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Drugs in palliative care 2nd ed Edition Andrew Dickman
Digital Instant Download
Author(s): Andrew Dickman
ISBN(s): 9780199660391, 0199660395
Edition: 2nd ed
File Details: PDF, 1.73 MB
Year: 2012
Language: english
OXFORD MEDICAL PUBLICATIONS

Drugs in
Palliative Care
This page intentionally left blank
Drugs in
Palliative Care
Second Edition

Andrew Dickman MSc MRPharmS

Consultant Pharmacist – Palliative Care
Blackpool Teaching Hospitals NHS Foundation Trust
Whinney Heys Road
Blackpool
Lancashire
UK

and

Marie Curie Palliative Care Institute

Department of Molecular and Clinical Cancer Medicine
University of Liverpool
Cancer Research Centre
Liverpool
UK

1
1
Great Clarendon Street, Oxford OX2 6DP
Oxford University Press is a department of the University of Oxford.
It furthers the University’s objective of excellence in research, scholarship,
and education by publishing worldwide. Oxford is a registered trade mark of
Oxford University Press in the UK and in certain other countries
© Andrew Dickman 2012
The moral rights of the author has been asserted
First Edition published in 2010
Second Edition published in 2012
Impression: 1
All rights reserved. No part of this publication may be reproduced, stored in
a retrieval system, or transmitted, in any form or by any means, without the
prior permission in writing of Oxford University Press, or as expressly permitted
by law, by licence or under terms agreed with the appropriate reprographics
rights organization. Enquiries concerning reproduction outside the scope of the
above should be sent to the Rights Department, Oxford University Press, at the
address above
You must not circulate this work in any other form
and you must impose this same condition on any acquirer
British Library Cataloguing in Publication Data
Data available
Library of Congress Cataloging in Publication Data
Data available
ISBN 978–0–19–966039–1
Printed in Great Britain by
Ashford Colour Press Ltd, Gosport, Hampshire
Oxford University Press makes no representation, express or implied, that the
drug dosages in this book are correct. Readers must therefore always check
the product information and clinical procedures with the most up-to-date
published product information and data sheets provided by the manufacturers
and the most recent codes of conduct and safety regulations. The authors and
the publishers do not accept responsibility or legal liability for any errors in the
text or for the misuse or misapplication of material in this work. Except where
otherwise stated, drug dosages and recommendations are for the non-pregnant
adult who is not breast-feeding.
Some of the medication discussed in this book may not be available through normal
channels and only available by special arrangements. Other examples used in
research studies and recommended in international guidelines are unlicensed or
may be subject to being used outside of their licensed dosage ranges within the UK.
We suggest consulting the BNF and local prescribing guidelines/protocols before
using unfamiliar medication. Some brands are included in the drug monographs,
however these do not constitute recommendations and other brands may be
available. We regret any inconvenience to overseas readers.
Links to third party websites are provided by Oxford in good faith and for
information only. Oxford disclaims any responsibility for the materials contained in
any third party website referenced in this work.
 Dedication
I would like to dedicate this book to my wife, Victoria,
for without her continued inexhaustible support,
this work would not have been possible.
vi

Foreword

It is widely recognized that palliative care encompasses the physical, psy-

chological, social, and spiritual needs of patients, together with support
for their carers. Fundamental to this is good symptom control—if patients
have uncontrolled symptoms then addressing the other domains of care
is often unachievable.
The key elements to symptom control include assessment, diagnosis,
and treatment. The treatment falls into pharmacological and non-
pharmacological modalities. When pharmacological intervention is
deemed necessary, the knowledge to choose the most suitable drug
and the skill to prescribe appropriately is fundamental to good symptom
control.
Drugs in Palliative Care aims to support healthcare professionals, including
doctors, nurses, and pharmacists involved in the management of palliative
care patients, by providing pertinent information in an easily accessible
format about many of the medicines likely to be encountered. The first
edition was highly commended at the BMA Book Awards in 2011. Building
on this success, the newly revised second edition offers up-to-date infor-
mation presented in a logical and comprehensive way, from basic clinical
pharmacology through to succinct monographs. There is clear indexing
to enable readers to access specific drugs and cross-referencing to other
relevant areas.
This book has a place in everyday practice in palliative care, both for
the specialist and also the generalist in supporting decision-making and
prescribing for palliative care patients. It will enable the healthcare pro-
fessional to make the most appropriate choice of drug at the right dose
for the right symptom. Good palliative care is only as good as the health-
care professionals providing it. This book can function as an essential
aide-mémoire and support to healthcare professionals in the provision of
excellent palliative care for patients and their families.
John E Ellershaw MA FRCP
Professor of Palliative Medicine, University of Liverpool
Director, Marie Curie Palliative Care Institute Liverpool (MCPCIL)
 vii

Contents

Detailed contents ix
Symbols and abbreviations xiii

1 Clinical pharmacology overview 1

2 Prescribing guidance 19
3 Drug monographs A–Z 61

Index 555
This page intentionally left blank
 ix

Detailed contents

Symbols and abbreviations xiii

1 Clinical pharmacology overview 1
Introduction 2
Pharmacokinetics 3
Pharmacodynamics 7
Pharmacogenetics 11
Drug interactions 14

2 Prescribing guidance 19
Unlicensed use of medicines 20
Legal categories of medicines 21
Travelling abroad with medicines 23
Drugs and driving 25
Management of pain 28
Management of pain: selection of a NSAID 29
Management of pain: opioid substitution 32
Management of pain: breakthrough pain 35
Management of pain: neuropathic pain 38
Management of pain: poorly controlled pain 40
Management of nausea and vomiting 41
Management of constipation 43
Discontinuing and/or switching antidepressants 45
Continuous subcutaneous infusions 51
Use of drugs in end-of-life care 53

3 Drug monographs A–Z 61

Monographs 63 Bicalutamide 87
Alfentanil 65 Bisacodyl 89
Allopurinol 69 Bisoprolol 91
Amitriptyline 71 Buprenorphine 94
Amoxicillin 74 Cannabis extract 98
Anastrozole 76 Carbamazepine 101
Antacid and oxetacaine 78 Carbocisteine 105
Azathioprine 80 Celecoxib 106
Baclofen 82 Ciprofloxacin 110
Benzydamine 85 Citalopram 113
Betahistine 86 Clarithromycin 117
x DETAILED CONTENTS

Clonazepam 120 Haloperidol 246

Co-amoxiclav 123 Hydromorphone 250
Co-danthramer 126 Hyoscine butylbromide 253
Codeine 128 Hyoscine hydrobromide 256
Cyclizine 132 Ibandronic acid
Cyproheptadine 135 (ibandronate) 259
Cyproterone 137 Ibuprofen 263
Dalteparin 140 Imatinib 266
Demeclocycline 145 Insulin: biphasic
Dexamethasone 147 insulin aspart 269
Diamorphine 152 Insulin: biphasic
Diazepam 156 insulin lispro 272
Diclofenac 159 Insulin: biphasic
Diethylstilbestrol 163 isophane insulin 275
Dihydrocodeine 165 Insulin: insulin aspart 278
Docusate sodium 168 Insulin: insulin detemir 280
Domperidone 170 Insulin: insulin glargine 282
Donepezil 172 Insulin: insulin lispro 285
Doxycycline 174 Insulin: isophane insulin 287
Duloxetine 176 Insulin: soluble 290
Enoxaparin 180 Ipratropium bromide 293
Erlotinib 183 Itraconazole 295
Erythromycin 186 Ketamine 298
Esomeprazole 189 Ketorolac 302
Etamsylate 192 Lactulose 305
Etoricoxib 193 Lansoprazole 307
Exemestane 196 Letrozole 310
Fentanyl (transdermal/ Levetiracetam 312
parenteral) 198 Levomepromazine 315
Fentanyl (transmucosal) 203 Lidocaine 318
Finasteride 211 Loperamide 320
Flucloxacillin 212 Lorazepam 322
Fluconazole 214 Macrogol 3350 324
Flumazenil 217 Magnesium hydroxide 326
Fluoxetine 219 Magnesium-L-aspartate 328
Flutamide 223 Magnesium sulphate 330
Furosemide 225 Medroxyprogesterone 332
Gabapentin 228 Megestrol 335
Gliclazide 232 Metformin 337
Glimepiride 234 Methadone 340
Glipizide 236 Methylnaltrexone 345
Glyceryl trinitrate 238 Methylphenidate 347
Glycopyrronium 241 Metoclopramide 350
Granisetron 244 Metronidazole 353
 DETAILED CONTENTS xi
Miconazole 356 Ranitidine 462
Midazolam 358 Rasagiline 465
Mirtazapine 362 Reboxetine 468
Misoprostol 366 Repaglinide 470
Modafinil 368 Rifampicin 472
Morphine 371 Risperidone 475
Nabumetone 377 Rivastigmine 479
Naloxone 380 Ropinirole 482
Naproxen 381 Salbutamol 485
Nifedipine 384 Salmeterol 488
Nitrofurantoin 387 Senna (sennosides) 490
Nortriptyline 389 Sertraline 491
Nystatin 392 Sevelamer 495
Octreotide 393 Sodium valproate 496
Olanzapine 396 Spironolactone 500
Omeprazole 400 Sucralfate 503
Ondansetron 403 Tamoxifen 505
Oxybutynin 406 Tamsulosin 507
Oxycodone 409 Tapentadol 509
Pamidronate disodium 414 Temazepam 512
Pantoprazole 418 Thalidomide 514
Paracetamol 421 Theophylline 517
Paroxetine 423 Tinzaparin 520
Phenobarbital 427 Tiotropium 523
Phenytoin 430 Tolterodine 525
Pramipexole 433 Tramadol 528
Prednisolone 437 Tranexamic acid 532
Pregabalin 441 Trazodone 534
Prochlorperazine 444 Trimethoprim 538
Propantheline 447 Venlafaxine 540
Propranolol 449 Warfarin 544
Quetiapine 452 Zoledronic acid 547
Quinine sulphate 457 Zolpidem 550
Rabeprazole 459 Zopiclone 552

