A Textbook of Clinical Pharmacology and Therapeutics

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children 54 diazepam 108 iron preparations 390–1 phenytoin 137 intrinsic factor 391–2 iodine 292–3 radioactive 294–5 ion-exchange resins 279 ipratropium 237–8 hay fever 406 irinotecan 378 iris 423 iron 389–91 deficiency 389–90 pregnancy 392 preparations 390–1 tetracyclines on absorption 329, 389 iron dextran 391 iron sucrose 391 irreversible binding 6 irritable bowel syndrome 259 ischaemic heart disease 196–203 aspirin 65, 198, 199, 200, 201–2 isoflurane 146–7 isoniazid 335, 336 acetylation 80–1 hepatotoxicity 263 peripheral neuropathy 267 isosorbide mononitrate 200 isotretinoin 412 itraconazole 342–3 jaundice chlorpromazine 112 Crigler–Najjar syndrome 27 jet lag 107 joints, injection of glucocorticoids 169 kanamycin 338 kernicterus 52, 73 aspirin 158 ketamine 149 ketoacidosis 287 ketoconazole 342, 384 ciclosporin and 402 ketotifen, confusion with ketoprofen 243 kidney adverse drug reactions 69 aminoglycosides on 328 amphotericin on 341 cephalosporins 327 cisplatin 373 disease on pharmacokinetics 35–7 diuretics, sites of action 274 drug elimination 31–3 children 53 elderly patients 57 heart failure 35 lithium 122 pregnancy 47 renal failure 36–7 foscarnet on 346 hypertension 186 methotrexate 375 non-steroidal anti-inflammatory drugs on 168 transplantation, interaction of anticonvulsants and corticosteroids 74 triazole diluent on 343 Korsakoff’s psychosis 440 lacrimal gland 423 �-lactam antibiotics 325–7 �-lactamase inhibitors 326 �-lactamase-resistant penicillins 326 lactate solution, Ringer’s 277 lactation, suppression 312 lactic acidosis, metformin 289 lactulose 257, 260 lamivudine 349, 354 viral hepatitis 261 lamotrigine 133, 138 lanosterol 14-�-demethylase (fungal) 341 lanreotide 316 lansoprazole 251 latanoprost 426 laxatives 256–8 abuse 257–8 pregnancy and 49 leishmania infections, drugs for 365 Lennox–Gastaut syndrome 138 lenograstim 394 leprosy 339 leptin 262–3 leucovorin see folinic acid leukopenia, antithyroid drugs 294 leukotriene receptor antagonists, asthma 235, 240 leukotrienes 240 leuprolide 384 leuprorelin 317 levamisole 385 levodopa 124–6 free-radical hypothesis 124 levonorgestrel 310 lice 417 lichenoid eruptions, drugs causing 418 lidocaine 153 �-adrenoceptor antagonists and 191, 224 as antidysrhythmic drug 222, 223 pharmacokinetics in heart failure 35 linezolid 332 lipid-solubility of drugs 11 elderly patients 57 inhalational anaesthetics 146 renal clearance and 31 volume of distribution and 13 lipids 177–9 lipodystrophy 288 lipoproteins high-density (HDL) 179 low-density, diuretics 192 pathways 178 liposomal amphotericin 341 5’-lipoxygenase inhibitors 240–1 liquid preparations, oral route 52, 54 lispro insulin 92–3, 286 literature on drugs 5 lithium 121–2 depression 117 diuretics and 192 loop diuretics and 275 non-steroidal anti-inflammatory drugs and 168 plasma concentration monitoring 42 liver blood flow, drugs on 29 drug metabolism 24–5 children 53 elderly patients 57 heart failure 35 methotrexate 375 pregnancy 47 see also hepatotoxicity liver disease 260–2 albumin 37–8, 274 cirrhosis 274 drug-induced 262, 263 first-pass metabolism 29 on pharmacokinetics 37–8, 40 liver flukes, drug for 366 loading doses 12, 14 digoxin 14 renal failure 36 local anaesthesia 152–4 INDEX 459 extradural route 22 eye 428 lofepramine 120 lofexidine 436 logarithmic dose–response curves 8 Lomotil 258 loop diuretics 275 heart failure 213 loperamide 256, 258 lopinavir 356, 360 loratadine 241, 405, 406 lorazepam 108, 114, 139 low-density lipoprotein, diuretics 192 low-molecular-weight heparins (LMWH) 205–6 pregnancy 209 Lown–Ganong–Levine syndrome 218 lubricant laxatives 257 Lugol’s iodine solution 293 lungs, adverse effects of drugs 243 lupus erythematosus drugs causing 418 systemic, drug-induced 69 luteinizing hormone 307, 312, 317 lymphadenopathy, adverse drug reactions 68 lymphocytes, adverse drug reactions 63 lysergic acid diethylamide (LSD) 437 MABEL (minimum anticipated biological effect level) 93, 94 macrogols 257 macrolides 328–9 see also amphotericin macula age-related degeneration 428 bull’s-eye 362 magnesium deficiency, hyperosmolar non-ketotic coma 288 magnesium salts as antacids 250 chloride 221, 227–8 sulphate 227 as laxative 257 trisilicate, iron absorption 389 maintenance doses 12 malaria 361–4 G6PD deficiency and 366 pregnancy 48 relapse 364 malignant disease from chemotherapy 371 chemotherapy for 367–85 see also cytotoxic drugs combined oral contraceptives 309 erythropoietin and 393 fibrates and 182 from immunosuppressive drugs 400 oestrogens 308, 384 malignant hyperthermia 80, 83–4, 152 malignant neuroleptic syndrome 112 Mallory–Weiss syndrome 440 mania 114–15, 116 mannitol 276, 426 maprotiline 119 mebeverine 259 mechlorethamine 372 Medicines and Health Care Regulation Agency (MHRA) 86 medroxyprogesterone acetate 308, 310 mefloquine 362, 363 melatonin 107 melphalan 372 bone marrow suppression 370 memantine 131, 132 membrane permeability 11 menopause, hormone replacement therapy 311, 315
