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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

Cushing’s syndrome 302

Cushing’s syndrome 302 cyclic adenosine monophosphate (cAMP) � 2-adrenoceptor agonists on 236–7 lithium on 121 Parkinson’s syndrome 124 cyclizine 254, 405 cyclo-oxygenases 157, 167 inhibitors see COX-2 inhibitors, selective; nonsteroidal anti-inflammatory drugs platelets vs endothelium 202 cyclopentolate 425 cyclophosphamide 372–3 aplastic anaemia 395 cycloplegia 425 cycloserine 338 CYP2C9 polymorphism 80 CYP2C19 polymorphism 80 CYP2D6 gene 79, 80 CYP450 enzymes see cytochrome P450 enzymes cyproheptadine, migraine prophylaxis 144 cyproterone 314, 384, 411, 412 cysteinuria, acetazolamide for 274 cysteinyl leukotrienes 240 cystic fibrosis drug disposition 34 gene therapy 94–5 cysticercosis, drugs for 365 cytarabine 377 cytochrome-haem P450 enzymes (fungal) 341 cytochrome P450 enzymes 24–5, 26, 29 antituberculous drugs and 339 carbamazepine on 135 ciclosporin and 402 cimetidine on 250 combined oral contraceptives and 310 fluconazole on 342 herbal remedies see under alternative medicines imatinib and 381 induction 27–8 inhibition 28, 76 protease inhibitors and 356 rifampicin on 337 warfarin 208 cytokine inhibitors 171 cytokine release syndrome 403 cytomegalovirus 359 cytoplasmic tyrosine kinase inhibitors 380–1 cytosine arabinoside 377 cytotoxic drugs adverse effects 369–71 alkylating agents 372–3 antibiotics 377–8 antimetabolites 374–7 general principles 367–9 hyperuricaemia from 172 intravenous route 22 microtubular inhibitors 379–80 platinum compounds 373–4 topoisomerase inhibitors 378–9 D 4 dopamine receptors, schizophrenia 110 daclizumab 404 dantrolene 128, 152 dapsone 339, 364 darbepoietin 392–4 dasatinib 381 DC cardioversion 221 death certificates, adverse drug reactions 66 decongestants 406 deep vein thrombosis, heparins for 205 defibrillation 221 dehydration 277 see also oral rehydration preparations dehydropeptidase I 327 delavirdine 355 delayed hypersensitivity reactions 66–7, 400 delirium tremens 441 delivery (childbirth), drugs on 46 demeclocycline 277, 318 dental procedures, infective endocarditis 325 5-deoxy fluorodeoxyuridine (5-dFdU) 376 dependence on drugs 433–4 benzodiazepines 108 depolarizing muscle relaxants 150–1, 152 depot injections antipsychotics 21, 111 contraceptives 310–11 testosterone 314 depression 107, 116–23 self-poisoning and 449 dermatitis 66–7, 413–14, 417, 418 desensitization drug allergies 67 receptors 9 desflurane 147 desmopressin 277–8, 318, 395 dexamethasone 305 as anti-emetic 255 dexmetomidine 150 dextromethorphan 242 dextropropoxyphene interaction with warfarin 208 poisoning 448–9 diabetes insipidus 277–8 thiazides for 276 diabetes mellitus 285–91 ACEIs 187, 189 �-adrenoceptor antagonists 75, 190 elderly patients 59 thiazides 192 dialysis, poison elimination 13, 446, 448 diamorphine (heroin) 161, 434, 435, 442 diarrhoea 258–9 camptothecins 378 diazepam 108, 149 rectal 54, 140 for spasticity 128 didanosine 354 diet atheroma 179 cirrhosis 274 diabetes mellitus 286 fibre 256, 257, 264 protein restriction 260 diethylstilbestrol 46–7 diffusion drug absorption 19 placenta 45 diffusion hypoxia, nitrous oxide 147 digoxin amiodarone and 225 calcium chloride and 227 for cardiac dysrhythmias 226 elderly patients 59 glomerular filtration 31 heart failure 214–15 loading doses 14 renal failure 36 plasma concentration monitoring 42 tissue concentration vs 41–2 quinidine and 73 renal failure 36 thyroid disease 39 verapamil and 225 dihydrocodeine 162 dihydrofolate reductase 374 dihydropyridine dehydrogenase deficiency 376 diltiazem 198 ciclosporin and 402 dinoprostone 312 dioctyl sodium sulphosuccinate 257 INDEX 455 diphenhydramine 405 diphenoxylate 258 Diphyllobothrium latum, drugs for 365 dipipanone 434 dipivefrine 305 dipyridamole 209 adenosine and 209, 226 disease-modifying antirheumatic drugs (DMARDs) 169–71 disopyramide 222 dissecting aortic aneurysms, �-adrenoceptor antagonists 189–90 dissociation equilibrium constant (KB) 9 distal tubular reabsorption 32–3 distribution of drugs 11 children 52 drug interactions 75 elderly patients 57 heart failure 35 liver disease 38 renal failure 35–6 see also volume of distribution (V d) disulfiram 441 diuresis for poisoning 446 on renal clearance 32 diuretics 274–6, 280 ACEIs and 187, 188 cirrhosis 274 elderly patients 59 heart failure 213 hypertension 192 nephrotic syndrome 35, 37 non-steroidal anti-inflammatory drugs and 168 potassium-sparing 276, 278, 280 for volume overload 273 weight loss 264 DNA, particle-mediated epidermal delivery 95 DNA therapies 92–6 DNA topoisomerase I inhibitors 378 DNA topoisomerase II inhibitors 379 DNA vaccines 93, 95 docetaxel 380 domperidone 126, 142, 254 donepezil 131–2 L-dopa see levodopa dopa decarboxylase inhibitors 125–6 dopamine drug dependence 434 drugs increasing release 126 schizophrenia 110, 111 dopamine antagonists 254 dopamine receptors agonists 125, 126–7 D 4, schizophrenia 110 Parkinson’s syndrome 124 dorzolamide 274, 426 dosage children 54 renal failure 37 dose-dependent pharmacokinetics see non-linear pharmacokinetics dose ratio 8, 9 dose–response curves 6, 8 steepness and adverse effects 72, 73 double-blind design of trials 88 doxazosin 193 doxorubicin 377, 378 doxycycline 329 malaria prophylaxis 362 Dracunculus medinensis, metronidazole 365 driving, epilepsy 140 drospirenone 308 drug abuse 433–43 drug development 4, 86–91 process 89–90

