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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

should be given to

should be given to insertion of an implantable cardioverter defibrillator (ICD), if the patient is considered at high risk of further episodes and/or serious ventricular dysrhythmias remain inducible on electrophysiological testing. Ventricular fibrillation: See above under Advanced life support. As discussed above for ventricular tachycardia, implantation of an ICD should be considered. BRADYDYSRHYTHMIAS ASYSTOLE See above under Advanced life support. Sinus bradycardia 1. Raising the foot of the bed may be successful in increasing cardiac output and cerebral perfusion. 2. Give atropine (see below). 3. Discontinue digoxin, beta-blockers, verapamil or other drugs that exacerbate bradycardia. 4. Pacemaker insertion is indicated if bradycardia is unresponsive to atropine and is causing significant hypotension. Sick sinus syndrome (tachycardia–bradycardia syndrome) Treatment is difficult. Drugs that are useful for one rhythm often aggravate the other and a pacemaker is often needed. Atrioventricular conduction block • First-degree heart block by itself does not require treatment. • Second-degree Mobitz type I block (Wenckebach block) is relatively benign and often transient. If complete block occurs, the escape pacemaker is situated relatively high up in the bundle so that the rate is 50–60 per minute with narrow QRS complexes. Atropine (0.6–1.2 mg intravenously) is usually effective. Mobitz type II block is more serious and may progress unpredictably to complete block with a slow ventricular escape rate. The only reliable treatment is a pacemaker. • Third-degree heart block (complete AV dissociation) can cause cardiac failure and/or attacks of unconsciousness (Stokes–Adams attacks). Treatment is by electrical pacing; if delay in arranging this is absolutely unavoidable, lowdose adrenaline intravenous infusion is sometimes used as a temporizing measure. Congenital complete heart block, diagnosed incidentally, does not usually require treatment. SELECTED ANTI-DYSRHYTHMIC DRUGS LIDOCAINE For more information about lidocaine, see Chapter 24. Use Lidocaine is important in the treatment of ventricular tachycardia and fibrillation, often as an adjunct to DC cardioversion. An effective plasma concentration is rapidly achieved by giving a bolus intravenously followed by a constant rate infusion. Mechanism of action Lidocaine is a class Ib agent that blocks Na� channels, reducing the rate of increase of the cardiac action potential and increasing the effective refractory period. It selectively blocks open or inactivated channels and dissociates very rapidly. Adverse effects These include the following: SELECTED ANTI-DYSRHYTHMIC DRUGS 223 1. central nervous system – drowsiness, twitching, paraesthesia, nausea and vomiting; focal followed by generalized seizures; 2. cardiovascular system – bradycardia, cardiac depression (negative inotropic effect) and asystole. Pharmacokinetics Oral bioavailability is poor because of presystemic metabolism and lidocaine is given intravenously. It is metabolized in the liver, its clearance being limited by hepatic blood flow. Heart failure reduces lidocaine clearance, predisposing to toxicity unless the dose is reduced. The difference between therapeutic and toxic plasma concentrations is small. Monoethylglycylxylidide (MEGX) and glycylxylidide (GX) are active metabolites with less anti-dysrhythmic action than lidocaine, but with central nervous system toxicity. The mean half-life of lidocaine is approximately two hours in healthy subjects. Drug interactions Negative inotropes reduce lidocaine clearance by reducing hepatic blood flow and consequently predispose to accumulation and toxicity. OTHER CLASS I DRUGS Other class I drugs have been widely used in the past, but are now used much less frequently. Some of these drugs are shown in Table 32.1. β-ADRENORECEPTOR ANTAGONISTS For more information, see also Chapters 28, 29 and 31. Use Anti-dysrhythmic properties of β-adrenoceptor antagonists are useful in the following clinical situations: • patients who have survived myocardial infarction (irrespective of any ECG evidence of dysrhythmia); β-adrenoceptor antagonists prolong life in this situation;