Index 555
This page intentionally left blank
 xiii

Symbols and abbreviations

9 adverse effects
b cross-reference
5 dose/dose adjustments
A pharmacology
¥ unlicensed indication
5-HT 5-hydroxytryptamine (serotonin)
ACE angiotensin-converting enzyme
ACEI angiotensin-converting enzyme inhibitor
ADH antidiuretic hormone
ALP alkaline phosphatase
ALT alanine transaminase
ALT DIE every other day (alternus die)
AST aspartate transaminase
AV atrioventricular
BD twice a day (bis die)
BP blood pressure
BTcP breakthrough cancer pain
Ca2+ Calcium (ion)
CD1 controlled drug—Schedule 1
CD2 controlled drug—Schedule 2
CD3 controlled drug—Schedule 3
CD4a controlled drug—Schedule 4 part 1
CD4b controlled drug—Schedule 4 part 2
CD5 controlled drug—Schedule 5
CHF congestive heart failure
CNS central nervous system
COPD chronic obstructive pulmonary disease
COX-1 cyclo-oxygenase-1
COX-2 cyclo-oxygenase-2
CrCl creatinine clearance
CSCI continuous subcutaneous infusion
CTZ chemoreceptor trigger zone
CV cardiovascular
CVA cerebrovascular accident
DVT deep vein thrombosis
e/c enteric coated
xiv SYMBOLS AND ABBREVIATIONS

eGFR estimated glomerular filtration rate

g gram(s)
G6PD glucose 6-phosphate dehydrogenase
GFR glomerular filtration rate
GGT gamma glutamyl transpeptidase
GI gastrointestinal
gp glycoprotein
GSL general sales list (medicine)
GTN glyceryl trinitrate
H+ hydrogen (proton)
HPA hypothalamic–pituitary–adrenal
IM intramuscular
INR international normalized ratio
IV intravenous
K+ potassium (ion)
L litre(s)
LFT liver function test(s)
LHRH luteinizing hormone-releasing hormone
LMWH low-molecular-weight heparin
m/r modified release
MAOI monoamine oxidase inhibitor
MHRA Medicines and Healthcare products Regulatory Agency
mg milligram(s)
Mg2+ magnesium (ion)
micromol micromole(s)
min minute(s)
mL millilitre(s)
mm millimetre(s)
mmol millimole(s)
Na+ sodium (ion)
NaCl sodium chloride
NG nasogastric
NICE National Institute for Health and Clinical Excellence
NRI noradrenaline reuptake inhibitor
NRT nicotine replacement therapy
NSAID non-steroidal anti-inflammatory drug
NYHA New York Heart Association
OD daily (omni die)
OM in the morning (omni mane)
ON in the evening (omni nocte)
 SYMBOLS AND ABBREVIATIONS xv
OTC over-the-counter
P pharmacy only (medicine)
PAH polycyclic aromatic hydrocarbon
PDD Parkinson’s disease dementia
PE pulmonary embolism
PM poor metabolizer
PO orally (per os)
POM prescription-only medicine
PPI proton pump inhibitor
PR rectally (per rectum)
PRN when necessary (pro re nata)
QDS four times daily (quarta die sumendus)
SC subcutaneously
SeCr serum creatinine
SIADH syndrome of inappropriate anti-diuretic hormone
hypersecretion
SL sublingually
SPC Summary of Product Characteristics
s/r standard release
SSRI selective serotonin reuptake inhibitor
TCA tricyclic antidepressant
TDS three times daily (ter die sumendus)
U&Es urea and electrolytes
UGT uridine diphosphate glucuronosyltransferase
UM ultrarapid metabolizer
UTI urinary tract infection
VTE venous thromboembolism
WFI Water for Injections
WHO World Health Organization
This page intentionally left blank
 Chapter 1 1

Clinical pharmacology
overview

Introduction 2
Pharmacokinetics 3
Pharmacodynamics 7
Pharmacogenetics 11
Drug interactions 14
2 CHAPTER 1 Clinical pharmacology overview

Introduction
Interpatient variation is a substantial clinical problem when considering
drug therapy. Examples of variation include failure to respond to treat-
ment, increased incidence of undesirable effects, and increased suscep-
tibility to drug interactions. The concept of ‘one dose fits all’ is clearly
incorrect and is demonstrated by the unacceptable rate of hospital admis-
sions caused by adverse drug reactions (75% in the UK and 77% in the
US). This variation is hardly surprising, given all the factors that ultimately
determine an individual’s response to a drug (see Fig. 1.1).

Age Gender Diet

nutrition

Pharmacokinetics
DRUG Pharmacodynamics
RESPONSE

Co- Concurrent Genetic

morbidity medication factors

Fig. 1.1 Factors that influence an individual’s response to drug therapy.

 PHARMACOKINETICS 3

Pharmacokinetics
The rate and manner that a drug is absorbed, distributed, and eliminated
is described by pharmacokinetics. In other words, what the body does to
the drug.
Absorption
The bioavailability of a drug describes the proportion of a dose of a drug
that enters the systemic circulation, e.g. for intravenous (IV) morphine this
would be 100% compared to 15–65% for oral morphine.
For drugs taken orally that are intended for systemic action, a significant
proportion of a given dose may not even enter the systemic circulation.
This may be due to poor absorption from the gastrointestinal (GI) tract,
or metabolism in the gut wall or liver (called first-pass metabolism—see
Box 1.1).

Box 1.1 First-pass metabolism

First-pass metabolism is a term used to describe the metabolism that
occurs between the gut lumen and the systemic circulation. It can reduce
the bioavailability of a drug so much so that oral administration is not
feasible. Although gastric secretions inactivate certain drugs (e.g. insulin),
the main sites of first-pass metabolism are the gut wall and liver.
The cytochrome P450 isoenzyme CYP3A4 (see Box 1.3) is located
in the gut wall and liver. It metabolizes many drugs and therefore alter-
ations in CYP3A4 activity can significantly influence bioavailability. It is
susceptible to inhibition and induction by a variety of drugs and foods.
For example, one glass of grapefruit juice can cause significant inhibi-
tion of intestinal CYP3A4 while repeated consumption can interfere
with hepatic CYP3A4. The majority of orally administered drugs must
pass through the liver before entering the systemic circulation. Some
drugs are susceptible to extensive first-pass metabolism such that only a
small proportion of the oral dose enters the systemic circulation which
renders oral administration impossible (e.g. lidocaine, fentanyl).
First-pass metabolism can be affected by disease, genetic influences, and
enzyme inhibition or induction. This helps to explain the wide interpa-
tient variation in drug absorption and hence bioavailability of several
drugs (e.g. morphine 15–65%).

