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Clinical pharmacology 11th edition Edition Peter N
Bennett Digital Instant Download
Author(s): Peter N Bennett, Morris J Brown, Pankaj Sharma
ISBN(s): 9780808924319, 0808924311
Edition: 11th edition
File Details: PDF, 10.16 MB
Year: 2012
Language: english
Clinical pharmacology
And I will use regimens for the benefit of the ill in accordance with my ability and my judgement.
Hippocrates’ Oath

They used to have a more equitable contract in (ancient) Egypt: for the first three days, the doctor took on the patient at the patient’s risk
and peril: when the three days were up, the risks and perils were the doctor’s. But doctors are lucky: the sun shines on their successes and
the earth hides their failures.
Michael de Montaigne 1533–92

Nature is not only odder than we think, but it is odder than we can think.
JBS Haldane 1893–1964

Morals do not forbid making experiments on one’s neighbour or on one’s self . . . among the experiments that may be tried on man,
those that can only harm are forbidden, those that are innocent are permissible, and those that may do good are obligatory.

Men who have excessive faith in their theories or ideas are not only ill prepared for making discoveries; they make very poor observations . . .
they can see in [their] results only a confirmation of their theory . . . This is what made us say that we must never make experiments to confirm
our ideas, but simply to control them.
Medicine is destined to get away from empiricism little by little; like all other sciences, it will get away by the scientific method.

Considered in itself, the experimental method is nothing but reasoning by whose help we methodically submit our ideas to experience –
the experience of facts.
Claude Bernard 1865

I do not want two diseases – one nature-made, one doctor-made.

Napoleon Bonaparte 1820

The ingenuity of man has ever been fond of exerting itself to varied forms and combinations of medicines.
William Withering 1785

All things are poisons and there is nothing that is harmless, the dose alone decides that something is no poison.
Paracelsus 1493–1541

Commissioning Editor: Jeremy Bowes

Development Editor: Fiona Conn
Project Manager: Andrew Riley
Designer/Design Direction: Russell Purdy
Illustration Manager: Jennifer Rose
Illustrator: Antbits Ltd.
Clinical
pharmacology
11th edition

Peter N Bennett MD FRCP

Formerly Reader in Clinical Pharmacology, University of Bath, and Consultant Physician,
Royal United Hospital, Bath, UK

Morris J Brown MA MSc FRCP FAHA FMedSci

Professor of Clinical Pharmacology, University of Cambridge; Consultant Physician,
Cambridge University Hospitals NHS Foundation Trust, Cambridge; and Director of Clinical Studies,
Gonville and Caius College, University of Cambridge, Cambridge, UK

Pankaj Sharma MD PhD FRCP

Reader in Clinical Neurology at Imperial College London; Consultant Neurologist
at Hammersmith Hospitals, London, UK

Edinburgh London New York Oxford Philadelphia St Louis Sydney Toronto 2012
# 2012 Dr P N Bennett, Professor Morris J Brown and Dr Pankaj Sharma.
Published by Elsevier Ltd. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
permission in writing from the publisher. Details on how to seek permission, further information about
the Publisher’s permissions policies and our arrangements with organizations such as the Copyright
Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/
permissions.
This book and the individual contributions contained in it are protected under copyright by the
Publisher (other than as may be noted herein).
First edition 1960
Second edition 1962
Third edition 1966
Fourth edition 1973
Fifth edition 1980
Sixth edition 1987
Seventh edition 1992
Eighth edition 1997
Ninth edition 2003
Tenth edition 2008
ISBN 978-0-7020-4084-9
International ISBN 978-0-8089-2431-9
British Library Cataloguing in Publication Data
A catalogue record for this book is available from the British Library
Library of Congress Cataloging in Publication Data
A catalog record for this book is available from the Library of Congress

Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden
our understanding, changes in research methods, professional practices, or medical treatment may become
necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating
and using any information, methods, compounds, or experiments described herein. In using such
information or methods they should be mindful of their own safety and the safety of others, including
parties for whom they have a professional responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most
current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be
administered, to verify the recommended dose or formula, the method and duration of administration,
and contraindications. It is the responsibility of practitioners, relying on their own experience and
knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each
individual patient, and to take all appropriate safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume
any liability for any injury and/or damage to persons or property as a matter of products liability,
negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas
contained in the material herein.

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paper manufactured
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Printed in China
 Contributors

Mark Abrahams MB ChB DA FRCA FFPMRCA Chrysothemis Brown MBBS BA

Lead Clinician, Department of Pain Medicine, Cambridge NIHR Academic Clinical Fellow, Imperial College London, UK
University Hospitals NHS Foundation Trust, Cambridge, UK Chapter 39 Vitamins, calcium, bone
Chapter 18 Pain and analgesics

Graeme Alexander MA MD FRCP Diana C Brown MD MSc FRCP

Consultant Hepatologist, Division of Gastroenterology and Consultant Endocrinologist, Cromwell Hospital, London, UK
Hepatology, Department of Medicine, Cambridge University Chapter 35 Adrenal corticosteroids, antagonists, corticotrophin,
Hospitals NHS Foundation Trust, Cambridge UK Chapter 37 Thyroid hormones, antithyroid drugs
Chapter 34 Liver and biliary tract

Sani H Aliyu MBBS FRCP FRCPath Simon Davies DM, MBBS, MRCPsych MSc DipEpidemiol
Consultant in Microbiology and Infectious Diseases, Cambridge Clinical Lecturer in Psychiatry, University of Bristol, Bristol, UK
University Hospitals NHS Foundation Trust, Cambridge, UK Chapter 20 Psychotropic drugs
Chapter 15 Viral, fungal, protozoal and helminthic infections
Wendy N Erber MD DPhil FRCPath FRCPA
John Louis-Auguste BA MB ChB MRCP Professor of Pathology and Laboratory Medicine University
Specialist Registrar in Gastroenterology, Charing Cross Hospital, of Western Australia Western Australia 6009 Australia
London, UK Chapter 30 Red blood cell disorders
Chapter 32 Oesophagus, stomach and duodenum, Chapter 33
Intestines
Mark Evans MD FRCP
University Lecturer, University of Cambridge; Consultant
Trevor Baglin MA MB Ch B PhD FRCP FRCPath
Physician, Cambridge University Hospitals Foundation Trust,
Consultant Haematologist, Cambridge University Hospitals NHS
Cambridge, UK
Foundation Trust, Cambridge University Teaching Hospitals NHS
Chapter 36 Diabetes mellitus, insulin, oral antidiabetes agents,
Trust, Cambridge, UK
obesity
Chapter 29 Drugs and haemostasis
Mark Farrington MA MB BChir FRCPath
Devinder Singh Bansi BM DM FRCP Consultant Medical Microbiologist, Health Protection Agency,
Consultant Gastroenterologist, Imperial College Healthcare NHS Cambridge University Hospitals NHS Foundation Trust,
Trust, London, UK Cambridge, UK
Chapter 32 Oesophagus, stomach and duodenum, Chapter 33
Chapter 12 Chemotherapy of infections, Chapter 13
Intestines Antibacterial drugs, Chapter 14 Chemotherapy of bacterial
infections
Paul Bentley MA, MRCP, PhD
Clinical Senior Lecturer and Honorary Consultant in Neurology Andrew Grace PhD FRCP FACC
and Stroke Medicine, Charing Cross Hospital, London, UK Research Group Head, University of Cambridge; Consultant
Chapter 21 Neurological disorders - epilepsy, Parkinson’s disease Cardiologist, Papworth Hospital, Cambridge, UK
and multiple sclerosis Chapter 25 Cardiac arrhythmia

Blanca Bolea-Alamanac MD Thomas K K Ha MD FRACP FRCP

Consultant Psychiatrist and Honorary Lecturer, University of Consultant Dermatologist, Cambridge University Hospitals NHS
Bristol, Bristol, UK Foundation Trust, Cambridge, UK
Chapter 20 Psychotropic drugs Chapter 17 Drugs and the skin

vii
 Contributors

Stephen Haydock PhD FRCP June Raine

Consultant Physician, Musgrove Park Hospital, Taunton, UK Chapter 4 Evaluation of drugs in humans, Chapter 6 Official
Chapter 10 Poisoning, overdose, antidotes, Chapter 11 Drug regulation of medicines
dependence
Sir Michael Rawlins MD FRCP FMedSci
Michael C Lee MBBS FRCA PhD FFPMRCA Chairman, National Institute for Clinical Excellence (NICE),
Consultant, Churchill Hospital, Oxford, UK London, UK
Chapter 18 Pain and analgesics Chapter 5 Health technology assessment

Justin C Mason PhD FRCP Sir Peter C Rubin MA DM FRCP

Professor of Vascular Rheumatology, Imperial College London, Professor of Therapeutics, University of Nottingham, UK; Chair,
General Medical Council, UK
UK
Chapter 16 Drugs for inflammation and joint disease Chapter 2 Topics in drug therapy: Practical prescribing

Mike Schachter MB BSc FRCP

Karim Meeran MD FRCP FRCPath Senior Lecturer in Clinical Pharmacology, Imperial College,
Professor of Endocrinology, Faculty of Medicine, Imperial London, UK
College London, UK Chapter 1 Clinical pharmacology, Chapter 2 Topics in drug
Chapter 38 Hypothalamic, pituitary and sex hormones therapy, Chapter 8 General pharmacology, Chapter 9 Unwanted
effects and adverse drug reactions
Jerry P Nolan FRCA FCEM FRCP FFICM
Consultant in Anaesthesia & Intensive Care Medicine, Royal Surender K Sharma MD PhD
United Hospital, Bath, UK Chief, Division of Pulmonary, Critical Care and Sleep Medicine;
Chapter 19 Anaesthesia and neuromuscular block Head, Department of Medicine; All India Institute of Medical
Sciences, New Delhi, India
Chapter 14 Chemotherapy of bacterial infections
David Nutt, DM FRCP FRCPsych FMedSci
The Edmond J Safra Chair in Neuropsychopharmacology,
Imperial College London, UK Clare Thornton MA MRCP
Chapter 20 Psychotropic drugs Wellcome Trust Clinical Research Fellow, Imperial College
London, UK
Chapter 16 Drugs for inflammation and joint disease
Kevin M O’Shaughnessy MA BM BCh DPhil FRCP
Senior Lecturer in Clinical Pharmacology, University of
Cambridge, UK Patrick Vallance
Chapter 22 Cholinergic and antimuscarinic (anticholinergic) President, Pharmaceuticals R&D GlaxoSmithKline, Brentford UK
mechanisms and drugs, Chapter 23 Adrenergic mechanisms and Chapter 3 Discovery and development of drugs
drugs, Chapter 24 Arterial hypertension, angina pectoris,
Harpreet Wasan MBBS FRCP
myocardial infarction and heart failure, Chapter 26
Consultant & Reader in Medical Oncology, Hammersmith
Hyperlipidaemias, Chapter 27 Kidney and genitourinary tract,
Hospital, Imperial College Healthcare NHS trust, London, UK
Chapter 28 Respiratory system
Chapter 31 Neoplastic disease and immunosuppression

