A Textbook of Clinical Pharmacology and Therapeutics

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Ezetimibe Fat Muscle Dietary fat Intestine Lipoprotein lipase Bile acid Chylomicron Remnant Resins Fibrates Liver FFA Fat FFA Muscle HMG CoA reductase inhibitors statins Figure 27.6: Sites of action of lipid-lowering drugs (see Figure 27.3 for abbreviations). Table 27.2: Drugs used in dyslipidaemia DRUGS USED TO TREAT DYSLIPIDAEMIA 181 VLDL IDL HDL Lipoprotein lipase LDL Tissue Class/drug Biochemical Effect on Effect on Adverse effects Special situations effect coronary artery disease longevity Statin/simvastin, LDLpp pp q (4S,WOSCOPS) Rare: myositisq liver Contraindicated in pravastatin transaminase pregnancy, caution in children Resin/cholestyramine LDLp TGq p NP Constipation, flatulence, Contraindicated in biliary nausea obstruction Fibrate/gemfibrozil, TGppLDLp p NP Myocitis; gastro-intestinal Contraindicated in bezafibrate HDLq symptoms alcoholics, renal/liver impairment Nicotinic acid TGppLDLp p NP Flushing (PGD2- Useful in familial derivatives/high-dose HDLq mediated); diarrhoea; hypercholesterolaemia; nicotinic acid, urticaria; epigastric pain; PG-related adverse acipimox hyperuricaemia; effects ameliorated by hyperglycaemia aspirin before the dose Fish oil/eicosapentanoic TGp NP NP Belching with a fishy Used in patients with acid-rich supplements after-taste pancreatitis caused by raised TG. Contraindicated in patients with familial hypercholesterolaemia, in whom it increases cholesterol levels Ezetimibe LDLp NP NP Mild GI effects, myalgia Adjunct to statin in resistant dyslipidaemia LDL, low-density lipoprotein; TG, triglycerides; HDL, high-density lipoprotein; NP, not proven.
182 PREVENTION OF ATHEROMA: LOWERING PLASMA CHOLESTEROL AND OTHER APPROACHES Adverse effects and contraindications Mild and infrequent side effects include nausea, constipation, diarrhoea, flatulence, fatigue, insomnia and rash. More serious adverse events are rare, but include rhabdomyolysis, hepatitis and angioedema. Liver function tests should be performed before starting treatment and at intervals thereafter, and patients should be warned to stop the drug and report at once for determination of creatine kinase if they develop muscle aches. HMG CoA reductase inhibitors should be avoided in alcoholics and patients with active liver disease, and are contraindicated during pregnancy. Pharmacokinetics Statins are well absorbed, extracted by the liver (their site of action) and are subject to extensive presystemic metabolism by CYP3A4 or CYP2D6. Simvastatin is an inactive lactone prodrug which is metabolized in the liver to its active form, the corresponding β-hydroxy fatty acid. Drug interactions The risk of rhabdomyolysis is increased by concurrent use of a fibrate or inhibitors of statin metabolism, e.g. azoles (Chapter 45), macrolides (Chapter 43). Their potency is increased by concurrent use of a drug that interferes with cholesterol absorption (see below). DRUGS THAT REDUCE CHOLESTEROL ABSORPTION EZETIMIBE Use Ezetimibe is most often used in combination with diet and statins for severe hypercholesterolaemia; also in occasional patients who cannot tolerate statins or where statins are contraindicated, and in (rare) cases of homozygous sitosterolaemia. Mechanism of action It blocks the NPLC1L sterol transporter in the brush border of enterocytes, preventing cholesterol and plant sterols (phytosterols) transport from the intestinal lumen. This mechanism is distinct from that of phytosterol and phytostanol esters (present in ‘health’ foods such as Benecol) which interfere with the micellar presentation of sterols to the cell surface, or of resins (see below) which bind bile acids in the gut lumen. Pharmacokinetics Ezetimibe is administered by mouth and is absorbed into intestinal epithelial cells, where it localizes to the brush border. It is metabolized, followed by enterohepatic recycling and slow elimination. It enters breast milk. Adverse effects and contraindications Diarrhoea, abdominal pain or headaches are occasional problems; rash and angioedema have been reported. It is contraindicated in breast-feeding. ANION-EXCHANGE RESINS Use Colestyramine or colestipol were used for hypercholesterolaemia, but have been almost completely superseded by statins. Resins retained an important niche as add-in treatment in severe disease (e.g. heterozygous familial hypercholesterolaemia (FH)) which was inadequately responsive to statin monotherapy. This role has now been taken by ezetimibe (see above) which is effective and well tolerated in milligram doses in contrast to resins which are administered in doses of several grams, are unpalatable and commonly cause abdominal bloating and diarrhoea. They retain a highly limited usefulness in children and in breast-feeding women. Completely separate indications include bile salt diarrhoea and pruritus in incomplete biliary obstruction. (They are ineffective in patients with complete biliary obstruction, in whom there are no bile salts to bind in the gut lumen.) They cause malabsorption of fat soluble vitamins and interfere with the absorption of many drugs (Chapter 13). FIBRATES Use Bezafibrate, gemfibrozil and fenofibrate are available in the UK and are used mainly for patients with mixed dyslipidaemia with severely raised triglycerides especially if they are poorly responsive to statins. Clofibrate, which was used in a World Health Organization (WHO) trial, is less often used because it increases biliary cholesterol secretion and predisposes to gallstones. Its use is therefore limited to patients who have had a cholecystectomy. Furthermore, while it reduced the number of myocardial infarctions in the WHO trial, this