Instant Clinical Pharmacology

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Instant ClinicalPharmacology

Evan J. BeggBSc, MB, ChB (Auckland), MD (Otago), FRACPProfessor in Medicine/Clinical PharmacologyChristchurch School of MedicineUniversity of OtagoChristchurchNew Zealand

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2003 by Blackwell Publishing LtdBlackwell Publishing, Inc., 350 Main Street, Malden, Massachusetts 02148-5018, USABlackwell Publishing Ltd, Osney Mead, Oxford OX2 0EL, UKBlackwell Publishing Asia Pty Ltd, 550 Swanston Street, Carlton, Victoria 3053, AustraliaBlackwell Verlag GmbH, Kurfrstendamm 57, 10707 Berlin, Germany

The right of the Author to be identied as the Author of this Work has been asserted in accordancewith the Copyright, Designs and Patents Act 1988.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, ortransmitted, in any form or by any means, electronic, mechanical, photocopying, recording orotherwise, except as permitted by the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher.

First published 2003 by Blackwell Publishing Ltd

ISBN 1-4051-0275-6

Catalogue records for this title are available from the British Library and the Library of Congress

Set in 9/12pt Sabon by Graphicraft Limited, Hong KongPrinted and bound in Great Britain by MPG Books Ltd, Bodmin, Cornwall

Commissioning Editor: Fiona GoodgameProduction Editor: Julie ElliottProduction Controller: Chris Downs

For further information on Blackwell Publishing, visit our website:www.blackwellpublishing.com

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Contents

Inducers of drug metabolism/inhibitors ofdrug metabolism, 52

Drug/food interactions, 54

4 Pharmacovigilance, 57Drug development, 58Therapeutic drug monitoring (TDM), 60Drugs involved in therapeutic drug

monitoring, 62Overdose/poisoning, 64Common poisonings, 66Pharmacological aspects of drug

dependence, 68

5 Optimal therapeutics, 71Principles of drug action, 72Applied pharmacology, 74Compliance with medication, 76Principles of therapeutics, 78Patients and their drugs, 80The drug profile, 82Evidence-based medicine, 84Pharmacoeconomics, 86Drug information/resources, 88

6 Appendix, 91Important equations in pharmacology, 92The pharmacokinetic triangle, 93Glossary/abbreviations, 94Test questions, 96Test answers, 98

Index, 101

Introduction, viWhat is clinical pharmacology?, vii

1 Clinical pharmacokinetics, 1General overview of pharmacokinetics, 2Pharmacokinetics, 4Drug clearance, 6Volume of distribution, 8The half-life, 10Oral availability, 12Protein binding, 14pH and pharmacokinetics, 16

2 Factors affecting dosing, 19Drug metabolism, 20Saturable metabolism, 22Pharmacogenetics, 24Dosing in liver disease and other disease

states, 26Renal drug elimination, 28Dosing in renal impairment, 30Dosing in the elderly, 32Dosing in children, 34Drugs in pregnancy, 36Drugs in human milk, 38

3 Altered drug effect, 41Adverse drug reactions, 42Drug-induced allergy, 44Adverse drug events, 46Preventing adverse drug events, 48Drug/drug interactions, 50

v

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This book is written mainly for medical stu-dents and doctors undergoing postgraduatetraining. Students of allied health profes-sionals, such as pharmacy, nursing, dentistryand physiotherapy may also nd it useful.

The aim is to provide essential informa-tion about the core topics in clinical pharma-cology. There is general agreement acrossthe world about what constitutes this corecurriculum. These topics are covered, theemphasis reecting my own biases.

The book assumes a knowledge of basicpharmacology and does not embrace spe-cic therapeutics. It aims to bridge the gapbetween basic pharmacology and the thera-peutic use of drugs in humans.

Some readers may be put off by theslightly mathematical nature of the initialsection on clinical pharmacokinetics. I apo-logize for this, but unfortunately this is thebasis of clinical pharmacology. The bookgets easier after this.

Any feedback would be appreciated, par-ticularly in terms of improving the user-friendliness of the book.

I acknowledge with warm gratitude theinput and inspiration of all the members ofmy department, both past and present. Thebook is dedicated to my students, whosehumour and wide-eyed enthusiasm makesteaching so worthwhile.

How to use the book

Mindful of the ckle nature of the learningprocess, I have tried to keep things simpleand to encapsulate each topic within twofacing pages. Hopefully, this will enable thereader to complete a topic in a short learn-ing session before the inevitable build-up ofboredom!

Happy learning!

Evan J. Begg

vi

Introduction

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vii

For example, once a diagnosis has beenmade and drug therapy is considered appro-priate, a particular drug must be chosen. Theideal drug is chosen, based on the best evid-ence. This drug is then examined to see if it isappropriate for this patient. Is the patient allergic to this drug or class? Are there any potential interactions withthe patients other drugs? Does the patient have other diseases thatmight be made worse (or better) by the addi-tion of the new drug? Is compliance likely to be a problem?If the drug passes this rst test, then a dosageregimen must be chosen. The starting pointis the normal dose regimen that would beappropriate for the average patient. Thisdosage regimen is then adjusted to tailor it to this patient. Is the patient old? (may need a lower dose) Is there any renal impairment/liver im-pairment? (may need a lower dose or alonger dose interval) Are there any drug interactions that mightrequire dose alteration?

Problems with these ideals

It is easy to preach a holier than thouapproach to therapeutics, but harder toachieve this in practice. Individualizingdrugs to the patient may be different in different settings. Prescribing in outbackAustralia is likely to be very different fromprescribing in central Sydney. Access to laboratories and medical follow-up will bedifferent. The ideal drug, based on evidence,may be totally impractical for your particu-lar patient.

Clinical pharmacology is concerned with therational, safe and effective use of medicines.

Clinical pharmacologyThe principles behind the prescribing process

as opposed to

TherapeuticsThe process of medical treatment

Clinical pharmacology involves the com-plex interaction between the patient and thedrug. The patient is a unique individual,with many distinguishing features that needto be taken into account during prescribing.The patient can be described in terms of thepatient prole. The drug, likewise, is unique,with its own distinguishing features. It maybe described in terms of the drug prole.

Good prescribing involves tailoring thedrug and dosing regimen to the unique pati-ent. Clinical pharmacology provides thebasis of this.

Patient profile Drug profileAge Name (generic)

Weight ClassSex ActionRace Pharmacokinetics

Allergies IndicationsSmoking history Contraindications/Alcohol history precautions

Diseases InteractionsPregnant/lactating Side effectsCurrent therapy Dosing regimen

Intelligence MonitoringOverdose

What is Clinical Pharmacology?

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The rational, safe and effective use ofmedicines must be tolerant of all this. Pre-scribers should not be expected to achieveperfection, but to pursue the greatest poss-ible effectiveness, with minimal risks, and

to respect the patients choice. The wordrational is relevant here, denoting not onlyscientic rationality, but also situationalrationality.

What is Clinical Pharmacology?

viii

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1 Clinical pharmacokinetics

General overview of pharmacokinetics, 2Pharmacokinetics, 4Drug clearance, 6Volume of distribution, 8The half-life, 10Oral availability, 12Protein binding, 14pH and pharmacokinetics, 16

1

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Clinical pharmacokinetics General Overview of Pharmacokinetics

2

1

General Overview ofPharmacokinetics

The aim of drug therapy is to achieve ef-cacy without toxicity. This involves achiev-ing a plasma concentration (Cp) that is abovethe minimal effective concentration (MEC),but below the minimal toxic concentration(MTC).

Clinical pharmacokinetics is about all thefactors that determine the Cp and its time-course, i.e. it is about variability. The vari-ous factors are dealt with in subsequentchapters.

Constant IV infusion

In order to achieve early effect (e.g. treatingstatus epilepticus with phenytoin) it is im-portant to get the Cp up to the effect zone assoon as possible. This is achieved with aloading dose.

The factor determining the loading dose isthe volume of distribution (Vd).

Oral dosing

Cp

Time

MTC

CpSS

MEC

Cp

Time

MTC

CpSS

MEC

The Cp rises to reach the desired steady stateconcentration (CpSS). The main determinantof the CpSS is the dose and the clearance (Cl).

Loading dose (IV injection followed by aconstant infusion)

Cp

Time

MTC

MEC

Dose Dose Dose Dose

The curve reects assimilation and elimina-tion, and intermittent administration.

Cp higher than desired

Cp

Time

MTC

CpSS

MEC

The two factors involved are excessive dos-age and/or decreased Cl.

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General Overview of Pharmacokinetics Clinical pharmacokinetics

3

1

Factors causing decreased Cl are: normal variation saturable metabolism genetic enzyme deciency renal failure liver failure old age very young age (neonate) enzyme inhibition.

Cp lower than desired

This is determined by the t1/2 of the drug. Ittakes 4 t1/2 to achieve >90% of the steady-state concentration.

Time for drug elimination

Cp

Time

MTC

CpSS

MEC

Dose may be too low, or Cl too high. Factors causing increased Cl are: normal variation poor absorption high rst-pass metabolism genetic hypermetabolism enzyme induction non-compliance.

Time to steady state

Cp

0

MTC

MEC

1 2 3 4 5 6Half-lives

Cp

Half-lives

MTC

MEC

1 0 1 2 3 4 5

1.0

0.5

0.250.125

0.0625Drug stopped

This is determined by the t1/2 of the drug. Ittakes 4 t1/2 for concentrations to reduce to

Clinical pharmacokinetics Pharmacokinetics

4

1 of the body. From a dosing point of view it is the concentration of drug at the site ofaction that is important. This is difcult tomeasure. Under steady-state conditions theplasma concentration (Cp) is in equilibriumwith sites of action. In practice it is usuallythe Cp that is measured.

Input(dose)

Drug inbody

Output(elimination)

Pharmacokinetics involves the study of themovement of the drug into, within and out

Cp Cbiophase Receptors

Site of action (biophase)

The pharmacokinetics of a drug are usuallystudied using an intravenous injection orinfusion, as the dose can then be consideredto be 100% assimilated into the body. Thevalues of Cl, Vd and t1/2 for a drug are derivedfrom the curve of concentration versus time.

