antihistaminesPenicillin skin testing , Solensky, Franklin Adkinson Jr, UpToDate, Feb 2014

•BLOOD ALLERGY TESTING (ImmunoCAP) is available for penicillin G, penicillin V, amoxicillin and Cefaclor •most accurate -close to the time of the event. •Tryptase elevation collected within 1–4 hours after a reaction is consistent with mast cell degranulation. • blood count (looking for eosinophilia) and biochemistry (looking for raised liver enzymes) •Eosinophilia and/or abnormal liver function tests -T-cell/non-IgE-mediated reactions.•results of allergy testing may become negative with time. Even in current allergies•For IgE-mediated antibiotic allergy, used where skin and intradermal tests are negative, or H/O of low risk and alternative drugs are clearly inferior.

•under medical supervision (clinical immunology/allergy specialist)

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Cross-reactivity

•Semi synthetic penicillins such as ticarcillin and piperacillin contain the same nucleus as penicillin G.•Cephalosporins share a common beta-lactam ring with the penicillins - cross-reactivity is quite low.•3-7% of those with penicillin allergy, may have allergic reactions to cephalosporins as well.

•Monobactams such as aztreonam may be safely administered to penicillin allergic subjects.

•carbapenems (imipenem) represent a significant risk to penicillin-allergic patients.

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Suggested management of penicillin hypersensitivity

Clinical situation Possible course of actionA clear history of an immediate (IgE-mediated) reaction to penicillin (NB1) ORA vague history and an urgent situation (NB1)

1. Do not administer penicillin, a cephalosporin or a carbapenem.2. Reconsider clinical necessity for antibiotic therapy.3. If treatment is definitely required, administer an alternative antibiotic. Penicillin is definitely preferred, undertake desensitisation.

A vague history of an immediate (IgE-mediated) reaction to penicillin and a non-urgent situation (NB1)

Same as above If a penicillin is definitely preferred, skin testing should occur under the supervision of a clinical immunology/allergy specialist. Negative-graded challenge; if positive,- desensitisation program.

A clear history of a non-immediate reaction to penicillin (NOT drug rash with eosinophilia and systemic symptoms [DRESS], Stevens-Johnson syndrome or variants)

1. Reconsider clinical necessity for antibiotic therapy.2. If treatment is definitely required, administer an alternative non-penicillin antibiotic (e.g. cephalosporin, aztreonam or non–beta-lactam antibiotic). If a penicillin is definitely indicated, proceed with therapy, treating any mild reactions symptomatically

A vague history of a non-immediate reaction to penicillin (not DRESS, Stevens-Johnson syndrome or variants)

Same as above

A clear or vague history of DRESS, Stevens-Johnson syndrome or variants

Same as above

Triple Antibiotic Paste

• metronidazole, ciprofloxacin, and minocycline•combination would be needed -diverse flora in root canal•metronidazole -at a high concentration, it cannot kill all the bacteria, indicating the necessity for combination of other drugs•TAP first tested by Sato et al. • Metronidazole (nitroimidazole) -a broad spectrum against protozoa &anaerobic bacteria. •Minocycline (semisynthetic tetracycline) with a similar spectrum of activity.• Ciprofloxacin, a synthetic fluoroquinolone, has a bactericidal mode of action•increase in root thickness and length, resembling normal maturation of the root.• the infected area requires a normal blood supply which is no longer in necrotic pulps.•Therefore, local application of antibiotics most effective mode for delivering the drug. •30% reduxtion in bacteria -2 weeks.•successful treatment- sterilization of canals and healing of periapical pathology, immature root development, necrotic pulps, and apical periodontitis •managing non-vital young permanent tooth is based on the availability of viable stem cells. •drawbacks of this technique- Development of resistant bacterial strains and tooth discoloration J Phrm Bioallied Science Aug 2012,4(suppl2) S230-233

ANALGESICS

DENTAL PAIN

89

During InterventionPreoperative

Pain

Post-Operative

PAIN CONTROL STRATEGY

90

Oral Sedation

Preoperative Analgesics

• IV Sedation

• Nitrous Oxide

• Local Anesthesia

• Analgesic Prescription• Opioids • Non-opioids

Algesia : It is defined as an ill defined, unpleasant sensation, usually evoked by an external or internal noxious stimuli.