Several transporter proteins are present in the intestines which influence

the absorption of drugs. P-glycoprotein (P-gp) is an efflux transporter
molecule that can affect the bioavailability of many drugs (see Box 1.2).
Less well categorized influx transporter proteins are also present and
their activity may well be influenced by drugs and food.
4 CHAPTER 1 Clinical pharmacology overview

Box 1.2 The P-glycoprotein (P-gp) drug transporter

P-gp is one of many protein transporters that can influence the bioavail-
ability, distribution, and elimination of many drugs relevant to palliative
care, e.g. P-gp is believed to be a major determinant of the bioavailability
of morphine and tramadol. It is found in the GI tract, kidney, liver, and
blood–brain barrier. There is wide patient variation because P-gp is genet-
ically encoded and is subject to polymorphism (see b Pharmacogenetics,
p.11). Drug interactions can occur through induction or inhibition of
P-gp, the clinical significance of which are just being realized.

Distribution
Many drugs, such as albumin, bind to plasma proteins. Bound drug is inac-
tive; only unbound drug is available to bind to receptors or cross cell
membranes.
Changes in protein binding can alter a drug’s distribution, although this is
rarely clinically important (with the exception of phenytoin).
P-gp is involved in the distribution of several drugs across the blood–brain
barrier, e.g. P-gp limits the entry of morphine into the brain.
Elimination
Various processes are involved in drug elimination, although hepatic and
renal processes are the most important.
Metabolism
The liver is the main organ of drug metabolism. There are generally two
types of reaction (Phase I and Phase II) that have two important effects:
• Make the drug more water soluble—to aid excretion by the kidneys.
• Inactivate the drug—in most cases the metabolite is less active than the
parent drug, although in some cases the metabolite can be as active, or
more so, than the parent. Prodrugs are inactive until metabolized to
the active drug (e.g. codeine is metabolized to morphine).
Phase I metabolism involves oxidation, reduction, or hydrolysis reac-
tions. Oxidation reactions are most common and are catalysed by cyto-
chrome P450 isoenzymes (see Box 1.3) located primarily in the liver.
The main exception is CYP3A4, which is also located in the GI tract (see
b Absorption, p.3).
Phase II metabolism involves conjugation reactions, such as glucuronida-
tion or sulphation, which produce more water-soluble compounds, ena-
bling rapid elimination.
Many drugs are dependent on cytochrome P450 isoenzymes (see
b inside back cover) for metabolism and/or elimination. Genetic varia-
tions or co-administration of inducers or inhibitors can lead to the devel-
opment of significant toxicity or lack of effect.
 PHARMACOKINETICS 5

Drug excretion
The main route of excretion of drugs is the kidney. Renal elimination is
dependent on multiple factors that include:
• Glomerular filtration rate (GFR)
• Active tubular secretion (may involve P-gp)
• Passive tubular secretion.
If a drug is metabolized to mainly inactive compounds (e.g. fentanyl), renal
function will not greatly affect the elimination. If, however, the drug is
excreted unchanged (e.g. pregabalin), or an active metabolite is excreted
via the kidney (e.g. morphine), changes in renal function will influence the
elimination. Dose adjustments may be necessary.

Box 1.3 The cytochrome P450 system

The cytochrome P450 system consists of a large group of >500 isoen-
zymes that are involved in the metabolism of endogenous (e.g. steroids,
eicosanoids) and exogenous (e.g. drugs) compounds. They are grouped
according to amino acid sequence; a family is defined by >40% homology
and a subfamily is defined by >55% homology. Five subfamilies, CYP1A,
CYP2C, CYP2D, CYP2E, and CYP3A have a major role in hepatic drug
metabolism, with others having a lesser role. The following list briefly
describes the isoenzymes involved. Also see b inside back cover for a
list of important substrates, inducers, and inhibitors.
CYP1A subfamily
• CYP1A1: mainly found in lungs and metabolizes tobacco to poten-
tially carcinogenic substances.
• CYP1A2: responsible for metabolism of 715% of drugs; is induced
by tobacco smoke. Also involved in activation of procarcinogens.
Polymorphisms exist, but distribution remains undetermined.
Important substrates include olanzapine and theophylline.
CYP2A subfamily
• CYP2A6: metabolizes small number of drugs including nicotine
and the prodrug tegafur. Also metabolizes tobacco to potentially
carcinogenic substances. Polymorphisms exist, with 1% of the
Caucasian population being poor metabolizers (PMs).
CYP2B subfamily
• CYP2B6: involved in the metabolism of an increasing number
of drugs including ketamine and methadone. Clopidogrel is a
potentially potent inhibitor, while rifampicin induces this isoenzyme.
Polymorphisms exist, but distribution and consequence remain
undetermined.
CYP2C subfamily
• CYP2C8: a major hepatic cytochrome and shares substrates with
CYP2C9. Polymorphisms exist, but distribution and consequence
remain undetermined.
6 CHAPTER 1 Clinical pharmacology overview

Box 1.3 (cont.)

• CYP2C9: the most important of the CYP2C subfamily. Responsible
for the metabolism of many drugs, including warfarin, celecoxib,
ibuprofen, diclofenac, and phenytoin. Is inhibited by several drugs
including fluconazole; rifampicin induces activity of CYP2C9.
Polymorphisms exist; 1–3% of Caucasians have reduced activity and
are poor PMs.
• CYP2C19: involved in the metabolism of several drugs, including
omeprazole, lansoprazole, diazepam, and citalopram. Inhibitors
include modafinil, omeprazole, and fluoxetine. Carbamazepine can
induce this isoenzyme. 3–5% of Caucasians lack the enzyme and are
PMs.
CYP2D subfamily
• CYP2D6: no known inducer. Responsible for the metabolism of
725% of drugs, including codeine, tramadol, and tamoxifen. 5–10% of
Caucasians lack this enzyme and are termed PMs; 1–5% have multiple
copies of the gene and are termed ultrarapid metabolizers (UMs).
CYP2E subfamily
• CYP2E1: has a minor role in drug metabolism. Main importance is
paracetamol metabolism and potential toxicity. Polymorphisms exist,
but distribution and consequence remain undetermined.
CYP3A subfamily
This subfamily is the most abundant in the liver and is responsible for the
metabolism of >50% of drugs, including midazolam and alfentanil. There
are 4 CYP3A genes, although only 2 are likely to be of importance in
human adults. Nonetheless, these isoenzymes are so closely related that
they are often referred to collectively as CYP3A. Polymorphisms exist,
but distribution and consequence remain undetermined.
• CYP3A4: most significant isoenzyme involved in drug metabolism and
is frequently implicated in drug interactions. It is located mainly in the
liver, but significant amounts are present in the GI tract, where it has
an important role in first-pass metabolism. There are several inducers
(e.g. carbamazepine, rifampicin) and inhibitors (e.g. clarithromycin,
grapefruit juice).
• CYP3A5: similar substrate spectrum to CYP3A4, but is possibly
less efficient, so is unlikely to have such a dramatic effect on drug
metabolism.
 PHARMACODYNAMICS 7

Pharmacodynamics
The effect of the drug and how it works in terms of its interaction with
a receptor or site of action is described by pharmacodynamics. In other
words, what the drug does to the body.
Most drugs act upon proteins:
• Receptor (e.g. morphine and μ-opioid receptor)
• Ion channel (e.g. lidocaine and Na+ channel; capsaicin and TRPV1)
• Enzyme (e.g. non-steroidal anti-inflammatory drug (NSAID) and
cyclo-oxygenase)
• Transporter complex (e.g. SSRI0).
The exceptions include antibiotics, cytotoxic drugs, and immunosup-
pressants. The term ‘receptor’ is used loosely to describe the earlier
listed protein targets.
• Agonists bind to and activate receptors to produce an effect.
• Antagonists also bind to receptors without causing activation. They may
prevent the action of, or displace, an agonist.
• Partial agonists activate receptors to a limited extent, but may also
interfere with the action of the full agonist. The circumstances in which
a partial agonist may act as an antagonist or an agonist depends on
both the efficacy (see later in list) of the drug and the pre-existing state
of receptor occupation by an agonist, e.g. buprenorphine will generally
act as an antagonist if a patient is using excessive doses of morphine.
At lower doses of morphine, buprenorphine will act as an agonist.
• Affinity is a term used to describe the tendency of a drug to bind to its
receptors, e.g. naloxone has higher affinity for opioid receptors than
morphine, hence its use in opioid toxicity.
• The intrinsic activity of a drug describes its ability to elicit an effect.
• Efficacy refers to the potential maximum activation of a receptor and
therefore desired response i.e. a full agonist has high efficacy, a partial
agonist has medium efficacy, and an antagonist has zero efficacy.
• Potency refers to the amount of drug necessary to produce an effect,
e.g. fentanyl is more potent than morphine since the same analgesic
effect occurs at much lower doses (micrograms vs. milligrams).
• Very few drugs are specific for a particular receptor or site of action
and most display a degree of relative selectivity. Selectivity refers to
the degree by which a drug binds to a receptor relative to other
receptors. In general, as doses increase, the relative selectivity reduces
such that other pharmacological actions may occur, often manifesting
as undesirable effects, e.g. meloxicam at doses of 7.5mg/day is selective
for COX-2, but at higher doses it loses this selectivity and also binds
to COX-1.
• Tolerance is the decrease in therapeutic effect that may occur, over a
period of time, by identical doses of a drug. Although often expected,
this has yet to be conclusively identified for opioid analgesia
• Tachyphylaxis is the rapid development of tolerance. It can occur with
salcatonin (calcitonin), leading to a rebound hypercalcaemia.
8 CHAPTER 1 Clinical pharmacology overview

