A Textbook of

Clinical Pharmacology

and Therapeutics

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A Textbook of

Clinical Pharmacology

and Therapeutics

FIFTH EDITION

JAMES M RITTER MA DP HIL FRCP FMedSciFBPHARMACOLS

Professor of Clinical Pharmacology at King’s College London School of Medicine,

Guy’s, King’s and St Thomas’ Hospitals, London, UK

LIONEL D LEWIS MA MB BCH MD FRCP

Professor of Medicine, Pharmacology and Toxicology at Dartmouth Medical School and

the Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA

TIMOTHY GK MANT BSC FFPM FRCP

Senior Medical Advisor, Quintiles, Guy's Drug Research Unit, and Visiting Professor at

King’s College London School of Medicine, Guy’s, King’s and St Thomas’ Hospitals,

London, UK

ALBERT FERRO PHD FRCP FBPHAR MACOLS

Reader in Clinical Pharmacology and Honorary Consultant Physician at King’s College

London School of Medicine, Guy’s, King’s and St Thomas’ Hospitals, London, UK

PART OF HACHETTE LIVRE UK

First published in Great Britain in 1981

Second edition 1986

Third edition 1995

Fourth edition 1999

This fifth edition published in Great Britain in 2008 by

Hodder Arnold, an imprint of Hodden Education, part of Hachette Livre UK,

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going to press, neither the authors nor the publisher can accept any legal responsibility or liability

for any errors or omissions that may be made. In particular, (but without limiting the generality

of the preceding disclaimer) every effort has been made to check drug dosages; however it is

still possible that errors have been missed. Furthermore, dosage schedules are constantly being

revised and new side-effects recognized. For these reasons the reader is strongly urged to consult

the drug companies’ printed instructions before administering any of the drugs recommended in

this book.

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CONTENTS

FOREWORD viii

PREFACE ix

ACKNOWLEDGEMENTS x

PART I GENERAL PRINCIPLES 1

1 Introduction to therapeutics 3

2 Mechanisms of drug action (pharmacodynamics) 6

3 Pharmacokinetics 11

4 Drug absorption and routes of administration 17

5 Drug metabolism 24

6 Renal excretion of drugs 31

7 Effects of disease on drug disposition 34

8 Therapeutic drug monitoring 41

9 Drugs in pregnancy 45

10 Drugs in infants and children 52

11 Drugs in the elderly 56

12 Adverse drug reactions 62

13 Drug interactions 71

14 Pharmacogenetics 79

15 Introduction of new drugs and clinical trials 86

16 Cell-based and recombinant DNAtherapies 92

17 Alternative medicines: herbals and

nutraceuticals 97

PART II THE NERVOUS SYSTEM 103

18 Hypnotics and anxiolytics 105

19 Schizophrenia and behavioural emergencies 110

20 Mood disorders 116

21 Movement disorders and degenerative CNS

disease 124

22 Anti-epileptics 133

23 Migraine 142

24 Anaesthetics and muscle relaxants 145

25 Analgesics and the control of pain 155

PART III THE MUSCULOSKELETAL SYSTEM 165

26 Anti-inflammatory drugs and the treatment

of arthritis 167

PART IV THE CARDIOVASCULAR SYSTEM 175

27 Prevention of atheroma: lowering plasma

cholesterol and other approaches 177

28 Hypertension 185

29 Ischaemic heart disease 196

30 Anticoagulants and antiplatelet drugs 204

31 Heart failure 211

32 Cardiac dysrhythmias 217

PART V THE RESPIRATORY SYSTEM 231

33 Therapy of asthma, chronic obstructive pulmonary

disease (COPD) and other respiratory disorders 233

PART VI THE ALIMENTARY SYSTEM 245

34 Alimentary system and liver 247

35 Vitamins and trace elements 265

PART VII FLUIDS AND ELECTROLYTES 271

36 Nephrological and related aspects 273

PART VIII THE ENDOCRINE SYSTEM 283

37 Diabetes mellitus 285

38 Thyroid 292

39 Calcium metabolism 297

40 Adrenal hormones 302

41 Reproductive endocrinology 307

42 The pituitary hormones and related drugs 316

PART IX SELECTIVE TOXICITY 321

43 Antibacterial drugs 323

44 Mycobacterial infections 334

45 Fungal and non-HIV viral infections 340

46 HIV and AIDS 351

47 Malaria and other parasitic infections 361

48 Cancer chemotherapy 367

PART X HAEMATOLOGY 387

49 Anaemia and other haematological disorders 389

PART XI IMMUNOPHARMACOLOGY 397

50 Clinical immunopharmacology 399

PART XII THE SKIN 409

51 Drugs and the skin 411

PART XIII THE EYE 421

52 Drugs and the eye 423

PART XIV CLINICAL TOXICOLOGY 431

53 Drugs and alcohol abuse 433

54 Drug overdose and poisoning 444

INDEX 451

John Trounce, who was the senior author of the first edition of this textbook, died on the

16 April 2007.

He considered a text in clinical pharmacology suitable for his undergraduate and postgradu-

ate students to be an important part of the programme he developed in his department at

Guy’s Hospital Medical School, London. It is difficult to imagine today how much resistance

from the medical and pharmacological establishments Trounce had to overcome in order to set

up an academic department, a focussed course in the medical curriculum and a separate exam

in final MB in clinical pharmacology. In other words, he helped to change a ‘non-subject’ into

one of the most important areas of study for medical students. He was also aware of the need

for a high quality textbook in clinical pharmacology that could also be used by nurses, phar-

macists, pharmacology science students and doctors preparing for higher qualifications. (For

example, it has been said that nobody knows more about acute pharmacology than an

anaesthetist.)

The present edition of the textbook reflects the advances in therapeutics since the publica-

tion of the fourth edition. It is interesting to follow in all the editions of the book, for example,

how the treatment of tumours has progressed. It was about the time of the first edition that

Trounce set up the first oncology clinic at Guy’s Hospital in which he investigated the value of

combined radiation and chemotherapy and drug cocktails in the treatment of lymphomas.

John Trounce was pleased to see his textbook (and his subject) in the expert hands of Professor

Ritter and his colleagues.

Roy Spector

Professor Emeritus in Applied Pharmacology, University of London

FOREWORD

Clinical pharmacology is the science of drug use in humans. Clinicians of all specialties pre-

scribe drugs on a daily basis, and this is both one of the most useful but also one of the most

dangerous activities of our professional lives. Understanding the principles of clinical pharma-

cology is the basis of safe and effective therapeutic practice, which is why this subject forms an

increasingly important part of the medical curriculum.

This textbook is addressed primarily to medical students and junior doctors of all special-

ties, but also to other professionals who increasingly prescribe medicines (including pharma-

cists, nurses and some other allied professionals). Clinical pharmacology is a fast moving

subject and the present edition has been completely revised and updated. It differs from the

fourth edition in that it concentrates exclusively on aspects that students should know and

understand, rather than including a lot of reference material. This has enabled us to keep its

length down. Another feature has been to include many new illustrations to aid in grasping

mechanisms and principles.

The first section deals with general principles including pharmacodynamics, pharmaco-

kinetics and the various factors that modify drug disposition and drug interaction. We have

kept algebraic formulations to a minimum. Drug metabolism is approached from a practical

viewpoint, with discussion of the exciting new concept of personalized medicine. Adverse

drug reactions and the use of drugs at the extremes of age and in pregnancy are covered, and

the introduction of new drugs is discussed from the viewpoint of students who will see many

new treatments introduced during their professional careers. Many patients use herbal or

other alternative medicines and there is a new chapter on this important topic. There is a chap-

ter on gene and cell-based therapies, which are just beginning to enter clinical practice. The

remaining sections of the book deal comprehensively with major systems (nervous, musculo-

skeletal, cardiovascular, respiratory, alimentary, renal, endocrine, blood, skin and eye) and

with multi-system issues including treatment of infections, malignancies, immune disease,

addiction and poisoning.

AMES M RITTER

LIONELD LEWIS

TIMOTHYGK MANT

ALBERTFERRO

PREFACE

We would like to thank many colleagues who have helped us with advice and criticism in the

revision and updating of this fifth edition. Their expertise in many specialist areas has enabled

us to emphasize those factors most relevant. For their input into this edition and/or the previ-

ous edition we are, in particular, grateful to Professor Roy Spector, Professor Alan Richens,

Dr Anne Dornhorst, Dr Michael Isaac, Dr Terry Gibson, Dr Paul Glue, Dr Mark Kinirons,

Dr Jonathan Barker, Dr Patricia McElhatton, Dr Robin Stott, Mr David Calver, Dr Jas Gill,

Dr Bev Holt, Dr Zahid Khan, Dr Beverley Hunt, Dr Piotr Bajorek, Miss Susanna Gilmour-

White, Dr Mark Edwards, Dr Michael Marsh, Mrs Joanna Tempowski. We would also like to

thank Dr Peter Lloyd and Dr John Beadle for their assistance with figures.

ACKNOWLEDGEMENTS

PART I

GENERAL PRINCIPLES

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●

Use of drugs 3

●

Adverse effects and risk/benefit 3

●

Drug history and therapeutic plan 4

●

Formularies and restricted lists 4

●

Scientific basis of use of drugs in humans 4

CHAPTER 1

INTRODUCTION TO THERAPEUTICS

USE OF DRUGS

People consult a doctor to find out what (if anything) is wrong

(the diagnosis), and what should be done about it (the treat-

ment). If they are well, they may nevertheless want to know

how future problems can be prevented. Depending on the diag-

nosis, treatment may consist of reassurance, surgery or other

interventions. Drugs are very often either the primary therapy

or an adjunct to another modality (e.g. the use of anaesthetics

in patients undergoing surgery). Sometimes contact with the

doctor is initiated because of a public health measure (e.g.

through a screening programme). Again, drug treatment is

sometimes needed. Consequently, doctors of nearly all special-

ties use drugs extensively, and need to understand the scien-

tific basis on which therapeutic use is founded.

A century ago, physicians had only a handful of effective

drugs (e.g. morphia, quinine, ether, aspirin and digitalis leaf)

at their disposal. Thousands of potent drugs have since been

introduced, and pharmaceutical chemists continue to discover

new and better drugs. With advances in genetics, cellular and

molecular science, it is likely that progress will accelerate and

huge changes in therapeutics are inevitable. Medical students

and doctors in training therefore need to learn something

of the principles of therapeutics, in order to prepare them-

selves to adapt to such change. General principles are dis-

cussed in the first part of this book, while current approaches

to treatment are dealt with in subsequent parts.

ADVERSE EFFECTS AND RISK/BENEFIT

Medicinal chemistry has contributed immeasurably to human

health, but this has been achieved at a price, necessitating a

new philosophy. Aphysician in Sir William Osler’s day in the

nineteenth century could safely adhere to the Hippocratic

principle ‘first do no harm’, because the opportunities for

doing good were so limited. The discovery of effective drugs

has transformed this situation, at the expense of very real risks

of doing harm. For example, cures of leukaemias, Hodgkin’s

disease and testicular carcinomas have been achieved through

a preparedness to accept a degree of containable harm. Similar

considerations apply in other disease areas.

All effective drugs have adverse effects, and therapeutic

judgements based on risk/benefit ratio permeate all fields of

medicine. Drugs are the physician’s prime therapeutic tools,

and just as a misplaced scalpel can spell disaster, so can a

thoughtless prescription. Some of the more dramatic instances

make for gruesome reading in the annual reports of the med-

ical defence societies, but perhaps as important is the morbid-

ity and expense caused by less dramatic but more common

errors.

How are prescribing errors to be minimized? By combining

a general knowledge of the pathogenesis of the disease to be

treated and of the drugs that may be effective for that disease

with specific knowledge about the particular patient. Dukes

and Swartz, in their valuable work Responsibility for drug-

induced injury,list eight basic duties of prescribers:

1. restrictive use – is drug therapy warranted?

2. careful choice of an appropriate drug and dose regimen

with due regard to the likely risk/benefit ratio, available

alternatives, and the patient’s needs, susceptibilities and

preferences;

3. consultation and consent;

4. prescription and recording;

5. explanation;

6. supervision (including monitoring);

7. termination, as appropriate;

8. conformity with the law relating to prescribing.

As a minimum, the following should be considered when

deciding on a therapeutic plan:

1. age;

2. coexisting disease, especially renal and or hepatic

impairment;

3. the possibility of pregnancy;

4. drug history;

5. the best that can reasonably be hoped for in this

individual patient;

6. the patient’s beliefs and goals.

DRUG HISTORY AND THERAPEUTIC PLAN

In the twenty-first century, a reliable drug history involves

questioning the patient (and sometimes family, neighbours,

other physicians, etc.). What prescription tablets, medicines,

drops, contraceptives, creams, suppositories or pessaries are

being taken? What over-the-counter remedies are being used

including herbal or ‘alternative’ therapies? Does the patient

use drugs socially or for ‘life-style’ purposes? Have they suf-

fered from drug-induced allergies or other serious reactions?

Have they been treated for anything similar in the past, and if

so with what, and did it do the job or were there any prob-

lems? Has the patient experienced any problems with anaes-

thesia? Have there been any serious drug reactions among

family members?

The prescriber must be both meticulous and humble, espe-

cially when dealing with an unfamiliar drug. Checking

contraindications, special precautions and doses in a formu-

lary such as the British National Formulary (BNF) (British

Medical Association and Royal Pharmaceutical Society of

Great Britain 2007) is the minimum requirement. The proposed

plan is discussed with the patient, including alternatives,

goals, possible adverse effects, their likelihood and measures

to be taken if these arise. The patient must understand what is

intended and be happy with the means proposed to achieve

these ends. (This will not, of course, be possible in demented

or delirious patients, where discussion will be with any

available family members.) The risks of causing harm must

be minimized. Much of the ‘art’ of medicine lies in the ability

of the prescriber to agree to compromises that are accept-

able to an individual patient, and underlies concordance

(i.e. agreement between patient and prescriber) with a thera-

peutic plan.

Prescriptions must be written clearly and legibly, conform-

ing to legal requirements. Electronic prescribing is currently

being introduced in the UK, so these are changing. Generic

names should generally be used (exceptions are mentioned

later in the book), together with dose, frequency and duration

of treatment, and paper prescriptions signed. It is prudent to

print the prescriber’s name, address and telephone number to

facilitate communication from the pharmacist should a query

arise. Appropriate follow up must be arranged.

FORMULARIES AND RESTRICTED LISTS

Historically, formularies listed the components of mixtures

prescribed until around 1950. The perceived need for hospital

formularies disappeared transiently when such mixtures

were replaced by proprietary products prepared by the

pharmaceutical industry. The BNF summarizes products

licensed in the UK. Because of the bewildering array, includ-

ing many alternatives, many hospital and primary care trusts

have reintroduced formularies that are essentially restricted

lists of the drugs stocked by the institution’s pharmacy, from

which local doctors are encouraged to prescribe. The objec-

tives are to encourage rational prescribing, to simplify pur-

chasing and storage of drugs, and to obtain the ‘best buy’

among alternative preparations. Such formularies have the

advantage of encouraging consistency, and once a decision

has been made with input from local consultant prescribers

they are usually well accepted.

SCIENTIFIC BASIS OF USE OF DRUGS IN

HUMANS

The scientific basis of drug action is provided by the discipline

of pharmacology. Clinical pharmacology deals with the effects

of drugs in humans. It entails the study of the interaction of

drugs with their receptors, the transduction (second messen-

ger) systems to which these are linked and the changes that

they bring about in cells, organs and the whole organism.

These processes (what the drug does to the body) are called

‘pharmacodynamics’. The use of drugs in society is encom-

passed by pharmacoepidemiology and pharmacoeconomics –

both highly politicized disciplines!

Man is a mammal and animal studies are essential, but

their predictive value is limited. Modern methods of molecu-

lar and cell biology permit expression of human genes, includ-

ing those that code for receptors and key signal transduction

elements, in cells and in transgenic animals, and are revolu-

tionizing these areas and hopefully improving the relevance

of preclinical pharmacology and toxicology.

Important adverse effects sometimes but not always occur

in other species. Consequently, when new drugs are used to treat

human diseases, considerable uncertainties remain. Early-phase

human studies are usually conducted in healthy volunteers,

except when toxicity is inevitable (e.g. cytotoxic drugs used

for cancer treatment, see Chapter 48).

Basic pharmacologists often use isolated preparations,

where the concentration of drug in the organ bath is controlled

precisely. Such preparations may be stable for minutes to

hours. In therapeutics, drugs are administered to the whole

organism by a route that is as convenient and safe as possible

(usually by mouth), for days if not years. Consequently, the

drug concentration in the vicinity of the receptors is usually

unknown, and long-term effects involving alterations in receptor

density or function, or the activation or modulation of homeo-

static control mechanisms may be of overriding importance.

The processes of absorption, distribution, metabolism and elim-

ination (what the body does to the drug) determine the drug

concentration–time relationships in plasma and at the recep-

tors. These processes comprise ‘pharmacokinetics’. There is

considerable inter-individual variation due to both inherited

4 INTRODUCTIONTO THERAPEUTICS

and acquired factors, notably disease of the organs responsible

for drug metabolism and excretion. Pharmacokinetic modelling

is crucial in drug development to plan a rational therapeutic

regime, and understanding pharmacokinetics is also import-

ant for prescribers individualizing therapy for a particular

patient. Pharmacokinetic principles are described in Chapter 3

from the point of view of the prescriber. Genetic influences on

pharmacodynamics and pharmacokinetics (pharmacogenet-

ics) are discussed in Chapter 14 and effects of disease are

addressed in Chapter 7, and the use of drugs in pregnancy

and at extremes of age is discussed in Chapters 9–11.

There are no good animal models of many important human

diseases. The only way to ensure that a drug with promising

pharmacological actions is effective in treating or preventing

disease is to perform a specific kind of human experiment,

called a clinical trial. Prescribing doctors must understand the

strengths and limitations of such trials, the principles of which

are described in Chapter 15, if they are to evaluate the litera-

ture on drugs introduced during their professional lifetimes.

Ignorance leaves the physician at the mercy of sources of infor-

mation that are biased by commercial interests. Sources of

unbiased drug information include Dollery’s encyclopaedic

Therapeutic drugs, 2nd edn (published by Churchill Livingstone

in 1999), which is an invaluable source of reference. Publications

such as the Adverse Reaction Bulletin, Prescribers Journal and

the succinctly argued Drug and Therapeutics Bulletin provide

up-to-date discussions of therapeutic issues of current

importance.

FURTHER READING

Dukes MNG, Swartz B. Responsibility for drug-induced injury.

Amsterdam: Elsevier, 1988.

Weatherall DJ. Scientific medicine and the art of healing. In: Warrell

DA, Cox TM, Firth JD, Benz EJ (eds), Oxford textbook of medicine,4th

edn. Oxford: Oxford University Press, 2005.

SCIENTIFIC BASIS OF USE OF DRUGS IN H UMANS 5

Key points

• Drugs are prescribed by physicians of all specialties.

• This carries risks as well as benefits.

• Therapy is optimized by combining general knowledge

of drugs with knowledge of an individual patient.

• Evidence of efficacy is based on clinical trials.

• Adverse drug effects may be seen in clinical trials, but

the drug side effect profile becomes clearer only when

widely prescribed.

• Rational prescribing is encouraged by local formularies.

Case history

A general practitioner reviews the medication of an

86-year-old woman with hypertension and multi-infarct

dementia, who is living in a nursing home. Her family used

to visit daily, but she no longer recognizes them, and needs

help with dressing, washing and feeding. Drugs include

bendroflumethiazide, atenolol, atorvastatin, aspirin, haloperi-

dol,imipramine, lactulose and senna. On examination, she

smells of urine and has several bruises on her head, but

otherwise seems well cared for. She is calm, but looks pale

and bewildered, and has a pulse of 48 beats/min regular,

and blood pressure 162/96mmHg lying and 122/76 mmHg

standing, during which she becomes sweaty and distressed.

Her rectum is loaded with hard stool. Imipramine was started

three years previously. Urine culture showed only a light

mixed growth. All of the medications were stopped and

manual evacuation of faeces performed. Stool was nega-

tive for occult blood and the full blood count was normal.

Two weeks later, the patient was brighter and more mobile.

She remained incontinent of urine at night, but no longer

during the day, her heart rate was 76 beats/min and her

blood pressure was 208/108mmHg lying and standing.

Comment

It is seldom helpful to give drugs in order to prevent some-

thing that has already happened (in this case multi-infarct

dementia), and any benefit in preventing further ischaemic

events has to be balanced against the harm done by the

polypharmacy. In this case, drug-related problems probably

include postural hypotension (due to imipramine, ben-

droflumethiazide and haloperidol), reduced mobility (due to

haloperidol), constipation (due to imipramine and haloperi-

dol), urinary incontinence (worsened by bendroflumethi-

azide and drugs causing constipation) and bradycardia (due

to atenolol). Drug-induced torsades de pointes (a form of

ventricular tachycardia, see Chapter 32) is another issue.

Despite her pallor, the patient was not bleeding into the

gastro-intestinal tract, but aspirin could have caused this.

●

Introduction 6

●

Receptors and signal transduction 6

●

Agonists 7

●

Antagonism 8

●

Partial agonists 9

●

Slow processes 9

●

Non-receptor mechanisms 10

CHAPTER 2

MECHANISMS OF DRUG ACTION

(PHARMACODYNAMICS)

INTRODUCTION

Pharmacodynamics is the study of effects of drugs on biological

processes. An example is shown in Figure 2.1, demonstrating

and comparing the effects of a proton pump inhibitor and of a

histamine H

receptor antagonist (both drugs used for the treat-

ment of peptic ulceration and other disorders related to gastric

hyperacidity) on gastric pH. Many mediators exert their effects

as a result of high-affinity binding to specific receptors in

plasma membranes or cell cytoplasm/nuclei, and many thera-

peutically important drugs exert their effects by combining with

these receptors and either mimicking the effect of the natural

mediator (in which case they are called ‘agonists’) or blocking it

(in which case they are termed ‘antagonists’). Examples include

oestrogens (used in contraception, Chapter 41) and anti-

oestrogens (used in treating breast cancer, Chapter 48), alpha-

and beta-adrenoceptor agonists and antagonists (Chapters 29

and 33) and opioids (Chapter 25).

Not all drugs work via receptors for endogenous medi-

ators: many therapeutic drugs exert their effects by combining

with an enzyme or transport protein and interfering with its

function. Examples include inhibitors of angiotensin convert-

ing enzyme and serotonin reuptake. These sites of drug action

are not ‘receptors’ in the sense of being sites of action of

endogenous mediators.

Whether the site of action of a drug is a receptor or another

macromolecule, binding is usually highly specific, with precise

steric recognition between the small molecular ligand and the

binding site on its macromolecular target. Binding is usually

reversible. Occasionally, however, covalent bonds are formed

with irreversible loss of function, e.g. aspirin binding to cyclo-

oxygenase (Chapter 30).

Most drugs produce graded concentration-/dose-related

effects which can be plotted as a dose–response curve. Such

curves are often approximately hyperbolic (Figure 2.2a). If plot-

ted semi-logarithmically this gives an S-shaped (‘sigmoidal’)

shape (Figure 2.2b). This method of plotting dose–response

curves facilitates quantitative analysis (see below) of full agonists

(which produce graded responses up to a maximum value),

antagonists (which produce no response on their own, but

reduce the response to an agonist) and partial agonists (which

produce some response, but to a lower maximum value than that

of a full agonist, and antagonize full agonists) (Figure 2.3).

RECEPTORS AND SIGNAL TRANSDUCTION

Drugs are often potent (i.e. they produce effects at low concen-

tration) and specific (i.e. small changes in structure lead to pro-

found changes in potency). High potency is a consequence of

high binding affinity for specific macromolecular receptors.

112233

Median gastric pH

Predose Postdose

≥ 5.0

4.1-5.0

2.0-4.0

< 2.0 21

9090

Predose Postdose Predose Postdose

Figure 2.1:Effect of omeprazole and cimetidine on gastric pH in a

group of critically ill patients. This was a study comparing the

effect of immediate-release omeprazole with a loading dose of

40mg, a second dose six to eight hours later, followed by 40mg

daily, with a continuous i.v. infusion of cimetidine. pH monitoring

of the gastric aspirate was undertaken every two hours and

immediately before and one hour after each dose. Red,

omeprazole; blue, cimetidine. (Redrawn with permission from

Horn JR, Hermes-DeSantis ER, Small, RE ‘New Perspectives in the

Management of Acid-Related Disorders: The Latest Advances in

PPI Therapy’. Medscape Today

http://www.medscape.com/viewarticle/503473_9 17 May 2005.)

AGONISTS 7

Receptors were originally classified by reference to the relative

potencies of agonists and antagonists on preparations contain-

ing different receptors. The order of potency of isoprenaline 

adrenaline noradrenaline on tissues rich in β-receptors, such

as the heart, contrasts with the reverse order in α-receptor-

mediated responses, such as vasoconstriction in resistance

arteries supplying the skin. Quantitative potency data are best

obtained from comparisons of different competitive antag-

onists, as explained below. Such data are supplemented, but not

replaced, by radiolabelled ligand-binding studies. In this way,

adrenoceptors were divided first into αand β, then subdivided

intoα

/α

andβ

/β

. Many other useful receptor classifications,

including those of cholinoceptors, histamine receptors, sero-

tonin receptors, benzodiazepine receptors, glutamate receptors

and others have been proposed on a similar basis. Labelling

with irreversible antagonists permitted receptor solubilization

and purification. Oligonucleotide probes based on the deduced

sequence were then used to extract the full-length DNA

sequence coding different receptors. As receptors are cloned

and expressed in cells in culture, the original functional classifi-

cations have been supported and extended. Different receptor

subtypes are analogous to different forms of isoenzymes, and a

rich variety has been uncovered – especially in the central ner-

vous system – raising hopes for novel drugs targeting these.

Despite this complexity, it turns out that receptors fall into

only four ‘superfamilies’ each linked to distinct types of signal

transduction mechanism (i.e. the events that link receptor acti-

vation with cellular response) (Figure 2.4). Three families are

located in the cell membrane, while the fourth is intracellular

(e.g. steroid hormone receptors). They comprise:

• Fast (millisecond responses) neurotransmitters (e.g.

nicotinic receptors), linked directly to a transmembrane

ion channel.

• Slower neurotransmitters and hormones (e.g. muscarinic

receptors) linked to an intracellular G-protein (‘GPCR’).

• Receptors linked to an enzyme on the inner membrane

(e.g. insulin receptors) are slower still.

• Intranuclear receptors (e.g. gonadal and glucocorticosteroid

hormones): ligands bind to their receptor in cytoplasm and

the complex then migrates to the nucleus and binds to

specific DNAsites, producing alterations in gene

transcription and altered protein synthesis. Such effects

occur over a time-course of minutes to hours.

AGONISTS

Agonists activate receptors for endogenous mediators – e.g.

salbutamol is an agonist at β

-adrenoceptors (Chapter 33).

The consequent effect may be excitatory (e.g. increased

heart rate) or inhibitory (e.g. relaxation of airway smooth

muscle). Agonists at nicotinic acetylcholine receptors (e.g.

suxamethonium, Chapter 24) exert an inhibitory effect

(neuromuscular blockade) by causing long-lasting depolariza-

tion at the neuromuscular junction, and hence inactivation of

the voltage-dependent sodium channels that initiate the action

potential.

Endogenous ligands have sometimes been discovered long

after the drugs that act on their receptors. Endorphins and

enkephalins (endogenous ligands of morphine receptors)

were discovered many years after morphine. Anandamide is a

central transmitter that activates CB (cannabis) receptors

(Chapter 53).

510

100

Effect (%)

[Drug]

(a)

1 10 100

100

Effect (%)

[Drug]

(b)

Figure 2.2:Concentration/dose–response curves plotted (a) arithmetically and (b) semi-logarithmically.

10 100

100

Effect (%)

[Drug]

Figure 2.3:Concentration/dose–response curves of two full

agonists (A, B) of different potency, and of a partial agonist (C).

8 MECHANISMSOF DRUG ACTION (PHARMACODYNAMIC S)

ANTAGONISM

Competitive antagonists combine with the same receptor as an

endogenous agonist (e.g. ranitidineat histamine H

-receptors),

but fail to activate it. When combined with the receptor, they

prevent access of the endogenous mediator. The complex

between competitive antagonist and receptor is reversible.

Provided that the dose of agonist is increased sufficiently, a

maximal effect can still be obtained, i.e. the antagonism is sur-

mountable. If a dose (C) of agonist causes a defined effect when

administered alone, then the dose (C) needed to produce the

same effect in the presence of antagonist is a multiple (C/C)

known as the dose ratio (r). This results in the familiar parallel

shift to the right of the log dose–response curve, since the add-

ition of a constant length on a logarithmic scale corresponds to

multiplication by a constant factor (Figure 2.5a). β-Adrenoceptor

antagonists are examples of reversible competitive antagonists.

By contrast, antagonists that do not combine with the same

receptor (non-competitive antagonists) or drugs that combine

irreversibly with their receptors, reduce the slope of the log

dose–response curve and depress its maximum (Figure 2.5b).

Physiological antagonism describes the situation where two

drugs have opposing effects (e.g. adrenaline relaxes bronchial

smooth muscle, whereas histamine contracts it).

Fast (ms)

neurotransmitter

(e.g. glutamate)

Slow (s)

neurotransmitter

or hormone

(e.g.-adrenoceptor)

Ion channel

Direct effect (min)

on protein

phosphorylation

(e.g. insulin)

Control (hours)

of DNA/new

protein synthesis

(e.g. steroid hormones)

Cell

membrane

Cytoplasm

Second messengers

Protein

phosphorylation

2

release

Cellular effects

Nucleus

Change in

membrane

potential

Figure 2.4:Receptors and signal transduction. G, G-protein; E, enzyme; Ca, calcium.

1 10 100

100

Effect (%)

AA[B]

A[B]

[Agonist](a)

10 100

100

A[C]

[Agonist](b)

Figure 2.5:Drug antagonism. Control concentration/dose–response curves for an agonist A together with curves in the presence of (a) a

competitive antagonist B and (b) a non-competitive antagonist C. Increasing concentrations of the competitive antagonist ([B]

, [B]

)

cause a parallel shift to the right of the log dose–effect curve (a), while the non-competitive antagonist ([C]

, [C]

) flattens the curve

and reduces its maximum (b).

SLOW PROCESSES 9

The relationship between the concentration of a competi-

tive antagonist [B], and the dose ratio (r) was worked out by

Gaddum and by Schildt, and is:

r 1  [B]/K

where K

is the dissociation equilibrium constant of the

reversible reaction of the antagonist with its receptor. K

has

units of concentration and is the concentration of antagonist

needed to occupy half the receptors in the absence of agonist.

The lower the value of K

, the more potent is the drug. If sev-

eral concentrations of a competitive antagonist are studied

and the dose ratio is measured at each concentration, a plot of

(r 1) against [B] yields a straight line through the origin with

a slope of 1/K

(Figure 2.6a). Such measurements provided

the means of classifying and subdividing receptors in terms of

the relative potencies of different antagonists.

PARTIAL AGONISTS

Some drugs combine with receptors and activate them, but are

incapable of eliciting a maximal response, no matter how high

their concentration may be. These are known as partial agonists,

and are said to have low efficacy. Several partial agonists are

used in therapeutics, including buprenorphine(a partial agonist

at morphine μ-receptors, Chapter 25) and oxprenolol (partial

agonist at β-adrenoceptors).

Full agonists can elicit a maximal response when only a

small proportion of the receptors is occupied (underlying the

concept of ‘spare’ receptors), but this is not the case with par-

tial agonists, where a substantial proportion of the receptors

need to be occupied to cause a response. This has two clinical

consequences. First, partial agonists antagonize the effect of a

full agonist, because most of the receptors are occupied with

low-efficacy partial agonist with which the full agonist must

compete. Second, it is more difficult to reverse the effects of a

partial agonist, such as buprenorphine, with a competitive

antagonist such as naloxone, than it is to reverse the effects of

a full agonist such as morphine. Alarger fraction of the recep-

tors is occupied by buprenorphine than by morphine, and a

much higher concentration of naloxoneis required to compete

successfully and displace buprenorphinefrom the receptors.

SLOW PROCESSES

Prolonged exposure of receptors to agonists, as frequently

occurs in therapeutic use, can cause down-regulation or

desensitization. Desensitization is sometimes specific for a

particular agonist (when it is referred to as ‘homologous

desensitization’), or there may be cross-desensitization to dif-

ferent agonists (‘heterologous desensitization’). Membrane

receptors may become internalized. Alternatively, G-protein-

mediated linkage between receptors and effector enzymes

(e.g. adenylyl cyclase) may be disrupted. Since G-proteins link

several distinct receptors to the same effector molecule, this

can give rise to heterologous desensitization. Desensitization

is probably involved in the tolerance that occurs during

prolonged administration of drugs, such as morphine or

benzodiazepines (see Chapters 18 and 25).

Therapeutic effects sometimes depend on induction of tol-

erance. For example, analogues of gonadotrophin-releasing

hormone (GnRH), such as goserelin or buserelin, are used to

treat patients with metastatic prostate cancer (Chapter 48).

Gonadotrophin-releasing hormone is released physiologically

in a pulsatile manner. During continuous treatment with

buserelin, there is initial stimulation of luteinizing hormone

(LH) and follicle-stimulating hormone (FSH) release, followed

by receptor desensitization and suppression of LH and FSH

release. This results in regression of the hormone-sensitive

tumour.

100

9

8

510

9

[Antagonist]→

Slope 1/K

Dose ratio –1

(a)

log[Antagonist]→

9 8 7

Slope 1

log (dose ratio) –1

(b)

Figure 2.6:Competitive antagonism. (a) A plot of antagonist concentration vs. (dose ratio 1) gives a straight line through the origin.

(b) A log–log plot (a Schildt plot) gives a straight line of unit slope. The potency of the antagonist (pA

) is determined from the intercept

of the Schildt plot.

10 MECHANISMS OF DRUG ACTION (PHARMACODYNAMICS)

Conversely, reduced exposure of a cell or tissue to an agon-

ist (e.g. by denervation) results in increased receptor numbers

and supersensitivity. Prolonged use of antagonists may pro-

duce an analogous effect. One example of clinical importance

is increased β-adrenoceptor numbers following prolonged use

of beta-blockers. Abrupt drug withdrawal can lead to tachy-

cardia and worsening angina in patients who are being treated

for ischaemic heart disease.

NON-RECEPTOR MECHANISMS

In contrast to high-potency/high-selectivity drugs which com-

bine with specific receptors, some drugs exert their effects via

simple physical properties or chemical reactions due to their

presence in some body compartment. Examples include antacids

(which neutralize gastric acid), osmotic diuretics (which increase

the osmolality of renal tubular fluid), and bulk and lubricating

laxatives. These agents are of low potency and specificity, and

hardly qualify as ‘drugs’ in the usual sense at all, although some

of them are useful medicines. Oxygen is an example of a highly

specific therapeutic agent that is used in high concentrations

(Chapter 33). Metal chelating agents, used for example in the

treatment of poisoning with ferrous sulphate, are examples of

drugs that exert their effects through interaction with small

molecular species rather than with macromolecules, yet which

possess significant specificity.

General anaesthetics (Chapter 24) have low molar poten-

cies determined by their oil/water partition coefficients, and

low specificity.

Key points

• Most drugs are potent and specific; they combine with

receptors for endogenous mediators or with high affinity

sites on enzymes or other proteins, e.g. ion-transport

mechanisms.

• There are four superfamilies of receptors; three are

membrane bound:

– directly linked to ion channel (e.g. nicotinic

acetylcholine receptor);

– linked via G-proteins to an enzyme, often adenylyl

cyclase (e.g. β

-receptors);

– directly coupled to the catalytic domain of an

enzyme (e.g. insulin)

• The fourth superfamily is intracellular, binds to DNA

and controls gene transcription and protein synthesis

(e.g. steroid receptors).

• Many drugs work by antagonizing agonists. Drug

antagonism can be:

– competitive;

– non-competitive;

–

physiological.

• Partial agonists produce an effect that is less than the

maximum effect of a full agonist. They antagonize full

agonists.

• Tolerance can be important during chronic

administration of drugs acting on receptors, e.g.

central nervous system (CNS) active agents.

Case history

A young man is brought unconscious into the Accident and

Emergency Department. He is unresponsive, hypoventilat-

ing, has needle tracks on his arms and pinpoint pupils.

Naloxone is administered intravenously and within 30

seconds the patient is fully awake and breathing normally.

He is extremely abusive and leaves hospital having

attempted to assault the doctor.

Comment

The clinical picture is of opioid overdose, and this was con-

firmed by the response to naloxone, a competitive antag-

onist of opioids at μ-receptors (Chapter 25). It would have

been wise to have restrained the patient before adminis-

tering naloxone, which can precipitate withdrawal symp-

toms. He will probably become comatose again shortly

after discharging himself, as naloxone has a much shorter

elimination half-life than opioids such as morphine or

diacetyl-morphine (heroin), so the agonist effect of the

overdose will be reasserted as the concentration of the

opiate antagonist falls.

FURTHER READING

Rang HP. The receptor concept: pharmacology’s big idea. British

Journal of Pharmacology2006; 147 (Suppl. 1): 9–16.

Rang HP, Dale MM, Ritter JM, Flower RD. Chapter 2, How drugs act:

general principles. Chapter 3, How drugs act: molecular aspects.

In: Rang and Dale’s pharmacology, 6th edn. London: Churchill

Livingstone, 2007.

CONSTANT-RATE INFUSION

If a drug is administered intravenously via a constant-rate

pump, and blood sampled from a distant vein for measure-

ment of drug concentration, a plot of plasma concentration

versus time can be constructed (Figure 3.1). The concentration

rises from zero, rapidly at first and then more slowly until a

plateau (representing steady state) is approached. At steady

state, the rate of input of drug to the body equals the rate of

elimination. The concentration at plateau is the steady-state

concentration (C

). This depends on the rate of drug infusion

and on its ‘clearance’. The clearance is defined as the volume

of fluid (usually plasma) from which the drug is totally elimi-

nated (i.e. ‘cleared’) per unit time. At steady state,

administration rate elimination rate

elimination rate C

clearance

clearance administration rate/C

●

Introduction 11

●

Constant-rate infusion 11

●

Single-bolus dose 12

●

Repeated (multiple) dosing 13

●

Deviations from the one-compartment model

with first-order elimination 14

●

Non-linear (‘dose-dependent’) pharmacokinetics 15

CHAPTER 3

PHARMACOKINETICS

INTRODUCTION

Pharmacokinetics is the study of drug absorption, distribu-

tion, metabolism and excretion (ADME) – ‘what the body does

to the drug’. Understanding pharmacokinetic principles, com-

bined with specific information regarding an individual drug

and patient, underlies the individualized optimal use of the

drug (e.g. choice of drug, route of administration, dose and

dosing interval).

Pharmacokinetic modelling is based on drastically simplif-

ying assumptions; but even so, it can be mathematically cum-

bersome, sadly rendering this important area unintelligible to

many clinicians. In this chapter, we introduce the basic con-

cepts by considering three clinical dosing situations:

• constant-rate intravenous infusion;

• bolus-dose injection;

• repeated dosing.

Bulk flow in the bloodstream is rapid, as is diffusion over

short distances after drugs have penetrated phospholipid mem-

branes, so the rate-limiting step in drug distribution is usually

penetration of these membrane barriers. Permeability is deter-

mined mainly by the lipid solubility of the drug, polar water-

soluble drugs being transferred slowly, whereas lipid-soluble,

non-polar drugs diffuse rapidly across lipid-rich membranes.

In addition, some drugs are actively transported by specific

carriers.

The simplest pharmacokinetic model treats the body as a

well-stirred single compartment in which an administered

drug distributes instantaneously, and from which it is elimi-

nated. Many drugs are eliminated at a rate proportional to

their concentration – ‘first-order’ elimination. A single (one)-

compartment model with first-order elimination often approx-

imates the clinical situation surprisingly well once absorption

and distribution have occurred. We start by considering this,

and then describe some important deviations from it.

[Drug] in plasma

Constant infusion of drug

Time →

Figure 3.1:Plasma concentration of a drug during and after a

constant intravenous infusion as indicated by the bar.

12 PHARMACOKINETICS

Clearance is the best measure of the efficiency with which a

drug is eliminated from the body, whether by renal excretion,

metabolism or a combination of both. The concept will be

familiar from physiology, where clearances of substances with

particular properties are used as measures of physiologically

important processes, including glomerular filtration rate and

renal or hepatic plasma flow. For therapeutic drugs, knowing

the clearance in an individual patient enables the physician

to adjust the maintenance dose to achieve a desired target

steady-state concentration, since

required administration rate desired C

clearance

This is useful in drug development. It is also useful in clinical

practice when therapy is guided by plasma drug concentrations.

However, such situations are limited (Chapter 8). Furthermore,

some chemical pathology laboratories report plasma concentra-

tions of drugs in molar terms, whereas drug doses are usually

expressed in units of mass. Consequently, one needs to know the

molecular weight of the drug to calculate the rate of administra-

tion required to achieve a desired plasma concentration.

When drug infusion is stopped, the plasma concentration

declines towards zero. The time taken for plasma concentration

to halve is the half-life (t

1/2

). A one-compartment model with

first-order elimination predicts an exponential decline in con-

centration when the infusion is discontinued, as shown in

Figure 3.1. After a second half-life has elapsed, the concentration

will have halved again (i.e. a 75% drop in concentration to 25%

of the original concentration), and so on. The increase in drug

concentration when the infusion is started is also exponential,

being the inverse of the decay curve. This has a very important

clinical implication, namely that t

1/2

not only determines the

time-course of disappearance when administration is stopped,

but also predicts the time-course of its accumulation to steady

state when administration is started.

Half-life is a very useful concept, as explained below.

However, it is not a direct measure of drug elimination, since

differences in t

1/2

can be caused either by differences in the effi-

ciency of elimination (i.e. the clearance) or differences in another

important parameter, the apparent volume of distribution (V

Clearance and not t

1/2

must therefore be used when a measure

of the efficiency with which a drug is eliminated is required.

SINGLE-BOLUS DOSE

The apparent volume of distribution (V

) defines the relation-

ship between the mass of a bolus dose of a drug and the

plasma concentration that results. V

is a multiplying factor

relating the amount of drug in the body to the plasma concen-

tration, C

(i.e. the amount of drug in the body C

V

Consider a very simple physical analogy. By definition, con-

centration (c) is equal to mass (m) divided by volume (v):

Thus if a known mass (say 300mg) of a substance is dissolved

in a beaker containing an unknown volume (v) of water, vcan

be estimated by measuring the concentration of substance in a

sample of solution. For instance, if the concentration is

0.1mg/mL, we would calculate that v  3000 mL (v  m/c).

This is valid unless a fraction of the substance has become

adsorbed onto the surface of the beaker, in which case the

solution will be less concentrated than if all of the substance

had been present dissolved in the water. If 90% of the sub-

stance is adsorbed in this way, then the concentration in

solution will be 0.01mg/mL, and the volume will be corre-

spondingly overestimated, as 30000 mLin this example. Based

on the mass of substance dissolved and the measured concen-

tration, we might say that it is ‘as if’ the substance were dis-

solved in 30L of water, whereas the real volume of water in

the beaker is only 3L.

Now consider the parallel situation in which a known

mass of a drug (say 300mg) is injected intravenously into a

human. Suppose that distribution within the body occurs

instantaneously before any drug is eliminated, and that blood

is sampled and the concentration of drug measured in the

plasma is 0.1mg/mL. We could infer that it is as if the drug

has distributed in 3L, and we would say that this is the appar-

ent volume of distribution. If the measured plasma concen-

tration was 0.01mg/mL, we would say that the apparent

volume of distribution was 30L, and if the measured concen-

tration was 0.001mg/mL, the apparent volume of distribution

would be 300L.

What does V

mean? From these examples it is obvious that

it is not necessarily the real volume of a body compartment,

since it may be greater than the volume of the whole body. At the

lower end, V

is limited by the plasma volume (approximately

3L in an adult). This is the smallest volume in which a drug

could distribute following intravenous injection, but there is no

theoretical upper limit on V

, with very large values occurring

when very little of the injected dose remains in the plasma, most

being taken up into fat or bound to tissues.



Key points

• Pharmacokinetics deals with how drugs are handled by

the body, and includes drug absorption, distribution,

metabolism and excretion.

• Clearance (Cl ) is the volume of fluid (usually plasma)

from which a drug is totally removed (by metabolism 

excretion) per unit time.

• During constant i.v. infusion, the plasma drug

concentration rises to a steady state (C

) determined by

the administration rate (A) and clearance (C

A/Cl ).

• The rate at which C

is approached, as well as the rate

of decline in plasma concentration when infusion is

stopped are determined by the half-life (t

1/2

• The volume of distribution (V

) is an apparent volume

that relates dose (D) to plasma concentration (C): it is

‘as if’ dose Dmg was dissolved in V

L to give a

concentration of Cmg /L.

• The loading dose is C

V

whereC

is the desired

plasma concentration.

• The maintenance dose  C

Cl, where C

is the

steady-state concentration.

In reality, processes of elimination begin as soon as the

bolus dose (d) of drug is administered, the drug being cleared

at a rate Cl

(total systemic clearance). In practice, blood is

sampled at intervals starting shortly after administration

of the dose. Cl

is determined from a plot of plasma concentra-

tion vs. time by measuring the area under the plasma concen-

tration vs. time curve (AUC). (This is estimated mathematically

using a method called the trapezoidal rule – important in drug

development, but not in clinical practice.)

If the one-compartment, first-order elimination model holds,

there is an exponential decline in plasma drug concentration,

just as at the end of the constant rate infusion (Figure 3.2a). If

the data are plotted on semi-logarithmic graph paper, with

time on the abscissa, this yields a straight line with a negative

slope (Figure 3.2b). Extrapolation back to zero time gives the

concentration (c

) that would have occurred at time zero, and

this is used to calculate V

Half-life can be read off the graph as the time between any

point (c

) and the point at which the concentration c

has

decreased by 50%, i.e. c

2. The slope of the line is the

elimination rate constant, k

1/2

andk

are related as follows:

is related partly to characteristics of the drug (e.g. lipid sol-

ubility) and partly to patient characteristics (e.g. body size,

0 693

el el





AUC



plasma protein concentration, body water and fat content). In

general, highly lipid-soluble compounds that are able to pen-

etrate cells and fatty tissues have a larger V

than more polar

water-soluble compounds.

determines the peak plasma concentration after a bolus

dose, so factors that influence V

, such as body mass, need to

be taken into account when deciding on dose (e.g. by express-

ing dose per kg body weight). Body composition varies from

the usual adult values in infants or the elderly, and this also

needs to be taken into account in dosing such patients (see

Chapters 10 and 11).

identifies the peak plasma concentration expected

following a bolus dose. It is also useful to know V

when

considering dialysis as a means of accelerating drug

elimination in poisoned patients (Chapter 54). Drugs with a

large V

(e.g. many tricyclic antidepressants) are not removed

efficiently by haemodialysis because only a small fraction of

the total drug in the body is present in plasma, which is the

fluid compartment accessible to the artificial kidney.

If both V

andt

1/2

are known, they can be used to estimate

the systemic clearance of the drug using the expression:

Note that clearance has units of volume/unit time (e.g.

mL/min),V

has units of volume (e.g. mLor L ), t

1/2

has units

of time (e.g. minutes) and 0.693 is a constant arising because

ln(0.5)  ln 2  0.693. This expression relates clearance to V

andt

1/2

, but unlike the steady-state situation referred to above

during constant-rate infusion, or using the AUC method fol-

lowing a bolus, it applies only when a single-compartment

model with first-order elimination kinetics is applicable.

0693

REPEATED(MULTIPLE) DOSING 13

Key points

• The ‘one-compartment’ model treats the body as a

single, well-stirred compartment. Immediately

following a bolus dose D, the plasma concentration

rises to a peak (C

) theoretically equal to D/V

and then

declines exponentially.

• The rate constant of this process (k

) is given by Cl/V

is inversely related to t

1/2

, which is given by 0.693/k

Thus,Cl  0.693  V

1/2

• Repeated bolus dosing gives rise to accumulation

similar to that observed with constant-rate infusion,

but with oscillations in plasma concentration rather

than a smooth rise. The size of the oscillations is

determined by the dose interval and by t

1/2

. The steady

state concentration is approached (87.5%) after three

half-lives have elapsed.

REPEATED (MULTIPLE) DOSING

If repeated doses are administered at dosing intervals much

greater than the drug’s elimination half-life, little if any accu-

mulation occurs (Figure 3.3a). Drugs are occasionally used in

[Drug] in plasma

Time(a)

Log [Drug] in plasma

Time(b)

Figure 3.2:One-compartment model. Plasma concentration–time

curve following a bolus dose of drug plotted (a) arithmetically

and (b) semi-logarithmically. This drug fits a one-compartment

model, i.e. its concentration falls exponentially with time.

this way (e.g. penicillinto treat a mild infection), but a steady

state concentration greater than some threshold value is often

needed to produce a consistent effect throughout the dose

interval. Figure 3.3b shows the plasma concentration–time

curve when a bolus is administered repeatedly at an interval

less than t

1/2

. The mean concentration rises toward a plateau,

as if the drug were being administered by constant-rate infu-

sion. That is, after one half-life the mean concentration is 50%

of the plateau (steady-state) concentration, after two half-lives

it is 75%, after three half-lives it is 87.5%, and after four

half-lives it is 93.75%. However, unlike the constant-rate infu-

sion situation, the actual plasma concentration at any time

swings above or below the mean level. Increasing the dosing

frequency smoothes out the peaks and troughs between doses,

while decreasing the frequency has the opposite effect. If the

peaks are too high, toxicity may result, while if the troughs are

too low there may be a loss of efficacy. If a drug is adminis-

tered once every half-life, the peak plasma concentration (C

max

)

will be double the trough concentration (C

min

). In practice, this

amount of variation is tolerable in many therapeutic situa-

tions, so a dosing interval approximately equal to the half-life

is often acceptable.

Knowing the half-life alerts the prescriber to the likely

time-course over which a drug will accumulate to steady

state. Drug clearance, especially renal clearance, declines with

age (see Chapter 11). A further pitfall is that several drugs

have active metabolites that are eliminated more slowly than

the parent drug. This is the case with several of the benzodi-

azepines (Chapter 18), which have active metabolites with

half-lives of many days. Consequently, adverse effects (e.g. con-

fusion) may appear only when the steady state is approached

after several weeks of treatment. Such delayed effects may

incorrectly be ascribed to cognitive decline associated with

ageing, but resolve when the drug is stopped.

Knowing the half-life helps a prescriber to decide whether

or not to initiate treatment with a loading dose. Consider

digoxin (half-life approximately 40 hours). This is usually

prescribed once daily, resulting in a less than two-fold varia-

tion in maximum and minimum plasma concentrations, and

reaching 90% of the mean steady-state concentration in

approximately one week (i.e. four half-lives). In many clinical

situations, such a time-course is acceptable. In more urgent

situations a more rapid response can be achieved by using a

loading dose. The loading dose (LD) can be estimated by mul-

tiplying the desired concentration by the volume of distribu-

tion (LD C

V

DEVIATIONS FROM THE

ONE-COMPARTMENT MODEL WITH

FIRST-ORDER ELIMINATION

TWO-COMPARTMENT MODEL

Following an intravenous bolus a biphasic decline in plasma

concentration is often observed (Figure 3.4), rather than a sim-

ple exponential decline. The two-compartment model (Figure

3.5) is appropriate in this situation. This treats the body as a

smaller central plus a larger peripheral compartment. Again,

these compartments have no precise anatomical meaning,

although the central compartment is assumed to consist of

14 PHARMACOKINETICS

[Drug] in plasma

(a)

[Drug] in plasma

Time

(b)

Figure 3.3:Repeated bolus dose injections (at arrows) at (a)

intervals much greater than t

1/2

and (b) intervals less than t

1/2

012345678910

Plasma concentration (log scale)

Time,t

Mainly distribution

 some elimination

Mainly elimination

 some distribution

(kinetic homogeneity attained)

Figure 3.4:Two-compartment model. Plasma concentration–time

curve (semi-logarithmic) following a bolus dose of a drug that fits

a two-compartment model.

blood (from which samples are taken for analysis) plus the

extracellular spaces of some well-perfused tissues. The periph-

eral compartment consists of less well-perfused tissues into

which drug permeates more slowly.