Analgesic : A drug that selectively relieves pain by acting in the CNS or peripheral pain mechanism,without significantly altering the conciousness.

91

CLASSIFICATION

92

ANALGESICS

Non-opioid analgesics(NSAIDS) Opioid analgesics

Non-selective COX Inhibitors

Preferential COX-2 Inhibitors

Selective COX-2 Inhibitors

Analgesic –antipyretics with poor antiinflammatory action

Natural opioids Semi-synthetic opioids

Synthetic opioids

The major analgesic drug class for treating endodontic pain

93

NSAIDS

Beneficiary actions due to PG synthesis inhibition

• Analgesia.• Antipyresis.• Antiinflammatory.• Antithrombotic.

95

Toxicities due to PG synthesis inhibition• Gastric mucosal damage.• Bleeding: inhibition of platelet function.• Limitation of renal blood flow.• Delay / Prolongation of labour.• Premature ductus arteriosus closure.• Asthma & anaphylactoid reactions in

susceptible individuals.

NSAIDS

• Non narcotic/non opioid/ aspirin like drugs.• Weaker analgesics except for

inflammatory pain.• Analgesic, antipyretic & antiinflammatory

properties.• Physical Dependence, abuse liability• Primary action: peripheral pain mechanism

interruption.

98

99

Non selective

COX inhibitors (traditional

NSAIDs)

SalicylatesAspirin

Pyrazolone derivativesPhenylbutazone,

OxyphenbutazoneIndole derivatives

Indomethacin Propionic acid derivatives

Ibuprofen, Naproxen, Ketoprofen

Anthranilic acid derivativeMephenamic acid

Aryl-acetic acid derivativesDiclofenac

Oxicam derivatives Piroxicam, Tenoxicam

Pyrrolo-pyrrole derivative Ketorolac

100

Preferential COX-2 Inhibitors-Nimesulide, Meloxicam, Nabumetone

SelectiveCOX-2 Inhibitors- Celecoxib, Rofecoxib, Va;decoxib, Etoricoxib

Analgesic-AntipyreticBut Poor Antiinflammatory

Paraaminophenol Derivative Paracetamol (acetaminophen) Pyrazolone derivative , metamizol ( dipyrone), propiphenazone

BENZOXAZOCINE DERIVATIVE :nefopam

SALICYLATES: History • In England 18th century- Reverend Freudman

first -cure of agues(Fever) • willow bark was a bitter glycoside -Salicin, 1st

isolated in 1829 by Leroux, -antipyretic effect. • Sodium salicylate was 1st used for -rheumatic

fever • And as antipyretic in 1875 &• its utility in the gout soon followed. • Hoffman -prepared acetyl salicylic acid. • 1899 introuduced by Dreses under the name

aspirin.

NON-SELECTIVE COX INHIBITORs

ASPIRIN

• Acetyl salicylic acid.

• Rapidly converted in the body to salicylic acid which is responsible for most of its action.

• Only drug amongst NSAIDs which irreversibly inhibit COX.

PHARMACOLOGICAL ACTIONS OF SALICYLATES

• Analgesic: 600mg equivalent to 60mg codeine.• Antipyretic: promotes heat loss, resets

hypothalamic thermostat.• Anti-inflammatory: 3-6gm/day; quenching of

free radicals.• Respiration is stimulated; dose dependant.• Metabolic: inflammatory doses; may decrease

blood sugar in diabetics.• CVS: no direct effect in therapeutic doses.• GIT: irritate gastric mucosa.• Blood: irreversibly inhibits thromboxane

synthesis.

Pharmacokinetics

• Absorption: Stomach and Small intestine.• Poor water solubility.• Solubility higher at high pH(alkaline

medium)• 80% plasma protein bound.• Enters brain, crosses placenta.• Excretion: Urine.• T ½ 15-20min.

Therapeutic Uses

• Analgesic, Antipyretic, Anti

inflammatory.

• Acute rheumatic fever.

• Rheumatoid arthritis.

• Osteoarthritis.

• Postmyocardial infarction and post

stroke patients.

Adverse effects

• Side effects: At analgesic dose(0.3-1.5 gm/day) causes nausea,vomiting,epigastric pain,increased blood loss in stool.

• Idiosyncrasy and hypersensitivity: Infrequent

• Salicylism at antiinflammatory doses.• Reye’s syndrome.• Acute salicylate poisoning: fatal dose

15-30g; serum >50mg/dl.

