CP

Clinical Pharmacology
Heidi De Boer and Jacqueline Wong, chapter editors Christophel' Kitamura and Michelle Lam, associate editors Janine Hutson, EBM editor Dr. David Juurllnk, staff editor
General 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 Principles
Drug 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 true
lfflctiv8nlss (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 Administration

Haute
Advulage

....
q

,,
a day It bedtime

Orai(PO}

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 action

Ractii[PR)
Convenilllll if patilllll is NPO,
vomililg or unconscious
lnlmaiiiUI(IV}

hs ar:/pc/cc pm gtt

befarw'aft&r/wilh meall
lln&CIIIIIY

drops

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

oinlmlllll
I I dinH:IJid

r9TtJlefVeach eye

ri!trt/lefVeach ear
lnlrHrllrial

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 complications

Pain at site Dl injaclion Pain at site Dl injection Smaller voh.mes than IM May have tissue damage from

lnlrilm111cular (IM}

Subcutan-..(SC}

Constant, even absorption

to IV

injections

llllrllhacel

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

Tapical

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

Efl&cts are mailly limited ID site of application

Trlllldannll

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

Overview of Drug Disposition

Pharmacology

= 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<a determine the ratio of ionized:non-ionized ratio (using the HendersonHasselbach equation) non-ionized forms cross cell membranes much faster than ionized (charged) forms total surface area for absorption the small intestine has villi, which increase the surface area for absorption, making it the primary site of absorption for most oral drugs

Pllrtition Coefficient IPI The ratio of a drug's solubility in lipid u companld to W1lbr More relevant when thought of in IBnna of a drug's IOiubility in membrane as compared ID exlncellulllr ftuid A l1rg1 P 11111ns that 1 drug is highly IOiubla in lipid and will1hus cro111 membranes easily

.....

,,

Drug lonizalian and 1111

HudlriOI)oHulnch Eudlln
lonjll!tion reaction tnr a W!!j!k acid HA .. A + H+; pl(ll =pH+ logiHNA-] (Henderso,..Hnselbech equation) For 1 weak acid of pK, = 4.4, at a gastric pH of 1.4, non-ionized:ionimd = HA:A- = 1: 0.001

lllls, thl drug is mainly non-ioniz8d and dilfuses ICrD$S membrane

BH+ .. B + H+; pK, = pH + log [BH+JB]
lonjmlion ruction fpr a weak IJos

CP4 Clinical Pharmacology

Pharmacokinetics (ADME)

Toronto Notes 2011

11,
The amount of drug that reaches the

Bioavailability (F)
definition: drug fraction of administered dose that reaches systemic circulation in an unchanged state after administration factors affecting bioavailability: drug absorption, metabolism in the gut wall, and hepatic first-pass effect IV dose have 100% bioavailahility (F = 1) drugs with a low bioavailability may require a much a much larger oral dose when compared to the intravenous dose (e.g. beta-blockers: metoprolol5 mg IV vs. metoprolol50 mg PO)

tYStemic cin:ulation (bioevailability)

is highly dlpllldlllt an absorption and the first-pilss effect. Properties af the

drug, raulll af lldminillration and patient facta!s should be considered to ensure

clinic;al l!lhK;tiveneM.

Hepatic First-Pass Effect

definition: drug metabolism by the liver following absorption, but before it reaches systemic circulation occurs with PO administration of a drug: GI tract (absorption) -+ portal vein in liver (first-pass metabolism) -+systemic circulation; significant first-pass effect can drastkally reduce a drug's bioavailability occurs to much lesser extent with PR administration, because drug absorbed in colon bypasses the portal system: colon (absorption) -+ internal pudendal veins -+ IVC -+ systemic circulation drugs with a high hepatic first-pass effect (hepatic extraction) include: levodopa, morphine, propranolol, lidocaine, organic nitrates drugs with low hepatic extraction (little or no first-pass effect) include: diazepam, digoxin, phenytoin, warfarin

Efflux Pump
P-glycoprotein (Pgp) is a protein in the GI tract and renal epithelium that acts as a multidrug efflux pump involved in the transport of drugs out of cells i.e. reduced intestinal absorption and enhanced renal elimination ofcertain drugs examples ofPgp substrates: digoxin, etoposide, paclitaxel, tacrolimus some drugs (e.g. macrolide antibiotics) inhibit Pgp and can increase absorption ofPgp substrates and reduce their renal elimination some tumours overexpress Pgp leading to multi-drug resistance to chemotherapy agents

Distribution
definition: process by which drugs move between different body compartments and to the site of action major body fluid compartments: plasma, interstitial fluid, intracellular fluid, transcellular fluid (e.g. CSF, peritoneal, pleural) tissue compartments: fat, brain

Factors Affecting the Rate and Extent of Drug Distribution

physicochemical properties of the drug (e.g. partition coefficient) pHoffluid plasma protein binding binding within compartments cardiac output regional blood flow percentage body fat

Volume of Distribution {Vd)

Tatal Body Willer 60'1. of body weight

maximum "actual vdD =total body water (40 L for average adult) (see Figure 1) Vd: the apparent volume of fluid into which a drug dissolves relates amount of drug in the body to the plasma concentration a calculated value that does not correspond to an anatomical space (when calculated, Vd can exceed a person's total body water or 40 L) the value takes into account drug distribution into tissues and protein binding volume ofdistribution of plasma-protein bound drugs can be altered by liver and kidney disease Vd = amount of drug in body/plasma drug concentration example: amiodarone distributes into total body water (TBW = actual Vd = 40 L), but it also concentrates in fat tissues giving instead an apparent Vd of 400 L; i.e. to achieve a given plasma concentration of amiodarone, we dose as if the drug distributes into 400 L of body fluid

