A Textbook of Clinical Pharmacology and Therapeutics

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non-steroidal anti-inflammatory drugs 167–9 asthma 168–9, 243 elderly patients 60 eye 427 hyperkalaemia 280 methotrexate and 375 peptic ulcers 247, 249, 252 post-operative pain 163 renal failure 37 topical 158 warfarin and 208 norelgestromin 308 norethisterone 308 ciclosporin and 402 nortestosterone derivatives 308 nose, drug absorption 21 nucleoside analogue reverse transcriptase inhibitors 353–4 nucleoside analogues 345–7 nucleotide reverse transcriptase inhibitor 354 nystatin 341 obesity 262–3 atheroma 179 oblimersen 382 obstructive uropathy �-adrenoceptor antagonists for 280 drug-induced 69 occlusion, drugs and skin 20, 22 occupational hazards, inhalational anaesthetics 147–8 octreotide 316–17 oesophageal varices 261, 317 oedema 211 oesophageal varices 261 octreotide 261, 317 oesophagitis bisphosphonates 299 reflux 252 pregnancy 49 oestrogens 307–8 with cyproterone for acne 411 hormone replacement therapy 311, 312 on liver 262 for malignant disease 384 malignant disease from 308 thrombosis 204–5 see also phytoestrogens olanzapine 114 olsalazine 19, 255 omalizumab, asthma 235, 241 omeprazole 251 on-off phenomena, levodopa 125 onchocerciasis, drug for 366 oncogenes 367 ophthalmopathy, Graves’ 295 opioids 159–64 abuse 434–7 for anaesthesia 149–50 antagonists 10, 162 compounds with paracetamol 448–9 for diarrhoea 258 on fetus 48 hypothyroidism 39 intensive care 150 liver disease 261 poisoning 446 pregnancy 48–9 receptors 159–60 opportunistic infections HIV infection 357–9 immunosuppression 400 oprelvekin 394 oral contraceptives combined 308–10, 311, 315 see also contraceptives (hormonal) oral hypoglycaemic agents 288–90 elderly patients 59 oral rehydration preparations 258 oral route 18, 19–20 absorption via 17 liquid preparations 52, 54 presystemic metabolism 17, 18, 28–9 organic anions and cations, proximal tubular secretion 31–2 organogenesis 46 organophosphates 449 orlistat 263–4, 265 oseltamivir phosphate 348 Osmosin 20 osmotic diuretics 276 osmotic laxatives 257 osteoarthritis, glucosamine 101 osteomalacia 300 osteoporosis 297, 300 heparin 206 pregnancy 50 oestrogens 307, 311 ototoxicity aminoglycosides 328 cisplatin 373–4 furosemide 275 overdoses aspirin 157, 158 barbiturates 442 Cafergot 144 iron preparations 390 local anaesthetics 153 opioids 435 paracetamol 27, 30, 156, 445, 446–7 dextropropoxyphene with 448–9 self-poisoning 444–9 overhydration 276–7 ovulation, induction 317 oxaliplatin 374 oxidation 25 microsomal 24–5 oxybutynin 279 oxygen therapy bleomycin lung 385 chronic obstructive pulmonary disease 236 myocardial infarction 198 respiratory failure 241–2 oxytocin 312–13, 318 paclitaxel 379–80 Paget’s disease, bisphosphonates 299 pain 155, 156 adenosine 226 post-operative 163–4 terminal disease 162–3 see also analgesics pancreatic enzyme replacement 259 H2-receptor antagonists and 250, 259 pancreatic insufficiency 259 pancreatin 259 pancreatitis, drugs associated 259 pancuronium 151 papaverine 159 papilloma virus 417 para-aminohippuric acid 31–2 para-aminosalicylic acid (PAS) 338 paracetamol 156 migraine 142 overdoses 27, 30, 156, 445, 446–7 co-proxamol 448–9 parallel-group studies 88 parasympathomimetic drugs, adverse effects on lungs 243 parathyroid hormone 297 parenteral iron 390–1 Parkinson’s syndrome 124–8 INDEX 461 paroxysmal supraventricular tachycardias 221–2 partial agonists 7, 9 �-adrenoceptor antagonists 190 dose–response curves 6 partial gastrectomy, iron absorption 389 partial pressure, anaesthetics 145 partial seizures, drugs for 134 particle-mediated epidermal