A Textbook of Clinical Pharmacology and Therapeutics

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and thromboxanes are CYP450 enzymes with distinct specificities. REDUCTION Reduction requires reduced NADP-cytochrome-c reductase or reduced NAD-cytochrome b5 reductase. HYDROLYSIS Pethidine (meperidine) is de-esterified to meperidinic acid by hepatic membrane-bound esterase activity. NON-ENDOPLASMIC RETICULUM DRUG METABOLISM OXIDATION Oxidation of ethanol to acetaldehyde and of chloral to trichlorethanol is catalysed by a cytosolic enzyme (alcohol dehydrogenase) whose substrates also include vitamin A. Monoamine oxidase (MAO) is a membrane-bound mitochondrial enzyme that oxidatively deaminates primary amines to aldehydes (which are further oxidized to carboxylic acids) or ketones. Monoamine oxidase is found in liver, kidney, intestine and nervous tissue, and its substrates include catecholamines (a) Phase I (predominantly CYP450) H O N O O – Oxidation – Reduction – Hydrolysis NH DRUG Renal (or biliary) excretion Phase II (transferase reactions) – Acetylation – Methylation – Glucuronidation – Sulphation – Mercaptopuric acid formation – Glutathione conjugation H Phase I O N O Phase II HO NH Phenobarbital p-Hydroxy phenobarbital O CO2H O OH OH OH PHASE II METABOLISM (TRANSFERASE REACTIONS) 25 (dopamine, noradrenaline and adrenaline), tyramine, phenylephrine and tryptophan derivatives (5-hydroxytryptamine and tryptamine). Oxidation of purines by xanthine oxidase (e.g. 6-mercaptopurine is inactivated to 6-thiouric acid) is non-microsomal. REDUCTION This includes, for example, enzymic reduction of double bonds, e.g. methadone, naloxone. HYDROLYSIS Esterases catalyse hydrolytic conversions of many drugs. Examples include the cleavage of suxamethonium by plasma cholinesterase, an enzyme that exhibits pharmacogenetic variation (Chapter 14), as well as hydrolysis of aspirin (acetylsalicylic acid) to salicylate, and the hydrolysis of enalapril to enalaprilat. PHASE II METABOLISM (TRANSFERASE REACTIONS) AMINO ACID REACTIONS Glycine and glutamine are the amino acids chiefly involved in conjugation reactions in humans. Glycine forms conjugates with nicotinic acid and salicylate, whilst glutamine forms conjugates with p-aminosalicylate. Hepatocellular damage depletes the intracellular pool of these amino acids, thus restricting this pathway. Amino acid conjugation is reduced in neonates (Chapter 10). ACETYLATION Acetate derived from acetyl coenzyme Aconjugates with several drugs, including isoniazid, hydralazine and procainamide (see Chapter 14 for pharmacogenetics of acetylation). Acetylating activity resides in the cytosol and occurs in leucocytes, gastrointestinal epithelium and the liver (in reticulo-endothelial rather than parenchymal cells). GLUCURONIDATION Conjugation reactions between glucuronic acid and carboxyl groups are involved in the metabolism of bilirubin, salicylates O O H N O p-Hydroxy phenobarbital glucuronide (b) Figure 5.1: (a) Phases I and II of drug metabolism. (b) A specific example of phases I and II of drug metabolism, in the case of phenobarbital. NH O
26 DRUG METABOLISM Table 5.1: CYP450 isoenzymes most commonly involved in drug metabolism with representative drug substrates and their specific inhibitors and inducers Enzyme Substrate Inhibitor Inducer CYP1A2 Caffeine Amiodarone Insulin Clozapine Cimetidine Cruciferous vegetables Theophylline Fluoroquinolones Nafcillin Warfarin (R) Fluvoxamine Omeprazole CYP2C9a Celecoxib Losartan Amiodarone Barbiturates NSAIDs Fluconazole Rifampicin Sulphonylureas Fluoxetine/Fluvoxamine Phenytoin Lansoprazole Warfarin (S) Sulfamethoxazole Ticlopidine CYP2C19a Diazepam Fluoxetine Carbamazepine Moclobamide Ketoconazole Prednisone Omeprazole Pantoprazole Proguanil Rifampicin CYP2D6a Codeine (opioids) Amiodarone Dexamethasone Dextromethorphan Celecoxib Rifampicin Haloperidol Cimetidine Metoprolol Ecstasy (MDMA) Nortriptyline Fluoxetine Pravastatin Propafenone Quinidine CYP2E1 Chlormezanone Diethyldithio-carbamate Ethanol Paracetamol Theophylline Isoniazid CYP3A4 Alprazolam Amiodarone Barbiturates Atorvastatin Diltiazem Carbamazepine Ciclosporin Erythromycin (and other Efavirenz macrolides) Glucocorticosteroids (and other steroids) Hydrocortisone Gestodene Nevirapine Lidocaine Grapefruit juice Phenytoin Lovastatin Fluvoxamine Pioglitazone Fluconazole/Itraconazole St John’s wort Midazolam Ketoconazole Nifedipine (many CCBs) Nefazodone Tamoxifen Nelfinavir/Ritonavir Tacrolimus Verapamil Vincristine Voriconazole a Known genetic polymorphisms (Chapter 14). Approximate percentage of clinically used drugs metabolized by each CYP isoenzyme: CYP3A4, 50%; CYP2D6, 20%; CYP2C, 20%; CYP1A2, 2%; CYP2E1, 2%; other CYPs, 6%.
