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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

The drugs that are most

The drugs that are most effective in prolonging survival in chronic heart failure work indirectly, by reducing preload, afterload or heart rate, rather than directly by increasing the force of contraction. THERAPEUTIC OBJECTIVES AND GENERAL MEASURES FOR CHRONIC HEART FAILURE Therapeutic objectives in treating heart failure are • to improve symptoms and • to prolong survival. General principles of treating heart failure: • restrict dietary salt; • if there is hyponatraemia, restrict fluid; • review prescribed drugs and if possible withdraw drugs that aggravate cardiac failure: • some negative inotropes (e.g. verapamil) • cardiac toxins (e.g. daunorubicin, ethanol, imatinib, gefitinib, trastuzumab) • drugs that cause salt retention (e.g. NSAID). • consider anticoagulation on an individual basis. DRUGS FOR HEART FAILURE DIURETICS For more information, see Chapter 28 for use of diuretics in hypertension and Chapter 36, for mechanisms, adverse effects and pharmacokinetics. Use in heart failure Chronic heart failure: a diuretic is used to control symptomatic oedema and dyspnoea in patients with heart failure. A thiazide (see Chapters 28 and 36) may be adequate in very mild cases, but a loop diuretic (e.g. furosemide) is usually needed. Unlike several of the drugs described below, there has been no randomized controlled trial investigating the influence of loop diuretics on survival in heart failure, but the other treatments were added to a loop diuretic and this is usually the starting point of drug treatment. Spironolactone improves survival in patients with cardiac failure and counters diuretic-induced hypokalaemia. Diuretic-induced hypokalaemia increases the toxicity of digoxin. Conversely, spironolactone and other K � -retaining diuretics (e.g. amiloride, triamterene) can cause severe hyperkalaemia, especially if given with ACEI or sartans (see below) to patients with renal impairment. It is therefore important to monitor plasma K � during treatment with all diuretic therapy. Acute heart failure: acute pulmonary oedema is treated by sitting the patient upright, administering oxygen (FiO 2, 28–40%) and intravenous furosemide which is often effective within a matter of minutes. Intravenous morphine (Chapter 25) is also useful. A slow intravenous infusion of furosemide by syringe pump may be useful in resistant cases. Once the acute situation DRUGS FOR HEART FAILURE 213 has resolved the situation is re-assessed and drugs used for chronic heart failure (see below), including oral diuretics, are usually indicated. ANGIOTENSIN-CONVERTING ENZYME INHIBITORS For the mechanism of action and other aspects of angiotensinconverting enzyme inhibitors, see Chapter 28. Use in heart failure The first approach shown to reduce mortality in heart failure was combined hydralazine and nitrate therapy (see below). Soon after, an angiotensin-converting enzyme inhibitor (ACEI) (captopril) was shown to do better. Other ACEI were also shown to improve survival and ACEI treatment for heart failure was rapidly adopted. When symptoms are mild, diuretics can be temporarily discontinued a day or two before starting an ACEI, reducing the likelihood of first-dose hypotension. In these circumstances, treatment with an ACE inhibitor can be started as an out-patient, as for hypertension (see Chapter 28). A small starting dose is used and the first dose is taken last thing before retiring at night, with advice to sit on the side of the bed before standing if the patient needs to get up in the night. The dose is gradually increased to one that improves symptoms (and survival) with careful monitoring of blood pressure. Serum potassium and creatinine are checked after one to two weeks. Hypotension is more of a problem when starting treatment in heart failure patients than when treating hypertension, especially with short-acting drugs (e.g. captopril). Not only is the blood pressure lower to start with, but concentrations of circulating renin are high and increased further by diuretics. ACEI cause ‘first-dose’ hypotension most severely in patients with the greatest activation of the renin–angiotensin system. These are consequently those most likely to benefit from an ACEI in the long term. Long-acting drugs (e.g. ramipril, trandolapril) cause less first-dose hypotension and can be given once daily. ACEI are usually well tolerated during chronic treatment, although dry cough is common and occasionally unacceptable (see Chapter 28 for other adverse effects). Important drug–drug interactions can occur with NSAIDs (Chapter 26), which may cause renal failure and severe hyperkalaemia, especially in heart failure patients treated with ACEI. ANGIOTENSIC RECEPTOR ANTAGONISTS, SARTANS See Chapter 28 for the mechanism of action. Use in heart failure As in hypertension, the pharmacodynamics of sartans are similar to those of ACEI apart from a lower incidence of some adverse effects, including, particularly, dry cough. Several of these drugs (e.g. candesartan, valsartan) have been shown to prolong life in randomized controlled trials, the magnitude of the effect being similar to ACEI. It is possible that they have some additive effect when combined with ACEI, but this is hard to prove at doses that are not supramaximal. Because of the greater experience with ACEI and the lower cost, many physicians prefer to use an ACEI, unless this is not tolerated.