Zero-order elimination

It would be very simple if the Cp declinedlinearly with time after a simple intravenousinjection. This situation, called zero-orderelimination, occurs only rarely. A familiarexample is ethanol, concentrations of whichdecline at a constant rate of approximately15 mg/100 mL/h.

Cp

Time

(NB linear scale)

Pharmacokinetics

Pharmacokinetics:The study of the movement of drugs into,

within and out of the bodyi.e. what the body does to the drug

as opposed to

Pharmacodynamics:The study of drug effect, and

mechanisms of actioni.e. what the drug does to the body

It is important to know the pharmacokinet-ics of a drug so that the drug can be used in arational and scientic manner, and the dosetailored to the patient.

The most important pharmacokineticparameters from a dosing point of view arethe clearance (Cl), the volume of distribu-tion (Vd) and the half-life of elimination(t1/2). The Cl determines the maintenancedose, the Vd the loading dose, and the t1/2 thedose interval.

One-compartment model

The most simple model is the one-compart-ment model. In this, the body is consideredas a single container (one compartment) inwhich the drug is instantaneously and uni-formly distributed.

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Pharmacokinetics Clinical pharmacokinetics

5

1First-order elimination

The more common situation is rst-orderelimination, in which the decline in plasmaconcentrations is not constant with time, butvaries with the concentration. The higherthe concentration, the greater the rate ofelimination. The concentration declines ex-ponentially with time.

where Cpt is the concentration at any time tCpo is the concentration at time zero

and k is the elimination rate constantThis equation is difcult to use (for most

of us!) and can be simplied by transformingit to a linear expression. This is done by tak-ing the natural logarithm of each side:

ln Cpt = ln Cpo kt

This now has the form of a linear equation y = mx + c, or in this case because the line isdeclining, y = c mx, where m is the slopeand c the intercept on the y-axis.

Cp

Time

(NB linear scale)

First-order elimination

This curve can be described by:Cpt = Cpo * e

kt

(In) Cp

Time

(NB log scale)

k

Cpo

Important pharmacokinetic abbreviations

Abbreviation Definition Abbreviation Definition

t1/2 the half-life of elimination ss Steady stateVd Volume of distribution Cp Plasma concentrationCl Clearance Cpt Plasma concentration at time = tAUC Area under the curve Cpo Plasma concentration at time = oF Fractional oral availability Cpss Plasma concentration at steady statefu fraction excreted unchanged Ab Amount in bodyPB Protein Binding e The natural logarithm Tmax Time to maximum concentration (value = 2.7183)Cmax Peak concentration ln log to the base e

(Concentration maximum) k the rate constant of elimination

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Clinical pharmacokinetics Drug Clearance

6

1

Cp

Time

(NB linear scale)

First-order elimination

The graph shows that the rate of elimination(RE) is different at different concentrations,i.e. it is driven by concentration.

rate of elimination Cp rate of elimination (mg/h) = constant

(L/h) * Cp (mg/L)

This constant is the clearance (Cl) and bydeduction has units of volume/time (e.g.L/h), since the units for rate of eliminationare mg/h, and for concentration mg/L.

0

Cp

3

CpSS

Half-lives21 4 5 6

Administration

Elimination

Drug Clearance

Drug clearance (from plasma) is defined as:The volume of plasma cleared of drug

per unit time; or

A constant relating the rate of elimination tothe plasma concentration (Cp)i.e. rate of elimination = Cl * Cp

Units: vol/time (e.g. L/h)

Clearance (Cl) is the single most importantpharmacokinetic parameter. Cl determinesthe maintenance dose-rate, i.e. dose per unittime, required to maintain a plasma concen-tration.

Clearance does not apply to drugs withzero-order kinetics, but only to those withrst-order (exponential) kinetics. This appliesto the majority of drugs.

i.e. rate of elimination = Cl * Cp

Thus, Cl is A constant relating the rate ofelimination to the plasma concentration;and

The volume of plasma cleared of drug perunit time.

The equation can be rearranged as follows:

Achievement of a constant steady-state plasma drug concentration(CpSS)

In order to maintain a target Cp, the drugmust be administered at a rate equal to therate of elimination at that concentration, i.e.

rate of administration = rate of eliminationSincerate of elimination = Cl * Cp, thenrate of administration = Cl * CpSS, or

Maintenance dose-rate = Cl * CpSS

Cl L/hrate of elimination mg/h

Cp (mg/l) ( )

( )=

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Drug Clearance Clinical pharmacokinetics

7

1

Cp

Time

Area1 2 3 4 5 6 7

Physiological relevance of drug clearance

The main organs responsible for drug clear-ance are the liver (metabolism) and the kid-neys (removal of unchanged drug). Totalbody Cl is the sum of all clearance processes,i.e.

Cl (total) = Cl (renal) + Cl (liver) +Cl (other)

Determination of Cl

Plasma Cl is usually determined from thearea under the plasma concentration vs timecurve (AUC) after IV administration.

The AUC is determined using the trape-zoidal rule.

AUC = Area 1 + Area 2 + Area 3 + . . .Area n, where each area is approximated bya trapezium.

Area under the curve (AUC)

The bigger the AUC, the smaller the Cl.

After oral administration:

where F = oral availability.

Cl

F * DoseAUC

=

Cl

DoseAUC

=

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Clinical pharmacokinetics Volume of Distribution

8

1 volume of the body (50100 L) is comparedwith Vds of drugs, e.g. heparin (5 L); gen-tamicin (15 L); digoxin (500 L); and quin-acrine (20 000 L).

Highly lipid soluble drugs such as quin-acrine have much larger Vds than very polar,water soluble drugs such as heparin.

Determination of Vd

To calculate Vd, the Ab and Cp need to beknown. The only time Ab is known accur-ately is immediately after the drug has beengiven intravenously (prior to elimination),i.e. the dose. If the Cp at time zero (Cpo) isknown, then the Vd can be calculated. TheCpo can be determined from the lnCp vs timecurve after intravenous (IV) administration.After initial distribution, there is a log-linear decline in plasma concentration. TheCpo can be determined by back-extrapolat-ing the linear portion of the curve to its inter-cept on the y-axis. Vd can then be calculated.

(In) Cp

Time

Cpo

i.e. At time zero, Ab = dosethen dose = Vd * Cpo

or Vd = dose/Cpo

Calculation of loading dose (LD)

It follows from the above that to achieve atarget Cp, the Vd of the drug must be known

Volume of Distribution

The volume of distribution is:The volume into which a drug appears to be distributed with a concentration

equal to that of plasma, or

A proportionality constant relating the plasma concentration (Cp) to the

amount of drug in the body (Ab).i.e. Ab = Vd * Cp

Units: Volume or vol/kg

The volume of distribution (Vd) is the secondmost important pharmacokinetic parameter(after Cl). It determines the loading dose, i.e.the dose required to achieve a target plasmaconcentration (Cp) as soon as possible.

In order to achieve a target Cp, the tissuesinto which the drug distributes (i.e. the vol-ume of distribution) must be lled up.

The Vd is therefore the volume intowhich a drug appears to be distributed witha concentration equal to that of plasma.

After distribution is complete, the amountof drug in the body (Ab) is proportional tothe plasma concentration (Cp).

i.e. Ab Cpor Ab = constant * Cp

This constant has units of volume (e.g. L)since the Ab is in mass units (e.g. mg) and Cpis in concentration units (e.g. mg/L).

Hence the Vd is A proportionality con-stant relating the plasma concentration tothe amount of drug in the body.

i.e. Ab = Vd * cp

or

The Vd is often called the apparent Vdsince the volume has no real anatomicalmeaning. This can be appreciated when the

Vd

AbCp

=

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Volume of Distribution Clinical pharmacokinetics

9

1

10

steady-stateCp

2.0

1.5

1.0

0.5

0.02 3 4 5

Time (units of t1/2)

line of

0.50.75

0.875

A

B

LD = Vd * target Cp

e.g. to achieve a target Cp of digoxin (Vd~ 500 L) of 1.5 g/L, a loading dose (LD) of750 g, or 0.75 mg is needed, i.e.

LD (g) = 500 (L) * 1.5 (g/L)= 750 g

With a loading dose, steady-state concentra-tions can be achieved quickly.

Curve A a loading dose followed by main-tenance dosing.Curve B a maintenance dosing every half-life.

In summary, the most important thingabout Vd is that it enables the calculation ofa loading dose to achieve any desired Cp.

LD = Vd * Cp

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Time-course of drug elimination

If a drug is discontinued after an infusion,the Cp will decline exponentially to 90% of steady state concentration) afterfour half-lives.

10

Cp

6543

2 3 4 7Time (h)

2

1.5

15 6

t1/2 = 2.5 h

(NB log scale)

Cp

Half-lives1 0 1 2 3 4 5

1.0

0.5

0.250.125

0.0625Drug stopped

Cp

0

CpSS

1 2 3 4 5 6Half-lives

The Half-Life

The half-life of elimination (t1/2) is:The time for the concentration of

the drug in plasma (or the amount of drug in the body) to halve.

Units: Time (usually h)

The t1/2 provides an index of:1 the time-course of drug elimination;2 the time-course of drug accumulation; and3 choice of dose interval.

Derivation of t1/2

The half-life of elimination (t1/2) can bederived by plotting actual concentrations onsemilog graph paper, or logged concentra-tions on linear graph paper. It is the timetaken for any concentration to halve, e.g.from 3 to 1.5 mg/L.

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The Half-Life Clinical pharmacokinetics

11

Components of the line of steady state

The line of steady state is effectively the com-bination of accumulation and elimination.i.e. it is the sum of the effect of dose and elim-ination at any time point.

Relationship between t1/2, Vd and Cl

1

Choice of dose interval

The dose interval is usually chosen based on:1 the t1/22 the therapeutic index of the drug3 compliance a it is best, if possible, to havedosing once or twice a day.If drug Cl decreases (say in renal dysfunc-tion), it may be possible for a drug that isnormally given three or four times a day to begiven twice or once daily, with greater chanceof compliance. This is good therapeutics.

