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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

● Introduction 285 ●

● Introduction 285 ● Pathophysiology 285 ● Principles of management 286 INTRODUCTION CHAPTER 37 DIABETES MELLITUS Before the discovery of insulin, type 1 diabetes – where insulin deficiency can lead to ketoacidosis – was invariably fatal. Since the introduction of insulin, the therapeutic focus has broadened from treating and preventing diabetic ketoacidosis to preventing long-term vascular complications. Type 2 diabetes – where insulin resistance and a relative lack of insulin lead to hyperglycaemia – not only causes symptoms related directly to hyperglycaemia (polyuria, polydipsia and blurred vision – see below), but is also a very powerful risk factor for atheromatous disease. Glucose intolerance and diabetes mellitus are increasingly prevalent in affluent and developing countries, and represent a major public health challenge. Addressing risk factors distinct from blood glucose, especially hypertension, is of paramount importance and is covered elsewhere (Chapters 27 and 28). In this chapter, we focus mainly on the types of insulin and oral hypoglycaemic agents. PATHOPHYSIOLOGY Insulin is secreted by β-cells (also called B-cells) of the islets of Langerhans. It lowers blood glucose, but also modulates the metabolic disposition of fats and amino acids, as well as carbohydrate. It is secreted together with inactive C-peptide, which provides a useful index of insulin secretion: its plasma concentration is low or absent in patients with type 1 diabetes, but very high in patients with insulinoma (an uncommon tumour which causes hypoglycaemia by secreting insulin). This should not be confused with ‘C-reactive peptide’ (CRP) which is an acute phase protein synthesized by the liver and used as a nonspecific index of inflammation. C-peptide concentration is not elevated in patients with hypoglycaemia caused by injection of insulin. Diabetes mellitus (fasting blood glucose concentration of �7 mmol/L) is caused by an absolute or relative lack of insulin. In type 1 diabetes there is an absolute deficiency of ● Diet in diabetes mellitus 286 ● Drugs used to treat diabetes mellitus 286 insulin. Such patients are usually young and non-obese at presentation. There is an inherited predisposition. However, concordance in identical twins is somewhat less than 50%, so it is believed that genetically predisposed individuals must also be exposed to an environmental factor. Viruses (including Coxsackie and Echo viruses) are one such factor and may initiate an autoimmune process that then destroys the islet cells. In type 2 diabetes there is a relative lack of insulin secretion, coupled with marked resistance to its action. The circulating concentration of immunoreactive insulin measured by standard assays (which do not discriminate well between insulin and pro-insulin) may be normal or even increased, but more discriminating assays indicate that there is an increase in proinsulin, and that the true insulin concentration is reduced. Such patients are usually middle-aged or older at presentation, and obese. Concordance of this form of diabetes in identical twins is nearly 100%. Type 2 diabetes is rarely if ever associated with diabetic ketoacidosis, although it can be complicated by non-ketotic hyperosmolar coma or, rarely (in association with treatment with a biguanide drug such as metformin, see below), with lactic acidosis. An increased concentration of glucose in the circulating blood gives rise to osmotic effects: 1. diuresis (polyuria) with consequent circulating volume reduction, causing thirst and polydipsia; 2. the refractive index of a high glucose concentration solution in the eye differs from healthy aqueous humour, causing blurred vision. In addition, glycosuria predisposes to Candida infection, especially in women. The loss of calories in the urine is coupled with inability to store energy as glycogen or fat, or to lay down protein in muscle, and weight loss with loss of fat and muscle (‘amyotrophy’) is common in uncontrolled diabetics. Both types of diabetes mellitus are complicated by vascular complications. Microvascular complications include retinopathy, which consists of background retinopathy (dot and blot haemorrhages and hard exudates which do not of themselves threaten vision), and proliferative retinopathy which

