Liverpool University Hospitals NHS Foundation Trust Liverpool UK
With contribution by James Baker MPharm PgDip
Principal Pharmacist for Medicines Optimisation
Stepping Hill Hospital
Stockport NHS Foundation Trust
Stockport UK
Great Clarendon Street, Oxford, OX2 6DP, United Kingdom
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First Edition published in 200
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Third Edition published in 2023
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Library of Congress Control Number: 202294535
ISBN 978–0–9–874640–9
DOI: 0.093/med/978098746409.00.000
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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.
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Dedication
I would like to dedicate this book to my wife Victoria, for without her continued steadfast support during the recent difficult times many of us have experienced, this work would not have been possible.
I would like to thank James Baker for his timely contributions to this work. Finally, I want to acknowledge and thank the two reviewers Penny Tuffin and Grace Ting for providing timely and critical feedback.
Foreword
Medicine is not only a science; it is also an art. It does not consist of compounding pills and plasters; it deals with the very processes of life, which must be understood before they may be guided
Paracelsus (493–54)
Swiss physician, alchemist, lay theologian, and philosopher
There are few fields of healthcare which do not, at some point, involve caring for the dying patient. Dying is the one clinical process that all people will face, yet the evidence base to inform how we look after our patients is woefully inadequate. This is not to say the medicines at our disposal are without evidence base; on the contrary, many have been rigorously evaluated in randomized clinical trials. However, such studies are usually conducted in patient populations with a better prognosis and performance status than those nearing the end of life. Patients under the care of generic and specialist palliative care services are rarely eligible for such studies and the clinical outcome measures used are often of limited utility in the palliative care context.
As healthcare practitioners, we need to embrace the concept of medicine being as much an art as a science; indeed, Sackett and colleagues’ seminal editorial highlighted, ‘The practice of evidence-based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research.’() This is particularly apt in the practice of palliative care where we need to appraise the existing evidence and apply it, where possible, to the complexities of a patient with advanced disease who may have multiple comorbidities, polypharmacy, deranged biochemistry, and variable absorption and metabolism, all of which may be in an ever changing state of flux. To be able to do this requires a meticulous understanding of the complex pharmacokinetics and pharmacodynamics of the medicines commonly used by our specialty. I believe this book achieves this admirably.
Its author Dr Dickman is one of the most respected pharmacists in the field, with several practical palliative care books under his belt already. This new tome not only offers an evidence-based approach to the drugs commonly used in the management of palliative care patients, but this ‘pharmacopedia’ is also preceded by a thorough overview of the basic (and not so basic) science which underpins the clinical practice of pharmacology.
By remaining clinically active, Dr Dickman has never lost sight of producing a book which is of use to the practising medic, nurse, pharmacist, or other allied healthcare professional. This book is well suited as a reference for any profession involved in the care of the patient with incurable illness,
as well as a welcome informative addition to the practice of all ward-based and community staff.
Professor Simon Noble
Marie Curie Professor Supportive and Palliative Medicine Cardiff University Wales, UK
References
. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence-based medicine: what it is and what it isn’t. BMJ. 996;32(7023):7–2.