The initial rapid fall is called the α phase, and mainly

reflects distribution from the central to the peripheral com-

partment. The second, slower phase reflects drug elimination.

It is called the βphase, and the corresponding t

1/2

is known as

1/2

. This is the appropriate value for clinical use.

NON-LINEAR (‘DOSE-DE PENDENT’)

PHARMACOKINETICS

Although many drugs are eliminated at a rate that is approxi-

mately proportional to their concentration (‘first-order’ kinet-

ics), there are several therapeutically important exceptions.

Consider a drug that is eliminated by conversion to an

inactive metabolite by an enzyme. At high concentrations, the

enzyme becomes saturated. The drug concentration and reac-

tion velocity are related by the Michaelis–Menten equation

(Figure 3.6). At low concentrations, the rate is linearly related

to concentration, whereas at saturating concentrations the rate

is independent of concentration (‘zero-order’ kinetics). The

same applies when a drug is eliminated by a saturable trans-

port process. In clinical practice, drugs that exhibit non-linear

kinetics are the exception rather than the rule. This is because

most drugs are used therapeutically at doses that give rise to

concentrations that are well below the Michaelis constant

), and so operate on the lower, approximately linear, part

of the Michaelis–Menten curve relating elimination velocity to

plasma concentration.

Drugs that show non-linear kinetics in the therapeutic

range include heparin, phenytoin and ethanol. Some drugs

(e.g. barbiturates) show non-linearity in the part of the toxic

range that is encountered clinically. Implications of non-linear

pharmacokinetics include:

1. The decline in concentration vs. time following a bolus

dose of such a drug is not exponential. Instead, elimination

NON-LINEAR (‘DOSE-DEPENDENT’) PHARMACOKINETI CS 15

Drug

Central

compartment

Peripheral (tissue)

compartment

Elimination

Blood

sample

Figure 3.5:Schematic representation of a two-compartment

model.

[S]→

Velocity (V)

max

Figure 3.6:Michaelis–Menten relationship between the velocity

(V) of an enzyme reaction and the substrate concentration ([S]).

[S] at 50% V

max

is equal to K

, the Michaelis–Menten constant.

[Drug] in plasma

100

Time

Figure 3.7:Non-linear kinetics: plasma concentration–time curve

following administration of a bolus dose of a drug eliminated by

Michaelis–Menten kinetics.

Steady-state plasma [Drug]

Dail

dose

Figure 3.8:Non-linear kinetics: steady-state plasma concentration

of a drug following repeated dosing as a function of dose.

FURTHER READING

Rowland M, Tozer TN. Therapeutic regimens. In: Clinical pharmacoki-

netics: concepts and applications, 3rd edn. Baltimore, MD: Williams

and Wilkins, 1995: 53–105.

Birkett DJ. Pharmacokinetics made easy (revised), 2nd edn. Sydney:

McGraw-Hill, 2002. (Lives up to the promise of its title!)

begins slowly and accelerates as plasma concentration

falls (Figure 3.7).

2. The time required to eliminate 50% of a dose increases

with increasing dose, so half-life is not constant.

3. Amodest increase in dose of such a drug disproportionately

increases the amount of drug in the body once the drug-

elimination process is saturated (Figure 3.8). This is very

important clinically when using plasma concentrations of,

for example, phenytoinas a guide to dosing.

16 PHARMACOKINETICS

Case history

A young man develops idiopathic epilepsy and treatment

is started with phenytoin, 200mg daily, given as a single

dose last thing at night. After a week, the patient’s serum

phenytoin concentration is 25

μmol/L. (Therapeutic range is

40–80

μmol/L.) The dose is increased to 300mg/day. One

week later he is complaining of unsteadiness, there is nys-

tagmus and the serum concentration is 125

μmol/L. The

dose is reduced to 250mg/day. The patient’s symptoms

slowly improve and the serum phenytoin concentration

falls to 60

μmol/L (within the therapeutic range).

Comment

Phenytoin shows dose-dependent kinetics; the serum con-

centration at the lower dose was below the therapeutic

range, so the dose was increased. Despite the apparently

modest increase (to 150% of the original dose), the plasma

concentration rose disproportionately, causing symptoms

and signs of toxicity (see Chapter 22).

Key points

• Two-compartment model. Following a bolus dose the

plasma concentration falls bi-exponentially, instead

of a single exponential as in the one-compartment

model. The first () phase mainly represents

distribution; the second () phase mainly represents

elimination.

• Non-linear (‘dose-dependent’) kinetics. If the

elimination process (e.g. drug-metabolizing enzyme)

becomes saturated, the clearance rate falls.

Consequently, increasing the dose causes a

disproportionate increase in plasma concentration.

Drugs which exhibit such properties (e.g. phenytoin)

are often difficult to use in clinical practice.

●

Introduction 17

●

Bioavailability, bioequivalence and generic vs.

proprietary prescribing 17

●

Prodrugs 18

●

Routes of administration 19

CHAPTER 4

DRUG ABSORPTION AND ROUTES

OF ADMINISTRATION

INTRODUCTION

Drug absorption, and hence the routes by which a particular

drug may usefully be administered, is determined by the rate

and extent of penetration of biological phospholipid mem-

branes. These are permeable to lipid-soluble drugs, whilst pre-

senting a barrier to more water-soluble drugs. The most

convenient route of drug administration is usually by mouth,

and absorption processes in the gastro-intestinal tract are

among the best understood.

BIOAVAILABILITY, BIOEQUIVALENCE AND

GENERIC VS. PROPRIETARY PRESCRIBING

Drugs must enter the circulation if they are to exert a systemic

effect. Unless administered intravenously, most drugs are

absorbed incompletely (Figure 4.1). There are three reasons

for this:

1. the drug is inactivated within the gut lumen by gastric

acid, digestive enzymes or bacteria;

2. absorption is incomplete; and

3. presystemic (‘first-pass’) metabolism occurs in the gut

wall and liver.

Together, these processes explain why the bioavailability of

an orally administered drug is typically less than 100%.

Bioavailability of a drug formulation can be measured experi-

mentally (Figure 4.2) by measuring concentration vs. time

curves following administration of the preparation via its

intended route (e.g. orally) and of the same dose given intra-

venously (i.v.).

Bioavailability AUCoral/AUCi.v.  100%

Many factors in the manufacture of the drug formulation influ-

ence its disintegration, dispersion and dissolution in the gastro-

intestinal tract. Pharmaceutical factors are therefore important

in determining bioavailability. It is important to distinguish

statistically significant from clinically important differences in

this regard. The former are common, whereas the latter are not.

However, differences in bioavailability did account for an epi-

demic of phenytoin intoxication in Australia in 1968–69.

Affected patients were found to be taking one brand of pheny-

toin: the excipient had been changed from calcium sulphate to

lactose, increasing phenytoin bioavailability and thereby pre-

cipitating toxicity. An apparently minor change in the manufac-

turing process of digoxin in the UK resulted in reduced potency

due to poor bioavailability. Restoring the original manufactur-

ing conditions restored potency but led to some confusion, with

both toxicity and underdosing.

These examples raise the question of whether prescribing

should be by generic name or by proprietary (brand) name.

When a new preparation is marketed, it has a proprietary name

Systemic

circulation

Oral

administration

Inactivation

in liver

Inactivation

in gut lumen

Inactivation

in stomach

Inactivation

in gut wall

Portal blood

Incomplete

absorption

Figure 4.1:Drug bioavailability following oral administration may

be incomplete for several reasons.

supplied by the pharmaceutical company, and a non-proprietary

(generic) name. It is usually available only from the company

that introduced it until the patent expires. After this, other com-

panies can manufacture and market the product, sometimes

under its generic name. At this time, pharmacists usually shop

around for the best buy. If a hospital doctor prescribes by propri-

etary name, the same drug produced by another company may

be substituted. This saves considerable amounts of money. The

attractions of generic prescribing in terms of minimizing costs

are therefore obvious, but there are counterarguments, the

strongestof which relates to the bioequivalence or otherwise of

the proprietary product with its generic competitors. The for-

mulation of a drug (i.e. excipients, etc.) differs between different

manufacturers’ products of the same drug, sometimes affecting

bioavailability. This is a particular concern with slow-release or

sustained-release preparations, or preparations to be adminis-

tered by different routes. Drug regulatory bodies have strict cri-

teria to assess whether such products can be licensed without

the full dataset that would be required for a completely new

product (i.e. one based on a new chemical entity).

It should be noted that the absolute bioavailability of two

preparations may be the same (i.e. the same AUC), but that the

kinetics may be very different (e.g. one may have a much

higher peak plasma concentration than the other, but a shorter

duration). The rate at which a drug enters the body determines

the onset of its pharmacological action, and also influences the

intensity and sometimes the duration of its action, and is

important in addition to the completeness of absorption.

Prescribers need to be confident that different preparations

(brand named or generic) are sufficiently similar for their sub-

stitution to be unlikely to lead to clinically important alter-

ations in therapeutic outcome. Regulatory authorities have

responded to this need by requiring companies who are seek-

ing to introduce generic equivalents to present evidence that

their product behaves similarly to the innovator product that

is already marketed. If evidence is presented that a new

generic product can be treated as therapeutically equivalent to

the current ‘market leader’, this is accepted as ‘bioequiva-

lence’. This does not imply that all possible pharmacokinetic

parameters are identical between the two products, but that

any such differences are unlikely to be clinically important.

It is impossible to give a universal answer to the generic vs.

proprietary issue. However, substitution of generic for brand-

name products seldom causes obvious problems, and excep-

tions (e.g. different formulations of the calcium antagonist

diltiazem, see Chapter 29) are easily flagged up in formularies.

PRODRUGS

One approach to improving absorption or distribution to a rel-

atively inaccessible tissue (e.g. brain) is to modify the drug

molecule chemically to form a compound that is better

absorbed and from which active drug is liberated after absorp-

tion. Such modified drugs are termed prodrugs (Figure 4.3).

Examples are shown in Table 4.1.

18 DRUG ABSORPTION AND ROUTES OF ADMINISTRATION

i.v.dosing

Oral dosing

[Drug] in plasma

100

Time→

Figure 4.2:Oral vs. intravenous dosing: plasma concentration–time

curves following administration of a drug i.v. or by mouth (oral).

Key points

• Drugs must cross phospholipid membranes to reach the

systemic circulation, unless they are administered

intravenously. This is determined by the lipid solubility of

the drug and the area of membrane available for

absorption, which is very large in the case of the ileum,

because of the villi and microvilli. Sometimes polar drugs

can be absorbed via specific transport processes (carriers).

• Even if absorption is complete, not all of the dose may

reach the systemic circulation if the drug is metabolized

by the epithelium of the intestine, or transported

back into lumen of the intestine or metabolized in the

liver, which can extract drug from the portal blood

before it reaches the systemic circulation via the

hepatic vein. This is called presystemic (or ‘first-pass’)

metabolism.

• ‘Bioavailability’ describes the completeness of

absorption into the systemic circulation. The amount of

drug absorbed is determined by measuring the plasma

concentration at intervals after dosing and integrating

by estimating the area under the plasma

concentration/time curve (AUC). This AUC is expressed as

a percentage of the AUC when the drug is administered

intravenously (100% absorption). Zero per cent

bioavailability implies that no drug enters the systemic

circulation, whereas 100% bioavailability means that all

of the dose is absorbed into the systemic circulation.

Bioavailability may vary not only between different

drugs and different pharmaceutical formulations of the

same drug, but also from one individual to another

depending on factors such as dose, whether the dose

is taken on an empty stomach, and the presence of

gastro-intestinal disease, or other drugs.

• The rate of absorption is also important (as well as the

completeness), and is expressed as the time to peak

plasma concentration (T

max

). Sometimes it is desirable

to formulate drugs in slow-release preparations to

permit once daily dosing and/or to avoid transient

adverse effects corresponding to peak plasma

concentrations. Substitution of one such preparation

for another may give rise to clinical problems unless the

preparations are ‘bioequivalent’. Regulatory authorities

therefore require evidence of bioequivalence before

licensing generic versions of existing products.

• Prodrugs are metabolized to pharmacologically active

products. They provide an approach to improving

absorption and distribution.

ROUTES OF ADMINISTRATION

ORAL ROUTE

FOR LOCAL EFFECT

Oral drug administration may be used to produce local effects

within the gastro-intestinal tract. Examples include antacids,

and sulphasalazine, which delivers 5-amino salicylic acid

(5-ASA) to the colon, thereby prolonging remission in patients

with ulcerative colitis (Chapter 34). Mesalazine has a pH-

dependent acrylic coat that degrades at alkaline pH as in the

colon and distal part of the ileum. Olsalazine is a prodrug con-

sisting of a dimer of two 5-ASAmoieties joined by a bond that is

cleaved by colonic bacteria.

FOR SYSTEMIC EFFECT

Oral administration of drugs is safer and more convenient for

the patient than injection. There are two main mechanisms of

drug absorption by the gut (Figure 4.4).

Passive diffusion

This is the most important mechanism. Non-polar lipid-soluble

agents are well absorbed from the gut, mainly from the small

intestine, because of the enormous absorptive surface area

provided by villi and microvilli.

Active transport

This requires a specific carrier. Naturally occurring polar

substances, including sugars, amino acids and vitamins, are

absorbed by active or facilitated transport mechanisms. Drugs

that are analogues of such molecules compete with them for

transport via the carrier. Examples include L-dopa, methotrex-

ate, 5-fluorouracil and lithium (which competes with sodium

ions for absorption).

Other factors that influence absorption include:

1. surgical interference with gastric function – gastrectomy

reduces absorption of several drugs;

2. disease of the gastro-intestinal tract (e.g. coeliac disease,

cystic fibrosis) – the effects of such disease are

unpredictable, but often surprisingly minor (see

Chapter 7);

3. the presence of food – the timing of drug administration in

relation to meal times can be important. Food and drink

dilute the drug and can bind it, alter gastric emptying and

increase mesenteric and portal blood flow;

ROUTES OF ADMINISTRATION 19

Passive diffusion of a

water-soluble drug

through an aquas

channel or pore

Passive diffusion

of a lipid-soluble

drug

Carrier-mediated

active transport

of drug

Lumen

Drug

Epithelial

cell

membrane

ATP

Figure 4.4:Modes of absorption of drugs

from the gut.

PRODRUG

DRUG

Relatively well-

absorbed and/or

good tissue

penetration

INACTIVE

Various

enzymes

in body

Relatively poorly

absorbed and/or

poor tissue

penetration

ACTIVE

Figure 4.3:Clinical use of prodrugs.

Table 4.1:Prodrugs

Prodrug Product

Enalapril Enalaprilat

Benorylate Aspirin and paracetamol

Levodopa Dopamine

Minoxidil Minoxidil sulphate

Carbimazole Methimazole

Vanciclovir Aciclovir

4. drug metabolism by intestinal flora – this may affect drug

absorption. Alteration of bowel flora (e.g. by concomitant

use of antibiotics) can interrupt enterohepatic recycling and

cause loss of efficacy of oral contraceptives (Chapter 13);

5. drug metabolism by enzymes (e.g. cytochrome P450 family

3A(CYP3A)) in the gastro-intestinal epithelium

(Chapter 5);

6. drug efflux back into the gut lumen by drug transport

proteins (e.g. P-glycoprotein (P-gp), ABCB1).

Prolonged action and sustained-release preparations

Some drugs with short elimination half-lives need to be adminis-

tered frequently, at inconveniently short intervals, making adher-

ence to the prescribed regimen difficult for the patient. Adrug

with similar actions, but a longer half-life, may need to be substi-

tuted. Alternatively, there are various pharmaceutical means of

slowing absorption of a rapidly eliminated drug. The aim of such

sustained-release preparations is to release a steady ‘infusion’ of

drug into the gut lumen for absorption during transit through

the small intestine. Reduced dosing frequency may improve

compliance and, in the case of some drugs (e.g. carbamazepine),

reduce adverse effects linked to high peak plasma concentra-

tions. Absorption of such preparations is often incomplete, so it is

especially important that bioavailability is established and sub-

stitution of one preparation for another may lead to clinical prob-

lems. Other limitations of slow-release preparations are:

1. Transit time through the small intestine is about six hours,

so once daily dosing may lead to unacceptably low trough

concentrations.

2. If the gut lumen is narrowed or intestinal transit is slow,

as in the elderly, or due to other drugs (tricyclic

antidepressants, opiates), there is a danger of high local

drug concentrations causing mucosal damage.

Osmosin™, an osmotically released formulation of

indometacin, had to be withdrawn because it caused

bleeding and ulceration of the small intestine.

3. Overdose with sustained-release preparations is difficult

to treat because of delayed drug absorption.

4. Sustained-release tablets should not be divided.

5. Expense.

BUCCAL AND SUBLI NGUAL ROUTE

Drugs are administered to be retained in the mouth for local

disorders of the pharynx or buccal mucosa, such as aphthous

ulcers (hydrocortisonelozenges or carbenoxolone granules).

Sublingual administration has distinct advantages over oral

administration (i.e. the drug to be swallowed) for drugs with

pronounced presystemic metabolism, providing direct and

rapid access to the systemic circulation, bypassing the intestine

and liver. Glyceryl trinitrate,buprenorphine and fentanyl are

given sublingually for this reason. Glyceryl trinitrateis taken

either as a sublingual tablet or as a spray. Sublingual adminis-

tration provides short-term effects which can be terminated by

swallowing the tablet. Tablets for buccal absorption provide

more sustained plasma concentrations, and are held in one

spot between the lip and the gum until they have dissolved.

RECTAL ROUTE

Drugs may be given rectally for local effects (e.g. to treat proc-

titis). The following advantages have been claimed for the rec-

tal route of administration of systemically active drugs:

1. Exposure to the acidity of the gastric juice and to digestive

enzymes is avoided.

2. The portal circulation is partly bypassed, reducing

presystemic (first pass) metabolism.

3. For patients who are unable to swallow or who are

vomiting.

Rectaldiazepam is useful for controlling status epilepticus in

children. Metronidazoleis well absorbed when administered

rectally, and is less expensive than intravenous preparations.

However, there are usually more reliable alternatives, and

drugs that are given rectally can cause severe local irritation.

SKIN

Drugs are applied topically to treat skin disease (Chapter 51).

Systemic absorption via the skin can cause undesirable effects,

for example in the case of potent glucocorticoids, but the

application of drugs to skin can also be used to achieve a sys-

temic therapeutic effect (e.g. fentanyl patches for analgesia).

The skin has evolved as an impermeable integument, so the

problems of getting drugs through it are completely different

from transport through an absorptive surface such as the gut.

Factors affecting percutaneous drug absorption include:

1. skin condition – injury and disease;

2. age – infant skin is more permeable than adult skin;

3. region –plantar  forearm  scalp  scrotum  posterior

auricular skin;

4. hydration of the stratum corneum – this is very important.

Increased hydration increases permeability. Plastic-film

occlusion (sometimes employed by dermatologists)

increases hydration. Penetration of glucocorticosteroids is

increased up to 100-fold, and systemic side effects are

more common;

5. vehicle – little is known about the importance of the

various substances which over the years have been

empirically included in skin creams and ointments. The

physical chemistry of these mixtures may be very complex

and change during an application;

6. physical properties of the drug – penetration increases with

increasing lipid solubility. Reduction of particle size

enhances absorption, and solutions penetrate best of all;

7. surface area to which the drug is applied – this is especially

important when treating infants who have a relatively

large surface area to volume ratio.

20 DRUG ABSORPTION AND ROUTES OF ADMINISTRATION

caused by timolol eyedrops given for open-angle glaucoma.

However, such absorption is not sufficiently reliable to make

use of these routes for therapeutic ends.

INTRAMUSCULAR INJECTION

Many drugs are well absorbed when administered intramus-

cularly. The rate of absorption is increased when the solution is

distributed throughout a large volume of muscle. Dispersion is

enhanced by massage of the injection site. Transport away from

the injection site is governed by muscle blood flow, and this

varies from site to site (deltoid vastus lateralis  gluteus max-

imus). Blood flow to muscle is increased by exercise and absorp-

tion rates are increased in all sites after exercise. Conversely,

shock, heart failure or other conditions that decrease muscle

blood flow reduce absorption.

The drug must be sufficiently water soluble to remain in

solution at the injection site until absorption occurs. This is a

problem for some drugs, including phenytoin, diazepamand

digoxin, as crystallization and/or poor absorption occur when

these are given by intramuscular injection, which should there-

fore be avoided. Slow absorption is useful in some circum-

stances where appreciable concentrations of drug are required

for prolonged periods. Depot intramuscular injections are

used to improve compliance in psychiatric patients (e.g. the

decanoate ester of fluphenazinewhich is slowly hydrolysed to

release active free drug).

Intramuscular injection has a number of disadvantages:

1. pain – distension with large volumes is painful, and

injected volumes should usually be no greater than 5mL;

2. sciatic nerve palsy following injection into the buttock –

this is avoided by injecting into the upper outer gluteal

quadrant;

3. sterile abscesses at the injection site (e.g. paraldehyde);

4. elevated serum creatine phosphokinase due to enzyme

release from muscle can cause diagnostic confusion;

5. severe adverse reactions may be protracted because there

is no way of stopping absorption of the drug;

6. for some drugs, intramuscular injection is less effective

than the oral route;

7. haematoma formation.

SUBCUTANEOUS INJECTION

This is influenced by the same factors that affect intramuscular

injections. Cutaneous blood flow is lower than in muscle so

absorption is slower. Absorption is retarded by immobiliza-

tion, reduction of blood flow by a tourniquet and local cooling.

Adrenaline incorporated into an injection (e.g. of local anaes-

thetic) reduces the absorption rate by causing vasoconstriction.

Sustained effects from subcutaneous injections are extremely

important clinically, most notably in the treatment of insulin-

dependent diabetics, different rates of absorption being

achieved by different insulin preparations (see Chapter 37).

Transdermal absorption is sufficiently reliable to enable system-

ically active drugs (e.g. estradiol,nicotine, scopolamine) to be

administered by this route in the form of patches. Transdermal

administration bypasses presystemic metabolism. Patches are

more expensive than alternative preparations.

LUNGS

Drugs, notably steroids, β

-adrenoceptor agonists and mus-

carinic receptor antagonists, are inhaled as aerosols or particles

for their local effects on bronchioles. Nebulized antibiotics are

also sometimes used in children with cystic fibrosis and recur-

rent Pseudomonas infections. Physical properties that limit sys-

temic absorption are desirable. For example, ipratropium is a

quaternary ammonium ion analogue of atropine which is

highly polar, and is consequently poorly absorbed and has

reduced atropine-like side effects. A large fraction of an

‘inhaled’ dose of salbutamol is in fact swallowed. However,

the bioavailability of swallowed salbutamolis low due to inac-

tivation in the gut wall, so systemic effects such as tremor are

minimized in comparison to effects on the bronchioles.

The lungs are ideally suited for absorption from the gas

phase, since the total respiratory surface area is about 60m

through which only 60mL blood are percolating in the capil-

laries. This is exploited in the case of volatile anaesthetics, as

discussed in Chapter 24. Anasal/inhaled preparation of insulin

was introduced for type 2 diabetes (Chapter 37), but was not

commercially successful.

NOSE

Glucocorticoids and sympathomimetic amines may be admin-

istered intranasally for their local effects on the nasal mucosa.

Systemic absorption may result in undesirable effects, such as

hypertension.

Nasal mucosal epithelium has remarkable absorptive

properties, notably the capacity to absorb intact complex pep-

tides that cannot be administered by mouth because they

would be digested. This has opened up an area of therapeutics

that was previously limited by the inconvenience of repeated

injections. Drugs administered by this route include desmo-

pressin (DDAVP, an analogue of antidiuretic hormone) for

diabetes insipidus and buserelin(an analogue of gonadotrophin

releasing hormone) for prostate cancer.

EYE, EAR AND VAGINA

Drugs are administered topically to these sites for their local

effects (e.g. gentamicinor ciprofloxacin eyedrops for bacterial

conjunctivitis, sodium bicarbonate eardrops for softening wax,

and nystatin pessaries for Candida infections). Occasionally,

they are absorbed in sufficient quantity to have undesirable sys-

temic effects, such as worsening of bronchospasm in asthmatics

ROUTES OF ADMINISTRATION 21

Sustained effects have also been obtained from subcutaneous

injections by using oily suspensions or by implanting a pellet

subcutaneously (e.g. oestrogen or testosterone for hormone

replacement therapy).

INTRAVENOUS INJECTION

This has the following advantages:

1. rapid action (e.g. morphine for analgesia and furosemide

in pulmonary oedema);

2. presystemic metabolism is avoided (e.g. glyceryl trinitrate

infusion in patients with unstable angina);

3. intravenous injection is used for drugs that are not

absorbed by mouth (e.g. aminoglycosides (gentamicin)

and heparins). It is also used for drugs that are too painful

or toxic to be given intramuscularly. Cytotoxic drugs must

not be allowed to leak from the vein or considerable local

damage and pain will result as many of them are severe

vesicants (e.g. vincristine,doxorubicin);

4. intravenous infusion is easily controlled, enabling

precise titration of drugs with short half-lives. This is

essential for drugs such as sodium nitroprussideand

epoprostenol.

The main drawbacks of intravenous administration are as

follows:

1. Once injected, drugs cannot be recalled.

2. High concentrations result if the drug is given too rapidly –

the right heart receives the highest concentration.

3. Embolism of foreign particles or air, sepsis or

thrombosis.

4. Accidental extravascular injection or leakage of toxic drugs

(e.g.doxorubicin) produce severe local tissue necrosis.

5. Inadvertent intra-arterial injection can cause arterial

spasm and peripheral gangrene.

INTRATHECAL INJECTION

This route provides access to the central nervous system for

drugs that are normally excluded by the blood–brain barrier.

This inevitably involves very high risks of neurotoxicity, and

this route should never be used without adequate training. (In

the UK, junior doctors who have made mistakes of this kind

have been held criminally, as well as professionally, negligent.)

The possibility of causing death or permanent neurological

disability is such that extra care must be taken in checking that

both the drug and the dose are correct. Examples of drugs used

in this way include methotrexate and local anaesthetics (e.g.

levobupivacaine) or opiates, such as morphine and fentanyl.

(More commonly anaesthetists use the extradural route to

administer local anaesthetic drugs to produce regional analge-

sia without depressing respiration, e.g. in women during

labour.) Aminoglycosides are sometimes administered by

neuro-surgeons via a cisternal reservoir to patients with Gram-

negative infections of the brain. The antispasmodic baclofenis

sometimes administered by this route.

Penicillinused to be administered intrathecally to patients

with pneumococcal meningitis, because of the belief that it

penetrated the blood–brain barrier inadequately. However,

when the meninges are inflamed (as in meningitis), high-dose

intravenous penicillin results in adequate concentrations in

the cerebrospinal fluid. Intravenous penicillin should now

always be used for meningitis, since penicillinis a predictable

neurotoxin (it was formerly used to produce an animal model

of seizures), and seizures, encephalopathy and death have

been caused by injecting a dose intrathecally that would have

been appropriate for intravenous administration.points

22 DRUG ABSORPTION AND ROUTES OF ADMINISTRATION

Key points

• Oral – generally safe and convenient

• Buccal/sublingual – circumvents presystemic metabolism

• Rectal – useful in patients who are vomiting

• Transdermal – limited utility, avoids presystemic

metabolism

• Lungs – volatile anaesthetics

• Nasal – useful absorption of some peptides (e.g.

DDAVP; see Chapter 42)

• Intramuscular – useful in some urgent situations (e.g.

behavioural emergencies)

• Subcutaneous – useful for insulin and heparin in

particular

• Intravenous – useful in emergencies for most rapid and

predictable action, but too rapid administration is

potentially very dangerous, as a high concentration

reaches the heart as a bolus

• Intrathecal – specialized use by anaesthetists

Case history

The health visitor is concerned about an eight-month-old

girl who is failing to grow. The child’s mother tells you that

she has been well apart from a recurrent nappy rash, but

on examination there are features of Cushing’s syndrome.

On further enquiry, the mother tells you that she has been

applying clobetasone, which she had been prescribed her-

self for eczema, to the baby’s napkin area. There is no bio-

chemical evidence of endogenous over-production of

glucocorticoids. The mother stops using the clobetasone

cream on her daughter, on your advice. The features of

Cushing’s syndrome regress and growth returns to normal.

Comment

Clobetasone is an extremely potent steroid (see Chapter

50). It is prescribed for its top-ical effect, but can penetrate

skin, especially of an infant. The amount prescribed that is

appropriate for an adult would readily cover a large frac-

tion of an infant’s body surface area. If plastic pants are

used around the nappy this may increase penetration

through the skin (just like an occlusive dressing, which is

often deliberately used to increase the potency of topical

steroids; see Chapter 50), leading to excessive absorption

and systemic effects as in this case.

FURTHER READING

Fix JA. Strategies for delivery of peptides utilizing absorption-

enhancing agents. Journal of Pharmaceutical Sciences 1996; 85:

1282–5.

Goldberg M, Gomez-Orellana I. Challenges for the oral delivery

of macromolecules. Nature Reviews Drug Discovery 2003; 2:

289–95.

Mahato RI, Narang AS, Thoma L, Miller DD. Emerging trends in oral

delivery of peptide and protein drugs. Critical Reviews in

Therapeutic Drug Carrier Systems2003; 20: 153–2.

Mathiovitz E, Jacobs JS, Jong NS et al. Biologically erodable micros-

pheres as potential oral drug delivery systems. Nature1997; 386:

410–14.

Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applica-

tions, 3rd edn. Baltimore, MD: Williams and Wilkins, 1995: 11–50.

Skyler JS, Cefalu WT, Kourides I Aet al. Efficacy of inhaled human

insulin in type 1 diabetes mellitus: a randomized proof-of-concept

study. Lancet2001; 357: 324–5.

Varde NK, Pack DW. Microspheres for controlled release drug deliv-

ery. Expert Opinion on Biological Therapy2004; 4: 35–51.

ROUTES OF ADMINISTRATION 23

4-hydroxyphenytoin-glucuronide, which is readily excreted

viathe kidney.

PHASE I METABOLISM

The liver is the most important site of drug metabolism.

Hepatocyte endoplasmic reticulum is particularly important,

but the cytosol and mitochondria are also involved.

ENDOPLASMIC RETICULUM

Hepatic smooth endoplasmic reticulum contains the cytochrome

P450 (CYP450) enzyme superfamily (more than 50 different

CYPs have been found in humans) that metabolize foreign

substances – ‘xenobiotics’, i.e. drugs as well as pesticides, fertil-

izers and other chemicals ingested by humans. These metabolic

reactions include oxidation, reduction and hydrolysis.

OXIDATION

Microsomal oxidation causes aromatic or aliphatic hydroxyla-

tion, deamination, dealkylation or S-oxidation. These reac-

tions all involve reduced nicotinamide adenine dinucleotide

phosphate (NADP), molecular oxygen, and one or more of a

group of CYP450 haemoproteins which act as a terminal oxi-

dase in the oxidation reaction (or can involve other mixed

function oxidases, e.g. flavin-containing monooxygenases or

epoxide hydrolases). CYP450s exist in several distinct iso-

enzyme families and subfamilies with different levels of amino

acid homology. Each CYP subfamily has a different, albeit

often overlapping, pattern of substrate specificities. The major

drug metabolizing CYPs with important substrates, inhibitors

and inducers are shown in Table 5.1.

CYP450 enzymes are also involved in the oxidative

biosynthesis of mediators or other biochemically important

intermediates. For example, synthase enzymes involved in the

oxidation of arachidonic acid (Chapter 26) to prostaglandins

●

Introduction 24

●

Phase I metabolism 24

●

Phase II metabolism (transferase reactions) 25

●

Enzyme induction 27

●

Enzyme inhibition 28

●

Presystemic metabolism (‘first-pass’ effect) 28

●

Metabolism of drugs by intestinal organisms 29

CHAPTER 5

DRUG METABOLISM

INTRODUCTION

Drug metabolism is central to biochemical pharmacology.

Knowledge of human drug metabolism has been advanced by

the wide availability of human hepatic tissue, complemented by

analytical studies of parent drugs and metabolites in plasma and

urine.

The pharmacological activity of many drugs is reduced or

abolished by enzymatic processes, and drug metabolism is one

of the primary mechanisms by which drugs are inactivated.

Examples include oxidation of phenytoin and of ethanol.

However, not all metabolic processes result in inactivation, and

drug activity is sometimes increased by metabolism, as in acti-

vation of prodrugs (e.g. hydrolysis of enalapril, Chapter 28, to

its active metabolite enalaprilat). The formation of polar metabo-

lites from a non-polar drug permits efficient urinary excretion

(Chapter 6). However, some enzymatic conversions yield active

compounds with a longer half-life than the parent drug, causing

delayed effects of the long-lasting metabolite as it accumulates

more slowly to its steady state (e.g. diazepamhas a half-life of

20–50 hours, whereas its pharmacologically active metabolite

desmethyldiazepam has a plasma half-life of approximately

100 hours, Chapter 18).

Itis convenient to divide drug metabolism into two phases

(phasesI and II: Figure 5.1), which often, but not always, occur

sequentially.Phase Ireactions involve a metabolic modification

of the drug (commonly oxidation, reduction or hydrolysis).

Productsof phase I reactions may be either pharmacologically

active or inactive. Phase II reactions are synthetic conjugation

reactions. Phase II metabolites have increased polarity com-

paredto the parent drugs and are more readily excreted in the

urine(or, less often, in the bile), and they are usually – but not

always – pharmacologically inactive. Molecules or groups

involvedin phase II reactions include acetate, glucuronic acid,

glutamine, glycine and sulphate, which may combine with

reactivegroups introduced during phase I metabolism (‘func-

tionalization’). For example, phenytoin is initially oxidized

to 4-hydroxyphenytoin which is then glucuronidated to

(dopamine, noradrenaline and adrenaline), tyramine, phenyl-

ephrine and tryptophan derivatives (5-hydroxytryptamine

and tryptamine). Oxidation of purines by xanthine oxidase

(e.g. 6-mercaptopurine is inactivated to 6-thiouric acid) is

non-microsomal.

REDUCTION

This includes, for example, enzymic reduction of double

bonds, e.g. methadone,naloxone.

HYDROLYSIS

Esterases catalyse hydrolytic conversions of many drugs.

Examples include the cleavage of suxamethonium by plasma

cholinesterase, an enzyme that exhibits pharmacogenetic varia-

tion (Chapter 14), as well as hydrolysis of aspirin(acetylsalicylic

acid) to salicylate, and the hydrolysis of enalaprilto enalaprilat.

PHASE II METABOLISM (TRANSFERASE

REACTIONS)

AMINO ACID REACTIONS

Glycine and glutamine are the amino acids chiefly involved in

conjugation reactions in humans. Glycine forms conjugates

with nicotinic acid and salicylate, whilst glutamine forms con-

jugates with p-aminosalicylate. Hepatocellular damage depletes

the intracellular pool of these amino acids, thus restricting this

pathway. Amino acid conjugation is reduced in neonates

(Chapter 10).

ACETYLATION

Acetate derived from acetyl coenzyme Aconjugates with several

drugs, including isoniazid,hydralazine and procainamide (see

Chapter 14 for pharmacogenetics of acetylation). Acetylating

activity resides in the cytosol and occurs in leucocytes, gastro-

intestinal epithelium and the liver (in reticulo-endothelial rather

than parenchymal cells).

GLUCURONIDATION

Conjugation reactions between glucuronic acid and carboxyl

groups are involved in the metabolism of bilirubin, salicylates

and thromboxanes are CYP450 enzymes with distinct

specificities.

REDUCTION

Reduction requires reduced NADP-cytochrome-c reductase or

reduced NAD-cytochrome b5 reductase.

HYDROLYSIS

Pethidine(meperidine) is de-esterified to meperidinic acid by

hepatic membrane-bound esterase activity.

NON-ENDOPLASMIC RETICULUM DRUG

METABOLISM

OXIDATION

Oxidation of ethanol to acetaldehyde and of chloral to

trichlorethanol is catalysed by a cytosolic enzyme (alcohol

dehydrogenase) whose substrates also include vitamin A.

Monoamine oxidase (MAO) is a membrane-bound mitochon-

drial enzyme that oxidatively deaminates primary amines to

aldehydes (which are further oxidized to carboxylic acids) or

ketones. Monoamine oxidase is found in liver, kidney, intestine

and nervous tissue, and its substrates include catecholamines

PHASE II METABOLISM(TRANSFERASE REACTIONS) 25

DRUG

Phase I

(predominantly

CYP450)

Phase II

(transferase

reactions)

– Oxidation

– Reduction

– Hydrolysis

– Acetylation

– Methylation

– Glucuronidation

– Sulphation

– Mercaptopuric

acid formation

– Glutathione

conjugation

Renal (or biliary)

excretion

(a)

Phase I Phase II

Phenobarbital p-Hydroxy

phenobarbital

p-Hydroxy phenobarbital

glucuronide

(b)

Figure 5.1:(a) Phases I and II of drug metabolism. (b) A specific example of phases I and II of drug metabolism, in the case of

phenobarbital.

26 DRUG METABOLISM

Table 5.1:CYP450 isoenzymes most commonly involved in drug metabolism with representative drug substrates and their

specific inhibitors and inducers

Enzyme Substrate Inhibitor Inducer

CYP1A2 Caffeine Amiodarone Insulin

Clozapine Cimetidine Cruciferous vegetables

Theophylline Fluoroquinolones Nafcillin

Warfarin (R) Fluvoxamine Omeprazole

CYP2C9

Celecoxib

Losartan Amiodarone Barbiturates

NSAIDs Fluconazole Rifampicin

Sulphonylureas Fluoxetine/Fluvoxamine

Phenytoin Lansoprazole

Warfarin (S) Sulfamethoxazole

Ticlopidine

CYP2C19

Diazepam Fluoxetine Carbamazepine

Moclobamide Ketoconazole Prednisone

Omeprazole Rifampicin

Pantoprazole

Proguanil

CYP2D6

Codeine (opioids) Amiodarone Dexamethasone

Dextromethorphan Celecoxib Rifampicin

Haloperidol Cimetidine

Metoprolol Ecstasy (MDMA)

Nortriptyline Fluoxetine

Pravastatin Quinidine

Propafenone

CYP2E1 Chlormezanone Diethyldithio-carbamate Ethanol

Paracetamol Isoniazid

Theophylline

CYP3A4 Alprazolam Amiodarone Barbiturates

Atorvastatin Diltiazem Carbamazepine

Ciclosporin Erythromycin (and other Efavirenz

macrolides) Glucocorticosteroids

(and other steroids)

Hydrocortisone Gestodene Nevirapine

Lidocaine Grapefruit juice Phenytoin

Lovastatin Fluvoxamine Pioglitazone

Fluconazole/Itraconazole St John’s wort

Midazolam Ketoconazole

Nifedipine (many CCBs) Nefazodone

Tamoxifen Nelfinavir/Ritonavir

Tacrolimus Verapamil

Vincristine Voriconazole

Known genetic polymorphisms (Chapter 14).

Approximate percentage of clinically used drugs metabolized by each CYP isoenzyme: CYP3A4, 50%; CYP2D6, 20%; CYP2C,

20%; CYP1A2, 2%; CYP2E1, 2%; other CYPs, 6%.

and lorazepam. Some patients inherit a deficiency of glu-

curonide formation that presents clinically as a non-

haemolytic jaundice due to excess unconjugated bilirubin

(Crigler–Najjar syndrome). Drugs that are normally conju-

gated via this pathway aggravate jaundice in such patients.

O-Glucuronides formed by reaction with a hydroxyl group

result in an ether glucuronide. This occurs with drugs such as

paracetamoland morphine.

METHYLATION

Methylation proceeds by a pathway involving S-adenosyl

methionine as methyl donor to drugs with free amino,

hydroxyl or thiol groups. Catechol O-methyltransferase is an

example of such a methylating enzyme, and is of physiologi-

cal as well as pharmacological importance. It is present in

the cytosol, and catalyses the transfer of a methyl group to

catecholamines, inactivating noradrenaline, dopamine and

adrenaline. Phenylethanolamine N-methyltransferase is also

important in catecholamine metabolism. It methylates the

terminal – NH

residue of noradrenaline to form adrenaline in

the adrenal medulla. It also acts on exogenous amines, includ-

ing phenylethanolamine and phenylephrine. It is induced by

corticosteroids, and its high activity in the adrenal medulla

reflects the anatomical arrangement of the blood supply to the

medulla which comes from the adrenal cortex and conse-

quently contains very high concentrations of corticosteroids.

SULPHATION

Cytosolic sulphotransferase enzymes catalyse the sulphation of

hydroxyl and amine groups by transferring the sulphuryl

group from 3-phosphoadenosine 5-phosphosulphate (PAPS)

to the xenobiotic. Under physiological conditions, sulphotrans-

ferases generate heparin and chondroitin sulphate. In addition,

they produce ethereal sulphates from several oestrogens,

androgens, from 3-hydroxycoumarin (a phase I metabolite of

warfarin) and paracetamol. There are a number of sulphotrans-

ferases in the hepatocyte, with different specificities.

MERCAPTURIC ACID FORMATION

Mercapturic acid formation is via reaction with the cysteine

residue in the tripeptide Cys-Glu-Gly, i.e. glutathione. It is

very important in paracetamol overdose (Chapter 54), when

the usual sulphation and glucuronidation pathways of paraceta-

mol metabolism are overwhelmed, with resulting production

of a highly toxic metabolite (N-acetyl-benzoquinone imine,

NABQI). NABQI is normally detoxified by conjugation with

reduced glutathione. The availability of glutathione is critical

in determining the clinical outcome. Patients who have

ingested large amounts of paracetamol are therefore treated

ENZYME INDUCTION 27

with thiol donors such as N-acetyl cysteine or methionine to

increase the endogenous supply of reduced glutathione.

GLUTATHIONE CONJUGATES

Naphthalene and some sulphonamides also form conjugates

with glutathione. One endogenous function of glutathione

conjugation is formation of a sulphidopeptide leukotriene,

leukotriene (LT) C4. This is formed by conjugation of glu-

tathione with LTA4, analogous to a phase II reaction. LTA4 is

an epoxide which is synthesized from arachidonic acid by a

‘phase I’-type oxidation reaction catalysed by the 5-lipoxyge-

nase enzyme. LTC4, together with its dipeptide product LTD4,

comprise the activity once known as ‘slow-reacting substance

of anaphylaxis’ (SRS-A), and these leukotrienes play a role as

bronchoconstrictor mediators in anaphylaxis and in asthma

(see Chapters 12 and 33).

ENZYME INDUCTION

Enzyme induction (Figure 5.2, Table 5.1) is a process by

which enzyme activity is enhanced, usually because of increased

enzyme synthesis (or, less often, reduced enzyme degrada-

tion). The increase in enzyme synthesis is often caused by

xenobiotics binding to nuclear receptors (e.g. pregnane X

receptor, constitutive androstane receptor, aryl hydrocarbon

receptor), which then act as positive transcription factors for

certain CYP450s.

There is marked inter-individual variability in the degree

of induction produced by a given agent, part of which is

genetically determined. Exogenous inducing agents include

not only drugs, but also halogenated insecticides (particularly

dichloro-diphenyl-trichloroethane (DDT) and gamma-benzene

hexachloride), herbicides, polycyclic aromatic hydrocarbons,

dyes, food preservatives, nicotine, ethanol and hyperforin in

St John’s wort. Apractical consequence of enzyme induction is

that, when two or more drugs are given simultaneously, then

if one drug is an inducing agent it can accelerate the metabo-

lism of the other drug and may lead to therapeutic failure

(Chapter 13).

Inducer

(slow –

1–2 weeks)

↑ synthesis

( or ↓ degradation)

of CYP450 isoenzyme(s)

↑ Metabolism

(↓t

)

of target drug

↓

Plasma concentration

of target drug

↓

Effect of target

drug

Figure 5.2:Enzyme induction.

28 DRUG METABOLISM

TESTS FOR INDUCTION OF DRUG-

METABOLIZING ENZYMES

The activity of hepatic drug-metabolizing enzymes can be

assessed by measuring the clearance or metabolite ratios of

probe drug substrates, e.g. midazolam for CYP3A4, dex-

tromethorphan for CYP2D6, but this is seldom if ever indi-

cated clinically. The

C-erythromycin breath test or the urinary

molar ratio of 6-beta-hydroxycortisol/cortisol have also been

used to assess CYP3A4 activity. It is unlikely that a single probe

drug study will be definitive, since the mixed function oxidase

(CYP450) system is so complex that at any one time the activity

of some enzymes may be increased and that of others reduced.

Induction of drug metabolism represents variable expression

of a constant genetic constitution. It is important in drug elim-

ination and also in several other biological processes, including

adaptation to extra-uterine life. Neonates fail to form glu-

curonide conjugates because of immaturity of hepatic uridyl

glucuronyl transferases with clinically important conse-

quences, e.g. grey baby syndrome with chloramphenicol

(Chapter 10).

ENZYME INHIBITION

Allopurinol, methotrexate, angiotensin converting enzyme

inhibitors, non-steroidal anti-inflammatory drugs and many

others, exert their therapeutic effects by enzyme inhibition

(Figure 5.3). Quite apart from such direct actions, inhibition of

drug-metabolizing enzymes by a concurrently administered

drug (Table 5.1) can lead to drug accumulation and toxicity.

For example, cimetidine, an antagonist at the histamine

-receptor, also inhibits drug metabolism via the CYP450

system and potentiates the actions of unrelated CYP450

metabolized drugs, such as warfarin and theophylline (see

Chapters 13, 30 and 33). Other potent CYP3A4 inhibitors

include the azoles (e.g. fluconazole, voriconazole) and HIV

protease inhibitors (e.g. ritonavir).

The specificity of enzyme inhibition is sometimes incom-

plete. For example, warfarin and phenytoin compete with

one another for metabolism, and co-administration results in

elevation of plasma steady-state concentrations of both drugs.

Metronidazole is a non-competitive inhibitor of microsomal

enzymes and inhibits phenytoin,warfarin and sulphonylurea

(e.g.glyburide) metabolism.

PRESYSTEMIC METABOLISM (‘FIRST-PASS’

EFFECT)

The metabolism of some drugs is markedly dependent on the

route of administration. Following oral administration, drugs

gain access to the systemic circulation via the portal vein, so the

entire absorbed dose is exposed first to the intestinal mucosa

and then to the liver, before gaining access to the rest of the

body. Aconsiderably smaller fraction of the absorbed dose goes

through gut and liver in subsequent passes because of distribu-

tion to other tissues and drug elimination by other routes.

If a drug is subject to a high hepatic clearance (i.e. it is rap-

idly metabolized by the liver), a substantial fraction will be

extracted from the portal blood and metabolized before it

reaches the systemic circulation. This, in combination with

intestinal mucosal metabolism, is known as presystemic or

‘first-pass’ metabolism (Figure 5.4).

The route of administration and presystemic metabolism

markedly influence the pattern of drug metabolism. For exam-

ple, when salbutamol is given to asthmatic subjects, the ratio

of unchanged drug to metabolite in the urine is 2:1 after intra-

venous administration, but 1:2 after an oral dose. Propranolol

undergoes substantial hepatic presystemic metabolism, and

small doses given orally are completely metabolized before

they reach the systematic circulation. After intravenous admin-

istration, the area under the plasma concentration–time curve

is proportional to the dose administered and passes through

the origin (Figure 5.5). After oral administration the relation-

ship, although linear, does not pass through the origin and

there is a threshold dose below which measurable concentra-

tions of propranolol are not detectable in systemic venous

plasma. The usual dose of drugs with substantial presystemic

metabolism differs very markedly if the drug is given by

the oral or by the systemic route (one must never estimate or

guess the i.v. dose of a drug from its usual oral dose for this

reason!) In patients with portocaval anastomoses bypassing

the liver, hepatic presystemic metabolism is bypassed, so

very small drug doses are needed compared to the usual

oral dose.

Presystemic metabolism is not limited to the liver, since the

gastro-intestinal mucosa contains many drug-metabolizing

enzymes (e.g. CYP3A4, dopa-decarboxylase, catechol-

O-methyl transferase (COMT)) which can metabolize drugs, e.g.

ciclosporin, felodipine, levodopa, salbutamol, before they

enter hepatic portal blood. Pronounced first-pass metabolism by

either the gastro-intestinal mucosa (e.g. felodipine,salbutamol,

levodopa) or liver (e.g. felodipine, glyceryl trinitrate, mor-

phine, naloxone, verapamil) necessitates high oral doses by

comparison with the intravenous route. Alternative routes of

drug delivery (e.g. buccal, rectal, sublingual, transdermal) partly

or completely bypass presystemic elimination (Chapter 4).

Drugs undergoing extensive presystemic metabolism usu-

ally exhibit pronounced inter-individual variability in drug dis-

position. This results in highly variable responses to therapy,

Inhibitor Direct inhibition

of CYP450

isoenzyme(s)

↓ Metabolism

(↑t

)

of target drug

Rapid

↑

Plasma concentration

of target drug

↑

Effect

↑

Toxicity

of target drug

Figure 5.3:Enzyme inhibition.

METABOLISMOF DRUGS BY INTE STINAL ORGANISMS 29

and is one of the major difficulties in their clinical use.

Variability in first-pass metabolism results from:

1. Genetic variations – for example, the bioavailability of

hydralazineis about double in slow compared to fast

acetylators. Presystemic hydroxylation of metoprololand

encainidealso depends on genetic polymorphisms

(CYP2D6, Chapter 14).

2. Induction or inhibition of drug-metabolizing enzymes.

3. Food increases liver blood flow and can increase the

bioavailability of drugs, such as propranolol,metoprolol

andhydralazine, by increasing hepatic blood flow and

exceeding the threshold for complete hepatic extraction.

4. Drugs that increase liver blood flow have similar effects to

food – for example, hydralazineincreases propranolol

bioavailability by approximately one-third, whereas drugs

that reduce liver blood flow (e.g. -adrenoceptor

antagonists) reduce it.

5. Non-linear first-pass kinetics are common (e.g. aspirin,

hydralazine,propranolol): increasing the dose

disproportionately increases bioavailability.

6. Liver disease increases the bioavailability of some drugs

with extensive first-pass extraction (e.g. diltiazem,

ciclosporin,morphine).

METABOLISM OF DRUGS BY INTESTINAL

ORGANISMS

This is important for drugs undergoing significant enterohep-

atic circulation. For example, in the case of estradiol, which is

excreted in bile as a glucuronide conjugate, bacteria-derived

enzymes cleave the glucuronide so that free drug is available

for reabsorption in the terminal ileum. Asmall proportion of

the dose (approximately 7%) is excreted in the faeces under

normal circumstances; this increases if gastro-intestinal dis-

ease or concurrent antibiotic therapy alter the intestinal flora.

Orally

administered

drug

Intestinal

mucosal

metabolism

Portal

vein

Hepatic

metabolism

Systemic

circulation

First-pass

metabolism

Parenterally

administered

drug

Figure 5.4:Presystemic (‘first-pass’) metabolism.

i.v.

Oral

500

1000

40 80 120 160

Area (ng/ml h)

Dose (mg)

Figure 5.5:Area under blood concentration–time curve after oral

(䊉) and intravenous (䊊) administration of propranolol to humans

in various doses. T is the apparent threshold for propranolol

following oral administration. (Redrawn from Shand DG, Rangno

RE.Pharmacology 1972; 7: 159, with permission of

S Karger AG, Basle.)

Key points

• Drug metabolism involves two phases: phase I often

followed sequentially by phase II.