delivery of DNA 95 PAS (para-aminosalicylic acid) 338 passive diffusion drug absorption 19 placenta 45 passive immunity 399 patient-controlled analgesia (PCA) 163 PC-SPES (herbal product), withdrawal 101 peak flow monitoring, asthma 235 peak plasma concentration 13, 14 monitoring 42 renal failure 37 time to (T max) 18 PEG-filgrastim 394 PEG-ylated interferons 349 pegaptanib 428 peginterferon alfa-2a, viral hepatitis 261 pegvisomant 316 pellagra 267 penciclovir 347 skin infections 417 penicillamine 170, 171 penicillin allergy 66 intrathecal 22 proximal tubular secretion 31–2 penicillin G 326 penicillinase 325 penicillins 325–7 pentamidine foscarnet and 346 Pneumocystis carinii 357–8 pentazocine 162 peppermint oil 259 pepsin, antacids on 249 peptic ulcer 247–52 pregnancy 49 percutaneous coronary intervention 197–8, 200 peripheral vascular resistance 185, 186 permissive hypothesis, mood disorders 116 pernicious anaemia 391 peroxisome proliferator-activated receptor � 182 perphenazine 254 personalized medicine 79, 92 pethidine 161 on fetus 48 pH stomach, renal disease on 35 urine see urinary pH phaeochromocytoma 305 pharmaceutical drug interactions 71, 74, 75 pharmacodynamics 4, 6–10 children 53 drug interactions 71 elderly patients 57–8 inhalational anaesthetics 146 pharmacogenetics 79–85 pharmacokinetics 4–5, 11–16 children 52–3 drug concentration measurement 41–2 drug interactions 71, 72, 75–7 elderly patients 56–7 formulations 18 gastrointestinal disease 34 gastrointestinal tract 19–20 grapefruit juice on 408 heart failure 34–5 lithium 122 liver disease 37–8, 40
462 INDEX pharmacokinetics (Contd) non-linear 15–16 first-pass metabolism 29 phenytoin 16, 136–7 placenta 45 pregnancy 47 renal disease 35–7 St John’s wort 101 thyroid disease 38–9 pharmacovigilance 63–6 phencyclidine 149, 437 phenindione 207 phenobarbital 137 metabolism 25 phenothiazines as anti-emetics 254 antipsychotic 111–13 phenoxybenzamine 193, 305 phenoxymethylpenicillin 326 phenylephrine 425 phenylethanolamine N-methyltransferase 27 phenytoin 133, 136–7 ciclosporin and 402 hepatotoxicity 263 intoxication epidemic 17 metabolism 24 osteomalacia 300 pharmacokinetics 16, 136–7 plasma concentration monitoring 42, 49 renal failure 36 sulphonamides and 330 pholcodine 242 phosphate enemas 257 phosphatidyl inositides, lithium on 121 phosphodiesterase inhibitors 215, 280, 315 photoallergy 419 photosensitivity 67, 417–19 amiodarone 224 drugs causing 418 physiological antagonism 8 phytoestrogens ginseng as 98 soy 100 phytomedicines 97 Pickwickian syndrome 241 pigmentation, drugs causing 418 pimozide, dysrhythmias 350 pioglitazone 290 pituitary hormones 316–19 pityriasis capitis 416 pizotifen 143 pK a, on renal excretion 32 placebos 88 placenta, pharmacokinetics 45 plant fibre, dietary 256, 257, 264 plasma concentration monitoring see therapeutic drug monitoring see concentrations of drugs plasma volume on apparent volume of distribution 12 pregnancy 47 plasminogen 179 Plasmodium spp. 361–2 platelets cyclo-oxygenases 202 heparin on 206 see also antiplatelet drugs; aspirin; clopidogrel platinum compounds 373–4 Pneumocystis carinii 357–8 drugs for 365 pneumonitis, interstitial, bleomycin 385 poisoning 444–50 accidental 449 dialysis for 13, 446, 448 drug concentration measurement 41 polar drugs see water-solubility polyenes 341 polypharmacy 5, 59–60, 71–2 poor metabolizers 79 porphyrias 81, 84, 154 thiopental 148 portal hypertension 261 octreotide 317 portocaval anastomoses 28, 38 posaconazole 343 positron emission tomography, Alzheimer’s disease 131 post-coital contraceptives 310 post-marketing surveillance 64–5, 90 post-operative antibiotics 