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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

Key points Diuretics

Key points Diuretics Diuretics are classed by their site of action. • Thiazides (e.g. bendroflumethiazide) inhibit Na � /Cl � reabsorption in the early distal convoluted tubule; they produce a modest diuresis and are used in particular in hypertension. • Loop diuretics (e.g. furosemide) inhibit Na � /K � /2Cl � cotransporter in the thick ascending limb of Henle’s loop. They cause a large effect and are used especially in heart failure and oedematous states. • Potassium-sparing diuretics inhibit Na � /K � exchange in the collecting duct either by competing with aldosterone (spironolactone), or non-competitively (e.g. amiloride, triamterene). They cause little diuresis. Spironolactone improves survival in heart failure and is used in hyperaldosteronism. These drugs are sometimes combined with thiazide or loop diuretics to prevent hypokalaemia. • Carbonic anhydrase inhibitors (e.g. acetazolamide) inhibit HCO 3 � reabsorption in the proximal tubule. They are weak diuretics, cause metabolic acidosis and are used to treat glaucoma, rather than for their action on the kidney. • Osmotic diuretics (e.g. mannitol) are used in patients with incipient acute renal failure, and acutely to lower intra-ocular or intracranial pressure. concentration falls without accumulation of any unmeasured anions, giving a non-anion gap metabolic acidosis, as in renal tubular acidosis. The reduction in plasma bicarbonate leads to a reduced filtered load of this ion, so less bicarbonate is available for reabsorption from proximal tubular fluid. The diuretic effect of acetazolamide is therefore self-limiting. Large doses cause paraesthesiae, fatigue and dyspepsia. Prolonged use predisposes to renal stone formation due to reduced urinary citrate (citrate increases the solubility of calcium in the urine). Hypersensitivity reactions and blood dyscrasias are a problem, as with other sulphonamides. LOOP DIURETICS Uses The main clinical use of loop diuretics (e.g. furosemide) is for heart failure (Chapter 31). Furosemide is also useful in patients with chronic renal failure who are suffering from fluid overload and/or hypertension. Large doses may be needed to produce diuresis in patients with severe renal impairment. In patients with incipient acute renal failure, intravenous infusion sometimes produces diuresis, and may prevent the development of established failure, although this is difficult to prove. Loop diuretics increase urinary calcium excretion (in contrast to thiazides). This is exploited in the treatment of hypercalcaemia when furosemide is given after volume replacement with 0.9% sodium chloride. Mechanism of action Loop diuretics have steep dose–response curves and much higher maximum effects than thiazide or other diuretics, being capable of increasing fractional sodium excretion to as much as 35%. They act from within the tubular fluid to inhibit a co-transporter in the thick ascending limb of the loop of Henle which transports Na � and K � together with 2Cl � ions from the lumen (‘Na � K � 2Cl � cotransport’), see Figure 36.1. Pharmacokinetics Furosemide is rapidly and extensively absorbed from the gut. It is 95% bound to plasma protein and elimination is mainly via the kidneys, by filtration and proximal tubular secretion. Approximately two-thirds of water reabsorption occurs isoosmotically in the proximal convoluted tubule, so furosemide is substantially concentrated before reaching its site of action in the thick ascending limb. This accounts for its selectivity for the renal Na � K � 2Cl � cotransport mechanism, as opposed to Na � K � 2Cl � cotransport at other sites, such as the inner ear. The luminal site of action of furosemide also contributes to diuretic insensitivity in nephrotic syndrome, where heavy albuminuria results in binding of furosemide to albumin within the lumen. Adverse effects 1. Acute renal failure – loop diuretics in high dose cause massive diuresis. This can abruptly reduce blood volume. Acute hypovolaemia can precipitate prerenal renal failure. 2. Hypokalaemia – inhibition of K � reabsorption in the loop of Henle and increased delivery of Na � to the distal nephron (where it can be exchanged for K � ) results in increased urinary potassium loss and hypokalaemia. 3. Hypomagnesaemia. 4. Hyperuricaemia and gout. 5. Otoxicity with hearing loss is associated with excessive peak plasma concentrations caused by too rapid intravenous injection. It may be related to inhibition of Na � K � 2Cl � cotransporter in the ear, which is involved in the formation of endolymph. 7. Metabolic alkalosis – the increased water and chloride excretion caused by loop diuretics results in contraction alkalosis. 8. Idiosyncratic blood dyscrasias occur rarely. Drug interactions Loop diuretics increase the nephrotoxicity of first-generation cephalosporins, e.g. cephaloridine, and increase aminoglycoside toxicity. Lithium reabsorption is reduced by loop diuretics and the dose of lithium carbonate often needs to be reduced. THIAZIDE DIURETICS DIURETICS 275 The mechanism, adverse effects, contraindications and interactions of thiazide diuretics are covered in Chapter 28, together with their first-line use in hypertension.