Munir Pirmohamed MB CHB PhD FRCP Sue Wilson PhD

NHS Chair of Pharmacogenetics, University of Liverpool, UK Research Fellow, University of Bristol, UK
Chapter 8 General pharmacology; Pharmacogenomics Chapter 20 Psychotropic drugs

viii
 Preface

For your own satisfaction and for mine, please read this preface!1
A preface should tell the prospective reader about the subject of a book, its purpose, and its plan.
This book is about the scientific basis and practice of drug therapy. It addresses medical students and
doctors in particular, but also anyone concerned with evidence-based drug therapy and prescribing.
The scope and rate of drug innovation increase. Doctors now face a professional lifetime of hand-
ling drugs that are new to themselves – drugs that do new things as well as drugs that do old things
better; and drugs that were familiar during medical training become redundant.
We write not only for readers who, like us, have a special interest in pharmacology. We try to make
pharmacology understandable for those whose primary interests lie elsewhere but who recognise that
they need some knowledge of pharmacology if they are to meet their moral and legal ‘duty of care’
to their patients. We are aware too, of medical curricular pressures that would reduce the time devoted
to teaching clinical pharmacology and therapeutics, and such diminution is surely a misguided policy
for a subject that is so integral to the successful practice of medicine. Thus, we try to tell readers what
they need to know without burdening them with irrelevant information, and we try to make the sub-
ject interesting. We are very serious, but seriousness does not always demand wearying solemnity.
All who prescribe drugs would be wise to keep in mind the changing and ever more exacting ex-
pectations of patients and of society in general. Doctors who prescribe casually or ignorantly now face
not only increasing criticism but also civil (or even criminal) legal charges. The ability to handle new
developments depends, now more than ever, on comprehension of the principles of pharmacology.
These principles are not difficult to grasp and are not so many as to defeat even the busiest doctors
who take upon themselves the responsibility of introducing manufactured medicines into the bodies
of their patients.
The principles of pharmacology and drug therapy appear in Chapters 1–11 and their application in
the subsequent specialist chapters where we draw on the knowledge and authority of a range of ex-
perts in these fields. The current edition includes new contributions from Sir Michael Rawlins,
Sir Peter Rubin, Professor Munir Pirmohamed and Professor Patrick Vallance. We seek to offer a rea-
sonably brief solution to the problem of combining practical clinical utility with an account of the
principles on which clinical practice rests.
The quantity of practical technical detail to include is a matter of judgment. In general, where ther-
apeutic practices are complex, potentially dangerous, and commonly updated, e.g. anaphylactic
shock, we provide more detail, together with websites for the latest advice; we give less or even no
detail on therapy that specialists undertake, e.g. anticancer drugs. Nevertheless, especially with mod-
ern drugs that are unfamiliar, the prescriber should consult formularies, approved guidelines, or the
manufacturer’s current literature.
Use of the book. Francis Bacon2 wrote that ‘Some books are to be tasted, others to be swallowed,
and some few to be chewed and digested.’ Perhaps elements of each activity can apply to parts of our
text. Students and doctors are, or should be, concerned to understand and to develop a rational,

1
St Francis of Sales: Preface to Introduction to the devout life (1609).
2
Francis Bacon (1561–1626) Essays (1625) ‘Of studies’. Philosopher and scientist, Bacon introduced the idea of the
experimental or inductive method of reasoning for understanding nature.

ix
 Preface

critical attitude to drug therapy and they should therefore chiefly address issues of how drugs act and
interact in disease and how evidence of therapeutic effect is obtained and evaluated.
To this end, they should read selectively and should not impede themselves by attempts to mem-
orise lists of alternative drugs and doses and minor differences between them, which should never be
required of them in examinations. Thus, we do not encumber the text with exhaustive lists of prep-
arations, which properly belong in a formulary, although we hope that enough has been mentioned
to cover much routine prescribing, and many drugs have been included solely for identification.
The role and status of a textbook. A useful guide to drug use must offer clear conclusions and
advice. If it is to be of reasonable size, it may often omit alternative acceptable courses of action. What
it recommends should rest on sound evidence, where this exists, and on an assessment of the opin-
ions of the experienced where it does not.
Increasingly, guidelines produced by specialist societies and national bodies have influenced the
selection of drugs. We provide or refer to these as representing a consensus of best practice in partic-
ular situations. Similarly, we assume that the reader possesses a formulary, local or national, that will
provide guidance on the availability, including doses, of a broad range of drugs. Yet the practice of
medicinal therapeutics by properly educated and conscientious doctors working in settings compli-
cated by intercurrent disease, metabolic differences or personality, involves challenges beyond the
rigid adherence to published recommendations. The role of a textbook is to provide the satisfaction
of understanding the basis for a recommended course of action and to achieve an optimal result by
informed selection and use of drugs. As the current edition of the book, initiated and for years main-
tained by Desmond Laurence, now crosses the landmark of 50 years in print, we can but reassert our
belief in this principle.

Bath, Cambridge, London. P.N.B., M.J.B., P.S. 2012

x
Acknowledgements

It is not possible for three individuals to cover the whole field of drug therapy from their own knowl-
edge and experience. As with previous editions, we invited selected experts to review chapters in their
specialty. They received free rein to add, amend or delete existing text, as they deemed appropriate. We
consider that the book has benefited greatly from the proficiency of these individuals; their names
appear in the list of Contributors alongside their chapters.
Additionally, we express our gratitude to others who have, with such good grace, given us of their
time and energy to supply valuable facts and opinions for this and previous editions; they principally
include: Professor Nigel S Baber, Dr Gerald S Conway, Dr Pippa G Corrie, Dr Francis Hall, Dr Ian
Hudson, the late Professor BNC Pritchard, Dr JPD Reckless, Dr Catriona Reid, Dr Charles Singer.
Much of any merit this book may have is due to the generosity of those referred to above, as well as
others too numerous to mention who have put their knowledge and practical experience of the use of
drugs at our disposal. We hope that this collective acknowledgement will be acceptable. Errors are our
own. We are grateful to readers who alert us to errors and make other suggestions for future editions.
In addition, we thank the authors and publishers who generously granted permission to quote
directly from their writings. If we have omitted any due acknowledgements, we will make amends
as soon as we can.

P.N.B
M.J.B.
P.S.

xi
 Chapter |1|
Clinical pharmacology
Mike Schachter

But during the intervals remaining, an average family

SYNOPSIS
experiences illness on 1 day in 4 and between the ages
Clinical pharmacology comprises all aspects of the scien- of 20 and 45 years a lower-middle-class man experiences
tific study of drugs in humans. Its objective is to optimise approximately one life-endangering illness, 20 disabling
drug therapy and it is justified in so far as it is put to (temporarily) illnesses, 200 non-disabling illnesses and
practical use. 1000 symptomatic episodes: the average person in the
The use of drugs1 to increase human happiness by elim- USA can expect to have about 12 years of bad health in
ination or suppression of diseases and symptoms and to an average lifespan,3 and medicines play a major role:
improve the quality of life in other ways is a serious matter ‘At any time, 40–50% of adults [UK] are taking a prescribed
and involves not only technical, but also psychosocial con- medicine.’4
siderations. Overall, the major benefits of modern drugs Over the centuries humans have sought relief from dis-
are on quality of life (measured with difficulty), and exceed comfort in ‘remedies’ concocted from parts of plants, an-
those on quantity of life (measured with ease).2 In some sit- imals and other sources; numerous formularies attest to
uations we can attempt both objectives. their numbers and complexity. Gradually, a more critical
Medicines are part of our way of life from birth, when we view emerged, recognising the need for proper investiga-
may enter the world with the aid of drugs, to death, where tion of medications. In 1690, John Locke5 was moved
drugs assist (most of) us to depart with minimal distress to write, ‘we should be able to tell beforehand that rhu-
and perhaps even with a remnant of dignity. In between barb will purge, hemlock kill, and opium make a man
these events we regulate our fertility, often, with drugs. sleep . . .’.
We tend to take such usages for granted. Yet it was only in the early years of the 20th century that
we began to see the use of specific chemical substances to
1
achieve particular biological effects; that is, the exact sci-
A World Health Organization scientific group has defined a drug as ‘any
substance or product that is used or intended to be used to modify or ence of drug action, which is pharmacology. Subsequently
explore physiological systems or pathological states for the benefit of the discipline underwent a major expansion resulting from
the recipient’ (WHO 1966 Technical Report Series no. 341:7). A less technology that allowed the understanding of molecular
restrictive definition is ‘a substance that changes a biological system by
interacting with it’. (Laurence DR, Carpenter J 1998 A dictionary of
action and the capacity to exploit this. The potential
pharmacology and allied topics. Elsevier, Amsterdam, p 106)
A drug is a single chemical substance that forms the active ingredient 3
of a medicine (a substance or mixture of substances used in restoring or Quoted in: USA Public Health Service 1995.
4
preserving health). A medicine may contain many other substances to George C F 1994 Prescribers’ Journal 34:7. A moment’s reflection will
deliver the drug in a stable form, acceptable and convenient to the bring home to us that this is an astounding statistic which goes a long
patient. The terms will be used more or less interchangeably in this way to account for the aggressive promotional activities of the highly
book. To use the word ‘drug’ intending only a harmful, dangerous or competitive international pharmaceutical industry; the markets for
addictive substance is to abuse a respectable and useful word. medicines are colossal.
2 5
Consider, for example, the worldwide total of suffering relieved and Locke J 1690 An Essay Concerning Human Understanding. Clarendon
prevented each day by anaesthetics (local and general) and by Press, Oxford, book iv, chapter iii, p. 556. The English philosopher John
analgesics, not forgetting dentistry which, because of these drugs, no Locke (1632–1704) argued that all human knowledge came only from
longer strikes terror into even the most stoical as it has done for centuries. experience and sensations.

