A Textbook of Clinical Pharmacology and Therapeutics

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atrial fibrillation 217, 221 digoxin 215 atrial flutter 217, 221 atrioventricular block 217, 223 atropine 226–7 cardiopulmonary resuscitation 221 for iridocyclitis 425 in Lomotil 258 as mydriatic 425 atypical antipsychotic drugs 113–14 azathioprine 402 allopurinol and 173 on liver 262 myasthenia gravis 130 azelaic acid 411 azithromycin 328, 329 azoles 341–3, 350 ciclosporin and 350, 402 aztreonam 327 � phase 15 bacteria chronic obstructive pulmonary disease 236 gastrointestinal tract drug absorption and 20 drug metabolism 29 infections, treatment algorithm 324 resistance to antibiotics 324–5 bactericidal vs bacteriostatic agents 323 balsalazide 255 barbiturates 442 Barker hypothesis 185 Bartter’s syndrome 258, 278 basic drugs, renal reabsorption 32 basic life support 219–20 basiliximab 404 BCNU, bone marrow suppression 370 beclometasone 240 behavioural emergencies 114–15 bendroflumethiazide 5, 59, 192, 258, 275, 315 benoxaprofen 64–5 benzalkonium chloride 238 benzocaine 154 benzodiazepines 108–9 active metabolites 14 alcohol withdrawal 441 in anaesthesia 149 as anti-emetics 255 as anticonvulsants 137–8 azoles and 350 elderly patients 57 liver disease 261 benzoyl peroxide 411 benzylpenicillin 326 beriberi 266 beta-blockers see �-adrenoceptor antagonists betahistine 254 bevacizumab 383, 428 bezafibrate 181, 182, 183 bicalutamide 384 bicarbonate plasma levels, acetazolamide on 274–5 see also sodium bicarbonate biliary obstruction, anion-exchange resins for 182 binding receptors 6 tissues, drug displacement 73 see also protein binding bioavailability 17–18 grapefruit juice on 408 bioequivalence, drug formulations 18, 90 biological immunosuppressants 403–4 biological response modifiers 384–5 biotechnology 92 birth weight 45 bismuth chelate 251 bisphosphonates 299–300 iron absorption 389 black triangle scheme 64–5, 90 bladder, drugs for 279 blastomycosis (North American), drugs for 340 bleomycin 378 interstitial pneumonitis 385 blood–brain barrier children 52 fetus 45 renal failure 36 blood flow intramuscular injection and 21 kidney, renal failure 37 liver, drugs on 29 placenta 45 pulmonary, anaesthesia 146 blood pressure, combined oral contraceptives 309 blood:gas solubility coefficient, anaesthetics 145 body surface area, normalization of glomerular filtration rate 57 bolus doses, pharmacokinetics 12–13 bone foscarnet binding 346 metabolic diseases 297 pain, terminal care 163 bone marrow cytotoxic drugs on 370–1 methotrexate on 374 penicillamine on 171 zidovudine on 353 boosted protease inhibitor therapy 356, 360 bortezomib 382 Boston Collaborative Drug Surveillance Program 65 botanical medicines 97 botulinum toxins 129 bradycardias 217, 223 bradykinin 187, 189 brand names see proprietary products breast carcinoma hormone replacement therapy and 311 hormone therapy for 383, 384 breast-feeding 53–4 antithyroid drugs 295 fluconazole 342 warfarin 209 brimonidine 426 bromhexine 242 bromocriptine 312, 315 bronchiolitis, ribavirin 347 bronchitis 235–6 bronchodilators 233, 236, 238 buccal route 20 budesonide inflammatory bowel disease 255 inhaled 240 bulk agents 256, 257, 264 for diarrhoea 258 bull’s-eye macula 362 bupivacaine 153 buprenorphine 162 bupropion 439 buserelin 317, 318 buspirone 109 busulfan 372 butyl nitrate 442 C-peptide 285 cabergoline 312 Cafergot 144 caffeine 439 malignant hyperthermia 84 neonates, theophylline metabolite 42 INDEX 453 supraventricular tachycardia 229 �-calcidol 298 calciferol 298 calcification 87–9 calcineurin inhibitors 401–2 see also ciclosporin calcipotriol, psoriasis 414 calcitonin 