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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

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Each of these classes of drug reduces clinical end-points such as stroke, but in uncomplicated hypertension B drugs may be less effective than other classes. Other antihypertensive drugs useful in specific circumstances include α-adrenoceptor antagonists, aldosterone antagonists and centrally acting antihypertensive drugs. Key points Pathophysiology of hypertension • Few patients with persistent systemic arterial hypertension have a specific aetiology (e.g. renal disease, endocrine disease, coarctation of aorta). Most have essential hypertension (EH), which confers increased risk of vascular disease (e.g. thrombotic or haemorrhagic stroke, myocardial infarction). Reducing blood pressure reduces the risk of such events. • The cause(s) of EH is/are ill-defined. Polygenic influences are important, as are environmental factors including salt intake and obesity. The intrauterine environment (determined by genetic/environmental factors) may be important in determining blood pressure in adult life. • Increased cardiac output may occur before EH becomes established. • Established EH is characterized haemodynamically by normal cardiac output but increased total systemic vascular resistance. This involves both structural (remodelling) and functional changes in resistance vessels. • EH is a strong independent risk factor for atheromatous disease and interacts supra-additively with other such risk factors. GENERAL PRINCIPLES OF MANAGING ESSENTIAL HYPERTENSION • Consider blood pressure in the context of other risk factors: use cardiovascular risk to make decisions about whether to start drug treatment and what target to aim for. (Guidance, together with risk tables, is available, for example, at the back of the British National Formulary). • Use non-drug measures (e.g. salt restriction) in addition to drugs. • Explain goals of treatment and agree a plan the patient is comfortable to live with (concordance). • Review the possibility of co-existing disease (e.g. gout, angina) that would influence the choice of drug. • The ‘ABCD’ rule provides a useful basis for starting drug treatment. A (and B) drugs inhibit the renin–angiotensin–aldosterone axis and are effective when this is active – as it usually is in young white or Asian people. An A drug is preferred for these unless there is some reason to avoid it (e.g. in a young woman contemplating pregnancy) or some additional reason (e.g. co-existing angina) to choose a B drug. Older people and people of Afro-Caribbean ethnicity often have a low plasma renin and in these patients a class C or D drug is preferred. • Use a low dose and, except in emergency situations, titrate this upward gradually. • Addition of a second drug is often needed. A drug of the other group is added, i.e. an A drug is added to patients started on a C or D drug, a C or D drug is added to a patient started on an A drug. A third or fourth drug may be needed. It is better to use such combinations than to use very high doses of single drugs: this seldom works and often causes adverse effects. • Loss of control – if blood pressure control, having been well established, is lost, there are several possibilities to be considered: • non-adherence; • drug interaction – e.g. with non-steroidal antiinflammatory drugs (NSAIDs) – see Chapter 26; • intercurrent disease – e.g. renal impairment, atheromatous renal artery stenosis. DRUGS USED TO TREAT HYPERTENSION A DRUGS DRUGS USED TO TREAT HYPERTENSION 187 ANGIOTENSIN-CONVERTING ENZYME INHIBITORS Use Several angiotensin-converting enzyme inhibitors (ACEI) are in clinical use (e.g. ramipril, trandolapril, enalapril, lisinopril, captopril). These differ in their duration of action. Longer-acting drugs (e.g. trandolapril, ramipril) are preferred. They are given once daily and produce good 24-hour control. Their beneficial effect in patients with heart failure (Chapter 31) or following myocardial infarction (Chapter 29) makes them or a sartan (below) particularly useful in hypertensive patients with these complications. Similarly an ACEI or sartan is preferred over other anti-hypertensives in diabetic patients because they slow the progression of diabetic nephropathy. Treatment is initiated using a small dose given last thing at night, because of the possibility of first-dose hypotension. If possible, diuretics should be withheld for one or two days before the first dose for the same reason. The dose is subsequently usually given in the morning and increased gradually if necessary, while monitoring the blood-pressure response. Mechanism of action ACE catalyses the cleavage of a pair of amino acids from short peptides, thereby ‘converting’ the inactive decapeptide angiotensin I to the potent vasoconstrictor angiotensin II (Figure 28.4). As well as activating the vasoconstrictor angiotensin in this way, it also inactivates bradykinin – a vasodilator peptide. ACEI lower blood pressure by reducing angiotensin II and perhaps also by increasing vasodilator