2
 Clinical pharmacology Chapter |1|

consequences for drug therapy are enormous. All cellular 1930s showed the qualities needed to be a clinical pharma-
mechanisms (normal and pathological), in their immense cologist. In 1952, he wrote in a seminal article:
complexity, are, in principle, identifiable. What seems al-
most an infinite number of substances, transmitters, local a special kind of investigator is required, one whose
hormones, cell growth factors, can be made, modified training has equipped him not only with the principles
and tested to provide agonists, partial agonists, inverse and technics of laboratory pharmacology but also with
agonists and antagonists. Moreover, the unravelling of knowledge of clinical medicine . . .
the human genome opens the way for interference with Clinical scientists of all kinds do not differ
disease processes in ways that were never thought possible fundamentally from other biologists; they are set apart
before now. only to the extent that there are special difficulties and
Increasingly large numbers of substances will deserve to limitations, ethical and practical, in seeking knowledge
be investigated and used for altering physiology to the ad- from man.9
vantage of humans. With all these developments, and
their potential for good, comes capacity for harm, whether Willingness to learn the principles of pharmacology,
inherent in the substances themselves or resulting from and how to apply them in individual circumstances of in-
human misapplication. Successful use of the power con- finite variety is vital to success without harm: to maximise
ferred (by biotechnology in particular) requires under- benefit and minimise risk. All of these issues are the
standing of the growing evidence base of the true concern of clinical pharmacology and are the subject of
consequences of interference. The temporary celebrity of this book.
new drugs is not a new phenomenon. Jean Nicholas More detailed aspects comprise:
Corvisart6 (1755–1821) reputedly expressed the issue in
1. Pharmacology
the dictum: ‘Here is a new remedy; take it fast, as long
• Pharmacodynamics: how drugs, alone and in
as it still works’.
combination, affect the body (young, old, well,
sick).
• Pharmacokinetics: absorption, distribution,
Clinical pharmacology provides the scientific
metabolism, excretion or how the body – well or
basis for:
sick – affects drugs.
• the general aspects of rational, safe and effective 2. Therapeutic evaluation
drug therapy
• Whether a drug is of value.
• drug therapy of individual diseases
• How it may best be used.
• the safe introduction of new medicines. • Formal therapeutic trials.
• Surveillance studies for both efficacy and safety
(adverse effects) – pharmacoepidemiology and
The drug and information explosion of the past six de- pharmacovigilance.
cades, combined with medical need, has called into being 3. Control
a new discipline, clinical pharmacology.7 The discipline • Rational prescribing and formularies.
finds recognition as both a health-care and an academic • Official regulation of medicines.
specialty; indeed, no medical school can be considered • Social aspects of the use and misuse of medicines.
complete without a department or sub-department of clin- • Pharmacoeconomics.
ical pharmacology. Clinical pharmacology finds expression in concert with
A signal pioneer was Harry Gold8 (1899–1972), of other clinical specialties. Therapeutic success with drugs
Cornell University, USA, whose influential studies in the is becoming more and more dependent on the user having
at least an outline understanding of both pharmacodynam-
6
He was Emperor Napoleon’s favourite physician. ics and pharmacokinetics. This outline is quite simple and
7
The term was first used by Paul Martini (1889–1964). He addressed easy to acquire. However humane and caring doctors may
issues that are now integral parts of clinical trials, including the use of
placebo, control groups, sample size, relationship between dose and
response, probability of efficacy. His monograph Methodology of 9
Self-experimentation has always been a feature of clinical
Therapeutic Investigation (Springer, Berlin, 1932), was published in pharmacology. A survey of 250 members of the Dutch Society of
German and went largely unnoticed by English speakers. (Shelly J H, Clinical Pharmacology evoked 102 responders of whom 55 had carried
Baur M P 1999 Paul Martini: the first clinical pharmacologist? Lancet out experiments on themselves (largely for convenience) (van
353:1870–1873). Everdingen J J, Cohen A F 1990 Self-experimentation by doctors.
8
Gold H 1952 The proper study of mankind is man. American Journal of Lancet 336:1448). A spectacular example occurred at the 1983
Medicine 12:619. The title is taken from An Essay on Man by Alexander meeting of the American Urological Association at Las Vegas, USA,
Pope (English poet, 1688–1744), which begins with the lines: ‘Know then during a lecture on pharmacologically induced penile erection, when
thyself, presume not God to scan,/The proper study of mankind is man’. the lecturer stepped out from behind the lectern to demonstrate
Indeed, the whole passage is worth appraisal, for it reads as if it were personally the efficacy of the technique (Zorgniotti A W 1990 Self-
relevant to modern clinical pharmacology and drug therapy. experimentation. Lancet 36:1200).

3
Section | 1 | General

be, they cannot dispense with scientific skill. Knowledge of only scientists, but now the whole community, can see
clinical pharmacology underpins decisions in therapeutics, its promise of release from distress and premature death
which is concerned with the prevention, suppression or over yet wider fields. The concomitant dangers of drugs (fe-
cure of disease and, from the point of view of society, is tal deformities, adverse reactions, dependence) only add to
the most vital aspect of medicine. the need for the systematic and ethical application of sci-
Pharmacology is the same science whether it investigates ence to drug development, evaluation and use, i.e. clinical
animals or humans. The need for it grows rapidly as not pharmacology.

GUIDE TO FURTHER READING

Baber, N.S., Ritter, J.M., Aronson, J.K., or rebrand and expand? Clin. Reidenberg, M.M., 2008. A new look
2004. Medicines regulation and Pharmacol. Ther. 81 (1), 19–20. at the profession of clinical
clinical pharmacology. Br. J. Clin. Honig, P., 2007. The value and future of pharmacology. Clin. Pharmacol. Ther
Pharmacol. 58 (6), 569–570 (and clinical pharmacology. Clin. 83 (2), 213–217 (and other articles in
other articles in this issue). Pharmacol. Ther. 81 (1), 17–18. this issue).
Dollery, C.T., 2006. Clinical Laurence, D.R., 1989. Ethics and law in Waldman, S.A., Christensen, N.B.,
pharmacology – the first 75 years and a clinical pharmacology. Br. J. Clin. Moore, J.E., Terzic, A., 2007. Clinical
view of the future. Br. J. Clin. Pharmacol. 27, 715–722. pharmacology: the science of
Pharmacol. 61, 650–665. Rawlins, M.D., 2005. Pharmacopolitics therapeutics. Clin. Pharmacol. Ther.
FitzGerald, G.A., 2007. Clinical and deliberative democracy. Clin. 81 (1), 3–6.
pharmacology or translational Med. (Northfield Il) 5, 471–475.
medicine and therapeutics: reinvent

4
 Chapter |2|
Topics in drug therapy
Mike Schachter, Sir Peter Rubin

SYNOPSIS • Benefits and risks.

• Public view of drugs and prescribers.
Drug therapy involves considerations beyond the strictly • Criticisms of modern drugs.
scientific pharmacological aspects of medicines. These in-
• Drug-induced injury.
clude numerous issues relating to prescribers and to
patients: • Complementary and alternative medicine.

• Practical prescribing. • Placebo medicines.

• The therapeutic situation. • Guidelines, ‘essential’ drugs and prescribing.

• Treating patients with drugs. • Compliance – patient and doctor.

• Iatrogenic disease. • Pharmacoeconomics.

5
Section | 1 | General

Practical prescribing

Sir Peter Rubin

First, on this topic, Professor Sir Peter Rubin, Chair of the guess. Never be afraid to ask. Never be too busy to look
General Medical Council, the body that regulates the practice up a dose – better to check now than make a trip to the
of medicine by doctors in the UK, writes on the prescribing of Coroner’s Court later.
medicines. • Explaining to your patient why you think this treatment
will work, the likelihood of it working, the more common
Prescribing is a task carried out many times each day and
side-effects and what your plans are if it does not work.
can seem mundane – a technical process that is far less stim-
ulating and interesting than reaching a diagnosis. However,
• Being alert to the development of adverse drug
reactions. If a patient develops new symptoms after
there is no such thing as a safe drug and prescribing has the
starting a drug, it is probably the drug. If the adverse
potential to cause harm or death as well as good. This section
effect is in a fairly new drug – or is not already well
includes some practical advice aimed at identifying common
known – you should report the event to the national
pitfalls and reducing risk.
body responsible for monitoring and recording adverse
The case histories are all real. The data given in the text drug reactions.
and figures come from a study commissioned by the • Being very clear about what it is you are prescribing.
General Medical Council.1 • If using a hand-written prescription, write clearly.
• If working in a different hospital, remember that the
prescription chart may not be the same as where you
PRESCRIBING have just been.
• If using electronic prescribing, beware drop-down
Getting it right menus and drugs with similar looking names, e.g.
carbimazole and carbamazepine.
Good prescribing starts with taking a good history:
• Does your patient have other medical conditions –
some may be worsened by treatment you would Examples of when things went wrong
normally give for their presenting complaint.
Focusing on the presenting complaint and
• What drugs is your patient taking now? What are they
forgetting other medical conditions
for? Are they all still needed? Could they be causing the
symptoms or signs that have brought the patient to A 79-year-old man was admitted to a surgical ward. He told
you? Could they interact with whatever you might the admitting doctor that he had long-standing arthritis
think of prescribing? which had got worse since his doctor stopped diclofenac
• What drugs has your patient taken in the past? Why and he asked for it to be re-started. The doctor did so,
were they stopped? Did they cause side-effects? but did not notice the patient’s significant renal impair-
• Is the patient allergic to any drugs? ment. The patient went into renal failure and died. A drug
• Are they taking any non-prescription (over-the-counter) which helps one condition may worsen another!
drugs? If so, could they interact with whatever you might
prescribe (for example, St John’s wort is an enzyme- Forgetting that women get pregnant
inducer)?
A 40-year-old woman is found to be hypertensive. She has
Good prescribing means:
three children, the youngest being 15. Her GP commences
• Making a diagnosis – or at least having a range of ramipril. Neither the patient nor the doctor suspected that
possibilities. Know what it is you are wishing to achieve she was, in fact, in the second trimester of pregnancy. The
and the evidence for the likely efficacy of the drug baby died at birth from major renal and other abnormali-
treatment you wish to give. ties. Subsequent litigation was settled out of court in the pa-
• Knowing your patient’s kidney and liver function – tient’s favour. Remember that pregnancy is always a possibility
most drugs are eliminated by these organs; and some in women of child-bearing age!
drugs can damage them.
• Getting the dose right. For many drugs you will not
know the dose, so do not pretend you do. Never, ever Not knowing what you are prescribing
A 29-year-old woman came to the hospital with a urinary
1
http://www.gmc-uk.org/about/research/research_commissioned_4.asp tract infection. The consultant told a young doctor looking
(accessed 4 October 2011). after her to prescribe PenbritinW. She did so and the patient

6
 Topics in drug therapy Chapter |2|

died from penicillin anaphylaxis despite having a bracelet • Doing several things at once.
warning of the allergy. Neither the young doctor nor the • Communication breakdown.
nurse who administered the drug had bothered to find There are also factors specific to the medical environment,
out what they were giving, namely ampicillin. Know what including:
you are prescribing!
• Not familiar with the drug chart (usually on moving to
a new hospital).
Forgetting that a newly prescribed drug
• Unfamiliar patient – and not taking the time to become
can interact with long-term drug familiar with the full medical and drug history.
treatment • Arithmetical errors in calculating dose.
A 64-year-old man had been taking warfarin for many • Omitting drugs for a newly admitted patient because of
years. He developed a chest infection and an out of hours inadequate information.
doctor prescribed amoxicillin. Later that week he was ad- When lack of knowledge does play a part, it is often
mitted with a large, painful right knee haemarthrosis and the flawed application of knowledge in that particular
an INR >10 (see p. 489). New drugs may interact with those patient – i.e. the right drug for the presenting condition,
the patient has been taking for a long time! but the wrong drug for that patient because of coexisting
medical or drug factors.
What all this adds up to is: prescribing is important, must be
Top ten prescribing errors in a UK taken seriously and must be given the time and care that your
hospital setting1 patient deserves.
The General Medical Council expects that, by the time
they graduate, medical students will be able to:2

Error % of errors • Prescribe drugs safely, effectively and economically.

