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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

Metformin should be

Metformin should be withdrawn and insulin substituted before major elective surgery. Plasma creatinine and liver function tests should be monitored before and during its use. Mechanism of action This remains uncertain. Biguanides do not produce hypoglycaemia and are effective in pancreatectomized animals. Effects of metformin include: • reduced glucose absorption from the gut; • facilitation of glucose entry into muscle by a non-insulinresponsive mechanism; • inhibition of gluconeogenesis in the liver; • suppression of oxidative glucose metabolism and enhanced anaerobic glycolysis. Adverse effects Metformin causes nausea, a metallic taste, anorexia, vomiting and diarrhoea. The symptoms are worst when treatment is initiated and a few patients cannot tolerate even small doses. Lactic acidosis, which has a reported mortality in excess of 60%, is uncommon provided that the above contraindications are respected. Treatment is by reversal of hypoxia and circulatory collapse and peritoneal or haemodialysis to alleviate sodium overloading and removing the drug. Phenformin (withdrawn in the UK and USA) was more frequently associated with this problem than metformin. Absorption of vitamin B12 is reduced by metformin, but this is seldom clinically important. Pharmacokinetics Oral absorption of metformin is 50–60%; it is eliminated unchanged by renal excretion, clearance being greater than the glomerular filtration rate because of active secretion into the tubular fluid. Metformin accumulates in patients with renal impairment. The plasma t1/2 ranges from 1.5 to 4.5 hours, but its duration of action is considerably longer, permitting twice daily dosing. Drug interactions Other oral hypoglycaemic drugs are additive with metformin. Ethanol predisposes to metformin-related lactic acidosis. SULPHONYLUREAS AND RELATED DRUGS Use Sulphonylureas (e.g. tolbutamide, glibenclamide, gliclazide) are used for type 2 diabetics who have not responded adequately to diet alone or diet and metformin with which they are additive. They improve symptoms of polyuria and polydipsia, but (in contrast to metformin) stimulate appetite. Chlorpropamide, the longest-acting agent in this group, has a higher incidence of adverse effects (especially hypoglycaemia) than other drugs of this class and should be avoided. This is because of a protracted effect and reduced renal clearance in patients with renal dysfunction and the elderly; thus it is hardly ever used. Tolbutamide and gliclazide are shorter acting than glibenclamide, so there is less risk of hypoglycaemia, and for this reason they are preferred in the elderly. Related DRUGS USED TO TREAT DIABETES MELLITUS 289 drugs (e.g. repaglinide, nateglinide) are chemically distinct, but act at the same receptor. They are shorter acting even than tolbutamide, but more expensive. They are given before meals. Mechanism of action The hypoglycaemic effect of these drugs depends on the presence of functioning B cells. Sulphonylureas, like glucose, depolarize B cells and release insulin. They do this by binding to sulphonylurea receptors (SUR) and blocking ATP-dependent potassium channels (KATP); the resulting depolarization activates voltage-sensitive Ca2� channels, in turn causing entry of Ca2� ions and insulin secretion. Adverse effects Sulphonylureas can cause hypoglycaemia. Chlorpropamide, the longest-acting agent, was responsible for many cases. It also causes flushing in susceptible individuals when ethanol is consumed, and can cause dilutional hyponatraemia (by potentiating ADH, see Chapter 42). Allergic reactions to sulphonylureas include rashes, drug fever, gastrointestinal upsets, transient jaundice (usually cholestatic) and haematopoietic changes, including thrombocytopenia, neutropenia and pancytopenia. Serious effects other than hypoglycaemia are uncommon. Pharmacokinetics Sulphonylureas are well absorbed from the gastrointestinal tract and the major differences between them lie in their relative potencies and rates of elimination. Glibenclamide is almost completely metabolized by the liver to weakly active metabolites that are excreted in the bile and urine. The activity of these metabolites is only clinically important in patients with renal failure, in whom they accumulate and can cause hypoglycaemia. Tolbutamide is converted in the liver to inactive metabolites which are excreted in the urine. The t1/2 shows considerable inter-individual variability, but is usually four to eight hours. Gliclazide is extensively metabolized, although up to 20% is excreted unchanged in the urine. The plasma t1/2 ranges from 6 to 14 hours. Repaglinide and nateglinide exhibit rapid onset and offset kinetics, rapid absorption (time to maximal plasma concentration approximately 55 minutes after an oral dose) and elimination (half-life approximately three hours). These features lead to short duration of action and a low risk of hypoglycaemia. They are administered shortly before a meal to reduce the postprandial glucose rise in type 2 diabetic patients. Drug interactions Monoamine oxidase inhibitors potentiate the activity of sulphonylureas by an unknown mechanism. Several drugs (e.g. glucocorticosteroids, growth hormone) antagonize the hypoglycaemic effects of sulphonylureas by virtue of their actions on insulin release or sensitivity. THIAZOLIDINEDIONES (GLITAZONES) Glitazones (e.g. piolitazone, rosiglitazone) were developed from the chance finding that a fibrate drug (Chapter 27) increased insulin sensitivity.