Figure 1. Distrilulion of Total Body

Water {TBW)

Principles of Protein Binding

drug molecules in the blood exist in two forms: 1. bound to plasma proteins acidic drugs bind to albumin basic drugs bind to a 1-add glycoprotein 2.freeorunbound only free drug can leave the circulation to distribute into tissues and exert an effect; free drug is subject to metabolism and elimination

Toronto Notes 2011

Ph.annawldnetics (ADMB)

CUnical Ph.annawlogy CPS

in plasma, the fractions of free and bound drugs exist in equilibrium, ie. as free drug leaves the circulation, more drug unbinds to equilibrate with the portion that is left the fraction of drug that is bound is determined by drug concentration, drug affinity for protein binding site, and number of binding sites or protein concentration saturation of binding sites may result in a large increase in free drug concentration, potentially leading to toxicity in hypoalbuminemia (liver failure or nephrotic syndrome), the dose of some highly bound drugs must be lowered to avoid toxicity multiple drugs and endogenous substances can compete for the same protein binding sites, leading to increased free drug concentration but it is rarely of clinical significance e.g. ASA displaces highly protein bound acidic drugs such as phenytoin, thus possibly increasing the risk of toxicity; sulfonamide displaces bilirubin from protein binding sites, which could potentially lead to jaundice and kernicterus in neonates usually only highly protein bound (>90%) drugs are involved in drug interactions due to competitive binding; however, plasma protein binding interactions are rarely of clinical significance

Spacial consideration must ba given in dosing patienl$ i1 hypoalbuminemic st11t11s to pn1V8111 drug toxicity. Highly protein-bound drugs wiliiiXIrt a greater affect in these patients than in healthy individuals because of higher levels of free drug.
Examples of highly protein-binding drugs: warfarin. digoxin, dill8pam, furosemide. amitriptyline.

,, ,

Depots
a body compartment (i.e. a type of tissue) where drug molecules tend to be stored and released slowly over a long period of time fat is a depot fur very lipid soluble drugs (e.g. diazepam) some oil-based medications are injected IM for slow release (e.g. depot medroxyprogesterone acetate q3mo; depot risperidone q2wks)

Main hctDrs Gonming l'llnlllrltion of Blood Br11m Bilrrier (B8BI 1. Small molecular size (< 500 D*onsl 2. High lipid solubility 3. Active trllnlll)ort mech.m.m. (e.g. l'vP nllltidrug efflux pumpI

Many Drugs Cross BB8. Elwnp..s: G-rllllnesthetics

Alcohol Nicotine Caffaina L-dopa

Barriers (relative) body structures that limit or prevent diffusion of drug molecules e.g. the placenta or blood brain barrier (BBB; a barrier composed of tight junctions between
capillary endothelial cells and astrocytes) many ofthese barriers result in part, from the activity of multidrug efflux pumps (e.g. Pgp) which serve as a natural defense mechanism against drugs and xenobiotics need to consider dosing route if drugs are meant to cross these barriers

Narcotics Psychotropic medicltions

Metabolism (Biotransformation)

--------------------------

definition: chemical transformation of a drug in vivo sites ofbiotransformation: liver (main), GI tract, lung, plasma, kidney goal is to make compounds more hydrophilic to enhance renal elimination as a result of the process of biotransformation: a pro-drug may be activated to an active drug (e.g. tamoxifen to endoxifen) a drug may be changed to another active metabolite (e.g. diazepam to oxazepam) a drug may be changed to a toxic metabolite (e.g. meperidine to normeperidine) a drug may be inactivated (e.g. procaine to PABA)

Drug Metabolizing Pathways

phase I (P450) reactions small molecular changes introduce or unmask polar chemical groups on a parent compound to increase its water solubility (e.g. oxidation-reduction, hydrolysis, hydroxylation); the change in the partition coefficient is typically minimal (demethylation, deamination, hydroxylation) compared to phase II, and often phase I places a polar 'handle' on a lipophilic drug to allow for phase II mediated by cytochrome P450 enzymes found in the endoplasmic reticulum or cell cytoplasm product ofthe reaction can be excreted or undergo further phase II reactions phase II (conjugation) reactions conjugation with large polar endogenous substrates (e.g. glucuronidation, glutathione conjugation, sulfation) dramatically increases water solubility and renal elimination

.....

,,

Cylllc:hnlma P450 s,-m Tha P450 III!Zynl&S araa superfllmily of hlrml prabins that 81'11Jl1111pad into families and lubfamilias according to their amilo acid sequence. These are r&III)DIIIible for the metabolism of drugs, chemicals and other liUbstanCH.