• Establish an accurate drug history, covering both
Omission on admission 29.8 prescribed and other medication.
Wrong dose 19.6 • Plan appropriate drug therapy for common
indications, including pain and distress.
No dose given 11.0 • Provide a safe and legal prescription.
Wrong/no formulation 7.5 • Calculate appropriate drug doses and record the
outcome accurately.
Omission on discharge 6.2 • Provide patients with appropriate information about
their medicines.
Wrong dosing intervals 6.1
• Access reliable information about medicines.
Duplication 5.5 • Detect and report adverse drug reactions.
Wrong drug 3.1
• Demonstrate awareness that many patients use
complementary and alternative therapies, and
No signature 1.7 awareness of the existence and range of these
therapies, why patients use them, and how this
Contraindication 1.1 might affect other types of treatment that patients
are receiving.

Why do mistakes happen?

Human error in one form or another – rather than a simple ‘The desire to take medicines is perhaps the greatest
lack of knowledge – is responsible for most prescribing feature that distinguishes man from animals’ (Sir
mistakes. Newly qualified doctors are no more likely than William Osler, 1849–1919).
their older colleagues to prescribe incorrectly. Many factors
associated with prescribing mistakes are common to mis-
takes in all walks of life and include the following:
• Rushing. 2
http://www.gmc-uk.org/education/undergraduate/tomorrows_
• Tired. doctors_2009.asp (accessed 4 October 2011).

7
Section | 1 | General

The therapeutic situation

Mike Schachter

Some background that if the whole materia medica, as now used, could be
sunk to the bottom of the sea, it would be all the better
Alleviating effects of disease and trauma has been a major for mankind, – and all the worse for the fishes. . .4
concern of human beings from the earliest times. Records
of the ancient civilisations of Mesopotamia (modern Iraq), The writer was exaggerating to emphasise his point, but
India, China, Mexico and Egypt, from about 3000 BC, the position was to change throughout the 20th century as
describe practices of diagnosis and treatment predicated understanding of human physiology and pathophysiology
on differing, often complex, concepts of disease: the super- deepened and agents that could be relied on to interfere
natural, religious theories (sin, punishment of sin, unclean- with these processes became available. Modern physicians
ness), omens, deities and rites. Among many modes of have at their disposal an array of medicines that empowers
therapy, a reliance on diet and use of herbs figured prom- them to intervene beneficially in disease but also carries
inently (the Mexicans knew of 1200 medicinal plants). new responsibilities.
From about 500 BC, the Greek system of humoural med-
icine began to replace the supernatural with thinking that
was rational, scientific and naturalistic. Its core concept Drug therapy involves a great deal more than matching
was that health was an equilibrium, and disease a disequi- the name of the drug to the name of a disease; it
librium, of the four constituent fluids or ‘humours’ of the requires knowledge, judgement, skill and wisdom, but
body (yellow bile, phlegm, blood and black bile). It fol- above all a sense of responsibility.
lowed that the condition was correctable by evacuation
techniques to re-establish the balance, and hence came
blooding, leeching, cathartics, sweating and emetics. Here,
the focus was on the patient, as the degree of humoural im- TREATING PATIENTS WITH DRUGS
balance was specific to that individual.
Remarkably, this system persisted among ‘learned and
rational’ (i.e. university-trained) physicians until it was A book can provide knowledge and contribute to the for-
challenged in the 17th century. Thomas Sydenham3 mation of judgement, but it can do little to impart skill
(1624–1689) showed that during epidemics, many people and wisdom, which are the products of example of teachers
could suffer the same disease, and different epidemics had and colleagues, of experience and of innate and acquired
distinct characteristics. Later, Giovanni Morgagni (1682– capacities. But: ‘It is evident that patients are not treated
1771), by correlating clinical and autopsy findings, demon- in a vacuum and that they respond to a variety of subtle
strated that diseases related to particular organs. Now the forces around them in addition to the specific therapeutic
study of disease, rather than the patient, became the centre agent.’5
of attention. Yet it was only in the 19th century that When a patient receives a drug, the response can be the
medicine developed as a science, when the microscope result of numerous factors:
revealed the cell as the basic construction unit of the body • The pharmacodynamic effect of the drug and
and specific entities of pathology became recognisable, interactions with any other drugs the patient may be
most notably in the case of infection with microorganisms taking.
(‘germ theory’). • The pharmacokinetics of the drug and its modification
The one major dimension of medicine that remained un- in the individual by genetic influences, disease, other
derdeveloped was therapeutics. An abundance of prepara- drugs.
tions in pharmacopoeias compared with a scarcity of • The act of medication, including the route of
genuinely effective therapies contributed to a state of ‘ther- administration and the presence or absence of the doctor.
apeutic nihilism’, expressed trenchantly by Oliver Wendell • What the doctor has told the patient.
Holmes (1809–1894): • The patient’s past experience of doctors.

Throw out opium . . . ; throw out a few specifics . . . ; 4

Medical Essays (1891). American physician and poet, and Dean of
throw out wine, which is a food, and the vapours which Harvard Medical School; he introduced the term anaesthesia instead of
produce the miracle of anaesthesia, and I firmly believe ‘suspended animation’ or ‘etherisation’. Address delivered before the
Massachusetts Medical Society, 30 May 1860 (Oliver Wendell Holmes,
Medical Essays. Kessinger Publishing, p. 140).
3 5
His work had such a profound influence on medicine that he was called Sherman L J 1959 The significant variables in psychopharmaceutic
the ‘English Hippocrates’. research. American Journal of Psychiatry 116:208–214.

8
 Topics in drug therapy Chapter |2|

• The patient’s estimate of what has been received and of Uses of drugs/medicines
what ought to happen as a result.
• The social environment, e.g. whether it is supportive or
dispiriting. Drugs are used in three principal ways:
The relative importance of these factors varies according to • To cure disease: primary and auxiliary.
circumstances. An unconscious patient with meningococ- • To suppress disease.
cal meningitis does not have a personal relationship with • To prevent disease (prophylaxis): primary and
the doctor, but patients sleepless with anxiety because they secondary.
cannot cope with their family responsibilities may respond
as much to the interaction of their own personality with
that of the doctor as to anxiolytics. Cure implies primary therapy, as in bacterial and parasitic
The physician may consciously use all of the factors listed infections, that eliminates the disease and the drug is with-
above in therapeutic practice. But it is still not enough that drawn; or auxiliary therapy, as with anaesthetics and with
patients get better: it is essential to know why they do so. ergometrine and oxytocin in obstetrics.
This is because potent drugs should be given only if their
pharmacodynamic effects are needed; many adverse reac- Suppression of diseases or symptoms is used continu-
tions have been shown to be due to drugs that are not ously or intermittently to avoid the effects of disease with-
needed, including some severe enough to cause hospital out attaining cure (as in hypertension, diabetes mellitus,
admission. epilepsy, asthma), or to control symptoms (such as pain
and cough) while awaiting recovery from the causative
disease.
Drugs can do good
Prevention (prophylaxis). In primary prevention, the per-
Medically, this good may sometimes seem trivial, as in the
son does not have the condition and avoids getting it.
avoidance of a sleepless night in a noisy hotel or of social
For malaria, vaccinations and contraception, the decision
embarrassment from a profusely running nose due to sea-
to treat healthy people is generally easy.
sonal pollen allergy (hay fever). Such benefits are not nec-
In secondary prevention, the patient has the disease and the
essarily trivial to recipients, concerned to be at their best in
objective is to reduce risk factors, so as to retard progression
important matters, whether of business, pleasure or pas-
or avoid repetition of an event, e.g. aspirin and lipid-
sion, i.e. with quality of life.
lowering drugs in atherosclerosis and after myocardial
Or the good may be literally life-saving, as in serious
infarction, antihypertensives to prevent recurrence of stroke.
acute infections (pneumonia, septicaemia) or in the pre-
Taking account of the above, a doctor might ask the fol-
vention of life-devastating disability from severe asthma,
lowing questions before treating a patient with drugs:
from epilepsy or from blindness due to glaucoma.
1. Should I interfere with the patient at all?
2. If so, what alteration in the patient’s condition do I
Drugs can do harm hope to achieve?
3. Which drug is most likely to bring this about?
This harm may be relatively trivial, as in hangover from a 4. How can I administer the drug to attain the right
hypnotic or transient headache from glyceryl trinitrate used concentration in the right place at the right time and for
for angina. the right duration?
The harm may be life-destroying, as in the rare sudden 5. How will I know when I have achieved the objective?
death following an injection of penicillin, rightly regarded 6. What other effects might the drug produce, and are
as one of the safest of antibiotics, or the destruction of the these harmful?
quality of life that occasionally attends the use of drugs that 7. How will I decide to stop the drug?
are effective in rheumatoid arthritis (adrenocortical ste- 8. Does the likelihood of benefit, and its importance,
roids, penicillamine) and Parkinson’s disease (levodopa). outweigh the likelihood of damage, and its importance,
There are risks in taking medicines, just as there are risks i.e. the benefit versus risk, or efficacy against safety?
in food and transport. There are also risks in declining to
take medicines when they are needed, just as there are risks
in refusing food or transport when they are needed.
Efficacy and safety do not lie solely in the molecular PHYSICIAN-INDUCED (IATROGENIC)
structure of the drug. Doctors must choose which drugs DISEASE
to use and must apply them correctly in relation not only
to their properties, but also to those of the patients and
their disease. Then patients must use the prescribed medi- They used to have a more equitable contract in Egypt:
cine correctly (see Compliance p. 21). for the first three days the doctor took on the patient at

9
Section | 1 | General

the patient’s risk and peril: when the three days were decades is now under better control such that prescribers
up, the risks and perils were the doctor’s. can, from their desktop computer terminals, enter the facts
But doctors are lucky: the sun shines on their about their patient (age, sex, weight, principal and secondary
successes and the earth hides their failures.6 diagnoses) and receive suggestions for which drugs should
be considered, with proposed doses and precautions.
It is a salutary thought that each year medical errors kill an
estimated 44 000–98 000 Americans (more than die in
motor vehicle accidents) and injure 1 000 000.7 Among in- BENEFITS AND RISKS OF MEDICINES
patients in the USA and Australia, about half of the injuries
caused by medical mismanagement result from surgery, Modern technological medicine has been criticised, justly,
but therapeutic mishaps and diagnostic errors are the next for following the tradition of centuries by waiting for dis-
most common. In one survey of adverse drug events, 1% ease to occur and then trying to cure it rather than seeking
were fatal, 12% life-threatening, 30% serious and 57% sig- to prevent it in the first place. Although many diseases are
nificant.8 About half of the life-threatening and serious partly or wholly preventable by economic, social and beha-
events were preventable. Errors of prescribing account for vioural means, these are too seldom adopted and are slow
one-half and those of administering drugs for one-quarter to take effect. In the meantime, people continue to fall sick,
of these. Inevitably, a proportion of lapses result in litiga- and to need and deserve treatment.
tion, and in the UK 20–25% of complaints received by We all have eventually to die from something and, even
the medical defence organisations about general practi- after excessive practising of all the advice on how to live a
tioners follow medication errors. healthy life, the likelihood that the mode of death for most
The most shameful act in therapeutics, apart from actu- of us will be free from pain, anxiety, cough, diarrhoea, pa-
ally killing a patient, is to injure a patient who is but little ralysis (the list is endless) seems so small that it can be dis-
disabled or who is suffering from a self-limiting disorder. regarded. Drugs already provide immeasurable solace in
Such iatrogenic disease,9 induced by misguided treatment, these situations, and the development of better drugs
is far from rare. should be encouraged.
Doctors who are temperamentally extremist will do less Doctors know the sick are thankful for drugs, just as even
harm by therapeutic nihilism than by optimistically over- the most dedicated pedestrians and environmentalists struck
whelming patients with well-intentioned polypharmacy. down by a passing car are thankful for a motor ambulance
If in doubt whether or not to give a drug to a person to take them to hospital. The reader will find reference to
who will soon get better without it, don’t. the benefits of drugs in individual diseases throughout
In 1917 the famous pharmacologist Sollmann felt able this book and further expansion is unnecessary here. But a
to write: general discussion of risk of adverse events is appropriate.