286 DIABETES MELLITUS can cause retinal haemorrhage and blindness. Cataracts are common. Diabetic neuropathy causes a glove and stocking distribution of loss of sensation with associated painful paraesthesiae. Approximately one-third of diabetic patients develop diabetic nephropathy, which leads to renal failure. Microalbuminuria is a forerunner of overt diabetic nephropathy. Macrovascular disease is the result of accelerated atheroma and results in an increased incidence of myocardial infarction, peripheral vascular disease and stroke. There is a strong association (pointed out by Reaven in his 1988 Banting Lecture at the annual meeting of the American Diabetes Association) between diabetes and obesity, hypertension and dyslipidaemia (especially hypertriglyceridaemia), and type 2 diabetes is strongly associated with endothelial dysfunction, an early event in atherogenesis (Chapter 27). PRINCIPLES OF MANAGEMENT It is important to define ambitious but achievable goals for each patient. In young type 1 patients there is good evidence that improved diabetic control reduces microvascular complications. It is well worth trying hard to minimize the metabolic derangement associated with diabetes mellitus in order to reduce the development of such complications. Education and support are essential to motivate the patient to learn how to adjust their insulin dose to optimize glycaemic control. This can only be achieved by the patient performing blood glucose monitoring at home and learning to adjust their insulin dose accordingly. The treatment regimen must be individualized. A common strategy is to combine injections of a short-acting insulin before each meal with a once daily injection of a long-acting insulin to provide a low steady background level during the night. Follow up must include structured care with assessment of chronic glycaemic control using HbA1c and regular screening for evidence of microvascular disease. This is especially important in the case of proliferative retinopathy and maculopathy, because prophylactic laser therapy can prevent blindness. By contrast, striving for tight control of blood sugar in type 2 patients is only appropriate in selected cases. Tight control reduces macrovascular complications, but at the expense of increased hypoglycaemic attacks, and the number of patients that needs to be treated in this way to prevent one cardiovascular event is large. In contrast, aggressive treatment of hypertension is of substantial benefit, and the target blood pressure should be lower than in non-diabetic patients (�130 mmHg systolic and �80 mmHg diastolic, see Chapter 28). In older type 2 patients, hypoglycaemic treatment aims to minimize symptoms of polyuria, polydipsia or recurrent Candida infection, and to prevent hyperosmolar coma. DIET IN DIABETES MELLITUS It is important to achieve and maintain ideal body weight on a non-atherogenic diet. Caloric intake must be matched with insulin injections. Patients who rely on injected insulin must time their food intake accordingly. Simple sugars should be restricted because they are rapidly absorbed, causing postprandial hyperglycaemia, and should be replaced by foods that give rise to delayed and reduced glucose absorption, analogous to slow release drugs (quantified by nutritionists as ‘glycaemic index’). (Artificial sweeteners are useful for those with a ‘sweet tooth’.) A fibre-rich diet reduces peak glucose levels after meals and reduces the insulin requirement. Beans and lentils flatten the glucose absorption curve. Saturated fat and cholesterol intake should be minimized. Low fat sources of protein are favoured. There is no place for commercially promoted ‘special diabetic foods’, which are expensive and also often high in fat and calories at the expense of complex carbohydrate. DRUGS USED TO TREAT DIABETES MELLITUS INSULINS Insulin is a polypeptide. Animal insulins have been almost entirely replaced by recombinant human insulin and related analogues. These are of consistent quality and cause fewer allergic effects. Insulin is available in several formulations (e.g. with protamine and/or with zinc) which differ in pharmacokinetic properties, especially their rates of absorption and durations of action. So-called ‘designer’ insulins are synthetic polypeptides closely related to insulin, but with small changes in amino acid composition which change their properties. For example, a lysine and a proline residue are switched in insulin lispro, which consequently has a very rapid absorption and onset (and can therefore be injected immediately before a meal), whereas insulin glargine is very slow acting and is used to provide a low level of insulin activity during the 24-hour period. Use Insulin is indicated in all patients with type 1 diabetes mellitus (although it is not strictly necessary during the early ‘honeymoon’ period before islet cell destruction is complete) and in about one-third of patients with type 2 disease. Insulin is usually administered by subcutaneous injection, although recently an inhaled preparation has been licensed for use in type 2 diabetics. (Note: This was not commercially successful, and has been withdrawn in the UK for this reason.) The effective dose of human insulin is usually rather less than that of animal insulins because of the lack of production of blocking antibodies. Consequently, the dose is reduced when switching from animal to human insulin. Soluble insulin is the only preparation suitable for intravenous use. It is administered intravenously in diabetic emergencies and given subcutaneously before meals in chronic management. Formulations of human insulins are available in various ratios of short-acting and longer-lasting forms (e.g. 30:70, commonly used twice daily). Some of these are marketed

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    A Textbook of Clinical Pharmacology

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    A Textbook of Clinical Pharmacology

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    This fifth edition is dedicated to

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    FOREWORD viii PREFACE ix ACKNOWLEDG

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    PREFACE Clinical pharmacology is th

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    PART I GENERAL PRINCIPLES

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    ● Use of drugs 3 ● Adverse effe

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    and acquired factors, notably disea

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    100 Effect (%) 0 0 5 10 1 10 100 (a

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    Dose ratio -1 100 50 The relationsh

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    ● Introduction 11 ● Constant-ra

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    In reality, processes of eliminatio

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    lood (from which samples are taken

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    ● Introduction 17 ● Bioavailabi

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    ROUTES OF ADMINISTRATION ORAL ROUTE

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    Transdermal absorption is sufficien

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    FURTHER READING Fix JA. Strategies

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    and thromboxanes are CYP450 enzymes

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    and lorazepam. Some patients inheri

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    Orally administered drug Parenteral

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    ● Introduction 31 ● Glomerular

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    ACTIVE TUBULAR REABSORPTION This is

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    DISTRIBUTION Drug distribution is a

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    Detailed recommendations on dosage

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    DIGOXIN Myxoedematous patients are