460 INDEX meperidine see pethidine 6-mercaptopurine 79, 84, 376–7 allopurinol and 173, 376–7 meropenem 327 mesalazine 19, 255 mesna 373 metabolism of drugs 24–30 alcohol 439, 440 children 53 drug interactions 75–6 elderly patients 57 heart failure 35 liver disease 38 pharmacogenetics 79–82 pregnancy 47 presystemic 17, 18, 28–9 renal failure 36 metabolites, active 14, 24 morphine 160–1 metal chelating agents 10 metformin 288–9 cimetidine and 250 methadone 161–2, 434 methaemoglobinaemia 81, 83 methimazole 293–4 methionine 447, 448 methotrexate acitretin and 416 cytokine inhibitors with 171 glucocorticoid requirement reduction 241 on liver 262, 375 for malignant disease 374–5 plasma concentration monitoring 42 psoriasis 414 sulphonamides and 330, 375 methylation 27 methylcellulose 257 methyldopa 194 haemolysis 69 hepatotoxicity 263 methylenedioxymethylamphetamine (MDMA) 437 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP), Parkinson’s syndrome 124 methysergide 144 metoclopramide 254 dystonia 132 migraine 142 reflux oesophagitis 252 stomach emptying 34 metronidazole 330 alcohol and 330, 442 Crohn’s disease 256 mianserin 119 micafungin 343–4 Michaelis constant (K m) 15 Michaelis–Menten equation 15 miconazole 342 microtubular inhibitors 379–80 midazolam 108, 149 echinacea and 99 mifepristone 310, 311 migraine 142–4 contraceptives 309 prophylaxis 143–4 stomach emptying 34, 142 mineralocorticoids 304, 305 minimum alveolar concentrations (MAC), inhalational anaesthetics 146 minimum anticipated biological effect level (MABEL) 93, 94 minimum inhibitory concentrations (MIC), antibiotics 323–4 minoxidil 194, 412 miosis 423, 425–6 mirtazepine 120 misoprostol 251 pregnancy and 49, 251 mitomycin 378 bone marrow suppression 370 mitoxantrone 378 mivacurium 151–2 moclobemide 120 molecularly targeted agents, malignant disease 380–2 monitoring adverse drug reactions 63–6 peak flow, asthma 235 see also therapeutic drug monitoring monoamine oxidase (MAO), ginkgo on 99 monoamine oxidase inhibitors 117, 118, 120 ‘cheese reaction’ 76 hypertensive crises 120, 123 type B 127–8 monoamine theory, depression 116 monobactams 327 monoclonal antibodies 93, 94 immunosuppressants 403–4 for malignant disease 382–3 omalizumab, asthma 235, 241 monoethylglycylxylidide 223 montelukast 240 morphine 159, 160–1 intensive care 150 terminal care 162, 163 motor neurone disease 129 mountain sickness, acetazolamide 274 mouth-to-mouth respiration 219–20 movement disorders 124–32 see also extrapyramidal symptoms moxifloxacin 332 moxonidine 194 MPTP (1-methyl-4-phenyl-1,2,5,6tetrahydropyridine), Parkinson’s syndrome 124 mucus layer, gastroprotection 247 multi-targeted TKIs 382 multicentre studies 87–8 multiple dosing, pharmacokinetics 13–14 multiple sclerosis, cannabis 437 muromonab-CD3 403 muscarinic receptors 7 antagonists 114, 128, 237–8 anti-emetics 253 bladder 279 see also anticholinergic drugs; atropine anticholinesterases on 130 muscle relaxants 150–2 intensive care 150 pentamidine and 358 mustine 372 myasthenia gravis 129–31 myasthenic crisis 130–1 mycobacterial infections 334–9 Mycobacterium avium-cellulare complex disease 359 mycophenolate mofetil 402–3 mydriasis 423–5 opioid overdose 435 myelosuppression see bone marrow myocardial infarction 196, 198–200 myoclonus drugs for 134 levodopa 126 myositis, fibrates 182–3 nabilone 254–5 NABQI (N-acetyl-benzoquinone imine) 27 naftifine 343 nails, fungal infections 416 nalidixic acid 330 naloxone 10, 162, 435, 446 pregnancy 49 naltrexone 162 naproxen 169 narcotics see opioids natalizumab 404 nateglinide 289 nausea cytotoxic drugs 369–70 dopamine receptor agonists 126 see also anti-emetics; vomiting nebivolol 190, 214 Necator americanus 365 nedocromil 239–40, 405, 428 nefopam 158 nelfinavir 356 neomycin 260 neonates absorption of drugs 52 administration of drugs 54 chloramphenicol 328 cocaine 438 glucuronidation and 28 haemolytic disease 400 opioid addiction 48, 161, 436 pethidine 161 protein binding 52 theophylline 42 neostigmine 130 nephrotic syndrome 35, 37, 273 drug-induced 69 furosemide insensitivity 275 neural tube defects 392 neuraminidase, influenza virus 348 neuroleptanalgesia 150 neuromodulators 159 neuromuscular blockers 7 neuropathy amiodarone 224 diabetes mellitus 286 isoniazid 72, 81, 267, 336 neurotransmitters analgesic 159 false 260 lithium on 121 pain 155 Parkinson’s syndrome 124 receptor types 7 schizophrenia 110 nevirapine 355 protease inhibitors and 356 niacin see vitamin B3 nicorandil 197 nicotine 438–9 nicotinic acid see vitamin B 3 nicotinic acid derivatives 181, 183, 267 nicotinic receptors 7 nifedipine 191 micafungin on 343 night sedation see hypnotics night work 107 nitrates 196–7, 198, 200–1, 442 hydralazine with 214 nitric oxide 201 nitroprusside 194 nitrous oxide 147, 163 potency 146 NMDA receptors 133 nociception 155, 156 non-depolarizing muscle relaxants 150, 151–2 non-linear pharmacokinetics 15–16 first-pass metabolism 29 non-nucleoside analogue reverse transcriptase inhibitors 355 non-receptor tyrosine kinase inhibitors 380–1 non-ST-segment-elevation myocardial infarction 198
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A Textbook of Clinical Pharmacology
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A Textbook of Clinical Pharmacology
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This fifth edition is dedicated to
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FOREWORD viii PREFACE ix ACKNOWLEDG
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PREFACE Clinical pharmacology is th
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PART I GENERAL PRINCIPLES
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● Use of drugs 3 ● Adverse effe
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and acquired factors, notably disea
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100 Effect (%) 0 0 5 10 1 10 100 (a
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Dose ratio -1 100 50 The relationsh
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● Introduction 11 ● Constant-ra
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In reality, processes of eliminatio
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lood (from which samples are taken
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● Introduction 17 ● Bioavailabi
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ROUTES OF ADMINISTRATION ORAL ROUTE
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Transdermal absorption is sufficien
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FURTHER READING Fix JA. Strategies
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and thromboxanes are CYP450 enzymes
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and lorazepam. Some patients inheri