Nomenclature: CYP3A4 "CYP" cytocllrome P450 prvtsin

2nd number - isolorm

IBIIIr = subfamily

111 number

family

Factors Affecting Drug Biotransformation genetic polymorphism of metabolizing enzymes

individuals may metabolize drugs faster or slower depending on their genotype, resulting in poor, intermediate, extensive or ultrarapid metabolizers may lead to toxicity or ineffectiveness of a drug at a normal dose (e.g. tamoxifen and codeine are prodrugs activated by 2D6 (nonfunctional alleles reduce effectiveness), while warfarin metabolized by 2C9 (nonfunctional alleles lead to lower dose requirements)

Tha CYP1. CYP2, and CYP3 families metabolize most drugs in humans. The most important isoforms n CYP3A4 l!ld CYP206; 1herefore, anticipate drug
illbnctiDIIIf pmcribing drug& using

CP6 Clinical Pharmacology

Pharmacokinetics (ADME)

Toronto Notes 2011

It'

So... Common EDmplell uf P450

Inhibitors and lnducan
P450 inhibitors "MINCE'" Metronidazole l1011i11Zid, lndiiiBVir Naringin or bero-ttin (bioflavenaid in g111p8fruit) Ciprofloxacin, CimBtidine Erythromycin (macrolidei) P4501ndlmen Phany!Din Ph-batbital Rmpin Smoking Note: Sallllllll madicBtiana ara knnwn 1D llffKt P450s. Thlabovl tilt is not exhau51ive.

enzyme inhibition may sometimes be due to other drugs e.g. CYP3A4 inhibition leads to an increased of the substrate drug erythromycin, ketoconazole and indinavir inhibit CYP3A4 and predispose a patient to drug toxicity from other drugs metabolized by it grapefruit juice inhibits gut CYP3A4 and effectively increases a substrate's bioavailability
enzyme induction certain medications enhance gene transcription leading to an increase in the activity of a

--{_.,
The very and the Vll'f old n VIIIY sensitive 1D lhe actions of drugs.

metabolizing enzyme a single drug may stimulate multiple P450 isoenzymes simultaneously a drug may induce its own metabolism (e.g. carbamazepine) or that of other drugs (e.g. phenobarbital can induce the metabolism of OCP and bilirubin) by inducing the P450 enzyme system other potent enzyme inducers: phenytoin, dexamethasone liver dysfunction caused by disease (such as hepatitis, alcoholic liver, biliary cirrhosis or hepatocellular carcinoma) may decrease drug metabolism, but this may not be clinically significant due to the liver's reserve capacity renal diaease often results in decreased drug clearance if it is cleared by the kidneys extremes of age (neonates or elderly) have reduced biotransformation capacity, and doses should be adjusted accordingly nutrition insufficient protein and fatty add intake decrease P450 biotransformation vitamin and mineral deficiencies may also impact metabolizing enzymes alcohol: while acute alcohol ingestion inhibits 2El, chronic consumption can induce this same enzyme and increase the risk ofhepatocellular damage from acetaminophen by increasing the generation of acetaminophen's toxic metabolite amoking can induce 1A2, thus increasing the metabolism of some drugs (e.g. smokers may require higher doses of theophylline, which is metabolized by 1A2)

Elimination
definition: removal of drug from the body

Avoid IDxicity from drug or metabolite accumulation bv adjusting a drug's dosage according 1D the eliminlltion characr.ristics of lha patient (1.g. in renal impairment).

.....

1hl Cackt:ruft.GIIult Equ.tilln can llllimllll cre*ine (CICI) in adub 20 ,_. uf ag1and older:

CrCI (ml/min) = 11140 -101 in ml x Wtiatn lkgU x 1.2 serum Cr (fiiTIOVLI

Far famllas, multiply llbovlequation
x0.85

Formelas

Only applies when renal function is at

Sl8ldy state

Routes of Drug Elimination kidney (main organ of elimination) two mechanisms for renal elimination 1. glomerular filtration - a passive process, so that only the free drug fraction can be filtered - drug filtration rate depends on GFR, degree of protein binding of drug, and size of drug 2. tubular secretion - an active process that is saturable, allowing both protein-bound and free drug fractions to be excreted - two distinct transport mechanisms for weak acids (e.g. penicillin, salicylic acid, probenecid, chlorothiazide) and weak bases (e.g. quinine, quaternary ammonium compounds such as choline) - drugs may competitively block mutual secretion if both use the same secretion system (e.g. probenecid can be used to reduce the excretion of penicillin, thereby prolonging the half-life and thus the effect of the antibiotic) tubular reabsorption: drugs can be passively reabsorbed back to the systemic circulation, countering elimination mechanisms elimination rate depends on renal function. which decreases with age and is affected by many disease states; renal function is assessed clinically using serum creatinine (Cr) levels thus, in those with renal impairment, dosage adjustments may be required for medications affected by renal elimination stool some drugs and metabolites are actively excreted in the bile (e.g. corticosteroids) or directly into the intestinal tract from systemic circulation enterohepatic circulation counteracts stool elimination. and thus can substantially prolong the drug's duration in the body some glucuronic add conjugates that are excreted in the bile will be hydrolyzed in the intestines by bacteria; this results in the drug being converted back to its original form and allows for systemic reabsorption lungs elimination of anesthetic gases and vapours by exhalation saliva saliva concentrations of some drugs parallel their plasma levels (e.g. rifampin)

Toronto Nota 2011

Pbarmacokinetia (ADME)

Pharmacokinetics Calculations
definition: the quantitative deac:ription of the rates of the wriOU!I steps of drug dispoWion, ie. how drugs move through the body the pharmacokinetic prlndples of ADME (absorption, distribution, metaboliam and elimination) can be graphically represented on the concentration VB. time graph (see Figure 2)

I\'' of PhlriiiCCIIdllllicl Pmciplll

vd = amount of drug in the boclvl
pl-.ma drug eonc:entndion
CL = l'8bl of elininatiGn of dru!VP-.ma drug concentration