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    ● Introduction 41 ● Role of dru

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    25 20 10 Life-threatening toxicity

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    ● Introduction 45 ● Harmful eff

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    vagina in girls in their late teens

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    an anti-analgesic effect when combi

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    Case history A 20-year-old female m

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    METABOLISM At birth, the hepatic mi

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    lifelong effects as a result of tox

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    DISTRIBUTION Ageing is associated w

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    DIGOXIN Digoxin toxicity is common

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    FURTHER READING Dhesi JK, Allain TJ

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    Factors involved in the aetiology o

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    analgesic. Following its release, t

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    antibiotics, such as penicillin or

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    predisposes to non-immune haemolysi

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    ● Introduction 71 ● Useful inte

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    Response Therapeutic range Toxic ra

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    Table 13.1: Interactions outside th

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    Table 13.5: Competitive interaction

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    ● Introduction: ‘personalized m

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    Table 14.2: Variations in drug resp

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    lipoprotein (LDL) is impaired. LDL

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    Key points • Genetic differences

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    • Discovery • • Screening Pre

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    Too many statistical comparisons pe

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    ETHICS COMMITTEES Protocols for all

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    Table 16.1: Recombinant proteins/en

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    duration and benefit. Adenoviral ve

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    ● Introduction 97 ● Garlic 97

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    A case report has suggested a possi

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    including hypericin and pseudohyper

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    PART II THE NERVOUS SYSTEM

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    ● Introduction 105 ● Sleep diff

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    and daytime sleeping should be disc

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    Key points • Insomnia and anxiety

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    Box 19.1: Dopamine theory of schizo

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    The Boston Collaborative Survey ind

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    Oral medication, especially in liqu

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    e.g. interpersonal difficulties or

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    Partial response to first-line trea

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    Key points Drug treatment of depres

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    Case history A 45-year-old man with

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    Levodopa PRINCIPLES OF TREATMENT IN

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    • pulmonary, retroperitoneal and

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    CHOREA The γ-aminobutyric acid con

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    Cholinergic crisis Treatment of mya

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    ● Introduction 133 ● Mechanisms

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    absolute arbiter. The availability

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    Table 22.2: Metabolic interactions

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    FURTHER ANTI-EPILEPTICS Other drugs

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    Case history A 24-year-old woman wh

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    Assessment of migraine severity and

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    ● General anaesthetics 145 ● In

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    is the theoretical concern of a ‘

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    • Respiratory system - apnoea fol

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    Competitive antagonists (vecuronium

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    have also proved useful in combinat

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    ● Introduction 155 ● Pathophysi

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    ASPIRIN (ACETYLSALICYLATE) Use Anti

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    Key points Drugs for mild pain •

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    increases, correlating with the hig

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    • If possible, use oral medicatio

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    PART III THE MUSCULOSKELETAL SYSTEM

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    ● Introduction: inflammation 167

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    Chapter 33). All NSAIDs cause wheez

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    • Stomatitis suggests the possibi

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    Pharmacokinetics Allopurinol is wel

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    PART IV THE CARDIOVASCULAR SYSTEM

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    ● Introduction 177 ● Pathophysi

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    esponsible for the strong predilect

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    Ezetimibe Fat Muscle Dietary fat In

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    educed). The risk of muscle damage

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    ● Introduction 185 ● Pathophysi

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    Each of these classes of drug reduc

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    AT 1 receptor) produce good 24-hour

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    Table 28.2: Examples of calcium-cha

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    Key points Drugs used in essential

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    Case history A 72-year-old woman se

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    Assess risk factors Investigations:

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    Persistent ST segment elevation Thr

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    Mechanism of action GTN works by re

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    Because of the risks of haemorrhage

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    Intrinsic pathway XIIa XIa the acti

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    that the pharmacodynamic response i

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    used with apparent benefit in acute

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    ● Introduction 211 ● Pathophysi

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    The drugs that are most effective i

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    therapeutic plasma concentration ca

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    ● Common dysrhythmias 217 ● Gen

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    BASIC LIFE SUPPORT CARDIOPULMONARY

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    arrest. The electrocardiogram is li

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    should be given to insertion of an

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    Drug interactions Amiodarone potent

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    effect when treating sinus bradycar

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    Case history A 24-year-old medical

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    PART V THE RESPIRATORY SYSTEM

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    CHAPTER 33 THERAPY OF ASTHMA, CHRON

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  • Page 282 and 283: PART VII FLUIDS AND ELECTROLYTES
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  • Page 286 and 287: Key points Diuretics Diuretics are
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  • Page 298 and 299: in prefilled injection devices (‘
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  • Page 304 and 305: deficiency. Potassium iodide (3 mg
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  • Page 334 and 335: ● Principles of antibacterial che
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  • Page 338 and 339: Pharmacokinetics Absorption of thes
  • Page 340 and 341: Mechanism of action Macrolides bind
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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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