• Phase I metabolism introduces a reactive group into a

molecule, usually by oxidation, by a microsomal system

present in the liver.

• The CYP450 enzymes are a superfamily of

haemoproteins. They have distinct isoenzyme forms

and are critical for phase I reactions.

• Products of phase I metabolism may be

pharmacologically active, as well as being chemically

reactive, and can be hepatotoxic.

• Phase II reactions involve conjugation (e.g. acetylation,

glucuronidation, sulphation, methylation).

• Products of phase II metabolism are polar and can be

efficiently excreted by the kidneys. Unlike the products

of phase I metabolism, they are nearly always

pharmacologically inactive.

• The CYP450 enzymes involved in phase I metabolism can

be induced by several drugs and nutraceuticals (e.g.

glucocorticosteroids, rifampicin, carbamazepine, St John’s

wort) or inhibited by drugs (e.g. cimetidine, azoles, HIV

protease inhibitors, quinolones, metronidazole) and

dietary constituents (e.g. grapefruit/grapefruit juice).

• Induction or inhibition of the CYP450 system are

important causes of drug–drug interactions (see

Chapter 13).

30 DRUG METABOLISM

Case history

A 46-year-old woman is brought to the hospital Accident

and Emergency Department by her sister, having swal-

lowed an unknown number of paracetamol tablets washed

down with vodka six hours previously, following an argu-

ment with her partner. She is an alcoholic and has been

taking St John’s wort for several weeks. Apart from signs

of intoxication, examination was unremarkable. Plasma

paracetamol concentration was 662μmol/L (100 mg/L).

Following discussion with the resident medical officer/

Poisons Information Service, it was decided to administer

N-acetylcysteine.

Comment

In paracetamol overdose, the usual pathway of elimination

is overwhelmed and a highly toxic product (N-acetyl benzo-

quinone imine, known as NABQI) is formed by CYP1A2, 2E1

and CYP3A4 metabolism. A plasma paracetamol concentra-

tion of 100mg/L six hours after ingestion would not usually

require antidote treatment, but this woman is an alcoholic

and is taking St John’s wort and her hepatic drug-

metabolizing enzymes (CYP1A2, CYP3A4 and probably

others) will have been induced, so the paracetamol concen-

tration threshold for antidote treatment is lowered (see

Chapter 54). N-Acetylcysteine is the specific antidote, as it

increases reduced glutathione which conjugates NABQI

within hepatocytes.

FURTHER READING

Carmichael DJS. Chapter 19.2 Handling of drugs in kidney disease.

In: AMADavison, J Stewart Cameron, J-P Grunfeld, C Ponticelli,

C Van Ypersele, E Ritz and C Winearls (eds). Oxford textbook of clin-

ical nephrology, 3rd edn. Oxford: Oxford University Press, 2005:

2599–618.

Eraly SA, Bush KT, Sampogna RV, Bhatnagar V, Nigam SK. The mole-

cular pharmacology of organic anion transporters: from DNAto

FDA?Molecular Pharmacology 2004; 65: 479–87.

Koepsell H. Polyspecific organic cation transporters: their functions

and interactions with drugs. Trends in Pharmacological Sciences

2004;25: 375–81.

van Montfoort JE, Hagenbuch B, Groothuis GMM, Koepsell H,

Meier PJ, Meijer DKF. Drug uptake systems in liver and kidney.

Current Drug Metabolism2003; 4: 185–211.

ACTIVE TUBULAR REABSORPTION 33

Key points

• The kidney cannot excrete non-polar substances

efficiently, since these diffuse back into blood as the

urine is concentrated. Consequently, the kidney

excretes polar drugs and/or the polar metabolites of

non-polar compounds.

• Renal impairment reduces the elimination of drugs that

depend on glomerular filtration, so the dose of drugs,

such as digoxin, must be reduced, or the dose interval

(e.g. between doses of aminoglycoside) must be

increased, to avoid toxicity.

• There are specific secretory mechanisms for organic

acids and organic bases in the proximal tubules which

lead to the efficient clearance of weak acids, such as

penicillin, and weak bases, such as cimetidine.

Competition for these carriers can cause drug

interactions, although less commonly than induction or

inhibition of cytochrome P450.

• Passive reabsorption limits the efficiency with which the

kidney eliminates drugs. W

eak acids are best eliminated

in an alkaline urine (which favours the charged form,



), whereas weak bases are best eliminated in an acid

urine (which favours the charged form, BH



• The urine may be deliberately alkalinized by infusing

sodium bicarbonate intravenously in the management

of overdose with weak acids such as aspirin (see

Chapter 54, to increase tubular elimination of

salicylate.

• Lithium ions are actively reabsorbed in the proximal

tubule by the same system that normally reabsorbs

sodium, so salt depletion (which causes increased

proximal tubular sodium ion reabsorption) causes

lithium toxicity unless the dose of lithium is reduced.

Case history

A house officer (HO) sees a 53-year-old woman in the

Accident and Emergency Department with a six-hour his-

tory of fevers, chills, loin pain and dysuria. She looks very ill,

with a temperature of 39.5°C, blood pressure of 80/60mmHg

and right loin tenderness. The white blood cell count is

raised at 15000/μL, and there are numerous white cells and

rod-shaped organisms in the urine. Serum creatinine is nor-

mal at 90μmol/L. The HO wants to start treatment with

aminoglycoside antibiotic pending the availability of a bed

on the intensive care unit. Despite the normal creatinine

level, he is concerned that the dose may need to be adjusted

and calls the resident medical officer for advice.

Comment

The HO is right to be concerned. The patient is hypotensive

and will be perfusing her kidneys poorly. Serum creatinine

may be normal in rapid onset acute renal failure. It is impor-

tant to obtain an adequate peak concentration to combat

her presumed Gram-negative septicaemia. It would there-

fore be appropriate to start treatment with the normal

loading dose. This will achieve the usual peak concentra-

tion (since the volume of distribution will be similar to

that in a healthy person). However, the subsequent and

maintenance doses should not be given until urgent post-

administration blood concentrations have been obtained –

the dosing interval may be appropriately prolonged if

renal failure does indeed supervene causing reduced

aminoglycoside clearance.

pancreatic secretions and bile flow, can impair the absorption

of fat-soluble vitamins. Significant reductions in the absorption

of cefalexin occur in cystic fibrosis, necessitating increased

doses in such patients. Patients with small bowel resection

may absorb lipophilic drugs poorly.

CARDIAC FAILURE

Cardiac failure affects pharmacokinetics in several ways and

these are discussed below.

ABSORPTION

Absorption of some drugs (e.g. furosemide) is altered in car-

diac failure because of mucosal oedema and reduced gastro-

intestinal blood flow. Splanchnic vasoconstriction accompanies

cardiac failure as an adaptive response redistributing blood to

more vital organs.

●

Introduction 34

●

Gastro-intestinal disease 34

●

Cardiac failure 34

●

Renal disease 35

●

Liver disease 37

●

Thyroid disease 38

CHAPTER 7

EFFECTS OF DISEASE ON DRUG

DISPOSITION

INTRODUCTION

Several common disorders influence the way in which the

body handles drugs and these must be considered before pre-

scribing. Gastro-intestinal, cardiac, renal, liver and thyroid

disorders all influence drug pharmacokinetics, and individu-

alization of therapy is very important in such patients.

GASTRO-INTESTINAL DISEASE

Gastro-intestinal disease alters the absorption of orally admin-

istered drugs. This can cause therapeutic failure, so alternative

routes of administration (Chapter 4) are sometimes needed.

GASTRIC EMPTYING

Gastric emptying is an important determinant of the rate and

sometimes also the extent of drug absorption. Several patho-

logical factors alter gastric emptying (Table 7.1). However,

there is little detailed information about the effect of disease

on drug absorption, in contrast to effects of drugs that slow

gastric emptying (e.g. anti-muscarinic drugs) which delay

max

. Absorption of analgesics is delayed in migraine, and a

more rapid absorption can be achieved by administeringanal-

gesics with metoclopramide, which increases gastric emptying.

SMALL INTESTINAL AND PANCREATIC DISEASE

The very large absorptive surface of the small intestine pro-

vides a substantial functional reserve, so even extensive

involvement with, for example, coeliac disease may be present

without causing a clinically important reduction in drug

absorption. Crohn’s disease typically affects the terminal

ileum. Absorption of several antibiotics actually increases in

Crohn’s disease. Cystic fibrosis, because of its effects on

Table 7.1: Pathological factors influencing the rate of gastric emptying

Decreased rate Increased rate

Trauma Duodenal ulcer

Pain (including myocardial Gastroenterostomy

infarction, acute abdomen) Coeliac disease

Diabetic neuropathy Drugs, e.g. metoclopramide

Labour

Migraine

Myxoedema

Raised intracranial pressure

Intestinal obstruction

Gastric ulcer

Anti-muscarinic drugs

RENAL DISEASE 35

DISTRIBUTION

Drug distribution is altered by cardiac failure. The apparent

volume of distribution (V

) of, for example, quinidine and

lidocainein patients with congestive cardiac failure is markedly

reduced because of decreased tissue perfusion and altered

partition between blood and tissue components. Usual doses

can therefore result in elevated plasma concentrations, pro-

ducing toxicity.

ELIMINATION

Elimination of several drugs is diminished in heart failure.

Decreased hepatic perfusion accompanies reduced cardiac

output. Drugs such as lidocainewith a high hepatic extraction

ratio of 70% show perfusion-limited clearance, and steady-

state levels are inversely related to cardiac output (Figure 7.1).

Duringlidocaine infusion, the steady-state concentrations are

almost 50% higher in patients with cardiac failure than in healthy

volunteers. The potential for lidocainetoxicity in heart failure

is further increased by the accumulation of its polar metab-

olites, which have cardiodepressant and pro-convulsant prop-

erties. This occurs because renal blood flow and glomerular

filtration rate are reduced in heart failure.

Theophylline clearance is decreased and its half-life is

doubled in patients with cardiac failure and pulmonary oedema,

increasing the potential for accumulation and toxicity. The

metabolic capacity of the liver is reduced in heart failure both

by tissue hypoxia and by hepatocellular damage from hepatic

congestion. Liver biopsy samples from patients with heart

failure have reduced drug-metabolizing enzyme activity.

Heart failure reduces renal elimination of drugs because of

reduced glomerular filtration, predisposing to toxicity from

drugs that are primarily cleared by the kidneys, e.g. amino-

glycosides and digoxin.

RENAL DISEASE

RENAL IMPAIRMENT

Renal excretion is a major route of elimination for many drugs

(Chapter 6), and drugs and their metabolites that are excreted

predominantly by the kidneys accumulate in renal failure.

Renal disease also affects other pharmacokinetic processes

(i.e. drug absorption, distribution and metabolism) in more

subtle ways.

ABSORPTION

Gastric pH increases in chronic renal failure because urea is

cleaved, yielding ammonia which buffers acid in the stomach.

This reduces the absorption of ferrous iron and possibly also of

other drugs. Nephrotic syndrome is associated with resistance

to oral diuretics, and malabsorption of loop diuretics through

the oedematous intestine may contribute to this.

DISTRIBUTION

Renal impairment causes accumulation of several acidic sub-

stances that compete with drugs for binding sites on albumin

0.1

60 120 180 240

Heart

failure

Control

Lidocaine concentration (g/ml)

Time after injection (min)

0 250 500 750 100012501500 1750

Estimated hepatic blood

flow (ml/min/m

)

1.0

1.4

1.8

2.2

2.6

3.0

3.4

Steady-state arterial

concentration of lidocaine (g/ml)

3.2

3.0

2.8

2.6

2.4

2.2

2.0

1.8

1.6

1.4

1.2

1.51.0 2.0 2.5 3.0 3.5 4.0 4.5

Cardiac index (I/min/m

)

Arterial lidocaine (g/ml)

(c)

(b)

(a)

Figure 7.1:(a) Mean values (and standard deviations) of plasma

lidocaine concentrations in seven heart failure patients and

controls following a 50-mg intravenous bolus. (b) Relationship

between arterial lidocaine level and cardiac index (dotted

vertical line is lower limit of normal cardiac index, square is mean

for low cardiac index patients, triangle is mean for patients with

normal cardiac index). (c) Relationship of steady-state arterial

lidocaine level following 50-mg bolus and infusion of

40mg/kg/min (vertical line is lower limit of normal hepatic blood

flow, square is mean for patients with low hepatic blood flow,

triangle is mean for patients with normal flow). (Reproduced

from: (a) Thompson PD et al. American Heart Journal1971; 82,

417; (b,c) Stenson RE et al. Circulation1971; 43: 205. With

permission of the American Heart Association Inc.)

and other plasma proteins. This alters the pharmacokinetics of

many drugs, but is seldom clinically important. Phenytoin

is an exception, because therapy is guided by plasma concen-

tration and routine analytical methods detect total (bound

and free) drug. In renal impairment, phenytoinprotein bind-

ing is reduced by competition with accumulated molecules

normally cleared by the kidney and which bind to the same

albumin drug-binding site as phenytoin. Thus, for any meas-

ured phenytoin concentration, free (active) drug is increased

compared to a subject with normal renal function and the

same measured total concentration. The therapeutic range

therefore has to be adjusted to lower values in patients with

renal impairment, as otherwise doses will be selected that

cause toxicity.

Tissue binding of digoxin is reduced in patients with

impaired renal function, resulting in a lower volume of distri-

bution than in healthy subjects. A reduced loading dose of

digoxinis therefore appropriate in such patients, although the

effect of reduced glomerular filtration on digoxinclearance is

even more important, necessitating a reduced maintenance

dose, as described below.

The blood–brain barrier is more permeable to drugs in

uraemia. This can result in increased access of drugs to the

central nervous system, an effect that is believed to contribute

to the increased incidence of confusion caused by cimetidine,

ranitidineand famotidine in patients with renal failure.

METABOLISM

Metabolism of several drugs is reduced in renal failure. These

include drugs that undergo phase I metabolism by CYP3A4.

Drugs that are mainly metabolized by phase II drug metabol-

ism are less affected, although conversion of sulindac to its

active sulphide metabolite is impaired in renal failure, as is the

hepatic conjugation of metoclopramidewith glucuronide and

sulphate.

RENAL EXCRETION

Glomerular filtration and tubular secretion of drugs usually

fall in step with one another in patients with renal impair-

ment. Drug excretion is directly related to glomerular filtra-

tion rate (GFR). Some estimate of GFR (eGFR) is therefore

essential when deciding on an appropriate dose regimen.

Serum creatinine concentration adjusted for age permits cal-

culation of an estimate of GFR per 1.73m

body surface area.

This is now provided by most chemical pathology labora-

tories, and is useful in many situations. Alternatively, Figure 7.2

shows a nomogram given plasma creatinine, age, sex and

body weight and is useful when a patient is markedly over- or

underweight. The main limitation of such estimates is that

they are misleading if GFR is changing rapidly as in acute

renal failure. (Imagine that a patient with normal serum creati-

nine undergoes bilateral nephrectomy: an hour later, his serum

creatinine would still be normal, but his GFR would be zero.

Creatinine would rise gradually over the next few days as it con-

tinued to be produced in his body but was not cleared.) Anor-

mal creatinine level therefore does not mean that usual doses

can be assumed to be safe in a patient who is acutely unwell.

36 EFFECTSOF DISEASE ON DRUG DISPOSITION

eGFR is used to adjust the dose regimen in patients with

some degree of chronic renal impairment for drugs with a low

therapeutic index that are eliminated mainly by renal excre-

tion. Dose adjustment must be considered for drugs for which

there is 50% elimination by renal excretion. The British

National Formulary tabulates drugs to be avoided or used

with caution in patients with renal failure. Common examples

are shown in Table 7.2.

Clearance

(ml/min)

Weight

(kg)

Serum

creatinine

(mg/100 ml)

Age

(years)

5.0

4.0

3.0

2.0

1.7

1.3

0.9

1.0

0.8

0.7

0.6

0.5

0.4

1.5

1.2

100

110

120

150

130

110

100

Figure 7.2:Nomogram for rapid evaluation of endogenous

creatinine clearance – with a ruler joining weight to age. Keep

ruler at crossing point on R, then move the right-hand side of the

ruler to the appropriate serum creatinine value and read off

clearance from the left-hand scale. To convert serum creatinine in

mol/L to mg/100mL, as is used on this scale, simply divide by

88.4. (Reproduced with permission from Siersbaek-Nielson K

et al. Lancet1971; 1: 1133. © The Lancet Ltd.)

Table 7.2:Examples of drugs to be used with particular caution or avoided

in renal failure

Angiotensin-converting enzyme Angiotensin receptor

inhibitors

blockers

Aldosterone antagonists Aminoglycosides

Amphotericin Atenolol

Ciprofloxacin Cytotoxics

Digoxin Lithium

Low molecular weight heparin Metformin

NSAIDs Methotrexate

ACEI and ARB must be used with caution, but can slow progressive renal

impairment (see Chapter 28).

Detailed recommendations on dosage reduction can be

found in textbooks of nephrology. These are useful for getting

treatment under way but, although precise, such recommenda-

tions are inevitably based only on the effects of reduced renal

function on drug elimination in ‘average’ populations.

Individual variation is substantial, and therapeutic monitoring

of efficacy, toxicity and sometimes of drug concentrations is

essential in patients with impaired renal function.

There are two ways of reducing the total dose to compensate

for impaired renal function. Either each dose can be reduced, or

the interval between each dose can be lengthened. The latter

method is useful when a drug must achieve some threshold con-

centration to produce its desired effect, but does not need to

remain at this level throughout the dose interval. This is the case

with aminoglycoside antibiotics. Therapy with these drugs

is appropriately monitored by measuring ‘peak’ concentrations

(in blood sampled at a fixed brief interval after dosing, sufficient

to permit at least partial tissue distribution), which indicate

whether the dose is large enough to achieve a therapeutic

plasma concentration, and ’trough’ concentrations immediately

before the next dose (see Chapter 8). If the peak concentration is

satisfactory but the trough concentration is higher than desired

(i.e. toxicity is present or imminent), the dose is not reduced but

the interval between doses is extended. This type of therapeutic

drug monitoring is modified to a single time point (after dosing

and beyond the distribution phase) when extended interval dos-

ing of aminoglycosides is used to treat patients (Chapter 43).

RENAL HAEMODYNAMICS

Patients with mild renal impairment depend on vasodilator

prostaglandin biosynthesis to preserve renal blood flow and

GFR. The same is true of patients with heart failure, nephrotic

syndrome, cirrhosis or ascites. Such patients develop acute

reversible renal impairment, often accompanied by salt and

water retention and hypertension if treated with non-steroidal

anti-inflammatory drugs (NSAIDs, see Chapter 26), because

these inhibit cyclo-oxygenase and hence the synthesis of

vasodilator prostaglandins, notably prostaglandin I

(prosta-

cyclin) and prostaglandin E

. Sulindac is a partial exception

because it inhibits cyclo-oxygenase less in kidneys than in

other tissues, although this specificity is incomplete and dose

dependent.

Angiotensin converting enzyme inhibitors (e.g. ramipril) can

also cause reversible renal failure due to altered renal haemody-

namics. This occurs predictably in patients with bilateral renal

artery stenosis (or with renal artery stenosis involving a single

functioning kidney). The explanation is that in such patients

GFR is preserved in the face of the fixed proximal obstruction by

angiotensin-II-mediated efferent arteriolar vasoconstriction.

Inhibition of angiotensin converting enzyme disables this home-

ostatic mechanism and precipitates renal failure.

NEPHROTIC SYNDROME

Plasma albumin in patients with nephrotic syndrome is low,

resulting in increased fluctuations of free drug concentration

LIVER DISEASE 37

following each dose. This could cause adverse effects, although

in practice this is seldom clinically important. The high albumin

concentration in tubular fluid contributes to the resistance to

diuretics that accompanies nephrotic syndrome. This is because

both loop diuretics and thiazides act on ion-transport processes

in the luminal membranes of tubular cells (see Chapter 36).

Protein binding of such diuretics within the tubular lumen

therefore reduces the concentration of free (active) drug in

tubular fluid in contact with the ion transporters on which

they act.

PRESCRIBING FOR PATIENTS WITH RENAL

DISEASE

1. Consider the possibility of renal impairment before drugs

are prescribed and use available data to estimate GFR.

2. Check how drugs are eliminated before prescribing them.

If renal elimination accounts for more than 50% of total

elimination, then dose reduction will probably be

necessary after the first dose, i.e. for maintenance

doses.

3. Monitor therapeutic and adverse effects and, where

appropriate, plasma drug concentrations.

4. If possible avoid potentially nephrotoxic drugs (e.g.

aminoglycosides, NSAIDs); if such drugs are essential use

them with great care.

Once a potential renal problem necessitating dose modifica-

tion has been identified, there are a number of accepted refer-

ence sources that provide guidance for dose adjustment.

These are useful approximations to get treatment under way,

but their mathematical precision is illusory, and must not lull

the inexperienced into a false sense of security – they do not

permit a full ‘course’ of treatment to be prescribed safely. The

patient must be monitored and treatment modified in the light

of individual responses. The British National Formulary has a

useful appendix which is concise, simple and accessible.

LIVER DISEASE

The liver is the main site of drug metabolism (Chapter 5). Liver

disease has major but unpredictable effects on drug handling.

Pharmacokinetic factors that are affected include absorption

and distribution, as well as the metabolism of drugs.

Attempts to correlate changes in the pharmacokinetics of

drugs with biochemical tests of liver function have been

unsuccessful (in contrast to the use of plasma creatinine in

chronic renal impairment described above). In chronic liver

disease, serum albumin is the most useful index of hepatic

drug-metabolizing activity, possibly because a low albumin

level reflects depressed synthesis of hepatic proteins, includ-

ing those involved in drug metabolism. Prothrombin time also

shows a moderate correlation with drug clearance by the liver.

However, in neither case has a continuous relationship been

38 EFFECTSOF DISEASE ON DRUG DISPOSITION

demonstrated, and such indices of hepatic function serve

mainly to distinguish the severely affected from the milder

cases. Clearances of indocyanine green, antipyrine and lido-

cainehave also been disappointing.

Currently, therefore, cautious empiricism coupled with an

awareness of an increased likelihood of adverse drug effects

and close clinical monitoring is the best way for a prescriber to

approach a patient with liver disease. Drugs should be used

only if necessary, and the risks weighed against potential bene-

fit. If possible, drugs that are eliminated by routes other than

the liver should be employed.

EFFECTS OF LIVER DISEASE ON DRUG

ABSORPTION

Absorption of drugs is altered in liver disease because of portal

hypertension, and because hypoalbuminaemia causes mucosal

oedema. Portal/systemic anastomoses allow the passage of

orally administered drug directly into the systemic circulation,

bypassing hepatic presystemic metabolism and markedly

increasing the bioavailability of drugs with high presystemic

metabolism such as propranolol, morphine, verapamil and

ciclosporin, which must therefore be started in low doses in

such patients and titrated according to effect.

DISTRIBUTION OF DRUGS IN PATIENTS WITH

LIVER DISEASE

Drug distribution is altered in liver disease. Reduced plasma

albumin reduces plasma protein binding. This is also influ-

enced by bilirubin and other endogenous substances that

accumulate in liver disease and may displace drugs from bind-

ing sites. The free fraction of tolbutamideis increased by 115%

in cirrhosis, and that of phenytoinis increased by up to 40%.

It is particularly important to appreciate this when plasma

concentrations of phenytoin are being used to monitor ther-

apy, as unless the therapeutic range is adjusted downward,

toxicity will be induced, as explained above in the section on

drug distribution in renal disease.

Reduced plasma protein binding increases the apparent V

if other factors remain unchanged. Increased V

of several

drugs (e.g. theophylline) is indeed observed in patients with

liver disease. Disease-induced alterations in clearance and V

often act in opposite directions with regard to their effect on

1/2

. Data on t

1/2

in isolation provide little information about

the extent of changes in metabolism or drug distribution

which result from liver disease.

DRUG METABOLISM IN LIVER DISEASE

CYP450-mediated phase I drug metabolism is generally

reduced in patients with very severe liver disease, but drug

metabolism is surprisingly little impaired in patients with

moderate to severe disease. There is a poor correlation

between microsomal enzyme activity from liver biopsy speci-

mens in vitro and drug clearance measurements in vivo. Even

in very severe disease, the metabolism of different drugs is not

affected to the same extent. It is therefore hazardous to extrapo-

late from knowledge of the handling of one drug to effects on

another in an individual patient with liver disease.

Prescribing for patients with liver disease

1. Weigh risks against hoped for benefit, and minimize non-

essential drug use.

2. If possible, use drugs that are eliminated by routes

other than the liver (i.e. in general, renally cleared

drugs).

3. Monitor response, including adverse effects (and

occasionally drug concentrations), and adjust therapy

accordingly.

4. Avoid sedatives and analgesics if possible: they are

common precipitants of hepatic coma.

5. Predictable hepatotoxins (e.g. cytotoxic drugs) should

only be used for the strongest of indications, and then

only with close clinical and biochemical monitoring.

6. Drugs that are known to cause idiosyncratic liver disease

(e.g.isoniazid, phenytoin, methyldopa) are not

necessarily contraindicated in stable chronic disease, as

there is no evidence of increased susceptibility. Oral

contraceptives are not advisable if there is active liver

disease or a history of jaundice of pregnancy.

7. Constipation favours bacterial production of false

neurotransmitter amines in the bowel: avoid drugs that

cause constipation (e.g. verapamil, tricyclic

antidepressants) if possible.

8. Drugs that inhibit catabolism of amines (e.g. monoamine

oxidase inhibitors) also provoke coma and should be

avoided.

9. Low plasma potassium provokes encephalopathy: avoid

drugs that cause this if possible. Potassium-sparing

drugs, such as spironolactone, are useful.

10. Avoid drugs that cause fluid overload or renal failure

(e.g. NSAID) and beware those containing sodium (e.g.

sodium-containing antacids and high-dose

carbenicillin).

11. Avoid drugs that interfere with haemostasis (e.g. aspirin,

anticoagulants and fibrinolytics) whenever possible,

because of the increased risk of bleeding (especially in the

presence of varices!).

THYROID DISEASE

Thyroid dysfunction affects drug disposition partly as a result

of effects on drug metabolism and partly via changes in renal

elimination. Existing data refer to only a few drugs, but it is

prudent to anticipate the possibility of increased sensitivity of

hypothyroid patients to many drugs when prescribing.

Information is available for the following drugs.

DIGOXIN

Myxoedematous patients are extremely sensitive to digoxin,

whereas unusually high doses are required in thyrotoxicosis.

In general, hyperthyroid patients have lower plasma digoxin

concentrations and hypothyroid patients have higher plasma

concentrations than euthyroid patients on the same dose.

There is no significant difference in half-life between these

groups, and a difference in V

has been postulated to explain

the alteration of plasma concentration with thyroid activity.

Changes in renal function, which occur with changes in thy-

roid status, complicate this interpretation. GFR is increased in

thyrotoxicosis and decreased in myxoedema. These changes

in renal function influence elimination, and the reduced plasma

levels of digoxincorrelate closely with the increased creatinine

clearance in thyrotoxicosis. Other factors including enhanced

biliary clearance, digoxin malabsorption due to intestinal

hurry and increased hepatic metabolism, have all been postu-

lated as factors contributing to the insensitivity of thyrotoxic

patients to cardiac glycosides.

ANTICOAGULANTS

Oral anticoagulants produce an exaggerated prolongation of

prothrombin time in hyperthyroid patients. This is due to

increased metabolic breakdown of vitamin K-dependent clot-

ting factors (Chapter 30), rather than to changes in drug phar-

macokinetics.

GLUCOCORTICOIDS

Glucocorticoids are metabolized by hepatic mixed-function

oxidases (CYP3A4) which are influenced by thyroid status.

In hyperthyroidism, there is increased cortisol production

and a reduced cortisol half-life, the converse being true in

myxoedema.

THYROXINE

The normal half-life of thyroxine(six to seven days) is reduced

to three to four days by hyperthyroidism and prolonged to

nine to ten days by hypothyroidism. This is of considerable

clinical importance when deciding on an appropriate interval

at which to increase the dose of thyroxine in patients treated

for myxoedema, especially if they have coincident ischaemic

heart disease which would be exacerbated if an excessive

steady-statethyroxine level were achieved.

ANTITHYROID DRUGS

The half-life of propylthiouracil and methimazole is pro-

longed in hypothyroidism and shortened in hyperthyroidism.

THYROID DISEASE 39

Key points

Disease profoundly influences the response to many drugs

by altering pharmacokinetics and/or pharmacodynamics.

• Gastro-intestinal disease:

(a)diseases that alter gastric emptying influence

the response to oral drugs (e.g. migraine reduces

gastric emptying, limiting the effectiveness of

analgesics);

(b)

ileum/pancreas – relatively minor effects.

• Heart failure:

(a)absorption of drugs (e.g. furosemide) is reduced as a

result of splanchnic hypoperfusion;

(b)elimination of drugs that are removed very

ficiently by the liver (e.g. lidocaine) is reduced as a

result of reduced hepatic blood flow, predisposing

to toxicity;

acidosis with metformin (cor pulmonale especially

predisposes to this because of hypoxia).

• Renal disease:

(a)chronic renal failure – as well as reduced excretion,

drug absorption, distribution and metabolism may

also be altered. Estimates of creatinine clearance or

GFR based on serum creatinine concentration/

weight/age/sex/ ethnicity provide a useful index of

the need for maintenance dose adjustment in

chronic renal failure;

(b)nephrotic syndrome leads to altered drug

distribution because of altered binding to albumin

and altered therapeutic range of concentrations for

drugs that are extensively bound to albumin (e.g.

some anticonvulsants). Albumin in tubular fluid

binds diuretics and causes diuretic resistance.

Glomerular filtration rate is preserved in nephrotic

syndrome by compensatory increased prostaglandin

synthesis, so NSAIDs (see Chapter 26) can precipitate

renal failure.

• Liver disease – as well as ef

fects on drug metabolism,

absorption and distribution may also be altered because

of portal systemic shunting, hypoalbuminaemia and

ascites. There is no widely measured biochemical marker

(analogous to serum creatinine in chronic renal failure)

to guide dose adjustment in liver disease, and a cautious

dose titration approach should be used.

• Thyroid disease:

(a)hypothyroidism increases sensitivity to digoxin and

opioids;

(b)hyperthyroidism increases sensitivity to warfarin and

reduces sensitivity to digoxin.

These values return to normal on attainment of the euthyroid

state, probably because of altered hepatic metabolism.

OPIATES

Patients with hypothyroidism are exceptionally sensitive to

opioid analgesics, which cause profound respiratory depres-

sion in this setting. This is probably due to reduced metab-

olism and increased sensitivity.

40 EFFECTSOF DISEASE ON DRUG DISPOSITION

FURTHER READING

Carmichael DJS. Chapter 19.2 Handling of drugs in kidney disease. In:

AMA Davison, J Stewart Cameron, J-P Grunfeld, C Ponticelli,

C Van Ypersele, E Ritz and C Winearls (eds). Oxford textbook of clin-

ical nephrology, 3rd edn. Oxford: Oxford University Press, 2005:

2599–618.

Rowland M, Tozer TN. Disease. In: Clinical pharmacokinetics: concepts

and applications, 3rd edn. Baltimore: Williams and Wilkins, 1995:

248–66.

Case history

A 57-year-old alcoholic is admitted to hospital because of

gross ascites and peripheral oedema. He looks chronically

unwell, is jaundiced, and has spider naevi and gynaecomas-

tia. His liver and spleen are not palpable in the presence of

marked ascites. Serum chemistries reveal hypoalbuminuria

(20g/L), sodium 132 mmol/L, potassium 3.5mmol/L, creati-

nine 105μmol/L, and international normalized ratio (INR) is

increased at 1.8. The patient is treated with furosemide

and his fluid intake is restricted. Over the next five days he

loses 10.5kg, but you are called to see him because he has

become confused and unwell. On examination, he is drowsy

and has asterixis (‘liver flap’). His blood pressure is

100/54mmHg with a postural drop. His serum potassium is

2.6mmol/L, creatinine has increased to 138 μmol/L and the

urea concentration has increased disproportionately.

Comment

It is a mistake to try to eliminate ascites too rapidly in patients

with cirrhosis. In this case, in addition to prerenal renal fail-

ure, the patient has developed profound hypokalaemia,

which is commonly caused by furosemide in a patient with

secondary hyperaldosteronism with a poor diet. The

hypokalaemia has precipitated hepatic encephalopathy. It

would have been better to have initiated treatment with

spironolactone to inhibit his endogenous aldosterone. Low

doses of furosemide could be added to this if increasing

doses of spironolactone up to the maximum had not pro-

duced adequate fluid/weight loss. Great caution will be

needed in starting such treatment now that the patient’s

renal function has deteriorated, and serum potassium

levels must be monitored closely.

●

Introduction 41

●

Role of drug monitoring in therapeutics 41

●

Practical aspects 41

●

Drugs for which therapeutic drug monitoring is used 42

CHAPTER 8

THERAPEUTIC DRUG MONITORING

INTRODUCTION

Drug response differs greatly between individuals. This vari-

ability results from two main sources:

1. variation in absorption, distribution, metabolism or

elimination (pharmacokinetic);

2. variation at or beyond tissue receptors or other

macromolecular drug targets (pharmacodynamic).

Monitoring of drug therapy by biological response encom-

passes both kinds of variability. There must be a continuous

variable that is readily measured and is closely linked to the

desired clinical outcome. Such responses are said to be good

‘surrogate markers’. (‘Surrogate’ because what the prescriber

really wants to achieve is to reduce the risk of a clinical event,

such as a stroke, heart attack, pulmonary embolism, etc.)

For example, antihypertensive drugs are monitored by their

effect on blood pressure (Chapter 28), statins by their effect

on serum cholesterol (Chapter 27), oral anticoagulants by

their effect on the international normalized ratio (INR) (Chapter

30). Many other examples will be encountered in later chapters.

In some circumstances, however, there is no good continu-

ous variable to monitor, especially for diseases with an unpre-

dictable or fluctuating course. Measuring drug concentrations

in plasma or serum identifies only pharmacokinetic variabil-

ity, but can sometimes usefully guide dose adjustment, for

example in treating an epileptic patient with an anticonvulsant

drug. Measuring drug concentrations for use in this way is

often referred to as ‘therapeutic drug monitoring’, and is the

focus of this chapter.

ROLE OF DRUG MONITORING IN

THERAPEUTICS

Measurement of drug concentrations is sometimes a useful

complement to clinical monitoring to assist in selecting the

best drug regimen for an individual patient. Accurate and

convenient assays are necessary. Measurements of drug con-

centrations in plasma are most useful when:

1. There is a direct relationship between plasma

concentration and pharmacological or toxic effect, i.e. a

therapeutic range has been established. (Drugs that work

via active metabolites, and drugs with irreversible actions,

are unsuited to this approach. Tolerance also restricts the

usefulness of plasma concentrations.)

2. Effect cannot readily be assessed quantitatively by clinical

observation.

3. Inter-individual variability in plasma drug concentrations

from the same dose is large (e.g. phenytoin).

4. There is a low therapeutic index (e.g. if the ratio of toxic

concentration/effective concentration is2).

5. Several drugs are being given concurrently and serious

interactions are anticipated.

6. Replacement treatment (for example, of thyroxine) is to be

optimized.

7. Apparent ‘resistance’ to the action of a drug needs an

explanation, when non-compliance is suspected.

Another indication, distinct from therapeutic drug monitor-

ing, for measuring drug concentrations in plasma is in clinical

toxicology. Such measurements can guide management when

specific intervention is contemplated in treating a poisoned

patient (e.g. with paracetamolor aspirin).

PRACTICAL ASPECTS

Drug distribution and the location (tissue and cell) of the

drug’s target influence the relationship between plasma drug

concentration and effect. A constant tissue to plasma drug

concentration ratio only occurs during the terminal β-phase of

elimination. Earlier in the dose interval, the plasma concentra-

tion does not reflect the concentration in the extracellular tis-

sue space accurately. Figure 8.1 illustrates an extreme example

of this in the case of digoxin. Measurements must be made

when enough time has elapsed after a dose for distribution to

have occurred. Greater care is therefore required in the timing

and labelling of specimens for drug concentration determina-

tion than is the case for ‘routine’ chemical pathology speci-

mens. Usually during repeated dosing a sample is taken just

before the next dose to assess the ‘trough’ concentration, and a

sample may also be taken at some specified time after dosing

(depending on the drug) to determine the ‘peak’ concentration.

Given this information, the laboratory should be able to

produce useful information. Advice on the interpretation of

this information is sometimes available from a local therapeutic

drug-monitoring service, such as is provided by some clinical

pharmacology and/or clinical pharmacy departments. In gen-

eral, the cost of measuring drug concentrations is greater than

for routine clinical chemical estimations, and to use expensive

facilities to produce ‘numbers’ resulting from analysis of sam-

ples taken at random from patients described only by name or

number is meaningless and misleading, as well as being a

waste of money.

Analytical techniques of high specificity (often relying on

high-performance liquid chromatography (HPLC), or HPLC-

tandem mass spectroscopy or radioimmunoassay) avoid the

pitfalls of less specific methods which may detect related com-

pounds (e.g. drug metabolites). Even so, quality control moni-

toring of anticonvulsant analyses performed by laboratories

both in the UK and in the USA have revealed that repeated

analyses of a reference sample can produce some startlingly

different results. The most important principle for the clin-

ician is that plasma drug concentrations must always be inter-

preted in the context of the patient’s clinical state.

There are few prospective studies of the impact of thera-

peutic drug-monitoring services on the quality of patient care.

A retrospective survey conducted at the Massachusetts

General Hospital showed that before the use of digoxin

monitoring, 13.9% of all patients receiving digoxin showed

evidence of toxicity, and that this figure fell to 5.9% following

the introduction of monitoring.

DRUGS FOR WHICH THERAPEUTIC DRUG

MONITORING IS USED

Table 8.1 lists those drugs which may be monitored

therapeutically.

1. Digoxin: measuring the plasma concentration can help

optimize therapy, especially for patients in sinus rhythm

where there is no easy pharmacodynamic surrogate

marker of efficacy, and is also useful in suspected toxicity

or poor compliance.

2. Lithium: plasma concentrations are measured 12 hours

after dosing.

3. Aminoglycoside antibiotics – for gentamicin, peak

concentrations measured 30 minutes after dosing of

7–10mg/L are usually effective against sensitive

organisms, and trough levels, measured immediately

before a dose, of 1–2mg/L reduce the risk of toxicity; for

amikacin, the desirable peak concentration is 4–12mg/L,

with a trough value of 4mg/L. With extended interval

aminoglycoside dosing (a single daily dose of 5–7mg/kg),

a single drug concentration determined at a time after the

completion of the distribution phase is used to define

further dosing intervals using validated nomograms.

4. Phenytoin: it is important to be aware of its non-linear

pharmacokinetics (Chapters 3 and 22), and of the possible

effects of concurrent renal or hepatic disease or of pregnancy

on its distribution. Therapeutic drug monitoring

is also widely used for some other anticonvulsants,

such as carbamazepineand sodium valproate.

5. Methotrexate: plasma concentration is an important

predictor of toxicity, and concentrations of 5μmol/L

24 hours after a dose or 100nmol/L 48 hours after dosing

usually require folinic acid administration to prevent

severe toxicity.

6. Theophylline: has a narrow therapeutic index (Figure 8.2)

and many factors influence its clearance (Figure 8.3).

Measurement of plasma theophyllineconcentration can

help to minimize toxicity (e.g. cardiac dysrhythmias or

seizures). Atherapeutic range of 5–20 mg/Lis quoted.

(Plasma concentrations 15mg/L are, however, associated

with severe toxicity in neonates due to decreased protein

binding and accumulation of caffeine, to which

theophyllineis methylated in neonates, but not in older

children.)

7. The therapeutic ranges of plasma concentrations of

several anti-dysrhythmic drugs (e.g. lidocaine) have been

established with reasonable confidence. The therapeutic

range of plasma amiodaroneconcentrations for ventricular

dysrhythmias (1.0–2.5mg/L) is higher than that needed

42 THERAPEUTICDRUG MONITORING

04812162024

Distribution

phase

Elimination phase

Sampling time

Time (h)

Digoxin concentration

(nmol/L)

Digoxin

administration

Figure 8.1: Serum concentration–time course following digoxin

administration.

Table 8.1:Therapeutic range of several important drugs,

for which therapeutic drug monitoring is often used.

Drug Therapeutic range

Digoxin 0.8–2 mg/L (1–2.6 nmol/L)

Lithium 0.4–1.4mmol/L

Phenytoin 10–20 mg/L (40–80μmol/L)

Theophylline 5–20mg/L (28–110 μmol/L)

Ciclosporin 50–200μg/L

An upper limit of 1.6mmol/L has also been advocated.

for atrial dysrhythmias (0.5–1.5mg/L). The clinical utility

of predicting toxicity by measuring a metabolite (desethyl

amiodarone) is under evaluation.

8. Immunosuppressants: Ciclosporin compliance is a

particular problem in children, and deterioration in renal

function can reflect either graft rejection due to inadequate

ciclosporinconcentration or toxicity from excessive

concentrations.Sirolimus use should be monitored,

especially when used with ciclosporinor when there is

hepatic impairment or during or after treatment with

inducers or inhibitors of drug metabolism.

DRUGS FOR WHICH THERAPEUTIC DRUG M ONITORINGIS U SED 43

Life-threatening toxicity possible

Coma

Dysrythymias

Convulsions

Dependent on drug concentration

Sinus tachycardia

Excitement

Hypokalaemia

Vomiting

Partially dependent on drug concentration

Nausea

Dyspepsia

Insomnia

Headache

Figure 8.2:Theophylline plasma concentrations (mg/L). Note that

there is a wide variation in the incidence and severity of adverse

effects. (Adapted from Mant T, Henry J, Cochrane G. In: Henry J,

Volans G (eds). ABC of poisoning. Part 1: Drugs. London: British

Medical Journal.)

Decreased

Cirrhosis

Heart failure

Age >50 years

Neonates

Obesity

Severe renal failure

Cimetidine

Erythromycin

Ciprofloxacin

Smoking

Marijuana

Age 1–20 years

High protein diet

Phenobarbitone

Shortened half-lifeProlonged half-life

Increased

Figure 8.3:Theophylline clearance. (Adapted from Mant T, Henry

J, Cochrane G. In: Henry J, Volans G (eds). ABC of poisoning. Part

1: Drugs. London: British Medical Journal.)

Key points

• Determining the plasma concentrations of drugs in

order to adjust therapy is referred to as therapeutic

drug monitoring. It has distinct but limited applications.

• Therapeutic drug monitoring permits dose

individualization and is useful when there is a clear

relationship between plasma concentration and

pharmacodynamic effects.

• The timing of blood samples in relation to dosing is

crucial. For aminoglycosides, samples are obtained for

measurement of peak and trough concentrations. To

guide chronic therapy (e.g. with anticonvulsants),

sufficient time must elapse after starting treatment or

changing dose for the steady state to have been

achieved, before sampling.

• Drugs which may usefully be monitored in this way

include digoxin, lithium, aminoglycosides, several

anticonvulsants, methotrexate, theophylline, several

anti-dysrhythmic drugs (including amiodarone) and

ciclosporin.

• Individualization of dosage using therapeutic drug

monitoring permits the effectiveness of these drugs to

be maximized, while minimizing their potential toxicity.

Case history

A 35-year-old asthmatic is admitted to hospital at 6 a.m.

because of a severe attack of asthma. She has been treated

with salbutamol and beclometasone inhalers supplemented

by a modified-release preparation of theophylline, 300mg

at night. She has clinical evidence of a severe attack and

does not improve with nebulized salbutamol and oxygen.

Treatment with intravenous aminophylline is considered.

Comment

Aminophylline is a soluble preparation of theophylline (80%)

mixed with ethylenediamine (20%), which has a role in

patients with life-threatening asthma. However, it is essential

to have rapid access to an analytical service to measure plasma

theophylline concentrations if this drug is to be used safely,

especially in this situation where the concentration of

theophylline resulting from the modified-release prepar-

ation that the patient took the night before admission must

be determined before starting treatment. Theophylline

toxicity (including seizures and potentially fatal cardiac

dysrhythmias) can result if the dose is not individualized in

relation to the plasma theophylline concentration.

44 THERAPEUTICDRUG MONITORING

Johannessen SI, Tomson T. Pharmacokinetic variability of newer

antiepileptic drugs – When is monitoring needed? Clinical

Pharmacokinetics2006; 45: 1061–75.

Kaplan B. Mycophenolic acid trough level monitoring in solid organ

transplant recipients treated with mycophenolate mofetil: associ-

ation with clinical outcome. Current Medical Research and Opinion

2006;22: 2355–64.

Mitchell PB. Therapeutic drug monitoring of psychotropic medica-

tions.British Journal of Clinical Pharmacology 2000; 49: 303–12.

Oellerich M, Armstrong VW. The role of therapeutic drug monitoring

in individualizing immunosuppressive drug therapy: Recent

developments.Therapeutic Drug Monitoring 2006; 28: 720–25.

Stamp L, Roberts R, Kennedy M, Barclay M, O’Donnell J, Chapman P.

The use of low dose methotrexate in rheumatoid arthritis – are we

entering a new era of therapeutic drug monitoring and pharma-

cogenomics?Biomedicine and Pharmacotherapy 2006; 60: 678–87.

FURTHER READING

Arns W, Cibrik DM, Walker RG et al. Therapeutic drug monitoring of

mycophenolic acid in solid organ transplant patients treated with

mycophenolate mofetil: Review of the literature. Transplantation

2006;82: 1004–12.

Aronson JK, Hardman M, Reynolds DJM. ABC of monitoring drug

therapy. London: BMJ Publications, 1993.

Bartelink IH, Rademaker CMA, Schobben AFAM et al. Guidelines on

paediatric dosing on the basis of developmental physiology and

pharmacokinetic considerations. Clinical Pharmacokinetics 2006;

45: 1077–97.

Fleming J, Chetty M. Therapeutic monitoring of valproate in psychia-

try: How far have we progressed? Clinical Neuropharmacology2006;

29: 350–60.

Herxheimer A. Clinical pharmacology and therapeutics. In: Warrell

DA (ed.). Oxford textbook of medicine, 4th edn. Oxford: Oxford

University Press, 2006.

●

Introduction 45

●

Harmful effects on the fetus 45

●

Recognition of teratogenic drugs 46

●

Pharmacokinetics in pregnancy 47

●

Prescribing in pregnancy 48

CHAPTER 9

DRUGS IN PREGNANCY

INTRODUCTION

The use of drugs in pregnancy is complicated by the potential for

harmful effects on the growing fetus, altered maternal physiol-

ogy and the paucity and difficulties of research in this field.

of the mother with atenololin pregnancy. Early in embryonic

development, exogenous substances accumulate in the neuro-

ectoderm. The fetal blood–brain barrier is not developed until

the second half of pregnancy, and the susceptibility of the cen-

tral nervous system (CNS) to developmental toxins may be

partly related to this. The human placenta possesses multiple

enzymes that are primarily involved with endogenous steroid

metabolism, but which may also contribute to drug metabo-

lism and clearance.

The stage of gestation influences the effects of drugs on

the fetus. It is convenient to divide pregnancy into four

stages, namely fertilization and implantation (17 days), the

organogenesis/embryonic stage (17–57 days), the fetogenic

stage and delivery.

Key points

• There is potential for harmful effects on the growing

fetus.

• Because of human variation, subtle effects to the fetus

may be virtually impossible to identify.

• There is altered maternal physiology.

• There is notable paucity of and dif

ficulties in research

in this area.

• Assume all drugs are harmful until proven otherwise.

HARMFUL EFFECTS ON THE FETUS

Because experience with many drugs in pregnancy is severely

limited, it should be assumed that all drugs are potentially

harmful until sufficient data exist to indicate otherwise. ‘Social’

drugs (alcohol and cigarette smoking) are definitely damaging

and their use must be discouraged.

In the placenta, maternal blood is separated from fetal

blood by a cellular membrane (Figure 9.1). Most drugs with a

molecular weight of less than 1000 can cross the placenta. This

is usually by passive diffusion down the concentration gradi-

ent, but can involve active transport. The rate of diffusion

depends first on the concentration of free drug (i.e. non-protein

bound) on each side of the membrane, and second on the

lipid solubility of the drug, which is determined in part by

the degree of ionization. Diffusion occurs if the drug is in the

unionized state. Placental function is also modified by changes

in blood flow, and drugs which reduce placental blood flow

can reduce birth weight. This may be the mechanism which

causes the small reduction in birth weight following treatment

Maternal

blood

space

Trophoblast

Fetal

capillary

Carrier

protein

Small

(MW <1000)

drugs

Larger

(MW >1000)

drugs

D+

D−

D+

D−

D+

D−

DDD

Passive

diffusion

Passive

diffusion

Figure 9.1:Placental transfer of drugs from mother to fetus.

Key points

• A cellular membrane separates the maternal and fetal

blood.

• Most drugs cross the placenta by passive diffusion.

• Placental function is modified by changes in blood flow.

• There are multiple placental enzymes, primarily

involved with endogenous steroid metabolism, which

may also contribute to drug metabolism.

FERTILIZATION AND IMPLANTATION

Animal studies suggest that interference with the fetus before

17 days gestation causes abortion, i.e. if pregnancy continues

the fetus is unharmed.

ORGANOGENESIS/EMBRYONIC STAGE

At this stage, the fetus is differentiating to form major organs,

and this is the critical period for teratogenesis. Teratogens cause

deviations or abnormalities in the development of the embryo

that are compatible with prenatal life and are observable post-

natally. Drugs that interfere with this process can cause gross

structural defects (e.g. thalidomidephocomelia).

Some drugs are confirmed teratogens (Table 9.1), but for

many the evidence is inconclusive. Thalidomidewas unusual

in the way in which a very small dose of the drug given on

only one or two occasions between the fourth and seventh weeks

of pregnancy predictably produced serious malformations.

FETOGENIC STAGE

In this stage, the fetus undergoes further development and

maturation. Even after organogenesis is almost complete, drugs

can still have significant adverse effects on fetal growth and

development.

• ACE inhibitors and angiotensin receptor blockers cause

fetal and neonatal renal dysfunction.

• Drugs used to treat maternal hyperthyroidism can cause

fetal and neonatal hypothyroidism.

• Tetracyclineantibiotics inhibit growth of fetal bones and

stain teeth.

• Aminoglycosides cause fetal VIIIth nerve damage.

• Opioids and cocaine taken regularly during pregnancy

can lead to fetal drug dependency.

• Warfarincan cause fetal intracerebral bleeding.

• Indometacin, a potent inhibitor of prostaglandin

synthesis, is used under specialist supervision to assist

closure of patent ductus arteriosus in premature infants.

• Some hormones can cause inappropriate virilization or

feminization.

• Anticonvulsants may possibly be associated with mental

retardation.

• Cytotoxic drugs can cause intrauterine growth retardation

and stillbirth.

DELIVERY

Some drugs given late in pregnancy or during delivery may

cause particular problems. Pethidine, administered as an anal-

gesic can cause fetal apnoea (which is reversed with naloxone,

see Chapter 25). Anaesthetic agents given during Caesarean

section may transiently depress neurological, respiratory and

muscular functions. Warfaringiven in late pregnancy causes a

haemostasis defect in the baby, and predisposes to cerebral

haemorrhage during delivery.

46 DRUGS IN PREGNANCY

Table 9.1:Some drugs that are teratogenic in humans.

Thalidomide Androgens

Cytotoxic agents Progestogens

Alcohol Danozol

Warfarin Diethylstilbestrol

Retinoids Radioisotopes

Most anticonvulsants Some live vaccines

Ribavarin Lithium

Key points

• Fertilization and implantation, 17 days.

• Organogenesis/embryonic stage, 17–57 days.

• Fetogenic stage.

• Delivery.