Pharmacology comprises some broad conceptions and

generalisations, and some detailed conclusions, of such Unavoidable risks
great and practical importance that every student and Consider, for the sake of argument, the features that a
practitioner should be absolutely familiar with them. completely risk-free drug would exhibit:
It comprises also a large mass of minute details, which
would constitute too great a tax on human memory, • The physician would know exactly what action is
required and use the drug correctly.
but which cannot safely be neglected.10
• The drug would deliver its desired action and nothing
else, either by true biological selectivity or by selective
The doctor’s aim must be not merely to give the patient what
targeted delivery.
will do good, but to give only what will do good – or at least
more good than harm. The information explosion of recent
• The drug would achieve exactly the right amount of
action – neither too little, nor too much.
These criteria may be completely fulfilled, for example in a
6
Michel de Montaigne (1533–1592). French essayist. streptococcal infection sensitive to penicillin in patients
7
Kohn L, Corrigan J, Donaldson M (eds) for the Committee on Quality whose genetic constitution does not render them liable
of Health Care in America, Institute of Medicine 2000 To Err is
Human: Building a Safer Health System. National Academy Press,
to an allergic reaction to penicillin.
Washington, DC. These criteria are partially fulfilled in insulin-deficient di-
8
Bates D W, Cullen D J, Laird N et al 1995 Incidence of adverse drug abetes. But the natural modulation of insulin secretion in
events and potential adverse drug events. Journal of the American response to need (food, exercise) does not operate with
Medical Association 274:29–34.
9
injected insulin and even sophisticated technology cannot
Iatrogenic means ‘physician-caused’, i.e. disease consequent on
following medical advice or intervention (from the Greek iatros, yet exactly mimic the normal physiological responses. The
physician). criteria are still further from realisation in, for example,
10
Sollman T A 1917 Manual of Pharmacology. Saunders, Philadelphia. some cancers and schizophrenia.

10
 Topics in drug therapy Chapter |2|

Some reasons why drugs fail to meet the criteria of being 2. Second are those risks that cannot be significantly altered by
risk-free include the following: individual action. We experience risks imposed by food
• Drugs may be insufficiently selective. As the concentration additives (preservatives, colouring), air pollution and
rises, a drug that acts at only one site at low concentrations some environmental radioactivity. But there are also
begins to affect other target sites (receptors, enzymes) and risks imposed by nature, such as skin cancer due to
recruit new (unwanted) actions; or a disease process excess ultraviolet radiation in sunny climes, as well as
(cancer) is so close to normal cellular mechanisms that some radioactivity.
perfectly selective cell kill is impossible. It seems an obvious course to avoid unnecessary risks, but
• Drugs may be highly selective for one pathway but the there is disagreement on what risks are truly unnecessary
mechanism affected has widespread functions and and, on looking closely at the matter, it is plain that many
interference with it cannot be limited to one site people habitually take risks in their daily and recreational
only, e.g. atenolol on the b-adrenoceptor, aspirin on life that it would be a misuse of words to describe as nec-
cyclo-oxygenase. essary. Furthermore, some risks, although known to exist,
• Prolonged modification of cellular mechanisms can lead are, in practice, ignored other than by conforming to
to permanent change in structure and function, e.g. ordinary prudent conduct. These risks are negligible in
carcinogenicity. the sense that they do not influence behaviour, i.e. they
• Insufficient knowledge of disease processes (some cardiac are neglected.12
arrhythmias) and of drug action can lead to
interventions that, although undertaken with the best Elements of risk
intentions, are harmful.
• Patients are genetically heterogeneous to a high degree and
may have unpredicted responses to drugs. Risk has two elements:
• Dosage adjustment according to need is often • The likelihood or probability of an adverse event.
unavoidably imprecise, e.g. in depression. • Its severity.
• Prescribing ‘without due care and attention’.11

In medical practice in general, concern ceases when risks

Reduction of risk fall below about 1 in 100 000 instances, when the proce-
dure then is regarded as ‘safe’. In such cases, when disaster
Strategies that can limit risk include those directed at occurs, it can be difficult indeed for individuals to accept
achieving: that they ‘deliberately’ accepted a risk; they feel ‘it should
• Better knowledge of disease (research) – as much as 40% of not have happened to me’ and in their distress they may
useful medical advances derive from basic research that seek to lay blame on others where there is no fault or neg-
was not funded towards a specific practical outcome. ligence, only misfortune (see Warnings and consent).
• Site-specific effect – by molecular manipulation. The benefits of chemicals used to colour food verge on or
• Site-specific delivery – drug targeting: even attain negligibility, although some cause allergy in
n by topical (local) application humans. Our society permits their use.
n by target-selective carriers. There is general agreement that drugs prescribed for
• Informed, careful and responsible prescribing. disease are themselves the cause of a significant amount
of disease (adverse reactions), of death, of permanent dis-
ability, of recoverable illness and of minor inconvenience.
Two broad categories of risk In one major UK study the prevalence of adverse drug reac-
tions as a cause of admission to hospital was 6.5% (see
1. First are those that we accept by deliberate choice. We do so Chapter 9 for other examples).
even if we do not exactly know their magnitude, or we
know but wish they were smaller, or, especially when
the likelihood of harm is sufficiently remote though the Three major grades of risk
consequences may be grave, we do not even think These are: unacceptable, acceptable and negligible. Where dis-
about the matter. Such risks include transport and ease is life-threatening and there is reliable information on
sports, both of which are inescapably subject to potent both the disease and the drug, then decisions, though they
physical laws such as gravity and momentum, and may be painful, present relatively obvious problems. But
surgery to rectify disorders that we could tolerate or where the disease risk is remote, e.g. mild hypertension,
treat in other ways, as with much cosmetic surgery.
12
Sometimes the term minimal risk is used to mean risk about equal to
11
This phrase is commonly used in the context of motor vehicle accidents, going about our ordinary daily lives; it includes travel on public
but applies equally well to the prescribing of drugs. transport, but not motor bicycling on a motorway.