• Therapeutic index or margin is the ratio between the dose producing

undesired effects and the dose producing therapeutic effects. Drugs
with narrow therapeutic margins are often implicated in drug
interactions.
• Competitive antagonism describes the situation that occurs when an
antagonist competes with the agonist for the binding site of receptors.
In such a situation, increasing the concentration of the agonist will
favour agonist binding (and vice versa).
• Irreversible competitive antagonism can occur when the antagonist
disassociates very slowly, or not at all, from receptors. Increasing the
dose of the agonist does not reverse the situation.
• Non-competitive antagonism occurs when the antagonist blocks the
effects of the agonist by interaction at some point other than the
receptor binding site of the agonist.
Effect of hepatic impairment
Impaired liver function can affect the pharmacokinetics and pharmacody-
namics of many drugs. Reduction in hepatic blood flow and a potential
fall in the number and the activity of hepatocytes can alter liver function
and impact on drug clearance. A reduced synthesis of albumin can result
in reduced drug–protein binding thereby affecting the volume of distri-
bution. Cholestasis can affect the biliary excretion of drugs and metabo-
lites. Patients with impaired hepatic function may also develop a degree of
renal impairment due to decreased renal plasma flow and GFR. Use of the
Cockcroft and Gault equation (see Box 1.4) can overestimate renal func-
tion due to a reduced synthesis of creatinine.
Unlike impaired renal function, there is no simple test that can determine
the impact of liver disease on drug handling. A combination of factors
needs to be considered before such impact can be assessed, which include
liver function tests (LFTs), diagnosis, and physical symptoms.
In general, the metabolism of drugs is unlikely to be affected unless the
patient has severe liver disease. Most problems are seen in patients with
jaundice, ascites, and hepatic encephalopathy. As such, doses of drugs
should be reviewed in the following situations:
• Hepatically metabolized drug with narrow therapeutic index.
• Renally excreted drug with narrow therapeutic index.
• There is a significant involvement of the cytochrome P450 system
(CYP3A4/5 is highly susceptible to liver disease, while CYP2D6 appears
relatively refractory).
• International normalized ratio (INR) >1.2.
• Bilirubin >100micromol/L.
• Albumin <30g/L.
• Signs of ascites and/or encephalopathy.
Where possible, dosage amendments will be discussed in each monograph.
Effect of renal impairment
The elimination of many drugs and metabolites is dependent upon renal func-
tion. Impaired renal function, coupled with rising urea plasma concentrations,
 PHARMACODYNAMICS 9

induces changes in drug pharmacokinetics and pharmacodynamics.

Implications for drug therapy include:
• Increased risk of undesirable effects and toxicity through reduced
excretion of the drug and/or metabolite(s), e.g. pregabalin, morphine.
• Increased sensitivity to drug effects, irrespective of route of elimination,
e.g. antipsychotics.
• Increased risk of further renal impairment, e.g. NSAIDs.
Many of these problems can be avoided by simple adjustment of daily
dose or frequency of administration. In other situations, however, an
alternative drug may need to be chosen. It is worth noting that patients
with end-stage renal disease may be at risk of increased drug toxicity due
to the reduced activity of CYP3A4/5 and CYP2D6.
Estimating renal function
Unlike liver impairment, the impact of declining renal function is quantifi-
able. Accurate methods of determining renal function, or GFR are unsuit-
able for routine clinical use. Serum creatinine (creatinine is a product of
muscle metabolism) has been used as a simple tool to estimate GFR.
However, there are serious limitations to this approach:
• As renal function deteriorates, serum creatinine increases. However,
many patients may have reduced GFR but serum creatinine concen-
trations fall inside the conventional laboratory normal ranges, e.g. an
increase from 50micromol/L to 100micromol/L is still within normal
limits, even though renal function has clearly deteriorated.
• Renal function declines with age, but serum creatinine generally
remains stable. Thus a 75-year-old may have the same serum creatinine
as a 25-year-old, despite having a reduced renal function.
Creatinine clearance serves as a surrogate for GFR. It can be determined
from the Cockcroft and Gault equation (see Box 1.4), which takes weight,
age, gender, and serum creatinine into consideration. The majority of
dosage adjustment guidelines in the monographs are based upon creati-
nine clearance. There are limitations, however, with this method as it may
report inaccurately for obese and underweight patients.

Box 1.4 Cockcroft and Gault equation for calculating

creatinine clearance
CrCl = ([140−‘age’] x [‘weight (kg)’] x F)/(SeCr (‘micromol/L’))
Where F = 1.23 (male)
1.04 (female)

In the UK, renal function is increasingly being reported in terms of esti-

mated GFR (eGFR), normalized to a body surface area of 1.73m2. The
formula used to calculate eGFR was derived from the Modification of Diet
in Renal Disease (MDRD) study. eGFR assumes the patient is of average
size (assumes an average body surface area of 1.73m2), allowing a figure to
be determined using only serum creatinine, age, gender, and ethnic origin.
It is primarily a tool for determining renal function, of which 5 categories
have been described (see Table 1.1).
10 CHAPTER 1 Clinical pharmacology overview

eGFR is only an estimate of the GFR and has not been validated for use in
the following groups or clinical scenarios:
• Children (<18 years of age)
• Acute renal failure
• Pregnancy
• Oedematous states
• Muscle wasting disease states
• Amputees
• Malnourished patients.

Table 1.1 Stages of renal failure

Stage eGFR (mL/min/1.73m2)
a
1 Normal GFR >90
2 Mild impairmenta 60–89
3 Moderate impairment 30–59
4 Severe impairment 15–29
5 Established renal failure <15
a
The terms stage 1 and stage 2 chronic kidney disease are only applied when there
are structural or functional abnormalities. If there are no such abnormalities, an
eGFR t60 mL/min/1.73m2 is regarded as normal.

While eGFR may be used to determine dosage adjustments in place of

creatinine clearance for most drugs in patients of average build, application
in palliative care patients may produce erroneous results. For example,
the eGFR may underestimate the degree of renal impairment in cachectic
or oedematous patients resulting in excessive doses. For palliative care
patients, providing height and weight are known, it would be prudent to
calculate the absolute GFR (GFRABS) (see Box 1.5) and use this to deter-
mine dosage adjustments.

Box 1.5 Calculating absolute GFR (GFRABS) and body

surface area (BSA)
BSA
GFRABS = eGFR ×
1.73

(height (cm) x weight (kg))

BSA =
3600
 PHARMACOGENETICS 11

Pharmacogenetics
If it were not for the great variability among individuals, medicine might as
well be a science and not an art.
Sir William Osler, 1892
Just over 50 years ago, two adverse drug reactions were described as
being caused by genetic mechanisms. G6PD deficiency and pseudo-
cholinesterase deficiency were shown to be manifestations of specific
gene mutations. Two years later, in 1959, the term ‘pharmacogenetics’
was introduced. It was only towards the end of the last century that sig-
nificant advances were made. As a result of the Human Genome Project,
a broader term, ‘pharmacogenomics’, was introduced (see Box 1.6).