PRECAUTIONS & CONTRAINDICATION

Reye’s syndrome.

Should be stopped 1 week before elective

surgery(Brennen et al. presented evidence

suggesting low-dose aspirin should be

continued during dental surgical procedures).

In Chronic liver diseases.

During pregnancy & avoided in breast feeding.

Avoided inG-6-PD deficient individuals.

Avoided in diabetics.

• Aminopyrine and antipyrine [1884]: agranulocytosis.

• Phenylbutazone and Oxyphenbutazone [1949].

• Potent antiinflammatory drug,but poor analgesic and

antipyretic action.

• Banned: risk of bone marrow depression.

PYRAZOLONE DERIVATIVES

METAMIZOL

• Potent and promptly acting analgesic and antipyretic.

• Few cases of agranulocytosis reported.

PROPIPHENAZONE• Similar to metamizol.

INDOLE DERIVATIVES (Indomethacin, Sulindac )

• Potent anti-inflammatory drug, comparable to phenylbutazone.

• Analgesic action is better than phenylbutazone, it relieves only inflammatory or tissue injury related pain.

• Highly potent inhibitor of PG synthesis and suppresses neutrophil motility.

Pharmacokinetics Absorbed orally.• Rectal absorption is slow but dependable. • 90% bound to plasma proteins • Partly metabolized in liver to inactive products

and excreted by kidney.• Plasma t1/2 is 2-5 hours.Adverse effects:

• High incidence of gastrointestinal & cardiovascular events

• Frontal headache, leukopenia, increased risk of bleeding

Contra indications:• Pregnant women & children

Uses:• – Acute gout, common drug in PDA closure.

Sulindac

• A prodrug that converts into an active sulfide metabolite.

• Antiinflammatory action < Indomethacin.

• At lower doses, selectively inhibit extrarenal prostaglandin synthesis.

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Propionic acid derivativesIbuprofen

• Rated as the safest (SADR reporting system in U.K.)

• Better tolerated than aspirin.• Anti- inflammatory,analgesic & antipyretic

efficacy is lower than high dose of aspirin.• Most commonly used NSAID . Dose: 400-800mg TD, Ibuprofen 250mg BD-TD, Naproxen• Naproxen : more potent, but inhibits platelet

aggregation & prolong BT.• 200mg Ibuprofen has same analgesic effect as

acetaminophen 650mg/ codeine 60mg• 400mg and 600mg doses produced greater

levels of analgesia.Hargreaves K,Abott PV; Aust Dent J 2005

Pharmacokinetics• Orally.

• 90% plasma protein bound.

• Enter brain, synovial fluid, placenta.

• Liver – hydroxylation, glucoronide conjugation.

• Excreted in urine.

Therpeutic uses• Rheumatoid arthritis, ankylosing spondylitis who

cannot tolerate aspirin.• Soft tissue injuries, fractures ,vasectomy, tooth

extraction, post partum and post operatively• It is available as an `Over The Counter Drug’

Adverse effects:• Gastric discomfort, nausea & vomiting.• Occult blood loss are rare.• Rashes.• Precipitate asthma.Contraindicated:• Not prescribed in pregnant women & should be

avoided in peptic ulcer patients.

Drug MOA Route Bioavailabity

T ½

Uses AE

Mephnemic AcidAnthranilic acid derivative

Non selective COX inhibitors

Peripheral as well as central analgesic action

Oral 2-4 hours

muscle pain, soft tissue pain , joint pain

Diarrhoea.

Diclofenac sodium- Aryl acetic acid derivatiove(extensively used)

Non selective COX inhibitors

Short antiplatelet action. Neutrophil chemotaxis & superoxide production at is reduced

Oral and i.m. Oral-50mg TDS

99% 2 hrs

RA, OA, bursitis, post traumatic, post operative inflammatory conditions.

Epigastric pain ,nausea, dizziness, headache, rashes.

Piroxicam(oxicam derivative) (e.g.piroxicam,tenoxicam)

Reversible inhibitor of cyclooxygenase

Metabolized in liver by hydroxylation and glucuronide conjugation. Excreted in urine and bile

Oral 20mg OD

99% 2 days

inhibits platelet aggregation-prolonging BT. Dec. IgM rheumatoid factor.