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Orally administered drug Parenteral
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● Introduction 31 ● Glomerular
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ACTIVE TUBULAR REABSORPTION This is
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DISTRIBUTION Drug distribution is a
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Detailed recommendations on dosage
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DIGOXIN Myxoedematous patients are
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● Introduction 41 ● Role of dru
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25 20 10 Life-threatening toxicity
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● Introduction 45 ● Harmful eff
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vagina in girls in their late teens
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an anti-analgesic effect when combi
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Case history A 20-year-old female m
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METABOLISM At birth, the hepatic mi
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lifelong effects as a result of tox
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DISTRIBUTION Ageing is associated w
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DIGOXIN Digoxin toxicity is common
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FURTHER READING Dhesi JK, Allain TJ
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Factors involved in the aetiology o
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analgesic. Following its release, t
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antibiotics, such as penicillin or
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predisposes to non-immune haemolysi
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● Introduction 71 ● Useful inte
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Response Therapeutic range Toxic ra
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Table 13.1: Interactions outside th
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Table 13.5: Competitive interaction
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● Introduction: ‘personalized m
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Table 14.2: Variations in drug resp
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lipoprotein (LDL) is impaired. LDL
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Key points • Genetic differences
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• Discovery • • Screening Pre
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Too many statistical comparisons pe
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ETHICS COMMITTEES Protocols for all
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Table 16.1: Recombinant proteins/en
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duration and benefit. Adenoviral ve
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● Introduction 97 ● Garlic 97
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A case report has suggested a possi
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including hypericin and pseudohyper
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PART II THE NERVOUS SYSTEM
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● Introduction 105 ● Sleep diff
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and daytime sleeping should be disc
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Key points • Insomnia and anxiety
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Box 19.1: Dopamine theory of schizo
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The Boston Collaborative Survey ind
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Oral medication, especially in liqu
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e.g. interpersonal difficulties or
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Partial response to first-line trea
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Key points Drug treatment of depres
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Case history A 45-year-old man with
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Levodopa PRINCIPLES OF TREATMENT IN
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• pulmonary, retroperitoneal and
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CHOREA The γ-aminobutyric acid con
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Cholinergic crisis Treatment of mya
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● Introduction 133 ● Mechanisms
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absolute arbiter. The availability
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Table 22.2: Metabolic interactions
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FURTHER ANTI-EPILEPTICS Other drugs
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Case history A 24-year-old woman wh
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Assessment of migraine severity and
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● General anaesthetics 145 ● In
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is the theoretical concern of a ‘
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• Respiratory system - apnoea fol
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Competitive antagonists (vecuronium
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have also proved useful in combinat
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● Introduction 155 ● Pathophysi
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ASPIRIN (ACETYLSALICYLATE) Use Anti
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Key points Drugs for mild pain •
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increases, correlating with the hig