299, 300 calcitriol 297, 298 calcium 297 supplements 298–9 tetracyclines on absorption 329 calcium carbonate 250 calcium-channel blockers 191–2 azoles and 350 ciclosporin and 402 ischaemic heart disease 198, 201 calcium chloride 227 calcium gluconate 279 calculi (biliary) see gallstones calculi (urinary), prevention with thiazides 276 calories, thiamine dosage calculation 266 camptothecins 378 cancer see malignant disease candesartan 188–9 candidiasis drugs for 340, 416 HIV infection 359 inhaled glucocorticoids 239 cannabinoids 254–5 rimonabant 263 cannabis 437 capecitabine 376 capreomycin 338 capsaicin 155 captopril hepatotoxicity 263 hyperkalaemia 280 sulphhydryl group effects 188 carbamazepine 135 action mechanism 133 cross-sensitivity, phenytoin 136 erythromycin and 141 SIADH 277 carbapenem 332 carbimazole 293–4 carbon monoxide 449, 450 carbonic anhydrase inhibitors 274–5 glaucoma 426 carboplatin 374 carboprost 313 carboxypeptidase-G2 374 carcinoma see breast carcinoma; malignant disease; prostate carcinoma cardiac afterload 212 cardiac arrest 218–21 bupivacaine 153 from potassium supplements 278 thiopental 148 cardiac compression 220 cardiac dysrhythmias 217–29 pimozide 350 poisoning 446 tricyclic antidepressants 448 see also atrial fibrillation cardiac failure see heart failure cardiac output 186 cardiac preload 212 cardiac valve prostheses, anticoagulants in pregnancy 50 cardiomyopathy, anthracyclines 378 cardiopulmonary resuscitation 218–21 cardioselective �-adrenoceptor antagonists 190 cardiotoxicity, anthracyclines 377–8 cardioversion 221 carotene 265
454 INDEX carteolol 429 carvedilol 214 case-control studies, adverse drug reactions 65 caspofungin 343–4 catechol O-methyltransferase inhibitors 125 catecholamines, metabolism 27 cavernosal injection, alprostadil 315 CD4 receptor, HIV infection 351 CD41 T-cells 400 cefalexin, cystic fibrosis 34 cefotaxime 327 ceftazidime 327 ceftriaxone 327 cefuroxime 327 celiprolol 214 cell-based therapies 92–6 cell cycle, phase specificity of cytotoxic drugs 368, 369 cellular immunity 399 central nervous system elderly patients 58 fetus 45 central pontine myelinolysis 277 cephalosporins 327 cerebellar ataxia 129 5-fluorouracil 376 cetirizine 241, 405, 406 cetuximab 383 charcoal, activated 445, 446 chelating agents, of metals 10 chemokine receptors, HIV infection 351 chemoreceptor trigger zone (CTZ) 253 chemotherapy, malignant disease 367–85 see also cytotoxic drugs children 52–5 cycloplegia 425 hypnotics 107 iron preparations 390 tetracyclines and 329 chimeric antibodies 382 chloral see cloral chlorambucil 372 bone marrow suppression 370 chloramphenicol 328 aplastic anaemia 328, 395 bacterial resistance 325 eye 427 2-chlorodeoxy adenosine 377 chloroprocaine 154 chloroquine acute malaria 362–3 G6PD deficiency 366 malaria prophylaxis 362 rheumatoid arthritis 170 chlorphenamine 405 anaphylactic shock 405 chlorpromazine 112–13 hepatotoxicity 263 chlorpropamide 289 alcohol and 442 elderly patients and 59 chlortalidone 191, 192 chlortetracycline, eye 427 cholecalciferol 297 cholecystokinin 263 cholesterol 177–8 diuretics 192 see also familial hypercholesterolaemia cholestyramine see colestyramine cholinergic crisis 130–1 cholinergic receptors, eye 424 cholinesterase 25 chondroitin 101 chorea (Huntington’s disease) 129 chorionic gonadotrophin 312 chronic obstructive pulmonary disease 235–6 �-adrenoceptor antagonists 190 glucocorticoids 236, 239 chronic viral hepatitis 261 chronotropes, negative 212 ciclosporin 401–2 azoles and 350, 402 on caspofungin 343 glucocorticoid requirement reduction 241 inflammatory bowel disease 256 plasma concentration monitoring 43 psoriasis 414 