Detailed contents
Symbols and abbreviations xv
Clinical pharmacology overview
Introduction 2
Pharmacokinetics 3
Pharmacodynamics 0
Opioid pharmacology 2
Pharmacogenetics 5
Hepatic impairment 9
Renal impairment 22
Drug interactions 25
Serotonin toxicity 29
2 Prescribing guidance 35
Unlicensed use of medicines 36
Legal categories of medicines 37
Travelling abroad with medicines 39
Drugs and driving 4
Managing pain 44
Selection of an NSAID 49
Opioid-induced hyperalgesia and tolerance 5
Breakthrough cancer pain 54
Equianalgesia and opioid switch 56
Neuropathic pain 60
Managing nausea and vomiting 62
Management of constipation in advanced cancer 64
QT interval 68
Polypharmacy and deprescribing 7
Discontinuing and/or switching antidepressants 74
Diabetes in palliative care 80
Care of the dying patient 88
3 Monographs A–Z 97
Monographs 99
Alfentanil 0
Allopurinol 06
Amitriptyline 09
Anastrozole 4
Antacid and oxetacaine 6
Apixaban 8
Aprepitant 2
Baclofen 23
Benzydamine 26
Bethanechol 27
Bicalutamide 29
Bisacodyl 32
Buprenorphine 34
Calcitonin (salcatonin or salmon calcitonin) 44
Cannabidiol (CBD) 47
Cannabis extract 5
Carbamazepine 54
Carbocisteine 59
Celecoxib 60
Citalopram 65
Clonazepam 7
Co-danthramer 75
Codeine 77
Cyclizine 83
Cyproheptadine 86
Cyproterone 89
Dalteparin 92
Demeclocycline 98
Denosumab 200
Dexamethasone 203
Diamorphine 209
Diazepam 24
Diclofenac 28
Dihydrocodeine 223
Docusate sodium 228
Domperidone 230
Donepezil 233
Duloxetine 236
Edoxaban 24
Enoxaparin 244
Enzalutamide 248
Escitalopram 25
Esomeprazole 256
Etoricoxib 26
Exemestane 265
Famotidine 267
Fentanyl (transdermal/ parenteral) 270
Fentanyl (transmucosal) 280
Finasteride 289
Fluconazole 29
Flumazenil 295
Fluoxetine 297
Flutamide 302
Furosemide 304
Gabapentin 309
Gliclazide 34
Glimepiride 37
Glipizide 39
Glyceryl trinitrate 32
Glycopyrronium bromide 324
Granisetron 328
Haloperidol 33
Hydromorphone 337
Hyoscine butylbromide 342
Hyoscine hydrobromide 346
Ibandronic acid (ibandronate) 350
Ibuprofen 353
Insulin 358
Itraconazole 369
Ketamine 373
Ketorolac 379
Lactulose 383
Lansoprazole 385
Letrozole 389
Levetiracetam 39
Levomepromazine 395
Lidocaine (infusion) 400
Lidocaine (topical) 405
Loperamide 408
Lorazepam 4
Macrogol 3350 44
Magnesium aspartate dihydrate 47
Magnesium hydroxide 49
Magnesium sulfate 42
Medroxyprogesterone 423
Megestrol 426
Metformin 428
Methadone 43
Methylnaltrexone 440
Methylphenidate 443
Metoclopramide 446
Miconazole (oral gel) 450
Midazolam 452
Mirtazapine 457
Modafinil 462
Morphine 465
Nabilone 473
Nabumetone 476
Naldemedine 480
Naloxegol 483
Naloxone 486
Naproxen 489
Nefopam 493
Nifedipine 496
Nizatidine 499
Nortriptyline 50
Nystatin 506
Octreotide 507
Olanzapine 50
Omeprazole 56
Ondansetron 52
Oxybutynin 524
Oxycodone 527
Pamidronate disodium 534
Pantoprazole 538
Paracetamol 542
Parecoxib 545
Paroxetine 549
Phenobarbital 554
Phenytoin 558
Pramipexole 562
Prednisolone 566
Pregabalin 570
Index 695
Pridinol 575
Prochlorperazine 577
Promethazine 58
Propantheline 585
Propranolol 587
Quetiapine 590
Rabeprazole 596
Ranitidine 599
Risperidone 602
Rivaroxaban 607
Rivastigmine 60
Ropinirole 63
Rotigotine 67
Senna (sennosides) 620
Sertraline 622
Sodium valproate 627
Spironolactone 633
Sucralfate 636
Tamoxifen 638
Tapentadol 64
Temazepam 646
Thalidomide 649
Theophylline 652
Tinzaparin 655
Tolterodine 659
Tramadol 662
Tranexamic acid 669
Trazodone 67
Venlafaxine 677
Warfarin 682
Zoledronic acid 685
Zolpidem 689
Zopiclone 692
Symbols and abbreviations
CredibleMeds®
category: known risk of TdP
CredibleMeds®
category: possible risk of TdP
CredibleMeds®
category: conditional risk of TdP
Drug only to be used under supervision of palliative care specialist