Box 1.6 Basic genetic concepts

The human genome consists of 23 pairs of chromosomes (or 22 pairs
of autosomes and 1 pair of sex-linked chromosomes) within which are
sequences of DNA that are referred to as genes. With the exception of
the sex-linked X- and Y-chromosomes, an individual inherits 2 copies
of each gene, 1 from each parent. A gene can exist in various forms, or
alleles. Only 3% of the human genome encodes proteins.
An individual’s inherited genetic profile, or genotype, may be described
as being:
• Homozygous dominant (i.e. a specific gene consists of 2 identical
dominant alleles).
• Heterozygous (i.e. a specific gene consists of 2 different alleles,
1 usually being dominant, the other recessive).
• Homozygous recessive (i.e. a specific gene consists of 2 identical
recessive alleles).
An individual’s phenotype describes the observable characteristics that
are a result of the genotype and environment. Particular inherited
phenotypical traits may be described as being autosomal dominant or
recessive.
Pharmacogenetics is the study of how variation in an individual gene
affects the response to drugs which can lead to adverse drug reactions,
drug toxicity, therapeutic failure, and drug interactions.
Pharmacogenomics is the study of how variation in the human genome
can be used in the development of pharmaceuticals.
Polymorphisms refer to commonly occurring genetic variants (i.e. differ-
ences in DNA sequences). In most regions of the genome, a polymor-
phism is of little clinical consequence. However, a polymorphism in a
critical coding or non-coding region can lead to altered protein synthesis
with clinical implications such as abnormal drug responses.
12 CHAPTER 1 Clinical pharmacology overview

Genetic variability can affect an individual’s response to drug treatment by

influencing pharmacokinetic and pharmacodynamic processes, e.g. varia-
tions in genes that encode cytochrome P450 isoenzymes, drug receptors,
or transport proteins can determine clinical response. Pharmacogenetics
can aid in the optimization of drug therapy through the identification of
individuals who are likely to respond to treatment, or those who are most
likely at risk of an adverse drug reaction. Although the exact proportion
of adverse drug reactions caused by genetic variability is unclear, emerging
evidence suggests an increasing role. Pharmacogenetic testing is currently
in early development, but current examples include:
• The need for human epidermal growth factor 2 (HER2) testing before
initiating trastuzumab (Herceptin®) therapy.
• Genetic testing of Han Chinese is recommended for patients before
commencing carbamazepine therapy due to an association between
toxic skin reactions and a specific genotype.
Pharmacogenetic testing has the potential to improve the safety and effi-
cacy of several drugs commonly encountered in palliative care, e.g. analge-
sics, antidepressants, and antipsychotics.
Genetic influences on pharmacokinetics
Variations in genes that encode transport proteins have been implicated in
altered therapeutic response, e.g. P-gp polymorphisms have been associ-
ated with altered morphine analgesia. However, the characterization and
implications of transporter protein variations are less developed when
compared to drug metabolism. There is no doubt that polymorphism of
metabolic enzymes has a great effect on interpatient variability.
Several polymorphisms that affect drug metabolism have been identified
and there is substantial ethnic variation in distribution. Functional changes
as a result of a polymorphism can have profound effects:
• Adverse drug reaction
• Toxicity
• Lack of effect
• Drug interaction.
The isoenzymes CYP2C9, CYP2C19, and CYP2D6 are responsible for
740% of cytochrome P450-mediated drug metabolism. They display high
levels of polymorphism which have been shown to affect the response
of individuals to many drugs (see Box 1.7). Pharmaceutical manufacturers
have realized the importance of pharmacogenetics; fewer drugs will be
developed that are affected by pharmacogenetic factors because potential
agents will be discarded at an early stage of development.

Box 1.7 Examples of the effect P450 polymorphisms have

on selected drugs
Analgesia
• Codeine: needs to be metabolized by CYP2D6 to morphine before
analgesia is observed. PMs derive no analgesia from codeine. Drugs
that inhibit CYP2D6 will mimic the PM phenotype. UMs are at risk
of life-threatening adverse drug reactions as codeine is metabolized
at a very high rate.
 PHARMACOGENETICS 13

Box 1.7 (cont.)

• Methadone: shows complex pharmacology. Mainly metabolized by
CYP3A, but CYP2B6 and CYP2D6 are also involved. PMs of CYP2B6
and CYP2D6 are at risk of developing toxicity if methadone is
titrated too quickly.
• NSAIDs: is a suggestion that specific CYP2C8/9 genotypes can cause
increased risk of toxicity to NSAIDs.
• Tamoxifen: the active metabolite, endoxifen, is produced by a
reaction involving CYP2D6. Patients with a PM phenotype are at risk
of therapeutic failure with tamoxifen. Drugs that inhibit CYP2D6 will
also mimic the PM phenotype and should be avoided.
• Theophylline: the metabolism of theophylline is highly dependent on
CYP1A2 activity, which varies with specific genotypes.
• Tramadol: is primarily metabolized by CYP2D6 to an active
compound, M1, which is a more potent opioid agonist. PMs show
a poor response to tramadol. As with codeine, drugs that inhibit
CYP2D6 can mimic the PM phenotype.

Genetic polymorphisms of cytochrome P450 isoenzymes (see b Box 1.3,

p.5) can be divided into 4 phenotypes:
• Poor metabolizers (PM) have 2 non-functional alleles and cannot
metabolize substrates.
• Intermediate metabolizers (IM) have 1 non-functional allele and
1 low-activity allele, so metabolize substrates at a low rate.
• Extensive metabolizers (EM) have 1 or 2 copies of a functional allele and
metabolize substrates at a normal rate.
• Ultrarapid metabolizers (UM) have 3 or more copies of a functional
allele and metabolize substrates at an accelerated rate.
The consequences of a particular phenotype depend upon the activity of
the drug. PMs are at an increased risk of therapeutic failure (through poor
metabolism to an active compound) or undesirable effects (due to excessive
dose). In contrast, UMs are at increased risk of therapeutic failure with con-
ventional doses due to excessive metabolism; in the case of a prodrug, rapid
production of the active compound could lead to toxicity. For example, a
patient with UM phenotype for CYP2D6 may rapidly convert codeine to
morphine, increasing the risk of developing toxicity; a patient with PM status
for CYP2D6 will derive little, if any analgesic benefit from codeine.
Genetic influences on pharmacodynamics
Genetic polymorphisms of drug receptors, or disease-related pathways,
can influence the pharmacodynamic action of drug. These are generally
less well categorized than pharmacokinetic consequences. Nonetheless,
genetic variations have been shown to be clinically relevant for mor-
phine analgesia and antidepressant therapy. In the latter case, associations
between serotonin transport gene polymorphisms and depression have
been demonstrated. It has also been shown that genotyping for polymor-
phisms of certain serotonin or noradrenaline pathways can inform clinical
choice of antidepressant, e.g. a patient that fails to respond to citalopram
(selective serotonin reuptake inhibitor (SSRI)) could in fact respond to
reboxetine (noradrenaline reuptake inhibitor (NRI)).
14 CHAPTER 1 Clinical pharmacology overview

Drug interactions
Be alert to the fact that all drugs taken by patients, including over-the-
counter medicines, herbal products, and nutritional supplements, have
the potential to cause clinically relevant drug interactions. The patient’s
diet can also affect drug disposition.

The pharmacological actions of a drug can be enhanced or diminished by

other drugs, food, herbal products, and nutritional supplements. Clinically
relevant and potentially significant drug–drug interactions are included in
the monographs.
In terms of a drug–drug interaction, the actions of the object drug are
altered by the precipitant in most cases. Occasionally, the actions of both
object and precipitant can be affected.
While it is possible to predict the likelihood of a drug interaction, it is
often difficult to predict the clinical relevance. Elderly patients or those
with impaired renal and/or hepatic function are more at risk. Drug interac-
tions may be overlooked and explained as poor compliance, or even pro-
gressive disease. Knowledge of drug interaction processes can aid in the
diagnosis of unexplained or unexpected response to drug therapy.
It is impossible to accurately determine the incidence of drug interactions.
Knowledge of many drug–drug interactions comes from isolated case
reports and/or small studies in healthy volunteers. It is, however, possible
to indirectly assess a patient’s risk; there are several factors that predis-
pose patients receiving palliative care to a drug interaction (see Box 1.8).

Box 1.8 Factors that predispose a patient to drug

interactions
• Advancing age
• Multiple medications
• Compromised renal/hepatic function
• More than one prescriber
• Comorbidity.

