5 - Toronto Notes 2011 - Clinical_Pharmacology

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Clinical PharmacologyHeidi De Boer and Jacqueline Wong, chapter editors Christophel' Kitamura and Michelle Lam, associate editors Janine Hutson, EBM editor Dr. David Juurllnk, staff editorGeneral Principles ....................... 2 Drug Nomenclature Phases of Clinical Testing Drug Administration and Site of Action Overview of Drug Disposition Pharmacokinetics (ADME) ................ 3 Absorption Mechanisms of Drug Absorption Factors Affecting the Rate and Extent of Drug Absorption Bioavailability Hepatic First-Pass Effect Efflux Pump Distribution Factors Affecting the Rate and Extent of Drug Distribution Volume of Distribution Principles of Protein Binding Depots Barriers Metabolism (Biotransformation) Drug Metabolizing Pathways Factors Affecting Drug Biotransformation Elimination Routes of Drug Elimination Pharmacokinetics Calculations Time-Course of Drug Action Half-Life Steady State Clearance Elimination Kinetics Pharmacodynamics ... 8 Dose-Response Relationship Effectiveness Potency Effects of Drugs on Receptors Agonists Antagonists Effectiveness and Safety Therapeutic Index (TI) Therapeutic Drug Monitoring (TOM) . . . . . . . 10 Adverse Drug Reactions (ADRs) . 10 Type A Drug Reactions Type B Drug Reactions Approach to Suspected ADRs Variability in Drug Response . . . . . . . . . . . . . 11 Autonomic Pharmacology................ 12 Parasympathetic Nervous System (PNS) Sympathetic Nervous System (SNS) Opioid Analgesics . . 14 Titrating Opioid Analgesics with Continuous Opioid Infusion Common Drug Endings ................. 15 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Toronto Notes 2011

Clinic:al Pharmacology CPI

CP2 Clinical Pharmacology

General Principles

Toronto Notes 2011

General PrinciplesDrug Nomenclature chemical name: describes the chemical structure; the same in all countries e.g. N (4-hydroxyphenyl) acetamide is acetaminophen drug company code: a number; usually for drugs that are not yet marketed non-proprietary (generic) name: shortened form of chemical name; listed in pharmacopoeia e.g. acetaminophen proprietary (trade) name: the brand name or registered trademark e.g. Tylenol street name: slang term used for a drug of abuse



Phases of Clinical Tasting phase I: first administration to healthy human volunteers, following animal studies; to detennine pharmacokinetics and pharmacodynamics phase II: first administration to patients, small studies; to detennine therapeutic efficacy, dose range, pharmacokinetics, pharmacodynamics phase III: large sample, often double-blind RCf; to compare a new drug to placebo or standard of care, establish safety and efficacy phase IV: post-marketing surveillance, wide distribution; to determine rare adverse reactions, effects oflong-term use, determine ideal dosing

At tha time of drug launch, only data from phases 1-111 are available; thus truelfflctiv8nlss (in conlnllt to lllllcacyl and safety may be unknown, because

patients and USIQ& pattams often do not reflect premarlcet phase.

Drug Administration and Site of Action choice ofroute of administration depends on properties of the drug local and systemic effects (limiting action or adverse events) desired onset and/or duration of action patient characteristics

Table 1. Routes of Drug AdministrationHauteAdvulage


,,a day It bedtime


Convenient, easy lllalhlinister Large surface area fir absorption Inexpensive relative to parentl!llll alhlinistnllian Rapid onset Dl action No hepatic first1)8ss effect Almost no hepatic first-pass effect

Drug metabolism by Gl secretions lncllq)lste absorption Hepatic first-pass effect l'lltl!ntial Gl irritation Must be lipid soluble Must be non-irritating

Cammon Lltin Abbr.vlllti-

1111Ch,evary odlbidltidfqid oncrllwicelthrall'four

Buccal Sublingiiii!SL)

Short duration of actionRactii[PR)Convenilllll if patilllll is NPO,vomililg or unconsciouslnlmaiiiUI(IV}

hs ar:/pc/cc pm gtt

befarw'aft&r/wilh mealllln&CIIIIIY


lncanvenient Irritation at site Dl application Erratic absorption Requires IV accass, as&ptic technique Hard to nmove ance administered Vasculll" injury, extravasation Expensiva Risk at irnction, bleeding

ung ud adfas/au ldfatlau

oinlmlllllI I dinH:IJid

r9TtJlefVeach eye

ri!trt/lefVeach earlnlrHrllrial

Diractto sy8tamic circulation No hepatic first1)8ss effect Slow infusion or rapid onset Dl action Easy to titrate dose Diractto specific organs {heart. bill in} No hepatic first1)8ss effect DepDt storage if ail-based = slow ralaase Dl drug Aqueous solution = rapid onset Dl actim Non-inillltilg drugs, small volwnes