0

Cp

3

CpSS

Half-lives21 4 5 6

Accumulation

Elimination

(In) Cp

Time

larger Vd

larger Cl

It is logical that the larger the Vd, the longerthe t1/2, i.e. it takes longer to remove drugfrom deep within the tissues. Similarly, it islogical that the larger the Cl, the shorter thet1/2. In other words:

This relationship can be turned into an equa-tion by multiplying the right side by 0.693.This strange number is the natural logarithmof 2 (i.e. ln 2) and gets into the equationbecause the t1/2 involves a halving, i.e. theinverse of 2.

This is one of the most important equationsin clinical pharmacokinetics. It indicates that the t1/2 is dependent on Vdand Cl. Vd and Cl are the independent variables.

t0.693Vd

Cl12/ =

tVd

Cl1 2/

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Clinical pharmacokinetics Oral Availability

12

1Absorption

This refers to the ability of the drug to crossa biological barrier into the blood. In thecase of oral absorption, it refers to crossingthe gut wall into the portal circulation.Absorption is usually a passive process gov-erned by the principles of diffusion (i.e. owsdown a concentration gradient). Sometimes,active transport is involved (e.g. l-dopa).Factors favouring absorption include highlipid solubility and low ionization. pH mayalso inuence absorption, but probablyaffects the rate more than the extent.

First-pass metabolism

This refers to metabolism of the drug priorto reaching the systemic circulation, i.e.presystemic elimination. Some drugs, suchas highly lipid-soluble drugs, are so highlymetabolized that on rst-pass through theliver there is substantial presystemic elim-ination. Presystemic elimination can occurin the gut wall (e.g. oestrogens), in the portalcirculation (e.g. aspirin salicylic acid) orin the liver (the majority).

Effect of food on oral availability

Interestingly, food affects absorption andrst-pass metabolism in opposite ways. Foodusually decreases the oral availability ofsparingly lipid-soluble drugs that are subjectto absorptive problems, e.g. food decreasesthe oral availability of atenolol by 50%.

However, food usually increases the oralavailability of drugs that are subject to highrst-pass metabolism. This is because foodincreases portal venous blood ow, therebyincreasing the presentation of absorbed drugto the liver, partially saturating metabolizing

Cp

Time

AUCpo

AUCIV

Determinants of oral availability

1 Absorption.2 First-pass metabolism.

Oral Availability

Oral availability is:The fraction of drug that reaches the

systemic circulation after oral ingestion

Oral availability denes how much drug getson board after oral ingestion. Absorptionand rst-pass metabolism are the maindeterminants of oral availability.

Oral availability is usually dened bycomparison with the total availability ofdrug in the systemic circulation after IV dos-ing, i.e. the fraction (F) of drug that gets intothe body after oral (po) versus IV adminis-tration:

i.e.

The total amount of drug in the systemic circulation is dened by the area under the concentrationtime curve (AUC). TheAUC may be different after oral comparedwith IV administration. The oral availab-ility may have a value of one, or less thanone.

FAUC

AUCpo

IV

=

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Oral Availability Clinical pharmacokinetics

13

1

Tmax is less important than the total oralavailability. A short Tmax may be usefulwhere an immediate effect is desired, e.g.analgesia for a headache. A short Tmax mayalso be a problem e.g. adverse effects relatedto the peak concentration.

Slow-release preparations

A delayed Tmax and a longer drug action maybe achieved using tablets or capsules de-signed to release their contents slowly. Thisattens the concentrationtime prole, givinga more even drug response.

Cp

Time

Tmax (time to peak concentration)

Cmax (peak concentration)

Cp

Time

Slow-release preparation(lower Cmax, delayed Tmax)

pathways and opening up shunts that by-pass metabolizing pathways. The net resultis greater oral availability, e.g. food increasesthe oral availability of metoprolol by 50%.

Some foods, e.g. grapefruit juice, competewith drugs for presystemic elimination,thereby causing increased oral availability ofthe drug (e.g. calcium antagonists, somestatins).

Confusing terminology

There is sometimes confusion between theterms oral availability, bioavailabilityand absorption. Oral availability is the pre-ferred term because it is unambiguous.

Bioavailability has a strict historicaldenition a the rate and extent of absorp-tion. One problem with bioavailability isits reference to absorption. As noted above,absorption is only one part of the process ofdrug attaining the systemic circulation. Theother problem with bioavailability is that itis a single term that denes two processes athe rate of absorption, and the extent. It ismore instructive to think of each of thesecomponents independently, i.e. oral avail-ability denes the extent, and another term,Tmax, denes the rate.

Time to peak concentration (Tmax)

Tmax defines the time to maximum (or peak) concentration

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Clinical pharmacokinetics Protein Binding

14

1 concentration of free drug, not total drug,that is actually important in terms of desiredeffects and side effects.

Free drug concentration is dependent onfree drug clearance (see Clearance, page 6),and does not vary in relation to changes inplasma proteins. Therefore, except for rareexceptions, no alteration in dosage is requiredin states of altered protein binding.

The fallacy of protein-binding drug interactions

Many so-called protein-binding drug inter-actions have been reported. While drugs cancompete for protein binding sites, especiallyon albumin, this does not affect the free concentration.

Bound drug Free drug

Measured drug

Altered albumin or 1-acid glycoprotein con-centrations will alter the measured (total)concentrations of drugs bound highly to theseproteins.

However, it is free drug that acts on recep-tors to produce effect. Therefore, it is the

Without displacer With displacer

This is anartificial

test-tubesituation

If a drug in the body was not subject to drug elimination, then introduction of aprotein-binding displacer would increasethe concentration of the free drug.

In reality drug elimination does occur.Since the steady-state free drug concen-tration is only dependent on maintenancedose and free drug clearance (remember,Maintenance dose = Cl * Cp), then free drugconcentration returns to its predisplacementlevel. However, the total drug concentrationis now lower than it was.

Protein Binding

The major message about protein binding(PB) is that it is usually not important.

Protein binding is only important in theinterpretation of measured plasma

concentrations

There is enormous confusion about theimportance of protein binding and the drugeffects attributed to it. While drugs may dis-place each other from protein-binding sites,this is almost always unimportant. Mostalleged protein binding interactions of clin-ical importance have an additional mech-anism operating, such as altered drug clearance, that is the reason underlying theobserved clinical effects.

Acidic drugs bind largely to albumin.Basic drugs bind mainly to 1-acid glycopro-tein (i.e. orosomucoid), an acute phase react-ant, and to albumin and -lipoproteins.

The signicance of protein binding lies inthe interpretation of plasma concentrationsof drugs. If plasma concentrations are notmeasured, protein binding can largely beignored.

NB: When plasma concentrations of drugsare measured, it is total drug, i.e. bound +unbound, that is measured. It is possible, butnot routine (except perhaps for phenytoin),to measure free or unbound drug.

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Protein Binding Clinical pharmacokinetics

15

1

Interpretation of measured plasmaconcentrations during therapeuticdrug monitoring

Protein binding problems arise from thefact that the measured drug concentration istotal drug (bound + unbound). In hypoalbu-minaemia (e.g. in renal disease) an acidic drugsuch as phenytoin will have a lower total drugconcentration because of lower protein bind-ing. Free drug concentration will, however, bethe same as in the non-hypoalbuminaemicstate (assuming free drug Cl is constant).The same principles apply with displacingdrugs in normoalbuminaemia. e.g. phenytoin(therapeutic range 1020 mg/L total con-centration, 12 mg/L free concentration).

In hypoalbuminaemia free concentration(and effect) is identical but total measuredconcentration is half. If the dose was in-creased to give a total concentration of 10 mg/L, the free concentration would be 2 mg/L and may be toxic. Note that the situation for hypoalbuminaemia is identicalto that involving drug displacement inter-actions (see above).

Drugs with saturable proteinbinding

Some drugs at clinical concentrations sat-urate the available protein-binding sites. In this situation total drug concentration(bound + unbound) does not increase lin-early with dose. Interpretation of measuredconcentrations is difcult. If free concentra-tions were measured, these would be seen torise linearly with dose.

Drugs with saturable protein bindinginclude ceftriaxone, hydrocortisone, pred-nisone, thioridazine and sodium valproate.Of these, the only one that has clinicalimportance is sodium valproate, becausethis is sometimes measured during thera-peutic drug monitoring. Saturable proteinbinding makes interpretation of valproateconcentrations difcult. For the other drugsprotein binding does not need to be takeninto account during dosing, because drugconcentrations are not usually measured,and free concentrations behave predictably.

Without displacer With displacer

Free conc.1 mg/L

Boundconc.4 mg/L

Totalconc.5 mg/L

Boundconc.

9 mg/L

Totalconc.

10 mg/L

Free conc.1 mg/L

Normalalbuminaemia(i.e. 90% PB)

Markedhypoalbuminaemia

(i.e. 80% PB)

Free conc.1 mg/L

Boundconc.4 mg/L

Totalconc.5 mg/L

Boundconc.

9 mg/L

Totalconc.

10 mg/L

Free conc.1 mg/L

ICPC01 21/5/05 12:15 PM Page 15

Clinical pharmacokinetics pH and Pharmacokinetics

16

1 may show variation in the ionized/unionizedratio at pHs encountered in physiology.Similarly, weak bases with pKa valuesbetween 5 and 11 may show variation in theunionized/ionized ratio.

When is this important?

Drug absorption from the stomach Drug elimination via the kidneys Drug distribution into milk Drug distribution across the placenta.

Drug absorption from the stomach

Gastric pH is usually between 1 and 4. Acidsare therefore largely unionized and may beabsorbed in the stomach (e.g. aspirin).However, because of the far greater absorpt-ive surface area in the small intestine, thebulk of absorption occurs there, even foracids.

Drug elimination in the kidney

The pH in the urine varies from 4.5 to 7.5.Weak acids may vary from unionized at pH 4.5 to largely ionized at pH 7.5.Reabsorption from the renal tubular lumeninto the blood will occur if the drug is in theunionized state. Therefore, reabsorptionwill occur in acid urine, while eliminationwill occur in alkaline urine. Conversely,weak bases will be reabsorbed in alkalineurine and eliminated in acid urine. This prin-ciple is sometimes used in enhancing theelimination of drugs after overdoses (e.g.aspirin elimination can be enhanced byadministration of bicarbonate).

pH and Pharmacokinetics

In some situations drug disposition varies inrelation to pH differences across biologicalbarriers. The disposition of some weak acidsand bases is susceptible to small pH dif-ferences because of variation in the state ofionization and hence the ability to crossmembranes.