✢ unlicensed usage
p adverse effects
g dose
u pharmacology
H warning
cross-reference
M online reference
female
male
5-HT 5-hydroxytryptamine (or serotonin)
6-MAM 6-mono-acetylmorphine
6-MNA 6-methoxy-2-naphthyl acetic acid
7-OH-CBD 7-hydroxy cannabidiol
ABW actual body weight
ACC anterior cingulate cortex
ACE angiotensin-converting enzyme
ACE-I angiotensin-converting enzyme inhibitor
ADH antidiuretic hormone
ADI acceptable daily intake
ADME absorption, distribution, metabolism, and excretion
MHRA Medicines and Healthcare products Regulatory Agency
micromol micromole(s)
min minute(s)
mL millilitre(s)
mm millimetre(s)
mmHg millimetre(s) of mercury
mmol millimole(s)
MOR mu opioid receptor
MOR-NRI MOR agonist–noradrenaline reuptake inhibitor
MRI magnetic resonance imaging
ms millisecond(s)
Na+ sodium (ion)
Nac nucleus accumbens
NaCl sodium chloride injection
BP (British Pharmacopoeia) 0.9% w/v
NAPQI N-acetyl-pbenzoquinone imine
NAT2 N-acetyl transferase 2
NDMA N-nitrosodimethylamine
NET noradrenaline reuptake transporter
ng nanogram(s)
NICE National Institute for Health and Care Excellence
NK neurokinin
NMDA N-methyl-D-aspartate
NMS neuroleptic malignant syndrome
NO nitric oxide
NOR nociceptin receptor
NRI noradrenaline reuptake inhibitor
NRLS National Reporting and Learning System
NRT nicotine replacement therapy
Symbols and abbreviations
NSAID non-steroidal antiinflammatory drug
NVAF non-valvular atrial fibrillation
NYHA New York Heart Association
OCT organic cation transporter
OD once daily (omni die)
OHA oral hypoglycaemic agent
OIBD opioid-induced bowel dysfunction
OIC opioid-induced constipation
OIH opioid-induced hyperalgesia
OM in the morning (omni mane)
ON in the evening (omni nocte)
ORL- opioid-like receptor-
OTC over-the-counter
P pharmacy only (medicine)
PAG periaqueductal grey
PAH polycyclic aromatic hydrocarbon
PAMORA peripherally acting mu opioid receptor antagonist
PE pulmonary embolism
PEG percutaneous endoscopic gastrostomy
PFC prefrontal cortex
pg picogram(s) (equal to 0−2 grams)
P-gp P-glycoprotein
PM poor metabolizer
PO orally (per os)
POM prescription-only medicine
PONV post-operative nausea and vomiting
PPI proton pump inhibitor
PR rectally (per rectum)
PRN when necessary (pro re nata)
PT prothrombin time
PTHrP parathyroid hormone-related peptide
PVC polyvinylchloride
QDS four times daily (quater die sumendus)
QTc QT corrected for heart rate
RANKL receptor activator of nuclear factor kappa-Β ligand
RBC red blood cell (count)
REM rapid eye movement
RINV radiotherapy-induced nausea and vomiting
RR respiratory rate
abbreviations
RVM rostral ventromedial medulla
SeCr serum creatinine
SERT serotonin reuptake transporter
SGLT2 sodium–glucose cotransporter 2
SIADH syndrome of inappropriate antidiuretic hormone hypersecretion
SLE systemic lupus erythematosus
SmPC summary of product characteristics
SNRI serotonin–noradrenaline reuptake inhibitor
SS serotonin syndrome
SSRI selective serotonin reuptake inhibitor
SST somatostatin
SSTR–5 somatostatin receptors ( to 5)
ST serotonin toxicity
SUBCUT subcutaneous(ly)
SUBLING sublingual(ly)
T4 thyroxine
TCA tricyclic antidepressant
TD transdermal
TdP torsades de pointes
TDS three times daily (ter die sumendus)
TENS transcutaneous electrical nerve stimulation
THC delta-9-tetrahydrocannabinol
TLR4 Toll-like receptor 4
TM transmembrane
TNF tumour necrosis factor
TRPV transient receptor potential cation channel subfamily V member
TSH thyroid-stimulating hormone
U&Es urea and electrolytes
UGT uridine diphosphate glucuronosyltransferase
UM ultrarapid metabolizer
VEGF vascular endothelial growth factor
VTE venous thromboembolism
v/v volume by volume
WBC white blood cell (count)