Risk at irnction, bleeding. vascular complicationsPain at site Dl injaclion Pain at site Dl injection Smaller voh.mes than IM May have tissue damage from

lnlrilm111cular (IM}


Constant, even absorptionto IV



Diract inlll cerebrospinal fluid !CSF) Bypass BBB and blood-CSF barrier

Infection Possibility of brain herniation and coning

Toronto Notes 2011

General Prindples/Pb.annacoJdnetic (ADME)

CUnical Phannacology CP3

Table 1. Routes of Drug Administration {continued)lnhllllilln lrnnediate action in lungs Rapid delivery to blood Local or syslllrric action No hepatic first-pass elfect Must be a gas, vapour or aerosol


Easy ID actnilister Localized limited systemic absorption Drug absorption 111'ough intact ski! Rapid onset of action No h!lpiltic first-pass elfectLocal elfect

Efl&cts are mailly limited ID site of application


Irritation at site of application Delayed onset of action Hydrophilic drugs aru not easily ab&OibsdRisk of infection

Overview of Drug DispositionPharmacology

= Pharmacokinetics + Pharmacodynamics

Pharmacokinetics the study of "what the body does to a the fate of a drug in the body subdivided into ADME: absorption, distribution, metabolism and elimination

Pharmacodynamics the study of"what a drug does to the body;" the interaction of a drug with its receptor and the resultant effect includes dose-response relationship, drug-receptor binding

Pharmacokinetics (ADME) definition: relationship between drug administration, time-course of distribution, and concentration achieved in the body (i.e. the manner in which the body handles a drug) examines rate and extent at which drug level concentrations change in the body by observing: input processes = absorption output processes responsible for drug delivery and removal from the body = distribution, metabolism, elimination

Absorption definition: movement of the drug from the site of administration into plasma important for the main routes of administration, except IV



Mechanisms of Drug Absorption most drugs are absorbed into the systemic circulation via passive diffusion other mechanisms: active transport. facilitated diffusion, pinocytosis/phagocytosis

Factors Affecting the Rata and Extant of Drug Absorption partition coefficient of a drug (Poillwater), i.e. its relative solubility in oil (lipid) vs. water drugs with high lipid solubility can rapidly diffuse across a cell membrane (e.g. anaesthetics are very lipid soluble and thus have a rapid onset of action) local blood flow at the site of administration (e.g. sublingual vessels provide significant blood flow and thus rapid absorption) molecular size (e.g. small molecular weight drugs absorb faster) pH and drug ionization drugs are usually weak acids (e.g. acetylsalicylic acid) or weak bases (e.g. ketoconazole) and thus have both ionized and non-ionized forms pH and pl D l 0 0




DDDIB of AQanist

:::;binding __ ClllllpBiition anllgoniat

A -> D ilcraaQ; d111a of iiTIIVIII'IIllaWilli Dll8 dose of aniBgonill, i1creasmg dou of IIQIIflilll d081 not co,.st&ly




Agonist l

. .-v



l -)c:::::>lAntagonist


avarcoma anllgonism, aAGonist cannot bind

S8llll in B. Eventually with high enough llllagoniat cDnCmlnrliana, no BITIIIUnt of agonist con elicit I 1111PIIn18, u 111111 II D.


0 .. 0 0

C:::::> !'cepto' which

Figura I. The LDI DasJiespo1111 CuMI for lmrversible Alltlla-ism


AniBgoniiJI binding




BINDING AnblgonillbolllldiD

3) Non-complllitiva ii'T'8YII&ible binding


4Ji ,



alblnwlivelila pm8ll!l

egonist from bindingtDI'IICiplar



Effectiveness and Safety


Effectiveness ED50 (Effective Dose - 5096): the dose of a drug needed to cause a therapeutic effect in 50% of atest population of subjects


Safety ID:;o (Lethal Dose - 5096): the dose of a drug needed to cause death in 5096 afa test population

Th& twa moll dinically

properties of a'l'f lhg- n affactiotaniiSS arw:l tlfety.

of subJects (usually rodents) TD50 (Tone Dose - 50%): the dose needed to cause a harmful e1fect in 5096 of a test population of subjects

CP10 Clinical Pharmacology PbarmacodyDamiaeutic Drug Mcmitoringi.Adwne Dl'lll

Toronto Notes 2011

Therapeutic Index (TI)Drugs with a 111JT0W TI hew a high likelihood of causing toxicity and need clou monitoring.