456 INDEX drug-eluting stents 197 drug interactions 71–8 alcohol 442 antacids 249 anticonvulsants 139, 141 benzodiazepines 108 enzyme induction 27–8 see also cytochrome P450 enzymes harmful 73–7 trivial 72–3 useful 72 warfarin see warfarin, drug interactions see also alternative medicines; specific drugs ductus arteriosus 46, 313 duloxetine 279 dutasteride 314 dyskinesias 129 tardive 112 see also extrapyramidal symptoms dyslipidaemia 179 drugs for 180–4 nicotinic acid derivatives for 267 dyspepsia, pregnancy 49 dysrhythmias see cardiac dysrhythmias dystonias antipsychotic drugs 112 idiopathic 129 levodopa 126 metoclopramide 132 ‘e’ antigen, hepatitis B virus 261 echinacea 99 echinocandins 343–4 ecstasy (MDMA) 437 ectopic beats, ventricular 218, 222 eczema (dermatitis) 66–7, 413–14, 417, 418 edrophonium 130 efalizumab 415 efavirenz 355 efflux, into gastrointestinal tract 20 eflornithine 412 eicosapentanoic acid 181 elderly patients 56–61 depression 122 hypnotics 58, 107 systolic hypertension 195 electrocardiography, cardiopulmonary resuscitation 221 electrolyte balance drug interactions 75 see also hypokalaemia electromechanical dissociation 221 elimination of drugs 11–12 children 53 dialysis 13, 446, 448 drug interactions 76–7 elderly patients 57 enhancement for poisoning 446 heart failure 35 lithium 122 by metabolism 24 see also kidney elimination rate constant (k el) 13 embryo, drugs on 46 embryonic stem cells 95–6 emergencies anaphylaxis 405 behavioural 114–15 delirium tremens 441 glaucoma 425, 426 status epilepticus 139, 140 see also poisoning; pulmonary oedema; resuscitation EMLA (topical anaesthetic) 153 emollients 413 emphysema 235–6 � 1-antitrypsin deficiency 243 emtricitabine 354 encephalopathy hepatic 260–2 Wernicke’s 440, 442 end-points, clinical trials 87 endogenous analgesic peptides 159–60 endoscopy, gastric ulcers 249 enfuvirtide 357 Enterobius vermicularis, drugs for 365 enterohepatic circulation 260 activated charcoal on 446 methotrexate 375 enzymes anticonvulsants on 137, 139 gastrointestinal tract mucosa 28 induction 27–8, 76 anticonvulsants 137 inhibition 28 saturation 15 see also cytochrome P450 enzymes; pancreatic enzyme replacement epidermal growth factor receptor TKIs 381 epidural anaesthesia 153 epidural analgesia 160 epilepsy 133–40, 142 antidepressants 122 epinephrine see adrenaline eplerenone 193, 200, 214, 276, 305 epoietin 393 epoietin alfa, red cell aplasia 394 epoprostenol 208–9 erectile dysfunction 280 drugs causing 314–15 ranitidine vs cimetidine 251 treatment 315 ergocalciferol 298 ergometrine 313 ergot derivatives fibrosis 126, 127, 144 migraine and 142, 144 for Parkinson’s syndrome 126 erlotinib 381 erythema, toxic, drugs causing 418 erythema multiforme, drugs causing 418 erythema nodosum, drugs causing 418 erythroderma, drugs causing 418 erythromycin 328–9 carbamazepine and 141 ciclosporin and 402 theophylline and 239 erythropoietin 392–4 hypertension 396 esmolol 224 essential fatty acids 268 essential hypertension 187 esterases 25 estimated glomerular filtration rate 57 etanercept autoimmune diseases 171 as immunosuppressant 404 psoriasis 415 ethacrynic acid, gastrointestinal bleeding 65 ethambutol 335 ethanol see alcohol; alcoholism ethics committees 91 ethinylestradiol 307, 308 for acne 411 for alopecia 412 ethionamide 338 ethosuximide 138 etidronate 299 etomidate 149 etoposide 379 everolimus 403 exclusion criteria, clinical trials 