WFI water for injections BP (British Pharmacopoeia)
WHO World Health Organization w/v weight by volume
Clinical pharmacology
overview
Introduction 2
Pharmacokinetics 3
Pharmacodynamics 0
Opioid pharmacology 2
Pharmacogenetics 5
Hepatic impairment 9
Renal impairment 22
Drug interactions 25
Serotonin toxicity 29
Introduction
Interpatient variation is a substantial clinical problem when considering drug therapy. examples of variation include failure to respond to treatment, increased incidence of adverse effects, and increased susceptibility to drug interactions. the concept of ‘one dose fits all’ is clearly incorrect and is demonstrated by the unacceptable rate of hospital admissions caused by adverse drug reactions (approximately 5% in the UK; 7% in the US). this variation is hardly surprising, given all the factors that ultimately determine an individual’s response to a drug (see Fig. .).
Fig. . Factors that influence an individual’s response to drug therapy.
Pharmacokinetics
the rate and manner that a drug is absorbed, distributed, and eliminated are described by pharmacokinetics—in other words, what the body does to the drug.
Absorption
the bioavailability of a drug describes the proportion of the dose of a drug that enters the systemic circulation; for example, for intravenous (IV) morphine, this would be 00%, compared to 5 to 65% after oral administration. 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 .).
Box .
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 significantly reduce the bioavailability of a drug, such 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 isoenzymes CYP3a4 and CYP3a5 (see Box .3), in addition to uridine diphosphate glucuronosyltransferases (UGts), such as UGt2B7 (see Box .4), are located in the gut wall and liver. many drugs are substrates of these isoenzymes and, as such, alterations in enteral cytochrome activity can significantly influence bioavailability. they are susceptible to inhibition and induction by a variety of drugs and foods. For example, one glass of grapefruit juice can cause significant inhibition of intestinal CYP3a4, whereas 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 interpatient variation in drug absorption, and hence bioavailability of several drugs (e.g. morphine 5 to 65%).
Several transporter proteins present in the intestines influence the absorption of drugs. P-glycoprotein (P-gp) is an efflux transporter molecule that can affect the bioavailability of many drugs (see Box .2). Less wellcategorized influx transporter proteins, such as organic cation transporters (OCts), are also present and their activity may also be influenced by drugs and food.
Box .2 P-glycoprotein efflux transporter
P-glycoprotein (P-gp) is one of many protein transporters that can influence the bioavailability, distribution, and elimination of numerous drugs relevant to palliative care; for example, P-gp is believed to be a major determinant of the bioavailability of loperamide, morphine, and tramadol. It is found in the gastrointestinal tract, kidney, liver, and blood–brain barrier. there is wide patient variation because P-gp is genetically encoded and subject to polymorphism (see E Pharmacogenetics, p. 5). Drug interactions can occur through induction or inhibition of P-gp, the clinical significance of which are being uncovered.
Distribution
many drugs bind to plasma proteins such as albumin. Bound drug is inactive; 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 (an exception being phenytoin). P-gp is involved in the distribution of several drugs across the blood–brain barrier; for example, 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.