THE MALE

Although it is generally considered that sperm cells damaged by

drugs will not result in fertilization, the manufacturers of griseo-

fulvin, an antifungal agent, advise men not to father children

during or for six months after treatment. Finasteride, an anti-

androgen used in the treatment of benign prostatic hyperplasia,

is secreted in semen, and may be teratogenic to male fetuses.

RECOGNITION OF TERATOGENIC DRUGS

Major malformations that interfere with normal function

occur in 2–3% of newborn babies, and a small but unknown

fraction of these are due to drugs. Two principal problems face

those who are trying to determine whether a drug is terato-

genic when it is used to treat disease in humans:

1. Many drugs produce birth defects when given experi-

mentally in large doses to pregnant animals. This does not

necessarily mean that they are teratogenic in humans at

therapeutic doses. Indeed, the metabolism and kinetics of

drugs at high doses in other species is so different from that

in humans as to limit seriously the relevance of such studies.

2. Fetal defects are common (2–3%). Consequently, if the

incidence of drug-induced abnormalities is low, a very

large number of cases has to be observed to define a

significant increase above this background level. Effects

on the fetus may take several years to become clinically

manifest. For example, diethylstilbestrolwas widely

used in the late 1940s to prevent miscarriages and preterm

births, despite little evidence of efficacy. In 1971, an

association was reported between adenocarcinoma of the

vagina in girls in their late teens whose mothers had been

givendiethylstilbestrol during the pregnancy. Exposure

tostilbestrol in utero has also been associated with a

T-shaped uterus and other structural abnormalities of the

genital tract, and increased rates of ectopic pregnancy and

premature labour.

ABSORPTION

Gastric emptying and small intestinal motility are reduced. This

is of little consequence unless rapid drug action is required.

Vomiting associated with pregnancy may make oral drug

administration impractical.

DISTRIBUTION

During pregnancy, the blood volume increases by one-third,

with expansion in plasma volume (from 2.5 to 4L at term) being

disproportionate to expansion in red cell mass, so that haemat-

ocrit falls. There is also an increase in body water due to a larger

extravascular volume and changes in the uterus and breasts.

Oedema, which at least one-third of women experience

during pregnancy, may add up to 8L to the volume of extra-

cellular water. For water-soluble drugs (which usually have a

relatively small volume of distribution), this increases the

apparent volume of distribution and, although clearance is

unaltered, their half-life is prolonged. During pregnancy, the

plasma protein concentration falls and there is increased com-

petition for binding sites due to competition by endogenous

ligands, such as increased hormone levels. These factors alter

the total amount of bound drug and the apparent volume of

distribution. However, the concentration of free drug usually

remains unaltered, because a greater volume of distribution of

free drug is accompanied by increased clearance of free drug.

Thus, in practice, these changes are rarely of pharmacological

significance. They may cause confusion in monitoring of

plasma drug levels, since this usually measures total (rather

than free) drug concentrations.

METABOLISM

Metabolism of drugs by the pregnant liver is increased, largely

due to enzyme induction, perhaps by raised hormone levels.

Liver blood flow does not change. This may lead to an increased

rate of elimination of those drugs (e.g. theophylline), for

which enzyme activity rather than liver blood flow is the main

determinant of elimination rate.

RENAL EXCRETION

Excretion of drugs via the kidney increases because renal plasma

flow almost doubles and the glomerular filtration rate increases

by two-thirds during pregnancy. This has been documented for

digoxin,lithium, ampicillin, cefalexin and gentamicin.

PHARMACOKINETICS I N PREGNANCY 47

Key points

• The background incidence of serious congenital

abnormality recognized at birth is 2–3%.

• Environmental and genetic factors can influence a

drug’s effect.

• Maternal disease can af

fect the fetus.

• Studies of large doses in pregnant animals are of

doubtful relevance.

• Effects may be delayed (e.g. diethylstilbestrol).

• Meticulous data collection is required for drugs

administered during pregnancy and outcome, including

long-term follow up. At present the Medicines and

Healthcare products Regulatory Agency (MHRA) requests

records of all drugs administered to a mother who

bears an abnormal fetus. More complete (but with

inherent practical difficulties) data collection by the

MHRA, the National Teratology Information Services,

the pharmaceutical industry and drug information

agencies on all prescriptions during pregnancy with

long-term follow up of of

fspring is required.

PHARMACOKINETICS I N PREGNANCY

Known differences in drug effects in pregnancy are usually

explained by altered pharmacokinetics (Figure 9.2).

Drug

Absorption↓

Metabolism↑

Excretion↑

↑Renal

blood flow

CYP450

induction

Plasma drug

concentration

↑ ↔ or↓

↑Volume of distribution

↓Plasma albumin

↑Vomiting

↓Gastric emptying

↓Small intestinal motility

Figure 9.2:Pharmacokinetic changes in pregnancy.

Key points

Known differences in drug effects can usually be explained

by altered pharmacokinetics. Increased volume of

distribution, hepatic metabolism and renal excretion all

tend to reduce drug concentration. Decreased plasma

albumin levels increase the ratio of free drug in plasma.

PRESCRIBING IN PREGNANCY

The prescription of drugs to a pregnant woman is a balance

between possible adverse drug effects on the fetus and the risk

to mother and fetus of leaving maternal disease inadequately

treated. Effects on the human fetus cannot be reliably pre-

dicted from animal studies – hence one should prescribe drugs

for which there is experience of safety over many years in

preference to new or untried drugs. The smallest effective

dose should be used. The fetus is most sensitive to adverse

drug effects during the first trimester. It has been estimated

that nearly half of all pregnancies in the UK are unplanned,

and that most women do not present to a doctor until five to

seven weeks after conception. Thus, sexually active women of

childbearing potential should be assumed to be pregnant until

it has been proved otherwise.

Delayed toxicity is a sinister problem (e.g. diethylstilbestrol)

and if the teratogenic effect of thalidomide had not produced

such an unusual congenital abnormality, namely phocomelia,

its detection might have been delayed further. If drugs (or envi-

ronmental toxins) have more subtle effects on the fetus (e.g. a

minor reduction in intelligence) or cause an increased incidence

of a common disease (e.g. atopy), these effects may never be

detected. Many publications demand careful prospective con-

trolled clinical trials, but the ethics and practicalities of such

studies often make their demands unrealistic. Amore rational

approach is for drug regulatory bodies, the pharmaceutical

industry and drug information agencies to collaborate closely

and internationally to collate all information concerning drug

use in pregnancy (whether inadvertent or planned) and associ-

ate these with outcome. This will require significant investment

of time and money, as well as considerable encouragement to

doctors and midwives to complete the endless forms.

Guidance on the use of drugs for a selection of conditions is

summarized below. If in doubt, consult the British National

Formulary, appendix 4 (which is appropriately conservative).

Information for health professionals in the UK about the

safety of drugs in pregnancy can also be obtained from the

National Teratology Information Service (Tel. 0191 232 1525).

ANTIMICROBIAL DRUGS

Antimicrobial drugs are commonly prescribed during preg-

nancy. The safest antibiotics in pregnancy are the penicillins

and cephalosporins. Trimethoprimis a theoretical teratogen

as it is a folic acid antagonist. The aminoglycosides can

cause ototoxicity. There is minimal experience in pregnancy

with the fluoroquinolones (e.g. ciprofloxacin) and they should

be avoided. Erythromycinis probably safe. Metronidazole is

a teratogen in animals, but there is no evidence of teratogenic-

ity in humans, and its benefit in serious anaerobic sepsis prob-

ably outweighs any risks. Unless there is a life-threatening

infection in the mother, antiviral agents should be avoided in

pregnancy. Falciparum malaria (Chapter 47) has an especially

high mortality rate in late pregnancy. Fortunately, the stan-

dard regimens of intravenous and oral quinine are safe in

pregnancy.

ANALGESICS

Opioids cross the placenta. This is particularly relevant in the

management of labour when the use of opioids, such as pethi-

dine, depresses the fetal respiratory centre and can inhibit

the start of normal respiration. If the mother is dependent on

opioids, the fetus can experience opioid withdrawal syn-

drome during and after delivery, which can be fatal. In

neonates, the chief withdrawal symptoms are tremor, irritabil-

ity, diarrhoea and vomiting. Chlorpromazine is commonly

used to treat this withdrawal state. Paracetamolis preferred to

aspirin when mild analgesia is required. In cases where a sys-

temic anti-inflammatory action is required (e.g. in rheumatoid

arthritis), ibuprofen is the drug of choice. Non-steroidal

anti-inflammatory drugs can cause constriction of the ductus

arteriosus. Occasionally, this may be used to therapeutic

benefit.

ANAESTHESIA

Anaesthesia in pregnancy is a very specialist area and should

only be undertaken by experienced anaesthetists. Local anaes-

thetics used for regional anaesthesia readily cross the pla-

centa. However, when used in epidural anaesthesia, the drug

remains largely confined to the epidural space. Pregnant

women are at increased risk of aspiration. Although com-

monly used, pethidine frequently causes vomiting and may

also lead to neonatal respiratory depression. Metoclopramide

should be used in preference to prochlorperazine(which has

48 DRUGS IN PREGNANCY

Key points

Prescribing in pregnancy is a balance between the risk of

adverse drug effects on the fetus and the risk of leaving

maternal disease untreated. The effects on the human

fetus are not reliably predicted by animal experiments.

However, untreated maternal disease may cause morbidity

and/or mortality to mother and/or fetus.

Therefore,

• minimize prescribing;

• use ‘tried and tested’ drugs whenever possible in

preference to new agents;

• use the smallest effective dose;

• remember that the fetus is most sensitive in the first

trimester;

• consider pregnancy in all women of childbearing

potential;

• discuss the potential risks of taking or withholding

therapy with the patient;

• seek guidance on the use of drugs in pregnancy in the

British National Formulary, Drug Information Services,

National Teratology Information Service (NTIS);

• warn the patient about the risks of smoking, alcohol,

over

-the-counter drugs and drugs of abuse.

an anti-analgesic effect when combined with pethidine), and

naloxone (an opioid antagonist) must always be available.

Respiratory depression in the newborn is not usually a prob-

lem with modern general anaesthetics currently in use in

Caesarean section. Several studies have shown an increased

incidence of spontaneous abortions in mothers who have had

general anaesthesia during pregnancy, although a causal rela-

tionship is not proven, and in most circumstances failure to

operate would have dramatically increased the risk to mother

and fetus.

ANTI-EMETICS

Nausea and vomiting are common in early pregnancy, but are

usually self-limiting, and ideally should be managed with

reassurance and non-drug strategies, such as small frequent

meals, avoiding large volumes of fluid and raising the head of

the bed. If symptoms are prolonged or severe, drug treatment

may be effective. An antihistamine, e.g. promethazine or

cyclizine may be required. If ineffective, prochlorperazine is

an alternative. Metoclopramide is considered to be safe and

efficacious in labour and before anaesthesia in late pregnancy,

but its routine use in early pregnancy cannot be recommended

because of the lack of controlled data, and the significant inci-

dence of dystonic reactions in young women.

DYSPEPSIA AND CONSTIPATION

The high incidence of dyspepsia due to gastro-oesophageal

reflux in the second and third trimesters is probably related to

the reduction in lower oesophageal sphincter pressure. Non-

drug treatment (reassurance, small frequent meals and advice

on posture) should be pursued in the first instance, particu-

larly in the first trimester. Fortunately, most cases occur later

in pregnancy when non-absorbable antacids, such as algi-

nates, should be used. In late pregnancy, metoclopromideis

particularly effective as it increases lower oesophageal sphinc-

ter pressure. H

-receptor blockers should not be used for non-

ulcer dyspepsia in this setting. Constipation should be managed

with dietary advice. Stimulant laxatives may be uterotonic

and should be avoided if possible.

PEPTIC ULCERATION

Antacids may relieve symptoms. Cimetidine and ranitidine

have been widely prescribed in pregnancy without obvious

damage to the fetus. There are inadequate safety data on the

use of omeprazole or other proton pump inhibitors in preg-

nancy. Sucralfate has been recommended for use in preg-

nancy in the USA, and this is rational as it is not systemically

absorbed. Misoprostol, a prostaglandin which stimulates the

uterus, is contraindicated because it causes abortion.

ANTI-EPILEPTICS

Epilepsy in pregnancy can lead to fetal and maternal morbid-

ity/mortality through convulsions, whilst all of the anticon-

vulsants used have been associated with teratogenic effects

(e.g. phenytoin is associated with cleft palate and congenital

heart disease). However, there is no doubt that the benefits of

good seizure control outweigh the drug-induced teratogenic

risk. Thorough explanation to the mother, ideally before a

planned pregnancy, is essential, and it must be emphasized

that the majority (90%) of epileptic mothers have normal

babies. (The usual risk of fetal malformation is 2–3% and in

epileptic mothers it is up to 10%.) In view of the association of

spina bifida with many anti-epileptics, e.g. sodium valproate

andcarbamazepine therapy, it is often recommended that the

standard dose of folic acid should be increased to 5mg daily.

Both of these anti-epileptics can also cause hypospadias. As

in non-pregnant epilepsy, single-drug therapy is preferable.

Plasma concentration monitoring is particularly relevant for

phenytoin, because the decrease in plasma protein binding and

the increase in hepatic metabolism may cause considerable

changes in the plasma concentration of free (active) drug. As

always, the guide to the correct dose is freedom from fits and

absence of toxicity. Owing to the changes in plasma protein

binding, it is generally recommended that the therapeutic

range is 5–15mg/L, whereas in the non-pregnant state it is

10–20mg/L. This is only a rough guide, as protein binding

varies.

The routine injection of vitamin K recommended at birth

counteracts the possible effect of some anti-epileptics on

vitamin K-dependent clotting factors.

Magnesium sulphate is the treatment of choice for the pre-

vention and control of eclamptic seizures.

PRESCRIBING IN PREGNANCY 49

Key points

• Epilepsy in pregnancy can lead to increased fetal

and maternal morbidity/mortality.

• All anticonvulsants are teratogens.

• The benefits of good seizure control outweigh

drug-induced teratogenic risk.

• Give a full explanation to the mother (preferably

before pregnancy): most epileptic mothers (90%)

have normal babies.

• Advise an increase in the standard dose of folic acid up

to 12 weeks.

• Make a referral to the neurologist and obstetrician.

• If epilepsy is well controlled, do not change

therapy.

• Monitor plasma concentrations (levels tend to fall,

and note that the bound: unbound ratio changes); the

guide to the correct dose is freedom from fits and

absence of toxicity

• An early ultrasound scan at 12 weeks may detect gross

neural tube defects.

• Detailed ultrasound scan and α-fetoprotein at 16–18

weeks should be considered.

ANTICOAGULATION

Warfarinhas been associated with nasal hypoplasia and chon-

drodysplasia when given in the first trimester, and with CNS

abnormalities after administration in later pregnancy, as well

as a high incidence of haemorrhagic complications towards

the end of pregnancy. Neonatal haemorrhage is difficult to

prevent because of the immature enzymes in fetal liver and

the low stores of vitamin K. It is not rcommended for use in

pregnancy unless there are no other options. Low molecular

weight heparin (LMWH), which does not cross the placenta,

is the anticoagulant of choice in pregnancy in preference to

unfractionated heparin. LMWH has predictable pharmacoki-

netics and is safer – unlike unfractionated heparin there has

never been a case of heparin-induced thrombocytopenia/

thrombosis (HITT) associated with it in pregnancy. Moreover

there has only been one case of osteoporotic fracture world-

wide, whereas there is a 2% risk of osteoporotic fracture with

nine months use of unfractionated heparin (see Chapter 30).

LMWHis given twice daily in pregnancy due to the increased

renal clearance of pregnancy. Women on long-term oral anti-

coagulants should be warned that these drugs are likely to

affect the fetus in early pregnancy. Self-administered subcuta-

neous LMWH must be substituted for warfarin before six

weeks’ gestation. Subcutaneous LMWH can be continued

throughout pregnancy and for the prothrombotic six weeks

post partum.Patients with prosthetic heart valves present a

special problem, and in these patients, despite the risks to the

fetus, warfarin is often given up to 36 weeks. The prothrom-

bin time/international normalized ratio (INR) should be mon-

itored closely if warfarinis used.

thiazide diuretics in women with essential hypertension, who

are already stabilized on these drugs. Modified-release prepara-

tions of nifedipine are also used for hypertension in preg-

nancy, but angiotensin-converting enzyme inhibitors and

angitensin II receptor antagonists must be avoided.

HORMONES

Progestogens, particularly synthetic ones, can masculinize the

female fetus. There is no evidence that this occurs with the small

amount of progestogen(or oestrogen) present in the oral con-

traceptive – the risk applies to large doses. Corticosteroids do

not appear to give rise to any serious problems when given via

inhalation or in short courses. Transient suppression of the

fetal hypothalamic–pituitary–adrenal axis has been reported.

Rarely, cleft palate and congenital cataract have been linked

with steroids in pregnancy, but the benefit of treatment usually

outweighs any such risk. Iodine and antithyroid drugs cross

the placenta and can cause hypothyroidism and goitre.

TRANQUILLIZERS AN D ANTIDEPRESSANTS

Benzodiazepines accumulate in the tissues and are slowly

eliminated by the neonate, resulting in prolonged hypotonia

(‘floppy baby’), subnormal temperatures (hypothermia), peri-

odic cessation of respiration and poor sucking. There is no evi-

dence that the phenothiazines, tricyclic antidepressants or

fluoxetineare teratogenic. Lithium can cause fetal goitre and

possible cardiovascular abnormalities.

NON-THERAPEUTIC DRUGS

Excessiveethanol consumption is associated with spontaneous

abortion, craniofacial abnormalities, mental retardation, con-

genital heart disease and impaired growth. Even moderate

alcohol intake may adversely affect the baby – the risk of hav-

ing an abnormal child is about 10% in mothers drinking

30–60mL ethanol per day, rising to 40% in chronic alcoholics.

Fetal alcohol syndrome describes the distinct pattern of abnor-

mal morphogenesis and central nervous system dysfunction

in children whose mothers were chronic alcoholics, and this

syndrome is a leading cause of mental retardation. After birth,

the characteristic craniofacial malformations diminish, but

microcephaly and to a lesser degree short stature persist.

Cigarette smoking is associated with spontaneous abortion,

premature delivery, small babies, increased perinatal mortal-

ity and a higher incidence of sudden infant death syndrome

(cot death). Cocaine causes vasoconstriction of placental ves-

sels. There is a high incidence of low birth weight, congenital

abnormalities and, in particular, delayed neurological and

behavioural development.

50 DRUGS IN PREGNANCY

Key points

• Pregnancy is associated with a hypercoagulable state.

• Warfarin has been associated with nasal hypoplasia and

chondrodysplasia in the first trimester, and with CNS

abnormalities in late pregnancy, as well as haemorrhagic

complications.

• Heparin does not cross the placenta. Low molecular

weight heparins (LMWH

) are preferable as they have

better and more predictable pharmacokinetics, are

safer with no evidence of heparin-induced thrombo-

cytopenia and thrombosis (HITT) and osteoporotic

fracture is very rare.

• Refer to the guidelines of the Royal College of

Obstetricians for thromboprophylaxis and management

of established venous thromboembolism in pregnancy.

CARDIOVASCULAR DRUGS

Hypertension in pregnancy (see Chapter 28) can normally be

managed with either methyldopa which has the most exten-

sive safety record in pregnancy, or labetalol. Parenteral

hydralazine is useful for lowering blood pressure in pre-

eclampsia. Diuretics should not be started to treat hypertension

in pregnancy, although some American authorities continue

FURTHER READING

Anon. Antiepileptics, pregnancy and the child. Drugs and Therapeutics

Bulletin2005; 43 no 2.

Koren G. Medication, safety in pregnancy and breastfeeding: the evidence-

based A–Z clinicians pocket guide. Maidenhead: McGraw-Hill, 2006.

Rubin PC. Prescribing in pregnancy, 3rd edn. London: Blackwell, BMJ

Books, 2000.

McElhatton PR. General principles of drug use in pregnancy.

Pharmaceutical Journal2003; 270: 305–7.

FURTHER INFORMATION FOR HEALTH

PROFESSIONALS

National Teratology Information Service

Regional Drug and Therapeutics Centre

Wolfson Unit

Clarement Place

Newcastle upon Tyne

NE1 4LP

Tel. 0191 232 1525

PRESCRIBING IN PREGRANCY 51

Case history

A 20-year-old female medical student attended her GP

requesting a course of Septrin® (co-trimoxazole) for cysti-

tis. She tells her GP that her last menstrual bleed was about

six weeks earlier. She did not think she was at risk of preg-

nancy as her periods had been irregular since stopping the

oral contraceptive one year previously due to fears about

thrombosis, and her boyfriend used a condom. Physical exam-

ination, which did not include a vaginal examination, was

normal. Urinalysis was 1positive for blood and a trace of

protein.

Question

Why should the GP not prescribe co-trimoxazole for this

patient?

Answer

Until proven otherwise, it should be assumed that this

woman is pregnant. Co-trimoxazole (a combination of sul-

famethoxazole and trimethoprim) has been superseded by

trimethoprim alone as a useful drug in lower urinary tract

infection (UTI). The sulfamethoxazole does not add signifi-

cant antibacterial advantage in lower UTI, but does have

sulphonamide-associated side effects, including the rare

but life-threatening Stevens–Johnson syndrome. Both sul-

famethoxazole and trimethoprim inhibit folate synthesis

and are theoretical teratogens. If pregnancy is confirmed

(urinary frequency is an early symptom of pregnancy in

some women, due to a progesterone effect) and if the

patient has a lower UTI confirmed by pyuria and bacteria

on microscopy whilst awaiting culture and sensitivity results,

amoxicillin is the treatment of choice. Alternatives include

an oral cephalosporin or nitrofurantoin. Note that lower

urinary tract infection in pregnancy can rapidly progress to

acute pyelonephritis.

●

Introduction 52

●

Pharmacokinetics 52

●

Pharmacodynamics 53

●

Breast-feeding 53

●

Practical aspects of prescribing 54

●

Research 54

CHAPTER 10

DRUGS IN INFANTS AND

CHILDREN

INTRODUCTION

Children cannot be regarded as miniature adults in terms

of drug response, due to differences in body constitution,

drug absorption and elimination, and sensitivity to adverse

reactions. Informed consent is problematic and commercial

interest has been limited by the small size of the market,

so clinical trials in children have lagged behind those in

adults. Regulatory agencies in the USAand Europe now rec-

ognize this problem and are attempting to address it, for

example, by introducing exclusivity legislation designed to

attract commercial interest. Traditionally, paediatricians have

used drugs ‘off-label’ (i.e. for unlicensed indications), often

gaining experience in age groups close to those for which a

product is licensed and then extending this to younger chil-

dren. That this empirical approach has worked (at least to

some extent) is testament to the biological fact that while

not just ‘miniature adults’ children do share the same drug

targets (e.g. receptors, enzymes), cellular transduction mecha-

nisms and physiological processes with their parents. Drug

responses are thus usually qualitatively similar in children

and adults, although there are important exceptions, including

some central nervous system (CNS) responses and immuno-

logical responses to ciclosporin. Furthermore, some adverse

effects occur only during certain stages of development, for

example, retrolental fibroplasia induced by excess oxygen

in the premature neonate and staining of teeth by

tetracycline which occurs only in developing enamel. The

processes of drug elimination are, however, immature at

birth so quantitative differences (e.g. in dose) are important.

Establishing optimal doses for drugs prescribed for children is

thus an extremely important clinical challenge. Current

regimes have been arrived at empirically, but guidelines are

evolving for paediatric dosing in clinical trials and in future

greater use may be made of pharmacokinetic/pharmacody-

namic modelling in children, so hopefully this Cinderella

of therapeutics will soon be making her (belated) entry to

the ball.

PHARMACOKINETICS

ABSORPTION

Gastro-intestinal absorption is slower in infancy, but absorption

from intramuscular injection is faster. The rate of gastric empty-

ing is very variable during the neonatal period and may be

delayed by disease, such as respiratory distress syndrome and

congenital heart disease. To ensure that adequate blood concen-

trations reach the systemic circulation in the sick neonate, it is

common practice to use intravenous preparations. In older and

less severely ill children, oral liquid preparations are commonly

used, resulting in less accurate dosing and a more rapid rate of

absorption. This is important for drugs with adverse effects that

occur predictably at high plasma concentration, and which show

lack of efficacy if trough concentration is low (e.g. carbamazepine

andtheophylline). Infant skin is thin and percutaneous absorp-

tion can cause systemic toxicity if topical preparations (e.g. of

potent corticosteroids) are applied too extensively.

DISTRIBUTION

Body fat content is relatively low in children, whereas water

content is greater, leading to a lower volume of distribution of

fat-soluble drugs (e.g. diazepam) in infants. Plasma protein

binding of drugs is reduced in neonates due to a lower plasma

albumin concentration and altered binding properties. The

risk of kernicterus caused by displacement of bilirubin from

albumin by sulphonamides (see Chapter 12) is well recog-

nized. The blood–brain barrier is more permeable in neonates

and young children, leading to an increased risk of CNS

adverse effects.

BREAST-FEEDING 53

METABOLISM

At birth, the hepatic microsomal enzyme system (see Chapter

5) is relatively immature (particularly in the preterm infant),

but after the first four weeks it matures rapidly.

Chloramphenicol can produce ‘grey baby syndrome’ in

neonates due to high plasma levels secondary to inefficient

elimination. Conversely, hepatic drug metabolism can be

increased once enzyme activity has matured in older infants

and children, because the ratio of the weight of the liver to

body weight is up to 50% higher than in adults. Drugs admin-

istered to the mother can induce neonatal enzyme activity

(e.g. barbiturates). Phenobarbitone metabolism is faster in

children than in adults because of greater induction of hepatic

enzyme activity.

PHARMACODYNAMICS

Documented evidence of differences in receptor sensitivity in

children is lacking, and the apparently paradoxical effects

of some drugs (e.g. hyperkinesia with phenobarbitone, sedation

of hyperactive children with amphetamine) are as yet

unexplained. Augmented responses to warfarinin prepubertal

patients occur at similar plasma concentrations as in adults,

implying a pharmacodynamic mechanism. Ciclosporin added

in vitro to cultured monocytes (hence there is no opportunity for

a pharmacokinetic effect) has greater effects in cells isolated from

infants, providing another example of an age-related pharmaco-

dynamic difference.

BREAST-FEEDING

Breast-feeding can lead to toxicity in the infant if the drug

enters the milk in pharmacological quantities. The milk con-

centration of some drugs (e.g. iodides) may exceed the mater-

nal plasma concentration, but the total dose delivered to the

baby is usually very small. However, drugs in breast milk may

cause hypersensitivity reactions even in very low doses.

Virtually all drugs that reach the maternal systemic circulation

will enter breast milk, especially lipid-soluble unionized low-

molecular-weight drugs. Milk is weakly acidic, so drugs that

are weak bases are concentrated in breast milk by trapping of

the charged form of the drug (compare with renal elimination;

see Chapter 6). However, the resulting dose administered to

the fetus in breast milk is seldom clinically appreciable,

although some drugs are contraindicated (Table 10.2), and

breast-feeding should cease during treatment if there is no

safer alternative. Appendix 5 of the British National

Formulary provides very helpful practical advice.

Key points

Prevalence of chronic illness in children requiring drug

therapy:

• one in eight children have asthma;

• one in 250 children have epilepsy;

• one in 750 children have diabetes mellitus.

Key points

At birth, renal and hepatic function are less efficient than

in adulthood. Drug effects may be prolonged and

accumulation may occur. These factors are exaggerated in

the premature infant.

EXCRETION

All renal mechanisms (filtration, secretion and reabsorption)

are reduced in neonates, and renal excretion of drugs is rela-

tively reduced in the newborn. Glomerular filtration rate

(GFR) increases rapidly during the first four weeks of life, with

consequent changes in the rate of drug elimination (Table 10.1).

Table 10.1: Changes in rate of drug elimination with development

Stage of development Plasma half-life of gentamicin

Premature infant

48 hours old 18 hours

5–22 days old 6 hours

Normal infant

1–4 weeks old 3 hours

Adult 2 hours

Table 10.2:Some drugs to be avoided during breast-feeding

Amiodarone

Aspirin

Benzodiazepines

Chloramphenicol

Ciclosporin

Ciprofloxacin

Cocaine

Combined oral contraceptives

Cytotoxics

Ergotamine

Octreotide

Stimulant laxatives

Sulphonylureas

Thiazide diuretics

Vitamin A/retinoid analogues (e.g. etretinate)

54 DRUGS IN INFANTS AND CHILDREN

The infant should be monitored if β-adrenoceptor antago-

nists, carbimazole, corticosteroids or lithium are prescribed

to the mother. β-Adrenoceptor antagonists rarely cause signif-

icant bradycardia in the suckling infant. Carbimazoleshould

be prescribed at its lowest effective dose to reduce the risk

of hypothyroidism in the neonate/infant. In high doses,

corticosteroids can affect the infant’s adrenal function and

lithium may cause intoxication. There is a theoretical risk of

Reye’s syndrome if aspirinis prescribed to the breast-feeding

mother. Warfarin is not contraindicated during breast-feed-

ing. Bromocriptine suppresses lactation and large doses of

diuretics may do likewise. Metronidazole gives milk an

unpleasant taste.

PRACTICAL ASPECTS OF PRESCRIBING

COMPLIANCE AND ROUTE OF AD MINISTRATION

Sick neonates will usually require intravenous drug adminis-

tration. Accurate dosage and attention to fluid balance are

essential. Sophisticated syringe pumps with awareness of

‘dead space’ associated with the apparatus are necessary.

Children under the age of five years may have diffi-

culty in swallowing even small tablets, and hence oral

preparations which taste pleasant are often necessary to

improve compliance. Liquid preparations are given by means

of a graduated syringe. However, chronic use of sucrose-

containing elixirs encourages tooth cavities and gingivitis.

Moreover, the dyes and colourings used may induce hyper-

sensitivity.

Pressurized aerosols (e.g. salbutamolinhaler, see Chapter

33) are usually only practicable in children over the age of ten

years, as co-ordinated deep inspiration is required unless a

device such as a spacer is used. Spacers can be combined with

a face mask from early infancy. Likewise, nebulizers may be

used to enhance local therapeutic effect and reduce systemic

toxicity.

Only in unusual circumstances, i.e. extensive areas of

application (especially to inflamed or broken skin), or in

infants, does systemic absorption of drugs (e.g. steroids,

neomycin) become significant following topical application

to the skin.

Intramuscular injection should only be used when

absolutely necessary. Intravenous therapy is less painful, but

skill is required to cannulate infants’ veins (and a confident

colleague to keep the target still!). Children find intravenous

infusions uncomfortable and restrictive. Rectal administration

(see Chapter 4) is a convenient alternative (e.g. metronidazole

to treat anaerobic infections). Rectal diazepamis particularly

valuable in the treatment of status epilepticus when intra-

venous access is often difficult. Rectal diazepammay also be

administered by parents. Rectal administration should also be

considered if the child is vomiting.

Paramount to ensuring compliance is full communication

with the child’s parents and teachers. This should include

information not only on how to administer the drug, but

also on why it is being prescribed, for how long the treat-

ment should continue and whether any adverse effects are

likely.

Case history

A two-year-old epileptic child is seen in the Accident and

Emergency Department. He has been fitting for at least 15

minutes. The casualty officer is unable to cannulate a vein

to administer intravenous diazepam. The more experi-

enced medical staff are dealing with emergencies else-

where in the hospital.

Question

Name two drugs, and their route of administration,

with which the casualty officer may terminate the convul-

sions.

Answer

Rectal diazepam solution.

Rectal or intramuscular paraldehyde.

DOSAGE

Even after adjustment of dose according to surface area,

calculation of the correct dose must consider the relatively

large volume of distribution of polar drugs in the first four

months of life, the immature microsomal enzymes and

reduced renal function. The British National Formulary and

specialist paediatric textbooks and formularies provide

appropriate guidelines and must be consulted by physicians

who are not familiar with prescribing to infants and

children.

ADVERSE EFFECTS

With a few notable exceptions, drugs in children generally

have a similar adverse effect profile to those in adults. Of par-

ticular significance is the potential of chronic corticosteroid

use, including high-dose inhaled corticosteroids, to inhibit

growth. Aspirinis avoided in children under 16 years (except

in specific indications, such as Kawasaki syndrome) due to an

association with Reye’s syndrome, a rare but often fatal illness

of unknown aetiology consisting of hepatic necrosis and

encephalopathy, often in the aftermath of a viral illness.

Tetracyclines are deposited in growing bone and teeth, caus-

ing staining and occasionally dental hypoplasia, and should

not be given to children. Fluoroquinolone antibacterial

drugs may damage growing cartilage. Dystonias with meto-

clopramide occur more frequently in children and young

adults than in older adults. Valproate hepatotoxicity is

increased in young children with learning difficulties receiv-

ing multiple anticonvulsants. Some adverse effects cause

RESEARCH 55

lifelong effects as a result of toxicity occurring at a sensitive

point in development (a ‘critical window’) during fetal

or neonatal life (‘programming’) as with thalidomide/

phocomelia or hypothyroid drugs/congenital hypothy-

roidism

RESEARCH

Research in paediatric clinical pharmacology is limited. Not

only is there concern about the potential for adverse effects

of new drugs on those who are growing and developing

mentally, but there are also considerable ethical problems

encountered in research involving individuals who are too

young to give informed consent. New drugs are often given to

children for the first time only when no alternative is available

or when unacceptable side effects have been encountered in a

particular individual with established drugs. Pharmaceutical

companies seldom seek to license their products for use in

children. When drugs are prescribed to children that are

not licensed for use in this age group, it is important to

make careful records of both efficacy and possible adverse

effects. Prescribers take sole responsibility for prescribing

unlicensed preparations (e.g. formulated to appeal to chil-

dren) or for prescribing licensed preparations outside the

licensed age range. Parents should be informed and their con-

sent obtained.

FURTHER READING

Baber N, Pritchard D. Dose estimation in children. British Journal of

Clinical Pharmacology2003; 56: 489–93.

British National Formulary for Children2007. www.bnfc.org

Kearns GL, Abdel-Rahmen SM. Developmental pharmacology – drug

disposition, action and therapy in infants and children. New

England Journal of Medicine2003; 349: 1157–67.

Paediatric Special Issue. British Journal of Clinical Pharmacology2005; 59 (6).

Paediatric formulary, 7th edn. London: Guy’s, St Thomas’, King’s

College and Lewisham Hospitals, revised 2005.

Case history

A 14-year-old boy with a history of exercise-induced

asthma, for which he uses salbutamol as necessary (on aver-

age two puffs twice daily and before exercise) is seen by his

GP because of malaise and nocturnal cough. On examina-

tion, he has a mild fever (38°C), bilateral swollen cervical

lymph nodes and bilateral wheeze. Ampicillin is prescribed

for a respiratory tract infection. The next day the boy

develops a widespread maculopapular rash.

Question 1

What is the cause of the rash?

Question 2

What is the likely cause of the nocturnal cough and how

may this be treated?

Answer 1

Ampicillin rash in infectious mononucleosis (glandular fever).

Answer 2

Poorly controlled asthma. Regular inhaled glucocorticos-

teroid or cromoglicate.

●

Introduction 56

●

Pharmacokinetic changes 56

●

Pharmacodynamic changes 57

●

Compliance in the elderly 58

●

Effect of drugs on some major organ systems in

the elderly 58

●

Practical aspects of prescribing for the elderly 60

●

Research 60

CHAPTER 11

DRUGS IN THE ELDERLY

INTRODUCTION

The proportion of elderly people in the population is increas-

ing steadily in economically developed countries. The elderly

are subject to a variety of complaints, many of which are

chronic and incapacitating, and so they receive a great deal of

drug treatment. There is a growing evidence base for the use of

drugs in elderly patients, with important implications for pre-

scribing of many important classes of drugs, including statins,

β-adrenoceptor antagonists, thrombolytics, ACE inhibitors,

angiotensin receptor blockers, vitamin D and bisphosphonates

(see reviews by Mangoni and Jackson, 2006). Adverse drug

reactions and drug interactions become more common with

increasing age. In one study, 11.8% of patients aged 41–50

years experienced adverse reactions to drugs, but this

increased to 25% in patients over 80 years of age. There are

several reasons for this.

1. Elderly people take more drugs. In one survey in general

practice, 87% of patients over 75 years of age were on

regular drug therapy, with 34% taking three to four

different drugs daily. The most commonly prescribed

drugs were diuretics (34% of patients), analgesics (27%),

tranquillizers and antidepressants (24%), hypnotics (22%)

and digoxin (20%). All of these are associated with a high

incidence of important adverse effects.

2. Drug elimination becomes less efficient with increasing

age, leading to drug accumulation during chronic dosing.

3. Homeostatic mechanisms become less effective with

advancing age, so individuals are less able to compensate

for adverse effects, such as unsteadiness or postural

hypotension.

4. The central nervous system becomes more sensitive to the

actions of sedative drugs.

5. Increasing age produces changes in the immune response

that can cause an increased liability to allergic reactions.

6. Impaired cognition combined with relatively complex

dose regimens may lead to inadvertent overdose.

PHARMACOKINETIC CHANGES

ABSORPTION

Absorption of carbohydrates and of several nutrients, includ-

ing iron, calcium and thiamine, is reduced in elderly people.

Lipid-soluble drugs are absorbed by simple diffusion down

the concentration gradient (Chapter 3), and this is not

impaired by age. Intestinal blood flow is reduced by up to 50%

in the elderly. However, age per se does not affect drug

absorption to a large extent (Figure 11.1).

Drug

Absorption↔

Metabolism↓

Excretion↓

↓Renal blood flow

↓GFR

↓Concentration of

fat-soluble drugs

↑Concentration of

water-soluble drugs

↓Weight

↓Lean body mass

↑Fat

↑Gastric motility

↓Intestinal blood flow

↓Hepatic blood flow

Figure 11.1:Pharmacokinetic changes with age.

PHARMACODYNAMIC CHANGES 57

DISTRIBUTION

Ageing is associated with loss of lean body mass, and with an

increased ratio of fat to muscle and body water. This enlarges

the volume of distribution of fat-soluble drugs, such as

diazepam and lidocaine, whereas the distribution of polar

drugs such as digoxinis reduced compared to younger adults.

Changes in plasma proteins also occur with ageing, especially

if associated with chronic disease and malnutrition, with a fall

in albumin and a rise in gamma-globulin concentrations.

HEPATIC METABOLISM

There is a decrease in the hepatic clearance of some but not all

drugs with advancing age. Aprolonged plasma half-life (Figure

11.2), can be the result either of reduced clearance or of increased

apparent volume of distribution. Ageing reduces metabolism of

some drugs (e.g. benzodiazepines) as evidenced by reduced

hepatic clearance. The reduced clearance of benzodiazepines

has important clinical consequences, as does the long half-life of

several active metabolites (Chapter 18). Slow accumulation may

lead to adverse effects whose onset may occur days or weeks

after initiating therapy. Consequently, confusion or memory

impairment may be falsely attributed to ageing rather than to

adverse drug effects.

RENAL EXCRETION

The most important cause of drug accumulation in the elderly

is declining renal function. Many healthy elderly individuals

have a glomerular filtration rate (GFR) 50mL/min. Although

glomerular filtration rate declines with age, this is not necessar-

ily reflected by serum creatinine, which can remain within the

range defined as ‘normal’ for a younger adult population

despite a marked decline in renal function. This is related to the

lower endogenous production of creatinine in the elderly sec-

ondary to their reduced muscle mass. Under-recognition of

renal impairment in the elderly is lessened by the routine

reporting by many laboratories of an estimated GFR (eGFR)

based on age, sex and serum creatinine concentration and

reported in units normalized to 1.73m

body surface area

(mL/min/1.73m

). When estimating doses of nephrotoxic

drugs, it is important to remember that the drug elimination

depends on the absolute GFR (in mL/min) rather than that nor-

malized to an ideal body surface area (in mL/min/1.73m

and to estimate this if necessary using a nomogram (see

Chapter 7) that incorporates height and weight, as well as age,

sex and creatinine.

Examples of drugs which may require reduced dosage in

the elderly secondary to reduced renal excretion and/or

hepatic clearance are listed in Table 11.1.

The principal age-related changes in pharmacokinetics are

summarized in Figure 11.1.Key points

120

100

01020304050

Age (years)

60 70 80 100

Diazepamt

1/2

(h)

Figure 11.2:Relationship between diazepam half-life and age in

33 normal individuals. Non-smokers,

; smokers,

•

. (Redrawn

with permission from Klotz U et al. Journal of Clinical

Investigation1975; 55: 347.)

Key points

Pharmacokinetic changes in the elderly include:

• Absorption of iron, calcium and thiamine is reduced.

• There is an increased volume of distribution of fat-

soluble drugs (e.g. diazepam).

• There is a decreased volume of distribution of polar

drugs (e.g. digoxin).

• There is reduced hepatic clearance of long half-life

benzodiazepines.

• Declining renal function is the most important cause of

drug accumulation.

PHARMACODYNAMIC CHANGES

Evidence that the elderly are intrinsically more sensitive to

drugs than the young is scarce. However, the sensitivity of the

elderly to benzodiazepines as measured by psychometric tests

is increased, and their effects last longer than in the young. It is

common clinical experience that benzodiazepines given to the

elderly at hypnotic doses used for the young can produce pro-

longed daytime confusion even after single doses. The inci-

dence of confusion associated with cimetidine is increased in

the elderly. Other drugs may expose physiological defects that

are a normal concomitant of ageing. Postural hypotension can

occur in healthy elderly people, and the incidence of postural

hypotension from drugs such as phenothiazines, β-adrenoceptor

Table 11.1: Examples of drugs requiring dose adjustment in the elderly

Aminoglycosides (e.g. gentamicin)

Atenolol

Cimetidine

Diazepam

Digoxin

Non-steroidal anti-inflammatory drugs

Oral hypoglycaemic agents

Warfarin

COMPLIANCE IN THE E LDERLY

Incomplete compliance is extremely common in elderly people.

This is commonly due to a failure of memory or to not under-

standing how the drug should be taken. In addition, many

patients store previously prescribed drugs in the medicine

cupboard which they take from time to time. It is therefore

essential that the drug regimen is kept as simple as possible

and explained carefully. There is scope for improved methods

of packaging to reduce over- or under-dosage. Multiple drug

regimens are confusing and increase the risk of adverse inter-

actions (see Chapter 13).

EFFECT OF DRUGS ON SOME MAJOR

ORGAN SYSTEMS IN THE ELDERLY

CENTRAL N ERVOUS SYSTEM

Cerebral function in old people is easily disturbed, resulting

in disorientation and confusion. Drugs are one of the factors

that contribute to this state; sedatives and hypnotics can easily

precipitate a loss of awareness and clouding of consciousness.

NIGHT SEDATION

The elderly do not sleep as well as the young. They sleep for a

shorter time, their sleep is more likely to be broken and they are

more easily aroused. This is quite normal, and old people should

not have the expectations of the young as far as sleep is con-

cerned. Before hypnotics are commenced, other possible factors

should be considered and treated if possible. These include:

1. pain, which may be due to such causes as arthritis;

2. constipation – the discomfort of a loaded rectum;

3. urinary frequency;

4. depression;

5. anxiety;

58 DRUGS IN THE ELDERLY

6. left ventricular failure;

7. dementia;

8. nocturnal xanthine alkaloids, e.g. caffeine in tea,

theophylline.

A little more exercise may help, and ‘catnapping’ in the day

reduced to a minimum and regularized (as in Mediterranen

cultures).

The prescription of hypnotics (see Chapter 18) should be

minimized and restricted to short-term use.

ANTIDEPRESSANTS

Although depression is common in old age and may indeed

need drug treatment, this is not without risk. Tricyclic anti-

depressants (see Chapter 20) can cause constipation, urinary

retention and glaucoma (due to their muscarinic blocking

action which is less marked in the case of lofepramine than

other drugs of this class), and also drowsiness, confusion, pos-

tural hypotension and cardiac dysrhythmias. Tricyclic antide-

pressants can produce worthwhile remissions of depression

but should be started at very low dosage.

Selective 5-hydroxytryptamine reuptake inhibitors (e.g.

fluoxetine) are as effective as the tricyclics and have a distinct

side-effect profile (see chapter 20). They are generally well

tolerated by the elderly, although hyponatraemia has been

reported more frequently than with other antidepressants.

ANTI-PARKINSONIAN DRUGS

The anticholinergic group of anti-parkinsonian drugs (e.g.

trihexyphenidyl,orphenadrine) commonly cause side effects

in the elderly. Urinary retention is common in men. Glaucoma

may be precipitated or aggravated and confusion may occur

with quite small doses. Levodopacombined with a peripheral

dopa decarboxylase inhibitor such as carbidopa can be effec-

tive, but it is particularly important to start with a small dose,

which can be increased gradually as needed. In patients with

dementia, the use of antimuscarinics, levodopaor amantidine

may produce adverse cerebral stimulation and/or hallucin-

ations, leading to decompensation of cerebral functioning,

with excitement and inability to cope.

CARDIOVASCULAR SYSTEM

HYPERTENSION

There is excellent evidence that treating hypertension in the

elderly reduces both morbidity and mortality. The agents used

(starting with a C or D drug) are described in Chapter 28. It is

important to start with a low dose and monitor carefully.

Some adverse effects (e.g. hyponatraemia from diuretics) are

much more common in the elderly, who are also much more

likely to suffer severe consequences, such as falls/fractures

from common effects like postural hypotension. Alpha-

blockers in particular should be used as little as possible.

Methyldopa might be expected to be problematic in this age

group but was in fact surprisingly well tolerated when used as

add-on therapy in a trial by the European Working Party on

Hypertension in the Elderly (EWPHE).

Key points

Pharmacodynamic changes in the elderly include:

• increased sensitivity to central nervous system (CNS)

effects (e.g. benzodiazepines, cimetidine);

• increased incidence of postural hypotension (e.g.

phenothiazines, beta-blockers, tricyclic antidepressants,

diuretics);

• reduced clotting factor synthesis, reduced warfarin for

anticoagulation;

• increased toxicity from NSAIDs;

• increased incidence of allergic reactions to drugs.

antagonists, tricyclic antidepressants and diuretics is increased

in elderly patients. The QT interval is longer in the elderly,

which may predispose to drug-induced ventricular tachy-

dysrhythmias. Clotting factor synthesis by the liver is reduced

in the elderly, and old people often require lower warfarin

doses for effective anticoagulation than younger adults.

DIGOXIN

Digoxintoxicity is common in the elderly because of decreased

renal elimination and reduced apparent volume of distribution.

Confusion, nausea and vomiting, altered vision and an acute

abdominal syndrome resembling mesenteric artery obstruction

are all more common features of digoxintoxicity in the elderly

than in the young. Hypokalaemia due to decreased potassium

intake (potassium-rich foods are often expensive), faulty homeo-

static mechanisms resulting in increased renal loss and the con-

comitant use of diuretics is more common in the elderly, and is

a contributory factor in some patients. Digoxin is sometimes

prescribed when there is no indication for it (e.g. for an irregu-

lar pulse which is due to multiple ectopic beats rather than

atrial fibrillation). At other times, the indications for initiation of

treatment are correct but the situation is never reviewed. In one

series of geriatric patients on digoxin, the drug was withdrawn

in 78% of cases without detrimental effects.

DIURETICS

Diuretics are more likely to cause adverse effects (e.g. postural

hypotension, glucose intolerance and electrolyte disturbances)

in elderly patients. Too vigorous a diuresis may result in urin-

ary retention in an old man with an enlarged prostate, and

necessitate bladder catheterization with its attendant risks.

Brisk diuresis in patients with mental impairment or reduced

mobility can result in incontinence. For many patients, a thia-

zide diuretic, such as bendroflumethiazide, is adequate. Loop

diuretics, such as furosemide, should be used in acute heart

failure or in the lowest effective dose for maintenance treatment

of chronic heart failure. Clinically important hypokalaemia is

uncommon with low doses of diuretics, but plasma potassium

should be checked after starting treatment. If clinically important

hypokalaemia develops, a thiazide plus potassium-retaining

diuretic (amilorideor triamterene) can be considered, but there

is a risk of hyperkalaemia due to renal impairment, especially

if an ACE inhibitor and/or angiotensin receptor antagonist

and aldosterone antagonist are given together with the diuretic

for hypertension or heart failure. Thiazide-induced gout and

glucose intolerance are important side effects.

ISCHAEMIC HEART DISEASE

This is covered in Chapter 29.

ANGIOTENSIN CONVERTING ENZYME INHIBITORS

(ACEI) AND ANGIOTENSIN RECEPTOR BLOCKERS (ARB)

These drugs plays an important part in the treatment of chronic

heart failure, as well as hypertension (see Chapters 28 and 31),

and are effective and usually well tolerated in the elderly.

However, hypotension, hyperkalaemia and renal failure are

more common in this age group. The possibility of atheroma-

tous renal artery stenosis should be borne in mind and serum

creatinine levels checked before and after starting treatment.

Potassium-retaining diuretics should be co-administered only

with extreme caution, because of the reduced GFR and plasma

potassium levels monitored. Despite differences in their phar-

macology, ACEI and ARB appear similar in efficacy, but ARB

do not cause the dry cough that is common with ACEI. The

EFFECT OF DRUGS ON SOME MAJOR O RGAN SYSTEMS I N THE ELDERLY 59

question of whether co-administration of ACEI with ARB has

much to add remains controversial; in elderly patients with

reduced GFR, the safety of such combined therapy is an impor-

tant consideration.

ORAL HYPOGLYCAEMIC AGENTS

Diabetes is common in the elderly and many patients are

treated with oral hypoglycaemic drugs (see Chapter 37). It is

best for elderly patients to be managed with diet if at all possi-

ble. In obese elderly diabetics who remain symptomatic on

diet, metformin should be considered, but coexisting renal,

heart or lung disease may preclude its use. Short-acting

sulphonylureas (e.g. gliclazide) are preferred to longer-acting

drugs because of the risk of hypoglycaemia: chlorpropamide

(half-life 36 hours) can cause prolonged hypoglycaemia and is

specifically contraindicated in this age group, glibenclamide

should also be avoided. Insulinmay be needed, but impaired

visual and cognitive skills must be considered on an individual

basis, and the potential need for dose reduction with advanc-

ing age and progressive renal impairment taken into account.

ANTIBIOTICS

The decline in renal function must be borne in mind when an

antibiotic that is renally excreted is prescribed, especially if it is

nephrotoxic (e.g. an aminoglycoside or tetracycline). Appendix 3

of the British National Formulary is an invaluable practical guide.

Over-prescription of antibiotics is a threat to all age groups,

but especially in the elderly. Broad-spectrum drugs including

cephalosporins and other beta-lactams, and fluoroquinones are

common precursors of Clostridium difficile infection which has a

high mortality rate in the elderly. Amoxicillinis the most com-

mon cause of drug rash in the elderly. Flucloxacillin induced

cholestatic jaundice and hepatitis is more common in the elderly.

Case history

An 80-year-old retired publican was referred with ‘congest-

ive cardiac failure and acute retention of urine’. His wife

said his symptoms of ankle swelling and breathlessness had

gradually increased over a period of six months despite the

GP doubling the water tablet (co-amilozide) which he was

taking for high blood pressure. Over the previous week he

had become mildly confused and restless at night, for

which the GP had prescribed chlorpromazine. His other

medication included ketoprofen for osteoarthritis and fre-

quent magnesium trisilicate mixture for indigestion. He

had been getting up nearly ten times most nights for a year

to pass urine. During the day, he frequently passed small

amounts of urine. Over the previous 24 hours, he had been

unable to pass urine. His wife thought most of his problems

were due to the fact that he drank two pints of beer each

day since his retirement seven years previously.

On physical examination he was clinically anaemic, but

not cyanosed. Findings were consistent with congestive

cardiac failure. His bladder was palpable up to his umbili-

cus. Rectal examination revealed an enlarged, symmetrical

prostate and black tarry faeces. Fundoscopy revealed a

grade II hypertensive retinopathy.