TlmCoune of Drug Action many kinetic parameters are measured using IV dosing, such that absorption is zero and disbibution for molt drugs is rapid; thus elimination is the main process being measured tlu: concentration uis is converted to a log10 concentration to allow fur easier mathematical calculations (see Figure 3) Half-Life (t,n) definition: time taken fur the serum drug level to fall to SO% during elimination fur drugs with tint order kinetics, takes five half-lives to reach steady state with repeated dosing, or for drug elimination once dosing is lttlpped only applies when drug abibits first order kinetics

= 0.7'/11/f.L

I\'' ftga. it tlbl5 1*1'-livlllto For mOlt

or 1o llininat. 1
lluppecL

ll8advlblte with rtp1818d doling

onll8 dosilg is

see sidebar for calculation

2 3 87.5'1 3.3 91R.
4 93.11%

15%

96.!1%
lima Ill Paak AbaorpliDn

Steady State the concentration at which tlu: same amount ofdrug enteriDg tlu: system is eliminated
time is imporbmt for therapeutic monitoring since drug levels are reliable only when the drug baa reached steady state (see Figure 4) special situations use a loading dose for drugs with a long half-life and when there is clinical need to rapidly achieve therapeutic levels (e.g. amiodarone, digoxin. phenytoin) use continuous infwlion fur drugs with a very short half-lifi: and when there is need fur a long-term effect and multiple or frequently repeated doses are too inconvenient (e.g. nitroprusside, insulin, unfractionated heparin)

from the 8f8tenl

F"11111ra 2. 1i111 Couna of 011111

AmiDII
/ concen1ration 1thl o

/
Tina (hrs)

K=alopl

Clearance (CL) a quantitative measurement of the rate of removal ofa substance from the body relates the rate ofelimination to the plasma concentration clearance =body fluid volume from which a substance is removed per unit time consider: clearance from a specific part of the body, and total body clearance CL = rate ofell.m.J.nation of drug/plasma drug concentratl.on Elimination Kinetics (see Figure 5) first-order kinetics (most common type) Unear and predictable relationship that leads to a constant fractl.on of drug eliminated per
unit time

Figure 3. Lot Concentration va. Tnna Grapll (IV bDI111II01a)

Slalltfllillll ria drug'r.itht,. all ln. ttllkas lbolt 151n115JIW Ill IIICh lltMdy11118.

J.
i

irTIIIvlll & t..31n

""I
.

Study Stile

tlu: amoWlt ofdrug eliminated is based on the concentration ofdrug zero-order klnet!cs (leas common, associated with t<W.dties, e.g. alcohol) non-linear kinetics that leads to a constant rate ofdrug eliminated regardless of concentration clcarana: slows as drug concentration rises some drugs can follow first-order kinetics until ellminaUon is saturated (usually at large doses) at which point the clearance decreases some drugs follow zero-order kirn:t:ics at therapeutic levels (e.g. phenytoin)
Tabla 2.

a
6 12 Time (hrs)

F"11111ra 4. Steady Stllta of a Drug

ws. Mamt111c=e Dasing

Cnidar aida: altar a IDIIilg doseOR bagirling with maittanara dasa
Stald'f'llat& lavelsiChieva:llft:ar -5 half lival

Use wlal yuu 118. . 11llt&1EIIIA1E aflal:l

Dftal pilll1lall madicltilll Ratiolllll: giw III'IJB dose c:f medicatiCII to 1ill upthe voh.me of clsbhdion

C.. be ;wn 111 eilla acontDIDus iUion 011 nu:h comll'IIDy 111 intllmiti!D doses

nn. slllrt

drugl
2 4 6 8

Tima(lnl

Flg1ra 5. First and Zero Dnl Kinetics. btnl:*a.bllllillhL

the dnJ:I islirilnclPI'1111 tirl.
illllll.kilfiQ ldiiNI hi. llilllllllltiiiWt tf

CPS Clinical Pharmacology

Pharmacodynamics

Toronto Notes 2011

it,
For LRt conversion fllctors, please see Appendix: Cammon Unit Canwmans.

Pharmacodynamics
Dose-Response Relationship
effectiveness and potency are two important pharmacodynamic characteristics of a drug that can be quantified using dose-response curves with gradual dose-response relationships, the response of the drug reflects the number of receptors that are effectively occupied

......

Effwctiq- .,....... Pvt.ney

drug's mBKirrnd uffac:t and ill ildapendsnt of concln1nltian. Potency measures a drug's concln1nltian n11dad to produc11 certain effel:t.

EffiCliviiiiiU maasurn 1

Effectiveness a measure of a drug's ability to elicit a concentration-independent effect at its receptor measured as E,.,. = the maximal response that a drug can elicit {see Figure 6) reflects drug response under ideal circumstances {e.g. controlled clinical trial) e.g. if Drug A causes a greater maximum intensity of response than Drug B regardless of dose, then Drug A is more efficacious than Drug B Potency a measure of the effect produced by a certain drug concentration measured as ED50 (or EC50) =the efl'ective concentration of a drug needed to produce 50% of the maximal possible effect {see Figure 6) can compare the ED50 of two or more drugs that have parallel log dose-response curves the drug that reaches its ED50 at the lower dose is the more potent if the potency of a drug is low, this may be overcome by increasing the dose ofthe drug (e.g. 30 mgvs. 15 mg); this is not problematic provided that the higher dose not cause adverse effects
&nax af A and C

100

c
Potency:

i!
0:::

.. "' " .. =
g.