While the majority of risks cannot be reduced, they can be anticipated

and managed. For example, a thorough medication history should be
taken upon presentation and must include over-the-counter medications,
herbal products, or nutritional supplements. In some cases, changes to
diet should be enquired about, e.g. the effect of warfarin can be reduced
by a diet suddenly rich in leafy, green vegetables (a source of vitamin K).
As part of the multidisciplinary team, the pharmacist is an excellent source
of information and is often involved in the recording of drug histories.
There are 2 main mechanisms involved in drug interactions:
• Pharmacokinetic
• Pharmacodynamic.
 DRUG INTERACTIONS 15

Pharmacokinetic
The precipitant drug alters the absorption, distribution, metabolism, or
excretion of the object drug. Pharmacokinetic drug interactions are likely
to be encountered in palliative care since many of the drugs used are
substrates or inducers/inhibitors of cytochrome P450 isoenzymes (see
b Metabolism, p.4). These interactions are often difficult to predict.
Absorption

CYP3A4, mainly found in the liver, is also present in the gut wall. It
is involved in reducing the absorption of many drugs and is subject
to both induction and inhibition (see b Metabolism, p.4). Grapefruit
juice inhibits the action of CYP3A4 in the bowel (and liver with repeated
consumption) and can lead to significant increases in bioavailability of
several drugs, e.g. ciclosporin, diazepam, sertraline, simvastatin. This
interaction is highly variable since the active component of the juice
cannot be standardized. This interaction can occur even after con-
suming just 200mL of grapefruit juice and inhibition can persist for up
to 72 hours. An interaction may occur, whatever the source, e.g. fresh
grapefruit and grapefruit juices including fresh, frozen, or diluted from
concentrate. Drugs with a narrow therapeutic index are more likely to
be affected.

The rate of absorption or amount of object drug absorbed can be altered

by the precipitant. Delayed absorption is rarely of clinical relevance unless
the effect of the object drug depends upon high peak plasma concentra-
tions (e.g. the effect of paracetamol can be enhanced by combination with
metoclopramide). If the amount of drug absorbed is affected, clinically
relevant effects can occur.
Absorption interactions involving simple insoluble complex formation
can be easily avoided by changing the administration time of the drugs
involved, e.g. ciprofloxacin and antacids.
Some interactions involve the induction or inhibition of P-gp (see
b Box 1.2, p.4), although the clinical significance of many such inter-
actions remains unclear. Enhanced activity of P-gp will reduce the absorp-
tion and bioavailability of a drug. The effect of drugs and food on influx
transporters is currently less well categorized but could well contribute to
unexplained and unanticipated drug effects.
Distribution
Such interactions are usually of little clinical relevance and often involve
alterations in protein binding.
The distribution of some drugs is dependent on the activity of P-gp, which
also appears to act as a component of the blood–brain barrier, e.g. P-gp
can limit the entry of hydrophilic opioids into the brain. The clinical signifi-
cance of induction or inhibition of P-gp is unclear.
Metabolism
Many drugs are metabolized via the hepatic cytochrome P450 system
(see b Box 1.3, p.5) which is subject to both inhibition and induction.
16 CHAPTER 1 Clinical pharmacology overview

CYP3A4 may account for up the metabolism of up to 50% of currently

used drugs; CYP2D6 may account for up to 25% (see b inside back
cover). The effect that smoking can have on drug therapy should not be
overlooked (see Box 1.9).

Box 1.9 Smoking and potential drug interactions

• Tobacco smoke contains several polycyclic aromatic hydrocarbons
(PAHs) that are potent inducers of CYP1A1, CYP1A2, and, to
a lesser extent, CYP2E1. PAHs can also induce glucuronide
conjugation.
• Induction of CYP1A1 in the lungs causes activation of pro-carcinogens
from tobacco smoke and is believed to be a major mechanism in the
development of lung cancer.
• Although CYP1A1 is not important for drug metabolism, several
drugs are substrates of CYP1A2 (see b inside back cover).
Metabolism of these drugs can be induced by tobacco smoke,
potentially resulting in increased clearance of the drug and
consequent clinically significant reductions in effects. Smokers may
require higher doses of these drugs.
• Note that exposure to ‘second-hand’ smoke can produce similar
effects.
• The PAHs cause these pharmacokinetic drug interactions, not the
nicotine. Thus, nicotine replacement therapy (NRT) will not cause
these effects.
• Tobacco smoke and NRT are both implicated in several
pharmacodynamic drug interactions. Nicotine can have an alerting
effect, thereby countering the action of other drugs.
• The prescriber should consider a dosage reduction of drugs
metabolized by CYP1A2 if a patient stops smoking. Similarly, doses
of anxiolytics and hypnotics should be reviewed, unless NRT is
initiated. If a patient starts smoking, doses of drugs metabolized
by CYP1A2 may need increasing whereas doses of anxiolytics and
hypnotics may need reviewing.

• Enzyme inhibition is the mechanism most often responsible for

life-threatening interactions. It can also result in reduced drug effect
where activation of a prodrug is required (e.g. codeine has a reduced
analgesic profile when administered with CYP2D6 inhibitors). Inhibition
is generally caused by competitive binding for the isoenzyme between
object and precipitant. It follows that high doses of the precipitant will
cause a greater degree of inhibition. Clinically relevant interactions
can be evident within 2 days. The effect of enzyme inhibition generally
depends upon the half-life of the precipitating drug and the therapeutic
index of the object drug. The effect will decrease as blood levels fall.
Note that drugs competing for the same isoenzyme can give rise to
competitive inhibition. The more drugs that are co-prescribed, the
greater the risk of this occurring.
 DRUG INTERACTIONS 17

• Induction can occur when the precipitant stimulates the synthesis of

more isoenzyme, increasing metabolic capacity. It can take several days
or even weeks to develop and may persist for a similar duration once
the precipitant has been withdrawn. Problems with toxicity can occur
if doses of the object drug are increased but are not reduced once the
precipitant is stopped.
• Many drugs are not always metabolized by one specific pathway and
for this reason it is often difficult to precisely predict the outcome
of a drug interaction. Nonetheless, although in vivo data may not be
available for many drugs, in vitro evidence of metabolism and specific
cytochrome P450 isoenzyme involvement can be used to anticipate and
avoid a potentially dangerous drug interaction. The drug monographs
(see b Chapter 3) mention actual and potential drug interactions.
Elimination
In palliative care, it is likely that the most common and potentially more
clinically relevant elimination drug interactions will involve renal function.
For example, with advancing age, renal function declines but compensa-
tory mechanisms are activated that involve the production of vasodila-
tory prostaglandins. NSAIDs can significantly impair this compensatory
measure, such that there is a marked reduction in renal function and con-
sequential risk of drug interactions.
Pharmacodynamic
The pharmacological actions of the object drug are changed by the pres-
ence of the precipitant. Pharmacodynamic interactions can be additive or
antagonistic in nature.
Additive
When 2 or more drugs with similar pharmacodynamic effects are
co-prescribed, the additive results may result in exaggerated response or
toxicity. Additive responses can occur with the main therapeutic action
of the drug as well as the undesirable effects, e.g. SSRI plus tramadol may
give rise to the serotonin syndrome (see Box 1.10).
Antagonistic
When 2 drugs with opposing pharmacodynamic effects are co-prescribed,
there may be a net reduction in response to 1 or both drugs, e.g. warfarin
and vitamin K, NSAIDs and angiotensin-converting enzyme (ACE) inhibitors,
metoclopramide and cyclizine.
18 Clinical pharmacology overview

Box 1.10 The serotonin syndrome

Serotonin syndrome is a potentially life-threatening condition associ-
ated with increased serotonergic activity in the central nervous system
(CNS). It can occur as the result of co-administration of drugs that have
the net effect of increasing serotonergic neurotransmission. It may also
occur after initiation of a single serotonergic drug or by simply increasing
the dose of a serotonergic drug.
The syndrome is characterized by a triad of mental, autonomic, and neu-
rological disorders with a sudden onset of <24 hours after the begin-
ning of treatment. Diagnosis is complex, but includes the addition of a
serotonergic agent to an already established treatment (or increase
in dosage) and manifestation of at least 4 major symptoms or 3 major
symptoms plus 2 minor ones:
• Mental (cognitive and behavioural) symptoms:
• Major symptoms: confusion, elevated mood, coma or semicoma
• Minor symptoms: agitation and nervousness, insomnia
• Autonomic symptoms:
• Major symptoms: fever, hyperhidrosis
• Minor symptoms: tachycardia, tachypnoea and dyspnoea,
diarrhoea, low or high blood pressure
• Neurological symptoms:
• Major symptoms: myoclonus, tremors, chills, rigidity,
hyper-reflexia
• Minor symptoms: impaired coordination, mydriasis, akathisia.
Implicated drugs include:
• Citalopram, fluoxetine, paroxetine
• Trazodone, venlafaxine
• Sumatriptan
• Tramadol
• Ondansetron, granisetron.
Treatment is largely symptomatic and includes the discontinuation of the
serotonergic agents; most patients improve completely within 24 hours
upon withdrawal. Benzodiazepines may be used for anxiety and although
effectiveness has not been demonstrated, cyproheptadine or olanzapine
(both 5-HT2A antagonists) may be useful.
 Chapter 2 19