Drug metabolism
many drugs are lipophilic, or non-polar, a property that allows them to readily cross cell membranes. metabolism involves chemical reactions that produce compounds that are more hydrophilic, or polar, improving water solubility and aiding elimination in, for example, urine or bile. metabolism is conveniently divided into two phases: phase I— functionalization; and phase II—conjugation. most drugs undergo phase I and II reactions, but some undergo either phase I or phase II metabolism. Phase I metabolism introduces, or exposes, a functional group through chemical reactions such as oxidation, reduction, or hydrolysis. these reactions are mainly catalysed by cytochrome P450 isoenzymes (see Box .3) located primarily in the liver, although other important sites include the GI tract (see E Absorption, p. 3) and the brain. there are three possible results of phase I metabolism:
• complete loss of pharmacological activity (i.e. the metabolites are pharmacologically inactive)
• metabolites retain some pharmacological activity, but less than the parent drug
• the parent compound (prodrug) is pharmacologically inactive, but one or more metabolites are pharmacologically active.
Phase II metabolism involves conjugation reactions (such as glucuronidation or sulfation) affecting functional groups within the parent compound, or phase I metabolite(s). Uridine diphosphate glucuronosyltransferases
(UGts) (see Box .4) are the main group of isoenzymes responsible for the glucuronidation of several drugs used in palliative care (e.g. morphine, diclofenac, haloperidol, and olanzapine). UGt2B7 is one of the most important human UGt isoenzymes with respect to drug clearance. metabolites produced during phase II metabolism are generally pharmacologically inactive and more water-soluble than the parent compound. an important exception is morphine. One of its conjugated metabolites morphine-6-glucuronide is pharmacologically active and has been shown to be responsible for the analgesic effect of morphine. many drugs are dependent on cytochrome P450 isoenzymes for metabolism and/or elimination. Genetic variations or co-administration of inducers or inhibitors can lead to the development of significant toxicity or lack of effect, necessitating dose adjustments. the clinical significance of genetic variations or co-administration of inducers or inhibitors on the function of UGts remains unclear for the majority of drugs.
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 and dose adjustments may be necessary.
Box .3 The cytochrome P450 system
the cytochrome P450 system consists of a large group of over 500 CYP enzymes 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. the five subfamilies CYPa, CYP2C, CYP2D, CYP2e, and CYP3a have a major role in hepatic drug metabolism, with others having a lesser role. the list below briefly describes the CYP enzymes involved. also see E Cytochrome P450 tables on the inside back cover for a non-exhaustive list of substrates, inducers, and inhibitors, and E Glossary of common terms for an explanation of terms used below. each CYP enzyme displays multiple polymorphisms that give rise to several phenotypes, usually described as:
• poor metabolizer (Pm)—absent or severely reduced metabolic capacity
• CYPa—mainly found in the lungs and metabolizes tobacco to potentially carcinogenic substances.
• CYPa2—responsible for metabolism of approximately 5% of drugs that are metabolized by CYP enzymes. It is also involved in activation of procarcinogens. although polymorphisms do exist, variations in CYPa2 activity are largely due to non-genetic causes. For example, CYPa2 is induced by tobacco smoke, cruciferous vegetables (e.g. broccoli, sprouts), grilled meat, and drugs such as omeprazole and carbamazepine. CYPa2 activity may be inhibited by drugs, e.g. amiodarone, ciprofloxacin, diclofenac. Important substrates include olanzapine and theophylline.
CYP2A subfamily
• CYP2a6—metabolizes a small number of drugs, including nicotine and the prodrug tegafur. also metabolizes tobacco to potentially carcinogenic substances. Polymorphisms exist, with % of the Caucasian population being Pms.
CYP2B subfamily
• CYP2B6—involved in the metabolism of an increasing number of drugs, including ketamine and methadone. Clopidogrel is a potential inhibitor, while tobacco smoke, rifampicin, and dexamethasone induce this CYP enzyme. Polymorphisms exist, but distribution and consequences remain undetermined.