60 50 30

EmnafB

A>B>C
(both Band C

11111leupotent
thanA)

Effectiveness:

A=C>B
ED,. afC
log of dose

Figure 6. Log Dose-Response Curve Illustrating Effectiveness and Patency

Effects of Drugs on Receptors

drugs that act on specific receptors can be broadly classified as agonists or antagonists (see Figure 7)

Agonists
drugs that mimic endogenous ligands and exert an effect have two main properties 1 affinity: the ability of the agonist to bind to the receptor (e.g. the salbutamol has greater affinity for than efficacy: the ability to cause a response via the receptor interaction (e.g. binding of salbutamol to results in smooth muscle relaxation) full agonists: can elicit a maximal effect at a receptor partial agonists: can only elicit a partial effect, no matter how high the concentration e.g. reduced efficacy compared to full agonists

Antagonists
drugs that have affinity (can bind to a receptor), but no efficacy these are drugs that block the action of an agonist or of an endogenous ligand chemical antagonism: direct chemical interaction between agonist and antagonist that prevents agonist binding to receptor 1 e.g. chelati.ng agents for removal of heavy metals

'IbroDlo Nota 2011

Pharmacodynamics

CliDkal Pharmacology CP9

functional a.ntagcmiam: interaction oftwo agonist& that act independently at different receptors

but have opposite physiologl.cal e1fecta e.g. acetylcholine at the muscarinic receptor decreases HR. constricts pupils, and stimulates inteatinal motility; whereas epinephrine at the a.dnmergic receptor increaaes HR, dilates pupils, and decreases intestinal motility
ren:nible cmnpetitive antapniam (most common in clinical practice, see Figure 8) antagonist reversibly binds to the same receptor as the agonist, thus displacing it (e.g. nalcwme is an antagonist to morphine or heroin) irrevenible competitive antaacmi&m (aee Figure 9) antagonist irreversibly binds to the same receptor as the agonist, blocldng it from binding (e.g. acetylsalicylic acid irreversibly binds cyclo-oxygenase In platelets) non-competitive antqonlun (see Figure 9) antagonist binds to an alternate site separate but near to the agonist receptor, producing alloat:eric effi:cts that change the ability of the agonist to bind (e.g. organophosphates

Dose of Agonist
A _. C ilcl'lllllll; dose of competitive llllagonist At aar:h dosa of enlagonist, i1ci'IIW!g- the conclllllrl:lian of aglri8t can the inhllilion.

irreversibly bind acetylcholinesterase)

AGONIST BINDING

. . . :) u 1J
BINDING
-/ AnlllgoniiJI binding

Figure 8. The Loa DasHiapans1 CuMI far ea..pllitin RnaiSibiD Antagonlam

<> "'"'A

ANTAGONIST BINDING
II
Agonist ./

l-..,

Anlaglri8tl)

D 1-'\(
1'8V81'1ibla binding nirreversibla

c:> D l 0 0

[) -8
0
REVBISIBU:

c
h:IIUIId

ohgornll

D
DDIB of AQanist

:::;
binding __ ClllllpBiition anllgoniat

A -> D ilcraaQ; d111a of iiTIIVIII'IIlla

Willi Dll8 dose of aniBgonill, i1creasmg dou of IIQIIflilll d081 not co,.st&ly

llec:epblr

2)

........

Agonist l

. .-v

c:::::>

I_

l -)
c:::::>
l
Antagonist

BINDING

avarcoma anllgonism, a
AGonist 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

Rec:eptur

AniBgoniiJI binding

IRREVERSIBLE

anllgonist

blockldby

BINDING Anblgonill
bolllldiD

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

AQoniltQD
Anlaglri8t

4Ji ,

>
AU.OSTBIIC

alblnwlive
lila pm8ll!l

egonist from bindingtD

I'IICiplar

bidlg

CHANGE

Effectiveness and Safety

---------------------------

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

r-t,

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.

------------------------------------

defined as TD5o/ED50 {see Figure 10) reflects the "margin of safety" for a drug - the likelihood of a high dose causing serious toxicity or death the larger the TI, the safer a drug (e.g. amoxicillin has a wide Tl, thus therapeutic monitoring is not needed, whereas warfarin has a narrow TI and must have accurate therapeutic monitoring) factors that can change the ED50, LD50 or TD50 presence of interacting drugs changes in drug absorption, distribution, metabolism, elimination
100%

Efficacy

Toxicity

a:

1 50'!1.
ED,.
TD., l.oq Dose
l.oq DoH
Drug A has a111.1ch narrower therapeutic indaxthan Drug B. The dasa at Drug A raquirvd to achiiMIB 1OO'J.Ihalllpeutic raspanse will ba toxic in 50'1. of patiallll. For Drug B, this is anly 1O'J..

Tha therapautic indax {TD,.IED.,) is a m11sure af 1ha marain alsaluly of a giwn drug.

Figura 10. EDsu. TDSGo- and the Therapeutic Index (Til

Therapeutic Drug Monitoring (TDM)

..... ,

..