Background theory

Acids are ionized in basic mediaBases are ionized in acidic media

i.e. H+ + X HX

(ionized) (unionized)

If more H+ ions are added (i.e. adding acid-ity), the equilibrium moves to the right. Ifbase (e.g. OH) is added, H+ ions are con-sumed, and the equilibrium moves to theleft. Unionized drug crosses lipid biologicalbarriers (e.g. membranes) better than ion-ized drug.

HendersonHasselbalch equation

For acids:

For bases:

NB The pKa is the pH at which a drug is 50% ionized and 50% unionized. Weakacids, with pKa values between 3 and 7.5,

pH pK[unionized]

[ionized]a log = +

10

pH pK[ionized]

[unionized]a log = +

10

ICPC01 21/5/05 12:15 PM Page 16

pH and Pharmacokinetics Clinical pharmacokinetics

17

Drug distribution into milk, acrossthe placenta, and into 3rd spaces

Milk, the fetus, and most 3rd spaces havepH values that are acidic (~7.0) in relation toplasma (~7.4). Therefore bases tend to con-centrate in these compartments becausethey are relatively ionized on the acidic side,and effectively trapped. This is called iontrapping. It applies to any situation where apH gradient exists across a biological bar-rier, and where the principles of diffusionapply, e.g. abscesses, synovial uid.

1Drugs with pH-dependentelimination

Acids (elimination enhanced by alkalinediuresis) phenobarbitone salicylates.

Bases (elimination enhanced by acid diuresis) amphetamines methadone mexiletine phencyclidine phenylpropanolamines (e.g. ephedrine,pseudoephedrine) quinidine.

ICPC01 21/5/05 12:15 PM Page 17

ICPC01 21/5/05 12:15 PM Page 18

22 Factors affecting dosing

Drug metabolism, 20Saturable metabolism, 22Pharmacogenetics, 24Dosing in liver disease and other disease states, 26Renal drug elimination, 28Dosing in renal impairment, 30Dosing in the elderly, 32Dosing in children, 34Drugs in pregnancy, 36Drugs in human milk, 38

ICPC02 21/5/05 12:14 PM Page 19

and methylation. Glucuronidation is quantit-atively the most important.

Cytochrome R450 metabolism(CYP)

CYP reactions are catalysed by the cytoch-rome p450 mixed function oxidases, mostlyin the liver. These are iron-containingenzymes, named p for pigment, and 450 forthe wavelength, in nM, at which spectro-photometric absorption occurs. At least 13 CYP gene families exist in humans, withvarious subfamilies. Each CYP family isencoded by a separate gene. The nomencla-ture is:

Factors affecting dosing Drug Metabolism

20

2

Phase I Derivative

Conjugate

Drug

Phase II

Phase II

Phase I reactions include oxidation, reduc-tion and hydrolysis. The most common areoxidation reactions (adding oxygen, orremoving hydrogen). Oxidation reactionsinclude dealkylation, hydroxylation, deam-ination and desulphuration. Most occur viathe cytochrome p450 enzymes.

Phase II reactions involve conjugations, suchas glucuronidation, acetylation, sulphation

CYP 3 A 4

cytochrome p450 family subfamily isoform

Drug clearance by the liver

The fraction of drug removed from blood inone passage across the liver is the extractionratio (ER).

where C = drug concentration

Hepatic drug clearance depends on theextraction ratio, but also on the hepaticblood ow (HBF) since the greater the bloodow the greater the presentation of drug tothe liver. Thus,

Hepatic Cl = HBF * ER

High Cl, ow-dependent elimination: If theextraction ratio approaches 1 (completeextraction), then hepatic Cl approaches hep-atic blood ow. In this case the elimination

ERC C

C

=

in out

in

Drug Metabolism

Variation in drug metabolism is a major cause of variation in drug clearance

Some drugs are excreted unchanged throughthe kidneys because they are polar and arenot reabsorbed in the renal tubules. Otherdrugs, especially those that are lipid-soluble,are reabsorbed in the renal tubules andwould circulate forever if they were not biotransformed to more readily excretableforms.

Metabolic biotransformation convertsdrugs to more polar and excretable forms.The resulting metabolite may be inactive,less active or occasionally more active (e.g.metabolite of a prodrug) than the parentmolecule.

Where does biotransformationoccur?

Metabolism occurs mainly in the liver, butalso in the kidney, lung, GI mucosa, plasma,the CNS and probably most tissues. Somedrugs undergo sequential biotransformation.

ICPC02 21/5/05 12:14 PM Page 20

Drug Metabolism Factors affecting dosing

21

is said to be blood ow dependent, or highclearance.

Low Cl, ow-independent elimination: Ifthe extraction ratio is small, there is noblood ow dependence, since presentationof more drug to the liver will not result ingreater elimination.

First-pass metabolism: Drugs entering theportal system after absorption have to passthrough the liver prior to reaching the sys-temic circulation. If the extraction ratioapproaches 1, little drug will reach the sys-temic circulation. In this case, rst-passelimination approaches 100%, and oral avail-ability (F) approaches zero. For example,lignocaine has an extraction ratio of 0.7, andtherefore an F of 0.3.

There are three situations in which theextent of rst-pass metabolism decreases,resulting in increased oral availability:1 High oral doses a Drugs such as prop-ranolol saturate the metabolizing enzymes,resulting in less rst-pass metabolism, andgreater oral availability.2 High blood ow a Increased liver bloodow, such as after food, delivers more drugto the metabolizing enzymes, sometimes saturating them. This results in less rst-pass

metabolism for high clearance drugs such aspropranolol.3 Chronic liver disease a There is lowerintrinsic clearance, as well as increasedshunting.

2Some examples of high and low clearance drugs.

High clearance Low clearance

Antidepressants NSAIDsAntipsychotics AnticonvulsantsCalcium antagonists Most benzodiazepinesNarcoticsNitratesMost antiparkinsonsMost statinsMany b-blockers

Clinical significance of high-clearance drugs

Subject to rst-pass metabolism Subject to ow-dependent elimination May require dose-reduction in situationsof decreased blood ow, e.g. congestiveheart failure (CHF) May be subject to pre-systemic drug interactions, e.g. with grapefruit juice.

ICPC02 21/5/05 12:14 PM Page 21

Enzyme inhibitors which act by compet-ing with other drugs for metabolism by thesame enzyme, will not change the Vmax, butwill increase the Km. Enzyme inhibitors thatact by direct inhibition of the enzyme willdecrease the Vmax and may or may not alterthe Km.

Factors affecting dosing Saturable Metabolism

22

2

Rat

e of

hep

atic

met

abol

ism

(dc

/dt)

Concentration (Cp)

dcdt

=Vmax * CpKm + Cp

Vmax (maximum rate of reaction)

Km

1/2 max

The curve asymptotes to a maximum rateof reaction (Vmax). The Km (Michaelis con-stant) is the concentration at which half themaximum rate of reaction occurs.

Vmax relates to the total amount of enzymesavailable for metabolism. Km is inverselyproportional to the afnity of the drug forthe enzyme, i.e. the higher the afnity thelower the Km.

Enzyme inducers, which increase theamount of available enzymes, will thereforeincrease Vmax but will not alter Km.

dc

dt

V * Cp

Km Cpmax

=

+

Rat

e of

rea

ctio

n

Cp

Enzyme induction(same Km, higher Emax)

Rat

e of

rea

ctio

n

Cp

Enzyme inhibition (non-competitive)(same Km, lower Emax)

Enzyme inhibition (competitive)(higher Km, same Emax)

NB Below the Km, the rate of elimination isalmost directly proportional to the plasmaconcentration (i.e. RE Cp. This is equival-ent to Cp to the rst power, or rst order).This is therefore a rst-order reaction, andgraphically is a straight line if log Cp is plot-ted against T.

Above the Km, the rate of elimination be-comes independent of concentration. This iscalled zero-order elimination because it is notdependent on Cp (equivalent to Cpo whereany number to the power of zero equals 1).

Saturable Metabolism

Saturable metabolism causes drug concentrations to rise

disproportionately (non-linearly) compared with dose

It is theoretically possible for all drugs to sat-urate their metabolizing pathways. For mostdrugs the concentration at which saturationbegins to be evident is usually above the con-centration range used in therapeutics. For a few drugs, however, saturation occurs attherapeutic concentrations.

Consider the MichaelisMenten curve:

ICPC02 21/5/05 12:14 PM Page 22

Saturable Metabolism Factors affecting dosing

23

In practice, most drugs have Km valueswell above their therapeutic concentrations,and therefore have rst-order kinetics.

A select group of well-known drugs saturate at or around their therapeutic con-centrations. For these, concentrations mayincrease more than proportionally for agiven increase in dose, e.g. phenytoin.

2

100

CP

(mg/

L)

Dose (mg)

Minimum toxic concentration

70

60

50

40

30

20

10

0500

Minimum effective concentration

4003002000

Phenytoin has a Km of around 7 mg/L andtherefore saturates at or around the lower endof the therapeutic range (1020 mg/L).

Aspirin saturates after only one or two300 mg tablets. Alcohol has a Km of approximately 0.01 g/100 mL, and therefore metabolism is essentially zero order at almost all con-centrations (usual driving limits 0.050.08 g/100 mL).

Some drugs with non-linear elimination (i.e. dose-dependent, saturable).

Drug Pathway

alcohol alcohol dehydrogenaseaspirin various conjugationsclonidine active renal tubular excretionfluoxetine CYP2D6methotrexate active renal tubular excretionparoxetine CYP2D6phenytoin CYP2C9/2C19propafenone CYP2D6verapamil CYP3A4

For drugs with saturable elimination doseincreases should be made in small increments

ICPC02 21/5/05 12:14 PM Page 23

topurine (6-MP) are metabolized to a varietyof active and inactive products. In patientswith TPMT deciency, 6-MP is shunteddown alternative pathways, increasing bothefcacy and adverse effects, especially bonemarrow depression. One in 300 Caucasiansare essentially without TPMT activity, while10% have intermediate activity.