Prescribing guidance

Unlicensed use of medicines 20

Legal categories of medicines 21
Travelling abroad with medicines 23
Drugs and driving 25
Management of pain 28
Management of pain: selection of a NSAID 29
Management of pain: opioid substitution 32
Management of pain: breakthrough pain 35
Management of pain: neuropathic pain 38
Management of pain: poorly controlled pain 40
Management of nausea and vomiting 41
Management of constipation 43
Discontinuing and/or switching antidepressants 45
Continuous subcutaneous infusions 51
Use of drugs in end-of-life care 53
20 CHAPTER 2 Prescribing guidance

Unlicensed use of medicines

In the UK, the Medicines and Healthcare products Regulatory Agency
(MHRA) grants a marketing authorization (previously referred to as
product licence) to pharmaceutical companies enabling them to market
and supply a product for the specific indication(s) mentioned in the
summary of product characteristics. It is also possible for pharmaceutical
companies to receive a European wide marketing authorization through
the European Medicines Agency.
The Medicines Act 1968 defines the actions of a doctor; this Act ensures
a doctor can legally prescribe unlicensed medicines (those without a mar-
keting authorization) or licensed medicines for ‘off-label’ purposes (e.g.
unlicensed dose, route, or indication). Supplementary prescribers can also
prescribe licensed medicines for off-label purposes as well as unlicensed
medicines provided it is part of a patient’s clinical management plan.
Independent nurse and pharmacist prescribers can prescribe licensed
medicines for off-label purposes (must be accepted practice) and unli-
censed medicines.
Although the use of unlicensed medicines in palliative care is rare, the use of
licensed medicines for unlicensed indications, i.e. ‘off label,’ is both common
and necessary and is generally encountered on a daily basis. Off-label use of
medicines is highlighted in relevant monographs by the symbol ¥.
The patient should be informed that a drug is to be used beyond its mar-
keting authorization and consent should be documented in the patient’s
case notes. Although some may feel this is impractical, given the wide-
spread use in palliative care, certain inpatient units gain consent during the
admission process.
 LEGAL CATEGORIES OF MEDICINES 21

Legal categories of medicines

Medicines for human use are classified in the following way. There are
3 classes of medicine, as defined by the Medicines Act 1968:
• General Sales List (GSL): a medicinal product that can be sold or
supplied without the supervision of a pharmacist.
• Pharmacy Medicine (P): a medicinal product that is available for sale
from a pharmacy under the supervision of a pharmacist.
• Prescription-Only Medicine (POM): a medicinal product that can be sold
or supplied from a pharmacy in accordance with a prescription from an
appropriate practitioner.
Controlled drugs (CDs) are further governed by the Misuse of Drugs
Regulations 2001, as amended. These drugs are classified into 5 schedules
according to different levels of control.
• Schedule 1 (CD1): production, possession, and supply of drugs in this
Schedule are limited in the public interest to purposes of research
or other special purposes. Includes drugs such as cannabis, LSD and
ecstasy-type substances which have virtually no therapeutic use.
• Schedule 2 (CD2): includes the opioids (e.g. alfentanil, diamorphine,
fentanyl, methadone, and morphine) and amphetamine (e.g.
methylphenidate). Note that parenteral codeine and dihydrocodeine
are classified as Schedule 2 drugs. These drugs are subject to
prescription requirements (see Box 2.1), safe custody (i.e. CD
cupboard), and the need for drug registers.
• Schedule 3 (CD3): includes barbiturates, buprenorphine, midazolam,
and temazepam. These drugs are subject to prescription
requirements (except temazepam), but not safe custody (except
temazepam, buprenorphine, flunitrazepam, and diethylpropion) nor is
there a need to keep drug registers (although certain centres may insist
upon this as good practice). Note that there is no requirement to store
midazolam or phenobarbital in a CD cupboard.
• Schedule 4 Part 1 (CD4a): includes the benzodiazepines (except
midazolam and temazepam), ketamine, and zolpidem. These drugs are
not subject to CD prescription or safe storage requirements and there
is no need for a register.
• Schedule 4 Part 2 (CD4b): includes androgenic and anabolic steroids.
These drugs are not subject to CD prescription or safe storage
requirements and there is no need for a register.
• Schedule 5 (CD5): includes certain CDs, e.g. codeine, co-phenotrope,
pholcodine, and morphine, which are exempt from full control when
present in medicinal products of low strength.
22 CHAPTER 2 Prescribing guidance

The quantity of Schedule 2, 3, or 4 CDs to be prescribed at any one time

should not exceed 30 days’ supply. This represents good practice rather
than a legal requirement as there may be circumstances where there is
a genuine need to prescribe more than 30 days’ supply. Note, however,
that prescriptions for Schedule 2, 3, or 4 CDs are only valid for 28 days.

Box 2.1 Prescription requirements for Schedule 2 and 3

controlled drugs
Prescriptions for CDs must be indelible, be signed by the prescriber,
be dated, and specify the prescriber’s address. The prescription must
always state:
• The name and address of the patient.
• In the case of a preparation, the form, and, where appropriate, the
strength of the preparation.
• Either the total quantity (in both words and figures) of the
preparation, or the number (in both words and figures) of dosage
units to be supplied; in any other case, the total quantity (in both
words and figures) of the CD to be supplied.
• The dose.
• The words ‘for dental treatment only’ if issued by a dentist.
 TRAVELLING ABROAD WITH MEDICINES 23

Travelling abroad with medicines

• When planning to travel abroad, patients need to be aware of the laws
that govern medicine use in both the UK and their destination(s). It is
the patient’s responsibility to take the necessary steps to ensure
compliance with these laws.
• Note that certain OTC medicines in the UK may be CDs in other
countries.
• If any medicines are to be taken abroad (including OTC medicines,
e.g. co-codamol 8/500), the patient should contact the Embassy,
Consulate, or High Commission of the country or countries to be
visited regarding local policies on the import of medicines (see
Box 2.2).
• UK requirements for export/import depend upon the medicines in
question and the duration of travel abroad.

Box 2.2 Useful contact details

Embassy, Consulate, and High Commission
• M http://www.homeoffice.gov.uk/publications/alcohol-drugs/drugs/
drug-licences/embassy-list
Application form for personal licence
• M http://www.homeoffice.gov.uk/drugs/licensing/personal
Home Office
• Home Office
Drugs Licensing
Peel Building
2 Marsham Street
LONDON
SW1P 4DF
• Email: licensing_enquiry.aadu@homeoffice.gsi.gov.uk
• Tel: 0207 035 0467

Less than 3 months

• For all POMs, patients are advised to carry a letter from the prescribing
doctor that states:
• patient’s name, address, and date of birth
• outbound and inbound dates of travel
• destination(s)
• name, form, dose, and total amount of medicine(s) being carried.
• Certain countries may require additional information, such as details
of the illness. This information can be obtained from the Embassy,
Consulate, or High Commission.
24 CHAPTER 2 Prescribing guidance