60 DRUGS IN THE ELDERLY

4.Use the fewest possible number of drugs the patient needs.

5. Consider the potential for drug interactions and

co-morbidity on drug response.

6. Drugs should seldom be used to treat symptoms without

first discovering the cause of the symptoms (i.e. first

diagnosis, then treatment).

7. Drugs should not be withheld because of old age, but it

should be remembered that there is no cure for old age

either.

8. A drug should not be continued if it is no longer necessary.

9. Do not use a drug if the symptoms it causes are worse

than those it is intended to relieve.

10. It is seldom sensible to treat the side effects of one drug

by prescribing another.

In the elderly, it is often important to pay attention to mat-

ters such as the formulation of the drug to be used – many old

people tolerate elixirs and liquid medicines better than tablets

or capsules. Supervision of drug taking may be necessary, as

an elderly person with a serious physical or mental disability

cannot be expected to comply with any but the simplest drug

regimen. Containers require especially clear labelling, and

should be easy to open – child-proof containers are often also

grandparent-proof!

RESEARCH

Despite their disproportionate consumption of medicines, the

elderly are often under-represented in clinical trials. This may

result in the data being extrapolated to an elderly population

inappropriately, or the exclusion of elderly patients from new

treatments from which they might benefit. It is essential that,

both during a drug’s development and after it has been licensed,

subgroup analysis of elderly populations is carefully examined

both for efficacy and for predisposition to adverse effects.

Initial laboratory results revealed that the patient had

acute on chronic renal failure, dangerously high potassium

levels (7.6mmol/L) and anaemia (Hb 7.4 g/dL). Emergency

treatment included calcium chloride, dextrose and insulin,

urinary catheterization, furosemide and haemodialysis.

Gastroscopy revealed a bleeding gastric ulcer. The patient

was discharged two weeks later, when he was symptomat-

ically well. His discharge medication consisted of regular

doxazosin and ranitidine, and paracetamol as required.

Question

Describe how each of this patient’s drugs prescribed before

admission may have contributed to his clinical condition.

Answer

Co-amilozide – hyperkalaemia: amiloride, exacerbation of

prostatic symptoms: thiazide

Chlorpromazine – urinary retention

Ketoprofen – gastric ulcer, antagonism of thiazide diuretic,

salt retention, possibly interstitial nephritis

Magnesium trisilicate mixture – additional sodium load

(6mmol Na



/10mL).

Comment

Iatrogenic disease due to multiple drug therapy is common

in the elderly. The use of amiloride in renal impairment

leads to hyperkalaemia. This patient’s confusion and rest-

lessness were most probably related to his renal failure.

Chlorpromazine may mask some of the symptoms/signs and

delay treatment of the reversible organic disease. The anal-

gesic of choice in osteoarthritis is paracetamol, due to its

much better tolerance than NSAID. The sodium content of

some antacids can adversely affect cardiac and renal failure.

NON-STEROIDAL ANTI-INFL AMMATORY DRUGS

The elderly are particularly susceptible to non-steroidal anti-

inflammatory drug (NSAID)-induced peptic ulceration, gastro-

intestinal irritation and fluid retention. An NSAID is frequently

prescribed inappropriately for osteoarthritis before physical

and functional interventions and oral paracetamolhave been

adequately utilized. If an NSAID is required as adjunctive

therapy, the lowest effective dose should be used. Ibuprofen

is probably the NSAID of choice in terms of minimizing gas-

tro-intestinal side effects. Aproton pump inhibitor should be

considered as prophylaxis against upper gastro-intestinal

complications in those most at risk.

PRACTICAL ASPECTS OF PRESCRIBING

FOR THE ELDERLY

Improper prescription of drugs is a common cause of morbid-

ity in elderly people. Common-sense rules for prescribing do

not apply only to the elderly, but are especially important in

this vulnerable group.

1. Take a full drug history (see Chapter 1), which should

include any adverse reactions and use of over-the-counter

drugs.

2. Know the pharmacological action of the drug employed.

3. Use the lowest effective dose.

Case history

A previously mentally alert and well-orientated 90-year-old

woman became acutely confused two nights after hospital

admission for bronchial asthma which, on the basis of peak

flow and blood gases, had responded well to inhaled salbu-

tamol and oral prednisolone. Her other medication was

cimetidine (for dyspepsia), digoxin (for an isolated episode

of atrial fibrillation two years earlier) and nitrazepam (for

night sedation).

Question

Which drugs may be related to the acute confusion?

Answer

Prednisolone, cimetidine, digoxin and nitrazepam.

Comment

If an H

-antagonist is necessary, ranitidine is preferred in the

elderly. It is likely that the patient no longer requires digoxin

(which accumulates in the elderly). Benzodiazepines should

not be used for sedation in elderly (or young) asthmatics.

They may also accumulate in the elderly. The elderly tend to

be more sensitive to adverse drug effects on the central ner-

vous system (CNS).

RESEARCH 61

FURTHER READING

Dhesi JK, Allain TJ, Mangoni AA, Jackson SHD. The implications of a

growing evidence base for drug use in elderly patients. Part 4.

Vitamin D and bisphosphonates for fractures and osteoporosis.

British Journal of Clinical Pharmacology2006; 61: 520–8.

Hanratty CG, McGlinchey P, Johnston GD, Passmore AP. Differential

pharmacokinetics of digoxin in elderly patients. Drugs and Aging

2000;17: 353–62.

Mangoni AA, Jackson SHD. The implications of a growing evidence

base for drug use in elderly patients. Part 1. Statins for primary

and secondary cardiovascular prevention. British Journal of Clinical

Pharmacology2006; 61: 494–501.

Mangoni AA, Jackson SHD. The implications of a growing evidence

base for drug use in elderly patients. Part 2. ACE inhibitors and

angiotensin receptor blockers in heart failure and high cardiovas-

cular risk patients. British Journal of Clinical Pharmacology2006; 61:

502–12.

Mangoni AA, Jackson SHD. The implications of a growing evidence

base for drug use in elderly patients. Part 3. β-adrenoceptor block-

ers in heart failure and thrombolytics in acute myocardial infarc-

tion.British Journal of Clinical Pharmacology 2006; 61: 513–20.

Sproule BA, Hardy BG, Shulman KI. Differential pharmacokinetics in

elderly patients. Drugs and Aging2000; 16: 165–77.

●

Introduction 62

●

Identification of the drug at fault 63

●

Adverse drug reaction monitoring/surveillance

(pharmacovigilance) 63

●

Allergic adverse drug reactions 66

●

Prevention of allergic drug reactions 67

●

Examples of allergic and other adverse

drug reactions 68

CHAPTER 12

ADVERSE DRUG REACTIONS

INTRODUCTION

Adverse drug reactions are unwanted effects caused by nor-

mal therapeutic doses. Drugs are great mimics of disease,

and adverse drug reactions present with diverse clinical

signs and symptoms. The classification proposed by Rawlins

and Thompson (1977) divides reactions into type Aand type B

(Table 12.1).

Type Areactions, which constitute approximately 80% of

adverse drug reactions, are usually a consequence of the drug’s

primary pharmacological effect (e.g. bleeding from warfarin)

or a low therapeutic index (e.g. nausea from digoxin), and they

are therefore predictable. They are dose-related and usually

mild, although they may be serious or even fatal (e.g. intracra-

nial bleeding from warfarin). Such reactions are usually due to

inappropriate dosage, especially when drug elimination is

impaired. The term ‘side effects’ is often applied to minor type

Areactions.

Type B (‘idiosyncratic’) reactions are not predictable from

the drug’s main pharmacological action, are not dose-related

and are severe, with a considerable mortality. The underlying

pathophysiology of type B reactions is poorly if at all under-

stood, and often has a genetic or immunological basis. Type B

reactions occur infrequently (1:1000–1:10000 treated subjects

being typical).

Adverse drug reactions due to specific drug–drug inter-

actions are considered in Chapter 13. Three further minor cat-

egories of adverse drug reaction have been proposed:

1. type C – continuous reactions due to long-term drug use

(e.g. neuroleptic-related tardive dyskinesia or analgesic

nephropathy);

2. type D – delayed reactions (e.g. alkylating agents

leading to carcinogenesis, or retinoid-associated

teratogenesis);

3. type E end-of-use reactions, such as adrenocortical

insufficiency following withdrawal of glucocorticosteroids,

or withdrawal syndromes following discontinuation of

treatment with benzodiazepines or β-adrenoceptor

antagonists.

In the UK there are between 30000 and 40000 medicinal

products available directly or on prescription. Surveys sug-

gest that approximately 80% of adults take some kind of medi-

cation during any two-week period. Exposure to drugs in the

population is thus substantial, and the incidence of adverse

reactions must be viewed in this context. Type Areactions are

reported to be responsible for 2–3% of consultations in general

practice. In a recent prospective analysis of 18820 hospital

admissions by Pirmohamed et al. (2004), 1225 were related to

an adverse drug reaction (prevalence 6.8%), with the adverse

drug reaction leading directly to admission in 80% of cases.

Median bed stay was eight days, accounting for 4% of hospi-

tal bed capacity. The projected annual cost to the NHS is £466

million. Overall fatality was 0.15%. Most reactions were either

definitely or probably avoidable. Adverse drug reactions are

most frequent and severe in the elderly, in neonates, women,

patients with hepatic or renal impairment, and individuals

with a history of previous adverse drug reactions. Such reac-

tions often occur early in therapy (during the first one to ten

days). Drugs most commonly implicated include low-dose

aspirin(antiplatelet agents), diuretics, warfarin and NSAIDs.

A systematic review by Howard et al. (2006) of preventable

adverse drug reactions which caused hospitalization, impli-

cated the same major drug classes.

Table 12.1: Some examples of type A and type B reactions.

Drug Type A Type B

Chlorpromazine Sedation Cholestatic jaundice

Naproxen Gastro-intestinal Agranulocytosis

haemorrhage

Phenytoin Ataxia Hepatitis,

lymphadenopathy

Thiazides Hypokalaemia Thrombocytopenia

Quinine Tinnitus Thrombocytopenia

Warfarin Bleeding Breast necrosis

ADVERSEDRUG R EACTION MONITORING/SURVEILLANCE(P HARMACOVIGILANCE) 63

Factors involved in the aetiology of adverse drug reactions

can be classified as shown in Table 12.2.

IDENTIFICATION OF THE DRUG AT FAULT

It is often difficult to decide whether a clinical event is drug

related, and even when this is probable, it may be difficult to

determine which drug is responsible, as patients are often tak-

ing multiple drugs. One or more of several possible approaches

may be appropriate.

1. A careful drug history is essential. The following

considerations should be made to assess causality of the

effect to the drug: did the clinical event and the time-

course of its development fit with the duration of suspected

drug treatment and known adverse drug effects? Did the

adverse effect reverse upon drug withdrawal and, upon

rechallenge with the drug, reappear? Were other possible

causes reasonably excluded? Apatient’s drug history may

not always be conclusive because, although allergy to a

drug implies previous exposure, the antigen may have

occurred in foods (e.g. antibiotics are often fed to livestock

and drug residues remain in the flesh), in drug mixtures

or in some casual manner.

2. Provocation testing. This involves giving a very small

amount of the suspected drug and seeing whether a

reaction ensues, e.g. skin testing, where a drug is applied

as a patch, or is pricked or scratched into the skin or

injected intradermally. Unfortunately, prick and scratch

testing is less useful for assessing the systemic reaction to

drugs than it is for the more usual atopic antigens (e.g.

pollens), and both false-positive and false-negative results

can occur. Patch testing is safe, and is useful for the

diagnosis of contact sensitivity, but does not reflect

systemic reactions and may itself cause allergy. Provocation

tests should only be undertaken under expert guidance,

after obtaining informed consent, and with resuscitation

facilities available.

3. Serological testing and lymphocytes testing. Serological

testing is rarely helpful, circulating antibodies to the drug

do not mean that they are necessarily the cause of the

symptoms. The demonstration of transformation occurring

when the patient’s lymphocytes are exposed to a drug

ex vivo suggests that the patient’s T-lymphocytes are

sensitized to the drug. In this type of reaction, the hapten

itself will often provoke lymphocyte transformation, as

well as the conjugate.

4. The best approach in patients on multiple drug therapy is

to stop all potentially causal drugs and reintroduce them

one by one until the drug at fault is discovered. This should

only be done if the reaction is not serious, or if the drug

is essential and no chemically unrelated alternative is

available. All drug allergies should be recorded in the case

notes and the patient informed of the risks involved in

taking the drug again.

Key points

• Type A reaction – an extension of the pharmacology of

the drug, dose related, and accounts for most adverse

reactions (e.g. β-adrenoreceptor antagonist-induced

bradycardia or AV block).

• Type B reaction – idiosyncratic reaction to the drug, not

dose related, rare but severe (e.g. chloramphenicol-

induced aplastic anaemia).

• Other types of drug reaction (much rarer):

– type C reaction – continuous reactions due to long-

term use: analgesic nephropathy;

– type D reaction – delayed reactions of

carcinogenesis or teratogenesis;

– type E reaction – drug withdrawal reactions (e.g.

benzodiazepines).

ADVERSE DRUG REACTION MONITORING/

SURVEILLANCE (PHARMACOVIGILAN CE)

The evaluation of drug safety is complex, and there are many

methods for monitoring adverse drug reactions. Each of these

has its own advantages and shortcomings, and no single

Table 12.2:Factors involved in adverse drug reactions.

Intrinsic Extrinsic

Patient factors

Age – neonatal, infant and elderly Environment – sun

Sex – hormonal environment Xenobiotics (e.g. drugs,

Genetic abnormalities (e.g. herbicides)

enzyme or receptor Malnutrition

polymorphisms)

Previous adverse drug reactions,

allergy, atopy

Presence of organ dysfunction –

disease

Personality and habits –

adherence (compliance),

alcoholic, drug addict,

nicotine

Prescriber factors

Incorrect drug or drug combination

Incorrect route of administration

Incorrect dose

Incorrect duration of therapy

Drug factors

Drug–drug interactions (see

Chapter 13)

Pharmaceutical – batch problems,

shelf-life, incorrect dispensing

64 ADVERSEDRUG REACTIONS

system can offer the 100% accuracy that current public opinion

expects. The ideal method would identify adverse drug reactions

with a high degree of sensitivity and specificity and respond

rapidly. It would detect rare but severe adverse drug reactions,

but would not be overwhelmed by common ones, the incidence

of which it would quantify together with predisposing factors.

Continued surveillance is mandatory after a new drug has

been marketed, as it is inevitable that the preliminary testing

of medicines in humans during drug development, although

excluding many ill effects, cannot identify uncommon adverse

effects. A variety of early detection systems have been intro-

duced to identify adverse drug reactions as swiftly as possible.

PHASE I/II/III TRIALS

Early (phase I/II) trials (Chapter 15) are important for assess-

ing the tolerability and dose–response relationship of new

therapeutic agents. However, these studies are, by design,

very insensitive at detecting adverse reactions because they

are performed on relatively few subjects (perhaps 200–300).

This is illustrated by the failure to detect the serious toxicity

of several drugs (e.g. benoxaprofen, cerivastatin, felbamate,

dexfenfluramineand fenfluramine, rofecoxib, temofloxacin,

troglitazone) before marketing. However, phase III clinical

trials can establish the incidence of common adverse reactions

and relate this to therapeutic benefit. Analysis of the reasons

given for dropping out of phase III trials is particularly valu-

able in establishing whether common events, such as

headache, constipation, lethargy or male sexual dysfunction

are truly drug related. The Medical Research Council Mild

Hypertension Study unexpectedly identified impotence as

more commonly associated with thiazide diuretics than with

placebo or β-adrenoceptor antagonist therapy. Table 12.3

illustrates how difficult it is to detect adverse drug reactions

with 95% confidence, even when there is no background inci-

dence and the diagnostic accuracy is 100%. This ‘easiest-case’

scenario approximates to the actual situation with thalido-

mide teratogenicity: spontaneous phocomelia is almost

unknown, and the condition is almost unmistakable. It is

sobering to consider that an estimated 10000 malformed

babies were born world-wide before thalidomide was with-

drawn. Regulatory authorities may act after three or more

documented events.

The problem of adverse drug reaction recognition is much

greater if the reaction resembles spontaneous disease in the

population, such that physicians are unlikely to attribute the

reaction to drug exposure: the numbers of patients that must

then be exposed to enable such reactions to be detected are

greater than those quoted in Table 12.3, probably by several

orders of magnitude.

YELLOW CARD SCHEME AND POST-MARKETING

(PHASE IV) SURVEILLANCE

Untoward effects that have not been detected in clinical trials

become apparent when the drug is used on a wider scale. Case

reports, which may stimulate further reports, remain the most

sensitive means of detecting rare but serious and unusual

adverse effects. In the UK, a Register of Adverse Reactions

was started in 1964. Currently, the Medicines and Healthcare

products Regulatory Agency (MHRA) operates a system of

spontaneous reporting on prepaid yellow postcards. Doctors,

dentists, pharmacists, nurse practitioners and (most recently)

patients are encouraged to report adverse events whether actu-

allyor potentially causally drug-related. Analogous schemes are

employed in other countries. The yellow card scheme consists

of three stages:

1. data collection;

2. analysis;

3. feedback.

Such surveillance methods are useful, but under-reporting is a

major limitation. Probably fewer than 10% of appropriate

adverse reactions are reported. This may be due partly to con-

fusion about what events to report, partly to difficulty in rec-

ognizing the possible relationship of a drug to an adverse

event – especially when the patient has been taking several

drugs, and partly to ignorance or laziness on the part of poten-

tial reporters. Afurther problem is that, as explained above, if

a drug increases the incidence of a common disorder (e.g.

ischaemic heart disease), the change in incidence must be very

large to be detectable. This is compounded when there is a

delay between starting the drug and occurrence of the event

(e.g. cardiovascular thrombotic events including myocardial

infarction following initiation of rofecoxib therapy). Doctors

are inefficient at detecting such adverse reactions to drugs,

and those reactions that are reported are in general the obvi-

ous or previously described and well-known ones. Initiatives

are in progress to attempt to improve this situation by involve-

ment of trained clinical pharmacologists and pharmacists in

and outside hospitals.

The Committee on Safety of Medicines (CSM), now part of

MHRA, introduced a system of high vigilance for newly mar-

keted drugs. For its first two years on the general market, any

newly marketed drug has a black triangle on its data sheet and

against its entry in the British National Formulary. This con-

veys to prescribers that any unexpected event should be

reported by the yellow card system. The pharmaceutical com-

pany is also responsible for obtaining accurate reports on all

patients treated up to an agreed number. This scheme was

successful in the case of benoxaprofen, an anti-inflammatory

Table 12.3:Numbers of subjects that would need to be exposed in order to

detect adverse drug reactions

Expected frequency Approximate number of patients

of the adverse effect required to be exposed

For one event For three events

1 in 100 300 650

1 in 1000 3000 6500

1 in 10000 30000 65000

ADVERSEDRUG R EACTION MONITORING/SURVEILLANCE(P HARMACOVIGILANCE) 65

analgesic. Following its release, there were spontaneous reports

to the CSM of photosensitivity and onycholysis. Further reports

appeared in the elderly, in whom its half-life is prolonged, of

cholestatic jaundice and hepatorenal failure, which was fatal

in eight cases. Benoxaprofen was subsequently taken off the

market when 3500 adverse drug reaction reports were received

with 61 fatalities. The yellow card/black triangle scheme was

also instrumental in the early identification of urticaria and

cough as adverse effects of angiotensin-converting enzyme

inhibitors. Although potentially the population under study

by this system consists of all the patients using a drug, in fact

under-reporting yields a population that is not uniformly

sampled. Such data can be unrepresentative and difficult to

work with statistically, contributing to the paucity of accurate

incidence data for adverse drug reactions.

Systems such as the yellow card scheme (e.g. FDAMedWatch

in the USA) are relatively inexpensive and easy to manage,

and facilitate ongoing monitoring of all drugs, all consumers

and all types of adverse reaction. Reports from the drug regu-

latory bodies of 22 countries are collated by the World Health

Organization (WHO) Unit of Drug Evaluation and Monitoring

in Geneva. Rapid access to reports from other countries should

be of great value in detecting rare adverse reactions, although

the same reservations apply to this register as apply to

national systems. In addition, this database could reveal geo-

graphical differences in the pattern of untoward drug effects.

CASE–CONTROL STUDIES

Avery large number of patients have to be monitored to detect

a rare type B adverse effect. An alternative approach is to iden-

tify patients with a disorder which it is postulated could be

caused by an adverse reaction to a drug, and to compare the fre-

quency of exposure to possible aetiological agents with a con-

trol group. Aprior suspicion (hypothesis) must exist to prompt

the setting up of such a study – examples are the possible con-

nection between irradiation or environmental pollution and

certain malignancies, especially where they are observed in

clusters. Artefacts can occur as a result of unrecognized bias

from faulty selection of patients and controls, and the approach

remains controversial among epidemiologists, public health

physicians and statisticians. Despite this, there is really no prac-

ticable alternative for investigating a biologically plausible

hypothesis relating to a disease which is so uncommon that it

is unlikely to be represented even in large trial or cohort popu-

lations. This methodology has had notable successes: the associ-

ation of stilboestrolwith vaginal adenocarcinoma, gatifloxacin

with hypo- and hyperglycaemia, and salmeterol or fenoterol

use with increased fatality in asthmatics.

INTENSIVE MONITORING

Several hospital-based intensive monitoring programmes are

currently in progress. The Aberdeen–Dundee system abstracts

data from some 70000 hospital admissions each year, storing

these on a computer file before analysis. The Boston

Collaborative Drug Surveillance Program (BCDSP), involving

selected hospitals in several countries, is even more compre-

hensive. In the BCDSP, all patients admitted to specially desig-

nated general wards are included in the analysis. Specially

trained personnel obtain the following information from hos-

pital patients and records:

1. background information (i.e. age, weight, height, etc.);

2. medical history;

3. drug exposure;

4. side effects;

5. outcome of treatment and changes in laboratory tests

during hospital admission.

A unique feature of comprehensive drug-monitoring sys-

tems lies in their potential to follow up and investigate adverse

reactions suggested by less sophisticated detection systems, or

by isolated case reports in medical journals. Furthermore, the

frequency of side effects can be determined more cheaply than

by a specially mounted trial to investigate a simple adverse

effect. Thus, for example, the risk of developing a rash with

ampicillin was found to be around 7% both by clinical trial

and by the BCDSP, which can quantify such associations

almost automatically from data on its files. New adverse reac-

tions or drug interactions are sought by multiple correlation

analysis. Thus, when an unexpected relationship arises, such

as the 20% incidence of gastro-intestinal bleeding in severely

ill patients treated with ethacrynic acid compared to 4.3%

among similar patients treated with other diuretics, this can-

not be attributed to bias arising from awareness of the hypoth-

esis during data collection, since the data were collected

before the hypothesis was proposed. Conversely, there is a

possibility of chance associations arising from multiple com-

parisons (‘type I’ statistical error), and such associations must

be reviewed critically before accepting a causal relationship. It

is possible to identify predisposing risk factors. In the associ-

ation between ethacrynic acid and gastro-intestinal bleeding,

these were female sex, a high blood urea concentration, previ-

ous heparin administration and intravenous administration of

the drug. An important aspect of this type of approach is that

lack of clinically important associations can also be investi-

gated. Thus, no significant association between aspirin and

renal disease was found, whereas long-term aspirinconsump-

tion is associated with a decreased incidence of myocardial

infarction, an association which has been shown to be of thera-

peutic importance in randomized clinical trials (Chapter 29).

There are plans to extend intensive drug monitoring to cover

other areas of medical practice.

However, in terms of new but uncommon adverse reac-

tions, the numbers of patients undergoing intensive monitor-

ing while taking a particular drug will inevitably be too small

for the effect to be detectable. Such monitoring can therefore

only provide information about relatively common, early reac-

tions to drugs used under hospital conditions. Patients are not

in hospital long enough for detection of delayed effects, which

are among the reactions least likely to be recognized as such

even by an astute clinician.

66 ADVERSEDRUG REACTIONS

MONITORING FROM NATIONAL STATISTICS

Agreat deal of information is available from death certificates,

hospital discharge diagnoses and similar records. From these

data, it may be possible to detect a change in disease trends

and relate this to drug therapy. Perhaps the best-known example

of this is the increased death rate in young asthmatics noted in

the mid-1960s, which was associated with overuse of bron-

chodilator inhalers containing non-specific β-adrenoceptor

agonists (e.g. adrenalineand/or isoprenaline). Although rel-

atively inexpensive, the shortcomings of this method are obvi-

ous, particularly in diseases with an appreciable mortality,

since large numbers of patients must suffer before the change is

detectable. Data interpretation is particularly difficult when

hospital discharges are used as a source of information, since

discharge diagnosis is often provisional or incomplete, and

may be revised during follow up.

However, they can combine with high molecular weight enti-

ties, usually proteins, to form an antigenic hapten conjugate.

The factors that determine the development of allergy to a

drug are not fully understood. Some drugs (e.g. penicillin)

are more likely to cause allergic reactions than others, and

type I (immediate anaphylactic) reactions are more common

in patients with a history of atopy. Acorrelation between aller-

gic reactions involving immunoglobulin E (IgE) and human

leukocyte antigen (HLA) serotypes has been reported, so genetic

factors may also be important. There is some evidence that

drug allergies are more common in older people, in women

and in those with a previous history of drug reaction. However,

this may merely represent increased frequencies of drug expo-

sure in these patient groups.

TYPES OF ALLERGY

Drugs cause a variety of allergic responses (Figure 12.1) and

sometimes a single drug can be responsible for more than one

type of allergic response.

TYPE I REACTIONS

Type I reactions are due to the production of reaginic (IgE)

antibodies to an antigen (e.g. penicillins and cephalosporins).

The antigen binds to surface bound IgE on mast cells causing

degranulation and release of histamine, eicosanoids and

cytokines. It commonly occurs in response to a foreign serum

orpenicillin, but may also occur with streptomycin and some

local anaesthetics. With penicillin, it is believed that the peni-

cilloyl moiety of the penicillinmolecule is responsible for the

production of antibodies. Treatment of anaphylactic shock is

detailed in Chapter 50.

TYPE II REACTIONS

These are due to antibodies of class IgG and IgM which, on

contact with antibodies on the surface of cells, bind comple-

ment, causing cell lysis (e.g. penicillin, cephalosporins,

methyldopaor quinine) causing, for example, Coombs’ posi-

tive haemolytic anaemia.

TYPE III IMMUN E COMPLEX ARTHUS REACTIONS

Circulating immune complexes can produce several clinical

allergic states, including serum sickness and immune complex

glomerulonephritis, and a syndrome resembling systemic lupus

erythematosus. The onset of serum sickness is delayed for sev-

eral days until features develop such as fever, urticaria,

arthropathy, lymphadenopathy, proteinuria and eosinophilia.

Recovery takes a few days. Examples of causative agents

include serum, penicillin, sulfamethoxazole/trimethopri m,

streptomycin and propylthiouracil. Amiodarone lung and

hydralazine-induced systemic lupus syndrome are also pos-

sibly mediated by immune complex-related mechanisms,

although these reactions are less well understood.

TYPE IV DELAYED HYPERSENSITIVITY REACTIONS

Type IV reactions are delayed hypersensitivity reactions, the

classical example of which is contact dermatitis (e.g. to topical

Key points

• Rare (and often severe) adverse drug events may not be

detected in early drug development but only defined in

the first few years post marketing (phase IV of drug

development).

• Be aware of and participate in the MHRA yellow card

system for reporting suspected adverse drug reactions.

• Use of any recently marketed drug, which is identified

with a black triangle on its data sheet or in the British

National Formulary, indicates the need to

be particularly

suspicious about adverse drug reactions and to report

any suspected adverse drug reaction via the yellow card

system.

• Constant vigilance by physicians for drug-induced

disease, particularly for new drugs, but also for more

established agents, is needed.

FEEDBACK

There is no point in collecting vast amounts of data on

adverse reactions unless they are analysed and conclusions

reported back to prescribing doctors. In addition to articles in

the medical journals and media, the Current Problems in

Pharmacovigilance series deals with important and recently

identified adverse drug reactions. If an acute and serious

problem is recognized, doctors will usually receive notifica-

tion from the MHRA/Commission on Human Medicines,

and often from the pharmaceutical company marketing the

product.

ALLERGIC ADVERSE DRUG REACTIONS

Immune mechanisms are involved in a number of adverse

effects caused by drugs (see below and Chapter 50). The

development of allergy implies previous exposure to the drug

or to some closely related substance. Most drugs are of low

molecular weight (300–500Da) and thus are not antigenic.

PREVENTIONOF ALLERGIC DRUG REACTIONS 67

antibiotics, such as penicillin or neomycin). The mechanism

here is that the drug applied to the skin forms an antigenic

conjugate with dermal proteins, stimulating formation of sen-

sitized T-lymphocytes in the regional lymph nodes, with a

resultant rash if the drug is applied again. Drug photosensitiv-

ity is due to a photochemical combination between the drug

(e.g. amiodarone, chlorpromazine, ciprofloxacin, tetracyc-

lines) and dermal protein. Delayed sensitivity can also result

from the systemic administration of drugs.

vitamin supplements and alternative remedies) is essential.

Ahistory of atopy, although not excluding the use of

drugs, should make one wary.

2. Drugs given orally are less likely to cause severe allergic

reactions than those given by injection.

3. Desensitization (hyposensitization) should only be used

when continued use of the drug is essential. It involves

giving a very small dose of the drug and increasing the

dose at regular intervals, sometimes under cover of a

glucocorticosteroid and β

-adrenoceptor agonist. An

antihistamine may be added if a drug reaction occurs, and

equipment for resuscitation and therapy of anaphylactic

shock must be close at hand. It is often successful,

although the mechanism by which it is achieved is not

fully understood.

4. Prophylactic skin testing is not usually practicable, and a

negative test does not exclude the possibility of an allergic

reaction.

Key points

How to attempt to define the drug causing the adverse

drug reaction:

• Attempt to define the likely causality of the effect to

the drug, thinking through the following: Did the

reaction and its time-course fit with the duration of

suspected drug treatment and known adverse drug

effects? Did the adverse effect disappear on drug

withdrawal and, if rechallenged with the drug,

reappear? W

ere other possible causes excluded?

• Provocation testing with skin testing – intradermal tests

are neither very sensitive nor specific.

• Test the patient’s serum for anti-drug antibodies, or test

the reaction of the patient’s lymphocytes in vitro to the

drug and/or drug metabolite if appropriate.

• Consider stopping all drugs and reintroducing essential

ones sequentially.

• Carefully document and highlight the adverse drug

reaction and the most likely culprit in the case notes.

Key points

Classification of immune-mediated adverse drug reactions:

• Type I – urticaria or anaphylaxis due to the production

of IgE against drug bound to mast cells, leading to

massive release of mast cell mediators locally or

systemically (e.g. ampicillin skin allergy or anaphylaxis).

• Type II – IgG and IgM antibodies to drug which, on

contact with antibodies on the cell surface, cause cell

lysis by complement fixation (e.g. penicillin, haemolytic

anaemia; quinidine, thrombocytopenia).

• Type III – circulating immune complexes produced by

drug and antibody to drug deposit in organs, causing

drug fever, urticaria, rash, lymphadenopathy,

glomerulonephritis, often with eosinophilia (e.g.

co-trimoxazole,β

-lactams).

• Type IV – delayed-type hypersensitivity due to drug

forming an antigenic conjugate with dermal proteins

and sensitized T cells reacting to drug, causing a rash

(e.g. topical antibiotics).

Central immune

apparatus

Type IV response

Type I, II and III responses

Humoral antibodies

Lymphocytes

Sensitized

lymphocytes

Cell

membrane

Drug or its

metabolites

Drug or its

metabolites

Drug

(large molecule)

Protein Antigen

Lymphocytes

Macrophages

Figure 12.1:The immune response to drugs.

PREVENTION OF ALLERGIC DRUG

REACTIONS

Although it is probably not possible to avoid all allergic drug

reactions, the following measures can decrease their incidence:

1. Taking a detailed drug history (prescription and

over-the-counter drugs, drugs of abuse, nutritional and

68 ADVERSEDRUG REACTIONS

EXAMPLES OF ALLERGIC AND OTHER

ADVERSE DRUG REACTIONS

Adverse drug reactions can be manifested in any one or mul-

tiple organ systems, and in extraordinarily diverse forms.

Specific instances are dealt with throughout this book. Some

examples to illustrate the diversity of adverse drug reactions

are given here.

RASHES

These are one of the most common manifestations of drug

reactions. A number of immune and non-immune mech-

anisms may be involved which produce many different types

of rash ranging from a mild maculopapular rash to a severe

erythema multiforme major (Stevens Johnson syndrome;

Figures 12.2 and 12.3). Commonly implicated drugs/drug

classes include beta-lactams, sulphonamides and other anti-

microbial agents; anti-seizure medications (e.g. phenytoin,

carbamazepine); NSAIDs. Some drugs may give rise to direct

tissue toxicity (e.g. DMPS, used as chelating therapy in patients

with heavy metal poisoning; Figure 12.4, see Chapter 54).

LYMPHADENOPATHY

Lymph-node enlargement can result from taking drugs (e.g.

phenytoin). The mechanism is unknown, but allergic factors

may be involved. The reaction may be confused with a lymph-

oma, and the drug history is important in patients with lym-

phadenopathy of unknown cause.

BLOOD DYSCRASIAS

Thrombocytopenia, anaemia (aplastic, iron deficiency, macro-

cytic, haemolytic) and agranulocytosis can all be caused by

drugs.

Thrombocytopenia can occur with many drugs, and in

many but not all instances the mechanism is direct suppres-

sion of the megakaryocytes rather than immune processes.

Drugs that cause thrombocytopenia include:

• heparin;

• gold salts;

• cytotoxic agents (e.g. azathioprine/6-mercaptopurine);

• quinidine;

• sulphonamides;

• thiazides.

Haemolytic anaemia can be caused by a number of

drugs, and sometimes immune mechanisms are responsible.

Glucose-6-phosphate dehydrogenase deficiency (Chapter 14)

Figure 12.2:Mouth ulcer as part of Stevens Johnson syndrome as

a reaction to phenytoin therapy (see Chapter 22).

Figure 12.3:Stevens Johnson syndrome following

commencement of penicillin therapy (see Chapter 43).

Figure 12.4:Mouth ulcer following DMPS treatment (see

Chapter 54).

EXAMPLES OF ALLERGIC AND OTHER ADVERSE D RUGREACTIONS 69

predisposes to non-immune haemolysis (e.g. primaquine).

Immune mechanisms include the following:

1. Combination of the drug with the red-cell membrane,

with the conjugate acting as an antigen. This has been

shown to occur with penicillin-induced haemolysis, and

may also occur with chlorpromazineand sulphonamides.

2. Alteration of the red-cell membrane by the drug so that it

becomes autoimmunogenic. This may happen with

methyldopa, and a direct positive Coombs’ test develops

in about 20% of patients who have been treated with this

drug for more than one year. Frank haemolysis occurs in

only a small proportion of cases. Similar changes can take

place with levodopa,mefenamic acid and beta-lactam

antibiotics.

3. Non-specific binding of plasma protein to red cells, and

thus causing haemolysis. This is believed to occur with

cephalosporins.

Aplastic anaemia as an isolated entity is not common, but

may occur either in isolation or as part of a general depression

of bone marrow activity (pancytopenia). Examples include

chloramphenicol and (commonly and predictably) cytotoxic

drugs.

Agranulocytosis can be caused by many drugs. Several

different mechanisms are implicated, and it is not known

whether allergy plays a part. The drugs most frequently impli-

cated include the following:

• most cytotoxic drugs (Chapter 48);

• antithyroid drugs (methimazole,carbimazole,

propylthiouracil; Chapter 38);

• sulphonamides and sulphonylureas (e.g. tolbutamide,

glipizide; Chapter 37);

• antidepressants (especially mianserin; Chapter 20) and

antipsychotics (e.g. phenothiazines, clozapine; Chapter 20);

• anti-epileptic drugs (e.g. carbamazepine,felbamate;

Chapter 22).

SYSTEMIC LUP US ERYTHEMATOSUS

Several drugs (including procainamide,isoniazid, hydralazine,

chlorpromazine and anticonvulsants) produce a syndrome

that resembles systemic lupus together with a positive anti-

nuclear factor test. The development of this is closely related

to dose, and in the case of hydralazineit also depends on the

rate of acetylation, which is genetically controlled (Chapter

14). There is some evidence that the drugs act as haptens, com-

bining with DNA and forming antigens. Symptoms usually

disappear when the drug is stopped, but recovery may

be slow.

VASCULITIS

Both acute and chronic vasculitis can result from taking

drugs, and may have an allergic basis. Acute vasculitis with

purpura and renal involvement occurs with penicillins,

sulphonamides and penicillamine. Amore chronic form can

occur with phenytoin.

RENAL DYSFUNCTION

All clinical manifestations of renal disease can be caused by

drugs, and common culprits are non-steroidal anti-inflammatory

drugs and angiotensin-converting enzyme inhibitors (which

cause functional and usually reversible renal failure in suscep-

tible patients; Chapters 26 and 28). Nephrotic syndrome

results from several drugs (e.g. penicillamine, high-dose cap-

topril, gold salts) which cause various immune-mediated

glomerular injuries. Interstitial nephritis can be caused by sev-

eral drugs, including non-steroidal anti-inflammatory drugs

and penicillins, especially meticillin. Cisplatin, aminoglyco-

sides, amphotericin, radiocontrast media and vancomycin

cause direct tubular toxicity. Many drugs cause electrolyte or

acid-base disturbances via their predictable direct or indirect

effects on renal electrolyte excretion (e.g. hypokalaemia and

hypomagnesaemia from loop diuretics, hyperkalaemia from

potassium-sparing diuretics, converting enzyme inhibitors

and angiotensin II receptor antagonists, proximal renal

tubular acidosis from carbonic anhydrase inhibitors), and

some cause unpredictable toxic effects on acid-base balance

(e.g. distal renal tubular acidosis from amphotericin).

Obstructive uropathy can be caused by uric acid crystals con-

sequent upon initiation of chemotherapy in patients with

haematological malignancy, and – rarely – poorly soluble

drugs, such as sulphonamides, methotrexateor indinavir, can

cause crystalluria.

OTHER REACTIONS

Fever is a common manifestation of drug allergy, and

should be remembered in patients with fever of unknown

cause.

Liver damage (hepatitis with or without obstructive fea-

tures) as a side effect of drugs is important. It may be insidi-

ous, leading slowly to end-stage cirrhosis (e.g. during chronic

treatment with methotrexate) or acute and fulminant (as in

some cases of isoniazid, halothane or phenytoin hepatitis).

Chlorpromazine or erythromycin may cause liver involve-

ment characterized by raised alkaline phosphatase and biliru-

bin (‘obstructive’ pattern). Gallstones (and mechanical

obstruction) can be caused by fibrates and other lipid-lowering

drugs (Chapter 27), and by octreotide, a somatostatin ana-

logue used to treat a variety of enteropancreatic tumours,

including carcinoid syndrome and VIPomas (vasoactive intes-

tinal polypeptide) (see Chapter 42). Immune mechanisms are

implicated in some forms of hepatic injury by drugs, but are

seldom solely responsible.

70 ADVERSEDRUG REACTIONS

FURTHER READING

There is a very useful website for CYP450 substrates with inhibitors

and inducers: http://medicine.iupui.edu/flockhart/

British Medical Association and Royal Pharmaceutical Society of

Great Britain. British National Formulary 54. London: Medical

Association and Royal Pharmaceutical Society of Great Britian,

2007. (Appendix 1 provides an up-to-date and succinct alphabet-

ical list of interacting drugs, highlighting interactions that are

potentially hazardous.)

Brown HS, Ito K, Galetin Aet al. Prediction of in vivo drug–drug inter-

actions from in vitro data: impact of incorporating parallel path-

ways of drug elimination and inhibitor absorption rate constant.

British Journal of Clinical Pharmacology2005; 60: 508–18.

Constable S, Ham A, Pirmohamed M. Herbal medicines and acute

medical emergency admissions to hospital. British Journal of

Clinical Pharmacology2007; 63: 247–8.

De Bruin ML, Langendijk PNJ, Koopmans RPet al. In-hospital cardiac

arrest is associated with use of non-antiarrhythmic QTc-prolonging

drugs. British Journal of Clinical Pharmacology2007; 63: 216–23.

Fugh-Berman A, Ernst E. Herb–drug interactions: Review and assess-

ment of report reliability. British Journal of Clinical Pharmacology

2001;52: 587–95.

Hurle AD, Navarro AS, Sanchez MJG. Therapeutic drug monitoring

of itraconazole and the relevance of pharmacokinetic interactions.

Clinical Microbiology and Infection2006; 12 (Suppl. 7): 97–106.

Jackson SHD, Mangoni AA, Batty GM. Optimization of drug prescrib-

ing.British Journal of Clinical Pharmacology 2004; 57: 231–6.

Karalleidde L, Henry J. Handbook of drug interactions. London: Edward

Arnold, 1998.

Mertens-Talcott SU, Zadezensky I, De Castro WV et al.

Grapefruit–drug interactions: Can interactions with drugs be

avoided?Journal of Clinical Pharmacology 2006; 46: 1390–1416.

HARMFULINTERACTIONS 77

Table 13.5:Competitive interactions for renal tubular transport

Primary drug Competing drug Effect of

interaction

Penicillin Probenecid Increased penicillin

blood level

Methotrexate Salicylates Bone marrow

suppression

Sulphonamides

Salicylate Probenecid Salicylate toxicity

Indometacin Probenecid Indometacin toxicity

Digoxin Spironolactone Increased plasma

Amiodarone digoxin

Verapamil

Key points

• There are three main types of adverse interaction:

– pharmaceutical;

– pharmacodynamic;

– pharmacokinetic.

• Pharmaceutical interactions are due to in vitro

incompatibilities, and they occur outside the body (e.g.

when drugs are mixed in a bag of intravenous solution,

or in the port of an intravenous cannula).

• Pharmacodynamic interactions between drugs with a

similar effect (e.g. drugs that cause drowsiness) are

common. In principle, they should be easy to anticipate,

but they can cause serious problems (e.g. if a driver fails

to account for the interaction between an

antihistamine and ethanol).

• Pharmacokinetic interactions are much more difficult to

anticipate. They occur when one drug influences the

way in which another is handled by the body:

(a) absorption(e.g. broad-spectrum antibiotics

interfere with enterohepatic recirculation of

oestrogens and can cause failure of oral

contraception);

(b) distribution– competition for binding sites seldom

causes problems on its own but, if combined with

an ef

fect on elimination (e.g. amiodarone/digoxin

or NSAID/methotrexate), serious toxicity may

ensue;

enzyme induction or inhibition. Important

inducing agents include ethanol, rifampicin,

rifabutin, many of the older anticonvulsants,

St John’s wort, nevirapine and pioglitazone.

Common inhibitors include many antibacterial

drugs (e.g. isoniazid, macrolides, co-trimoxazole

and metronidazole), the azole antifungals,

cimetidine, allopurinol, HIV protease inhibitors;

(d) excretion(e.g. diuretics lead to increased

reabsorption of lithium, reducing its clearance

and predisposing to lithium accumulation and

toxicity).

Case history

A 64-year-old Indian male was admitted to hospital with mil-

iary tuberculosis. In the past he had had a mitral valve

replaced, and he had been on warfarin ever since. Treatment

was commenced with isoniazid, rifampicin and pyrazi-

namide, and the INR was closely monitored in anticipation of

increased warfarin requirements. He was discharged after

several weeks with the INR in the therapeutic range on a

much increased dose of warfarin. Rifampicin was subse-

quently discontinued. Two weeks later the patient was again

admitted, this time drowsy and complaining of headache

after mildly bumping his head on a locker. His pupils were

unequal and the INR was 7.0. Fresh frozen plasma was

administered and neurosurgical advice was obtained.

Comment

This patient’s warfarin requirement increased during treat-

ment with rifampicin because of enzyme induction, and

the dose of warfarin was increased to maintain anticoagu-

lation. When rifampicin was stopped, enzyme induction

gradually receded, but the dose of warfarin was not

readjusted. Consequently, the patient became over-anti-

coagulated and developed a subdural haematoma in

response to mild trauma. Replacment of clotting factors

(present in fresh frozen plasma) is the quickest way to

reverse the effect of warfarin overdose (Chapter 30).

from urine (e.g. the excretion of salicylateis increased in an alka-

line urine). Such effects are used in the management of overdose

(Chapter 54).

Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-

lowering drugs: mechanisms and clinical relevance. Clinical

Pharmacology and Therapeutics2006; 80: 565–81.

Perucca E. Clinically relevant drug interactions with antiepileptic

drugs. British Journal of Clinical Pharmacology2006; 61: 246–55.

Stockley I. Drug interactions, 2nd edn. Oxford: Blackwell Scientific

Publications, 1991.

Westphal JF. 2000 Macrolide-induced clinically relevant drug interac-

tions with cytochrome P-450A(CYP) 3A4: an update focused on

clarithromycin, azithromycin and dirithromycin. British Journal of

Clinical Pharmacology2000; 50: 285–95.

Whitten DL, Myers SP, Hawrelak JAet al. The effect of St John’s wort

extracts on CYP3A: a systematic review of prospective clinical

trials.British Journal of Clinical Pharmacology 2006; 62: 512–26.

78 DRUG INTERACTIONS

●

Introduction: ‘personalized medicine’ 79

●

Genetic influences on drug metabolism 79

●

Genetic influences on drug disposition 82

●

Genetic influences on drug action 82

●

Inherited diseases that predispose to drug toxicity 83

CHAPTER 14

PHARMACOGENETICS

INTRODUCTION: ‘PERSONALIZED MEDICINE’

Variability in drug response between individuals is due to genetic

and environmental effects on drug absorption, distribution,

metabolism or excretion (pharmacokinetics) and on target protein

(receptor) or downstream protein signalling (pharmacodynam-

ics). Several idiosyncratic adverse drug reactions (ADRs) have

been explained in terms of genetically determined variation in the

activity of enzymes involved in metabolism, or of other proteins

(e.g. variants of haemoglobin and haemolysis). The study of vari-

ation in drug responses under hereditary control is known as

pharmacogenetics. Mutation results in a change in the nucleotide

sequence of DNA. Single nucleotide polymorphisms (SNPs) are

very common. They may change the function or level of expres-

sion of the corresponding protein. (Not all single nucleotide vari-

ations change the coded protein because the genetic code is

‘redundant’ – i.e. more than one triplet of nucleotides codes for

each amino acid – so a change in one nucleotide does not always

change the amino acid coded by the triplet, leaving the structure

of the coded protein unaltered.) Balanced polymorphisms, when

a substantial fraction of a population differs from the remainder

in such a way over many generations, results when heterozygotes

experience some selective advantage. Tables 14.1 and 14.2 detail

examples of genetic influences on drug metabolism and response.

It is hoped that by defining an individual’s DNAsequence from a

blood sample, physicians will be able to select a drug that will be

effective without adverse effects. This much-hyped ‘personalized

medicine’ has one widely used clinical application currently, that

of genotyping the enzyme thiopurine methyl-transferase (which

inactivates 6-mercaptopurine (6-MP)) to guide dosing 6-MP in

children with acute lymphocytic leukaemia, but could revolu-

tionize therapeutics in the future.

Throughout this chapter, italics are used for the gene and

plain text for the protein product of the gene.

GENETIC INFLUENCES ON DRUG

METABOLISM

Abnormal sensitivity to a drug may be the result of a

genetic variation of the enzymes involved in its metabolism.

Inheritance may be autosomal recessive and such disorders

are rare, although they are important because they may have

severe consequences. However, there are also dominant pat-

terns of inheritance that lead to much more common varia-

tions within the population. Balanced polymorphisms of drug

metabolizing enzymes are common. Different ethnic popula-

tions often have a different prevalence of the various enzyme

polymorphisms.

PHASE I DRUG METABOLISM

CYP2D6

The CYP2D6 gene is found on chromosome 22 and over 50

polymorphic variants have been defined in humans. The func-

tion of this enzyme (e.g. 4-hydroxylation of debrisoquine, an

adrenergic neurone-blocking drug previously used to treat

hypertension but no longer used clinically) is deficient in about

7–10% of the UK population (Table 14.1). Hydroxylation poly-

morphisms in CYP2D6 explain an increased susceptibility to

several ADRs:

• nortriptyline – headache and confusion (in poor

metabolizers);

• codeine – weak (or non-existent) analgesia in poor

metabolizers (poor metabolizers convert little of it to

morphine);

• phenformin – excessive incidence of lactic acidosis (in

poor metabolizers).

Several drugs (including other opioids, e.g. pethidine, mor-

phineand dextromethorphan; beta-blockers, e.g. metoprolol,

propranolol; SSRIs, e.g. fluoxetine; antipsychotics, e.g.

haloperidol) are metabolized by CYP2D6. The many geno-

typic variants yield four main phenotypes of CYP2D6 – poor

metabolizers (PM) (7–10% of a Caucasian population), inter-

mediate (IM) and extensive metabolizers (EM) (85–90% of

Caucasians) and ultra-rapid metabolizers (UM) (1–2% of

Caucasians, but up to 30% in Egyptians) due to possession of

multiple copies of the CYP2D6 gene. UM patients require

higher doses of CYP2D6 drug substrates for efficacy.

80 PHARMACOGENETICS

Table 14.1: Variations in drug metabolism/pharmacodynamics due to genetic polymorphisms

Pharmacogenetic Mechanism Inheritance Occurrence Drugs involved

variation

Phase I drug metabolism:

Defective CYP2D6 Functionally defective Autosomal recessive 7–10% Caucasians, Originally defined by

1% Saudi Arabians, reduced CYP2D6

30% Chinese debrisoquine hydroxylation;

Beta blockers: metoprolol;

TCAs: nortriptyline; SSRIs:

fluoxetine; Opioids: morphine;

Anti-dysrhythmics: encainide

Ultra-rapid metabolism:

CYP2D6 Duplication 2D6 1–2% Caucasians, Rapid metabolism of 2D6

30% Egyptians drug substrates above

Phase II drug metabolism:

Rapid-acetylator status Increased hepatic Autosomal dominant 45% Caucasians Isoniazid; hydralazine; some

N-acetyltransferase sulphonamides; phenelzine;

dapsone; procainamide

Impaired glucuronidation Reduced activity UGT1A1 7–10% Caucasians Irinotecan (CPT-11)

Abnormal pharmacodynamic responses:

Malignant hyperthermia Polymorphism in Autosomal dominant 1:20000 of Some anaesthetics, especially

with muscular rigidity ryanodine population inhalational, e.g. isoflurane,

receptors (RyR1) suxamethonium

Other:

Suxamethonium Several types of Autosomal recessive Most common Suxamethonium

sensitivity abnormal plasma form 1:2500

pseudocholinesterase

Ethanol sensitivity Relatively low rate of Usual in some ethnic Orientals Ethanol

ethanol metabolism by groups

aldehyde dehydrogenase

CYP2C9 POLYMORPHISM (TOLBUTAMIDE

POLYMORPHISM)

The CYP2C9 gene is found on chromosome 10 and six poly-

morphic variants have been defined. Pharmacogenetic vari-

ation was first described after the finding of a nine-fold range

between individuals in the rate of oxidation of a sulphony-

lurea drug, tolbutamide. CYP2C9 polymorphisms cause

reduced enzyme activity, with 1–3% of Caucasians being poor

(slow) metabolizers. Drugs metabolized by CYP2C9 are elim-

inated slowly in poor metabolizers, who are therefore suscep-

tible to dose-related ADRs. Such drugs include S-warfarin,

losartanand celecoxib, as well as the sulphonylureas.