Drug MOA Route Bioavailabity

T ½

Uses AE

Ketorolacpyrrolopyrrole derivative

Non selective COX inhibitors

EFFICIECNCY EQUA TO MORPHINE

Oral and i.m. Oral 10-20 mg 6hrly. (5days)

60% 5-7 hours

dental & acute musculo- skeletal pain (equals morphine)free of respiratory depression

hypotensiveconstipation

Nimesulide( week inhibitor)

Prefential cox 2 inhibitor

Free radical scavangingReduced generation of superoxide by neutrophils

orally 99% 2-5 hrs

short lasting painful inflammatory conditions like Sports injuries, Sinusitis and other ear, nose, throat disorders.Dental surgeries, Low backache. Post-OP pain and OA.

GI- EpigastralgiaHepato & NephrotoxicityFulminant hepatic failure

Celecoxib..

Selective COX-2 inhibitor

Slowly absorbed

orally 87-97%ppb

11hrs

RA,OA, musculo skeletal pain.

abdominal pain, dyspepsia, diarrhoea.

PARA-AMINO PHENOL DERIVATIVES (Paracetamol )• Introduced in 1887.• Acetaminophen- deethylated active metabolite of

phenacetin. • CNS-raises pain threshold.• negligible anti-inflammatory action.• Poor inhibitor of PG synthesis in peripheral

tissues, but more active on COX in brain.• Gastric irritation is insignificant –except in

overdose• Does not affect function or clotting factors and is

not uricosuric.

ANALGESIC –ANTIPYRETICS WITH POOR ANTIINFLAMMATORY ACTION

Pharmacokinetics

• Orally.• 1/3 is protein bound in plasma .• Glucuronidation.• Excreted rapidly in urine.• Plasma t l/2 is 2-3 hours. • Effects after an oral dose last 3-5hrs.

Adverse effects•Nausea, rashes, leukopenia.•Acute PCT poisoning – Dose >150 mg/kg or > 10g in adult. Fatality >250mg/kg , jaundice starts after 2 days. (In chronic alcoholics,even 5-6g/day taken for a few days can result in hepatotoxicity)N-acetylcysteine (150mg/kg iv) is the drug of choice.

Therapeutic Uses• Headache.• Musculoskeletal pain.• Dysmenorrhoea.• Safe in gastric irritation, ulceration, bleeding,

pregnancy & lactating mother.

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J Can Dent Assoc 2002

123Haas DA.J Can Dent Assoc 2002

For Elderly Patients:• Acetaminophen is the drug of choice.• Selective COX-2 inhibitors are the second option.Liver & Kidney Disases:• Regular strength Acetaminophe(2-2.5 grams in divided

doses/ day)• Codeine+Acetaminophen.• Oxycodone/Hydrocodone+Acetaminophen.Asthamatic Patients:• Nimesulide is the drug of choice.

124

Opioids

When additional pain control is needed

History of Opioids

• Mentioned in EBER’S papyrus 1500BC.• THEOPHRATUS writings 300BC.• GALEN 2nd century AD.• Pharmacist – SERTURNER 1806 isolated

active component “morphine” from opium; named after Greek god of dreams MORPHEUS.

CLASSIFICATION•

NATURALMorphinecodeine

SEMI SYNTHETICDi acetyl morphinepholcodeine

SYNTHETICPethidineFentanylMethadoneDetropropoxypheneTramadol

Mechanism Of Action

128

Morphine (Prototype)Pharmacological Action:CNS: interacts primarily with μ

opiod receptor • Analgesia: strong analgesic;

suppression of pain is selective, without affecting other sensations; degree increases with dose.

• Sedation: drowsiness, higher doses induce sleep and coma.

• Mood & subjective effects: mental clouding, loss of apprehension.

• Respiratory system: depresses RS in dose dependant manner.

• Cough centre: depressed.• Temperature regulating centre: hypothermia

occurs in cold surroundings.• Vasomotor centre:fall in BP at higher doses.

• CVS: vasodilatation due to direct action decreasing tone of blood vessels

• Neuro endocrine: hypothalamic action on pituitary is reduced

• GIT: constipation (direct action on intestines & in CNS)• ANS: central sympathetic stimulation- causes mild

hyperglycaemia.130

PHARMACOKINETICS

• First pass metabolism: high & variable.• Concentrations in Liver, spleen,

kidney>plasma.• Crosses placenta.• 30% ppb.• Metabolised in Liver by glucoronide

conjugation.• T ½ 2-3hrs.• Elimination complete by 24hrs.