214 HEART FAILURE Precautions in terms of first-dose hypotension and monitoring creatinine and electrolytes are similar to those for ACEI. β-ADRENOCEPTOR ANTAGONISTS For more information, see Chapter 28 for use in hypertension, Chapter 29 for use in ischaemic heart disease and Chapter 32 for use as antidysrhythmic drugs. Classification of β-adrenoceptor antagonists Adrenoceptors are classified as α or β, with a further subdivision of the latter into β1, mainly in the heart, β2 which are present in, for example, bronchioles and β3, which mediate metabolic effects in brown fat. Cardioselective beta-blockers (e.g. atenolol, metoprolol) inhibit β1-receptors relatively selectively, but are nonetheless hazardous for patients with asthma. Some beta-blockers (e.g. oxprenolol) are partial agonists and possess intrinsic sympathomimetic activity. This is seldom important in practice. Vasodilating beta-blockers include drugs (e.g. labetolol, carvedilol) with additional α-blocking activity. Celiprolol has additional agonist activity at β2-receptors. Nebivolol releases endothelium-derived nitric oxide, as well as being a highly selective β1-adrenoceptor blocker. Use in heart failure Beta-blockers are negative inotropes and so intuitively would be expected to worsen heart failure. There is, however, a rationale for their use in terms of antagonizing counterregulatory sympathetic activation and several randomized controlled trials have demonstrated improved survival when a β-adrenoceptor antagonist is added to other drugs, including an ACEI. Several β-adrenoceptor antagonists have been shown to be of benefit including bisoprolol, metoprolol and carvedilol. Bisoprolol and metoprolol are cardioselective β1 antagonists, whereas carvedilol is non-selective and has additional α antagonist properties. Carvedilol may be more effective than bisoprolol in heart failure, but is less well tolerated because of postural hypotension. Treatment is started with a low dose when the patient is stable and the patient reviewed regularly at short intervals (e.g. every two weeks or more frequently if needed), often by a heart failure nurse, with dose titration as tolerated. Adverse effects • Intolerance Fatigue and cold extremities are common and dose related. Erectile dysfunction occurs, but is less common than with thiazide diuretics. Central nervous system (CNS) effects (e.g. vivid dreams) can occur. • Airways obstruction β-adrenoceptor antagonists predispose to severe airways obstruction in patients with pre-existing obstructive airways disease, especially asthma. • Peripheral vascular disease and vasospasm β-adrenoceptor antagonists worsen claudication in patients with symptomatic atheromatous peripheral vascular disease and worsen Raynaud’s phenomenon. • Hypoglycaemia β-adrenoceptor antagonists mask symptoms of hypoglycaemia, and slow the rate of recovery from it, because adrenaline stimulates gluconeogenesis via β 2-adrenoceptors. • Heart block. ALDOSTERONE ANTAGONISTS For more information, see Chapter 36. Spironolactone (or the newer expensive agent, eplerenone), when added to conventional therapy with loop diuretic, ACEI and β-adrenoceptor antagonist, further improves survival. Concerns regarding hyperkalaemia in such patients may have been overstated, at least provided patients with appreciably impaired renal function are excluded from such treatment. COMBINED HYDRALAZINE WITH ORGANIC NITRATE THERAPY There is renewed interest in combined therapy with hydralazine (Chapter 28) and a long-acting nitrate (Chapter 29). The pharmacologic basis for investigating this was that hydralazine reduced afterload and the nitrate reduced preload. As mentioned above, this improved survival in one randomized controlled trial, but performed less well overall in a direct comparison with an ACEI. However, a subgroup analysis suggested that African-American patients did better with the hydralazine/nitrate combination, whereas Caucasians did better with ACEI. This observation led to a further study in African-Americans which confirmed the efficacy of hydralazine–nitrate treatment. It is now often used for patients of African origin. Hopefully, genetic testing will further improve the targeting of appropriate therapy (‘personalized medicine’) in future. DIGOXIN For more information on the use of digoxin, refer to Chapter 32. William Withering described an extract of foxglove as a ‘cure’ for ‘dropsy’ (congestive cardiac failure) in 1785. Digoxin remains useful for symptoms. Use in heart failure Rapid atrial fibrillation can worsen heart failure and digoxin can be used to control the ventricular response, which it does by stimulating vagal efferents to the heart (Chapter 32). Its positive inotropic action is an added benefit. Heart failure patients in sinus rhythm who remain symptomatic despite optimal treatment with life-prolonging medications also benefit. Addition of digoxin to diuretics and ACEI reduces hospitalization and improves symptoms, without prolonging life. It is usually given orally, but can be given i.v. if a rapid effect is required. Since the half-life is approximately 30–48 hours, repeated administration of a once-daily maintenance dose results in a plateau concentration in about five to ten days. The dose may be adjusted based on plasma concentration determinations once steady state has been reached (Chapter 8). Such determinations are also useful if toxicity is suspected (e.g. because of nausea, bradycardia or ECG changes). In urgent situations, a