CYP2C19POLYMORPHISM

CYP2C19 is found on chromosome 10 and four polymorphic

variants have been defined. These polymorphisms produce

reduced enzyme activity and 3–5% of Caucasians and 15–20%

of Asians have genotypes which yield a poor (slow) metabo-

lizer phenotype. Such patients require lower doses of drugs

metabolized by the CYP2C19 enzyme. These include proton

pump inhibitors (omeprazole, lansoprazole, pantoprazole)

and some anticonvulsants, e.g. phenytoin,phenobarbitone.

PHASE II DRUG METABOLISM

ACET YLAT OR S TATUS (N-ACETYLTRANSFERASE-2)

Administration of identical doses (per kilogram body weight)

of isoniazid (INH), an antituberculous drug, results in great

variation in blood concentrations. Adistribution histogram of

such concentrations shows two distinct groups (i.e. a ‘bimodal’

distribution; Figure 14.1). INH is metabolized in the liver by

rapid acetylators, particularly when the drug is not given

daily, but twice weekly. In addition, slow acetylators are more

likely to show phenytoin toxicity when this drug is given

with INH, because the latter inhibits hepatic microsomal

hydroxylation of phenytoin. Isoniazid hepatitis may be

more common among rapid acetylators, but the data are

conflicting.

Acetylator status affects other drugs (e.g. procainamide,

hydralazine) that are inactivated by acetylation. Approxi-

mately 40% of patients treated with procainamide for six

months or longer develop antinuclear antibodies. Slow acety-

lators are more likely to develop such antibodies than rapid

acetylators (Figure 14.2) and more slow acetylators develop

procainamide-induced lupus erythematosus. Similarly, lower

doses of hydralazine are needed to control hypertension in

slow acetylators (Figure 14.3) and these individuals are more

susceptible to hydralazine-induced systemic lupus erythe-

matosus (SLE).

SULPHATION

Sulphation by sulfotransferase (SULT) enzymes shows poly-

morphic variation. SULT enzymes metabolize oestrogens,

progesterones and catecholamines. The polymorphic forms

have reduced activity and contribute to the considerable

variability in metabolism of these compounds.

SUXAMETHONIUM SENSITIVITY

The usual response to a single intravenous dose of suxa-

methoniumis muscular paralysis for three to six minutes. The

effect is brief because suxamethonium is rapidly hydrolysed

by plasma pseudocholinesterase. Occasional individuals

show a much more prolonged response and may remain

GENETIC INFLUENCES ON DRUG METABOLISM 81

Table 14.2:Variations in drug response due to disease caused by genetic mutations

Pharmacogenetic Mechanism Inheritance Occurrence Drugs involved

variation

G6PD deficiency, favism, 80 distinct forms X-linked incomplete 10000 000 affected Many – including 8-

drug-induced of G6PD codominant world-wide aminoquinolines, antimicrobials

haemolytic anaemia and minor analgesics (see text)

Methaemoglobinaemia: Methaemoglobin Autosomal recessive 1:100 are heterozygotes Same drugs as for G6PD

drug-induced reductase deficiency (heterozygotes show deficiency

haemolysis some response)

Acute intermittent

porphyria: exacerbation Increased activity of Autosomal dominant Acute intermittent type Barbiturates, cloral,

induced by drugs D-amino levulinic 15:1000000 in Sweden; chloroquine, ethanol,

synthetase secondary Porphyria cutanea tarda sulphonamides, phenytoin,

to defective porphyrin 1:100 in Afrikaaners griseofulvin and many others

synthesis

Number of subjects

246

Plasma isoniazid concentration (μg/mL)

81012

Figure 14.1:Plasma isoniazid concentrations in 483 subjects six

hours after oral isoniazid (9.8mg/kg). Acetylator polymorphism

produces a bimodal distribution into fast and slow acetylators.

(Redrawn from Evans DAP et al. British Medical Journal1960; 2:

485, by permission of the editor.)

acetylation. Individuals who acetylate the drug more rapidly

because of a greater hepatic enzyme activity demonstrate lower

concentrations of INH in their blood following a standard dose

than do slow acetylators. Acetylator status may be measured

usingdapsone by measuring the ratio of monoacetyldapsone to

dapsonein plasma following a test dose.

Slow and rapid acetylator status are inherited in a simple

Mendelian manner. Heterozygotes, as well as homozygotes,

are rapid acetylators because rapid metabolism is autosomal

dominant. Around 55–60% of Europeans are slow acetylators

and 40–45% are rapid acetylators. The rapid acetylator pheno-

type is most common in Eskimos and Japanese (95%) and

rarest among some Mediterranean Jews (20%).

INH toxicity, in the form of peripheral neuropathy, most

commonly occurs in slow acetylators, whilst slower response

and higher risk of relapse of infection are more frequent in

Heterozygotes are unaffected carriers and represent about 4%

of the population.

GENETIC INFLUENCES ON DRUG

DISPOSITION

Several genotypic variants occur in the drug transporter pro-

teins known as ATPbinding cassette proteins (ABC proteins).

The best known is P-glycoprotein now renamed ABCB1. This

has several polymorphisms leading to altered protein expres-

sion/activity. Effects of drug transporter polymorphisms on

drug disposition depend on the individual drug and the

genetic variant, and are still incompletely understood.

GENETIC INFLUENCES ON DRUG ACTION

RECEPTOR/DRUG TARGET POLYMORPHISMS

There are many polymorphic variants in receptors, e.g. oestro-

gen receptors, β-adrenoceptors, dopamine D

receptors and

opioid μ receptors. Such variants produce altered receptor

expression/activity. One of the best studied is the β

-adreno-

ceptor polymorphism. SNPs resulting in an Arg-to-Gly amino

acid change at codon 16 yield a reduced response to salbuta-

molwith increased desensitization.

Variants in platelet glycoprotein IIb/IIIa receptors modify

the effects of eptifibatide. Genetic variation in serotonin

transporters influences the effects of antidepressants, such

as fluoxetine and clomiprimine. There is a polymorphism

of the angiotensin-converting enzyme (ACE) gene which

involves a deletion in a flanking region of DNAthat controls

the activity of the gene; suggestions that the double-deletion

genotype may be a risk factor for various disorders are

controversial.

WARFARIN SUSCEPTIBILITY

Warfarininhibits the vitamin K epoxide complex 1 (VKORC1)

(Chapter 30). Sensitivity to warfarin has been associated with

the genetically determined combination of reduced metabolism

of the S-warfarin stereoisomer by CYP2C9 *2/*3 and *3/*3

polymorphic variants and reduced activity (low amounts) of

VKORC1. This explains approximately 40% of the variability in

warfarindosing requirement. Warfarin resistance (requirement

for very high doses of warfarin) has been noted in a few pedi-

grees and may be related to poorly defined variants in CYP2C9

combined with VKORC1.

FAMILIAL HYPERCHOLESTEROLAEMIA

Familial hypercholesterolaemia (FH) is an autosomal disease

in which the ability to synthesize receptors for low-density

paralysed and require artificial ventilation for two hours or

longer. This results from the presence of an aberrant form of

plasma cholinesterase. The most common variant which

causes suxamethonium sensitivity occurs at a frequency of

around one in 2500 and is inherited as an autosomal recessive.

82 PHARMACOGENETICS

I I

Slow acetylators

Time to conversion (months)

Percentage of patients

with antinuclear antibodies

I I

100

2 4 6 8 10 12 77

Rapid acetylators

Figure 14.2:Development of procainamide-induced antinuclear

antibody in slow acetylators (䊊) and rapid acetylators (䊉) with

time. Number of patients shown at each point. (Redrawn with

permission from Woosley RL et al. New England Journal of

Medicine1978; 298: 1157.)

0.4

0.3

0.2

0.1

Slow

acetylators

Fast

acetylators

Serum concentration

dose

μg/mL

mg/kg/day

(

Figure 14.3:Relationship between acetylator status and dose-

normalized serum hydralazine concentration (i.e. serum

concentration corrected for variable daily dose). Serum

concentrations were measured one to two hours after oral

hydralazine doses of 25–100mg in 24 slow and 11 fast

acetylators. (Redrawn with permission from Koch-Weser J.

Medical Clinics of North America1974; 58: 1027.)

lipoprotein (LDL) is impaired. LDL receptors are needed for

hepatic uptake of LDL and individuals with FH consequently

have very high circulating concentrations of LDL, and suffer

from atheromatous disease at a young age. Homozygotes

completely lack the ability to synthesize LDL receptors and

may suffer from coronary artery disease in childhood, whereas

the much more common heterozygotes have intermediate

numbers of receptors between homozygotes and healthy indi-

viduals, and commonly suffer from coronary disease in young

adulthood. β-Hydroxy-β-methylglutaryl coenzyme A (HMG

CoA) reductase inhibitors (otherwise known as statins, an

important class of drug for lowering circulating cholesterol lev-

els) function largely by indirectly increasing the number of

hepatic LDL receptors. Such drugs are especially valuable for

treating heterozygotes with FH, because they restore hepatic

LDLreceptors towards normal in such individuals by increas-

ing their synthesis. In contrast, they are relatively ineffective in

homozygotes because such individuals entirely lack the genetic

material needed for LDL-receptor synthesis.

INHERITED DISEASES THAT PREDISPOSE

TO DRUG TOXICITY

GLUCOSE-6-PHOSPHATE DEHYDROGENASE

DEFICIENCY

Glucose-6-phosphatase dehydrogenase (G6PD) catalyses the

formation of reduced nicotinamide adenine dinucleotide phos-

phate (NADPH), which maintains glutathione in its reduced

form (Figure 14.4). The gene for G6PD is located on the

X-chromosome, so deficiency of this enzyme is inherited in a

sex-linked manner. G6PD deficiency is common, especially in

Mediterranean peoples, those of African or Indian descent and

in East Asia. Reduced enzyme activity results in methaemoglo-

binaemia and haemolysis when red cells are exposed to oxidiz-

ing agents (e.g. as a result of ingestion of broad beans (Vicia

faba), naphthalene or one of several drugs). There are over 80

distinct variants of G6PD, but not all of them produce haem-

olysis. The lower the activity of the enzyme, the more severe is

the clinical disease. The following drugs can produce haemol-

ysis in such patients:

1. analgesics – aspirin;

2. antimalarials – primaquine, quinacrine, quinine;

3. antibacterials – sulphonamides, sulphones,

nitrofurantoin, fluoroquinolones: ciprofloxacin

4. miscellaneous – quinidine, probenecid.

Patients with G6PD deficiency treated with an 8-aminoquino-

line (e.g. primaquine) should spend at least the first few

days in hospital under supervision. If acute severe haemolysis

occurs, primaquine may have to be withdrawn and blood

transfusion may be needed. Hydrocortisone is given intra-

venously and the urine is alkalinized to reduce the likelihood

of deposition of acid haematin in the renal tubules. The

high incidence of this condition in some areas is attributed

to a balanced polymorphism. It is postulated that the selec-

tive advantage conferred on heterozygotes is due to a protec-

tive effect of partial enzyme deficiency against falciparum

malaria.

METHAEMOGLOBINAEMIA

Several xenobiotics oxidize haemoglobin to methaemoglobin,

including nitrates, nitrites, chlorates, sulphonamides, sul-

phones, nitrobenzenes, nitrotoluenes, anilines and topical local

anesthetics. In certain haemoglobin variants (e.g. HbM, HbH),

the oxidized (methaemoglobin) form is not readily converted

back into reduced, functional haemoglobin. Exposure to the

above substances causes methaemoglobinaemia in individuals

with these haemoglobin variants. Similarly, nitrites, chlorates,

dapsoneand primaquine can cause cyanosis in patients with a

deficiency of NADH-methaemoglobin reductase.

MALIGNANT HYPERTHERMIA

This is a rare but potentially fatal complication of general

anaesthesia (Chapter 24). The causative agent is usually an

inhalational anaesthetic (e.g. halothane, isoflurane) and/or

suxamethonium. Sufferers exhibit a rapid rise in temperature,

muscular rigidity, tachycardia, increased respiratory rate,

sweating, cyanosis and metabolic acidosis. There are several

forms, one of the more common ones (characterized by

halothane-induced rigidity) being inherited as a Mendelian

dominant. The underlying abnormality is a variant in the

ryanodine R1 receptor (Ry1R) responsible for controlling

intracellular calcium flux from the sarcolemma. The preva-

lence is approximately 1:20000. Individuals can be genotyped

INHERITED DISEAS ES THAT PREDISPOSE TO DRUG TOXICITY 83

Methaemoglobin

GSH

Reduced glutathione

Glucose-

6-phosphate

Glucose-6-phosphate

dehydrogenase

6-phosphogluconate

NADP NADPH

GSSG

Oxidized glutathione

Haemoglobin

Figure 14.4:Physiological role of glucose-6-phosphate

dehydrogenase.

for Ry1R or undergo muscle biopsy to assess their predisposi-

tion to this condition. Muscle from affected individuals is

abnormally sensitive to caffeine in vitro, responding with a

strong contraction to low concentrations. (Pharmacological

doses of caffeine release calcium from intracellular stores

and cause contraction even in normal muscle at sufficiently

high concentration.) Affected muscle responds similarly to

halothaneor suxamethonium.

ACUTE PORPHYRIAS

This group of diseases includes acute intermittent porphyria,

variegate porphyria and hereditary coproporphyria. In each

of these varieties, acute illness is precipitated by drugs

because of inherited enzyme deficiencies in the pathway of

haem biosynthesis (Figure 14.5). Drugs do not precipitate

acute attacks in porphyria cutanea tarda, a non-acute por-

phyria, although this condition is aggravated by alcohol,

oestrogens, iron and polychlorinated aromatic compounds.

Drug-induced exacerbations of acute porphyria (neuro-

logical, psychiatric, cardiovascular and gastro-intestinal dis-

turbances that are occasionally fatal) are accompanied by

increased urinary excretion of 5-aminolevulinic acid (ALA)

and porphobilinogen. An extraordinarily wide array of drugs

can cause such exacerbations. Most of the drugs that have

been incriminated are enzyme inducers that raise hepatic ALA

synthetase levels. These drugs include phenytoin, sulphonyl-

ureas, ethanol, griseofulvin, sulphonamides, sex hormones,

methyldopa, imipramine, theophylline, rifampicin and

pyrazinamide. Often a single dose of one drug of this type can

precipitate an acute episode, but in some patients repeated

doses are necessary to provoke a reaction.

Specialist advice is essential. Avery useful list of drugs that

are unsafe to use in patients with porphyrias is included in the

British National Formulary.

GILBERT’S DISEASE

This is a benign chronic form of primarily unconjugated hyper-

bilirubinaemia caused by an inherited reduced activity/lack of

the hepatic conjugating enzyme uridine phosphoglucuronyl

transferase (UGT1A1). Oestrogens impair bilirubin uptake and

aggravate jaundice in patients with this condition, as does pro-

tracted fasting. The active metabolite of irinotecan is glu-

curonidated by UGT1A1, so irinotecantoxicity is increased in

Gilbert’s disease.

84 PHARMACOGENETICS

Figure 14.5:Porphyrin metabolism, showing sites of enzyme

deficiency.

Glycine succinyl CoA

-aminolevulinic acid (ALA)

Porphobilinogen (PBG)

Hydroxymethylbilane

Uroporphyrinogen (UPG) III

Coproporphyrinogen (CPG) III

Uroporphyrin

Coproporphyrin

UPG decarboxylase

UPG III synthetase

PBG

deaminase

CPG

oxidase

PPG

oxidase

Ferrochelatase

Protoporphyrinogen (PPG)

Protoporphyrin IX

Haem

ALA synthetase

Deficient in

acute intermittent

porphyria

Deficient in

hereditary

coproporphyria

Deficient in

variegate

porphyria

Case history

A 26-year-old Caucasian woman has a three-month history

of intermittent bloody diarrhoea and is diagnosed with

ulcerative colitis. She is initially started on oral prednisolone

30mg/day and sulfasalazine 1 g four times a day with little

improvement in her colitic symptoms. Her gastroenterolo-

gist, despite attempting to control her disease with increas-

ing doses of her initial therapy, reverts to starting low-dose

azathioprine at 25mg three times a day and stopping her

sulfasalazine. Two weeks later, on review, her symptoms of

colitis have improved, but she has ulcers on her oropharynx

with a sore mouth. Her Hb is 9.8g/dL and absolute neu-

trophil count is 250/mm

and platelet count 85000.

Question

What is the most likely cause of this clinical situation?

Answer

The patient has haematopoietic toxicity due to azathioprine

(a prodrug of 6-MP). 6-MP is inactivated by the enzyme

thiopurine methyltransferase (TPMT). In Caucasians 0.3%

(one in 300) of patients are genetically deficient in this

enzyme because of polymorphisms in the gene (*3/*4 is

most common) and 11% of Caucasians who have a het-

erozygous genotype have low levels of the enzyme. Patients

with absent or low TPMT expression are at a higher risk of

bone marrow suppression. In this patient, the azathioprine

should be stopped and her TPMT genotype defined. Once

her bone marrow has recovered (with or without

haematopoietic growth factors), she could be restarted on

very low doses (e.g 6.25–12mg azathioprine daily).

INHERITED DISEAS ES THAT PREDISPOSE TO DRUG TOXICITY 85

Key points

• Genetic differences contribute substantially to

individual (pharmacokinetic and pharmacodynamic)

variability (20–50%) in drug response.

• Mendelian traits that influence drug metabolism

include:

(a) deficient thiopurine methyltransferase (TPMT)

which inactivates 6-MP (excess haematopoietic

suppression);

(b) deficient CYP2D6 activity which hydroxylates

several drug classes, including opioids, β

-blockers,

tricyclic antidepressants and SSRIs;

drugs including sulphonylureas, S-warfarin,

losartan;

(d) acetylator status (NAT-2), a polymorphism that

affects acetylation of drugs, including isoniazid,

hydralazine and dapsone;

(e) pseudocholinesterase deficiency; this leads to

prolonged apnoea after suxamethonium, which is

normally inactivated by this enzyme.

• Several inherited diseases predispose to drug toxicity:

(a) glucose-6-phosphate dehydrogenase deficiency

predisposes to haemolysis following many drugs,

including primaquine;

(b) malignant hyperthermia is a Mendelian dominant

fecting the ryanodine receptor in striated muscle,

leading to potentially fatal attacks of hyperthermia

and muscle spasm after treatment with

suxamethonium and/or inhalational anaesthetics;

triggered by enzyme-inducing agents, as well as

drugs, e.g. sulphonamides, rifampicin and anti-

seizure medications.

FURTHER READING

Evans DA, McLeod HL, Pritchard S, Tariq M, Mobarek A. Inter-ethnic

variability in human drug responses. Drug Metabolism and

Disposition2001; 29: 606–10.

Evans WE, McLeod HL. Drug therapy: pharmacogenomics – drug

disposition, drug targets, and side effects. New England Journal of

Medicine2003; 348: 538–49.

Wang L, Weinshilboum R. Thiopurine S-methyltransferase pharmaco-

genetics: insights, challenges and future directions. Oncogene2006;

25: 1629–38.

Weinshilboum R. Inheritance and drug response. New England Journal

of Medicine2003; 348: 529–37.

Weinshilboum R, Wang L. Pharmacogenomics: bench to bedside.

Nature Reviews. Drug Discovery2004; 3: 739–48.

Wilkinson GR. Drug therapy: drug metabolism and variability among

patients in drug response. New England Journal of Medicine 2005;

352: 2211–21.

HISTORY

Many years before Christ, humans discovered that certain

plants influence the course of disease. Primitive tribes used

extracts containing active drugs such as opium, ephedrine,

cascara,cocaine, ipecacuanha and digitalis. These were prob-

ably often combined with strong psychosomatic therapies and

the fact that potentially beneficial agents survived the era of

magic and superstition says a great deal about the powers of

observation of those early ‘researchers’.

Many useless and sometimes deleterious treatments also

persisted through the centuries, but the desperate situation of

the sick and their faith in medicine delayed recognition of the

harmful effects of drugs. Any deterioration following drug

administration was usually attributed to disease progression,

rather than to adverse drug effects. There were notable excep-

tions to this faith in medicine and some physicians had a short

life expectancy as a consequence!

Over the last 100 years, there has been an almost exponential

growth in the number of drugs introduced into medicine.

Properly controlled clinical trials, which are the cornerstone of

new drug development and for which the well-organized vac-

cine trials of the Medical Research Council (MRC) must take

much credit, only became widespread after the Second World

War. Some conditions did not require clinical trials (e.g. the early

use of penicillinin conditions with a predictable natural history

and high fatality rate). (Florey is credited with the remark that

‘if you make a real discovery, you don’t need to call in the

statisticians’.) Ethical considerations relating to the use of a ‘non-

treatment’ group in early trials were sometimes rendered irrele-

vant by logistic factors such as the lack of availability of drugs.

It was not until the 1960s that the appalling potential of

drug-induced disease was realized world-wide. Thalidomide

was first marketed in West Germany in 1956 as a sedative/

hypnotic, as well as a treatment for morning sickness. The

drug was successfully launched in various countries, includ-

ing the UK in 1958, and was generally accepted as a safe and

effective compound, and indeed its advertising slogan was

●

History 86

●

UK regulatory system 86

●

The process of drug development 86

●

Preclinical studies 87

●

Clinical trials 87

●

Clinical drug development 89

●

Generic drugs 90

●

Ethics committees 91

●

Globalization 91

CHAPTER 15

INTRODUCTION OF NEW DRUGS

AND CLINICAL TRIALS

‘the safe hypnotic’. However, in 1961, it became clear that its

use in early pregnancy was causally related to rare congenital

abnormality, phocomelia, in which the long bones fail to

develop. At least 600 such babies were born in England and

more than 10000 afflicted babies were born world-wide.

The thalidomide tragedy stunned the medical profession, the

pharmaceutical industry and the general public. In 1963, the

Minister of Health of the UK established a Committee on

the Safety of Drugs, since it was clear that some control over

the introduction and marketing of drugs was necessary. These

attempts at regulation culminated in the Medicines Act (1968).

UK REGULATORY SYSTEM

The UK comes under European Community (EC) legislation

regarding the control of human medicines, which is based upon

safety, quality and efficacy. The UK Medicines and Healthcare

products Regulation Agency (MHRA) or the European Agency

for the Evaluation of Medicinal Products (EMEA) must approve

any new medicine before it can be marketed in the UK. All UK

clinical trials involving a medicinal product must be approved

by the MHRA. The MHRA is assisted by expert advisory

groupsthrough the Commission on Human Medicines (CHM)

to assess new medicines during their development and licens-

ing. The MHRAis also responsible for the quality and safety

monitoring of medicines after licensing. Product labels,

patient leaflets, prescribing information and advertising are

subject to review by the MHRA. In the UK, there is also exten-

sive ‘self-regulation’ of the pharmaceutical industry through

the Association of the British Pharmaceutical Industry (ABPI).

The National Institute for Health and Clinical Excellence

(NICE) is independent of the MHRA.

THE PROCESS OF DRUG DEVELOPMENT

Drug development is a highly regulated process which

should be performed under internationally recognized codes

CLINICAL TRIALS 87

CLINICAL TRIALS

Physicians read clinical papers, review articles and pharma-

ceutical advertisements describing clinical trial results. Despite

peer review, the incompetent or unscrupulous author can con-

ceal deficiencies in design and possibly publish misleading

data. The major medical journals are well refereed, although

supplements to many medical journals are less rigorously

reviewed for scientific value. An understanding of the essen-

tial elements of clinical trial design enables a more informed

interpretation of published data.

Assessment of a new treatment by clinical impression is

not adequate. Diseases may resolve or relapse spontaneously,

coincidental factors may confound interpretation, and the

power of placebo and enthusiastic investigators are a major

influence on subjective response. In order to minimize these

factors and eliminate bias, any new treatment should be rigor-

ously assessed by carefully designed, controlled clinical trials.

All physicians involved in clinical trials must follow the

guidelines of the Declaration of Helsinki and subsequent

amendments.

OBJECTIVES

The first step in clinical trial design is to determine the ques-

tions to be addressed. Primary and achievable objectives must

be defined. The question may be straightforward. For example,

does treatment Aprolong survival in comparison with treat-

ment B following diagnosis of small-cell carcinoma of the

lung? Survival is a clear and objective end-point. Less easily

measured end-points such as quality of life must also be

assessed as objectively as possible. Prespecified subgroups of

patients may be identified and differences in response deter-

mined. For example, treatment A may be found to be most

effective in those patients with limited disease at diagnosis,

whereas treatment B may be most effective in those with

widespread disease at diagnosis. Any physician conducting a

clinical trial must not forget that the ultimate objective of all

studies is to benefit patients. The patients’ welfare must be of

paramount importance.

RANDOMIZATION

Patients who agree to enter such a study must be randomized

so that there is an equal likelihood of receiving treatment Aor B.

If treatment is not truly randomized, then bias will occur. For

example, the investigator might consider treatment B to be

less well tolerated and thus decide to treat particularly frail

patients with treatment A. Multicentre studies are often neces-

sary in order to recruit adequate numbers of patients, and it is

essential to ensure that the treatments are fairly compared. If

treatment Ais confined to one centre/hospital and treatment

B to another, many factors may affect the outcome of the

study due to differences between the centres, such as interval

of practice, namely Good Manufacturing Practice (GMP),

Good Laboratory Practice (GLP) and Good Clinical Practice

(GCP). Good Clinical Practice is an international ethical and

scientific quality standard for designing, conducting, record-

ing and reporting trials that involve the participation of

human subjects. The stages of drug development are outlined

in Figure 15.1.

DRUG DISCOVERY, DESIGN AND SYNTHESIS

Whilst random screening and serendipity remain important

in the discovery of new drugs, new knowledge of the role of

receptors, enzymes, ion channels and carrier molecules in

both normal physiological processes and disease now permits

a more focused approach to drug design. Using advances in

combinatorial chemistry, biotechnology, genomics, high out-

put screening and computer-aided drug design, new drugs

can now be identified more rationally.

PRECLINICAL STUDIES

New chemical entities are tested in animals to investigate their

pharmacology, toxicology, pharmacokinetics and potential

efficacy in order to select drugs of potential value in humans.

Although there is considerable controversy concerning the

value of some studies performed in animals, human drug devel-

opment has an excellent safety record, and there is under-

standable reluctance on the part of the regulatory authorities

to reduce requirements. At present, the European guidelines

require that the effects of the drug should be assessed in two

mammalian species (one non-rodent) after two weeks of dos-

ing before a single dose is administered to a human. In addition,

safety pharmacology and mutagenicity tests will have been

assessed. Additional and longer duration studies are conducted

before product licence approval. The timing, specific tests and

duration of studies may relate to the proposed human usage

in both the clinical trials and eventual indications.

Proof of principle

Proof of concept

Cost is approximately £500 million, 60% of which is spent in

clinical trials. Time from discovery to registration approximatel

10–13 years

• Discovery

• Screening

• Preclinical testing

• Phase I

(usually healthy volunteers)

• Phase IIa

• Phase IIb

• Phase III

(1000–5000 patients)

* Registration

• Phase IV

Early (exploratory)

development

Late (confirmatory)

development

Figure 15.1:Stages of drug development.

88 INTRODUCTIONOF NEW DRUGS AND CLINICAL TRIALS

between diagnosis and treatment, individual differences in

determining entry criteria, facilities for treatment of complica-

tions, differing attitude to pain control, ease of transport, etc.

INCLUSION AND EXCLUSION CRITERIA

For any study, inclusion and exclusion criteria must be defined.

It is essential to maximize safety and minimize confounding

factors, whilst also ensuring that the criteria are not so strict

that the findings will be applicable only to an unrepresenta-

tive subset of the patient population encountered in usual

practice. The definition of a healthy elderly subject is problem-

atic. Over the age of 65 years, it is ‘normal’ (in the sense that it

is common) to have a reduced creatinine clearance, to be on

some concomitant medication and to have a history of allergy.

If these are exclusion criteria, a trial will address a ‘superfit’

elderly population and not a normal population.

DOUBLE-BLIN D DESIGN

A‘double-blind’ design is often desirable to eliminate psycho-

logical factors such as enthusiasm for the ‘new’ remedy. This

is not always possible. For example, if in the comparison of

treatment A and treatment B described above, treatment A

consists of regular intravenous infusions whilst treatment B

consists of oral medication, the ‘blind’ is broken. As ‘survival’

duration is ‘hard’ objective data, this should not be influenced

markedly, whereas softer end-points, such as the state of well-

being, are more easily confounded. In trials where these are

especially important, it may be appropriate to use more elabor-

ate strategies to permit blinding, such as the use of a ‘double

dummy’ where there is a placebo for both dosage forms. In

this case patients are randomized to active tablets plus placebo

infusion or to active infusion plus placebo tablets.

WITHDRAWALS

The number of patients who are withdrawn from each treat-

ment and the reason for withdrawal (subjective, objective or

logistic) must be taken into account. For example, if in an anti-

hypertensive study comparing two treatments administered

for three months only the data from those who completed three

months of therapy with treatment X or Yare analysed, this may

suggest that both treatments were equally effective. However,

if 50% of the patients on treatment X withdrew after one week

because of lack of efficacy, that conclusion is erroneous. Again,

if patients are withdrawn after randomization but before dos-

ing, this can lead to unrecognized bias if more patients in one

group die before treatment is started than in the other group,

leading to one group containing a higher proportion of fitter

‘survivors’. Conversely, if patients are withdrawn after ran-

domization but before dosing, adverse events cannot be attrib-

uted to the drug. Hence both an ‘intention-to-treat’ analysis

and a ‘treatment-received’ analysis should be presented.

PLACEBO

If a placebo control is ethical and practical, this simplifies

interpretation of trial data and enables efficacy to be deter-

mined more easily (and with much smaller numbers of sub-

jects) than if an effective active comparator is current standard

treatment (and hence ethically essential). It is well recognized

that placebo treatment can have marked effects (e.g. lowering

of blood pressure). This is partly due to patient familiarization

with study procedures, whose effect can be minimized by a

placebo ‘run-in’ phase.

TRIAL DESIGN

There is no one perfect design for comparing treatments.

Studies should be prospective, randomized, double-blind and

placebo-controlled whenever possible. Parallel-group studies

are those in which patients are randomized to receive different

treatments. Although tempting, the use of historical data as a

control is often misleading and should only be employed in

exceptional circumstances. Usually one of the treatments is

the standard, established treatment of choice, i.e. the control,

whilst the other is an alternative – often a new treatment which

is a potential advance. In chronic stable diseases, a crossover

design in which each subject acts as his or her own control can

be employed. Intra-individual variability in response is usu-

ally much less than inter-individual variability. The treatment

sequence must be evenly balanced to avoid order effects and

there must be adequate ‘washout’ to prevent a carry-over

effect from the first treatment. This design is theoretically

more ‘economical’ in subject numbers, but is often not appli-

cable in practice.

STATISTICS

It is important to discuss the design and sample size of any

clinical trial with a statistician at the planning phase.

Research papers often quote Pvalues as a measure of whether

or not an observed difference is ‘significant’. Conventionally,

the null hypothesis is often rejected if P 0.05 (i.e. a difference

of the magnitude observed would be expected to occur by

chance in less than one in 20 trials – so-called type I error, see

Figure 15.2). This is of limited value, as a clinically important

difference may be missed if the sample size is too small (type II

error, see Figure 15.2). To place reliance on a negative result,

the statistical power of the study should be at least 0.8 and

preferably 0.9 (i.e. a true difference of the magnitude pre-

specified would be missed in 20% or 10% of such trials,

respectively). It is possible to calculate the number of patients

required to establish a given difference between treatments at

a specified level of statistical confidence. For a continuous

variable, one needs an estimate of the mean and standard

deviation which one would expect in the control group. This is

usually available from historical data, but a pilot study may be

necessary. The degree of uncertainty surrounding observed

CLINICAL DRUG DEVELOPMENT 89

differences should be reported as confidence intervals (usu-

ally 95% confidence intervals). Such intervals will diminish as

the sample size is increased. Confidence intervals reflect the

effects of sampling variability on the precision of a procedure,

and it is important to quote them when a ‘non-significant’

result is obtained, and when comparing different estimates of

effectiveness (e.g. drug A in one trial may have performed

twice as well as placebo, whereas drug B in another trial may

have performed only 1.5 times as well as placebo; whether

drug Ais probably superior to drug B will be apparent from

inspection of the two sets of confidence intervals).

If many parameters are analysed, some apparently ‘signifi-

cant’ differences will be identified by chance. For example, if

100 parameters are analysed in a comparison of two treat-

ments, one would expect to see a ‘significant’ difference in

approximately five of those parameters. It is therefore very

important to prespecify the primary trial end-point and sec-

ondary end-points that will be analysed. Statistical corrections

can be applied to allow for the number of comparisons made.

One must also consider the clinical importance of any statistic-

ally significant result. For example, a drug may cause a statis-

tically significant decrease in blood pressure in a study, but if

it is only 0.2mmHg it is not of any clinical relevance.

CLINICAL DRUG DEVELOPM ENT

For most new drugs, the development process – following a

satisfactory preclinical safety evaluation – proceeds through

four distinct phases. These are summarized below. Figure 15.3

illustrates the overall decision-making process for determin-

ing whether or not a new therapy will be clinically useful.

PHASE I

The initial studies of drugs in humans usually involve healthy

male volunteers unless toxicity is predictable (e.g. cytotoxic

agents, murine monoclonal antibodies). The first dose to be

administered to humans is usually a fraction of the dose that

produced any effect in the most sensitive animal species

tested. Subjective adverse events, clinical signs, haematology,

biochemistry, urinalysis and electrocardiography are used to

assess tolerability. Depending on the preclinical data, further,

more specific evaluations may be appropriate. The studies are

placebo controlled to reduce the influence of environment and

normal variability. If the dose is well tolerated, a higher dose

will be administered either to a different subject in a parallel

design, or to the same group in an incremented crossover

design.

This process is repeated until some predefined end-point

such as a particular plasma concentration, a pharmacody-

namic effect or maximum tolerated dose is reached. Data from

the single-dose study will determine appropriate doses and

dose intervals for subsequent multiple-dose studies. If the

drug is administered by mouth, a food interaction study

should be conducted before multiple-dose studies.

The multiple-dose study provides further opportunity for

pharmacodynamic assessments, which may demonstrate a

desired pharmacological effect and are often crucial for the

selection of doses for phase II. Having established the dose

range that is well tolerated by healthy subjects, and in some

cases identified doses that produce the desired pharmacol-

ogical effect, the phase II studies are initiated.

Key points

Phase I studies:

• initial exposure of humans to investigational drug;

• assessment of tolerance, pharmacokinetics and

pharmacodynamics in healthy subjects or patients;

• usually healthy male volunteers;

• usually single site;

• 40–100 subjects in total.

PHASE II

Phase II studies are usually conducted in a small number of

patients by specialists in the appropriate area to explore efficacy,

tolerance and the dose–response relationship. If it is ethical and

practicable, a double-blind design is used, employing either a

placebo control or a standard reference drug therapy as con-

trol. These are the first studies in the target population, and it

is possible that drug effects, including adverse drug reactions

and pharmacokinetics, may be different to those observed in

the healthy subjects. If the exploratory phase II studies are

promising, larger phase III studies are instigated, using a

dosage regimen defined on the basis of the phase II studies.

Key points

Phase II studies:

• initial assessment of tolerance in ‘target’ population;

• initial assessment of efficacy;

• identification of doses for phase III studies;

• well controlled with a narrowly defined patient

population;

• 100–300 patients in total;

• usually double-blind, randomized and controlled.

PHASE III

Phase III is the phase of large-scale formal clinical trials in which

the efficacy and tolerability of the new drug is established.

Too many statistical

comparisons performed

Too small sample size

(insufficient power)

False-positive result

(significant difference found

when no difference present)

False-negative result

(no significant difference found

when difference present)

TYPE II ERRORTYPE I ERROR

Figure 15.2:Different types of statistical error.

90 INTRODUCTIONOF NEW DRUGS AND CLINICAL TRIALS

Patient groups who respond more or less well may be identi-

fied, patient exposure (both numbers and duration of therapy)

is increased, and less common type B (see Chapter 12) adverse

reactions may be identified. During this period, the manufac-

turers will be setting up plant for large-scale manufacture and

undertaking further pharmaceutical studies on drug formula-

tion, bioavailability and stability. The medical advisers to the

company, in association with their pharmacological, pharma-

ceutical and legal colleagues, will begin to collate the large

amount of data necessary to make formal application to the

MHRA or EMEA for a product licence. Marketing approval

may be general or granted subject to certain limitations which

may include restriction to hospital practice only, restriction in

indications for use, or a requirement to monitor some particular

action or organ function in a specified number of patients.

Doctors are reminded (by means of a black triangle symbol

beside its entry in the British National Formulary) that this is

a recently introduced drug, and that any suspected adverse

reaction should be reported to the MHRAor Commission on

Human Medicines.

and may also help in the detection of previously unrecognized

adverse events (see Chapter 12).

Does the therapy have

unacceptable adverse effects?

Yes

Does the therapy exhibit

potentially useful clinical effects?

Are the benefits statistically significant

over existing therapy/placebos in

well-designed clinical trials?

Are these benefits of useful

magnitude?

Not usefulUseful

Figure 15.3:Flow chart for deciding

usefulness of a new therapy.

Key points

Phase III studies:

• confirmation of effective doses;

• expanded tolerability profile;

• collection of data on a more varied patient population

with indication;

• data on overall benefit/risk;

• can be placebo or more usually active controls;

• multicentre;

• commonly 1000–5000 patients in total;

• usually double-blind.

PHASE IV

Phase IV studies are prospective trials performed after mar-

keting approval (the granting of a product licence). These may

assess the drug’s clinical effectiveness in a wider population

Key points

Phase IV studies:

• performed after marketing approval and related to the

approved indications;

• exposure of drug to a wider population;

• different formulations, dosages, duration of treatment,

drug interactions and other drug comparisons are

studied;

• detection and definition of previously unknown or

inadequately quantified adverse events and related risk

factors.

POSTMARKETING SURVEILLANCE

The MHRAclosely monitors newly licensed drugs for adverse

events through the yellow card reporting system (see Chapter

12). Direct reporting by patients of adverse events was intro-

duced in 2004. SAMM (Safety Assessment of Marketed

Medicines) studies may be initiated which can involve many

thousands of patients.

GENERIC DRUGS

Once the patent life of a drug has expired, anyone may manu-

facture and sell their version of that drug. The generic drug

producer does not have to perform any of the research and

development process other than to demonstrate that their ver-

sion of the drug is ‘bioequivalent’ to the standard formulation.

The convention accepted for such ‘bioequivalence’ is gener-

ous, and the issue is the subject of current debate by biostatis-

ticians. In practice, the essential point is that clinically

untoward consequences should not ensue if one preparation

is substituted for the other.

GLOBALIZATION 91

ETHICS COMMITTEES

Protocols for all clinical trials must be reviewed and approved

by a properly constituted independent ethics committee.

Research Ethics Committees are coordinated by NRES

(National Research Ethics Services) working on behalf of the

Department of Health in the UK.

NRES maintains a UK-wide system of ethical review that

protects the safety, dignity and well-being of research partici-

pants whilst facilitating and promoting research within the

NHS.

Interestingly, studies have shown that patients taking part

in clinical trials often have better health outcomes than those

not involved in a trial.

GLOBALIZATION

In order to facilitate world-wide drug development and

encourage good standards of practice, a series of international

conferences on harmonization of requirements for registration

of pharmaceuticals for human use have been conducted.

International Conferences on Harmonisation (ICH) are lead-

ing to a globally accepted system of drug development,

hopefully without stifling research with excessive bureaucracy

FURTHER READING

Collier J (ed.). Drug and therapeutics bulletin; from trial outcomes to clin-

ical practice. London: Which? Ltd, 1996.

Griffin JP, O’Grady J (eds). The textbook of pharmaceutical medicine, 5th

edn. London: BMJ Books, 2005.

Wilkins MR (ed.). Experimental therapeutics. Section 1: Drug discovery

and development. London: Martin Dunitz, 2003.

Case history

Rather than a clinical case history, consider a chapter in the

history of drug regulation which is instructive in illustrating

the value of toxicity testing. Triparanol is a drug that

lowers the concentration of cholesterol in plasma. It was

marketed in the USA in 1959. In 1962, the Food and Drug

Administration (FDA) received a tip-off and undertook an

unannounced inspection. This revealed that toxicology

data demonstrating cataract formation in rats and dogs

had been falsified. Triparanol was withdrawn, but some of

the patients who had been taking it for a year or longer

also developed cataracts.

and without any lowering of standards. The goal is to facili-

tate the early introduction of valuable new therapies, while at

the same time maximizing patient protection.

CHAPTER 16

CELL-BASED AN D RECOMBINANT

DNA THERAPIES

●

Gene therapy 94

●

Human stem cell therapy 95

The term ‘biotechnology’ encompasses the application of

advances in our knowledge of cell and molecular biology since

the discovery of DNA to the diagnosis and treatment of dis-

ease. Recent progress in molecular genetics, cell biology and

the human genome has assisted the discovery of the mecha-

nisms and potential therapies of disease. The identification of

a nucleotide sequence that has a particular function (e.g. pro-

duction of a protein), coupled with our ability to insert that

human nucleotide sequence into a bacterial or yeast chromo-

some and to extract from those organisms large quantities of

human proteins, has presented a whole array of new opportu-

nities in medicine. (Human gene sequences have also been

inserted into mice to develop murine models of human dis-

ease.) In 1982, the first recombinant pharmaceutical product,

human recombinant insulin, was marketed. Since then, more

than 100 medicines derived via biotechnology have been

licensed for use in patients, whilst hundreds more are cur-

rently undergoing clinical trials. Successes include hormones,

coagulation factors, enzymes and monoclonal antibodies,

extending the range of useful therapeutic agents from low

molecular weight chemical entities to macromolecules. Once

discovered, some biotechnology products are manufactured

by chemical synthesis rather than by biological processes.

Examples of recombinant products are listed in Table 16.1. In

parallel with these advances, the human genome project is

establishing associations between specific genes and specific

diseases. Detailed medical histories and genetic information

are being collected and collated from large population sam-

ples. This will identify not only who is at risk of a potential dis-

ease and may thus benefit from prophylactic therapy, but also

who may be at risk of particular side effects of certain drugs.

This carries potentially momentous implications for selecting

the right drug for the individual patient – a ‘holy grail’ known

as personalized medicine. Achieving this grail is not immi-

nent. It is not just the physical presence but, more importantly,

the expression of a gene that is relevant. Often a complex inter-

action between many genes and the environment gives rise to

disease. Despite these complexities, the human genome proj-

ect linked with products of recombinant DNA technology,

including gene therapy, offers unprecedented opportunities

for the treatment of disease.

Most recombinant proteins are not orally bioavailable, due

to the efficiency of the human digestive system. However, the

ability to use bacteria to modify proteins systematically may

aid the identification of orally bioavailable peptides. Nucleic

acids for gene therapy (see below) are also inactive when

administered by mouth. Drug delivery for such molecules is

very specialized and at present consists mainly of incorporat-

ing the gene in a virus which acts as a vector, delivering the

DNAinto the host cell for incorporation into the host genome

and subsequent transcription and translation by the cellular

machinery of the host cell.

Human proteins from transgenic animals and bacteria are

used to treat diseases that are caused by the absence or

impaired function of particular proteins. Before gene cloning

permitted the synthesis of these human proteins in large

quantities, their only source was human tissues or body flu-

ids, carrying an inherent risk of viral (e.g. hepatitis B and C

and HIV) or prion infections. An example in which protein

replacement is life-saving is the treatment of Gaucher’s dis-

ease, a lysosomal storage disease, which is caused by an

inborn error of metabolism inherited as an autosomal reces-

sive trait, which results in a deficiency of glucocerebrosidase,

which in turn results in the accumulation of glucosylceramide

in the lysosomes of the reticulo-endothelial system, particu-

larly the liver, bone marrow and spleen. This may result in

hepatosplenomegaly, anaemia and pathological fractures.

Originally, a modified form of the protein, namely alglucerase,

had to be extracted from human placental tissue. The deficient

enzyme is now produced by recombinant technology.

The production of recombinant factor VIII for the treatment

of haemophilia has eliminated the risk of blood-borne viral

infection. Likewise, the use of human recombinant growth

hormone has eliminated the risk of Creutzfeldt–Jakob disease

that was associated with human growth hormone extracted

from bulked cadaver-derived human pituitaries.

Recombinant technology is used to provide deficient pro-

teins (Table 16.1) and can also be used to introduce modifica-

tions of human molecules. In the human insulin analogue,

lispro insulin, produced using recombinant technology, the

order of just two amino acids is reversed in one chain of the

insulin molecule, resulting in a shorter duration of action than

CELL-BASED AND RECOMB INANT DNA THERAPIES 93

soluble insulin, a real advance for some patients (see

Chapter 37). Other ‘designer’ insulins have longer actions or

other kinetic features that are advantageous in specific

circumstances.

In addition to producing recombinant human hormones

(see Table 16.2) and other recombinant proteins (e.g. hirudin,

the anticoagulant protein of the leech), recombinant mono-

clonal antibodies for treating human diseases have been pro-

duced originally in immortalized clones of mouse plasma

cells. Not surprisingly, the original murine antibodies induced

antibody responses in humans which in turn caused disease

or neutralizing antibodies, rendering the monoclonal antibod-

ies ineffective if used repeatedly (Table 16.3). Immunoglobulins

have been gradually humanized to reduce the risk of an

immune response on repeated treatments.

In cancer therapy, monoclonal antibodies have been devel-

oped against a tumour-associated antigen, e.g. trastuzumab

against the HER2 protein (over-expressed in certain breast

cancers in particular). Most facilitate the body’s immune sys-

tem in destroying the cancer cells or reduce the blood supply

to the tumour. Abciximab (see Chapter 30) inhibits platelet

aggregation by blocking the glycoprotein receptor that is a key

convergence point in different pathways of platelet aggrega-

tion. It is used as an adjunct to heparin and aspirin for the

prevention of ischaemic complications in high-risk patients

undergoing percutaneous coronary intervention. It is a

murine monoclonal antibody and can only be used in an indi-

vidual patient once. Most recently developed monoclonal

antibodies have been fully humanized. In comparison to most

conventional ‘small molecule’ drugs, the antibodies’ activities

are very specific and toxicity is usually directly related to the

targeted effect either through excessive effect or a ‘down-

stream’ consequence of the effect. The effects are usually very

species-specific, so extrapolation from animal studies is more

difficult. The initial doses in humans should be a fraction of

the minimum anticipated biological effect level (MABEL, see

Figure 16.1) taking into account concentration, receptor occu-

pancy, relative potency, likely dose–response curve, and

effects of excessive pharmacology rather than just the ‘no

observable adverse effect level’ (NOAEL) which is the main-

stay of first dose calculation for conventional small molecule

drugs.

Recombinant techniques have also been of value in the

development of vaccines, thereby avoiding the use of intact

virus. Suspensions of hepatitis B surface antigen prepared

from yeast cells by recombinant DNAtechniques are already

widely used to prevent hepatitis B infection in high-risk

groups in the UK. In comparison to traditional egg-based and

cell-based vaccines, DNAvaccines using plasmid DNA coding

for specific epitopes of influenza virus may be developed,

manufactured and distributed much more rapidly and effec-

tively. With the current likelihood of an influenza pandemic

caused by a new strain of virus predicted by the World Health

Organization (WHO), the ability to produce such DNA vac-

cines may save millions of lives.

Table 16.1: Recombinant proteins/enzymes licensed in the UK (examples)

Protein/enzyme Indication

Recombinant coagulation factors VIII Haemophilia

and VIIa

Imiglucerase Gaucher’s disease

Interferon alfa Hepatitis B and C, certain lymphomas and

solid tumours

Interferon beta Multiple sclerosis

Epoetin alfa and beta (recombinant human Anaemia of chronic renal failure. To increase

erythropoietin) yield of autologous blood, e.g. during

cancer chemotherapy

Drotrecogin alfa (activated) (recombinant Severe sepsis

activated protein Cwhich reduces

microvascular dysfunction)

Table 16.2:Hormones/hormone antagonists (examples)

Mode of action Indication

Somatropin Synthetic human Growth hormone

growth hormone (hGH) deficiency

Pegvisomant Genetically modified Acromegaly

hGH that blocks hGH

receptors

Follitropin Recombinant human Infertility

alfa and follicle stimulating

beta hormone

Insulin aspart, Recombinant human Diabetes (helps

glulisine and insulin analogues, glucose control in

lispro faster onset of action some patients/

situations)

94 CELL-BASEDAND RECOMB INANT DNA THERAPIES

Table 16.4:Prevalence of some genetic disorders which result from a defect

in a single gene

Disorder Estimated prevalence

Familial hypercholesterolaemia 1 in 500

Polycystic kidney disease 1 in 1250

Cystic fibrosis 1 in 2000

Huntington’s chorea 1 in 2500

Hereditary spherocytosis 1 in 5000

Duchenne muscular dystrophy 1 in 7000

Haemophilia 1 in 10000

Phenylketonuria 1 in 12000

GENE THERAPY

The increasing potential to exploit advances in genetics and

biotechnology raises the possibility of prevention by gene

therapy both of some relatively common diseases which are

currently reliant on symptomatic drug therapy, and of genetic

disorders for which there is currently no satisfactory treat-

ment, let alone cure.

Gene therapy is the deliberate insertion of genes into

human cells for therapeutic purposes. Potentially, gene ther-

apy may involve the deliberate modification of the genetic

material of either somatic or germ-line cells. Germ-line

genotherapy by the introduction of a normal gene and/or

deletion of the abnormal gene in germ cells (sperm, egg or

zygote) has the potential to correct the genetic defect in many

devastating inherited diseases and to be subsequently trans-

mitted in Mendelian fashion from one generation to the next.

The prevalence figures for inherited diseases in which a single

gene is the major factor are listed in Table 16.4. However,

germ-line gene therapy is prohibited at present because of the

unknown possible consequences and hazards, not only to the

individual but also to future generations. Thus, currently,

gene therapy only involves the introduction of genes into

human somatic cells. Whereas gene therapy research was ini-

tially mainly directed at single-gene disorders, most of the

research currently in progress is on malignant disease. Gene

therapy trials in cancer usually involve destruction of tumour

cells by the insertion of a gene that causes protein expression

that induces an immune response against those cells, or by the

introduction of ‘suicide genes’ into tumour cells.

Cystic fibrosis (CF) is the most common life-shortening

autosomal-recessive disease in Europeans. It is caused by a

mutation in the cystic fibrosis transmembrane conductance

regulator (CFTR) gene. Over 600 different CF mutations

have been recognized, although one mutation (F508) is pres-

ent on over 70% of CF chromosomes. Phase I studies using

adenoviral or liposomal vectors to deliver the normal CFTR

gene to the airway epithelium have shown that gene transfer

is feasible, but with current methods is only transient in

Table 16.3:Licensed monoclonal antibodies (examples)

Monoclonal antibody Mode of action Indication

Abciximab Inhibits glycoprotein IIb/IIIa, platelet Angioplasty

aggregation

Omalizumab Anti-IgE Prophylaxis of severe allergic asthma

Infliximab, Adalimumab Anti-TNF

α Rheumatoid arthritis, psoriatic arthritis

Basiliximab, Daclizumab Bind to IL-2R

αreceptor on T cells, prevent Prophylaxis of acute rejection in

T-cell proliferation, causing allogenic renal transplantation

immunosuppression

Bevacizumab (Avastin®) Inhibits vascular endothelial growth factor Metastatic colorectal cancer

(VEGF), hence inhibits angiogenesis

Pegaptanib and ranibizumab lnhibit VEGF Neovascular age-related macular

degeneration

100

MABEL

Therapeutic

range

Dose or exposure

Unacceptable

toxicity

Effect

10 100 1000 1000

Figure 16.1:Explanation of minimum anticipated biological

effect level (MABEL) (kindly provided by P Lloyd, Novartis, Basel,

Switzerland). Unbroken line, desired effect; dashed line,

undesired effect.

HUMAN STEM CELL TH ERAPY 95

duration and benefit. Adenoviral vectors are more efficient

than liposomes but themselves cause serious inflammatory

reactions.