11
Another Random Scribd Document
with Unrelated Content
 490 PART II. TESTIMONIAL EVIDEXCE No. 248. Among
uncultivated persons habitual errors of expression are not
uncommon. They use words in an improper or provincial sense.
They employ exaggerating epithets and adjectives. They describe
objects, not by delineating their characteristic features, but in
fragmentary outlines, or by portraying their most universal
indistinctive attributes. They reproduce events, not in their proper
order and relations, but with whatever sequence and connection the
inspiration of the moment may direct. They do not lead, but mislead,
the deductions of their hearers, with the best intentions and
sufficient knowledge unwittingly producing false impressions on the
minds of those whose mistake originates in the assumption that the
words are spoken in the same sense in which they are understood.
248. Hans Gross. Criminal Pfiiichologii. (transl. Kallen. 1911. §59, p.
287.) Thf Forms of Girincj Testimony. Wherever we turn we face the
absolute importance of language for our work. Whatever we hear or
read concerning a crime is expressed in words, and everything
perceived with the eye, or any other sense, must be clothed in
words before it can be put to use. . . . Yet, who needs this
knowledge ? The lawyer. Other disciplines can find in it only a
scientific interest, but it is practically and absolutely valuable only for
us lawyers, who must, by means of language, take evidence,
remember it, and variously interpret it. A failure in a proper
understanding of language may give rise to false conceptions and
the most serious of mistakes. Hence, nobody is so bound as the
criminal lawyer to study the general character of language, and to
familiarize himself with its force, nature, and development. Without
this knowledge the lawyer may be able to make use of language,
but, failing to understand it, will slip up before the slightest difficulty.
.... (r/) Varirti) in Forms of Expression. Men being different in nature
and bringing-up on the one hand, and language, being on the other,
a living organism which varies with its soil, i.e. with the human
individual who makes use of it, it is inevitable that each man should
haveespecial and private forms of expression. These forms, if the
man comes before us as witness or prisoner, we must study, each by
itself. Fortunately, this study must be combined with another that it
implies, i.e. the character and nature of the individual. The one
without the other is unthinkable. Whoever aims to study a man's
character must first of all attend to his ways of expression, inasmuch
as these are most significant of a man's qualities, and most
illuminating. . . . The especial use of certain forms is incHvidual as
well as social. Every person has his private usage. One makes use of
"certainly," another of " yes, indeed ; " one prefers " dark," another "
darkish.". . . Even when it is simple to bring out what is intended by
an expression, it is still quite as simple to overlook the fact that
people use peculiar expressions for ordinary things. . . . Numerous
examples may develop with comparative speed in each indivi(hud
speaker, and, if the development is not traced, may lead, in the law
court, to very serious misunderstandings. People who nowadays
name abstract things, conceive, according to their intelligence, now
this an
 No. 249. II. TESTIMONIAL PROCESS. C. NARRATION 491
what an influence the interval between observation and
announcement exercises on the form of exposition. The witness who
is immediately examined may, perhaps, say the same thing that he
would say several weeks after — but his presentation is different, he
uses different words, he understands by the different words different
concepts, and so his testimony becomes altered. A similar eff'ect
may be brought about by the surrounding circurmta7iccs under
which the evidence is given. Every one of us knows what surprising
differences occur between the statements of the witness made in
the silent office of the examining justice and his secretary, and what
he says in the open trial before the jury. There is frequently an
inclination to attack angrily the witnesses who make such divergent
statements. Yet more accurate observation would show that the
testimony is essentially the same as the former, but that the manner
of giving it is different, and hence the apparently different story. The
difference between the members of the audience has a powerful
influence. It is generally true that reproductive construction is
intensified by the sight of a larger number of attentive hearers, . . .
but only when the speaker is certain of his subject and of the favor
of his auditors. . . . The interest belongs only to the subject, and the
speaker himself receives, perhaps, the undivided antipathy, hatred,
disgust, or scorn, of all the listeners. Nevertheless, attention is
intense and strained, and inasmuch as the speaker knows that this
does not pertain to him or his merits, it confuses and depresses him.
It is for this reason that so many criminal trials turn out quite
contrary to expectation. Those who have seen the trial only, and
were not at the prior examination, understand the result still less
when they are told that "nothing has altered" since the prior
examination — and yet much has altered ; the witnesses, excited or
frightened by the crowd of listeners, have spoken and expressed
themselves otherwise than before, until, in this manner, the whole
case has become diff'erent. In a similar fashion, some fact may be
shown in another light by the 7nanner of narration used by a
particular witness. Take, as example, some energetically influential
quality like humor. It is self-evident that joke, witticism, comedy, are
excluded from the court room, but if somebody has actually
introduced real, genuine humor by way of the dry form of his
testimony, without having crossed in a single word the permissible
limit, he may, not rarely, narrate a very serious story so as to reduce
its dangerous aspect to a minimum. Frequently the testimony of
some funny witness makes the rounds of all the newspapers for the
pleasure of their readers. Everybody knows how a really humorous
person may so narrate experiences, doubtful situations of his
student days, unpleasant traveling experiences, difficult positions in
quarrels, etc., that every listener must laugh. At the same time, the
events told of were troublesome, difficult, even quite dangerous.
The narrator does not in the least lie, but he manages to give his
story the twist that even the victim of the situation is glad to laugh
at. 249. Arthur C. Train. The Prisoner at the Bar. (2ded. 1908. p.
236.) The final question to be determined by the juror in regard to
the testimony of any witness is how far the latter has succeeded in
conveying his actual recollections through the medium of speech and
gesture. This necessarily depends upon a variety of considerations.
Among these are his familiarity
 492 PART II. TESTIMONIAL EVIDENCE No. 210. with the
EngUsh hinguage ; inadvertent accentuation of wrong words or of
tlie less important features of his testimony ; his physical condition,
which in nine cases out of ten is one of extreme nervousness and
timidity, if not of actual fear; and a hunih-ed other trifling, but, in the
aggregate, material matters. The most effective testimony is that
which is given with what the jury regard as the evidences of candor.
It is a familiar fact that the surer a person is of anything, particularly
among the laboring classes, the more loudly will he assert its truth.
This is so well known to the jury as ordinarily constituted that unless
testimony is given with positiveness it might as well not be given at
all. Much as it is to be deprecated, an assertive lie is of much more
weight with a jury than an anemic statement of the truth. The juror
imagines himself telling the story, and feels that if he were doing so
and his testimony were true, he would be so convincing that the jury
could have no doubt about it at all. Ofttimes a witness leads the jury
to suspect that he is a liar simply because he has too strong a sense
of the proprieties of his position vehemently to resent a suggestion
of untruthfulness. The gentleman who mildly replies "That is not so"
to a challenge of his veracity, makes far less impression on the jury
than the coal heaver wdio leans forward and shakes his fist in the
shyster's face, exclaiming : " If ye said that outside, ye little
spalpeen, I'd knock yer head ofl." "Ah," say the jury, "there's a man
for you." Just as your puritan is at a disadvantage in an alehouse,
and your dandy in a mob, so are the hypcrconscientious and the
oversensitive and refined before a jury. The most effective witness is
he whom the general run of jurors can understand, who speaks their
own language, feels about the same emotions, and is not so
morbidly conscientious about details that in qualifying testimony he
finds himself entangled and rendered helpless in his own
refinements. A distinguished lawyer testifying in a recent case was
so careful to qualify every statement and refine every bit of his
evidence that the jurj^ took the word of a perjured loafer and a
street-walker in preference. This kind of thing happens again and
again, and the wily witness who thinks himself clever in appearing
overdisinterested is "hoist by his own petard." The jury at once
distrust him. They feel either that he is making it all up, or is in fact
not sure of his evidence, else, they argue, he would be more positive
in giving it. Most witnesses in the general run of criminal cases have
no comprehension of the meaning of words of more than three
syllables. It is hopeless to make use of even such modest nieinl)ers
of our national vocabulary as "preceding," ".subsequent," "various,"
etc. A negro when asked if certain shots were "simultaneous"
replied: "Yas, boss. Dat's it ! 'Zactly simultaneous! One rif/lif after de
odder." The ordinary witness usually says "minutes" when he means
"seconds." He will testify without hesitation that the defendant drew
liis revolver and immediately shot the complainant, illustrating on the
stand the rapidity of the movement. When asked how long it took,
he will answer: "Oh, about two or three niiiuitcs." A i)ropcr Micdium
in wliich to converse l)etween the lawyer and W'itness is sometimes
diflicult to find, and invariably much tact is required in handling
witnesses of limited education. The writer remembers one witness
who was Cfjiiipletely disconcerted by the use of the word "cravat,"
and at the precise
 :;o. 2.M. II. TESTIMONIAL PROCESS. C. NARRATION 493
moment the attorney was so confused as not to be able to
remember any synonym. The Tenderloin and the Bowery have a
vocabulary of their own differing somewhat from that of beggars
and professional criminals. The language of the ordinary policeman
is a polyglot of all three. Popular writers on the "powers that prey,"
and dabblers in criminology in general, are apt to become the
victims of self-alleged "ex-convicts" and "criminals" w^ho are
anxious to sell unreliable information for honest liquor. A large part
of the lingo in realistic treatises on prison life and "life among the
burglars," originates in the doped imagination of whatever fanciful
"reformed" thief happens to be the personal gold mine of that
particular author. Thieves, like any distinct class, make use of slang,
some of which is peculiar to them alone. But for the most part the "
tough" elements in the community make themselves easily
understood either in the office or on the witness stand. Where the
witness speaks a foreign language, the task of discovering exactly
what he knows, or even what he actually says, is herculean. In the
first place interpreters, as a rule, give the substance — as they
understand it — of the witness's testimony rather than his exact
words. It is also practically impossible to cross-examine through an
interpreter, for the whole psychological significance of the answer is
destroyed, ample opportunity being given for the witness to collect
his wits and carefully to frame his reply. One could cross-examine a
deaf mute by means of the finger alphabet about as effectively as an
Italian through a court interpreter, who probably speaks (defectively)
seventeen languages. 250. G. L. DuPRAT. Le Mcnsongc: fiude dc
psychosociologie. (1909. 2d ed. pp. 15, 120.) Kinds of Lies. Some
liars add to a true statement by adorning facts, by giving to people,
acts, or things non-existent qualities ; or by exaggerating the extent,
value, etc., of a fact or a relation; or by inventing new facts. They
are like the artists, who sometimes simplify or "purify" nature,
idealizing it while preserving its essentials, but also sometimes enrich
the data of experience l)y combining them in a new order to make
new forms. Thus there are lies (1) of attribution, (2) of addition, (3)
of exaggeration, (4) of recombination, (5) of pure fiction. Lies
applying to personal qualities or acts include slander, false
prosecution, false witnessing. Lies applying to external facts include
false representations, fraud in general, and (when a prior oath to
deal honestly has been taken) disloyalty. They thus pass beyond
mere expressions of the speaker's own thought and include
statements of external fact, and it is not possible to draw a boundary
between false testimony and fraud. There is an intermediate type,
simulation, in which a mendacious assertion combines with false
conduct adapted to give it credence. . . . But the lie of dissimulation
must also be included, — the lie by suppressing facts, even without
express negation in words or conduct. The false witness, by his
words or by his silence, may deny the existence of a fact ; the false
historian may deny the existence of persons or events which would
embarrass his proof of the view to which he is committed ; . . . the
smuggler is typically a dissimulator, who conceals a part of the truth.
Dissimulation, in short, is a negative or inhibitiye suggestion, in
contrast to simulation or lie in the ordinary sense, which is a positive
suggestion.
 494 PART II. TESTIMONIAL EVIDENCE No. 250. The two
extreme types of lie are therefore the positive, which creates a
complete fiction, interpolated by imagination in the world of reality,
and the lugaiiir, which removes from outward expression whatever
might furnish a clew to the truth. Between these two extremes may
be arranged the other types, in the order of their affinities ; thus :
Classification of Lies {or, Modes of Suggesting Error) A. Positive
Suggestion contrasted with B. Negative Suggestion Invention
(slander, fraud, false prosecution, false witness) Fiction, simulation