Examples of drugs whosa lavels need to be monitored: Wllrfllrin {via INR levels), digoxin, lithium, and many othars.

definition: using serum drug concentration data to optimize drug therapy (e.g. dose adjustment, monitor compliance) serum drug samples are usually taken when the drug has reached steady state (e.g. trough level- the lowest level before the next dose), and thus, before the next dose TDM can serve to monitor for side effects (e.g. vancomycin trough levels) and for desired effect (e.g. INR when on warfarin therapy) TDM is often used for drugs that have narrow therapeutic index (Tl) unpredictable dose-response relationship significant consequences associated with therapeutic failure or toxicity wide inter-patient pharmacokinetic variability

Adverse Drug Reactions (ADRs)

\,
In Canada, an estimllled 1.6'!1. of

patiants admittad 1D hospitals axperienca a wious edVllfl8 drug raaction. Furthennora, up to 24'1. of hospitalizations are drug relall!d, of which 35.5% ara edv11111 drug ructions.

classification of adverse drug reactions type A: undesirable normal/augmented responses to the drug (>80% of all ADRs) type B: reaction unrelated to the known pharmacological actions ofthe drug additional adverse drug reaction categories type C (chronic effects), typeD (delayed effects), type E (end-of-treatment effects), and type F (failure of therapy)
Table 3. Comparison of charactaristics of type A and type B reactions
Predictable extension of drug's pharmacologic effect Usually dose dependent Low mortality (except heroin overdose! Respands ID dose reduction Rarely dose dependent

H9J mortality (some exceptions!

Rasponds ID drug withdrawal

Toronto Notes 2011

.Adverse Drug Readions/Variabillty in Drug Resp0118e

Clinical Pharmawlogy CP11

Type A Drug Reactions

extension of a drug's pharmacological effects: excessive but characteristic pharmacological effect from usual dose of a drug (e.g. beta-blockers causing bradycardia; acetaminophen causing hepatitis} overdose/toxicity: exaggerated but characteristic pharmacological effect from SUPRAtherapeutic dose teratogen: drug may produce developmental defects in fetus (not always in a dose-related manner)

Type B Drug Reactions

idiosyncratic: uncharacteristic response to drug, unrelated to pharmacology (e.g. sulfacontaining medications causing toxic epidermal necrolysis) pseudoallergenic: mimics immune-mediated reaction allergidimmune-mediated: does not occur on first exposure (up to 7 d), immediate with subsequent exposure, may occur with low doses, often resolves within 3-4 days of discontinuation

I'\'' Sulla-Contlllnlna Medications

Sulflmelhoxazole Sulfaaalazin
Dapsone

Approach to Suspected ADRs

history and physical examination: signs and symptoms of the reaction (e.g. rash, fever, hepatitis, anaphylaxis, etc.), timing, risk factors, detailed medication history including all drugs and timing, dechallenge (response when drug is removed) and rechallenge (response when drug is given again) check with literature, Health Canada and FDA; contact the pharmaceutical company differentiate between drug therapy vs. disease pathophysiology treatment: stop the drug, supportive care, symptomatic relief Canadian Adverse Drug Reaction Monitoring Program online report all suspected ADRs that are: 1} unexpected, 2} serious, or 3} reactions to recently marketed drugs (on the market <5 years) regardless of nature or severity
Tabla 4. Sampla of Clinically Ralavant Advaru Drug Raactions and Interactions

Cln.ilicetian Drugll A BlltHiaclaiiS

A B ACEI

Adverw Drug Reac:tioo

Bllldyl:ardia
Cough Red Man Syndrome

Co11111entJ

Do&e dspend8111
Switch ACEI to ARB

V.11:omydn

erythematous rash on upper body related to rapid irlusion Ill first dose Not considered "allergy
Life 11Yeetening; do not rechallenge under any circumstalce Many children with EBV infection will develop a rash when given amoxicilil; this i8 NOT atrue penicillin allergy

B B
B
B

Sulfa Drugs
Palicillil Aninoglyl:osilas Acatamilaphan, Valproic acid, Chinese herlll

Stevens.Johnson Syntt'ome Toxic Epidermal Necrolysis

Rash

Ototoxicity and nephrotoxicity Dose depend8111 Hepatotoxicity

Many otha" !tugs are hepatotoxic {e.g. stzrtins, OCPs,

isoniazid)

Variability in Drug Response

recommended patient dosing is based on clinical research and represents mean values for a select population, but each person may be unique in their dosing requirements the majority (but not all) of the patients will experience the desired therapeutic effect of a drug with minimal ADRs on the recommended dose may need to adjust dosing or alter medication altogether there may be multiple causes of individual variability in drug response at a given dose, and they should be considered when prescribing and dosing medications

CP12 Clinical Pharmacology

Variability in Drug Raponse/Autonomic Pharmacolo8f

Toronto Notes 2011

possible causes of variable drug responses include problems with: intake patient adherence, e.g. hard to follow dosing schedule, non-palatable drug, costly drug pharmacokinetics absorption - decreased by vomiting, diarrhea or steatorrhea - hepatic first pass effect too high due to enzyme induction, or too low due to liver disease - absorption change due to drug interactions (e.g. calcium carbonate chelates iron) distribution - very high or low percentage body fat, intact or disrupted BBB metabolism - patient is elderly or a neonate, or has liver dysfunction - certain genetic polymorphisms or lack of enzymes to metabolize drugs (e.g. acetylcholinesterase deficiency, CYP polymorphism) - metabolism increased by enzymatic induction or decreased by enzymatic inhibition elimination kidney or liver dysfunction, or obstruction of bile elimination pathway pharmacodynamics genetic variability in drug response (e.g. malignant hyperthermia due to specific anesthetic agents) drug interactions (e.g. polypharmacy) or disease process that affects drug pharmacodynamics drug tolerance

Autonomic Pharmacology

Somlllic

P.-ipharal Nervous System

I
Autonomic (ANS)

Symplllhetic {SNS)

Fight or Flight

t
I

Parasympalhetic (PNS) Rest and Digest

Figura 11. Subdivisions of tha Paripllaral Nervous System

'\
ACh

Autonomic 1 Ganglion
I

,,

'