Adramatic example of the potential benefit and danger of

gene therapy has been seen in the treatment of severe com-

bined immunodeficiency (SCID) secondary to adenosine

deaminase deficiency by reinfusing genetically corrected

autologous T cells into affected children. Whilst the gene ther-

apy was effective in the immunological reconstitution of the

patients, allowing a normal life including socializing with

other children rather than living in an isolation ‘bubble’, T-cell

leukaemia has developed in some patients. This probably

reflects problems with the retrovirus vector.

Asuccess in gene therapy has occurred with recipients of

allogenic bone marrow transplants with recurrent malignan-

cies. T cells from the original bone marrow donor can mediate

regression of the malignancy, but can then potentially damage

normal host tissues. Asuicide gene was introduced into the

donor T cells, rendering them susceptible to ganciclovir

before they were infused into the patients, so that they could

be eliminated after the tumours had regressed and so avoid

future damage to normal tissues.

From the above, it will be appreciated that a major problem

in gene therapy is introducing the gene into human cells. In

some applications, ‘gene-gun’ injection of ‘naked’ (i.e. not

incorporated in a vector) plasmid DNA may be sufficient.

Minute metal (e.g. gold) particles coated with DNAare ‘shot’

into tissues using gas pressure (Figure 16.2). Some DNAis rec-

ognized as foreign by a minority of cells, and this may be suf-

ficient to induce an immune response. This method underpins

DNAvaccines. The other major problem is that for most dis-

eases it is not enough simply to replace a defective protein, it

is also necessary to control the expression of the inserted gene.

It is for reasons such as these that gene therapy has been

slower in finding clinical applications than had been hoped,

but the long-term prospects remain bright.

Despite the inherent problems of gene therapy and societal

concerns as to how information from the genotyping of indi-

viduals will be used, the development of gene therapy has

dramatic potential – not only for the replacement of defective

genes in disabling diseases such as cystic fibrosis, Duchenne

muscular dystrophy and Friedreich’s ataxia, but also for the

treatment of malignant disease, and for prevention of cardio-

vascular disease and other diseases for which there is a genetic

predisposition or critical protein target.

Another gene-modulating therapy that is currently

being evaluated is the role of anti-sense oligonucleotides.

These are nucleotides (approximately 20mers in length)

whose sequence is complementary to part of the mRNAof the

gene of interest. When the anti-sense enters cells it binds to the

complementary sequence, forming a short piece of double-

stranded DNA that is then degraded by RNase enzymes,

thus inhibiting gene expression. Examples of such agents in

development or near approval include fomiversen, which

binds to cytomegalovirus (CMV) RNA(used intraocularly for

CMV infection) and anti-Bcl-2, used to enhance apoptosis in

lymphoma cells.

HUMAN STEM CELL THERAPY

The discovery of stem cells’ ability to replace damaged cells

has led to much interest in cell-based therapies. Stem cells

retain the potential to differentiate, for example into cardiac

muscle cells or pancreatic insulin-producing cells, under

particular physiological conditions.

In the UK, stem cell therapy is already established in the

treatment of certain leukaemias and has also been used suc-

cessfully in skin grafting, certain immune system and corneal

disorders. Autologous and allogenic haemopoietic stem cells

collected from bone marrow or via leukophoresis from

peripheral blood following granulocyte colony-stimulating

factor (G-CSF) stimulation (see Chapter 49) have been used

for some years in the management of certain leukaemias.

Allogenic stem cell transplantation is associated with graft-

versus-host disease, hence concomitant immunosuppressant

treatment with prophylactic anti-infective treatment includ-

ing anti-T-cell antibodies is required. Graft-versus-host

disease and opportunistic infections remain the principal

complications.

Non-myeloblastic allogenic stem cell transplantation is

being increasingly used, particularly in the elderly. This has

an additional benefit from a graft-versus-tumour effect as

immunosuppression is less severe.

Although there has been much publicity over the potential

of stem cell regenerative and reparative effects in chronic

central nervous system disorders, such as Parkinson’s disease,

Alzheimer’s disease, motor neurone disease and multiple

sclerosis, to date there is no convincing evidence of benefit

for these conditions. There is ongoing ethical debate over

the use of embryonic stem cells, which have more therapeutic

Antigen

presenting

cell

Gold particle

coated with

DNA

Nucleus

Transcribed

to mRNA

Translated

to protein

Processed into

antigen peptides

MHC

MHC: antigen

presentation

Antigens

presented to

the immune

system invoke

humoral and

cellular

response

Figure 16.2:Particle-mediated epidermal delivery (PMED) of DNA

into an antigen presenting cell (APC). The DNA elutes from the

gold particle and enters the nucleus where it is transcribed into

mRNA. The mRNA is then translated using the cellular synthetic

pathways to produce the encoded protein of interest. This

intracellular foreign protein is then processed by proteasomes

into small antigenic peptides that are presented on the cell

surface by the major histocompatibility complex (MHC).

96 CELL-BASEDAND RECOMB INANT DNA THERAPIES

potential than adult stem cells for research and possible

therapy.

The Gene Therapy Advisory Committee (GTAC) is the

national research ethics committee for gene therapy clinical

research. GTAC’s definition of gene therapy is as follows: ‘The

deliberate introduction of genetic material into human

somatic cells for therapeutic, prophylactic or diagnostic pur-

poses.’ This definition, and hence the remit of GTAC, encom-

passes techniques for delivering synthetic or recombinant

nucleic acids into humans:

• genetically modified biological vectors, such as viruses or

plasmids;

• genetically modified stem cells;

• oncolytic viruses;

• nucleic acids associated with delivery vehicles;

• naked nucleic acids;

• antisense techniques (for example, gene silencing, gene

correction or gene modification);

• genetic vaccines;

• DNAor RNA technologies, such as RNA interference;

• xenotransplantation of animal cells, but not solid organs.

FURTHER READING

Anon. Understanding monoclonal antibodies. Drugs and Therapeutics

Bulletin2007; 45.

Anson DS. The use of retroviral vectors for gene therapy – what are

the risks? Areview of retroviral pathogenesis and its relevance to

retroviral vector-mediated gene delivery. Genetic Vaccines and

Therapy2004; 2: 9.

Check E. Atragic setback. Nature 2002; 420: 116–18.

Guttmacher AE, Collins FS. Genomic medicine a primer. New England

Journal of Medicine2002; 347: 1512–20.

Marshall E. Gene therapy death prompts review of adenovirus vector.

Science1999; 286: 2244–5.

Nathwani AC, Davidoff AM, Linch DC. Areview of gene therapy for

haematological disorders. British Journal of Haematology2005; 128:

3–17.

Rang HP, Dale MM, Ritter JM, Flower RJ. Chapter 55

Biopharmaceuticals and gene therapy. In: Pharmacology, 6th edn.

Oxford: Elsevier, 2007.

Safer medicines. Areport from the Academy. London: The Academy of

Medical Sciences, 2005.

Walsh G. Second-generation biopharmaceuticals. European Journal of

Pharmaceutics and Biopharmaceutics2004; 58: 185–96.

●

Introduction 97

●

Garlic 97

●

Ginseng 98

●

Ginkgo biloba 99

●

Echinacea 99

●

Soy 99

●

Saw palmetto 100

●

St John’s wort 100

●

Glucosamine 101

●

Miscellaneous herbs recently found to be toxic or

meriting their withdrawal from the market 101

CHAPTER 17

ALTERNATIVE MEDICINES: HERBALS

AND N UTRACEUTICALS

INTRODUCTION

‘Alternative’ therapies (i.e. alternative to licensed products of

proven quality, safety and efficacy) span a huge range from

frank charlatanry (e.g. products based on unscientific postu-

lates, composed of diluent or of snake oil), through physical

therapies such as massage and aroma therapies which certainly

please (‘placebo’ means ‘I will please’) and do a great deal less

harm than some conventional therapies (e.g. surgery, chemo-

therapy), through to herbal medications with undoubted

pharmacological activity and the potential to cause desired or

adverse effects, albeit less predictably than the licensed prod-

ucts that have been derived from them in the past and will no

doubt be so derived in the future. Medicine takes an empirical,

evidence-based view of therapeutics and, if supported by suffi-

ciently convincing evidence, alternative therapies can enter the

mainstream of licensed products. Overall, efforts to test homeo-

pathic products have been negative (Ernst, 2002) and it has been

argued that no more resource should be wasted on testing prod-

ucts on the lunatic fringe, even when they come with royal

endorsement and (disgracefully) public funding. Here we focus

on herbal and nutraceutical products that may cause pharmaco-

logical effects.

Herbal remedies include dietary supplements (any product

other than tobacco intended for ingestion as a supplement to

the diet, including vitamins, minerals, anti-oxidants – Chapter

35 – and herbal products), phytomedicines (the use of plants or

plants components to achieve a therapeutic effect/outcome)

and botanical medicines (botanical supplements used as

medicine). The recent increase in the use of herbal remedies by

normal healthy humans, as well as patients, is likely to be mul-

tifactorial and related to: (1) patient dissatisfaction with con-

ventional medicine; (2) patient desire to take more control of

their medical treatment; and (3) philosophical/cultural bias. In

the USA, approximately one-third of the population used some

form of complementary or alternative medicine (the majority

consuming herbal products) in the past 12 months. At a clinical

therapeutic level, it is disconcerting that 15–20 million

Americans regularly take herbal remedies, while concomi-

tantly receiving modern prescription drugs, implying a signif-

icant risk for herb–drug interactions. In Scotland, some 12% of

general practitioners and 60% of general practices prescribe

homeopathic medicines! Herbal remedies are particularly

used by certain groups of patients, notably HIV and cancer

patients. The stereotypical user is a well-educated, career pro-

fessional, white female. From a therapeutic perspective, many

concerns arise from the easy and widespread availability,

lack of manufacturing or regulatory oversight, potential

adulteration and contamination of these herbal products.

Furthermore, there is often little or no rigorous clinical trial

evidence for efficacy and only anecdotes about toxicity. Many

patients who are highly attuned to potential harms of conven-

tional drugs (such as digoxin, a high quality drug derived his-

torically from extracts of dried foxglove of variable quality

and potency) fail to recognize that current herbals have as

great or greater potential toxicities, often putting their faith in

the ‘naturalness’ of the herbal product as an assurance of

safety. This chapter briefly reviews the most commonly used

herbals (on the basis of sales, Table 17.1) from a therapeutic

perspective and addresses some of the recently identified

problems caused by these agents.

GARLIC

Garlic has been used as a culinary spice and medicinal herb for

thousands of years. One active compound in garlic is allicin,

and this is produced along with many additional sulphur

compounds by the action of the enzyme allinase when fresh

garlic is crushed or chewed. Initial clinical trials suggested the

potential of garlic to lower serum cholesterol and triglyceride,

but a recent trial has shown limited to no benefit. Garlic has

been advocated to treat many conditions, ranging from many

cardiovascular diseases, e.g. atherosclerosis including periph-

eral vascular disease, hypertension, lipid disorders and sickle

cell anaemia. Garlic can alter blood coagulability by decreas-

ing platelet aggregation and increasing fibrinolysis.

Adverse effects

The adverse effects of garlic use involve gastro-intestinal

symptoms including halitosis, dyspepsia, flatulence and

heartburn. Other reported adverse effects include headache,

haematoma and contact dermatitis.

Drug interactions

Garlic inhibits many drug-metabolizing (CYP450) enzymes in

vitro, but induces CYP450s when administered chronically in

vivo (reminiscent of many anticonvulsant drugs – Chapter 22 –

as well as ethanol). Clinical studies using probe-drug cocktails

have shown that garlic has no significant effect on the activity

of CYP1A2 (caffeine), CYP2D6 (debrisoquine, dextromethor-

phan) and CYP3A4 (alprazolam,midazolam). Clinical studies

suggest that garlic significantly decreases the bioavailability of

saquinavirand ritonavir. These HIV protease inhibitors are not

only metabolized by CYP3A4, but are also substrates for P-gly-

coprotein. The clinical importance of these interactions is uncer-

tain, but potentially appreciable.

GINSENG

There are several types of ginseng (Siberian, Asian, American

and Japanese), the most common type used in herbal prepara-

tions being the Asian variety (Panax ginseng). In humans,

ginseng has been suggested to be a sedative-hypnotic, an

aphrodisiac, an antidepressant and a diuretic, and therapeutic

benefits have been claimed for many indications (see below).

Its pharmacologic properties include actions as a phytoestro-

gen, suggesting that its use, as with soy supplementation,

could be disadvantageous in women with oestrogen-sensitive

cancers (e.g. breast or endometrium). The active component

of ginseng, ginsenoside, inhibits cAMP phosphodiesterase

and monamine oxidase. These properties may partly explain

purported central nervous system (CNS) stimulant actions

of ginseng (though not sedative/hypnotic effects), potential

modulation of the immune system and increase of glycogen

storage. However, possible efficacy of ginseng in improving

physical or psychomotor performance, cognitive function,

immune function, diabetes mellitus and herpes simplex type 2

infections is not established beyond reasonable doubt.

Adverse effects

The adverse effects of ginseng are primarily CNS effects –

agitation, irritability, insomnia and headache. Others noted

include hypertension and mastalgia.

Drug interactions

In vitro evidence suggests that ginseng extracts inhibit CYP3A4

in human hepatocytes. These in vitro data are consistent with

study data during an 18-day course of ginseng where it signifi-

cantly increased the peak plasma concentration of nifedipine, a

CYP3A4 substrate, in healthy volunteers. As with other herbs

(e.g. echinacea), substantial variability in ginsenoside content

has been reported among commercially available ginseng

preparations, indicating that clinically significant effects on the

pharmacokinetics of drugs that are metabolized by CYP3A4

could be highly variable between batches.

98 ALTERNATIVEMEDICINES: HE RBALS AND N UTRACEUTICALS

Table 17.1: Most commonly used herbal products based on dollar sales

Product Plant Intended condition to Annual sales in

be used for USA ($ millions)

Garlic Allium sativum Hyperlipidaemia– 34.5

hypercholesterolaemia

Ginkgo Ginkgo biloba Dementia and claudication 33.0

Echinacea Echinacea purpurea Prevention of common cold 32.5

Soy Glycine max Symptoms of menopause 28.0

Saw palmetto Serenoa repens Prostatic hypertrophy 23.0

Ginseng Panax ginseng Fatigue 22.0

St John’s wort Hypericum perforatum Depression (mild) 15.0

Black cohosh Actaea racemosa Menopausal symptoms 12.3

Cranberry Vaccinia macrocarpon Cystitis and UTI 12.0

Valerian Valeriana officinalis Stress and sleeplessness 8.0

Milk thistle Silybum marianum Hepatitis and cirrhosis 7.5

Evening primrose Oenothera biennis Premenstrual symptoms 6.0

Bilberry Vaccinia myrtillus Diabetic retinopathy 3.5

Grape seed Vitis vinifera Allergic rhinitis 3

UTI: urinary tract infection

Acase report has suggested a possible interaction between

ginseng consumption and warfarin, but animal studies do not

support this.

GINKGO BILOBA

Originating from Chinese medicine, ginkgo (derived from the

nuts of Ginkgo biloba – a beautiful and threatened tree rather

than the western culinary stereotype of a ‘herb’) is used for a

variety of ailments and has multiple purported actions,

including antihypoxic, antioxidant, antiplatelet, free radical-

scavenging and microcirculatory properties. It has been used

in patients with asthma, brain trauma, cochlear deafness,

depression, retinitis, impotence, myocardial reperfusion and

vertigo. The evidence for efficacy in many of these conditions

is unconvincing. A recent clinical trial, in which a leading

ginkgo extract did not improve cognitive function, may have

contributed to a decline of ginkgo from the top-selling pos-

ition it had held among such products since 1995. One of the

principal components of ginkgo, ginkgolide B, is a moderately

potent antagonist of platelet-activating factor. ‘Anti-stress’

effects claimed for ginkgo products are postulated to be due to

monamine oxidase inhibition by ginkgolides.

Adverse effects

Serious or fatal side effects of gingko include spontaneous

bleeding, fatal intracerebral bleeding, seizures and anaphyl-

actic shock. Less serious side effects are nausea, vomiting, flat-

ulence, diarrhoea, headaches and pruritus.

Drug interactions

In vitro data suggest ginkgo can inhibit hepatic drug metab-

olizing enzymes. Long-term administration of ginkgo to volun-

teers(for up to 28 days) had no effect on the pharmacokinetics

ofmidazolam, a marker of CYP3A4 activity. In another study,

however, ginkgo increased the plasma concentrations of the

CYP3A4 substrate nifedipineby 53%, confirming the potential

for enzyme inhibition observed in vitro. The discrepant find-

ings for effects of ginkgo on CYP3A4 observed in this trial and

in the phenotyping studies is possibly related to the highly

variable phytochemical composition of commercially available

ginkgo extracts. The potential importance of the change in

CYP2C19 activity noted previously in a cocktail screening

approach, was verified by the observation that ginkgo signifi-

cantly reduced the metabolism of omeprazole, a CYP2C19

substrate, in Chinese patients. Collectively, these clinical data

indicate that ginkgo may interfere with the pharmacokinetics

of drugs metabolized by CYP2C19 or CYP3A4. If it does inhibit

MAO at therapeutic doses, adverse interactions with tyramine-

containing foods and possibly with selective serotonin reup-

take inhibitors (SSRI) (Chapter 20) are to be anticipated.

ECHINACEA

Echinacea is one of the most commonly used alternative medi-

cines, representing 10% of the herbal market. There are nine

species of the genus Echinacea, a member of the sunflower fam-

ily, found in North America. The most common and widespread

of these are Echinacea angustifolia,E. purpurea and E. pallida, each

of which has a long history of medicinal use. The majority of

pharmacologic studies since 1939 have been conducted on

E. purpureapreparations made from the fresh pressed juice of the

flowering plant. Many chemical compounds have been identi-

fied from Echinacea species and it is currently not possible to

attribute the pharmacological effects to any specific substance.

Constituents that have been identified include volatile oil, caffeic

acid derivatives, polysaccharides, polyines, polyenes, isobuty-

lamides and flavonoids of the quercetin and kaempferol type.

Many studies of echinacea have pointed to effects on the immune

system. Proposed mechanisms of action include increased circu-

lating granulocytes, enhanced phagocytosis, inhibition of virus

proliferation, cytokine activation, increased T-lymphocyte pro-

duction and an increase in the CD4/CD8 T-cell ratio. Echinacea

is currently most widely used in attempts to prevent the com-

mon cold and influenza symptoms, but is also used for Candida

infections, chronic respiratory infections, prostatitis and rheuma-

toid arthritis. Well-controlled studies have shown little, if any,

benefit. One recent placebo-controlled study of echinacea in the

treatment of the common cold actually suggested echinacea did

not prevent people catching a ‘cold’ and if they did get symp-

toms they lasted slightly longer in patients taking echinacea.

Adverse effects

Adverse effects of echinacea use involve rashes, including

erythema multiforme, arthralgias, allergic reactions, gastro-

intestinal disturbances including dysgeusia, dyspepsia and

diarrhoea.

Drug interactions

Some flavonoids present in echinacea extracts can either

inhibit or activate human CYPs and drug transporters,

depending on their structures, concentrations and assay con-

ditions. Midazolam, a substrate for CYP3A4 and CYP3A5,

was cleared 42% faster during an eight-day echinacea treat-

ment in 12 volunteers and there was a 23% reduction in mida-

zolamarea under the curve (AUC). The oral bioavailability of

midazolam in this study was significantly increased from 24

to 36% in the presence of echinacea, indicating that the hepatic

and intestinal availabilities were altered in opposite direc-

tions. These data suggest that echinacea is likely to interact

with other oral drugs that are substrates for CYP3A4 and that

the interaction will depend on the relative extraction of drugs

at the hepatic and intestinal sites and the route of administra-

tion. Echinacea from retail stores often does not contain the

labelled species (a similar situation affects other herbal prepa-

rations). The high variability observed in concentration of

constituents of the herb has implications for echinacea’s abil-

ity to modulate drug absorption and disposition.

SOY

The use of soy (Glycine max) and soy-derived products for the

treatment of menopause in women is growing with the fear of

SOY 99

possible side effects of traditional hormone replacement ther-

apy. The principal constituents of soy, the isoflavones genis-

tein and daidzein, are structurally similar to 17α-oestradiol

and produce weak oestrogenic effects (i.e. they are phytoestro-

gens). It is prudent to discourage soy-derived products in

patients with oestrogen-dependent tumours (e.g. breast can-

cer or endometrial cancer) because experimental data indicate

that soy can stimulate the growth of these tumours in mice.

Furthermore, as genistein can negate the inhibitory effect of

tamoxifen on breast cancer growth, women taking this agent

should especially avoid soy. Acute vasodilatation caused by

17β-oestradiol is mediated by nitric oxide, and genistein

(which is selective for the oestrogen receptor ER

, as well as

having quite distinct effects attributable to tyrosine kinase

inhibition) is as potent as 17β-oestradiol in this regard, raising

the possibility of beneficial vascular effects.

Adverse reactions

Adverse reactions in soy use include allergic reactions (prur-

itus, rash, anaphylaxis) and gastro-intestinal disturbances

(nausea, dyspepsia, diarrhoea).

Drug interactions

Isoflavones, such as genistein and daidzein, also inhibit oxida-

tive and conjugative metabolism in vitro and in vivo. In 20

healthy volunteers, a 14-day course of soy extract (50mg twice a

day) did not alter the ratio of the amounts of 6β-hydroxycortisol

and cortisol excreted in the urine, suggesting that soy is not an

inducer of CYP3A4 in humans. However, genistein interacts

with transporters such as P-glycoprotein (MDR-1, ABCB1),

MRP1 (ABCC1) and MRP2 (ABCC2). Given that these trans-

porters are involved in the intestinal absorption and biliary secre-

tion of many drugs, it is reasonable to suspect that soy may alter

drug absorption and/or disposition of such agents in humans.

SAW PALMETTO

Saw palmetto (Serenoa repens) is derived from a tree native to

southeastern North America, particularly Florida. The main

constituents of saw palmetto include carbohydrates, fixed oils,

steroids, flavonoids, resin, tannin and volatile oil. Saw palmetto

is used in men with the hope of ‘toning and strengthening the

reproductive system, and specifically for symptoms of prostate

enlargement’. It has oestrogenic activity and reduces plasma

testosterone concentration. In women, the principal use of saw

palmetto is to (hopefully) reduce ovarian enlargement and to

increase the size of small breasts. Although no drug interactions

with, or medical contraindications to, the use of saw palmetto

have been reported, it would be prudent to avoid concomitant

use with other hormonal therapies, especially oestrogens, and

in patients with oestrogen-dependent cancers.

Adverse effects

The adverse effects of saw palmetto involve gastro-intestinal

intolerance, nausea and diarrhoea, hepatitis and cholestasis,

gynaecomastia and impotence.

ST JOHN’S WORT

St John’s wort (Hypericum perforatum, Figure 17.1), a perennial

plant native to Europe, North America and western Asia, is

one of the most extensively studied herbal products and many

of its uses are based on observations noted in early Greek and

Roman medicine. Currently, St John’s wort is still widely used

for the treatment of mild to moderate depression and other

nervous conditions. Reported cases and trials have shown

varying results of therapy with St John’s wort for depressive

and mood disorders. Ameta-analysis of trials in 1757 patients

concluded that treatment of depression with St John’s wort

was comparable to standard, prescription antidepressants and

superior to placebo. More recently, a randomized, double-

blind, placebo-controlled trial evaluating the safety and effi-

cacy of St John’s wort in the treatment of patients with major

depressive disorders revealed that St John’s wort was no more

effective than placebo.

St John’s wort extract is a very complex mixture of over

20 constituent compounds. These include catechin-type tannins

and condensed-type proanthocyanidins, flavonoids (mostly

hyperoside, rutin, quercetin and kaempferol), biflavonoids

(e.g. biapigenin), phloroglutinol derivatives like hyperforin,

phenolic acids, volatile oils and naphthodianthrones,

100 ALTERNATIVE MEDICINES: HERBALS AN D NUTRACEUTICALS

Figure 17.1: Drawing of perforate St John’s wort (Hypericum

with permission.)

including hypericin and pseudohypericin. With regard to

the putative antidepressant effects of St John’s wort, the phar-

macological activities of hypericin and hyperforin, which

inhibit synaptic 5HT and catecholamine reuptake, could

contribute.

Adverse effects

Adverse CNS effects include headaches, drowsiness, restless-

ness, serotonin syndrome (Chapter 20) if used with SSRIs or

TCAs, skin photosensitivity. Gastro-intestinal disturbances

involve abdominal pain or discomfort, and xerostomia. Drug

interactions with therapeutic failure of concomitant drugs,

e.g. HIV protease inhibitors, ciclosporin, warfarin, theo-

phylline, antidepressants, oral contraceptives and anti-cancer

agents, such as irinotecan.

Drug interactions

Many clinical trials are now reporting significant pharmacoki-

netic interactions with long-term treatment with St John’s

wort and drugs from a variety of therapeutic classes. These

studies followed a number of case reports of serious inter-

actions between St John’s wort and digoxin, theophylline,

ciclosporin, oral contraceptives, phenprocoumon, warfarin

andsertraline, thought to be secondary to enzyme induction.

The mechanism for most of the interactions observed in subse-

quent clinical trials remains unclear, although for some

agents, induction of CYP3A4 (e.g. indinavir, midazolam,

simvastatin), P-glycoprotein-ABCB1 (e.g. digoxin, fexofena-

dine), or both (e.g. ciclosporin) may explain their increased

clearance. St John’s wort produced significantly greater

increases in CYP3A4 expression in women compared to men,

unexplained by differences in body mass index. More recently,

it was shown that St John’s wort enhanced the activity of tran-

scription factors, including the pregnane X receptor to tran-

scribe the CYP3A4 and P-gp (ABCB1) genes. Other drug

metabolism enzymes induced by St John’s wort include

CYP1A2, CYP2C9 and 2C19 and possibly UGT1A1 (Chapter

13). It should be noted that studies of St John’s wort on CYP

activity in vitro suggest acute inhibition, followed by induc-

tion in the long term.

GLUCOSAMINE

Glucosamine is available as a non-prescription dietary supple-

ment and in many products is obtained from shellfish. It is one

of several naturally occurring 6-carbon amino sugars found in

the body. Amino sugars are essential building blocks for

mucopolysaccharides, mucoproteins and mucolipids. Some

commercial products contain glucosamine in combination

with chondroitin. The precise mechanism of action of glu-

cosamine is unknown. In vitro data suggest glucosamine can

stimulate cartilage cells to synthesize glycosaminoglycans and

proteoglycans. It is more likely that the cell produces smaller,

soluble subunits; assembly of these smaller, soluble subunits

outside of the cell into a soluble form of collagen has been

proposed. Solubilized collagen, or tropocollagen, is a precursor

of mature collagen fibres. Chondroitin inhibits the enzymes

that degrade cartilage.

Several clinical studies have documented the efficacy of

glucosamine in the treatment of patients with osteoarthritis:

data from double-blind studies showed glucosamine was super-

ior to placebo and to ibuprofen in patients with osteoarthritis

of the knee. Although there is a scientific basis for administering

glucosamine in combination with chrondroitin, there is cur-

rently no evidence that the combination is more effective than

glucosamine alone for osteoarthritis. Arandomized, placebo-

controlled, double-blind study evaluated the effects of glu-

cosamine on disease progression and supported the use of

glucosamine long term (three years) for slowing progression

of knee osteoarthritis.

Adverse effects

The adverse effects associated with glucosamine involve

gastro-intestinal disturbances, including dyspepsia, nausea,

constipation and diarrhoea, skin rashes and allergic reactions

in patients with known shellfish allergy.

Drug interactions

No drug interactions have been defined with the use of

glucosamine.

MISCELLANEOUS HERBS RECENTLY

FOUND TO BE TOXIC OR MERITING THEIR

WITHDRAWAL FROM THE MARKET

Warnings about the toxicity of herbal products such as

kava kava (hepatotoxicity), aristocholic acid (nephrotoxicity)

and phen phen (pulmonary hypertension) have recently

been communicated to prescribers and the public. PC-SPES,

which was used by many prostate cancer patients because

of anecdotal and uncontrolled studies of evidence of

activity in prostate cancer, was withdrawn from sale by its

suppliers after the FDA found it contained alprazolam and

phytoestrogens.

MISCELLANEOUS HERBS 101

Key points

• Herbal and nutraceutical products are widely

available over the counter in many shops and are not

regulated.

• The most commonly used products are garlic, ginkgo

biloba, echinacea, soy, saw palmetto, ginseng and St

John’s wort.

• The ef

ficacy of such products in many cases is not

supported by rigorous clinical trials.

• Patients believe herbals are safe and are unaware of

documented or potential toxicities.

• Many patients take herbal products in conjunction with

prescription medications, unknowingly risking

herb–drug interactions.

• When a patient develops an unusual reaction to his or

her drug therapy (either therapeutic failure or toxicity)

a careful history concerning the use of herbal products

should be obtained.

FURTHER READING

Fricchione G. Clinical practice. Generalized anxiety disorder. New

England Journal of Medicine2004; 351: 675–82.

National Institute for Clinical Excellence. 2004: Guidance on the use of

zaleplon, zolpidem and zopiclone for the short-term management

of insomnia. www.nice.org.uk/TA077guidance, 2004.

Sateia MJ, Nowell PD. Insomnia. Lancet2004; 364: 1959–73.

Stevens JC, Pollack MH. Benzodiazepines in clinical practice: consid-

eration of their long-term use and alternative agents. Journal of

Clinical Psychiatry2005; 66 (Suppl. 2), 21–7.

●

Schizophrenia 110

●

Behavioural emergencies 114

CHAPTER 19

SCHIZOPHRENIA AND

BEHAVIOURAL EMERGENCIES

SCHIZOPHRENIA

INTRODUCTION

Schizophrenia is a devastating disease that affects approxi-

mately 1% of the population. The onset is often in adolescence

or young adulthood and the disease is usually characterized by

recurrent acute episodes which may develop into chronic dis-

ease. The introduction of antipsychotic drugs such as chlorpro-

mazine revolutionized the treatment of schizophrenia so that

the majority of patients, once the acute symptoms are relieved,

can now be cared for in the community. Previously, they would

commonly be sentenced to a lifetime in institutional care.

PATHOPHYSIOLOGY

The aetiology of schizophrenia, for which there is a genetic pre-

disposition, is unknown, although several precipitating factors

are recognized (Figure 19.1). Neurodevelopmental delay has

been implicated and it has been postulated that the disease is

triggered by some life experience in individuals predisposed by

an abnormal (biochemical/anatomical) mesolimbic system.

There is heterogeneity in clinical features, course of disease

and response to therapy. The concept of an underlying

neurochemical disorder is advanced by the dopamine theory

of schizophrenia, summarized in Box 19.1. The majority of

antipsychotics block dopamine receptors in the forebrain.

5-Hydroxytryptamine is also implicated, as indicated in Box

19.2. Glutamine hypoactivity, GABAhypoactivity and α-adren-

ergic hyperactivity are also potential neurochemical targets.

About 30% of patients with schizophrenia respond inad-

equately to conventional dopamine D

receptor antagonists. A

high proportion of such refractory patients respond to clozap-

ine, an ‘atypical’ antipsychotic drug which binds only tran-

siently to D

receptors, but acts on other receptors, especially

muscarinic, 5-hydroxytryptamine receptors (5HT

) and D

and displays an especially high affinity for D

receptors. The

receptor is localized to cortical regions and may be over-

expressed in schizophrenia. Regional dopamine differences

may be involved, such as low mesocortical activity with high

mesolimbic activity. Magnetic resonance imaging (MRI) stud-

ies indicate enlargement of ventricles and loss of brain tissue,

whilst functional MRI and positron emission tomography

(PET) suggest hyperactivity in some cerebral areas, consistent

with loss of inhibitory neurone function.

012345

Odds Ratio

Winter

Urban

Place/time of birth

Infection

Prenatal

Obstetric

Influenza

Respiratory

Rubella

Poliovirus

CNS

Famine

Bereavement

Flood

Unwantedness

Maternal depression

Rhesus Incompatibility

Hypoxia

CNS damage

Low birth weight

Pre-eclampsia

Family history

678910

Figure 19.1:Predispositions to

schizophrenia. Redrawn with permission

from Sullivan PF. The genetics of

schizophrenia.PLoS Medicine 2005; 2: e212.

SCHIZOPHRENIA 111

Figure 19.2 shows a summary of putative pathways for the

development of schizophrenia.

GENERAL PRINC IPLES OF MANAGEMENT

ACUTE TREATMENT

The main principles are:

• Prompt drug treatment should be instigated, usually as an

in-patient.

• Oral ‘atypical antipsychotics’ should be administered, e.g.

risperidoneor olanzapine.

• If the patient is very disturbed/aggressive, add

benzodiazepine, e.g. lorazepam.

• Chlorpromazine may be preferred if sedation is

advantageous, e.g. in very agitated patients.

• Antimuscarinic drugs, e.g. procyclidine, should be used if

acute dystonia or Parkinsonian symptoms develop.

• Psychosocial support/treatment should be offered.

• Behaviour usually improves quickly, but hallucinations,

delusions and affective disturbance may take weeks or

months to improve.

• Once first-rank symptoms have been relieved, the patient

can usually return home and resume work on low-dose

antipsychotic treatment.

• Conventional drugs, e.g. chlorpromazineor haloperidol,

are as effective in treatment of acute positive symptoms as

atypical antipsychotic drugs and are less expensive, but

adverse effects may be troublesome.

MAINTENANCE TREATMENT

• Only 10–15% of patients remain in permanent remission

after stopping drug therapy following a first

schizophrenic episode.

• The decision to attempt drug withdrawal should be taken

with regard to the individual patient, their views, adverse

drug effects, social support, relatives and carers.

• Cognitive behavioural therapy is a treatment option.

• Most patients require lifelong drug therapy, so the correct

diagnosis is essential (e.g. beware drug-induced psychosis,

as amphetamines in particular can produce acute

schizophreniform states). All antipsychotic drugs have

adverse effects. Continuing psychosocial support is critical.

• Oral or intramuscular depot therapy (Box 19.3), e.g.

olanzapine(oral) or flupentixol (i.m.) should be

considered. The latter ensures compliance.

Box 19.1: Dopamine theory of schizophrenia

• There is excess dopamine activity in the mesolimbic

system in schizophrenia.

• Antipsychotic potency is often proportional to

-blocking potency.

• Amphetamine (which increases dopamine release) can

produce acute psychosis that is indistinguishable from

acute schizophrenia (positive symptoms).

• D

agonists (bromocriptine and apomorphine)

aggravate schizophrenia in schizophrenic patients.

• There is an increase in D

and D

receptors on PET in

schizophrenic patients.

•

L-Dopa can cause hallucinations and acute psychotic

reactions and paranoia, but does not cause all the

features of these conditions.

• There is no definite increase in brain dopamine in vivo

and post mortem.

• Dopamine receptor blockade does not fully alleviate

symptoms.

Box 19.3: Intramuscular depot treatment

• Esters of the active drug are formulated in oil.

• There is slow absorption into the systemic circulation.

• It takes several months to reach steady state.

• After an acute episode, reduce the oral dose gradually

and overlap with depot treatment.

• Give a test dose in case the patient is allergic to the oil

vehicle or very sensitive to extrapyramidal effects.

• Rotate the injection site, e.g. flupentixol is given once

every two to four weeks (ester of active drug

formulated in an oil) or risperidone once every two

weeks.

Box 19.2: 5-Hydroxytryptamine and schizophrenia

• LSD acts on 5HT receptors, causing hallucinations and

dramatic psychological effects which may mimic some

features of schizophrenia.

• 5HT has a modulatory effect on dopamine pathways.

• Many effective antipsychotic drugs have dopamine and

5HT

receptor-blocking properties.

• 5HT

receptor blockade is not essential for drug efficacy.

Genetic predisposition

Obstetric complications

and other early insults

affecting CNS

Neurodevelopmental

abnormalities

Neurocognitive

impairment

Social anxiety

Isolation

Odd ideas

Frank

psychosis

Abuse of dopaminergic drugs

Social stress/isolation

Figure 19.2:Pathways for development of

schizophrenia.

112 SCHIZOPHRENIA AND B EHAVIOURALEMERGENCIES

DRUGS USED IN TREATMENT

CONVENTIONAL ANTIPSYCHOTIC DRUGS

The principal action of the conventional antipsychotic drugs

(see Table 19.1), such as chlorpromazine(a phenothiazine) and

haloperidol(a butyrophenone), is an antagonism of D

recep-

tors in the forebrain. The effect on D

receptors is variable.

Blockade of the D

receptors induces extrapyramidal effects.

Repeated adminstration causes an increase in D

-receptor sen-

sitivity due to an increase in abundance of these receptors. This

appears to underlie the tardive dyskinesias that are caused by

prolonged use of the conventional antipsychotic drugs.

The choice of drug is largely determined by the demands of

the clinical situation, in particular the degree of sedation

needed and the patient’s susceptibility to extrapyramidal tox-

icity and hypotension.

Uses

These include the following:

1. schizophrenia – antipsychotic drugs are more effective

against first-rank (positive) symptoms (hallucinations,

thought disorder, delusions, feelings of external control)

than against negative symptoms (apathy and

withdrawal);

2. other excited psychotic states, including mania and

delirium;

3. anti-emetic and anti-hiccough;

4. premedication and in neuroleptanalgesia;

5. terminal illness, including potentiating desired actions of

opioids while reducing nausea and vomiting;

6. severe agitation and panic;

7. aggressive and violent behaviour;

8. movement and mental disorders in Huntington’s disease.

Adverse effects

1. The most common adverse effects are dose-dependent

extensions of pharmacological actions:

• extrapyramidal symptoms (related to tight binding to,

and receptor occupancy of, D

receptors) – parkinsonism

including tremor, acute dystonias, e.g. torticollis,

fixed upward gaze, tongue protrusion; akathisia

(uncontrollable restlessness with feelings of anxiety

and agitation) and tardive dyskinesia. Tardive

dyskinesia consists of persistent, repetitive, dystonic

athetoid or choreiform movements of voluntary

muscles. Usually the face and mouth are involved,

causing repetitive sucking, chewing and lip smacking.

The tongue may be injured. The movements are

usually mild, but can be severe and incapacitating.

This effect follows months or years of antipsychotic

treatment;

• anticholinergic – dry mouth, nasal stuffiness,

constipation, urinary retention, blurred vision;

• postural hypotension due to α-adrenergic blockade.

Gradual build up of the dose improves tolerability;

• sedation (which may be desirable in agitated patients),

drowsiness and confusion. Tolerance usually develops

after several weeks on a maintenance dose. Emotional

flattening is common, but it may be difficult to

distinguish this feature from schizophrenia.

Depression may develop, particularly following

treatment of hypomania, and is again difficult to

distinguish confidently from the natural history of the

disease. Acute confusion is uncommon.

2. Jaundice occurs in 2–4% of patients taking

chlorpromazine, usually during the second to fourth

weeks of treatment. It is due to intrahepatic cholestasis

and is a hypersensitivity phenomenon associated with

eosinophilia. Substitution of another phenothiazine may

not reactivate the jaundice.

3. Ocular disorders during chronic administration include

corneal and lens opacities and pigmentary retinopathy.

This may be associated with cutaneous light sensitivity.

4. About 5% of patients develop urticarial, maculopapular

or petechial rashes. These disappear on withdrawal of

the drug and may not recur if the drug is reinstated.

Contact dermatitis and light sensitivity are common

complications. Abnormal melanin pigmentation may

develop in the skin.

5. Hyperprolactinaemia.

6. Blood dyscrasias are uncommon, but may be lethal,

particularly leukopenia and thrombocytopenia. These

usually develop in the early days or weeks of treatment.

The incidence of agranulocytosis is approximately 1 in

10000 patients receiving chlorpromazine.

7. Cardiac dysrhythmia, including torsades de pointes

(see Chapter 32) and arrest.

8. Malignant neuroleptic syndrome is rare but potentially

fatal. Its clinical features are rigidity, hyperpyrexia,

stupor or coma, and autonomic disorder. It responds to

treatment with dantrolene(a ryanodine receptor

antagonist that blocks intracellular Ca

2

mobilization).

9. Seizures, particularly in alcoholics. Pre-existing epilepsy

may be aggravated.

10. Impaired temperature control, with hypothermia in cold

weather and hyperthermia in hot weather.

Table 19.1: Conventional antipsychotic drugs

Sedation Extrapyramidal Hypotension

symptoms

Phenothiazines

Chlorpromazine   

Fluphenazine

  

Butyrophenones

Haloperidol   

Thioxanthines

Fluphenthixol

 

Depot preparation available.

All increase serum prolactin levels

Note: Pimozide causes a prolonged QT and cardiac arrhythmias.

The Boston Collaborative Survey indicated that adverse

reactions are most common in patients receiving high doses,

and that they usually occur soon after starting treatment.

The most common serious reactions were fits, coma, severe

hypotension, leukopenia, thrombocytopenia and cardiac

arrest.

Contraindications and cautions

These include the following:

• coma due to cerebral depressants, bone marrow

depression, phaeochromocytoma, epilepsy, chronic

respiratory disease, hepatic impairment or Parkinson’s

disease;

• caution is needed in the elderly, especially in hot or cold

weather;

• pregnancy, lactation;

• alcoholism.

Pharmacokinetics

The pharmacokinetics of conventional antipsychotic drugs

have been little studied. They have multiple metabolites and

their large apparent volumes of distribution (V

) (e.g. for

chlorpromazine V

22 L/kg) result in low plasma concen-

trations, presenting technical difficulties in estimation. Most is

known about chlorpromazine, see Box 19.4.

Drug interactions

These include the following:

• alcohol and other CNS depressants – enhanced sedation;

• hypotensive drugs and anaesthetics – enhanced

hypotension;

• increased risk of cardiac arrhythmias with drugs that

prolong the QT interval (e.g. amiodarone,sotalol);

• tricyclic antidepressants – increased antimuscarinic

actions;

• metoclopramide – increased extrapyramidal effects and

akathisia;

• antagonism of anti-Parkinsonian dopamine agonists (e.g.

L-dopa) (these are in any case contraindicated in

schizophrenia).

ATYPICAL ANTIPSYCHOTIC DRUGS

The term ‘atyptical antipsychotic’ is used very imprecisely.

‘Newer’ or ‘second-generation’ antipsychotics are synonymous

in some texts. In comparison to the conventional antipsychotics

where potency is closely related to D

receptor blockade, atyp-

ical antipsychotics bind less tightly to D

receptors and have

additional pharmacological activity which varies with the drug.

Efficacy against negative symptoms, as well as less extrapyra-

midal side effects, are characteristic. These may be the result of

the transient (‘hit and run’) binding to D

receptors.

Clozapine is the original ‘atypical’ antipsychotic and is

described below. Its use is limited to resistant patients due to

the risk of agranulocytosis. A variety of other atypical anti-

psychotic drugs are available. Features of clozapineare:

• D

5HT

blockade;

• D

D

blockade;

• α-adrenoceptor blockade;

• effective in resistant patients;

• effective against negative and positive symptoms;

• virtually free from extrapyramidal effects;

• agranulocytosis (3%) – use is restricted to patients licensed

with a monitoring service: blood count (weekly for first

18 weeks, then every two weeks till one year, then every

four weeks);

• severe postural hypotension – initiate therapy under

supervision;

• sedation, dizziness, hypersalivation;

• weight gain, glucose intolerance, possible intestinal

obstruction;

• myocarditis and cardiomyopathy;

• pulmonary embolism;

• seizures.

Many newer alternatives, but none with the unique properties

of clozapine, e.g. risperidone, olanzapine, aripiprazole,

amisulpride,quetiapine and zotepine, have been introduced.

Their pharmacology, efficacy and adverse effects vary.

Although more expensive, in June 2002 NICE recommended

Box 19.4: Pharmacokinetics (chlorpromazine)

• Dose regimes are largely empirical.

• There is variable absorption.

• There are 70 metabolites, some of which are

active.

• Enterohepatic circulation is involved.

• There is enormous variability in plasma concentrations

andt

1/2

• There is a vast volume of distribution.

• Brain:plasma concentration is 5:1.

• Reduced doses should be prescribed in the elderly

(for both pharmacokinetic and pharmacodynamic

differences).

Case history

A 50-year-old woman whose schizophrenia is treated

with oral haloperidol is admitted to the Accident and

Emergency Department with a high fever, fluctuating level

of consciousness, muscular rigidity, pallor, tachycardia,

labile blood pressure and urinary incontinence.

Question 1

What is the likely diagnosis?

Question 2

How should this patient be managed?

Answer 1

Neuroleptic malignant syndrome.

Answer 2

1. Stop the haloperidol.

2. Initiate supportive therapy.

3. Bromocriptine (value uncertain).

4. Dantrolene (value uncertain).

SCHIZOPHRENIA 113

114 SCHIZOPHRENIA AND B EHAVIOURALEMERGENCIES

that atypical antipsychotics should be considered in newly

diagnosed schizophrenic patients and in those who have

unacceptable effects from, or inadequate response to, conven-

tional antipsychotic drugs. Risperidone blocks D

, D

and in

particular 5HT

receptors. Careful dose titration reduces the

risk of adverse effects, but extrapyramidal side effects are com-

mon at high doses. It is available as an intramuscular injection

for acute control of agitation and disturbed behaviour. Weight

gain and, more worryingly, an increased incidence of stroke in

elderly patients with dementia have been reported wih both

risperidone and olanzapine. Aripiprazole is a long-acting

atypical antipsychotic which is a partial agonist at D

recep-

tors, as well as blocking 5HT

. It is not associated with

extrapyramidal effects, prolactin secretion or weight gain.

treatment. The control of hypomanic and manic episodes with

chlorpromazineis often dramatic.

ACUTE PSYCHOTIC EPISODES

Patients with organic disorders may experience fluctuating

confusion, hallucinations and transient paranoid delusions.

Violent incidents sometimes complicate schizophrenic illness.

Key points

Pharmacological treatment

• Receptor blockade:

–D

, D

, 5HT

• Although there may be a rapid behavioural benefit, a

delay (usually of the order of weeks) in reduction of

many symptoms implies secondary effects (e.g. receptor

up/downregulation).

• Conventional antipsychotics (e.g. chlorpromazine,

haloperidol, fluphenazine), act predominantly by D

blockade.

• Atypical antipsychotics (e.g. clozapine, risperidone,

olanzapine) are less likely to cause extrapyramidal side

effects.

Key points

Adverse effects of antipsychotic drugs

• Extrapyramidal motor disturbances, related to

dopamine blockade.

• Endocrine distributions (e.g. gynaecomastia), related to

prolactin release secondary to dopamine blockade.

• Autonomic effects, dry mouth, blurred vision,

constipation due to antimuscarinic action and postural

hypotension due to α-blockade.

• Cardiac dysrhythmias, which may be related to

prolonged QT, e.g. sertindole (an atypical antipsychotic),

pimozide.

• Sedation.

• Impaired temperature homeostasis.

• Weight gain.

• Idiosyncratic reactions;

–

jaundice (e.g. chlorpromazine);

– leukopenia and agranulocytosis (e.g. clozapine);

–

skin reactions;

– neuroleptic malignant syndrome.

BEHAVIOURAL EMERGENCIES

MANIA

Acute attacks are managed with antipsychotics, but lithium

is a common and well-established long-term prophylactic

MANAGEMENT

Antipsychotics and benzodiazepines, either separately or

together, are effective in the treatment of patients with violent

and disturbed behaviour. Lorazepamby mouth or parenteral

injection is most frequently used to treat severely disturbed

behaviour as an in-patient.

Haloperidol can rapidly terminate violent and psychotic

behaviour, but hypotension, although uncommon, can be

severe, particularly in patients who are already critically ill.

Doses should be reduced in the elderly.

Intramuscular olanzapine or liquid risperidone are grad-

ually supplanting more conventional antipsychotics in the

acute management of psychosis.

When treating violent patients, large doses of anti-

psychotics may be sometimes needed. Consequently, extrapyra-

midal toxicity, in particular acute dystonias, develops in up to

one-third of patients. Prophylactic anti-parkinsonian drugs,

such as procyclidine, may be given, especially in patients who

are particularly prone to movement disorders.

The combination of lorazepam and haloperidol has

been successful in treating otherwise resistant delirious

behaviour.

Case history

A 60-year-old man with schizophrenia who has been

treated for 30 years with chlorpromazine develops involun-

tary (choreo-athetoid) movements of the face and tongue.

Question 1

What drug-induced movement disorder has developed?

Question 2

Will an anticholinergic drug improve the symptoms?

Question 3

Name three other drug-induced movement disorders

associated with antipsychotic drugs.

Answer 1

Tardive dyskinesia.

Answer 2

No. Anticholinergic drugs may unmask or worsen tardive

dyskinesia.

Answer 3

1. Akathisia.

2. Acute dystonias.

3. Chronic dystonias.

4. Pseudo-parkinsonism.

BEHAVIOURALEMERGENCIES 115

a vailability of flumazenilif (particularly i.v.) benzodiazepines

are used.

FURTHER READING

Anon. Which atypical antipsychotic for schizophrenia? Drugs and

Therapeutics Bulletin2004; 42: 57–60.

Freedman R. Drug therapy: schizophrenia. New England Journal of

Medicine2003; 334: 1738–49.

Oral medication, especially in liquid form, is the

preferred mode of administration, if the patient will accept

it, but intramuscular or intravenous routes may have to

be used.

Antipsychotics, such as chlorpromazineshould be avoided

in alcohol withdrawal states, in alcoholics or in those depend-

ent on benzodiazepines because of the risk of causing fits.

Ensure resuscitation facilities including those for mechan-

ical ventilation are available. Many centres insist on the

●

Depressive illnesses and antidepressants 116

●

Lithium, tryptophan and St John’s wort 121

●

Special groups 122

CHAPTER 20

MOOD DISORDERS

DEPRESSIVE ILLNESSES AN D

ANTIDEPRESSANTS

Many forms of depression are recognized clinically and most

respond well to drugs. From a biochemical viewpoint, there

are probably different types of depression (which do not corres-

pond predictably to clinical variants) depending on which

neurotransmitter is involved, and these may respond differ-

ently to different drugs.

PATHOPHYSIOLOGY: INSIGHTS FROM

ANTIDEPRESSANT DRUG ACTIONS

The monoamine theory of mood is mainly based on evidence

from the actions of drugs.

1. Reserpine, which depletes neuronal stores of noradrenaline

(NA) and 5-hydroxytryptamine (5HT) and α-methyltyrosine,

which inhibits NAsynthesis, cause depression.

2. Tricyclic antidepressants (TCA) of the amitriptyline type

(which raise the synaptic concentration of NAand 5HT)

are antidepressant.

3. Monoamine oxidase inhibitors (MAOIs, which increase

total brain NAand 5HT) are antidepressant.

On the basis of these actions, it was suggested that depression

could be due to a cerebral deficiency of monoamines. One dif-

ficulty with this theory is that amfetamineand cocaine, which

act like tricyclic drugs in raising the synaptic NAcontent, are

not antidepressive, although they do alter mood. Even worse,

the tricyclic antidepressants block amine reuptake from synapses

within one or two hours of administration, but take from ten

days to four weeks to alleviate depression. Such a long time-

course suggests a resetting of postsynaptic or presynaptic

receptor sensitivity.

Another theory of depression is the serotonin-only hypothesis.

This theory emphasizes the role of 5HT and downplays that of

NAin the causation of depression, and is backed by the effect-

iveness of the selective serotonin reuptake inhibitors, or SSRI

class of drugs, in the treatment of depression. However, it also

does not explain the delay in onset of the clinical effect of

antidepressant drugs, including the SSRIs, and again receptor

resetting has to be invoked. Also, many strands of evidence sug-

gest that NAdoes indeed have an important role in depression.