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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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    Table 34.7: Dose-independent hepato

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    ● Introduction 265 ● General ph

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    dinucleotide (NAD) and nicotinamide

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    Table 35.1: Common trace element de

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    PART VII FLUIDS AND ELECTROLYTES

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    ● Introduction 273 ● Volume ove

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    Key points Diuretics Diuretics are

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    is sometimes caused by drugs, notab

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    or with potassium-sparing diuretics

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    Greger R, Lang F, Sebekova, Heidlan

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    PART VIII THE ENDOCRINE SYSTEM

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    ● Introduction 285 ● Pathophysi

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    in prefilled injection devices (‘

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    Metformin should be withdrawn and i

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    FURTHER READING American Diabetes A

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    deficiency. Potassium iodide (3 mg

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    fertility. It is contraindicated du

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    ● Introduction 297 ● Vitamin D

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    effective in life-threatening hyper

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    Further reading Block GA, Martin KJ

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    Table 40.1: Actions of cortisol and

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    injection may be useful, but if don

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    CHAPTER 41 REPRODUCTIVE ENDOCRINOLO

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    elease by the pituitary via negativ

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    Treatment with depot progestogen in

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    infusion using an infusion pump to

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    significant proportion of men who r

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    with symptoms caused by the release

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    FURTHER READING Birnbaumer M. Vasop

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    PART IX SELECTIVE TOXICITY

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    ● Principles of antibacterial che

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    2. transfer of resistance between o

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    Pharmacokinetics Absorption of thes

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    Mechanism of action Macrolides bind

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    asic quinolone structure dramatical

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    Case history A 70-year-old man with

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    PRINCIPLES OF MANAGEMENT OF MYCOBAC

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    Pharmacokinetics Absorption from th

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    MYCOBACTERIUM LEPRAE INFECTION Lepr

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    POLYENES AMPHOTERICIN B Uses Amphot

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    therapy is adequate though more fre

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    NUCLEOSIDE ANALOGUES ACICLOVIR Uses

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    Table 45.3: Summary of available ac

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    Uses Interferon-α when combined wi

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    ● Introduction 351 ● Immunopath

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    Table 46.1: Examples of combination

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    NON-NUCLEOSIDE ANALOGUE REVERSE TRA

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    FUSION INHIBITORS Uses Currently, e

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    salvage therapy include azithromyci

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    ● Malaria 361 ● Trypanosomal in

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    Pharmacokinetics Chloroquine is rap

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    Table 47.2: Drug therapy of non-mal

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    ● Introduction 367 ● Pathophysi

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    Table 48.1: Classification of commo

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    Polymorph count/mm 3 (a) (b) 10 000

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    doses are used to prepare patients

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    Adverse effects Methotrexate Inhibi

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    Table 48.7: Summary of clinical pha

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    Table 48.9: Summary of the clinical

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    Plasma membrane Signal transduction

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    Table 48.10: Monoclonal antibodies

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    INTERFERON-ALFA 2B Interferon-alfa

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    PART X HAEMATOLOGY

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    ● Haematinics - iron, vitamin B 1

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    one marrow to produce red cells. Th

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    EPO Erythroid precursors Erythrocyt

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    Therapeutic principles The extent o

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    PART XI IMMUNOPHARMACOLOGY

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    ● Introduction 399 ● Immunity a

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    Key points Antigen recognition Expr

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    Table 50.1: Novel anti-proliferativ

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    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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