CYP2C subfamily
• CYP2C8—a major hepatic cytochrome. Polymorphisms exist, but distribution and consequences remain undetermined. It is responsible for the metabolism of numerous drugs (e.g. amiodarone, olanzapine).
• CYP2C9—the most important of the CYP2C subfamily, responsible for metabolism of 0 to 20% of drugs, including warfarin, celecoxib, ibuprofen, diclofenac, and phenytoin. It is inhibited by several drugs, including fluconazole; rifampicin induces activity of CYP2C9. Polymorphisms exist and three phenotypes (Pm, Inm, em) are described. Between % and 3% of Caucasians are Pms. approximately 65% of Caucasians are considered ems. Reduced activity of CYP2C9 can lead to unexpected nSaID toxicity. the Pm phenotype is almost non-existent in the asian population and affects roughly 0% of africans.
• CYP2C9—involved in the metabolism of several drugs, including clopidogrel (prodrug), omeprazole, lansoprazole, diazepam, and citalopram. Inhibitors include modafinil, omeprazole, and fluoxetine. Carbamazepine can induce this CYP enzyme. Between 3% and 5% of Caucasians and africans and up to 20% of asians lack the CYP enzyme and are Pms. the Um phenotype may be present in up to 5% of Caucasians and africans, but virtually non-existent in asians.
Box .3 (Contd.)
CYP2D subfamily
• CYP2D6—this isoenzyme is responsible for the metabolism of approximately 25% of drugs, including codeine, tramadol, and tamoxifen. Inhibitors include paroxetine, levomepromazine, and celecoxib. Unlike the other isoenzymes, CYP2D6 cannot be induced. many polymorphisms exist and four phenotypes have been identified: Pm, Inm, em, and Um. about 5 to 0% of Caucasians are Pms and lack this isoenzyme. the incidence of Pm in african populations is highly variable (from 0% to 20%), but rare in asians (%). Between 5% to 0% of Caucasians and up to 30% of africans are Ums. Such a phenotype is extremely rare in asians. Clinically important drug–drug interactions involving CYP2D6 occur because of the phenotype and/or co-administration of inhibitors.
CYP2E subfamily
• CYP2e—has a minor role in drug metabolism. Its main importance is in paracetamol metabolism and potential toxicity. Polymorphisms exist, but the distribution and consequence remain undetermined.
CYP3A subfamily
this subfamily is the most abundant in the liver and is responsible for the metabolism of over 50% of drugs. there are four CYP3a genes, although only two 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 the distribution and consequence remain undetermined.
• CYP3a4—the most significant isoenzyme involved in drug metabolism and frequently implicated in drug interactions. although three phenotypes (Pm, Inm, Um) have been described, the activity of each allele is unknown and there is little genetic variation across ethnic groups. In fact, the causes of variations in activity are largely nongenetic. It is located mainly in the liver, but significant amounts are present in the gastrointestinal tract where it has an important role in first-pass metabolism. Indeed, the complex interaction between hepatic and intestinal isoenzyme levels helps to account for such wide variations in activity. there are several inducers (e.g. carbamazepine, rifampicin) and inhibitors (e.g. clarithromycin, grapefruit juice).
• CYP3a5—as with CYP3a4, three phenotypes have been described, loosely based on the system above (no metabolic capacity, reduced capacity, normal capacity). Interestingly, the ‘no metabolic capacity’ phenotype is the most common in the Caucasian (85%) and asian populations (50%). about 20% of africans and 0% of asians, but <% of Caucasians, are CYP3a5 ‘normal metabolizers’. CYP3a5 is also located in the liver and gastrointestinal tract, and has a similar substrate and inducer/inhibitor spectrum to CYP3a4. For transplant patients, the efficacy of ciclosporin and tacrolimus may well depend on the CYP3a5 phenotype, especially as the ‘no metabolic activity’ phenotype is the most common in Caucasian and asian populations. Other substrates that can be affected by the CYP3a5 phenotype include alfentanil and midazolam.