276 NEPHROLOGICAL AND RELATED ASPECTS Uses Thiazides are used in: 1. hypertension (Chapter 28) 2. mild cardiac failure (Chapter 31); 3. resistant oedema – thiazides or related drugs (e.g. metolazone) are extremely potent when combined with a loop diuretic; 4. prevention of stones – thiazides reduce urinary calcium excretion and thus help to prevent urinary stone formation in patients with idiopathic hypercalciuria; 5. diabetes insipidus – paradoxically, thiazides reduce urinary volume in diabetes insipidus by preventing the formation of hypotonic fluid in the distal tubule; they are therefore sometimes used to treat nephrogenic diabetes insipidus. POTASSIUM-SPARING DIURETICS Some diuretics inhibit distal Na � /K � tubular exchange (Figure 36.1), causing potassium retention at the same time as natriuresis. They fall into two categories: 1. competitive antagonists, structurally related to aldosterone: spironolactone, eplerenone; 2. Na � /K � exchange antagonists that do not compete with aldosterone: amiloride, triamterene. These are not potent diuretics, since only a small fraction of the filtered Na � is reabsorbed by this mechanism, but spironolactone prolongs survival in heart failure (Chapter 31) and is useful when there is hyperaldosteronism, whether primary (Conn’s syndrome, resistant hypertension) or secondary (e.g. in cirrhosis with ascites). High doses of spironolactone causes gynaecomastia and breast tenderness in men and menstrual irregularity in women – oestrogenic side effects. Eplerenone is more selective and lacks these oestrogenic effects. It is much more expensive but has been shown to improve survival following myocardial infarction (Chapter 29). Amiloride and triamterene also inhibit Na � /K � exchange, but not by competition with aldosterone. They are marketed as combination tablets with loop or thiazide diuretics as a means of avoiding hypokalaemia. Hypokalaemia is important if drugs such as digoxin (Chapters 31 and 32) or sotalol (Chapter 32) are co-prescribed, because their toxicity is increased by hypokalaemia. Conversely K � -retaining diuretics predispose to hyperkalaemia if used with ACEI or sartans in patients with renal impairment. OSMOTIC DIURETICS Use and mechanism of action Osmotic diuretics undergo glomerular filtration but are poorly reabsorbed from the renal tubular fluid. Their main diuretic action is exerted on the proximal tubule. This section of the tubule is freely permeable to water, and under normal circumstances sodium is actively reabsorbed accompanied by an Key points Salt overload and diuretics • Several diseases are associated with retention of excess salt and water, including: – heart failure; – renal failure; – nephrotic syndrome; – cirrhosis. • Treatment involves restriction of dietary salt and administration of diuretics to increase salt excretion. • The main classes of diuretics for these indications are: – thiazides; – loop diuretics; – K � -sparing diuretics. • In addition to treating salt/water overload, diuretics are also used in: – systemic hypertension; – glaucoma (carbonic anhydrase inhibitors); – acute reduction of intracranial or intra-ocular pressure (osmotic diuretics); – hypercalcaemia (furosemide); – nephrogenic diabetes insipidus (thiazides). isoosmotic quantity of water. The presence of a substantial quantity of a poorly absorbable solute opposes this, because as water is reabsorbed the concentration and hence the osmotic activity of the solute increases. Osmotic diuretics (e.g. mannitol) also interfere with the establishment of the medullary osmotic gradient which is necessary for the formation of concentrated urine. Mannitol is poorly absorbed from the intestine and is given intravenously in gram quantities. Unlike other diuretics, osmotic diuretics increase the plasma volume (by increasing the entry of water to the circulation as a result of increasing intravascular osmolarity), so they are unsuitable for the treatment of most causes of oedema, especially cardiac failure. It is possible that, if used early in the course of incipient acute renal failure, osmotic diuretics may stave off the occurrence of acute tubular necrosis by increasing tubular fluid flow and washing away material that would otherwise plug the tubules. Osmotic diuretics are mainly used for reasons unconnected with their ability to cause diuresis. Because they do not enter cells or some anatomical areas, such as the eye and brain, they cause water to leave cells down the osmotic gradient. This ‘dehydrating’ action is used in two circumstances: 1. reduction of intra-ocular pressure: pre-operatively for urgent reduction of intra-ocular pressure and in closedangle glaucoma; 2. emergency reduction of intracranial pressure. SIADH: OVERHYDRATION Overhydration without excess salt is much less common than salt and water overload, but occurs when antidiuretic hormone (ADH) is secreted inappropriately (e.g. by a neoplasm or following head injury or neurosurgery), giving rise to the syndrome of inappropriate secretion of ADH (SIADH). This

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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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  • Page 334 and 335: ● 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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    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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