Factors affecting dosing Pharmacogenetics

24

2

AZATHIOPRINE

Hypoxanthine-guaninePhosphoribosyItransferase

(HGPRT)

6-MERCAPTOPURINE(6-MP)

6-METHYLMERCAPTOPURINE 6-THIOGUANINENUCLEOTIDES

6-THIOURIC ACID

Thiopurinemethyltransferase(TPMT)

Xanthine oxidase (XO)

Glutathione-S-transferase

Dihydropyrimidine dehydrogenase(DPD) 5-uorouracil is metabolized by DPD. Abso-lute and partial DPD deciency occurs inaround 0.13% of the Caucasian popula-tion, and in these patients excessive toxicitymay be observed.

Cytochrome P450 metabolism(CYP)The most important isoforms for drug meta-bolism are CYP3A4, CYP2D6, CYP2C19,CYP2C9, CYP1A2 and CYP2E1. Of these,only CYP2D6, CYP2C9 and CYP2C19 haveclearcut and clinically important geneticpolymorphisms. More will undoubtably befound, however.

Cytochrome P450 (CYP)polymorphismThe rst evidence of CYP polymorphismwas the discovery of slow hydroxylation of sparteine and debrisoquine. Both are

Pharmacogenetics

Some pathways of drug metabolism are affected by genetic polymorphism, with marked dosing implications

Fast/slow acetylationAcetylation is a phase II conjugation re-action catalysed by N-acetyl transferase.Among Caucasians, approximately 50% are fast and 50% are slow acetylators.Acetylation status is determined by parent/metabolite ratios in the plasma or urine.Drugs affected by acetylator status include: procainamide and hydralazine (increasedrisk of SLE in slow acetylators) sulphonamides (increased risk of haemo-lysis in slow acetylators) isoniazid (increased risk of peripheralneuropathy in slow acetylators; increasedrisk of hepatitis in fast acetylators).

GlucuronidationGlucuronidation, the other major phase IIreaction, is also subject to genetic polymor-phism. Patients with Gilberts disease havedecient glucuronyl transferase, reected byhigher bilirubin concentrations.

Aldehyde dehydrogenaseAround 50% of persons of Mongoloiddescent have aldehyde dehydrogenase de-ciency. They are unable to metabolize acet-aldehyde produced from ethanol and maydevelop a disulram reaction a build-up ofacetaldehyde causing ushing and vomiting.

Pseudocholinesterase deficiencyOne in 3000 individuals cannot metabolizesuccinylcholine and require articial respira-tion for some hours after succinylcholineusage (e.g. during anaesthesia).

Thiopurine methyl transferase(TPMT) Azathioprine and its metabolite 6-mercap-

ICPC02 21/5/05 12:14 PM Page 24

Pharmacogenetics Factors affecting dosing

25

mediated by CYP2D6. Around 40% of CYPmetabolism is carried out by polymorphicenzymes. Interestingly, the major CYP group,CYP3A4, does not appear to be subject togenetic polymorphism.

Determination of CYP statusCYP status may be determined by examin-ing the phenotype (metabolic ratio) or thegenotype. The metabolic ratio is the ratio ofthe parent drug to the metabolite.

CYP2D6Homozygotes and heterozygotes exist, withappropriate fast and intermediate metabolicratios. Total absence of the gene results inslow metabolism. There may also be geneduplication or multiple copies resulting inultrarapid metabolism and very low drugconcentrations.

Five to ten per cent of Caucasians and 13% of Mongoloid, Polynesian and Negroidpeople are poor metabolizers. Clinically relevant examples of CYP2D6 poor meta-bolism include:

Perhexiline a neuropathy/liver toxicity Phenformin a lactic acidosis Timolol eye drops a systemic -blockade Flecainide a ? arrhythmic deaths.Codeine requires CYP2D6 to be metabol-ized to its active metabolite morphine. Sincepoor CYP2D6 metabolizers have no activeCYP2D6 enzyme, codeine does not relievepain in these patients.

CYP2C9Around 13% of patients on warfarinrequire only around 1 mg per day for clinicalanticoagulation (cf a mean of 7 mg/day innormals), due to poor metabolism.

CYP2C19Eighteen to 23% of Mongoloid and 35%of Caucasian and Negroid people are slowmetabolizers. The area under the curve(AUC) of omeprazole (a proton pumpinhibitor [PPI]) is increased around 12-foldin patients with slow metabolism.

2

Characteristics of major CYP drug metabolizing enzymes.

3A4 2D6 2C9 2C19 1A2 2E1Chromosome 7 22 10 10 15 10

Probe(s) Nifedipine Sparteine Tolbutamide Mephenytoin Phenytoin EthanolDebrisoquine (Phenytoin) CaffeineDextromethorphan

Subject to enzyme ++ + +++induction

Subject to enzyme ++ ++ + + + inhibition

Subject to genetic No but wide Yes Yes Yes ? ?polymorphism variability

% of total CYP 50% 25% 510% 23% 510% 5%drugs metabolized by this CYP

Major substrates Diverse Lipophilic bases Mainly acids Diverse Diverse Mainly Steroids Lipophilic b-blockers NSAIDs PPIs Xanthines hydrocarbonsCa2+ antagonists Antidepressants S-warfarin R-warfarin Paracetamol HydrocarbonsMacrolides Neuroleptics Phenytoin Phenytoin AnaestheticsStatins Antiarrhythmics Losartin MoclobemideProtease Codeineinhibitors Tramadol

ICPC02 21/5/05 12:14 PM Page 25

to synthesize drug metabolizing enzymes.However, these measures are insensitive torapid changes in liver function and only indicate severe, chronic dysfunction. Analbumin concentration of

Dosing in Liver Disease and Other Disease States Factors affecting dosing

27

Decreased tissue perfusion causing de-creased Vd of lipophilic drugs, e.g. lignocaine Decreased mesenteric blood ow causingaltered rates of absorption, e.g. frusemide.

Dosing in cardiovascular disease

The main caution is with high clearance,ow-dependent drugs (see Table). Apply the start slow, go slow strategy. For otherdrugs, dose in relation to CrCl and albumin/INR status.

Dosing in gastroenterologicaldisease

The small intestine is the most important siteof drug absorption. This applies even to acidicdrugs, since the huge surface area of thesmall intestine overshadows other physico-chemical factors (e.g. pKa, ionization, etc.)which might appear to favour absorptionfrom the stomach. Altered rates of stomachemptying will affect the RATE of availabil-ity of oral drugs, e.g. migraine decreasedrate of absorption of analgesics.

However, for most drugs the EXTENT ofavailability is more important, and this israrely altered signicantly in GI disease.Diseases most studied have been Crohnsdisease, coeliac disease, and gastroenteritis.No simple rules can be made except per-haps that in any circumstance of shortenedbowel transit time the potential exists fordecreased extent of availability of sparinglysoluble or poorly absorbed drugs (e.g. someantibiotics).

2

Dosing in liver disease

A useful rule, which is somewhat arbitrary,is to:1 reduce the dose by 50% for high clearancedrugs (affected by both blood ow andenzyme capacity).2 reduce the dose by 25% for low Cl drugs(affected by enzyme capacity only).Extra caution is advised with drugs with alow therapeutic index. The usual tenet ofstart low, go slow applies in liver disease.Sometimes it may be more predictable to useglucuronidated rather than oxidized drugs,e.g. lorazepam rather than diazepam, orchange to a renally eliminated drug e.g. frommetoprolol to atenolol.

Dosing in liver disease (if [albumin]

process is not restricted by protein bind-ing because it is so rapid that drug is easily removed from the protein-bindingsite. There is also a pathway for basic drugs, e.g. digoxin, dependent on a carrier proteincalled P-glycoprotein. This is the site of thedigoxinquinidine interaction. An increas-ing number of drugs are observed to com-pete at the P-glycoprotein pathway. Activetransport enables renal clearance to be largerthan the GFR, and theoretically as large asrenal blood ow (up to 1500 mL/min).

Reabsorption

Passive reabsorption can occur in the renaltubules. This follows standard principles ofdiffusion a i.e. depends on concentrationgradient, lipid solubility, and sometimes urin-ary pH (see pH and Pharmacokinetics, page16). Active reabsorption can occur, e.g. pro-benecid inhibits the reabsorption of uric acid.

Drug clearance and renal function

For drugs excreted entirely through the kidneys unchanged drug clearance varies inproportion to creatinine clearance (CrCl).

Drug Cl CrCl

Fraction excreted unchanged (fu)

The fu is the index describing the fractionexcreted unchanged through the kidneys.An fu = 1 describes a drug totally clearedrenally unchanged. An fu = 0 describes adrug without renal elimination. An fu some-where in between (e.g. 0.5) describes mixedelimination.

Factors affecting dosing Renal Drug Elimination

28

2

Renal Drug Elimination

For drugs that are not metabolized and are cleared renally unchanged

Drug CI CrCl

Some drugs, e.g. digoxin, are cleared almostentirely unchanged through the kidneys.Others, e.g. phenytoin, are cleared entirelyby metabolism. Some prodrugs, e.g. enala-pril, are converted to active metabolites thatare cleared unchanged through the kidneys.Other drugs may be cleared by a combina-tion of the above processes.

Renal clearance of drugs

Glomerular filtration

Drugs pass through the glomerulus wheretheir non-protein-bound component (i.e.free drug) equilibrates across the glomerularmembrane. Maximum drug clearance viaglomerular ltration alone is therefore equalto the glomerular ltration rate (GFR), i.e.around 1.5 mL/s. Protein binding restrictsclearance in proportion to the percentageprotein bound, i.e. if protein drug binding is50%, then drug clearance via glomerularltration is 50% of the GFR.