Addition Deformation Exaggeration Complete dissimulation ;
denegation ; suppression of testimony. Omission Mutilation
Attenuation To this classification of lies would correspond that of
liars. Those who make positive suggestions exhibit capacity of
invention ; those who make negative suggestions are frequently
lacking in imagination. ... Of course, many lies are mixed in
character, partaking both of positive and of negative suggestion.
Moreover, every lie in so far as it creates a new form for some
supposed fact is deformative, and thus is in a sense a positive
suggestion ; so that every liar to this extent uses imagination.
Nevertheless there is always, within the same group, a relative
contrast between the liar who needs more or less mental activity to
construct or amplify, and the one who needs merely deny, suppress,
or mutilate, without having to invent anything but what is furnished
him in the very experience which he desires to impress falsely on the
other person. . . . The lie, then, may be thus defined : A
psychosociologic fact of suggestion, oral or otherwise, by means of
which one tends, more or less intentionally, to introduce into
another's mind a l)elief, positive or negative, not in harmony with
what the actor supposes to be the truth. Neuromuscular -
phenomena of the lie. Does the liar's mental state manifest itself by
any biologic modifications ? As to persons of strong character, skillful
to the point of dissimulating the very sentiment which they
experience in the act itself of dissimidation, it is certainly difficult to
discover in them the traces of the lie. On the other hand, children
usually betray themselves readily enough.^ Some children are
reported as lying "with apparent Ccindor" ; but these are the
scarcely conscious lies, for young beings are rare who dissimulate to
the point of giving every appearance of candor. Many are
embarrassed ; they are uneasy under the inquirer's gaze ; their eyes
will not meet jours ; and they show a haste to escape from further
scrutiny, by making involuntary movements to get away or to elude
attention or to take up some new activity. Some, in spite of an
apparent coolness, cannot avoid contracting the muscles, tapping
the sole of the foot in a certain rhythm, crunching something in their
fingers, or plunging their hands in their pockets and then taking
them out in alternate movements. Others ' Tho invosti)?ation.s of
the Society for the Psychological Study of Children will here yield still
oihi-r valiial)lc results.
 No. 250. II. TESTIMONIAL PROCESS. C. NARRATION 495
show their uneasiness by an excitement, an exaggerated boldness
amounting to insolence : in their emotion they go beyond all
moderation in the passionate expression of their assertions, in the
volubility of their language, in the quickness of their answers, or in
the audacity of their questions ; a sudden release of control seems
to give vent to a flow of words which threaten to become
incoherent, as in lunatics afflicted with acute mania. In some
children, while speech becomes copious, the voice is low, yet with
others it is high pitched with outbursts like spasms. The excitement
may induce only vasomotor modifications, blushes, or paleness, or
each alternatively. Sometimes the only perceptible mark is a
trembling of the hand, or a winking of the eyes, or a rapid dilation of
the nostrils, or a slight creasing of the hairy skin, or an odd smile
either fugitive or lasting and then almost inscrutable. The protrusion
of the lips, or their contraction with discoloration of the mucus,
sometimes replaces the smile. In some instances, the liar tosses his
head ; sometimes he watches for some sign of acc^uiescence ;
sometimes he fluctuates between boldness and confusion. This
diversity of physiologic manifestations of the mental state of lying
demonstrates plainly that it involves an affective (emotional)
condition. As William James has shown, affective phenomena consist
essentially, from the physiological point of view, in a greater or less
number of muscular and vasomotor reflexes, forming combinations
so varied that anj- classification of the emotions is impossible. In the
state of lying there are phenomena either of excitation or of
depression or of the one alternating with the other. Nevertheless, we
must not confuse affective phenomena, strictly so-called, with the
phenomena of expressive mimicry due to simulation and aimed at
producing or increasing the confidence of a watching auditor. . . . For
example, a liar may simulate laughter ; and when the simulation is a
poor one, we have the "forced laugh," in which only facial
displacements occur without the expression of a true geniality ; the
lips are merely parted, the nasolabial furrow is bent convexly inward
for most of its length, the creased skin radiates in wrinkles around
the eyes towards the temples. After allowing for these physiologic
modifications which may accompany the lie without being an
intrinsic mark of it, we may still concede that 7io intentional
derogation from the truth can take place without a tendency to
muscidar contractions or expansions, — phenomena of inhibition or
excitation. The reason for this must be sought in that cerebral
physiology which is the basis for a psychological explanation of the
lie. Psychology of the lie. We have seen that the lie is either a
positive, more or less complex invention, or a negative invention. But
throughout all it includes an act of imagination. Lying invention
shows all the species of imagination so well classified and described
by Ribot in his great work on " The Creative Imagination." . . . There
is the plastic imagination, the difiluent imagination, the mystical
imagination, the scientific imagination, the practical imagination, the
commercial imagination, the Utopian imagination. We may safely
assert — a truism, to be sure, but a necessary one — that all species
of imagination may serve, not only to discover truths, but to invent
lies. But what seems to be the peculiarity of imagination used in
lying is that it can go to the length of completely negating the
existence of the object in question. ... In contrast with the other
species, it alone can be
 496 PART II. TESTIMONIAL EVIDENCE No. 251. simply
negative. In certain cases, then, we have inhibition, rather than
production. Among the nenromuscuUir phenomena characteristic of
a psycho-phy^ioh)gic lying state, we have often above noted acts of
contradiction, of repression of incipient movements, — in short, of
inhil)ition. The liar must keep from expressing aloud his thought. He
is not merely imagining ; he is at the same moment conceiving
something which he ought truly to express and something different
which he is to succeed in suggesting to others. The process is thus
more complex than in merely creative imagination. Now if there is
any law of psychopathology that is well established by experiment or
observation, it is this,^ that every clear and living idea engenders
the corresponding morcmrnt. Hence it must be conceded that a very
clear mental representation of something which one ought to be
telling — and it is very clear in many instances of derogation from
the truth, and clearer in proportion as the sense of duty may be
prompting obedience — engenders a strong tendency to pronounce
the suitable words and to make the gestures or postures naturally
accompanying that thought. Thence occurs often a violent
antagonism between this natural propensity and the other inclination
(casual or habitual) to disguise the truth l)y affirming something
different. Before this antagonism can attenuate to the point where
dissimulation becomes easy, the habit of telling the thing contrary to
what one ought to tell must have become a strong one. Hence we
come to a distinction between the casual liar and the habitual liar, —
the liar who promptly confounds himself, and the tenacious liar who
persists in his lie. The casual liar may be a person having a vivid
imagination or experiencing a lively emotion, who impulsively affirms
or denies without precise reflection on his erroneous assertion and
the distance between it and the truth. It is only when he receives
some check that he definitely conceives the truth. Then he may
either persist in his falsity, through vanity, pride, self-esteem, or
shame ; or may hasten to some other topic ; or may recant. If he
recants, one may perhaps detect slight symptoms of lack of
frankness ; if he hastens to leave the subject, he usually betrays
himself by his precipitateness or worried air ; if he persists, he tends
to become the habitual liar and needs now a great power of
inhibition. With the tenaciou,s liar, the lie is generally habitual.
Fatigue, worry, uneasiness, recur as infrequently as the inhibition
has been frequent. The physiological marks of lying are less
apparent, the muscular contractions less forcil)le and particularly less
spasmodic. He is more at home in supporting his assertions by a
persuasive mimicry, — facial expressions appropriate to frankness,
smiles less false, intonations less artificial, etc. Mendacious invention
here tends to free itself from almost all the shackles customarily
provided by a consciousness of the truth. 251. A. ( '. Plowden. Grain
or Chaff; the Autobiography of a Police Magistrate. (1903. p. 225.) ...
It would be unreasonable, however, to turn your eyes away
altogether. Indeed, it is not possible to do it. You cannot watch a
face too closely, provided you can trust yourself not to be led away
by tf)0 hasty inferences. Much of the interest of my work I feel to lie
in a close .scrutiny of the iiumnii countenance, whether in the dock
or the witness ' See P. .laiK't, L'automalisme psijchologique.
 No. 253. II. TESTIMONIAL PROCESS. C. NARRATION xdt
box. I make a mental note if a prisoner has abnormal ears. They are
often significant. And if I am doubtful about a witness speaking the
truth, I direct my attention to his mouth and to his hands. The
mouth is perhaps the most expressive feature, and the hands of a
har are seldom at rest. But where I often think much is to be learned
from a witness is after he has given his evidence and left the box. I
continue to watch him as he sits unsuspectingly in his place in the
court, while other witnesses, especially those that are opposed to
him, are examined. The expressions that pass over his face on these
occasions are often very instructive. 252. Amos C. Miller.
Examination of Witnesses. (Illinois Law Review. 1907. Vol. II, p.
257.) It is, of course, of the greatest importance to be able to
determine whether a witness is willfully falsifying or whether he is
honestly mistaken. Of course, there are all degrees between an
honest mistake and a willful lie. How to correctly measure the
elements of this honesty in a witness's testimony is largely a matter
of experience which each man is compelled to gain for himself. But
there are a few suggestions which may be of assistance. A witness
who is testifying falsely will, as a rule, try to evade, on cross-
examination, questions on collateral matters ; this, of course, in
order to avoid the danger of being entrapped. He will frequently ask
the cross-examiner to repeat plain, simple questions in order to give
him a chance to think up a consistent reply. He will often carefully
and slowly repeat over a question on cross-examination for the
purpose of giving him time to think ; or he will answer irresponsively
in order to steer the crossexaminer off the track. I have also
observed that the witness who is swearing to a clear-cut lie will,
while so doing, throw back his head with an indifferent air and close
his eyes or blink. My experience has taught me to believe that that is
an almost certain sign of deliberate dishonesty. Topic 2. Narration as
affected by Interrogation and Suggestion 253. Richard Harris. Hints
on Advocacy. (Amer. ed. 1892. p. 29). I. One of the most important
branches of advocacy is the examination of a witness in chief. . . .
One fact should be remembered to start with, and it is this : the
witness whom he has to examine has probably a plain,
straightforward story to tell, and that upon the telling it depends the
belief or disbelief of the jury, and their consequent verdict. If it were
to be told amid a social circle of friends, it would be narrated with
more or less circumlocution and considerable exactness. But all the
facts would come out; and that is the first thing to insure, if the case
be, as I must all along assume it to be, an honest one. I have often
known half a story told, and that the worst half, too, the rest having
to be got out by the leader in reexamination, if he have the
opportunity. If the story were being told as I have suggested, in
private, all the company would understand it, and if the narrator
were known as a man of truth, all would believe him. It would
require no advocate to elicit the facts or to confuse the dates ; the
events would flow pretty much in their natural order. Now change
the audience ; let the same man attempt to tell the same story in a
court of justice. His first feeling is that he must not tell it in his own
way. He is going to be examined upon it ; he
 498 PART II. TESTIMONIAL EVIDENCE No. 2.53. is to have
it dragged out of him piecemeal, disjointedly, by a series of
questions — in fact, he is to be interrupted at every point in a worse
manner than if everybody in the room, one after another, had
questioned him about what he was going to tell, instead of waiting
till he had told it. It is not unlike a post mortem ; only the witness is
alive, -and keenly sensitive to the painful operation. He knows that
every word will be disputed, if not flatly contradicted. He has never
had his veracity questioned, perhaps, but now it is very likely to be
suggested that he is committing rank perjury. This is pretty nearly
the state of mind of many a witness, when for the first time he
enters the box to be examined. In the first place, then, he is in the
worst possible frame of mind to be examined — he is agitated,
confused, and bewildered. Now put to examine him an agitated,
confused, and bewildered young advocate, and you have got the
worst of all elements together for the production of what is Avanted,
namely evidence. First of all, the man is asked his name, as if he
were going to say his catechism, and much confusion there often is
about that, the witness feeling that the judge is surprised, if not
angry, at his not having a more agreeable one, or for having a name
at all. He blushes, feels humiliated, but escaping a reprimand thinks
he has got off remarkal)ly well so far. Then he faces the young
counsel, and wonders what he will be asked next. Now the best