188 HYPERTENSION Angiotensin receptor blocker � Vasoconstriction Cell growth Angiotensinogen Angiotensin I Angiotensin II AT 1 -receptor Sodium and fluid retention Renin ACE ACE inhibitor Sympathetic activation Figure 28.4: Generation of angiotensin II, and mode of action of ACE inhibitors and of angiotensin receptor blockers. peptides, such as bradykinin. Angiotensin II causes aldosterone secretion from the zona glomerulosa of the adrenal cortex and inhibition of this contributes to the antihypertensive effect of ACE inhibitors. Metabolic effects ACEI cause a mild increase in plasma potassium which is usually unimportant, but may sometimes be either desirable or problematic depending on renal function and concomitant drug therapy (see Adverse effects and Drug interactions below). Adverse effects ACE inhibitors are generally well tolerated. Adverse effects include: • First-dose hypotension. • Dry cough – this is the most frequent symptom (5–30% of cases) during chronic dosing. It is often mild, but can be troublesome. The cause is unknown, but it may be due to kinin accumulation stimulating cough afferents. Sartans (see below) do not inhibit the metabolism of bradykinin and do not cause cough. • Functional renal failure – this occurs predictably in patients with haemodynamically significant bilateral renal artery stenosis, and in patients with renal artery stenosis in the vessel supplying a single functional kidney. Plasma creatinine and potassium concentrations should be monitored and the possibility of renal artery stenosis considered in patients in whom there is a marked rise in creatinine. Provided that the drug is stopped promptly, such renal impairment is reversible. The explanation of acute reduction in renal function in this setting is that glomerular filtration in these patients is critically dependent on angiotensin-II-mediated efferent arteriolar � vasoconstriction, and when angiotensin II synthesis is inhibited, glomerular capillary pressure falls and glomerular filtration ceases. This should be borne in mind particularly in ageing patients with atheromatous disease. • Hyperkalaemia is potentially hazardous in patients with renal impairment and great caution must be exercised in this setting. This is even more important when such patients are also prescribed potassium supplements and/or potassium-sparing diuretics. • Fetal injury – ACEI cause renal agenesis/failure in the fetus, resulting in oligohydramnios. ACEI are therefore contraindicated in pregnancy and other drugs are usually preferred in women who may want to start a family. • Urticaria and angio-oedema – increased kinin concentration may explain the urticarial reactions and angioneurotic oedema sometimes caused by ACEI. • Sulphhydryl group-related effects – high-dose captopril causes heavy proteinuria, neutropenia, rash and taste disturbance, attributable to its sulphhydryl group. Pharmacokinetics Currently available ACE inhibitors are all active when administered orally, but are highly polar and are eliminated in the urine. A number of these drugs (e.g. captopril, lisinopril) are active per se, while others (e.g. enalapril) are prodrugs and require metabolic conversion to active metabolites (e.g. enalaprilat). In practice, this is of little or no importance. None of the currently available ACEI penetrate the central nervous system. Many of these agents have long half-lives permitting once daily dosing; captopril is an exception. Drug interactions The useful interaction with diuretics has already been alluded to above. Diuretic treatment increases plasma renin activity and the consequent activation of angiotensin II and aldosterone limits their efficacy. ACE inhibition interrupts this loop and thus enhances the hypotensive efficacy of diuretics, as well as reducing thiazide-induced hypokalaemia. Conversely, ACEI have a potentially adverse interaction with potassium-sparing diuretics and potassium supplements, leading to hyperkalaemia, especially in patients with renal impairment, as mentioned above. As with other antihypertensive drugs, NSAIDs increase blood pressure in patients treated with ACE inhibitors. ANGIOTENSIN RECEPTOR BLOCKERS Several angiotensin receptor blockers (ARB or ‘sartans’) are in clinical use (e.g. losartan, candesartan, irbesartan, valsartan). Use Sartans are pharmacologically distinct from ACEI, but clinically similar in hypotensive efficacy. However, they lack the common ACEI adverse effect of dry cough. Long-acting drugs (e.g. candesartan, which forms a stable complex with the