Active secretion

Drug not cleared by glomerular ltrationcontinues in the blood to the capillaries ad-jacent to the proximal renal tubules. Someacids (e.g. penicillins, NSAIDs, probenecid,methotrexate) are actively transported fromthe blood to the tubular lumen, and subjectto energy dependence, saturability, competi-tion, and relative substrate specicity. The

ICPC02 21/5/05 12:14 PM Page 28

Renal Drug Elimination Factors affecting dosing

29

Drug elimination entirely unchanged bythe kidney (fu == 1) (e.g. gentamicin)

For a drug with fu = 0.5, 50% of the drug isexcreted unchanged through the kidneys. IfCrCl is half normal, that fraction of the doseshould be halved. The metabolized fractionis unaffected, so the total dose should be75% of normal.

2

Creatinine clearance

Drug Cl

For these drugs, doses should be reduced indirect proportion to the degree of impair-ment in CrCl. For example, if CrCl is halfnormal, dose should be half normal.

Drugs eliminated entirely by metabolism(fu == 0) (e.g. phenytoin)

Creatinine clearance

Drug Cl

No dose reduction is necessary in renalimpairment.

Drug eliminated by both metabolism and by renal elimination (e.g. fu == 0.5)(e.g. captopril)

Creatinine clearance

Drug Cl

ICPC02 21/5/05 12:14 PM Page 29

Factors affecting dosing Dosing in Renal Impairment

30

2

* Cockcroft DW, Gault MH. Prediction of creatinineclearance from serum creatinine. Nephron 1976, 16:3141.

Dosing in RenalImpairment

Drugs excreted unchanged through the kidneymay need dose alteration in renal impairment

Whenever any active drug moiety is excretedrenally unchanged, dose adjustment in rela-tion to renal function may be necessary,especially if the drug has a low therapeuticindex.

Dose adjustment in renalimpairment

1 Check fu of drug or active metaboliteexcreted unchanged renally (see Table).2 Calculate CrCl using an equation such asthe Cockcroft & Gault equation* which takesinto account the patients age, weight andsex [use of serum Cr alone is not accurate].

NB: (a) Multiply by 0.85 for females(because of decreased muscle mass)(b) If patient is obese, use ideal body weight,or an approximation of this(c) Replace 50 000 by 815 for CrCl inmL/min

CrCl(mL/s)

age wt[kgCr](mmol/L)

( ) ]

[=

14050 000

(d) The equation is not valid for children1.5 mL/s(f) If [Cr] is

Dosing in Renal Impairment Factors affecting dosing

31

Drugs which may require dose-adjustment in renal impairment.

Low therapeutic index(and fu > 0.5)(Dose-adjustment essential)

Drug fu

Aminoglycosidesgentamicin 0.9tobramycin 0.9netilmicin 0.9

Cytotoxicscisplatin 0.9carbiplatin 0.9methotrexate 0.90.5**flucytosine 0.95

ACE inhibitorslisinopril 0.9enalapril* (enalaprilat) 0.9quinapril* (quinaprilat) 0.9cilazapril* (cilazaprilat) 0.9ramipril* (ramiprilat) 0.9captopril 0.5

Otherdigoxin 0.8allopurinol* (oxypurinol) 0.8lithium 1.0vancomycin 0.9metformin 0.9vigabatrin 0.6

* metabolite with high fu; ** less with higher doses.

2

High therapeutic index(and fu > 0.7)(Dose-adjustment may decrease side effects)

Drug fu

b-Blockersatenolol 0.9nadolol 0.75sotalol 0.9bisoprolol 0.6

Penicillinsbenzylpenicillin 0.9amoxycillin 0.9(clavulanate) 0.5flucloxacillin 0.7dicloxacillin 0.7piperacillin 0.8

Cephalosporinscephalothin 0.75cefuroxime 0.9cefaclor 0.7cefoxitin 0.8cephazolin 0.9

H2-Antagonistscimetidine 0.7ranitidine 0.7famotidine 0.7

Otheraciclovir 0.7amantadine 0.9baclofen 0.8dalteparin 0.7fluconazole 0.8pethidine (norpethidine) 0.9

ICPC02 21/5/05 12:14 PM Page 31

Factors affecting dosing Dosing in the Elderly

32

2

Dosing in the Elderly

Physiological function declines with age

More than 90% of the elderly population(>65 yrs) receive prescription medicines andit is estimated that 30% of these patients suffer from adverse drug reactions (cf. 10%of patients aged 2030 years).

Elderly patients are not the same as theyounger population in their response to andhandling of drugs. Pharmacokinetics andpharmacodynamics may both be altered inthe elderly patient.

Pharmacokinetics

Clearance (Cl): this is by far the most import-ant parameter with respect to dosing. Bothrenal and liver clearance decline with age.

Renally eliminated drugs (i.e. large fu)

Drug Cl of drugs with high fu is consistently impaired in the elderly

The principles outlined in Dosing in RenalImpairment, see page 30, apply. The elderlypatient may have a normal serum creatinine[Cr] but the CrCl may be considerably im-paired. This is because [Cr] is a reection of both production (from muscles) and eli-mination through the kidneys. Productionof creatinine is considerably lower in theelderly than in t young adults. The Cock-croft & Gault equation adjusts for age andweight to allow for the decrease in creatinineproduction.

0.85 (in females because of a higher ratioof fat to lean body weight).

CrCl(mL/s)age wt[kg

Cr](mmol/L)

( ) ] [

=

14050000

The dose-rate (DR) is then calculated as inrenal impairment:For drugs with fu close to 1

For drugs with fu >0.5 but

Dosing in the Elderly Factors affecting dosing

33

The half-life (t1/2): The t1/2 is often pro-longed in the elderly. Longer t1/2 means thatthe time to steady-state is longer, drug elim-ination takes longer, and dose-intervals maybe longer. Often a longer half-life can beused to advantage if it allows for a once dailyor twice daily regimen instead of three orfour times daily.

Pharmacodynamics

Homeostatic adaptation is less efcient andtarget organ sensitivity may be altered in theelderly.

Homeostatic responses tend to be blunted,e.g. orthostatic hypotension is more pro-nounced in elderly patients due to a reducedability of the baroreceptors to compensatefor changes in blood pressure.

Target organ sensitivity is often altered (usually blunted). Alterations in receptorfunction may occur with age, e.g. im-pairment of cholinergic and adrenergic function.

2

Enhancing compliance (see Compliance with Medication, page 76)

It is especially useful in the elderly to followall the rules for enhancing compliance.Economy in the use of drugs, single-doseregimens, once or twice daily dosing, clearinstructions and the use of compliance aidscan enhance therapeutics markedly. Com-pliance aids include cards listing all thedrugs and their dosing regimens, patient in-formation leaets and unit dose packaging.

General guidelines1 Consider dosing reduction in patients over 55 yrs2 Use estimate of CrCl to adjust dose of drugs with high fu3 Start low, go slow for metabolized drugs4 Aim for twice or once daily dosing5 Monitor more frequently, especially for drugs with a low therapeutic index6 Use as few drugs as possible7 Provide a card listing the patients drugs and dose regimen8 Give patient information leaflets if available9 Consider unit dose packaging

ICPC02 21/5/05 12:14 PM Page 33

e.g. theophylline (p450 oxidation)chloramphenicol (glucuronidation)gentamicin (glomerular ltration)

These are all impaired in the neonate.

Approximate values of Cl at different ages.

Post-conceptual age Cl (cf adults)

2428 weeks 5%2834 weeks 10%3440 weeks 33%4044 weeks 50%4468 weeks 66%>68 weeks 100%

Volume of distribution (Vd): The infant hasmore body water and less fat than an adultas a percentage of total weight, i.e. up to85% water in the premature neonate (cf60% in an adult). The Vd is thereforeincreased for water soluble drugs anddecreased for lipid soluble drugs. However,these effects are small compared with thechanges in Cl in this age group, and dose-adjustment, if any, is small.

Protein binding (PB): PB is decreased inneonates due to decreased albumin, de-creased binding capacity and the presence of displacers such as free fatty acids andbilirubin. However, this has little signic-ance apart from in the interpretation of drug concentrations (see Protein Binding,page 14).

Drug availability: The extent of oral availab-ility is not altered signicantly. Skin absorp-tion of some compounds may be enhancedbecause of a thinner stratum corneum, and ahigher degree of hydration of the skin. Drugsshould be applied sparingly.

Factors affecting dosing Dosing in Children

34

2

Dosing in Children

A child is not a little adult

The seven ages of pharmacological manPremature neonate 24/4040/40Neonate 02/12Infant 2/121 yearChild 112 yearsAdolescent 1220 yearsAdult 2065 yearsAged >65 years

There are seven distinct age groups that areassociated with different drug Cl and hencedosing requirements. Note that four of theseages are related to the paediatric age group.This reects that the child is a continuallychanging pharmacokinetic and pharmaco-dynamic environment. The younger the child,the greater the rate of change.

Dosing in children under 6 months of ageis very complicated a specialist advice isusually needed.

Pharmacokinetics

Clearance (Cl): The major mechanisms ofdrug elimination begin to develop duringfetal life and continue to develop postpartum.Functional maturity is reached between 6months and 1 year of age. After this, Cl isactually greater than that of adults on a mg/kg basis. It then relates better to surface area.

The major metabolic pathways, p450 oxi-dation and glucuronidation, and the renalpathways, all mature at a similar rate andcan be considered together in their effects ondrug Cl and dosage.

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Dosing in Children Factors affecting dosing

35

2

2 Without nomograms:A useful guide is:

Body weight (kg) SA

10 0.520 0.7530 1.040 1.25

Interpolate and extrapolate as necessary anduse in above equation.3 Using a calculator:

In the absence of an estimate of surfacearea, an adjusted body weight can be used asfollows:

This equation is derived from the fact thatweight to the power of 0.7 (wt0.7) relates bet-ter to surface area than to weight alone.

Maintenance doseWt[kg]

70adult dose

0.7

=

Pharmacodynamics

Paediatric patients may be more sensitive to the effects of some drugs, e.g. aspirin toxicity. The bloodbrain barrier is slow to develop enabling enhanced CNS effectswith some drugs, e.g. increased transport of bilirubin into the brain may result in kernicterus. There may be paradoxical reac-tions, e.g. stimulation with benzodiazepines;control of hyperactivity with amphetamines.

Dosing guidelines

Under 6 months

Specialist advice necessary.