Uridine 5′-diphosphate glucuronosyltransferases (UGts) are a superfamily of enzymes that perform phase II conjugative metabolism (glucuronidation). there are four families of UGts in humans: UGt, UGt2, UGt3, and UGt8. In total, there are 22 enzymes in these four families, but UGt and UGt2 comprise 9 and are involved in a range of clinically important drug interactions. Genetic variation in UGt function is thought to contribute to interindividual differences in drug response, as well as to the risk of certain diseases. the clinical significance, however, of genetic variation or inhibition/induction of UGts currently remains unclear.
UGTA family
• UGta—involved in the elimination of bilirubin. Genetic variations are associated with unconjugated hyperbilirubinaemia in Gilbert’s syndrome. It is involved in the conjugation of several drugs, including paracetamol and buprenorphine. Imatinib and ketoconazole act as inhibitors; enzalutamide is an inducer.
• UGta3—metabolizes several endogenous compounds such as oestrogens and vitamin D metabolites. Drug substrates include opioids (e.g. hydromorphone, buprenorphine, morphine) and nonsteroidal anti-inflammatory drugs (e.g. etodolac, naproxen, ibuprofen).
• UGta4—has several endogenous substrates, including progestins, dihydrotestosterone, and 25-hydroxyvitamin D3. It is involved in the conjugation of several drugs, including amitriptyline, haloperidol, lamotrigine, midazolam, nicotine, and olanzapine. may be inhibited by sodium valproate and induced by, for example, carbamazepine, phenobarbital, phenytoin, and rifampicin.
• UGta6—involved in the metabolism of 5-Ht. Drug substrates include paracetamol, naproxen, and tapentadol. may be induced by drugs such as carbamazepine and phenobarbital.
• UGta7—is an extrahepatic UGt, mainly expressed in the stomach. Involved in the metabolism of cannabidiol and S-lorazepam.
• UGta8—expressed in the colon. Substrates include morphine, tamoxifen, thyroxine, and valproate. may have a role in first-pass metabolism.
• UGta9—found in the liver and intestine. Likely to be the main UGt for ethanol glucuronidation and have a role in first-pass metabolism. Drug substrates include cannabidiol, diazepam, haloperidol, naproxen, nicotine, paracetamol, propofol, sorafenib, tapentadol, and valproate. Cannabidiol may be an inhibitor of UGta9.
• UGta0—is an extrahepatic UGt, expressed mainly in the intestine, and contributes to first-pass metabolism. Drug substrates include tamoxifen, thyroxine, and valproate.
UGT2B family
• UGt2B4—mainly located within the liver, this enzyme is involved in the metabolism of bile acids and androgen metabolites. Substrates include codeine, ibuprofen, lorazepam, midazolam, morphine, and oxycodone.
Box .4 (Contd.)
• UGt2B7—this enzyme is highly expressed in the liver and involved in the metabolism of a range of exogenous dietary and environmental compounds. Drug substrates include codeine, diazepam, diclofenac, haloperidol, hydromorphone, ibuprofen, lorazepam, midazolam, morphine, naproxen, oxycodone, tamoxifen, tapentadol, and valproate. Ketoconazole and cannabidiol may inhibit UGt2B7.
• UGt2B0—important enzyme in the glucuronidation of tobacco nitrosamines (including nicotine) and arachidonic acid metabolites. Drug substrates include amitriptyline and olanzapine.
• UGt2B5—important enzyme involved in the glucuronidation of androgens. Involved in the glucuronidation of numerous drugs, including diazepam, lorazepam, phenytoin, tamoxifen, and valproate. Valproate is believed to be an important inhibitor. UGt2B5*2, a variant that results in reduced activity, is believed to be present in approximately 50% of Caucasians, with only a slightly lesser prevalence in other populations.
• UGt2B7—shares over 95% homology with UGt2B5 and is also involved in the glucuronidation of androgens. Knowledge of drug substrates is limited; ibuprofen and megestrol are believed to be substrates.