Adverse effects• Side effects: sedation, mental clouding,

lethargy, dysphoria, blurring of vision.• Idiosyncrasy and allergy: rare.• Apnoea: in newborns if mother is on it during labor.• Acute morphine poisoning: 50mg in non-tolerant adult. Human lethal dose: 250mg.• Tolerance and dependence: high.

Contraindication• Infants more susceptible to resp depression.• Respiratory disease.• Head injury: intracranial tension• Hypotensive and hypovolaemia: exaggerate fall in BP.• Elderly male: chances of urinary retention.• Liver, kidney disease.

•Codeine •Pethidine •Methadone •Tramadol

•Methyl morphine.•60mg codeine comparable to 600mg aspirin.•Selective cough supressant.•Constipation is the prominent side effect at analgesic dose.

•Chemically unrelated to morphine.•Nearly similar to morphine in analgesic property,but more than codeine.•Not a cough supressant. •T ½ 2-3hrs.•Side effects – accumulation of norpethidine(tremors, mydriasis, hyperreflexia).

•Binds to tissue protiens.•T ½ 24-36hrs•90% plasma protein bound•Liver – demethylation •1mg methadone = 4mg morphine• 2mg heroine • 20mg pethidine

•Additional mechanism of pain control.•Medium intensity , short acting.•Partially reversed by opioid antagonist•T ½ 3-5hrs.•100mg IV = 10mg IM morphine.•Not effective in severe pain.

134Haas DA.J Can Dent Assoc 2002

COMBINATION ANALGESIA

135

• NSAID-OPIOID COMBINATION• NSAID-NSAID COMBINATION 1000mg paracetamol + 600mg ibuprofen

Two general methods for drug combination : 1. Alternating regimen consisting of an

NSAID followed by an acetaminophen-opioid combination.

2. Single NSAID-opioid combination e.g. Combunox (5mg oxycodone+400mg ibuprofen)

OTHER DRUGS WITH ANALGESIC EFFECT

136

The potent antiinflammatory properties of glucocorticoids were first appreciated & utilized as an

adjunct to endodontic therapy more than 50years ago.

Used as an intracanal medicament & systemically as a means to decrease pain & inflammation in endodontic

patients.137

Ingle’s endodontics 6th Ed.

GLUCOCORTICOIDS

Intracanal administration

In the form of a paste mixed with antibiotics• Dexamethasone solution.• Kenacomb: Each gram contains 100 000 units

nystatin, 2.5 mg neomycin base (as sulphate), 0.25 mg gramicidin, and 1.0 mg triamcinolone acetonide.

• Ledermix paste: triamcinolone 10mg, demeclocycline calcium 30mg.

Systemic administration Dexamethasone• Very potent & highly selective

glucocorticoid.• Long acting. • Pituitary depression.• Used in inflammatory & allergic

condition.• Dose: 8mg loading dose,followed by 4

mg every eight hours (upto max. 5 days).

STRATEGY TO CONTROL DENTAL PAIN

140

• Considerations for Effective “Three-D” Pain Control  

1.   Diagnosis  2.   Definitive dental treatment  3.   Drugs  

a. Pretreat with NSAIDs or acetaminophen when appropriate.  b. Use long-acting local anesthetics when indicated.  C.  Use a flexible prescription plan.  d. Prescribe “by the clock” rather than as needed.

141Cohen, 10th Ed.

142

Cohen,10th Ed.

143Haas DA.J Can Dent Assoc 2002

Procedure/ condition Initial choice If more needed1.Canal debridement Aspirin/ NSAID Analgesic with ½

gm Codeine2.Canal debridement where considerable over- instrumentation has occurred*

Analgesic +½ gm Codeine

Analgesic with 1gm Codeine

3.Canal fillings where overfillings has occurred & periapical tissue is normal

Analgesic +½ gm Codeine

Analgesic with 1gm Codeine

4.Root amputation without flap

Nothing ASA,NSAID

5.Periapical/amputational surgery with minimal trauma

ASA,NSAID Analgesic with ½ gm Codeine

6.Extensive surgery with considerable trauma

Vicodin ,Lortab [steroids]

Meperedine,

7.Call after office hours with moderate pain

Analgesic with 1g of cod.