The permissive hypothesis of mania/depression suggests

that the control of emotional behaviour results from a balance

between NA and 5HT. According to this theory, both the

manic phase and the depressive phase of bipolar disorder are

characterized by low central 5HT function. Evidence suggests

that brain 5HT systems dampen or inhibit a range of functions

involving other neurotransmitters. Mood disorders result from

the removal of the serotonin damper. This hypothesis postu-

lates that low levels of 5HT permit abnormal levels of NAto

cause depression or mania. If 5HT cannot control NAand NA

falls to abnormally low levels, the patient becomes depressed.

On the other hand, if the level of 5HT falls and the level of

NA becomes abnormally high, the patient becomes manic.

According to this hypothesis, antidepressant drugs are effect-

ive to the degree that they restore the ability of 5HT to control

NA, thus restoring the critical balance that controls emotional

behaviour. Arecently available class of antidepressant drugs,

serotonin-noradrenaline reuptake inhibitors (SNRI), work by

selectively blocking reuptake of both NA and 5HT, thereby

increasing levels of both monoamines. The SNRIs have very

little affinity for other postsynaptic receptor sites and are there-

fore less likely to produce some of the side effects associated

with TCA.

Dysregulation of the hypothalamic–pituitary–adrenal axis

is a common biological marker of depression and the value of

antiglucocorticoid drugs is under investigation.

GENERAL PRINC IPLES OF MANAGEMENT

Depression is common, but under-diagnosed. It can be recog-

nized during routine consultations, but additional time may

be needed. Genetic and social factors are often relevant. Drug

treatment is not usually appropriate at the mild end of the

severity range. Drugs are used in more severe depression,

especially if it has melancholic (‘endogenous’) features. Even

if depression is attributable to external factors (‘exogenous’),

DEPRESSIVE ILLNESSES AND ANTIDEPRESSANTS 117

e.g. interpersonal difficulties or other life stresses (including

physical illness), antidepressant drugs may be useful. Drugs

used in the initial treatment of depression include TCAs and

related drugs, SSRIs and SNRIs. Although clinical experience

is most extensive with the TCAs, the side-effect profile of the

SSRIs is usually less troublesome, and these drugs are safer in

overdose. Therefore many psychiatrists and general practi-

tioners use SSRIs rather than TCAs as first-line treatment for

depression. SSRIs are more expensive than TCAs. The relative

side effects of the different antidepressant drugs are summar-

ized in Table 20.1.

In refractory depression, other drug treatment or electro-

convulsive therapy (ECT) are considered. Alternative drug

strategies include (1) adding lithium to a tricyclic to give a

lithium blood level of 0.6–0.8 mmol/L; (2) combining anti-

depressants; (3) augmenting with T3 (or T4), a mood stabilizer

such as lamotrigine,buspirone or estradiol; (4) MAOIs, usu-

ally prescribed only by psychiatrists; (5) MAOI plus a TCA–

but only in expert psychiatric hands; or (6) small doses of flu-

pentixol(for short-term treatment only).

Figures 20.1 and 20.2 show a treatment algorithm for man-

agement of depressive illness.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS

(SSRIs)

These drugs are safer in overdose than the tricyclic group.

Selective serotonin reuptake inhibitors (SSRIs) do not stimulate

appetite and have much fewer antimuscarinic side effects than

the tricyclics and other catecholamine-uptake inhibitors. They

are also well tolerated in the elderly. Examples include fluox-

etine, fluvoxamine, paroxetine, sertraline, citalopram and

escitalopram.

Uses

These include the following:

1. in depression (they have similar efficacy to tricyclics, but

are much more expensive);

2. in chronic anxiety, and as prophylaxis for panic attacks;

3. obsessive-compulsive states;

4. bulimia nervosa;

5. seasonal affective disorder, especially if accompanied by

carbohydrate craving and weight gain;

6. possibly effective as prophylactic agents in recurrent

depression.

Adverse effects

1. The most common adverse reactions to SSRIs are nausea,

dyspepsia, diarrhoea, dry mouth, headache, insomnia and

dizziness. Sweating, erectile dysfunction and delayed

orgasm are well-recognized associations. These tend to

become less severe after one to two months of treatment.

2. They have less anticholinergic and cardiotoxic actions

than tricyclic drugs.

Table 20.1:Relative antidepressant side effects

Drug Anticholinergic Cardiac Nausea Sedation Overdose Pro-convulsant Tyramine

effects effects risk interaction

Tricyclics and related

antidepressants

Amitriptyline       

Clomipramine       

Dothiepin       

Imipramine       

Lofepramine     

Trazodone       

Selective serotonin

reuptake inhibitors

Citalopram 

Fluoxetine ? 

Paroxetine ? 

Sertraline ? 

Monoamine oxidase

inhibitors

Phenelzine       

Moclobemide    ? 

Others

Venlafaxine ? 

, little or nothing reported; , mild; , moderate; , high; ?, insufficient information available.

118 MOOD DISORDERS

3. Epilepsy can be precipitated.

4. They are usually non-sedating, but may cause insomnia

and do not usually cause orthostatic hypotension.

5. All antidepressants can cause hyponatraemia, probably

due to induction of inappropriate antidiuretic hormone

secretion, but it is reported more frequently with SSRIs

than with other antidepressants.

Contraindications

These include the following:

• hepatic and renal failure;

• epilepsy;

• manic phase.

Drug interactions

• Combinations of SSRI with lithium,tryptophan or MAOIs

may enhance efficacy, but are currently contraindicated

because they increase the severity of 5HT-related toxicity.

In the worst reactions, the life-threatening 5HT syndrome

develops. This consists of hyperthermia, restlessness, tremor,

myoclonus, hyperreflexia, coma and fits. After using MAOIs,

it is recommended that two weeks should elapse before

starting SSRIs. Avoid fluoxetinefor at least five weeks

before using MAOI because of its particularly long half-

life (about two days).

• The action of warfarin is probably enhanced by

fluoxetineand paroxetine.

• There is antagonism of anticonvulsants.

• Fluoxetine raises blood concentrations of haloperidol.

SEROTONIN-NORADRENALINE REUPTAKE

INHIBITORS AND RELATED ANTIDEPRESSANTS

Venlafaxine: A potent 5HT and NAuptake inhibitor that

appears to be as effective as TCAs, but without anticholinergic

effects. It may have a more rapid onset of therapeutic action

than other antidepressants, but this has yet to be confirmed. It

is associated with more cardiac toxicity than the SSRIs.

Duloxetineinhibits NA and 5HT reuptake.

TRICYCLICS AND RELATED ANTIDEPRESSANTS

(TCAs)

Uses

These include the following:

1. depressive illnesses, especially major depressive episodes

and melancholic depression;

2. atypical oral and facial pain;

3. prophylaxis of panic attacks;

4. phobic anxiety;

5. obsessive–compulsive disorders;

6. imipramine has some efficacy in nocturnal enuresis.

Although these drugs share many properties, their

profiles vary in some respects, and this may alter their use in

different patients. The more sedative drugs include amitripty-

line, dosulepin and doxepin. These are more appropriate

for agitated or anxious patients than for withdrawn or apa-

thetic patients, for whom imipramine or nortriptyline,

which are less sedative, are preferred. Protriptylineis usually

stimulant.

Only 70% of depressed patients respond adequately to

TCAs. One of the factors involved may be the wide variation in

individual plasma concentrations of these drugs that is

obtained with a given dose. However, the relationship between

plasma concentration and response is not well defined. Amul-

ticentre collaborative study organized by the World Health

Organization failed to demonstrate any relationship whatso-

ever between plasma amitriptyline concentration and clinical

effect.

Diagnosis of unipolar

depression

Psychotherapy

and medication

Continue same

treatment

Advance dose

as tolerated

Go to second phase

of treatment

Evaluate response

to medication after

3–4 weeks

Evaluate response

to medication after

6–8 weeks

Significant symptoms

persist after 6 weeks

Psychotherapy

Symptoms resolving

Symptoms persist

Partial response No response

Add medication

Medication

Figure 20.1:General algorithm for the initial phase of treatment

of depression. When symptoms persist after first-line treatment,

re-evaluate the accuracy of the diagnosis, the adequacy of the dose

and the duration of treatment before moving to the second

phase of treatment. (Redrawn with permission from Aronson SC

and Ayres VE. ‘Depression: A Treatment Algorithm for the Family

Turner White Communications, Inc.)

DEPRESSIVE ILLNESSES AND ANTIDEPRESSANTS 119

Imipramineand amitriptyline (tertiary amines) have more

powerful anticholinergic and cardiac toxic effects than second-

ary amines (e.g. nortriptyline).

Mechanism of action

The tricyclics block uptake-1 of monoamines into cerebral (and

other) neurones. Thus, the concentration of amines in the

synaptic cleft rises. As discussed above, they may also induce a

slow adaptive decrease in pre- and/or postsynaptic amine

receptor sensitivity.

Adverse effects

Autonomic (anticholinergic)/cardiovascularDry mouth,

constipation (rarely paralytic ileus, gastroparesis),

tachycardia, paralysis of accommodation, aggravation of

narrow-angle glaucoma, retention of urine, dry skin due

to loss of sweating, and (due to α-blockade) postural

hypotension. Rarely, sudden death due to a cardiac

dysrhythmia. In overdose, a range of tachydysrhythmias

and intracardiac blocks may be produced.

Central nervous systemFine tremor and sedation, but also

(paradoxically) sometimes insomnia, decreased rapid eye

movement (REM) sleep, twitching, convulsions, dysarthria,

paraesthesia, ataxia. Increased appetite and weight gain,

particularly with the sedative tricyclics, are common. On

withdrawal of the drug, there may be gastro-intestinal

symptoms such as nausea and vomiting, headache,

giddiness, shivering and insomnia. Sometimes anxiety,

agitation and restlessness follow sudden withdrawal.

Allergic and idiosyncratic reactionsThese include bone marrow

suppression and jaundice (both rare).

HyponatraemiaHyponatraemia is an adverse effect due to

inappropriate ADH secretion, and is more common in the

elderly.

Contraindications

These include the following:

• epilepsy;

• recent myocardial infarction, heart block;

• mania;

• porphyria.

RELATED NON-TRICYCLIC ANTIDEPRESSANT DRUGS

This is a mixed group which includes 1-, 2- and 4-ring struc-

tured drugs with broadly similar properties. Characteristics of

specific drugs are summarized below.

Maprotiline– sedative, with less antimuscarinic effects, but

rashes are more common and fits are a significant risk.

Mianserin– blocks central α

-adrenoceptors. It is sedative,

with much fewer anticholinergic effects, but can cause

postural hypotension and blood dyscrasias, particularly in

the elderly. Full blood count must be monitored.

Assess risk factors for

treatment resistance

Assess symptom severity

Partial response to

first-line treatment

Advance dose

as tolerated

Symptoms persist after

6–8 weeks

Ensure safe maximum

tolerated dose

Trial of an alternative

medication

Nonresponders:

mild-to-moderate

symptoms, low risk

All patients:

moderate-to-severe

symptoms, or high risk

No response to

first-line treatment

Persistent symptoms

AUGMENTATION

Persistent symptoms

Trial of an alternative

medication

Partial responders:

mild symptoms, low risk

Figure 20.2:General algorithm for

the second phase of treatment of

depression. Augmentation*

involves the use of a combination

of medications to enhance the

efficacy of an antidepressant.

(Redrawn with permission from

Aronson SC and Ayres VE,

‘Depression: A Treatment

Algorithm for the Family

Physician’,Hospital Physician

2000 Turner White

Communications, Inc.)

120 MOOD DISORDERS

Lofepramine– less sedative, and with less cardiac toxicity,

but occasionally hepatotoxic.

Mirtazapine– increases noradrenergic and serotonergic

neurotransmission via central α

adrenoceptors. The

increased release of 5HT stimulates 5HT

receptors, whilst

5HT

and 5HT

receptors are blocked. H

receptors are

also blocked. This combination of actions appears to be

associated with antidepressant activity, anxiolytic and

sedative effects. Reported adverse effects include increased

appetite, weight gain, drowsiness, dry mouth and (rarely)

blood dyscrasias.

Drug interactions

These include the following:

• antagonism of anti-epileptics;

• potentiation of sedation with alcohol and other central

depressants;

• antihypertensives and diuretics increase orthostatic

hypotension;

• hypertension and cardiac dysrhythmias with adrenaline,

noradrenaline and ephedrine.

MONOAMINE OXIDASE INHIBITORS (MAOIs)

These drugs were little used for many years because of their

toxicity, and particularly potentially lethal food and drug inter-

actions causing hypertensive crises. Non-selective MAOIs

should only be prescribed by specialists who are experienced

in their use. They can be effective in some forms of refractory

depression and anxiety states, for which they are generally

reserved. The introduction of moclobemide, a reversible select-

ive MAO-Ainhibitor, may lead to more widespread use of this

therapeutic class.

Tranylcypromineis the most hazardous MAOI because of

its stimulant activity. The non-selective MAOIs of choice are

phenelzineand isocarboxazid.

Uses

These include the following:

1. MAOIs can be used alone or (with close psychiatric

supervision) with a TCA, in depression which has not

responded to TCAs alone;

2. in phobic anxiety and depression with anxiety;

3. in patients with anxiety who have agoraphobia, panic

attacks or multiple somatic symptoms;

4. hypochondria and hysterical symptoms may respond well;

5. for atypical depression with biological features such as

hypersomnia, lethargy and hyperphagia.

Adverse effects

1. Common effects include orthostatic hypotension, weight

gain, sexual dysfunction, headache and aggravation of

migraine, insomnia, anticholinergic actions and oedema.

2. Rare and potentially fatal effects include hypertensive

crisis and 5HT syndrome, psychotic reactions,

hepatocellular necrosis, peripheral neuropathy and

convulsions.

3. Stopping a MAOI is more likely to produce a withdrawal

syndrome than is the case with tricyclics. The syndrome

includes agitation, restlessness, panic attacks and

insomnia.

Contraindications

These include the following:

• liver failure;

• cerebrovascular disease;

• phaeochromocytoma;

• porphyria;

• epilepsy.

Drug interactions

Many important interactions occur with MAOI. Atreatment

card for patients should be carried at all times, which describes

precautions and lists some of the foods to be avoided. The

interactions are as follows:

• hypertensive and hyperthermic reactions sufficient to

cause fatal subarachnoid haemorrhage, particularly with

tranylcypromine. Such serious reactions are precipitated

by amines, including indirectly acting sympathomimetic

agents such as tyramine (in cheese), dopamine (in broad

bean pods and formed from levodopa), amines formed

from any fermentation process (e.g. in yoghurt, beer,

wine),phenylephrine (including that administered as

nosedrops and in cold remedies), ephedrine,amfetamine

(all can give hypertensive reactions), other amines,

pethidine(excitement, hyperthermia), levodopa

(hypertension) and tricyclic, tetracyclic and bicyclic

antidepressants (excitement, hyperpyrexia). Buspirone

should not be used with MAOIs. Hypertensive crisis may

be treated with α-adrenoceptor blockade analogous to

medical treatment of patients with phaeochromocytoma

(see Chapter 40). Interactions of this type are much less

likely to occur with moclobemide, as its MAO inhibition

is reversible, competitive and selective for MAO-A, so that

MAO-B is free to deaminate biogenic amines;

• failure to metabolize drugs that are normally oxidized,

including opioids, benzodiazepines, alcohol (reactions

with alcoholic drinks occur mainly because of their

tyramine content). These drugs will have an exaggerated

and prolonged effect;

• enhanced effects of oral hypoglycaemic agents, anaesthetics,

suxamethonium, caffeine and anticholinergics (including

benzhexol and similar anti-Parkinsonian drugs);

• antagonism of anti-epileptics;

• enhanced hypotension with antihypertensives;

• central nervous system (CNS) excitation and hypertension

withoxypertine (an antipsychotic) and tetrabenazine (used

for chorea);

• increased CNS toxicity with triptans (5HT

agonists) and

withsibutramine.

LITHIUM, TRYPTOPHAN AND ST JOHN’S

WORT

LITHIUM

Althoughlithium is widely used in affective disorders, it has

a low toxic to therapeutic ratio, and serum concentration moni-

toring is essential. Serum is used rather than plasma because

of possible problems due to lithium heparin, which is often

used as an anticoagulant in blood sample tubes. Serum

lithium levels fluctuate between doses and serum concentra-

tions should be measured at a standard time, preferably 12

hours after the previous dose. This measurement is made fre-

quently until steady state is attained and is then made every

three months, unless some intercurrent event occurs that

could cause toxicity (e.g. desal-ination or diuretic therapy).

Use

Lithiumis effective in acute mania, but its action is slow (one

to two weeks), so antipsychotic drugs, such as haloperidol,

are preferred in this situation (see Chapter 19). Its main use

is in prophylaxis in unipolar and bipolar affective illness

LITHIUM, TRYPTOPHANAND ST J OHN’S WORT 121

(therapeutic serum levels 0.4–1mmol/L). Lithium is also

used on its own or with another antidepressant in refractory

depression to terminate a depressive episode or to prevent

recurrences and aggressive or self-mutilating behaviour.

Patients should avoid major dietary changes that alter

sodium intake and maintain an adequate water intake.

Different lithiumpreparations have different bioavailabili-

ties, so the form should not be changed.

Mechanism of action

Lithium increases 5HT actions in the CNS. It acts as a 5HT

agonist and is also a 5HT

antagonist. This may be the basis for

its antidepressant activity and may explain why it increases

the CNS toxicity of selective 5HT uptake inhibitors.

The basic biochemical activity of lithium is not known. It

has actions on two second messengers.

1. Hormone stimulation of adenylyl cyclase is inhibited,

so that hormone-stimulated cyclic adenosine

monophosphate (cAMP) production is reduced. This

probably underlies some of the adverse effects of lithium,

such as goitre and nephrogenic diabetes insipidus, since

thyroid-stimulating hormone (TSH) and antidiuretic

hormone activate adenylyl cyclase in thyroid and

collecting duct cells, respectively. The relevance of this

to its therapeutic effect is uncertain.

2. Lithium at a concentration of 1 mmol/L inhibits

hydrolysis of myoinositol phosphate in the brain, so

lithiummay reduce the cellular content of phosphatidyl

inositides, thereby altering the sensitivity of neurones

to neurotransmitters that work on receptors linked

to phospholipase C (including muscarinic and

α-adrenoceptors).

From these actions, it is clear that lithiumcan modify a wide

range of neurotransmitter effects, yet its efficacy both in mania

and in depression indicates a subtlety of action that is cur-

rently unexplained, but may be related to activation of the brain

stem raphe nuclei.

Adverse effects

1. When monitored regularly lithium is reasonably safe in

the medium term. However, adverse effects occur even in

the therapeutic range – in particular, tremor, weight gain,

oedema, polyuria, nausea and loose bowels.

2. Above the therapeutic range, tremor coarsens, diarrhoea

becomes more severe and ataxia and dysarthria appear.

Higher levels cause gross ataxia, coma, fits, cardiac

dysrhythmias and death. Serum lithiumconcentrations

greater than 1.5mmol/L may be dangerous and if greater

than 2mmol/L, are usually associated with serious

toxicity.

3. Goitre, hypothyroidism and exacerbation of psoriasis are

less common.

4. Renal tubular damage has been described in association

with prolonged use.

Key points

Antidepressant contraindications

• Tricyclic antidepressants – recent myocardial infarction,

dysrhythmias, manic phase, severe liver disease.

• SSRIs – manic phase.

• Monamine oxidase inhibitors – acute confused state,

phaeochromocytoma.

• Caution is needed – cardiac disease, epilepsy, pregnancy

and breast-feeding, elderly, hepatic and renal

impairment, thyroid disease, narrow-angle glaucoma,

urinary retention, prostatism, porphyria, psychoses,

electroconvulsive therapy (ECT) and anaesthesia.

Key points

Drug treatment of depression

• Initial drug treatment is usually with SSRIs, tricyclic

antidepressants or related drugs.

• The choice is usually related to the side-effect profile of

relevance to the particular patient.

• Tricyclic antidepressants are more dangerous in overdose.

• Tricyclic antidepressants commonly cause antimuscarinic

and cardiac effects.

• Tricyclic antidepressants tend to increase appetite and

weight, whereas SSRIs more commonly reduce appetite

and weight.

• SSRIs are associated with nausea, sexual dysfunction

and sleep disturbance.

• There is a variable delay (between ten days and four

weeks) before therapeutic benefit is obtained.

• Following remission, antidepressant therapy should be

continued for at least four to six months.

ST JOHN’S WORT

St John’s wort (Hypericum perforatum) is an unlicensed herbal

remedy in popular use for treating depression (Chapter 17).

However, it can induce drug-metabolizing enzymes, and many

important drug interactions have been identified, including

with antidepressant drugs, with which St John’s wort should

therefore not be given. The amount of active ingredient can

vary between different preparations, thus changing the prepa-

ration can alter the degree of such interactions. Importantly,

when St John’s wort is discontinued, the concentrations of

interacting drugs may increase.

SPECIAL GROUPS

THE ELDERLY

Depression is common in the elderly, in whom it tends to be

chronic and has a high rate of recurrence. Treatment with drugs

is made more difficult because of slow metabolism and sensi-

tivity to anticholinergic effects. Lower doses are therefore needed

than in younger patients.

Lack of response may indicate true refractoriness of the

depression, or sadness due to social isolation or bereavement.

The possibility of underlying disease, such as hypothyroidism

(the incidence of which increases with age), should be

considered.

Lofepramine and SSRIs cause fewer problems in patients

with prostatism or glaucoma than do the tricyclic antidepres-

sants because they have less antimuscarinic action. Dizziness

and falls due to orthostatic hypotension are less common with

nortriptyline than with imipramine. Mianserin has fewer

anticholinergic effects, but blood dyscrasias occur in about one

in 4000 patients and postural hypotension can be severe.

EPILEPSY

No currently used antidepressive is entirely safe in epilepsy,

but SSRIs are less likely to cause fits than the amitriptyline

group, mianserinor maprotiline.

Contraindications

These include the following:

• renal disease;

• cardiac disease;

• sodium-losing states (e.g. Addison’s disease, diarrhoea,

vomiting);

• myasthenia gravis;

• during surgical operations;

• avoid when possible during pregnancy and breast-feeding.

Pharmacokinetics

Lithium is readily absorbed after oral administration and

injectable preparations are not available. Peak serum concen-

trations occur three to five hours after dosing. The t

1/2

varies

with age because of the progressive decline in glomerular fil-

tration rate, being 18–20 hours in young adults and up to 36

hours in healthy elderly people. Sustained-release prepar-

ations are available, but in view of the long t

1/2

they are not

kinetically justified. Lithiumtakes several days to reach steady

state and the first samples for serum level monitoring should

be taken after about one week unless loading doses are given.

Lithium elimination is almost entirely renal. Like sodium,

lithiumdoes not bind to plasma protein, and it readily passes

into the glomerular filtrate; 70–80% is reabsorbed in the proxi-

mal tubules but, unlike sodium, there is no distal tubular reab-

sorption and its elimination is not directly altered by diuretics

acting on the distal tubule. However, states such as sodium

deficiency and sodium diuresis increase lithiumretention (and

cause toxicity) by stimulating proximal tubular sodium and

lithium reabsorption. An important implication of the renal

handling of lithiumis that neither loop diuretics, thiazides nor

potassium-sparing diuretics can enhance lithiumloss in a toxic

patient, but all of them do enhance its toxicity. Dialysis reduces

elevated serum lithiumconcentration effectively.

Drug interactions

• Lithium concentration in the serum is increased by

diuretics and non-steroidal anti-inflammatory drugs.

• Lithium toxicity is increased by concomitant

administration of haloperidol, serotonin uptake

inhibitors, calcium antagonists (e.g. diltiazem) and

anticonvulsants (phenytoinand carbamazepine) without

a change in serum concentration.

• Lithium increases the incidence of extrapyramidal effects

of antipsychotics.

L-TRYPTOPHAN

Tryptophan is the amino acid precursor of 5HT. On its own

or with other antidepressants or lithium it sometimes bene-

fits refractory forms of depression. However,

L-tryptophan

should only be initiated under specialist supervision because

of its association with an eosinophilic myalgic syndrome char-

acterized by intense and incapacitating fatigue, myalgia and

eosinophilia. Arthralgia, fever, cough, dyspnoea and rash may

also develop over several weeks. A few patients develop

myocarditis.

122 MOOD DISORDERS

Case history

A 75-year-old woman with endogenous depression is

treated with amitriptyline. After three weeks, she appears

to be responding, but then seems to become increasingly

drowsy and confused. She is brought to the Accident

and Emergency Department following a series of

convulsions.

Question

What is the likely cause of her drowsiness, confusion and

convulsions?

Answer

Hyponatraemia.

Comment

Hyponatraemia (usually in the elderly) has been associated

with all types of antidepressant but most frequently with

SSRIs.

SPECIAL GROUPS 123

Case history

A 45-year-old man with agoraphobia, anxiety and depres-

sion associated with hypochondriacal features is treated

with phenelzine. He has no history of hypertension. He is

seen in the Accident and Emergency Department because

of a throbbing headache and palpitations. On examination

he is hypertensive 260/120mmHg with a heart rate of 40

beats/minute. He is noted to have nasal congestion.

Question 1

What is the likely diagnosis?

Question 2

What is the most appropriate treatment?

Answer 1

Hypertensive crisis, possibly secondary to taking a cold cure

containing an indirectly acting sympathomimetic.

Answer 2

Phentolamine, a short-acting alpha-blocker, may be given

by intravenous injection, with repeat doses titrated against

response.

FURTHER READING

Aronson SC, Ayres VD. Depression: a treatment algorithm for the

family physician. Hospital Physician2000; 44: 21–38.

Ebmeier KP, Donaghey C, Steele JD. Recent developments and current

controversies in depression. The Lancet2005; 367: 153–67.

PARKINSON’S SYNDROME AND ITS

TREATMENT

PATHOPHYSIOLOGY

James Parkinson first described the tremor, rigidity and

bradykinesia/akinesia that characterize the syndrome known

as Parkinson’s disease. Most cases of Parkinson’s disease are

caused by idiopathic degeneration of the nigrostriatal path-

way. Atherosclerotic, toxic (e.g. related to antipsychotic drug

treatment, manganese or carbon monoxide poisoning) and

post-encephalitic cases also occur. Treatment of parkinsonism

caused by antipsychotic drugs differs from treatment of the

idiopathic disease, but other aetiologies are treated similarly to

●

Parkinson’s syndrome and its treatment 124

●

Spasticity 128

●

Chorea 129

●

Drug-induced dyskinesias 129

●

Treatment of other movement disorders 129

●

Myasthenia gravis 129

●

Alzheimer’s disease 131

CHAPTER 21

MOVEMENT DISORDERS AND

DEGENERATIVE CNS DISEASE

Striatum

Substantia nigra

Motor

cortex

ACh

GABA

Figure 21.1:Representation of relationships between cholinergic

(ACh), dopaminergic (DA) and GABA-producing neurones in the

basal ganglia.

the idiopathic disease. Parkinsonian symptoms manifest after

loss of 80% or more of the nerve cells in the substantia nigra.

The nigrostriatal projection consists of very fine nerve fibres

travelling from the substantia nigra to the corpus striatum.

This pathway is dopaminergic and inhibitory, and the motor

projections to the putamen are more affected than either those

to the cognitive areas or to the limbic and hypolimbic regions

(Figure 21.1). Other fibres terminating in the corpus striatum

include excitatory cholinergic nerves and noradrenergic and

serotoninergic fibres, and these are also affected, but to vary-

ing extents, and the overall effect is a complex imbalance

between inhibitory and excitatory influences.

Parkinsonism arises because of deficient neural transmission

at postsynaptic D

receptors, but it appears that stimulation of

both D

and D

is required for optimal response. D

receptors

activate adenylyl cyclase, which increases intracellular cyclic

adenosine monophosphate (cAMP). The antagonistic effects of

dopamine and acetylcholine within the striatum have suggested

that parkinsonism results from an imbalance between these

neurotransmitters (Figure 21.2). The therapeutic basis for treat-

ing parkinsonism is to increase dopaminergic activity or to

reduce the effects of acetylcholine. 1-Methyl-4-phenyl-1,2,5,6-

tetrahydropyridine (MPTP) has been used illicitly as a drug of

abuse and it causes severe parkinsonism. MPTPis converted by

monoamine oxidase-B (MAO-B) in neuronal mitochondria to a

toxic free-radical metabolite (MPP



), which is specifically toxic

to dopamine-producing cells. This led to the hypothesis that

idiopathic Parkinson’s disease may be due to chronically

increased free-radical damage to the cells of the substantia nigra.

However, clinical studies of anti-oxidants have so far been

disappointing.

The free-radical hypothesis has raised the worrying possibil-

ity that treatment with levodopa (see below) could accelerate

disease progression by increasing free-radical formation as the

drug is metabolized in the remaining nigro-striatal nerve fibres.

This is consistent with the clinical impression of some neurolo-

gists, but in the absence of randomized clinical trials it is

difficult to tell whether clinical deterioration is due to the natu-

ral history of the disease or is being accelerated by the therapeu-

tic agent.

PARKINSON’S SYNDROME AND ITS TREATMENT 125

PRINCIPLES OF TREATMENT IN PARKINSONISM

Idiopathic Parkinson’s disease is a progressive disorder, and is

treated with drugs that relieve symptoms and if possible

slow disease progression. Treatment is usually initiated when

symptoms disrupt normal daily activities. Initial treatment is

often with a dopamine receptor agonist, e.g. bromocriptine,

particularly in younger (70) patients. Alevodopa/decarboxy-

lase inhibitor combination is commonly used in patients with

definite disability. The dose is titrated to produce optimal

results. Occasionally, amantadine or anticholinergics may be

useful as monotherapy in early disease, especially in younger

patients when tremor is the dominant symptom. In patients on

levodopa the occurrence of motor fluctuations (on–off phenom-

ena) heralds a more severe phase of the illness. Initially, such

fluctuations may be controlled by giving more frequent doses

of levodopa (or a sustained-release preparation). The addition

of either a dopamine receptor agonist (one of the non-ergot

derivatives, e.g. ropinirole) or one of the calechol-O-methyl

transferase (COMT) inhibitors (e.g. entacapone, tolcapone) to

the drug regimen may improve mobility. In addition, this usu-

ally allows dose reduction of the levodopa, while improving

‘end-of-dose’ effects and improving motor fluctuations. If on–off

phenomena are refractory, the dopamine agonist apomorphine

can terminate ‘off’ periods, but its use is complex (see below).

Selegiline, a MAO-B inhibitor, may reduce the end-of-dose

deterioration in advanced disease. Physiotherapy and psycho-

logical support are helpful. The experimental approach of

implantation of stem cells into the substantia nigra of severely

affected parkinsonian patients (perhaps with low-dose

immunosuppression) is being investigated. The potential of

stereotactic unilateral pallidotomy, for severe refractory cases of

Parkinson’s disease is being re-evaluated.

Drugs that cause parkinsonism, notably conventional

antipsychotic drugs (e.g. chlorpromazine, haloperidol) (see

Chapter 19) are withdrawn if possible, or substituted by the

newer ‘atypical’ antipsychotics (e.g. risperidoneor olanzapine),

since these have a lower incidence of extrapyramidal side effects.

Antimuscarinic drugs (e.g. trihexyphenidyl) are useful if chang-

ing the drug/reducing the dose is not therapeutically acceptable,

whereas drugs that increase dopaminergic transmission are con-

traindicated because of their effect on psychotic symptoms.

ANTI-PARKINSONIAN DRUGS

DRUGS AFFECTING THE DOPAMINERGIC SYSTEM

Dopaminergic activity can be enhanced by:

• levodopa with a peripheral dopa decarboxylase inhibitor;

• increasing release of endogenous dopamine;

• stimulation of dopamine receptors;

• inhibition of catechol-O-methyl transferase;

• inhibition of monoamine oxidase type B.

LEVODOPA AND DOPA DECARBOXYLASE INHIBITORS

Use

Levodopa (unlike dopamine) can enter nerve terminals in the

basal ganglia where it undergoes decarboxylation to form

dopamine.Levodopa is used in combination with a peripheral

(extracerebral) dopa decarboxylase inhibitor (e.g. carbidopaor

benserazide). This allows a four- to five-fold reduction in levo-

dopadose and the incidence of vomiting and dysrhythmias is

reduced. However, central adverse effects (e.g. hallucinations)

are (predictably) as common as when larger doses of levodopa

are given without a dopa decarboxylase inhibitor.

Combined preparations (co-careldopa or co-beneldopa)

are appropriate for idiopathic Parkinson’s disease. (Levodopa

is contraindicated in schizophrenia and must not be used for

parkinsonism caused by antipsychotic drugs.) Combined

preparations are given three times daily starting at a low dose,

increased initially after two weeks and then reviewed at

intervals of six to eight weeks. Without dopa decarboxylase

inhibitors, 95% of levodopa is metabolized outside the brain.

In their presence, plasma levodopaconcentrations rise (Figure

21.3), excretion of dopamine and its metabolites falls, and the

availability of levodopa within the brain for conversion to

dopamine increases. The two available inhibitors are similar.

Adverse effects

These include the following:

• nausea and vomiting;

• postural hypotension – this usually resolves after a few

weeks, but excessive hypotension may result if

antihypertensive treatment is given concurrently;

Normal

Parkinsonism due to

excess acetylcholine

Cholinergic

system

(excitatory)

Anticholinergic

drugs

Dopaminergic

system

(inhibitory)

Parkinsonism due to

dopamine deficiency

Levodopa

Figure 21.2:Antagonistic actions of the dopaminergic

and cholinergic systems in the pathogenesis of

parkinsonian symptoms.

Key points

Parkinson’s disease

• Clinical diagnosis is based on the triad of tremor,

rigidity and bradykinesia.

• Parkinsonism is caused by the degeneration of

dopaminergic pathways in basal ganglia leading to

imbalance between cholinergic (stimulatory) and

dopaminergic (inhibitory) transmission.

• It is induced/exacerbated by centrally acting dopamine

antagonists (e.g. haloperidol), but less so by clozapine,

risperidone or olanzapine.

126 MOVEMENT DISORDERS AND DEGEN ERATIVEC NS DISEASE

• involuntary movements (dystonic reactions) – these

include akathisia (abnormal restlessness and inability to

keep still), chorea and jerking of the limbs (myoclonus).

Involuntary movements may become worse as treatment

is continued, and may necessitate drug withdrawal;

• psychological disturbance, including vivid dreams,

agitation, paranoia, confusion and hallucinations;

• cardiac dysrhythmias;

• endocrine effects of levodopa, including stimulation of

growth hormone and suppression of prolactin.

• sedation and sudden onset of sleep (avoid driving at onset

of treatment and if these symptoms recur).

Pharmacokinetics

Levodopais absorbed from the proximal small intestine and is

metabolized both by decarboxylases in the intestinal wall and

by the gut flora. Oral absorption is variable. Absorption/

bioavailability are improved by co-administration of decar-

boxylase inhibitors. Addition of a COMT inhibitor further

increases t

1/2

and AUC.

Drug interactions

Monoamine oxidase inhibitors can produce hypertension if

given concurrently with levodopa. The hypotensive actions of

other drugs are potentiated by levodopa.

INCREASED RELEASE OF E NDOGENOUS

DOPAMINE

AMANTADINE

Use

Amantadine has limited efficacy, but approximately 60% of

patients experience some benefit. Severe toxicity is rare.

Mechanism of action

Endogenous dopamine release is stimulated by amantadine,

which also inhibits reuptake of dopamine into nerve terminals.

Adverse effects

These include the following:

• peripheral oedema;

• gastro-intestinal upset and dry mouth;

• livedo reticularis;

• CNS toxicity – nightmares, insomnia, dizziness,

hallucinations, convulsions;

• leukopenia (uncommon).

Pharmacokinetics

The t

1/2

of amantadine varies from 10 to 30 hours, so steady-

state concentrations are reached after four to seven days of treat-

ment. About 95% is eliminated by the kidneys and it should not

be used in patients with renal failure.

DOPAMINE RECEPTOR AGONISTS

Uses

Dopamine receptor agonists are used as initial therapy or as

adjuncts to levodopa–dopa decarboxylase inhibitor combin-

ations in patients with severe motor fluctuations (on–off

phenomena). Dopamine agonists share many of their adverse

effects with levodopa, particularly nausea due to stimulation of

dopamine receptors in the chemoreceptor trigger zone. This

brain region is unusual in that it is accessible to drugs in the sys-

temic circulation, so domperidone(a dopamine antagonist that

does not cross the blood–brain barrier) prevents this symptom

without blocking dopamine receptors in the striatum, and hence

worsening the movement disorder. Neuropsychiatric disorders

are more frequent than with levodopamonotherapy. (See also

Chapter 42 for use in pituitary disorders, and Chapter 41 for use

in suppression of lactation). Pulmonary, retroperitoneal and

pericardial fibrotic reactions have been associated with some

ergot-derived dopamine agonists. Dopamine receptor agonists

are started at a low dose that is gradually titrated upwards

depending on efficacy and tolerance. If added to levodopa, the

dose of the latter may be reduced.

Ergot derivatives include bromocriptine,lisuride, pergolide

and cabergoline. Other licensed dopamine agonists include

pramipexole,ropinirole and rotigotine.

There is great individual variation in the efficacy of

dopamine receptor agonists. The initial dose is gradually

titrated upwards depending on response and adverse effects.

Adverse effects

These are primarily due to D

agonist activity, although 5HT

and 5HT

effects are also relevant.

• gastro-intestinal – nausea and vomiting, constipation or

diarrhoea;

• central nervous system – headache, drowsiness,

confusion, psychomotor excitation, hallucination;

• orthostatic hypotension (particularly in the elderly),

syncope;

• cardiac dysrhythmias – bradycardia;

-dopa (100 mg)  MK 485

-dopa (1000 mg)

-dopa (100 mg)

0.2

0.4

0.6

0.8

1.2

1.0

2468

Plasma dopa concentration (g/mL)

Time after

-dopa dose (h)

Figure 21.3:Increased plasma dopa concentrations following

combination with a peripheral dopa decarboxylase inhibitor

(MK 485) in one patient. (Redrawn with permission from Dunner DL

et al. Clinical Pharmacology and Therapeutics1971; 12: 213.)

PARKINSON’SSYNDROME AND ITS TREATMENT 127

• pulmonary, retroperitoneal and pericardial fibrotic

reactions have been associated with the ergot-derived

dopamine agonists (bromocriptine,cabergoline, lisuride

andpergolide).

APOMORPHINE

Apomorphine is a powerful dopamine agonist at both D

and

receptors, and is used in patients with refractory motor oscil-

lations (on–off phenomena). It is difficult to use, necessitating

specialist input. The problems stem from its pharmacokinetics

and from side effects of severe nausea and vomiting. The gastro-

intestinal side effects can be controlled with domperidone.

Apomorphine is started in hospital after pretreatment with

domperidonefor at least three days, and withholding other anti-

parkinsonian treatment at night to provoke an ‘off’ attack. The

subcutaneous dose is increased and when the individual dose

requirement has been established, with reintroduction of other

drugs if necessary, administration is sometimes changed from

intermittent dosing to subcutaneous infusion via a syringe pump,

with patient-activated extra boluses if needed. Apomorphine is

extensively hepatically metabolized and is given parenterally.

The mean plasma t

1/2

is approximately 30 minutes.

CATECHOL-O-METHYL TRANSFERASE INHIBITORS

Use

Tolcaponeand entacapone are used for adjunctive therapy in

patients who are already taking

L-dopa/dopa decarboxylase

inhibitor combinations with unsatisfactory control (e.g. end-of-

dose deterioration). These agents improve symptoms with less

on–off fluctuations, as well as reducing the levodopa dose

requirement by 20–30%. Adverse effects arising from increased

availability of

L-dopa centrally can be minimized by decreas-

ing the dose of levodopacombination treatment prospectively.

Because of hepatotoxicity associated with tolcapone it is

only used by specialists when entacapone is ineffective as an

adjunctive treatment.

Mechanism of action

Reversible competitive inhibition of COMT, thereby reducing

metabolism of

L-dopa and increasing its availability within

nigrostriatal nerve fibres. It is relatively specific for central ner-

vous system (CNS) COMT, with little effect on the peripheral

COMT, thus causing increased brain concentrations of

L-dopa,

while producing less of an increase in plasma concentration.

Adverse effects

These include the following:

• nausea, vomiting, diarrhoea and constipation;

• increased levodopa-related side effects;

• neuroleptic malignant syndrome;

• dizziness;

• hepatitis – rare with entacapone, but potentially life-

threatening with tolcapone(liver function testing is

mandatory before and during treatment);

• urine discolouration.

Pharmacokinetics

Tolcaponeis rapidly absorbed and is cleared by hepatic metab-

olism. At recommended doses it produces approximately

80–90% inhibition of central COMT.

Drug interactions

Apomorphine is metabolized by O-methylation, so inter-

action with COMT inhibitors is to be anticipated. COMT

inhibitors should not be administered with MAOIs, as block-

ade of both pathways of monoamine metabolism simultane-

ously has the potential to enhance the effects of endogen-

ous and exogenous amines and other drugs unpredictably.

MONOAMINE OXIDASE INHIBITORS – TYPE B

SELEGILINE AND RASAGILINE

Use

Initial small controlled studies in Parkinson’s disease reported

that disease progression was slowed in patients treated with

selegiline alone, delaying the need to start levodopa. Larger-

scale studies have not confirmed this conclusion. MAO type B

inhibitors, such as selegiline and rasagiline, may be used in

conjunction with levodopato reduce end-of-dose deterioration.

Mechanism of action

There are two forms of monoamine oxidase (MAO), namely

type A (substrates include 5-hydroxytryptamine and tyram-

ine) and type B (substrates include phenylethylamine). MAO-B,

is mainly localized in neuroglia. MAO-Ametabolizes endoge-

nous adrenaline, noradrenaline and 5-hydroxytryptamine,

while the physiological role of MAO-B is unclear. Both isoen-

zymes metabolize dopamine. Inhibition of MAO-B raises

brain dopamine levels without affecting other major transmit-

ter amines. Because selegiline and rasagiline selectively

inhibit MAO-B, they are much less likely to produce a hyper-

tensive reaction with cheese or other sources of tyramine than

non-selective MAOIs, such as phenelzine.

Adverse effects

Selegiline is generally well tolerated, but side effects include

the following:

• agitation and involuntary movements;

• confusion, insomnia and hallucinations;

• nausea, dry mouth, vertigo;

• peptic ulceration.

Pharmacokinetics

Oralselegiline is well absorbed (100%), but is extensively metab-

olized by the liver, first to an active metabolite, desmethylselegi-

line (which also inhibits MAO-B) and then to amphetamine and

metamphetamine. Its plasma t

1/2

is long (approximately 39h).

Drug interactions

At very high doses (six times the therapeutic dose), MAO-B

selectivity is lost and pressor responses to tyramine are

128 MOVEMENT DISORDERS AND DEGEN ERATIVEC NS DISEASE

Adverse effects

These include the following:

• dry mouth, blurred vision, constipation;

• precipitation of glaucoma or urinary retention – they are

therefore contraindicated in narrow angle glaucoma and

in men with prostatic hypertrophy;

• cognitive impairment, confusion, excitement or psychosis,

especially in the elderly.

Pharmacokinetics

Table 21.1 lists some drugs of this type that are in common

use, together with their major pharmacokinetic properties.

SPASTICITY

Spasticity is an increase in muscle tone, for example, due to

damage to upper motor neurone pathways following stroke or

in demyelinating disease. It can be painful and disabling.

Treatment is seldom very effective. Physiotherapy, limited sur-

gical release procedures or local injection of botulinum toxin

(see below) all have a role to play. Drugs that reduce spasticity

include diazepam, baclofen, tizanidine and dantrolene, but

they have considerable limitations.

Diazepam (see Chapter 18, Hypnotics and anxiolytics)

facili-tatesγ-aminobutyric acid (GABA) action. Although spas-

ticity and flexor spasms may be diminished, sedating doses are

often needed to produce this effect.

Baclofen facilitates GABA-B receptors and also reduces

spasticity. Less sedation is produced than by equi-effective

doses of diazepam, but baclofencan cause vertigo, nausea and

hypotension. Abrupt withdrawal may precipitate hyperactiv-

ity, convulsions and autonomic dysfunction. There is specialist

interest in chronic administration of low doses of baclofen

intrathecally via implanted intrathecal cannulae in selected

patients in order to maximize efficacy without causing side

effects.

Dantrolene (a ryanodine receptor antagonist) is generally

less useful for symptoms of spasticity than baclofen because

muscle power is reduced as spasticity is relieved. It is used

intravenously to treat malignant hyperthermia and the neu-

roleptic malignant syndrome, for both of which it is uniquely

effective (see Chapter 24). Its adverse effects include:

• drowsiness, vertigo, malaise, weakness and fatigue;

• diarrhoea;

• increased serum potassium levels.

potentiated. Hypertensive reactions to tyramine-containing

products (e.g. cheese or yeast extract) have been described,

but are rare. Amantadine and centrally active antimuscarinic

agents potenti-ate the anti-parkinsonian effects of selegiline.

Levodopa-induced postural hypotension may be potentiated.

DRUGS AFFECTING THE CHOLINERGIC SYSTEM

MUSCARINIC RECEPTOR ANTAGONISTS

Use

Muscarinic antagonists (e.g. trihexyphenidyl, benzatropine,

orphenadrine, procyclidine) are effective in the treatment of

parkinsonian tremor and – to a lesser extent – rigidity, but pro-

duce only a slight improvement in bradykinesia. They are

usually given in divided doses, which are increased every two

to five days until optimum benefit is achieved or until adverse

effects occur. Their main use is in patients with parkinsonism

caused by antipsychotic agents.

Mechanism of action

Non-selective muscarinic receptor antagonism is believed to

restore, in part, the balance between dopaminergic/cholinergic

pathways in the striatum.

Table 21.1: Common muscarinic receptor ant agonists, dosing and pharmacokinetics

Drug Route of Half-life (hours) Metabolism and Special features

administration excretion

Trihexyphenidyl Oral 3–7 Hepatic

Orphenadrine Oral 13.7–16.1 Hepatic-active Central

metabolite stimulation

Procyclidine Oral 12.6 Hepatic

Key points

Treatment of Parkinson’s disease

• A combination of levodopa and a dopa-decarboxylase

inhibitor (carbidopa or benserazide) or a dopamine

agonist (e.g. ropinirole) are standard first-line therapies.

• Dopamine agonists and COMT inhibitors (e.g.

entacapone) are helpful as adjuvant drugs for patients

with loss of effect at the end of the dose interval, and

to reduce ‘on–off’ motor fluctuations.

• The benefit of early treatment with an MAO-B

inhibitor

, selegiline, to retard disease progression is

unproven, and it may even increase mortality.

• Polypharmacy is almost inevitable in patients with

longstanding disease.

• Ultimately

, disease progression requires increasing drug

doses with a regrettable but inevitable increased

incidence of side effects, especially involuntary

movements and psychosis.

• Anticholinergic drugs reduce tremor, but dose-limiting

CNS side ef

fects are common, especially in the elderly.

These drugs are first-line treatment for parkinsonism

caused by indicated (essential) antipsychotic drugs.

cervical dystonia (torticollis), jaw-closing oromandibular dysto-

nia and adductor laryngeal dysphonia. Botulinum A toxin is

given by local injection into affected muscles, the injection site

being best localized by electromyography. Recently, it has also

proved successful in the treatment of achalasia. Injection of

botulinum A toxin into a muscle weakens it by irreversibly

blocking the release of acetylcholine at the neuromuscular junc-

tion. Muscles injected with botulinum A toxin atrophy and

become weak over a period of 2–20 days and recover over two

to four months as new axon terminals sprout and restore trans-

mission. Repeated injections can then be given. The best long-

term treatment plan has not yet been established. Symptoms

are seldom abolished and adjuvant conventional therapy

should be given. Adverse effects due to toxin spread causing

weakness of nearby muscles and local autonomic dysfunction

can occur. In the neck, this may cause dysphagia and aspiration

into the lungs. Electromyography has detected evidence of

systemic spread of the toxin, but generalized weakness does

not occur with standard doses. Occasionally, a flu-like reaction

with brachial neuritis has been reported, suggesting an acute

immune response to the toxin. Neutralizing antibodies to botu-

linum toxin Acause loss of efficacy in up to 10% of patients.

Botulinum B toxin does not cross-react with neutralizing anti-

bodies to botulinum toxin A, and is effective in patients with

torticollis who have botulinum toxin A-neutralizing antibodies.

The most common use of botulinum is now cosmetic.

AMYOTROPHIC LATERAL SCLEROSIS (MOTOR

NEURONE DISEAS E)

Riluzole is used to extend life or time to mechanical ventila-

tion in patients with the amyotrophic lateral sclerosis (ALS)

form of motor neurone disease (MND). It acts by inhibiting

the presynaptic release of glutamate. Side effects include nau-

sea, vomiting, dizziness, vertigo, tachycardia, paraesthesia

and liver toxicity.

MYASTHENIA GRAVIS

PATHOPHYSIOLOGY

Myasthenia gravis is a syndrome of increased fatiguability and

weakness of striated muscle, and it results from an autoimmune

process with antibodies to nicotinic acetylcholine receptors.

These interact with postsynaptic nicotinic cholinoceptors at the

neuromuscular junction. (Such antibodies may be passively

transferred via purified immunoglobulin or across the placenta

to produce a myasthenic neonate.) Antibodies vary from one

patient to another, and are often directed against receptor-pro-

tein domains distinct from the acetylcholine-binding site.

Nonetheless, they interfere with neuromuscular transmission

by reducing available receptors, by increasing receptor turnover

by activating complement and/or cross-linking adjacent recep-

tors. Endplate potentials are reduced in amplitude, and in some

fibres may be below the threshold for initiating a muscle action

CHOREA

Theγ-aminobutyric acid content in the basal ganglia is reduced

in patients with Huntington’s disease. Dopamine receptor

antagonists (e.g. haloperidol) or tetrabenazine suppress the

choreiform movements in these patients, but dopamine antag-

onists are best avoided, as they themselves may induce dyski-

nesias.Tetrabenazineis therefore preferred. It depletes neuronal

terminals of dopamine and serotonin. It can cause severe dose-

related depression. Diazepammay be a useful alternative, but

there is no effective treatment for the dementia and other mani-

festations of Huntington’s disease.

DRUG-INDUCED DYSKINESIAS

• The most common drug-induced movement disorders are

‘extrapyramidal symptoms’ related to dopamine receptor

blockade.

• The most frequently implicated drugs are the

‘conventional’ antipsychotics (e.g. haloperidoland

fluphenazine).Metoclopramide, an anti-emetic, also

blocks dopamine receptors and causes dystonias.

• Acute dystonias can be effectively treated with parenteral

benzodiazepine (e.g. diazepam) or anticholinergic (e.g.

procyclidine).

• Tardive dyskinesia may be permanent.

• Extrapyramidal symptoms are less common with the newer

‘atypical’ antipsychotics (e.g. olanzapineor aripiprazole).

NON-DOPAMINE-RELATED MOVEMENT

DISORDERS

• ‘Cerebellar’ ataxia – ethanol, phenytoin

• Tremor

• β-Adrenoceptor agonists, e.g. salbutamol;

• caffeine;

• thyroxine;

• SSRls, e.g. fluoxetine;

• valproate;

• withdrawal of alcohol and benzodiazepines.

• vestibular toxicity – aminoglycosides;

• myasthenia – aminoglycosides;

• proximal myopathy – ethanol, corticosteroids;

• myositis – lipid-lowering agents – statins, fibrates;

• tenosynovitis – fluoroquinolones.

TREATMENT OF OTHER MOVEMENT

DISORDERS

TICS AND IDIOPATHIC DYSTONIAS

Botulinum A toxin is one of seven distinct neurotoxins pro-

duced by Clostridium botulinum and it is a glycoprotein. It is

used by neurologists to treat hemifacial spasm, blepharospasm,

MYASTHENIA GRAVIS 129