6 months12 years

Use surface area (SA) approach1 Using nomograms:

Read SA from a nomogram

Maintenance dose

SA[m ]

1.73 madult dose

2

2 =

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(a) Teratogenicity: This is difcult to predictprior to marketing. Information comes fromretrospective studies and/or animal data(often unreliable). The FDA classify drugs (see below), in increasing order of potentialtoxicity.(b) Pharmacological risks: These are risksthat are generally predictable based on theknown pharmacology of the drug, e.g.NSAIDs may cause premature closure of theductus arteriosus in the latter stages of preg-nancy (patency requires the presence ofprostaglandins).

At term, excessive effects (e.g. tricyclics)and withdrawal syndromes (e.g. opiates,selective serotonin reuptake inhibitors[SSRIs]) may be seen in neonates followingmaternal use.

Effects of pregnancy on drugs

Clearance (Cl): Pregnancy is generally ahyperdynamic physiological state. Drugclearance may be increased, whether it be viarenal elimination or liver metabolism. Thematernal cardiac output is increased by upto 30% during pregnancy, increasing therenal blood ow and GFR. The hormonalstate in pregnancy is also associated withenzyme induction of some drugs. Main-tenance doses of drugs often need to be

Factors affecting dosing Drugs in Pregnancy

36

2

Category A Controlled studies in animals and women have not shown risk. Category B Animal studies have not shown risk but there are no controlled studies in pregnantwomen or animal studies have shown risk but controlled studies in women have not. (e.g. paracetamol,-lactams, methyldopa, NSAIDs [NSAIDs not safe in 3rd trimester]). Category C Animal studies have shown risk but studies in women have not done so. (e.g.antipsychotics, most cardiac medicines, laxatives, antihistamines). Category D Positive evidence of some human risk exists but benefits may in some circumstancesoutweigh risk. (e.g. anticonvulsants, ethanol, warfarin, antidepressants, tetracyclines, diuretics, lithium). Category X Too dangerous contraindicated. (e.g. thalidomide, vitamin A analogues, somecytotoxics).

Drugs in Pregnancy

All drugs pass across the placenta to some extent, and therefore some fetal exposure will occur

Up to 95% of women take four or moredrugs (not counting vitamin supplements) atsome stage during pregnancy.

There are two major considerationsregarding drugs in pregnancy.1 The effects that the drugs have on the pregnancy.2 The effects that the pregnancy has on thedrugs.

Effects of drugs on the pregnancy

The majority of drugs attain concentrations inthe fetus similar to those of maternal plasma.

It is important to remember that approx-imately 35% of all live births are associatedwith a fetal abnormality. Drugs are thoughtto be responsible for only 15% of these (i.e.0.030.25% of all malformations). Associ-ation does not necessarily imply causation.

Exposure during the rst 16 weeks ofpregnancy is associated with an increasedincidence of physical malformations. How-ever, less obvious effects such as decreasedneuronal function or impaired intellectualdevelopment may occur following exposureat any time during pregnancy.

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Drugs in Pregnancy Factors affecting dosing

37

increased during pregnancy, to compensatefor increased Cl.

Volume of distribution (Vd): Vd may beincreased by ~20% for both lipid- andwater-soluble drugs. Increased loading dosesmay be required because of an increase inboth body fat and water.

Protein binding (PB) [see page 14]: Maternalalbumin concentrations decrease through-out pregnancy to a low at term. Measureddrug concentrations of highly protein-bound drugs (e.g. phenytoin) may be lower,but this is usually unimportant, as free concentrations are not affected (see Protein

2

Drugs associated with teratogenicity.

Drug Outcome

Alcohol Fetal alcohol syndromeAnticonvulsants

carbamazepine Fetal carbamazepine syndrome similar to fetal hydantoin syndrome microcephaly, short nose

phenobarbitone Similar to fetal hydantoin syndromephenytoin Fetal hydantoin syndrome

impaired growth, craniofacial defects, mental deficiency, hypoplastic phalanges/nails

sodium valproate Neural tube defectsAntithyroid drugs Goitre, hypothyroidismCytotoxics Multiple abnormalities, especially craniofacial/skeletalDiethylstilboestrol Masculinized genitalia

Vaginal adhesions/carcinomaLithium Ebsteins anomaly (structural cardiac deformity)Penicillamine Skin hyperelasticityTetracyclines Tooth staining in offspringThalidomide Phocomelia (limb reduction defects)Vitamin A derivatives

retinoic acid Spontaneous abortiontretinoin Craniofacial abnormalitiesetretinate

Warfarin Fetal warfarin syndrome skeletal abnormalities hypoplastic nose

Binding, page 14). Assessment requires specialist advice.

The risk/benefit ratio must be considered when drugs are used in pregnancy

General advice

1 Avoid all drugs if possible, includingsocial drugs (e.g. smoking, alcohol, caffeine)2 Avoid drugs in the rst trimester3 Choose drugs of proven safety or leasttoxicity4 Use short courses and the smallest doses.

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Factors affecting dosing Drugs in Human Milk

38

2

Drugs in Human Milk

All drugs diffuse into breast milk to some extent it is the extent that is important

Infant exposure to drugs during breast feeding is almost always less than

exposure during pregnancy

The infant derives no benefit from the drug an innocent bystander

Most drugs pass into milk by passive diffu-sion of the free (unbound) and unionizedform. They are distributed within the aque-ous, protein and lipid phases of milk. Milkcontains more fat and less protein thanblood. Therefore drugs that are highly lipid soluble, with low protein binding, and unionized at physiological pH achievehigher concentrations in milk. Few drugshave concentrations in milk higher thanthose of maternal plasma.

The risk to the infant of medicine ingestedvia maternal milk may be considered fromthree viewpoints.1 The dose of medicine ingested by theinfant.2 The resulting infant plasma concentration.3 The potential toxicity of that con-centration.

The dose ingested by the infant

The most commonly used index that enablesthe dose to be calculated is the milk/plasmaratio (M/P). The most valid M/P ratio is thatbased on the AUC of drug in milk comparedwith the AUC in maternal plasma (i.e.M/PAUC). The M/P ratio enables the concen-tration of the drug in milk to be estimatedfrom knowledge of the maternal plasmaconcentration (Cmat).

The infant dose can be estimated from thematernal plasma concentration, the M/Pratio and the volume of milk (Vmilk) ingested(150 mL/kg/day).

Doseinfant = Cmat * M/P * Vmilk

A better index of dose is the actual amountof drug present in the milk over the maternaldosage interval.

The infant dose can be put into clinicalperspective by comparison with the mater-nal dose (mg/kg), or with doses used thera-peutically in the infant.

The weight-adjusted maternal dose(WAMD) is the dose the infant receives viamilk, compared with the mothers dose, corrected for respective weights. It is usuallyexpressed as a percentage, which if

Drugs in Human Milk Factors affecting dosing

39

Post-conceptual age Cl (cf adults)

2428 weeks 5%2834 weeks 10%3440 weeks 33%4044 weeks 50%4468 weeks 66%>68 weeks 100%

The potential toxicity of the drug in the infant

Breast-feeding during maternal ingestion ofeven small amounts of some very toxic drugs(e.g. antineoplastic drugs), is probably not

2

wise even if the likely concentration in theinfant is low. For other drugs, an arbitrarydecision has to be made as to safe concen-trations in the infant. Predicted infantplasma concentrations of 10% of maternalconcentrations are a useful cut-off point.

General advice regarding drugs in milk1 Avoid drugs if possible2 Weigh up the risk/benefit ratio3 Exercise more caution with toxic agents4 Feed baby just prior to the next dose5 Alternate breast feeding with bottle feedingto decrease possible exposure

Drugs considered to be safe when breast-feeding full-term healthy babies. (This table is a guideonly, consult experts readily.)

Drug classes Individual drugs

ACE inhibitors aciclovir mebendazoleAntihistamines 5-aminosalicylic acid methadoneBenzodiazepines carbamazepine methyldopab-lactam antibiotics chlorothiazide metoprololCalcium antagonists citalopram moclobemideOral contraceptives clarithromycin morphineNSAIDs (except piroxicam) codeine nefopamPhenothiazines cotrimoxazole nitrofurantoinTricyclic antidepressants digoxin paracetamol

domperidone paroxetineerythromycin phenytoinfamotidine propranololheparin trimethopriminsulin valproic acidlabetalol warfarinlignocaine

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Drugs considered to be unsafe during breast-feeding.

AmiodaroneAntineoplastic drugsErgotamineFluoroquinolonesImmunosuppressantsIodine-containing agentslithiumRetinoidsTetracyclinesSocial drugs, e.g. alcohol, cannabis,Illegal drugs

Factors affecting dosing Drugs in Human Milk

2

40

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33 Altered drug effect

Adverse drug reactions, 42Drug-induced allergy, 44Adverse drug events, 46Preventing adverse drug events, 48Drug/drug interactions, 50Inducers of drug metabolism/inhibitors of drug metabolism, 52Drug/food interactions, 54

ICPC03 21/5/05 12:14 PM Page 41

slow hydroxylator a perhexiline peri-pheral neuropathy saturable kinetics a phenytoin ataxia drug interactions a erythromycin/ter-fenadine torsades de pointes.

Pharmacodynamic mechanisms: Some pati-ents experience a type A ADR at a normalconcentration, while others do not, reect-ing natural variability. Similarly, underlyingdisease may shift the concentrationresponsecurve to favour an ADR at a normal concentration, e.g. sedation in hepaticencephalopathy.

Prevention

Take a careful history for predisposingfactors. Use as small a dose as possible commen-surate with desired effect. Adjust dosage to therapeutic end-points,e.g. BP or INR. Adjust dosage to optimum plasma con-centrations, e.g. digoxin. Adjust dosage in relation to renal func-tion, hepatic function, other disease states,or other drugs.

Management

Decrease dose Substitute drug with different pharma-cokinetics (e.g. metoprolol (metabolized) byatenolol (renally cleared)) Consider alternative route of administra-tion (e.g. transdermal vs oral) Substitute a more specic agent (e.g.moclobemide for tranylcypromine) Add drugs (carefully) to antagonizeunwanted effects (e.g. addition of decar-boxylase inhibitor to levodopa therapy (e.g.Sinemet, Madopar)

Altered drug effect Adverse Drug Reactions

42

3

Adverse Drug Reactions

An ADR is any response to a drug which isnoxious, unintended, and occurs at doses usedin man for prophylaxis, diagnosis or therapy.