Tradol, Vicodin

8. Call after office hours with severe pain

Vicodin ,Lortab Demerol, Percodan/percocet

Weine,6th Ed.

Review of Literature

Antibiotic prophylaxis Infective endocarditis -updated by the American Heart Association (AHA) and National Institute for Health (NIH) and Clinical Excellence. Aim To determine the specific infective endocarditis antibiotic prophylaxis prescribing practices of dentists in Singapore. Methods A questionnaire survey was sent through an email link and by postal mail. Statistical analysis was carried out using SPSS 19.0. Results Responses were received from 458 dentists The accuracy of prescriptions for 13 cardiac conditions and 12 dental procedures were evaluated.. The median number of accurate answers for dental procedures was generally high, both for dentists who followed the AHA 1999 guidelines (median = 10) and AHA 2007 (median = 9) guidelines. 82.8% felt that developing a local guideline would be beneficial to the local dental community. Conclusion Dentists were accurate in their prescriptions of antibiotic prophylaxis for dental procedures, but not for cardiac conditions. It may be helpful to attain a consensus among local cardiologists and dentists to unify the antibiotic prophylaxis prescription practices in Singapore.

Antibiotic prophylaxis prescribing practices of dentists in Singapore.

International Dental Journal. Apr2014, Vol. 64 Issue 2, p108-114. 7p

The purpose of this in vitro study was to compare the ability of triple antibiotic paste (TAP) to calcium hydroxide (CH) in disinfecting dentinal tubules. Sixty root blocks were obtained from extracted single-rooted human teeth. The root canals were enlarged with Gates-Glidden drills up to size 3 and were contaminated with (E. faecalis), and then left for 21 days. The contaminated blocks were treated with saline (as negative control), CH or TAP. Dentin debris was obtained at the end of first and 7th days, using Gates-Glidden drills sizes 4 and 5 from two different depths of 100 and 200 um. The vital bacterial load was assessed by counting the number of colony forming units (CFUs). The data was analyzed with the Kruskal-Wallis H and Dunn Post-Hoc tests & Wilcoxon Signed Ranks test (P<0.05). Results: TAP significantly decreased the number of CFUs in both depths and time intervals (P<0.001), while the CH group showed a moderate antibacterial effect. Conclusion: TAP is more effective in disinfecting the canal against E. faecalis compared to CH.

The Ability of Triple Antibiotic Paste and Calcium Hydroxide in Disinfection of Dentinal Tubules.

Iranian Endodontic Journal. 2014, Vol. 9 Issue 2, p123-126. 4p.

• The authors recruited parent-child pairs visiting the Pediatric Clinic at the College of Dentistry at The University of Tennessee Health Science Center, Memphis, and three private dental offices. They made parents to measure 5 milliliters of liquid by using a medicine cup with clear markings, a medicine cup with printed markings, a cylindrical measuring spoon and an oral syringe,each device weighed before and after the measuring exercise and compared the difference in weight with 5 mL. Results-McNemar test revealed a significant difference in parents' ability to measure accurate doses with the various devices.

• Conclusions- Medicine cups had a higher occurrence of dosing errors when compared with the other devices.

• We improve pain management in pediatric patients by educating parents about accurate measuring devices, weight-based dosing and correct interpretation of medication dosing charts.

Parents' understanding of an accuracy in using measuring devices to administer liquid oral pain medication.

Journal of the American Dental Association (JADA). Feb2014, Vol. 145 Issue 2, p141-149.

• An 8-month-old boy underwent cleft palate repair and placement of bilateral myringotomy tubes. His anesthetic course was uneventful, consisting of maintenance with desflurane and fentanyl. He received acetaminophen for routine postoperative pain management and was tolerating liquids and discharged home on postoperative day 1.

• Day 3, child - profoundly lethargic with multiple episodes of emesis ,45-second tonic-clonic seizure in transport to the medical center, and initial lab results - total bilirubin 3.1 mg/dL, and a serum acetaminophen level -83 µg/mL. Aggressive measures -blood products and periprocedural fresh frozen plasma, peracillin/tazobactam, and intravenous infusions of N-acetylcysteine, sodium phenylacetate and sodium benzoate, carnitine, and citrulline were administered. metabolic acidosis and acute hepatitis began to correct by day 4, and discharged on day 15.

