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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

● Introduction 211 ●

● Introduction 211 ● Pathophysiology and implications for treatment 211 ● Therapeutic objectives and general measures for chronic heart failure 213 INTRODUCTION Heart failure occurs when the heart fails to deliver adequate amounts of oxygenated blood to the tissues during exercise or, in severe cases, at rest. Such failure of the pump function may be chronic, in which case symptoms of fatigue, ankle swelling, effort dyspnoea and orthopnoea predominate, or it may be acute, with sudden onset of shortness of breath due to pulmonary oedema (Figure 31.1). Both acute and chronic heart failure severely reduce life expectancy (Figure 31.2). The most severe form of heart failure (low cardiac output circulatory failure, ‘cardiogenic shock’) is managed with pressor drugs (e.g. adrenaline) or with mechanical support (e.g. intra-aortic balloon pump), in an intensive care unit. Such treatment is highly individualized (and specialized) and mortality even with the best treatment is very high. In this chapter, we cover the more common syndrome of chronic congestive heart failure and discuss the treatment of acute pulmonary oedema, since this is a common emergency. CHAPTER 31 HEART FAILURE (a) (b) ● Drugs for heart failure 213 PATHOPHYSIOLOGY AND IMPLICATIONS FOR TREATMENT Heart failure is an end result of many diseases (not only of the myocardium, pericardium and valves, but also of extracardiac disorders, including systemic or pulmonary hypertension, fluid overload, vascular shunts, anaemia and thyrotoxicosis). The most common of these are ischaemic heart disease (Chapter 29), idiopathic congestive cardiomyopathy and cor pulmonale (Chapter 33). Specific measures are needed in each case and these are covered in other chapters. Here, Figure 31.1: Peripheral oedema with evidence of pitting (left) and pulmonary oedema on chest x-ray (right), both important consequences of uncontrolled and inadequately treated heart failure.

212 HEART FAILURE we focus on aspects common to heart failure irrespective of aetiology. Heart failure triggers ‘counter-regulatory’ responses (Figure 31.3), which make the situation worse, not better. Our ancestors encountered low cardiac output during haemorrhage rather than as a result of heart failure. Mechanisms to conserve blood volume and maintain blood pressure would have provided selective advantage. However, reflex and endocrine changes that are protective in the setting of haemorrhage (volume depletion ‘shock’) negatively impact patients with low cardiac output due to pump failure. Proportion surviving 1.00 0.75 0.50 No CHF CHS only 0.25 Framingham only Concordant 0.00 0 2 4 6 Time since index date (years) Figure 31.2: Kaplan–Meier survival curves for subjects in the Cardiovascular Health Study (CHS), United States, 1989–2000. Subjects either had no congestive heart failure (CHF) or had CHF diagnosed by different criteria (Framingham only, CHS only or both, i.e. concordant). (Redrawn with permission from Schellenbaum GD et al. American Journal of Epidemiology 2004; 160: 628–35.) ↓ Cardiac output ↓ Renal perfusion Activation of renin–angiotensin– aldosterone system ↓ Firing of arterial baroreceptors (Carotid sinus, Aortic arch) Endothelial dysfunction Activation of sympathetic nervous system ↑ Endothelin ↓ Nitric oxide Figure 31.3: Compensatory counter-regulatory responses in heart failure and their consequences. Treatment of heart failure is aimed at reversing these counterregulatory changes, which include: • activation of the renin–angiotensin–aldosterone system; • activation of the sympathetic nervous system; • release of vasopressin (an antidiuretic hormone, see Chapter 42). Cardiac performance is determined by preload, afterload, myocardial contractility and heart rate. Treatment targets these aspects, often by blocking one or other of the counterregulatory mechanisms. PRELOAD Cardiac preload, the cardiac filling pressure, is determined by blood volume – increased by salt and water retention – and capacitance vessel tone, increased by sympathetic nervous system activation. Drugs can reduce blood volume (diuretics) and reduce capacitance vessel tone (venodilators). AFTERLOAD Afterload is determined by the systemic vascular resistance and by aortic stiffness. Drugs that relax arterial smooth muscle reduce cardiac afterload. MYOCARDIAL CONTRACTILITY Positive inotropes (i.e. drugs that increase the force of contraction of the heart) can improve cardiac performance temporarily by increasing contractility, but at the expense of increased oxygen consumption and risk of dysrhythmia. HEART RATE Cardiac function deteriorates as heart rate increases beyond an optimum, due to insufficient time for filling during diastole. Heart rate can usefully be slowed by negative chronotropes (i.e. drugs that slow the heart). Vasoconstriction Salt and water retention Short-term Maintenance of blood pressure Longer-term Worsening of tissue perfusion Worsening of fluid retention Progressive cardiomyocyte death and fibrosis Death

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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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    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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    ● 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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