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• If possible, use oral medicatio
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PART III THE MUSCULOSKELETAL SYSTEM
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● Introduction: inflammation 167
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Chapter 33). All NSAIDs cause wheez
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• Stomatitis suggests the possibi
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Pharmacokinetics Allopurinol is wel
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PART IV THE CARDIOVASCULAR SYSTEM
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esponsible for the strong predilect
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Ezetimibe Fat Muscle Dietary fat In
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educed). The risk of muscle damage
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Each of these classes of drug reduc
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AT 1 receptor) produce good 24-hour
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Table 28.2: Examples of calcium-cha
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Key points Drugs used in essential
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Case history A 72-year-old woman se
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Assess risk factors Investigations:
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Persistent ST segment elevation Thr
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Mechanism of action GTN works by re
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Because of the risks of haemorrhage
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Intrinsic pathway XIIa XIa the acti
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that the pharmacodynamic response i
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used with apparent benefit in acute
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The drugs that are most effective i
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therapeutic plasma concentration ca
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● Common dysrhythmias 217 ● Gen
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BASIC LIFE SUPPORT CARDIOPULMONARY
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arrest. The electrocardiogram is li
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should be given to insertion of an
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Drug interactions Amiodarone potent
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effect when treating sinus bradycar
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Case history A 24-year-old medical
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PART V THE RESPIRATORY SYSTEM
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CHAPTER 33 THERAPY OF ASTHMA, CHRON
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STEP 5: CONTINUOUS OR FREQUENT USE
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Adenylyl cyclase Table 33.1: Compar
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Drug interactions Although synergis
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use in asthma has declined consider
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α 1-antitrypsin deficiency, neutro
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PART VI THE ALIMENTARY SYSTEM
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● Peptic ulceration 247 ● Oesop
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PEPTIC ULCERATION 249 • With rega
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Ranitidine has a similar profile of
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Vestibular stimulation ? via cerebe
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cortical centres affecting vomiting
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• in hepatocellular failure to re
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Ciprofloxacin is occasionally used
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withdrawal), small doses of benzodi
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Table 34.7: Dose-independent hepato
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● Introduction 265 ● General ph
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dinucleotide (NAD) and nicotinamide
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Table 35.1: Common trace element de
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PART VII FLUIDS AND ELECTROLYTES
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● Introduction 273 ● Volume ove
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Key points Diuretics Diuretics are
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is sometimes caused by drugs, notab
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or with potassium-sparing diuretics
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Greger R, Lang F, Sebekova, Heidlan
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PART VIII THE ENDOCRINE SYSTEM
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in prefilled injection devices (‘
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Metformin should be withdrawn and i
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FURTHER READING American Diabetes A
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deficiency. Potassium iodide (3 mg
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fertility. It is contraindicated du
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● Introduction 297 ● Vitamin D
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effective in life-threatening hyper
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Further reading Block GA, Martin KJ
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Table 40.1: Actions of cortisol and
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injection may be useful, but if don