WHO, 1976

Adverse drug reactions (ADRs) are a signi-cant cause of morbidity and mortality andare responsible for around 5% of hospitaladmissions. Patients predisposed to ADRsare the elderly, females, and those with mul-tiple disease, taking other drugs, and with ahistory of previous adverse reactions.

Classification

Type A (Augmented) Type B (Bizarre)Predictable UnpredictableDose-dependent Dose-independentHigh incidence Low incidence

(90% ADRs) Often seriousMay respond to Generally need

dose adjustment to stop drug

Type A (Augmented)

These reactions are predictable from theknown pharmacology of the drug. They mayresult from an excessive desired response(e.g. hypotension from an antihypertensive)or non-specicity (e.g. anticholinergic effectswith tricyclic antidepressants).

Pharmacokinetic mechanisms: Any patientwith higher plasma concentrations thanusual, due to inappropriate dosage or im-paired clearance, is liable to type A adversereactions. Examples are: renal dysfunction a aminoglycosidenephro/ototoxicity hepatic failure a prolonged sedation withbenzodiazepines slow acetylator a isoniazid peripheralneuropathy

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Adverse Drug Reactions Altered drug effect

43

Add another drug to allow reduced dose(e.g. diuretics + -blockers).

Type B (Bizarre)

These are less common, less predictable, maybe severe and result from various mechan-isms. Examples are: immunologic a penicillin allergy pseudoallergy a asthma with NSAIDs genetic a haemolysis in G6PDdeciency disease a amoxycillin rash in glandularfever idiosyncratic a malignant hyperpyrexiain anaesthesia.

Prevention

Take a careful drug history, especially ofallergies Family history a allergies and genetic disease Avoid drugs susceptible to ADRs in par-ticular disease states, e.g. clozapine in bonemarrow depression.

Management

Stop drug and treat symptomatically Avoid drugs with chemically similargroups, e.g. sulphonylureas and thiazidediuretics

Do not rechallenge Notify CARM (Centre for Adverse Reac-tion Monitoring) Consider a Medic-Alert bracelet.

Assessing an ADR

The probability increases if the reaction: is appropriate to timing of drug adminis-tration follows a recognized pattern of response disappears on withdrawal of the drug reappears on rechallenge with drug responds appropriately to a specic antidote has happened before with the same or likedrug is supported by measured toxic concen-trations cannot be explained otherwise.

Reporting an ADR (to centre of adverse reactions)

The following information is needed: Case identication and patient data Description of ADR and its outcome Patients diagnosis Concomitant drugs Predisposing/contributing factors Estimation of probability of drug causingthe ADR The reporting doctor/pharmacist.

3

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Type III (immune complex)

Mediated by IgG immune complexes andcomplement. The immune complexes blocksmall blood vessels and cause a local inam-matory response. Serum sickness (urticaria,arthralgia, lymphadenopathy and fever), is aclassical presentation (e.g. serum sicknessdue to sulphonamides or penicillins).

Extreme form a StevensJohnson syn-drome.

Type IV (cell mediated)

Mediated by T-lymphocytes and macro-phages. Sensitized cells release cytokines oncontact with antigen (e.g. contact dermatitisby poison ivy).

Drug-induced autoimmune disease

This is not conveniently classiable into theabove. The drug alters a protein in the bodyso that the protein is no longer recognized asself (e.g. drug-induced SLE).

Pseudoallergic reactions(anaphylactoid)

These are sometimes indistinguishable clin-ically from type I reactions. They are, how-ever, mediated pharmacologically and notimmunologically (e.g. aspirin and NSAIDsin asthma). The fact that they do not occur ineveryone indicates some predisposition (e.g.genetic). This is why this type of reaction isconsidered to be type B rather than type A.Cross-sensitivity occurs with drugs whichhave the same action, but not structure, cf.true allergy.

Altered drug effect Drug-Induced Allergy

44

3

Drug-Induced Allergy

Drug allergy is an adverse reaction, type B,mediated by an immunological mechanism

Drug-induced allergy results from previoussensitization to a particular chemical, or onethat is structurally similar. The term hyper-sensitivity is sometimes used for allergybut has a broader meaning. Drug allergy isunder-recognized, under-reported and pro-bably represents about 20% of ADRs.

Most drugs have small molecular weights(often ~300 D) and are too small to be anti-genic in themselves. They act as haptens,binding to endogenous proteins to formantigenic complexes that incite antibodyproduction. This process usually takes 12weeks. Reexposure to the chemical results inan antigenantibody interaction that pro-vokes the typical manifestations of allergy arelease of mediators (e.g. histamine) celldamage or cell death.

Types of allergic reactions

Type I (immediate, anaphylactic)

Mediated by IgE and involves release of histamine, leukotrienes and prostaglandinscausing vasodilation, oedema and a general-ized inammatory response (e.g. anaphylaxis,urticaria and bronchospasm due to penicillin).

Type II (cytotoxic)

Mediated by IgG and IgM through comple-ment activation. The major targets are cellsin the circulatory system (e.g. penicillinhaemolytic anaemia, quinidine thrombocy-topenia, sulphonamide neutropenia).

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Drug-Induced Allergy Altered drug effect

45

Important points about drug-induced allergy

May be due to the drug itself, a metabo-lite, or an excipient in the formulation. Usually highly specic to a chemical, butthere may be cross-reactivity within a drugclass, e.g. penicillins ~50% chance. The probability of cross-reactivity withchemically unrelated drugs is low. Patients with atopy may be predisposed totype I reactions. Many patients develop antibodies todrugs, but only a few develop clinically evid-ent allergy. There is no correlation with known phar-macological properties of the drug. There is no consistent relationship withdrug dose (although severity varies with dose). Usually resolves on cessation of drug. Reappears on rechallenge (often worse). Short-term desensitization is sometimespossible. It is unclear how long allergy may last,?life-long, ?1020 years. Assessment as for ADRs (page 42).

Percutaneous testing

Skin testing is theoretically attractive but hasproblems: May cause a severe reaction. False positives: Some drugs cause skin irritation, resembling wheal and are (e.g.

morphine). Others may sensitize topicallywithout a systemic reaction (e.g. musclerelaxants). False negatives: Some drugs may not reacttopically, while producing a reaction sys-temically, e.g. allergy due to the metaboliterather than the drug (e.g. penicillin).

Prevention

Avoid the use of drugs where cross-sensit-ivity is likely, especially if previous reactionto a chemically similar drug was severe. Use a small test dose. Have treatment ready, e.g. adrenaline,antihistamine, steroids.

For example, if a patient about to betreated reports an allergy to penicillin, it isimportant to determine what reaction actu-ally occurred (e.g. mild rash versus anaphy-laxis), and how long ago it happened. Thiswill help decide whether a penicillin or other-lactam (e.g. cephalosporin) could be usedif they are drugs of choice for the condition.If the previous reaction was anaphylaxis,then both penicillins and cephalosporins(reported 510% cross-sensitivity) would becontraindicated. If, however, the previousreaction was minor, then a cephalosporin,or even a penicillin, might be considered rea-sonable. Of course in these circumstances asmall test dose should be used, and treat-ment (e.g. adrenaline) should be readilyavailable.

3

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Altered drug effect Adverse Drug Events

46

3

Adverse Drug Events

An adverse drug event (ADE) is actual orpotential damage resulting from medical

intervention related to medicines

Terminology is a problem here, because ofconfusion with adverse drug reactions (ADR)(see page 42). Other terms such as medica-tion error have been used but adverse drugevent (ADE) seems to have been adopted themost widely. ADE covers a wider spectrumthan adverse drug reaction and involves doctors, pharmacists, nurses, caregivers andpatients themselves. Omitting a dose is anADE, while a rash is an ADR.

What comprises an ADE?

Prescribing error: incorrect drug selection incorrect dose or frequency incorrect route of administration inappropriate duration of therapy incorrect prescription incomplete prescription illegible prescription unforeseen drug interaction.

Medication error: transcription error dispensing error infusion error failure to uplift prescription non-compliance inadequate monitoring.

Why are ADEs important?

ADEs are common and result in signicantmorbidity and mortality. Alarming statisticsfrom the US, UK and Australia suggest thatADEs may be one of the leading causes ofdeath (behind heart disease, cancer andstroke). The cost of this is huge and the incid-

ence is increasing. More important, how-ever, is that most of these are preventable.

Why do ADEs occur?

ADEs are primarily a result of system problems, not people problems.

Dr Lucian Leape, Harvard School of Public Health

On the surface ADEs appear to be the resultof human error. However human errorabounds when systems predispose.

Major systems failures: (from JAMA, 1995;274: 3543). The following are responsiblefor over 70% of errors: Lack of knowledge about drugs e.g. failureto recognize that a drug is renally cleared. Lack of information about patient e.g.failure to recognize that a patient has renalfailure. Violation of rules: e.g. incomplete pre-scription such as route not stated. Slips and memory lapses e.g. doctor for-gets to prescribe post-op analgesia. Transcription errors e.g. wrong dose. Faulty drug identication e.g. moclobe-mide for metoclopramide.

Preventing errors

Efforts that focus on the individual whomade the error (shoot the messenger) areusually unfruitful. The essence is to alter systems to minimize the chance of errorsoccurring. Each of the above system failuresshould be addressed. Drug knowledge: Information about allaspects of the drug prole must be readilyavailable at the time the drug is prescribed/used.

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Adverse Drug Events Altered drug effect

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Patient information: Clinical informa-tion, results of laboratory tests, drug historyand allergies, current medications and dosesmust be accessible and known at the time ofusing the drug. Following the rules: Poor prescribingshould not be tolerated and covered for bypharmacists. Quality assurance programswith feedback can assist. See PreventingAdverse Drug Events, page 48. Slips and memory lapses: Excessive work-loads should be avoided. Quality assurance

programs with no blame should be encouraged. Transcription errors: Single point of dataentry should be encouraged. Drug identity: Avoid illegibility e.