224 CARDIAC DYSRHYTHMIAS • inappropriate sinus tachycardia (e.g. in association with panic attacks); • paroxysmal supraventricular tachycardias that are precipitated by emotion or exercise; • rapid atrial fibrillation that is inadequately controlled by digoxin; • tachydysrhythmias of thyrotoxicosis; • tachydysrhythmias of phaeochromocytoma, after adequate α-receptor blockade. Atenolol is available for intravenous use after myocardial infarction. Esmolol is a cardioselective β-adrenoceptor antagonist for intravenous use with a short duration of action (its elimination half-life is approximately 10 minutes). β-Adrenoceptor antagonists are given more commonly by mouth when used for the above indications. Contraindications and cautions Contraindications include the following; • asthma, chronic obstructive pulmonary disease; • peripheral vascular disease; • Raynaud’s phenomenon; • uncompensated heart failure (β-blockers are actually beneficial in stable patients (see Chapter 31), but have to be introduced cautiously). Drug interactions • Beta-blockers inhibit drug metabolism indirectly by decreasing hepatic blood flow secondary to decreased cardiac output. This causes accumulation of drugs such as lidocaine that have such a high hepatic extraction ratio that their clearance reflects hepatic blood flow. • Pharmacodynamic interactions include increased negative inotropic effects with verapamil (if given intravenously this can be fatal), lidocaine, disopyramide or other negative inotropes. Exaggerated and prolonged hypoglycaemia occurs with insulin and oral hypoglycaemic drugs. AMIODARONE Use Amiodarone is highly effective, but its use is limited by the severity of its adverse effects during chronic administration. It is effective in a wide variety of dysrhythmias, including: • supraventricular dysrhythmias – resistant atrial fibrillation or flutter, re-entrant tachycardias (e.g. WPW syndrome); • ventricular dysrhythmias – recurrent ventricular tachycardia or fibrillation. It can be given intravenously, via a central intravenous line, in emergency situations as discussed above, or orally if rapid dysrhythmia control is not required. Mechanism of action Amiodarone is a class III agent, prolonging the duration of the action potential but with no effect on its rate of rise. Adverse effects and contraindications Adverse effects are many and varied, and are common when the plasma amiodarone concentration exceeds 2.5 mg/L. 1. Cardiac effects – the ECG may show prolonged QT, U-waves or deformed T-waves, but these are not in themselves an indication to discontinue treatment. Amiodarone can cause ventricular tachycardia of the variety known as torsades de pointes. Care is needed in patients with heart failure and the drug is contraindicated in the presence of sinus bradycardia or AV block. 2. Eye – Amiodarone causes corneal microdeposits in almost all patients during prolonged use. Patients may report coloured haloes without a change in visual acuity. The deposits are only seen on slit-lamp examination and gradually regress if the drug is stopped. 3. Skin – photosensitivity rashes occur in 10–30% of patients. Topical application of compounds which reflect both UV- A and visible light can help (e.g. zinc oxide), whereas ordinary sunscreen does not; and patients should be advised to avoid exposure to direct sunlight and to wear a broad-brimmed hat in sunny weather. Patients sometimes develop blue-grey pigmentation of exposed areas. This is a separate phenomenon to phototoxicity. 4. Thyroid – amiodarone contains 37% iodine by weight and therefore may precipitate hyperthyroidism in susceptible individuals; or conversely it can cause hypothyroidism, due to alterations in thyroid hormone metabolism, with a rise in thyroxine (T 4) and reverse tri-iodothyronine (rT 3), a normal or low T 3 and a flat thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH). Thyroid function (T 3, T 4 and TSH) should be assessed before starting treatment and annually thereafter, or more often if the clinical picture suggests thyroid dysfunction. 5. Pulmonary fibrosis – may develop with prolonged use. This potentially serious problem usually but not always improves on stopping the drug. 6. Hepatitis – transient elevation of hepatic enzymes may occur and occasionally severe hepatitis develops. It is idiosyncratic and non-dose-related. 7. Peripheral neuropathy – occurs in the first month of treatment and reverses on stopping dosing. Proximal muscle weakness, ataxia, tremor, nightmares, insomnia and headache are also reported. Pharmacokinetics Amiodarone is variably absorbed (20–80%) when administered orally. However, both the parent drug and its main metabolite, desethyl amiodarone (the plasma concentration of which exceeds that of the parent drug), are highly lipid soluble. This is reflected in a very large volume of distribution (approximately 5000 L). It is highly plasma protein bound (over 90%) and accumulates in all tissues, particularly the heart. It is only slowly eliminated via the liver, with a t1/2 of 28–45 days. Consequently, anti-dysrhythmic activity may continue for several months after dosing has been stopped, and a loading dose is needed if a rapid effect is needed.

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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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  • Page 204 and 205: Key points Drugs used in essential
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  • Page 224 and 225: The drugs that are most effective i
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  • Page 240 and 241: Case history A 24-year-old medical
  • Page 242 and 243: PART V THE RESPIRATORY SYSTEM
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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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