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CHAPTER 41 REPRODUCTIVE ENDOCRINOLO
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elease by the pituitary via negativ
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Treatment with depot progestogen in
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infusion using an infusion pump to
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significant proportion of men who r
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with symptoms caused by the release
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FURTHER READING Birnbaumer M. Vasop
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PART IX SELECTIVE TOXICITY
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● Principles of antibacterial che
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2. transfer of resistance between o
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Pharmacokinetics Absorption of thes
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Mechanism of action Macrolides bind
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asic quinolone structure dramatical
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Case history A 70-year-old man with
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PRINCIPLES OF MANAGEMENT OF MYCOBAC
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Pharmacokinetics Absorption from th
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MYCOBACTERIUM LEPRAE INFECTION Lepr
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POLYENES AMPHOTERICIN B Uses Amphot
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therapy is adequate though more fre
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NUCLEOSIDE ANALOGUES ACICLOVIR Uses
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Table 45.3: Summary of available ac
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Uses Interferon-α when combined wi
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● Introduction 351 ● Immunopath
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Table 46.1: Examples of combination
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NON-NUCLEOSIDE ANALOGUE REVERSE TRA
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FUSION INHIBITORS Uses Currently, e
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salvage therapy include azithromyci
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● Malaria 361 ● Trypanosomal in
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Pharmacokinetics Chloroquine is rap
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Table 47.2: Drug therapy of non-mal
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Table 48.1: Classification of commo
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Polymorph count/mm 3 (a) (b) 10 000
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doses are used to prepare patients
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Adverse effects Methotrexate Inhibi
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Table 48.7: Summary of clinical pha
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Table 48.9: Summary of the clinical
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Plasma membrane Signal transduction
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Table 48.10: Monoclonal antibodies
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INTERFERON-ALFA 2B Interferon-alfa
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PART X HAEMATOLOGY
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● Haematinics - iron, vitamin B 1
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one marrow to produce red cells. Th
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EPO Erythroid precursors Erythrocyt
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Therapeutic principles The extent o
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PART XI IMMUNOPHARMACOLOGY
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● Introduction 399 ● Immunity a
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Key points Antigen recognition Expr
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Table 50.1: Novel anti-proliferativ
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Key points Treatment of anaphylacti
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DRUGS THAT ENHANCE IMMUNE SYSTEM FU
Page 420 and 421: PART XII THE SKIN
Page 422 and 423: ● Introduction 411 ● Acne 411
Page 424 and 425: DERMATITIS (ECZEMA) PRINCIPLES OF T
Page 426 and 427: SPECIALISTS ONLY SPECIALISTS ONLY E
Page 428 and 429: TREATMENT OF OTHER SKIN INFECTIONS
Page 430 and 431: effect of too high a dose of UVB in
Page 432 and 433: PART XIII THE EYE
Page 434 and 435: ● Introduction: ocular anatomy, p
Page 436 and 437: to cause pupillary dilatation, name
Page 438 and 439: Table 52.3: Antibacterial agents us
Page 440 and 441: Table 52.6: Common drug-induced pro
Page 442 and 443: PART XIV CLINICAL TOXICOLOGY
Page 444 and 445: ● Introduction 433 ● Pathophysi
Page 446 and 447: Table 53.2: Central nervous system
Page 448 and 449: which provide anonymized data to th
Page 450 and 451: Peak plasma levels after smoking ci
Page 452 and 453: Key points Acute effects of alcohol
Page 454 and 455: FURTHER READING Goldman D, Oroszi G
Page 456 and 457: Table 54.2: Common indications for
Page 458 and 459: Table 54.5: Antidotes and other spe
Page 460 and 461: Commission on Human Medicines (CHM)
Page 462 and 463: Note: Page numbers in italics refer
Page 464 and 465: atrial fibrillation 217, 221 digoxi
Page 466 and 467: Cushing’s syndrome 302 cyclic ade
Page 468 and 469: 5-fluorouracil 375-6 fluoxetine, mo
Page 472 and 473: non-steroidal anti-inflammatory dru
Page 474 and 475: puberty (male), delay 314 puerperiu
Page 476: tolerance 9, 433 benzodiazepines 10
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