88 excretion see elimination of drugs exfoliative dermatitis, drugs causing 418 exophthalmos 295 expectorants 242 exponential curves, drug concentration 12 extracellular water, pregnancy 47 extradural route 22 epidural anaesthesia 153 epidural analgesia 160 extrapyramidal symptoms 112, 114, 129 metoclopramide 254 extravasation, cytotoxic drugs 370 eye 423–9 amiodarone 224 drug absorption 21, 423, 429 drugs having adverse effects on 428 Graves’ disease 295 topiramate on 138 vigabatrin on 138 see also glaucoma ezetimibe 181, 182 factor VIIa 395 factor VIII, recombinant 92, 395 factor IX 395 famciclovir 347 familial hypercholesterolaemia 82–3 fasciculations, suxamethonium 151, 152 fascioliasis, drug for 366 fatty acids, essential 268 febrile convulsions 140 felypressin, with local anaesthetics 153 fenofibrate 182 fentanyl 150, 161 ferritin 389 fetal alcohol syndrome 50, 440 fetogenic stage of pregnancy 46 fetus, drugs on 45–50 ACEIs 188 contraceptives 50 opioids 48 phenytoin 136 stilbestrol 47 tetracyclines 329 see also teratogenesis fexofenadine 405, 406 fibrates 181, 182–3 fibre, dietary 256, 257, 264 fibrinolytics, ischaemic heart disease 199, 202–3 fibrosis, ergot derivatives 126, 127, 144 filariasis, drug for 366 filgrastim 394 finasteride 314 first-order elimination of drugs 11 first-order kinetics, cytotoxic drugs 368 first-pass metabolism (presystemic) 17, 18, 28–9 fish oils 181 fixed eruptions, drugs causing 418 flucloxacillin 326 fusidic acid with 329 fluconazole 342 flucytosine 344 HIV infection 359 fludarabine 377 fludrocortisone 305 fluid balance, drug interactions 75 fluid replacement oral rehydration preparations 258 post-operative 277 flumazenil 109 5-fluorocytosine see flucytosine fluoroquinolones eye 427 theophylline and 239 4-fluoroquinolones 331

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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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    ● Introduction 177 ● Pathophysi

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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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    ● Introduction 185 ● Pathophysi

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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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    ● Introduction 211 ● Pathophysi

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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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    ● Introduction 285 ● Pathophysi

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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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    ● Introduction 367 ● Pathophysi

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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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  • 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
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  • 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
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  • 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
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  • 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 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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