thing the advocate can do under these circumstances is to
remember that the witness has something to tell, and that but for
him, the advocate, would probably tell it very well, "in his own way."
The fvicer interruptions, therefore, the better ; and the fewer
questions, the less questions will be needed. Watching should be the
chief work ; especially to see that the story be not confused with
extraneous and irrelevant matter. • . . . The most usefvd questions
for eliciting facts are the most commonplace, "What took place
next?" being infinitely better than putting a question from the
narrative in your brief, which leads the witness to contradict you.
The interrogative " Yes ? " as it asks nothing and yet everything is
better than a rigmarole praise, such as, " Do you remember what
the defendant did or said upon that ?" The witness after such a
question is generally puzzled, as if you were asking him a
conundrum which is to be passed on to the next person after he has
given it up. Judges frequently rebuke juniors for putting a question
in this form : "Do you remember the 2!)th of February lastf" In the
first place, it is not the day that has to be remembered at all, and
whether the witness recollects it or not is immaterial. It is generally
the /ads that took place about that time you want deposed to, and if
the date is at all material, you are putting the c|uestion in the worst
possible form to get it. A witness so interrogated begins to wonder
whether he remembers the day, or whether he does not, and
becomes jjuzzled. We don't rememl)er days. You might just as well
ask if he remembers the 1st of May, 1816, the day on which he was
born, instead of asking him the date of his birth. This is one of the
commonest, and at the same time one of the stupidest blunders that
can l)e made. I will, therefore, at the risk of repetition, give one
more illustration. Suppose you ask a witness if he rememl)ers the
10th of June, 1874 ; he probably does not, and both he and you are
bewildered, and think you are at cross-purposes ; hut a.sk him if he
was at Niagara in that year, and you will get the
 No. 253. II, TESTIMONIAL PROCESS. C. NARRATION 499
answer without hesitation ; inquire when it was, and he will tell you
the 10th of June. In this way you will avoid taxing a witness's
memory ; always a dangerous proceeding. Another common error is
worth noting, and that is the not permitting a witness to finish his
answer, or tell all he knows on a material matter. In the very midst
of an important answer a witness is very often interrupted by a
frivolous question upon something utterly immaterial. This seems so
absurd on paper that it needs an example. A witness is giving an
answer when some such question as this is interposed ! " What time
was this ? ' ' or, "Had you seen Mr. Smith before this?" A question is
often left half answered by such interruptions, the better half
perhaps being untold. " He never asked me about that," says the
witness after the case is over ; or, "I could have explained that if he
had let me.". . . All unnecessary interrup-' tions produce confusion in
the mind of the witness and jury and tend to the damage of your
case. But although it is by far the best to let a witness tell his story
in his own way as much as possible, it is absolutely necessary to
prevent him from rambling into irrelevant matter. Most uneducated
witnesses begin a story with some utterly irrelevant observation,
such as, if they are going to tell what took place at a fire, they will
say, " I was just fastening up my back door, when I heard a shout."
Get him as soon as you can at the fire and the evidence will come
with little trouble. Every question should not only be intelligible and
relevant in itself, but it should be put in such a form that its
relevancy to the case may be apparent to him. A question, without
being leading, should be a reminder of events rather than a test of
the witness's recollection. I will give an illustration which will show
how easy it is to blunder, and how necessary it is to avoid
blundering. A man brings an action against a railway company for
false imprisonment. The facts are these : He lost his ticket and
refused to pay ; the porter on the platform called the inspector, who
sent for a policeman, and then gave him into custody. The best way
not to get the facts out is to examine him in the following manner :
— "Were you asked for your ticket? — Yes." "Did you produce it? —
^ No." "Why not? — I had lost it." " Are you sure you took it ? —
Quite." " Positive ? (This is a good opening for the wedge of cross-
examination — a doubt thrown on your own witness.) — I am quite
sure." " What did the defendants say then ; I mean the porter ? "
(This blunder ought not to have been made.) At this point the
witness is in a hopeless muddle, and says: "I was given into
custody." The story is not half told, although it is one of the simplest
to tell. Now the counsel contradicts by way of explanation, and says,
"No, no; do attend." Witness strokes his chin as though about to be
shaved. Judge glances at him, and wonder's if he's lying. Counsel for
the defendants (sure to be eminent) smile, and the jury look
knowingly at one another, and begin to think it's a trumped-up
attorney's action. Now start again with another question. " When the
train stopped you got out ? — I didn't get out afore it stopped, sir."
 500 PART II. TESTIMONIAL EVIDENCE No. 253 "Did any
one ask you for your ticket ? — They did;" emphatically, as tliou^ih
he knows now where he is. ""Wj^^^y — j'„^ ^jire I don't know
who he is; never seen the man before in my life." "Well, well, did he
do anythinji ? — No, sir; he didn't do nothin' as I knows of;"
evidently puzzled, as if he had forgotten some important event upon
which the whole case turns. This looks so ridiculous on paper that it
is possible some readers will doubt if it ever happened. I can only
say there are many much more ridiculous incidents that occur in
courts of justice when young counsel have what is calleil a "stupid"
witness in the box. In court the stupidity always seems to l)e that of
the witness ; on paper it looks as if the learned counsel could
establish a better title to it. This leads me to notice a cardinal rule in
examination in chief. It is seldom regarded as such by beginners,
and only seems to be observed as the result of experience. Why it
should not be learned at once and implicitly obeyeil I do not know,
except it be that it has never been written down. The rule is this,
that in examining a witness the order of time ought always to be
observed. Stated in writing, it looks simple enough, and everybody
says "of course." Plain as one of the ten commandments, and as
often violated by young advocates. In putting questions long-drawn
sentences should be avoided. The following is an almost verbatim
report. The advocate was experienced, but he was anxious to get as
much as he could into a question ; and whenever your question is
too large the answer will be worthless : " Were you present at the
meeting of the trustees when an agreement was entered into
between them and the plaintiff?" Answer, "Yes." Q. "Will you be kind
enough to tell us what took place between the parties with reference
to the agreement that was then entered into between them ?" The
more neatly a question is put, the better, as it has to be understood
not only by the witness, but by the jury. All that was necessary to be
asked might have been put in the following words : "Was an
agreement entered into between the trustees and the plaintiff ?" —
"Yes." "What was it ?" It will api)car even more strange that after
the answer was given by one witness, which was all that was
necessary to prove that part of the case, the question was repeated
to another with additional verbiage. "Will you be good enough to
inform us what took place upon that occasion between the parties,
as nearly as you can, with reference to the agreement that was
then, as you have stated, entered into between them. Please tell us,
not exactly, but as nearly as you can in your' own way what his
exact words were ? " II. Next to examination-in-chief nothing is
more important or difficult in advocacy than rms-s-craiiiindfiou. It is
infinitely the most dangerous l)ranch, inasmuch as its errors are
almost always irremediable. It is in advocacy very like what "cutting
out" is in naval warfare, and you require a good many of the same
(|ualities ; courage with caution, boldness with dexterity, as well as
judgment and discrimination. . . . Cross-examination may almost be
regarded as a mental duel between advocate and witness. The first
rccpiisite therefore on the part of the attacking party (namely, the
 No. 253. II. TESTIMONIAL PROCESS. C. NARRATION 501
advocate) is a knowledge of human character. This is the first
requisite, and it is an indispensable one. But I suppose almost
everybody conceives himself to be a master of this science. With
respect to style, as before remarked, every man has his own, or
shoiUd have. . . . With regard to manner, a man should imitate the
best. The most eminent are as a rule the most unaffected, and the
quiet, moderate manner is generally the most effective. I do not
intend to imply that bluster and a high tone will not sometimes
unnerve a timid witness, but this is not crossexamination or true
advocacy. It is not art, but bullying — not intellectual power, but
mere physical momentum. Nor would I say that an advocate should
at all times treat a witness with the gentleness of a dove. Severity of
tone and manner, compatible with self-respect, is frequently
necessary to keep a witness in check, and to draw or drive the truth
out of him if he have any. But the severity will lose none of its force,
nay, it will receive an increase of it, by being furbished with the
polish of courtesy instead of roughened with the language of
uncompromising rudeness. Instances of the latter kind are extremely
rare at the English bar. But they do occasionally appear, and are
usually followed by a public outcry against them ; they do not,
however, cast discredit on the great body of a profession which is as
jealous of its high reputation for courtesy and honor as it is
deserving of it. I make these observations because I am about to
quote a passage from Archbishop's Whateley's "Elements of
Rhetoric" on Cross-examination, wherein he passes a severe
stricture upon advocates generally, and which, I am sure, so far as
my own experience and observation go, is utterly undeserved. At
page 165, he says : "In oral examination of witnesses a skillful cross-
examiner will often elicit from a reluctant witness most important
truths which the witness is desirous of concealing or disguising.
There is another kind of skill, which consists in so alarming,
misleading, or bewildering an honest witness as to throw discredit
on his testimony or prevent the effect of it. On this kind of art, which
may be characterized as the most, or one of the most, base and
depraved of all possible employments of intellectual power, I shall
only make one further observation." I pause here for a m.oment to
say that so far as my experience of the bar is concerned, and I think
it must be greater than that of the Right Reverend Father in God
who penned these words, a more undeserved slander against a body
of honorable men was never penned even by a Churchman. He
proceeds to say : " I am convinced that the most effectual mode of
eliciting truth is quite different from that by which an honest, simple-
minded witness is most easily baffled and confused. I have seen the
experiment .tried of subjecting a witness to such a kind of cross-
examination by a practiced lawyer as would have been, I am
convinced, the most likely to alarm and perplex many an honest
witness without any effect in shaking his testimony. . . . And
afterwards, by a totally opposite mode of examination, such as
would not have at all perplexed one who was honestly telling the
truth" (nothing, it seems, will perplex an honest witness but an
alarming style) — " that same witness was drawn on step by step to
acknowledge the utter falsity of the whole. Generally speaking, I
believe that a quiet, gentle, and straightforward — though full and
careful — examination, will be the most adapted to elicit truth, and
that the manoeuvers and the browbeating which are the most
adapted to
 502 PART II. TESTIMONIAL EVIDENCE No. 254. confuse an
honest witness are just what tlie dishonest one is the best prepared
for." When I read tho.se wordy sentences I couUl not help thinking It
was a pity that the Archbishop did not confine himself to theology.
He seems to think an honest witness easily baffled and frightened
into telling a lie. and to imagine that a lirutal liar is best induced to
tell the truth by wooing him with sweet words, and by a
straightforward, full, and careful examination. I can only say his
acquaintance with truthful witnes.ses must have been small indeed,
and the hypocrisy practiced upon his gentle questioning must have
misled him into the falsest views of human nature ever formed even
by those who assume to be the best acquainted with man's spiritual
existence. 254. BARBELL v. PICKWICK. Club. 1S37. c. XXIV.)
"Nathaniel Winkle I" said Mr. Skimpin. "Here I" replied a feeble voice.
Mr. Winkle entered the witness box, and having been duly sworn,
bowed to the judge with consideraljle deference. " Don't look at me.
sir," said the judge,' sharply, in acknowledgment of the salute ; "
look at the jury." Mr. Winkle obeyed the mandate, and looked at the
place where he thought it most probal)le the jury might be ; for
seeing anything in his then state of intellectual complication was
wholly out of the question. Mr. Winkle was then examined by. Mr.
Skimpin, who, being a promising young man of two or three and
forty, was of course anxious to confuse a witness who was
notoriously predispo.sed in favor of tlie other side, as much as he
coulfl. " Now, sir," said Mr. Skimpin, " have the goodness to let his
lyordship and the jury know what your name is, will you ?" And Mr.
Skimpin inclined his head on one side to listen with great sharpness
to the answer, and glanced at the jury meanwhile, as if to imply that
he rather expected Mr. Winkle's natural taste for perjury would
induce him to give some name which did not belong to him.
"Winkle," replied the witness. "What's your Christian name, sir?"
angrily in(piired the little judge. " Xatliani(>l, sir." " Danieb-r-any
other name ?" ' The riamf ".St.ireloiKh," givoa by the nov ni&ed Mr.
J. GoMclec. (Charles Dickens. The Pickwick " Nathaniel, sir — my
Lord, I mean." "Nathaniel Daniel, or Daniel Nathaniel?" "No, my
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