ACh orNE
Target

Figura 12. Alltonomic Nervous System (ANSI Efferent Tracts

most organs are innervated by both sympathetic and parasympathetic nerves; these have opposing effects (see Figure 13) almost all ANS efferent tracts are divided into preganglionic and postganglionic nerves, which synapse in the autonomic ganglion (see Figure 12) sympathetic preganglionic fibers originate in the spinal cord at spinal levels Tl-L3, and terminate in one oftwo ganglia 1. paravertebral ganglia. i.e. the sympathetic trunk, that lie in a chain close to the vertebral column 2. pre-vertebral ganglia, Le. celiac and mesenteric ganglia, that lie within the abdomen parasympathetic preganglionic fibers originate in the lower brainstem from cranial nerves III, VII, IX, X, and in the sacral spinal cord at levels S2-S4; they terminate in the ganglionic cells located near or within the target organ both sympathetic and parasympathetic pre-ganglionic nerves release ACh which acts on a nicotinic receptor post-ganglionic sympathetic nerves release NE, which acts on alpha and beta receptors, while post-ganglionic parasympathetic nerves release ACh which acts on muscarinic receptors the exceptions are post-ganglionic sympathetic nerves to blood vessels, sweat glands, spleen capsule, adrenals, which do NOT have parasympathetic innervation

'IbroDlo Nota 2011

Autonomic Pharmacology

Cllnlcal. Pbarmacology CP13

PARASYMPATHEnC

SYMPATHEnC

B S6nuiltas salivation C SIDWS h1111rt rBt8 D C...mcta bruflclli E S6nuiltas peristalsis

A Callllrids Pl4li

H llai1X8Sraclum I Cantnu:ts bllddar

F Stii!UIIIBI bils G Stimullllls inlllltir-.1 mllbilily

1 Dilates Z Wlibits aalivltion 3 Accelendel '-!: rate and inPfGWIS 4 Dilatrlll bruflchi 5 Stmullllls t8Cflllion of
Bdnmaline ..d

6 Stmulma mallballlm and glucaaa ra11 Inhibits peristalllil B lmillits irtsslinll mollilily 9 Cnracts nllllum 10 Rei11X81 bi..W.r

lj
J1
j

Figun 13. AII1Dnamic Narvous Sysblm

Parasympathetic Nervous System (PNS)

acetylcholine (ACh) is the main neurotransmitter of the parasympathetic nervous system ACh receptors include nicotinic (pre-ganglionic) receptors located In the autonomic ganglia, and nicotinic (port-ganglionic) receptors in the adrenal medulla muscarinic (only port-ganglionic) receptors M1 located in the CNS M 1 receptors located on smooth muscle, cardiac muscle and glandular epithelium acetylcholine action is terminated by metabolism in the synaptic cleft by acetylcholinesterase and in the plasma by pseudocbolinestera&e e.g. acetylcholinesterase iDhibltors (donepezll. galantamine, rivastlgmlne) are used to Increase ACh levels In condit:l.ons such as myasthenia gravis and Alzheimer's disease

Sympathetic Nervous System (SNS)

norepinephrine is the major neurotraiwnitter of the SNS receptors include il1: predominately in cardiac tissue P:z: predominately in smooth muscle and glands

a 1: prcdomirurtely on post-synaptic receptom in smooth II1I18clea and glands az: predominately on pre-synaptic terminals, where they feed back to inhibit further NE release; also exist as post-synaptic terminals ln the brain, uterus and w.scular smooth muscle norepinephrine action is terminated by reupt:ake by the presynaptic membrane, di1fusl.on from the synaptic cleft and degradation by monoamine oxidase (MAO) and catechol-0-methyl transferase (COMT)

CP14 Clinical Pharmacology

Autonomic Pharmacology/Opioid Analgeaics

Teble 5. Direct Effects of Autonomic lnnervltion on the Cerdiorespimory System Organ
H11rt 1. Sinoatrial 2. Atriuventricuilr" Node 3.Atria 4. Ventricles

Toronto Notes 2011

Symplltlullic NlmiUI SytllnJ

Receplllr
Ac:ti111
Increased HR Increased conduction Increased contractility lncrBil58d contractility

Narvau SyDm
Receptor
M M M M M M M M M M M

Action
Decreased HR Decreased cordlction Decreased cordlction Dsc1811sed cordlction DiiBIBtian DiiBIBtian DiiBIBtian DiiBIBtian Dilalirtian Constriction Still'lllation

Blaod Vaaals 1. Skin, Splanchnic 2. Skeletal Muscle

3. Coronary
Lungs 1. Bronchiolar Smooth Muscle 2. Bronchiolar Glands

a,,Qj

P, -large muscles a,,Qj

p, p,

Constriction Constriction Dilatalion Constriction Dilatalion ReiiiXIIIion Increased secretion

a,,Jl,

Opioid Analgesics
in general, when converting from PO to IV, divide by a factor of 2 when converting from one opioid to another, use 50-75% of the equivalent dose to allow for incomplete cross-tolerance rapid titration and prn use may be required to ensure effective analgesia for the first 24 hours dose equivalencies provided in the above table are approximate; individual patients vary opioids often used to manage mild to moderate pain include codeine, hydrocodone, and oxycodone moderate to severe pain is often managed using morphine, hydromorphone, oxycodone, fentanyl, methadone, or levorphanol

It'