325 post-operative fluid replacement 277 post-operative pain 163–4 post-partum period, anticoagulants 209 posterior pituitary hormones 318 postural hypotension, elderly patients 57–8 potassium 278–9 ACEIs 188 diuretics 192, 275, 276 drugs affecting levels 69 calcium chloride 227 elderly patients 59 heart failure treatment 213 ketoacidosis 287 laxative abuse 258 liver disease 38, 40 supplements 278 suxamethonium 152 tricyclic antidepressant poisoning 448 potassium iodide 293 potassium permanganate 413 potassium-sparing diuretics 276, 278, 280 potency 6–7 nitrous oxide 146 pravastatin 180 prazosin 193 preclinical studies 4, 87 prednisolone 169, 304–5 idiopathic thrombocytopenic purpura 395 inflammatory bowel disease 255 myasthenia gravis 130 pregnancy 45–51 alcohol 50, 440 anticoagulants 50, 209 antithyroid drugs 295 antituberculous drugs and 339 iron and folate 392 malaria prophylaxis 362 misoprostol 49, 251 radioactive iodine and 295 smoking 50, 438 vitamin A and 266 zidovudine 353 see also fetus; teratogenesis preload, cardiac 212 premature infants drug elimination 53 indometacin 46 premedication for anaesthesia 150 preoperative prophylaxis with antibiotics 325 prescriptions controlled drugs 436–7 error avoidance 3, 243 generic vs proprietary name 17–18 presystemic metabolism 17, 18, 28–9 prilocaine 153 primaquine G6PD deficiency and 83 malaria 362, 364 Pneumocystis carinii 358 probe drug substrates, enzyme induction 28 probenecid 173 aciclovir and 345 methotrexate and 375 proximal tubular secretion 31–2 zidovudine and 354 procainamide cimetidine and 250 slow acetylators 81, 82 procaine benzylpenicillin 326 procarbazine 373 prodrugs 18, 19 progestogen-only contraceptives 310–11 progestogens 307, 308, 309, 384 on fetus 50 hormone replacement therapy 308, 312 proguanil 362, 364 promethazine 254, 405 prophylaxis with antibiotics 325 malaria 361, 362 G6PD deficiency 366 migraine 143–4 propofol 148–9 proprietary products, bioavailability 17–18 propylthiouracil 294 pregnancy 295 prostacyclin 208–9 prostaglandins 313 analogues 426 see also misoprostol as drugs 312–13 gastroprotection 247 NSAIDs on synthesis 168 renal failure 37 prostate carcinoma hormone therapy 384 tumour flare reaction 318 prostatic obstruction 280 protamine sulphate 206 protease inhibitors (HIV) 355–6 boosted therapy 356, 360 interaction with garlic 98 proteasome inhibitors 382 protein binding displacement 73 liver disease 38 nephrotic syndrome 37 phenytoin 137 pregnancy 47 proximal tubular secretion and 32 renal failure 35–6 protein C 207 protein restriction, dietary 260 proteinuria, penicillamine 171 prothionamide 338 prothrombin time 37–8 see also international normalized ratio proton-pump inhibitors 250, 251 reflux oesophagitis 252 triazoles and 343 provocation testing 63 proximal renal tubules, drug secretion 31–2 drug interactions 76 renal failure 36 pruritus, drugs causing 418 pseudocholinesterases, suxamethonium sensitivity 80, 81–2, 152 pseudohypoparathyroidism 298 pseudomembranous colitis 259 Pseudomonas see antipseudomonal penicillins psoralen with UVA light (PUVA) 414–16 psoriasis 414–16 psychedelics 437 psychosis acute 114–15 amphetamines 438 Korsakoff’s 440 see also antipsychotic drugs; schizophrenia
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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
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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 470 and 471: children 54 diazepam 108 iron prepa
Page 474 and 475: puberty (male), delay 314 puerperiu
Page 476: tolerance 9, 433 benzodiazepines 10
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