seizures 408 cidofovir 347 cilastatin 327 ciliary body 423 cimetidine 249–50, 251 ciclosporin and 402 theophylline and 239 warfarin and 208, 252 cinacalcet 300 cinchonism 363 cinnarizine 254 ciprofloxacin 331 for diarrhoea 259 eye 427 cirrhosis 274 cisatracurium 151 cisplatin 373–4 methotrexate and 375 citric acid 279 cladribine 377 clarithromycin 328, 329 clearance of creatinine, nomogram 36 clearance of drugs 11–12, 13, 31 liver disease 38 see also elimination of drugs clindamycin, Pneumocystis carinii 358 clinical trials 5, 64, 86–8, 89–90 clofazimine 339 clofibrate 182 clomethiazole 109, 442 clomifene 312 clonazepam 137–8 clonidine 150 clopidogrel 209 ischaemic heart disease 198, 199 cloral (chloral) 109, 442 Clostridium difficile 259 clotrimazole 342 clotting factors 92, 394–5 clozapine 110, 113 co-amoxiclav 326 co-proxamol, overdose 448–9 co-trimoxazole 330 ganciclovir and 347 Pneumocystis carinii 357 teratogenesis 51 coagulation cascade 204–5 coagulation factors 92, 394–5 cocaine 153, 438 on fetus 50 coccidioidomycosis drugs for 340 HIV infection 359 codeine 162, 242 as antimotility drug 256, 258 colchicine 172 colestyramine 181, 182 inflammatory bowel disease 256 colfosceril palmitate 242 collagens, glucosamine and 101 colloid infusion 277 combination therapy 72 anti-emetic 370 antibacterial 325 with cytotoxic chemotherapy 371 highly active antiretroviral therapy 352–3 malignant disease 369 nucleoside analogue reverse transcriptase inhibitors 353 for Parkinson’s syndrome 125 tuberculosis 72, 335–6, 338 combined oral contraceptives 308–10, 311, 315 common cold, echinacea and 99 competitive antagonists 8, 9, 10 on effect of partial agonists 9 complementary medicines 97–102 compliance antituberculous therapy 336 elderly patients 58 concentrations of drugs constant-rate infusion 11 dissociation equilibrium constant 9 monitoring 41–4 in overdose 445 paracetamol overdose 447 repeated dosing 14 vs response to drugs 6 single-bolus dose 12 confidence intervals 89 confusion (mental), H 2-receptor antagonists 251 conjugation 24, 25–7 Conn’s syndrome 305 constant-rate infusion, pharmacokinetics 11–12 constipation 256–8 liver disease 38 contact dermatitis 66–7, 413, 417 contact lenses, drug-induced problems 429 contraceptives (hormonal) 308–11 anticonvulsants and 139 antituberculous drugs and 339 combined oral 308–10, 311, 315 on fetus 50 post-coital 310 progestogens 308 contrast media, X-rays, reactions 404 controlled drugs 436–7 controls, clinical trials 88 copper 269 coronary artery bypass grafting 197–8, 200 coronary syndrome, acute 198, 199 see also myocardial infarction corticosteroids children 54 interaction with anticonvulsants 74 occlusion on skin absorption 20, 22 on phenylethanolamine N-methyltransferase 27 pregnancy 50 see also glucocorticoids cough 242 ACEIs 188 asthma 55 COX-2 inhibitors, selective 167, 169 crack cocaine 438 creatine phosphokinase, intramuscular injections and 21 creatinine, serum levels elderly patients 57 renal failure 36 Crigler–Najjar syndrome 27 criminal poisoning 449 Crohn’s disease 255, 256 drug disposition 34 cromoglicate 405 asthma 239–40 eye 428 hay fever 406 cross-tolerance 433 crossover design, clinical trials 88 cryptococcosis 340, 359
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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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Page 416 and 417: Key points Treatment of anaphylacti
Page 418 and 419: 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 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 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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