Page 2 and 3: A Textbook of Clinical Pharmacology
Page 4 and 5: A Textbook of Clinical Pharmacology
Page 6 and 7: This fifth edition is dedicated to
Page 8 and 9: FOREWORD viii PREFACE ix ACKNOWLEDG
Page 10 and 11: PREFACE Clinical pharmacology is th
Page 12 and 13: PART I GENERAL PRINCIPLES
Page 14 and 15: ● Use of drugs 3 ● Adverse effe
Page 16 and 17: and acquired factors, notably disea
Page 18 and 19: 100 Effect (%) 0 0 5 10 1 10 100 (a
Page 20 and 21: Dose ratio -1 100 50 The relationsh
Page 22 and 23: ● Introduction 11 ● Constant-ra
Page 24 and 25: In reality, processes of eliminatio
Page 26 and 27: lood (from which samples are taken
Page 28 and 29: ● Introduction 17 ● Bioavailabi
Page 30 and 31: ROUTES OF ADMINISTRATION ORAL ROUTE
Page 32 and 33: Transdermal absorption is sufficien
Page 34 and 35: FURTHER READING Fix JA. Strategies
Page 38 and 39: and lorazepam. Some patients inheri
Page 40 and 41: Orally administered drug Parenteral
Page 42 and 43: ● Introduction 31 ● Glomerular
Page 44 and 45: ACTIVE TUBULAR REABSORPTION This is
Page 46 and 47: DISTRIBUTION Drug distribution is a
Page 48 and 49: Detailed recommendations on dosage
Page 50 and 51: DIGOXIN Myxoedematous patients are
Page 52 and 53: ● Introduction 41 ● Role of dru
Page 54 and 55: 25 20 10 Life-threatening toxicity
Page 56 and 57: ● Introduction 45 ● Harmful eff
Page 58 and 59: vagina in girls in their late teens
Page 60 and 61: an anti-analgesic effect when combi
Page 62 and 63: Case history A 20-year-old female m
Page 64 and 65: METABOLISM At birth, the hepatic mi
Page 66 and 67: lifelong effects as a result of tox
Page 68 and 69: DISTRIBUTION Ageing is associated w
Page 70 and 71: DIGOXIN Digoxin toxicity is common
Page 72 and 73: FURTHER READING Dhesi JK, Allain TJ
Page 74 and 75: Factors involved in the aetiology o
Page 76 and 77: analgesic. Following its release, t
Page 78 and 79: antibiotics, such as penicillin or
Page 80 and 81: predisposes to non-immune haemolysi
Page 82 and 83: ● Introduction 71 ● Useful inte
Page 84 and 85: Response Therapeutic range Toxic ra
Page 86 and 87:
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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Page 190 and 191:
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
Page 196 and 197:
Page 198 and 199:
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
Page 206 and 207:
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
Page 216 and 217:
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
Page 222 and 223:
Page 224 and 225:
The drugs that are most effective i
Page 226 and 227:
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
Page 236 and 237:
Drug interactions Amiodarone potent
Page 238 and 239:
effect when treating sinus bradycar
Page 240 and 241:
Case history A 24-year-old medical
Page 242 and 243:
PART V THE RESPIRATORY SYSTEM
Page 244 and 245:
CHAPTER 33 THERAPY OF ASTHMA, CHRON
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STEP 5: CONTINUOUS OR FREQUENT USE
Page 248 and 249:
Adenylyl cyclase Table 33.1: Compar
Page 250 and 251:
Drug interactions Although synergis
Page 252 and 253:
use in asthma has declined consider
Page 254 and 255:
α 1-antitrypsin deficiency, neutro
Page 256 and 257:
PART VI THE ALIMENTARY SYSTEM
Page 258 and 259:
● Peptic ulceration 247 ● Oesop
Page 260 and 261:
PEPTIC ULCERATION 249 • With rega
Page 262 and 263:
Ranitidine has a similar profile of
Page 264 and 265:
Vestibular stimulation ? via cerebe
Page 266 and 267:
cortical centres affecting vomiting
Page 268 and 269:
• in hepatocellular failure to re
Page 270 and 271:
Ciprofloxacin is occasionally used
Page 272 and 273:
withdrawal), small doses of benzodi
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Table 34.7: Dose-independent hepato
Page 276 and 277:
● Introduction 265 ● General ph
Page 278 and 279:
dinucleotide (NAD) and nicotinamide
Page 280 and 281:
Table 35.1: Common trace element de
Page 282 and 283:
PART VII FLUIDS AND ELECTROLYTES
Page 284 and 285:
● Introduction 273 ● Volume ove
Page 286 and 287:
Key points Diuretics Diuretics are
Page 288 and 289:
is sometimes caused by drugs, notab
Page 290 and 291:
or with potassium-sparing diuretics
Page 292 and 293:
Greger R, Lang F, Sebekova, Heidlan
Page 294 and 295:
PART VIII THE ENDOCRINE SYSTEM
Page 296 and 297:
Page 298 and 299:
in prefilled injection devices (‘
Page 300 and 301:
Metformin should be withdrawn and i
Page 302 and 303:
FURTHER READING American Diabetes A
Page 304 and 305:
deficiency. Potassium iodide (3 mg
Page 306 and 307:
fertility. It is contraindicated du
Page 308 and 309:
● Introduction 297 ● Vitamin D
Page 310 and 311:
effective in life-threatening hyper
Page 312 and 313:
Further reading Block GA, Martin KJ
Page 314 and 315:
Table 40.1: Actions of cortisol and
Page 316 and 317:
injection may be useful, but if don
Page 318 and 319:
CHAPTER 41 REPRODUCTIVE ENDOCRINOLO
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elease by the pituitary via negativ
Page 322 and 323:
Treatment with depot progestogen in
Page 324 and 325:
infusion using an infusion pump to
Page 326 and 327:
significant proportion of men who r
Page 328 and 329:
with symptoms caused by the release
Page 330 and 331:
FURTHER READING Birnbaumer M. Vasop
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PART IX SELECTIVE TOXICITY
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● Principles of antibacterial che
Page 336 and 337:
2. transfer of resistance between o
Page 338 and 339:
Pharmacokinetics Absorption of thes
Page 340 and 341:
Mechanism of action Macrolides bind
Page 342 and 343:
asic quinolone structure dramatical
Page 344 and 345:
Case history A 70-year-old man with
Page 346 and 347:
PRINCIPLES OF MANAGEMENT OF MYCOBAC
Page 348 and 349:
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
Page 362 and 363:
● Introduction 351 ● Immunopath
Page 364 and 365:
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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Page 380 and 381:
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
Page 392 and 393:
Plasma membrane Signal transduction
Page 394 and 395:
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
Page 402 and 403:
one marrow to produce red cells. Th
Page 404 and 405:
EPO Erythroid precursors Erythrocyt
Page 406 and 407:
Therapeutic principles The extent o
Page 408 and 409:
PART XI IMMUNOPHARMACOLOGY
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● Introduction 399 ● Immunity a
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Key points Antigen recognition Expr
Page 414 and 415:
Table 50.1: Novel anti-proliferativ
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
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SPECIALISTS ONLY SPECIALISTS ONLY E
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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
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Table 52.6: Common drug-induced pro
Page 442 and 443:
PART XIV CLINICAL TOXICOLOGY
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Table 53.2: Central nervous system
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which provide anonymized data to th
Page 450 and 451:
Peak plasma levels after smoking ci
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Key points Acute effects of alcohol
Page 454 and 455:
FURTHER READING Goldman D, Oroszi G
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Table 54.2: Common indications for
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Table 54.5: Antidotes and other spe
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Commission on Human Medicines (CHM)
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Note: Page numbers in italics refer
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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
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children 54 diazepam 108 iron prepa
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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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