Pharmacodynamics
the effect of a drug and how it works in terms of its interaction with a receptor or site of action are 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 (mOR))
• ion channel (e.g. lidocaine and sodium (na+) channel, capsaicin and transient receptor potential cation channel subfamily V member (tRPV))
• enzyme (e.g. non-steroidal anti-inflammatory drug (nSaID) and cyclo-oxygenase)
exceptions include antibiotics, cytotoxic drugs, and immunosuppressants. the term ‘receptor’ is used throughout the following to loosely describe the above protein targets. note that an autoreceptor is a receptor that, upon binding a ligand (i.e. a substance that binds to a receptor), reduces the release of that ligand into the synapse; for example, presynaptic 5-Hta autoreceptors in the raphe nuclei reduce serotonin release through a negative feedback mechanism. a heteroreceptor, upon binding a ligand, mediates the release of other neurotransmitters.
Glossary of common terms
• Agonists are ligands that bind to, and activate, receptors to produce an effect.
• Antagonists are ligands that also bind to receptors but do not lead to activation. they may prevent the action of, or displace, an agonist.
• Partial agonists are ligands that activate receptors to a limited extent but may also interfere with the action of a full agonist. the circumstances in which a partial agonist may act as an antagonist or an agonist depend on both the efficacy (see below) of the drug and the pre-existing state of receptor occupation by an agonist; for example, 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.
• Biased agonism or functional selectivity are terms used to describe the phenomenon whereby a ligand, after binding to a receptor, preferentially activates one of several cellular signalling pathways, whereas another agonist acting on the same receptor preferentially activates another pathway (see E Chapter , Opioid pharmacology, p. 2 for more information).
• Inverse agonist see Box .5.
• Competitive antagonism describes the situation that occurs when an antagonist competes with an 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 (allosteric) antagonism occurs when an antagonist blocks the effects of an agonist by interaction at some point other than the receptor binding site of the agonist.
• Affinity is a term used to describe the ability of a drug to bind to its receptors; for example, naloxone has a higher affinity for opioid receptors than morphine, hence its use in opioid toxicity.
• the intrinsic activity of a drug describes its ability to induce conformational changes in a receptor that induce receptor signalling. a drug may bind with high affinity but have low intrinsic activity. a drug with zero intrinsic activity is an antagonist.
• the intrinsic efficacy of a drug refers to the potential maximum activation of a receptor, and therefore desired response—that is, a full agonist has high intrinsic efficacy, a partial agonist has low to medium intrinsic efficacy, and an antagonist has zero intrinsic efficacy. For example, opioids with a low intrinsic efficacy (e.g. buprenorphine) must occupy more receptors to produce a given effect, compared to opioids with a higher intrinsic efficacy (e.g. fentanyl), and demonstrate a ceiling effect whereby larger doses of the drug do not produce a greater degree of analgesia because all the receptors are occupied.
• Potency refers to the amount of drug necessary to produce an effect; for example, fentanyl is more potent than morphine since the same analgesic effect occurs at much lower doses (micrograms vs milligrams). Potency depends not only on its affinity for the receptor and intrinsic efficacy, but also on pharmacokinetic variables that determine the quantity of the drug that is delivered to its site of receptor action.
• 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 adverse effects.
• Tolerance is the decrease in therapeutic effect that may occur, over a period of time, by repeated doses of a drug (see E Chapter 2, Opioidinduced hyperalgesia and tolerance, p. 5).
• Tachyphylaxis is the rapid development of tolerance. It can occur with calcitonin, leading to rebound hypercalcaemia once the drug is discontinued.
• 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.
• Polypharmacology is a strategy that employs one or multiple drugs to interact with multiple molecular targets towards a specific outcome; for example, tapentadol is a µ-opioid agonist and noradrenaline reuptake inhibitor (nRI) and both effects contribute to its overall analgesic efficacy.