was offset by an increased number of cancers of various kinds. The meaning of this has been extensively debated, but remains obscure. This issue is clouded by an effect of malignancy of lowering serum cholesterol. The original observations with clofibrate may have been a statistical accident and there is no excess of cancers in patients treated with gemfibrozil in other trials (e.g. the Helsinki Heart Study). These studies have shown that fibrates have a marked effect in lowering plasma triglycerides (TG), with a modest (approximately 10%) reduction in LDL and increase in HDL. Fenofibrate has an additional uricosuric effect. Mechanism of action Fibrates are agonists at a nuclear receptor (peroxisome proliferator-activated receptor α (PPARα)) which is present in many tissues including fat. The ensuing effects are incompletely understood. They stimulate lipoprotein lipase (hence their marked effect on TG) and increase LDL uptake by the liver. In addition to their effects on plasma lipids, fibrates lower fibrinogen. Adverse effects Fibrates can cause myositis (in severe cases rhabdomyolysis with acute renal failure), especially in alcoholics (in whom they should not be used) and in patients with impaired renal function (in whom elimination is prolonged and protein binding
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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
Page 142 and 143: Cholinergic crisis Treatment of mya
Page 144 and 145: ● Introduction 133 ● Mechanisms
Page 146 and 147: absolute arbiter. The availability
Page 148 and 149: Table 22.2: Metabolic interactions
Page 150 and 151: FURTHER ANTI-EPILEPTICS Other drugs
Page 152 and 153: Case history A 24-year-old woman wh
Page 154 and 155: Assessment of migraine severity and
Page 156 and 157: ● General anaesthetics 145 ● In
Page 158 and 159: is the theoretical concern of a ‘
Page 160 and 161: • Respiratory system - apnoea fol
Page 162 and 163: Competitive antagonists (vecuronium
Page 164 and 165: have also proved useful in combinat
Page 166 and 167: ● Introduction 155 ● Pathophysi
Page 168 and 169: ASPIRIN (ACETYLSALICYLATE) Use Anti
Page 170 and 171: Key points Drugs for mild pain •
Page 172 and 173: increases, correlating with the hig
Page 174 and 175: • If possible, use oral medicatio
Page 176 and 177: PART III THE MUSCULOSKELETAL SYSTEM
Page 178 and 179: ● Introduction: inflammation 167
Page 180 and 181: Chapter 33). All NSAIDs cause wheez
Page 182 and 183: • Stomatitis suggests the possibi
Page 184 and 185: Pharmacokinetics Allopurinol is wel
Page 186 and 187: PART IV THE CARDIOVASCULAR SYSTEM
Page 190 and 191: esponsible for the strong predilect
Page 194 and 195: educed). The risk of muscle damage
Page 198 and 199: Each of these classes of drug reduc
Page 200 and 201: AT 1 receptor) produce good 24-hour
Page 202 and 203: Table 28.2: Examples of calcium-cha
Page 204 and 205: Key points Drugs used in essential
Page 206 and 207: Case history A 72-year-old woman se
Page 208 and 209: Assess risk factors Investigations:
Page 210 and 211: Persistent ST segment elevation Thr
Page 212 and 213: Mechanism of action GTN works by re
Page 214 and 215: Because of the risks of haemorrhage
Page 216 and 217: Intrinsic pathway XIIa XIa the acti
Page 218 and 219: that the pharmacodynamic response i
Page 220 and 221: used with apparent benefit in acute
Page 224 and 225: The drugs that are most effective i
Page 226 and 227: therapeutic plasma concentration ca
Page 228 and 229: ● Common dysrhythmias 217 ● Gen
Page 230 and 231: BASIC LIFE SUPPORT CARDIOPULMONARY
Page 232 and 233: arrest. The electrocardiogram is li
Page 234 and 235: 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
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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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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
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● Introduction 411 ● Acne 411
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DERMATITIS (ECZEMA) PRINCIPLES OF T
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SPECIALISTS ONLY SPECIALISTS ONLY E
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TREATMENT OF OTHER SKIN INFECTIONS
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effect of too high a dose of UVB in
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PART XIII THE EYE
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● Introduction: ocular anatomy, p
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to cause pupillary dilatation, name
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Table 52.3: Antibacterial agents us
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Table 52.6: Common drug-induced pro
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PART XIV CLINICAL TOXICOLOGY
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Table 53.2: Central nervous system
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which provide anonymized data to th
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Peak plasma levels after smoking ci
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Key points Acute effects of alcohol
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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
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Cushing’s syndrome 302 cyclic ade
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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
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puberty (male), delay 314 puerperiu
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tolerance 9, 433 benzodiazepines 10
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