More than 3 months

• Patients carrying any amount of medicines listed in Schedules 2, 3 or 4
(part 1) of the Misuse of Drugs Regulations 2001 will require a personal
export/import licence. The application form can be downloaded from
the Home Office website (see Box 2.2).
• The application must be supported by a covering letter from the
prescriber, which should state:
• patient’s name and address
• quantity of medicine(s) to be carried
• name, strength, and form of medicine(s) to be carried
• destination(s)
• outbound and inbound dates of travel.
• The completed form, together with covering letter, should be sent to
the Home Office (see Box 2.2).
• Alternatively, the completed form, together with a scanned copy of the
covering letter may be emailed to the Home Office (see Box 2.2).
• The patient must be advised that application for a personal licence can
take at least 2 weeks.
• Patients taking other POMs abroad are advised to carry a letter from
the prescribing doctor that states:
• patient’s name, address, and date of birth
• outbound and inbound dates of travel
• destination(s)
• name, form, dose, and total amount of medicine(s) being carried.
• Certain countries may require additional information, such as details
of the illness. This information can be obtained from the Embassy,
Consulate, or High Commission.
• When travelling by air, POMs should be carried:
• in original packaging
• in hand luggage*
• with a valid personal licence (if applicable)
• with a covering letter from the prescriber, unless a personal licence
is held.
*Due to liquid restrictions, airport and airline regulations must be checked
prior to departure. As of June 2008, medicines essential for the journey
may be permitted in quantities >100mL. The patient must have secured
the prior agreement of the airline and airport, in addition to having the
documentation previously described.
 DRUGS AND DRIVING 25

Drugs and driving

It is an offence to drive, attempt to drive, or be in charge of a vehicle
when unfit through drugs; the law does not distinguish between illegal
drugs and prescribed medication. Patients should be advised that impair-
ment might be present even in the absence of subjective symptoms. The
effects may be more pronounced in the elderly.

Some prescription drugs and OTC medicines can impair skills needed
for safe driving. Examples of such effects include blurred vision, dizziness,
drowsiness, hypotension, and impaired judgement. In many cases, these
effects are dose-dependent and may diminish with time. In general, any
drug with a prominent CNS effect has the potential to impair an indi-
vidual’s ability to operate a vehicle. The Driver and Vehicle Licensing
Agency (DVLA) recommends that healthcare professionals prescribing or
dispensing medication should consider the risks associated with each drug,
or combination of drugs, and take the opportunity to appropriately advise
their patients.
Patients should generally be warned to avoid driving either after com-
mencing or when titrating potentially sedating medication. Driving should
not be attempted unless the patient feels safe to do and the undesirable
effects of the drug(s) have diminished. This may take up to a week after
commencing or increasing doses of certain drugs (e.g. opioids). If a patient
uses rescue doses of oral opioids to treat pain flares (whether due to
BTcP, or poorly controlled background pain), driving should be avoided
for up to 3 hours, or until after any effect subsides. Patients should also be
warned that cognitive effects will be exacerbated by the concurrent use of
alcohol, or other medication, whether prescribed or bought OTC.
When considering the prescription of new drugs, the patient’s existing
treatment should be reviewed. Drug interactions may affect drug metabo-
lism and excretion, or could produce additive or synergistic interactions.
Refer to the drug monographs in b Chapter 3 for relevant prescribing
information, including possible effects on driving and potential drug inter-
actions. A selection of drugs that may cause problems is described as
follows.
Anticholinergic drugs
• Examples include amitriptyline, cyclizine, glycopyrronium, hyoscine
(butyl- and hydrobromide), levomepromazine, nortriptyline (less than
amitriptyline), olanzapine, oxybutynin, paroxetine, and propantheline.
• Anticholinergic effects that can impair driving performance include
ataxia, blurred vision, confusion and sedation.
26 CHAPTER 2 Prescribing guidance

Antidepressants
• Examples include amitriptyline, citalopram, fluoxetine, mirtazapine,
nortriptyline, paroxetine, trazodone, and venlafaxine.
• In general, antidepressants that have antihistamine, anticholinergic, or
A-adrenergic properties are likely to be problematic. While the
undesirable effects of the SSRIs tend to be mild and well-tolerated,
patients should be made aware of potential problems that may impair
driving, such as sleep disturbances (e.g. insomnia, leading to daytime
drowsiness), anxiety, and restlessness.
• Mirtazapine should be given at night to avoid daytime drowsiness,
although this should improve as the dose increases.
• It is often unknown whether the risks are associated with the drug,
an interaction, or the condition itself. Patients should be advised not
to drive during the initial stages of dosage titration if they experience
undesirable effects that may impair driving.
Anti-emetics
• Many drugs from different classes are used as anti-emetics, e.g. 5-HT3
antagonists, anticholinergics, antihistamines, antipsychotics, and
dopamine antagonists.
• Undesirable effects that may impair driving performance include
blurred vision, confusion, dystonias, headache, and sedation.
Anti-epileptic drugs
• Examples include carbamazepine, clonazepam, levetiracetam, and
sodium valproate.
• Affected patients should not drive during treatment initiation, withdrawal,
or dosage titration due to the risk of potential undesirable effects that
may impair driving performance, or precipitate seizures.
Antihistamines
The first-generation antihistamines (e.g. chlorphenamine, cyclizine, cypro-
heptadine, promethazine) may have pronounced CNS effects and have
been shown to impair driving performance, e.g. including the inability to
maintain a constant distance from the vehicle in front and remain in lane.
Of concern, patients may experience impairment even in the absence of
subjective symptoms. Patients who take sedating antihistamines should be
advised not to drive. In contrast, most non-sedating antihistamines (e.g.
cetirizine, loratadine) cause less sedation and therefore lower risk of
driving impairment when used at recommended doses. Despite drowsiness
being reported as a rare adverse effect, patients should be advised not to
drive if affected.
Antipsychotics
Both typical and atypical antipsychotic medications have a strong potential
to impair driving performance through various CNS effects. Some of the
older generation of antipsychotics are sedating, and all produce extrapy-
ramidal symptoms (EPS). Although atypical drugs have a lower tendency
to cause EPS, many are also sedating. An additional problem with the
antipsychotics is the risk of hypotension which may cause light-headedness
or fatigue, further impairing driving performance.
 DRUGS AND DRIVING 27

Anxiolytics/benzodiazepines
Benzodiazepines impair driving and increase the risk of road traffic acci-
dents. At low doses they cause sedation, while at higher doses the effects
are comparable to alcohol intoxication.
Opioid analgesics
• The driving performance of cancer patients receiving long-term opioid
treatment at stable doses does not appear to be adversely effected.
• Following dose adjustments, performance may be affected for about
7 days. If rescue doses are used, the patient should be advised not to
drive for at least 3 hours afterwards, or until any undesirable effect has
resolved.
28 CHAPTER 2 Prescribing guidance

Management of pain
• The pain experience is a multifaceted process that can be due to a
multitude of factors.
• The International Association for the Study of Pain define pain as:
‘an unpleasant sensory and emotional experience associated with actual
or potential tissue damage, or described in terms of such damage’.
• There are many different ways to classify pain; common terms are
shown in Table 2.1.

Table 2.1 A list of common types of pain

Type of pain Definition
Acute pain Typically of short duration, arbitrarily taken to be <3 months.
It serves as a warning for injury, or potential for further harm.
It subsides as healing occurs. Responds well to analgesia
Chronic pain Chronic pain serves no purpose and generally does not relate to
injury (except cancer pain), persisting beyond the usual healing
period. Response to analgesia can be unpredictable
Total pain The total pain that the patient experiences is influenced by
emotional, psychological, and spiritual factors, in addition to the
physical pain caused by the disease
Nociceptive Caused by noxious stimuli in the periphery. Inflammatory
pain mediators, such as prostaglandins, sensitize nociceptors. Types
of nociceptive pain include somatic pain (e.g. skin, bone) and
visceral pain (e.g. bowel). Generally responds well to analgesia
Somatic pain Often described as aching or throbbing, somatic pain is
generally localized and constant. Usually responds well to
classic analgesics, although occasionally adjuvant analgesics are
required, e.g. bone pain (bisphosphonates)
Visceral pain May be described as a constant, sharp pain (e.g. bowel colic).
It is often diffuse and poorly localized and the pain may be
referred to other non-visceral areas. Usually responds well to
classic analgesics, although occasionally adjuvant analgesics are
required e.g. bowel colic (hyoscine butylbromide). Nausea may
accompany visceral pain
Neuropathic Caused by damage to, or changes in the central or peripheral
pain nervous system. Typically responds poorly to common
analgesics; adjuvant analgesics generally required. Described
by a variety of terms, depending upon the nerve affected,
e.g. hot/cold, sharp, shooting, stabbing, itch
Breakthrough A transient exacerbation of pain that occurs either
cancer pain spontaneously or in relation to a specific predictable or
unpredictable trigger, experienced by patients who have
relatively stable and adequately controlled background pain
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