290 DIABETES MELLITUS Use Glitazones lower blood glucose and haemoglobin A1c (HbA1c) in type 2 diabetes mellitus patients who are inadequately controlled on diet alone or diet and other oral hypoglycaemic drugs. An effect on mortality or diabetic complications has yet to be established, but they have rapidly become very widely used. Mechanism of action Glitazones bind to the peroxisome-proliferating activator receptor γ (PPARγ), a nuclear receptor found mainly in adipocytes and also in hepatocytes and myocytes. It works slowly, increasing the sensitivity to insulin possibly via effects of circulating fatty acids on glucose metabolism. Adverse effects The first two glitazones caused severe hepatotoxicity and are not used. Hepatotoxicity has not proved problematic with rosiglitazone or pioglitazone, although they are contraindicated in patients with hepatic impairment and liver function should be monitored during their use. The most common adverse effects are weight gain (possibly partly directly related to their effect on adipocytes) and fluid retention due to an effect of PPARγ receptors on renal tubular sodium ion absorption. They can also exacerbate cardiac dysfunction and are therefore contraindicated in heart failure. Recently, an association with increased bone fractures and osteoporosis has been noted. They are contraindicated during pregnancy. A possible increase in myocardial infarction with rosiglitazone has been noted, but the data are controversial. Pharmacokinetics Both rosiglitazone and pioglitazone are well absorbed, highly protein bound and subject to hepatic metabolism. Drug interactions Glitazones are additive with other oral hypoglycaemic drugs. They potentiate insulin, but this combination is contraindicated in Europe because of concerns that it might increase the risk of heart failure, although the combination is widely used in the USA. Pioglitazone is an inducer of CYP3A and may cause treatment failure with concomitantly administered drugs which are CYP3A substrates (e.g. reproductive steroids). ACARBOSE Acarbose is used in type 2 diabetes mellitus in patients who are inadequately controlled on diet alone or diet and other oral hypoglycaemic agents. Acarbose is a reversible competitive inhibitor of intestinal α-glucoside hydrolases and delays the absorption of starch and sucrose, but does not affect the absorption of ingested glucose. The postprandial glycaemic rise after a meal containing complex carbohydrates is reduced and its peak is delayed. Fermentation of unabsorbed carbohydrate in the intestine leads to increased gas formation which results in flatulence, abdominal distension and occasionally diarrhoea. As with any change in a diabetic patient’s medication, diet or activities, the blood glucose must be monitored. Key points Type 2 diabetes mellitus and oral hypoglycaemic agents • Type 2 (non-insulin-dependent) diabetes mellitus is caused by relative deficiency of insulin in the face of impaired insulin sensitivity. Such patients are usually obese. • About one-third of such patients finally require insulin treatment. This is especially important when they are losing muscle mass. • The dietary goal is to achieve ideal body weight by consuming an energy-restricted healthy diet low in saturated fat (Chapter 27). • Oral hypoglycaemic drugs are useful in some patients as an adjunct to diet. • Metformin, a biguanide, lowers blood glucose levels and encourages weight loss by causing anorexia. Diarrhoea is a common adverse effect. It is contraindicated in patients with renal impairment, heart failure, obstructive pulmonary disease or congenital mitochondrial myopathies because of the risk of lactic acidosis, a rare but life-threatening complication. • Acarbose, an α-glucosidase inhibitor, delays the absorption of starch and sucrose. It flattens the rise in plasma glucose following a meal and may improve control when added to diet with or without other drugs. However, it can cause bloating, flatulence and diarrhoea associated with carbohydrate malabsorption. • Sulphonylureas (e.g. tolbutamide) and related drugs (e.g. nateglinide) release insulin from β-cells by closing ATP-sensitive K � channels, thereby depolarizing the cell membrane. They are well tolerated and improve blood glucose at least initially, but stimulate appetite, promoting weight gain. They differ from one another in their kinetics, the longer-acting drugs being particularly likely to cause hypoglycaemia which can be severe, especially in the elderly and should not be used in these patients. • Thiazolidinediones (e.g. pioglitazone, rosiglitazone) activate PPARγ receptors and increase insulin sensitivity. They lower blood sugar but cause weight gain and fluid retention. They are contraindicated in heart failure. Effects on longevity or complications are unknown. Case history A 56-year-old woman with a positive family history of diabetes presents with polyuria, polydipsia, blurred vision and recurrent attacks of vaginal thrush. She is overweight at 92 kg, her fasting blood sugar is 12 mmol/L and haemoglobin A1C is elevated at 10.6%. She is treated with glibenclamide once daily in addition to topical antifungal treatment for the thrush. Initially, her symptoms improve considerably and she feels generally much better, but after nine months the polyuria and polydipsia recur and her weight has increased to 102 kg. Comment Treatment with a sulphonylurea without attention to diet is doomed to failure. This patient needs to be motivated to take dietary advice, restricting her energy intake and reducing her risk of atherosclerosis. If hyperglycaemia is still not improved, metformin (which reduces appetite) would be appropriate.

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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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  • Page 334 and 335: ● Principles of antibacterial che
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  • Page 340 and 341: Mechanism of action Macrolides bind
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  • Page 346 and 347: PRINCIPLES OF MANAGEMENT OF MYCOBAC
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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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    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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    ● Introduction 433 ● Pathophysi

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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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