When prescribing niiii:Otic.t, remember

NBAL: Nmotic ie.g. mO!Phine 5 mg PO q4h) Breakthrough ie.g. morplme 2.5 mg PO

q1hpm)
Anti-emutic [e.g. metocloprlllrlide 10 mg

Teble 6. Opioid A1111lgesics

Prapriat111y Nama Mlllphill
MS IR (immediate release" PO); MS Contin8 , M-Eslon8 (controled rulease PO); various nllll8S for Cammants
o

30 min before each meal and qhs)

Laxative [e.g. senokat PO qhs)

o
o

Parenllnl1 Dll"(l morphine is usual standard for comparison Morphine PO:IV 60:10 for opioid naive patient, 30:10 for others Do not crush, bnlllk, or chew 01111 controlled rlllease morphine

IV form
Cadaina Tylenol<#1,#2,#3 Codeine generics Metabolized to morphine by CYP2D6 (7-10% of Caucasians ara nonmetabolizn, due1D polymorphisms) Linited by potential toxicities of acetaminophen No additionel benefit at doses >200 ll"(l
o

'.,
Drug

Fenllllnyl
Fllllaql

Minimal experience outside the hospital setting Usually for stable pain, especially in patients with Gl dysfunction Transdannal50 flg/11 patch equivalent to 100 mg morphine PO/day Limited by potential of acelllminophan or buprofan Quick onsst of action and th.Js highly addictive PO aspecially usaful for initial dose titration and pm supplementation PI form often used subcutaneously Long

EquiualpUc o- .t OpiD.PODoee

Duragesic8

(mg)
Codeine
100
10

IV ODie (Ng)

50 3-5

Hydromorphone Hydromorphona
Lavorphanol

o
o o o o
o

MO!Phila
Oxycodone

5
2 10

ria ria

Hydromorphone Hydrocado1111

with relatively short dosing intarwl

Meperidine

Not a 1&t line opioid. May cause ieizuras due1D the accumulation of normeperidine, its breakdown product Avoid using >48h. >600 mw'24h and with MAOis

Methldane
Oxycodona

o o o

Long, Vlliable heft-life, which may complicate titration Beller used for withlhwaVabstinence therapy Often formulated in combination with acetamilophiiVaspirin, use caution

Oxv IR<,

Pen:ocetf',

(combination with ASA or acebl!inophen)

Toronto Notes 2011

Opioid Analgesics/Common Drq Bodings

CUnical Pharmawlogy CP15

Titrating Opioid Analgesics with Continuous Opioid Infusion

pain is most effectively managed using a combination of the basal/continuous rate plus PRN bolus/rescue/breakthrough doses at the initiation of the infusion, a loading dose of 2-5 times the hourly rate may be required for significant pain minimum 8 hours required for a new rate to reach steady state basal/continuous rate should be increased no sooner than 8 hours after the last basal increase (ideally 24 hours between increases) use PRN doses - nurse administered or patient controlled analgesia (PCA) - to provide: rapid response to the patient's need for pain relief between scheduled doses a basis for future increases ofthe basal rate rescue/breakthrough doses are equal to 10% ofthe 24-hour rate. available qlh 24 hours after the last basal rate adjustment, calculate the total opioid dose in those 24 hours (basal rate+ PRN doses); divide the total by 24 to reach the new hourly rate when the basal rate is increased, the rescue/breakthrough dose is changed proportionately to maintain that dose at 10% of the 24-hour dose

Common Drug Endings

Table 7. Common Drug Endings
Endilg
Category

Example sildemdil halothane kBtDconBZDia propanolol captopril albuterol cinetidine somatotropin prazosin

--(J)ol -pril

-alii

Erectile dysfunction Inhaled general!llesthetic BenzDdimf,ine Antifungal !!-blocker ACE irnbitor H,agonist
Pituitary ho11110na
a, antagonist

-ezepam
-tiZDie

-terol -tidine
-trapin -msin

Nate: Some medil:ltions are exceptions Ill the !Ue e.g. methinllllle ldhfroidl

References
l!llllillill, Nlllllln PG. FlinlllftV et al. n. Cmldiln Advlne Events sutv: the of advme M111111111111g llllpilll ]lllien1J in CnadL CMAJ 2004; 170:167H6. Canadi1n Adwna Drug lllection Mcrilllring Progr1111 {CA!JlMPI Advai'SIIIIection Dllllbue _1.html

H1rd1111n JG 111d Un.inll.H (ads( (1996). Ginn's the Bl$is of Thenpeutics ad). New Vorl Hardy B, Bedard M(2002). Swn [M.og Concentration Mcrilllring. In: Pharmaclllticals and Specilltits 2002. Repcllinsky C(ad.). Clllldian Pharmacists Associltion. 0t11w1. lralanl Hlllld W(eds] {1999]. Principles of Medics IPharmacology 16111 edl Oxfurd Univftly Press, New York. lraiZimg BG (ad) (2001). Buic lind Clinical Plllllcology (8th lid.). McGraw-Hill Campanili, Naw Vorl Ulwis, T. (20041 Using the NO TWS 1DDI far rndcstion ravisw. BMJ. 321(7463):434. ll!ng H, 1llle M, Ritter J (ell$) {1989). Phlrmlcology(41h ad.). CllurchilllMrv51ona, Edinburgh. Sarnoy W. Zld PJ, Wlbr I(. I! 11. Drug.IWibld Hospitlirltioos in a Trilry Carllnt811111 Madicina Service of 1Canadian Hospitll: AProspec1iva S1udy. PhiiiiiiCOihaRpy 2006; 26(11]: 1578-1586.

CP16 Clinical Pharmacology

u\foteg_ _ _ _ _ _ _ _ __