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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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  • Page 150 and 151: FURTHER ANTI-EPILEPTICS Other drugs
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  • Page 178 and 179: ● Introduction: inflammation 167
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  • Page 186 and 187: PART IV THE CARDIOVASCULAR SYSTEM
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  • Page 204 and 205: Key points Drugs used in essential
  • Page 206 and 207: Case history A 72-year-old woman se
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  • Page 224 and 225: The drugs that are most effective i
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    Adenylyl cyclase Table 33.1: Compar

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    Drug interactions Although synergis

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    use in asthma has declined consider

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    α 1-antitrypsin deficiency, neutro

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    PART VI THE ALIMENTARY SYSTEM

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    ● Peptic ulceration 247 ● Oesop

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    PEPTIC ULCERATION 249 • With rega

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    Ranitidine has a similar profile of

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    Vestibular stimulation ? via cerebe

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    cortical centres affecting vomiting

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    • in hepatocellular failure to re

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    Ciprofloxacin is occasionally used

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    withdrawal), small doses of benzodi

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    Table 34.7: Dose-independent hepato

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    ● Introduction 265 ● General ph

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    dinucleotide (NAD) and nicotinamide

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    Table 35.1: Common trace element de

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    PART VII FLUIDS AND ELECTROLYTES

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    ● Introduction 273 ● Volume ove

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    Key points Diuretics Diuretics are

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    is sometimes caused by drugs, notab

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    or with potassium-sparing diuretics

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    Greger R, Lang F, Sebekova, Heidlan

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    PART VIII THE ENDOCRINE SYSTEM

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    ● Introduction 285 ● Pathophysi

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    in prefilled injection devices (‘

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    Metformin should be withdrawn and i

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    FURTHER READING American Diabetes A

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    deficiency. Potassium iodide (3 mg

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    fertility. It is contraindicated du

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    ● Introduction 297 ● Vitamin D

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    effective in life-threatening hyper

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    Further reading Block GA, Martin KJ

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    Table 40.1: Actions of cortisol and

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    injection may be useful, but if don

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    CHAPTER 41 REPRODUCTIVE ENDOCRINOLO

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    elease by the pituitary via negativ

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    Treatment with depot progestogen in

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    infusion using an infusion pump to

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    significant proportion of men who r

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    with symptoms caused by the release

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    FURTHER READING Birnbaumer M. Vasop

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    PART IX SELECTIVE TOXICITY

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    ● Principles of antibacterial che

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    2. transfer of resistance between o

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    Pharmacokinetics Absorption of thes

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    Mechanism of action Macrolides bind

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    asic quinolone structure dramatical

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    Case history A 70-year-old man with

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    PRINCIPLES OF MANAGEMENT OF MYCOBAC

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    Pharmacokinetics Absorption from th

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    MYCOBACTERIUM LEPRAE INFECTION Lepr

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    POLYENES AMPHOTERICIN B Uses Amphot

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    therapy is adequate though more fre

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    NUCLEOSIDE ANALOGUES ACICLOVIR Uses

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    Table 45.3: Summary of available ac

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    Uses Interferon-α when combined wi

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    ● Introduction 351 ● Immunopath

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    Table 46.1: Examples of combination

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    NON-NUCLEOSIDE ANALOGUE REVERSE TRA

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    FUSION INHIBITORS Uses Currently, e

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    salvage therapy include azithromyci

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    ● Malaria 361 ● Trypanosomal in

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    Pharmacokinetics Chloroquine is rap

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    Table 47.2: Drug therapy of non-mal

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    ● 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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