• Conclusion: This report challenges existing guidelines for acetaminophen administration and emphasizes the importance of close follow-up and hydration after even relatively minor surgery.

Acute Liver Failure Following Cleft Palate Repair: A Case of Therapeutic Acetaminophen Toxicity.

Cleft Palate-Craniofacial Journal. Nov2013, Vol. 50 Issue 6, p747-750. 4p.

•therapeutic transactions between physician and patient. •The art of prescription writing is an ancient inheritance. •most significant written communications of the human race.• The ancient symbol, Rx, signifying the appeal, Latin was

adopted, •Present-day prescription contain single ingredient, written in

English, with doses given in the metric system. •ancient "Rx" and the Latin "Signatura," abbreviated as "Sig.,"

are all that remain of the ancient art of the prescription.•Accurate diagnosis; proper selection of medication, dosage

form and route of administration; proper size and timing of

dose; precise dispensing; accurate labeling; and correct

packaging all must be provided.

Prescription Writinghttp://www.sh.lsuhsc.edu/fammed/outpatientmanual/prescripwriting-pdr.htm

•Form of the Written Prescription- Barest form- the superscription, the inscription, the

subscription, the signa, and the name of the prescriber - written within the confines of a

form.

•Superscription- Date, the name, address and age of the patient; and the symbol Rx (an

abbreviation for "recipe," the Latin for "take thou."

•Inscription - body of the prescription, containing the name and amount or strength of

each ingredient.

•Subscription - The directions to the pharmacist, usually consisting of a short sentence

such as: "make a solution," "mix and place into 10 capsules," or "dispense 10 tablets."

•Signatura- From the Latin "signa,“, contains the directions to the patient. written in

English; however, physicians continue Latin abbreviations, e.g. "1 cap t.i.d. pc. Since

the pharmacist always writes the label in English, the use of such abbreviations or

symbols should be discouraged.

•"take as directed”-avoided.

•directions to the patient - phrases as "for pain,for relief of headache, to relieve

itching” 

•Labeling- physician wants his patient to know the name of the drug, the box on

the prescription form marked "label" should be checked.

•Refills- The physician should designate the number of refills he wishes the

patient to have.

•Proprietary vs. Non-Proprietary ("Generic") Prescriptions- In recent years,

some hospitals and private physicians indicate willingness to pharmacist to

dispense a non-proprietary or "generic-named" preparation instead of the trade

name item written on the prescription. Some have a box on the prescription

designated "N.P.P." e pharmacist can sell a less expensive drug to the patient.

•The amount to be dispensed should be clearly stated and needed by the patient.

Excessive amounts should never be dispensed,

•It is far better to have several refills of a prescription than to have an excessive

amount prescribed at one time.http://www.sh.lsuhsc.edu/fammed/outpatientmanual/prescripwriting-pdr.htm

Table 1. Common Terms and Abbreviations

Term or Phrase  Abbreviation Meaningad ad to, up toad libitum ad. lib. at pleasureana a.a. of each

ante cibos a.c. before meals

aqua aq. water bis in die b.i.d. twice a daycollyrium collyr. eye lotioncum c. with cum aqua cum aq. with water

dentur tales doses d.t.d. give such doses

dispensa disp. dispenseet et andgutta, guttae gtt. drop, dropshora somni h.s. at bedtimein vitro in vit. in glassmisce m. mix

non repetatur non. rep. do not repeat

oculus dexter o.d. right eye

oculus sinister o.s. left eye

omni die o.d. daily

omni mane o.m. every morning

omni nocte o.n. every nightper os p.o. by mouthplacebo placebo to pleasepost cibos p.c. after meals

pro re nata p.r.n. as the occasion arises

quantum sufficiat q.s. sufficient quantity

quater in die q.i.d. four times a dayrecipe Rx takesemis ss _ one-halfsine s,s withoutsi opus sit s.o.s. if necessaryter in die t.i.d. three times a day

trochiscus, torchisci troch. lozenge, lozengesunguentum ungt. ointmentut dictum ut dict. as directed

CONCLUSION

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• The pharmacologic basis of therapeutics 10thEd Goodman & Gilman

• Essentials of Medical Pharmacology 5th Ed K.D.Tripathi

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