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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

e.g. interpersonal

e.g. interpersonal difficulties or other life stresses (including physical illness), antidepressant drugs may be useful. Drugs used in the initial treatment of depression include TCAs and related drugs, SSRIs and SNRIs. Although clinical experience is most extensive with the TCAs, the side-effect profile of the SSRIs is usually less troublesome, and these drugs are safer in overdose. Therefore many psychiatrists and general practitioners use SSRIs rather than TCAs as first-line treatment for depression. SSRIs are more expensive than TCAs. The relative side effects of the different antidepressant drugs are summarized in Table 20.1. In refractory depression, other drug treatment or electroconvulsive therapy (ECT) are considered. Alternative drug strategies include (1) adding lithium to a tricyclic to give a lithium blood level of 0.6–0.8 mmol/L; (2) combining antidepressants; (3) augmenting with T3 (or T4), a mood stabilizer such as lamotrigine, buspirone or estradiol; (4) MAOIs, usually prescribed only by psychiatrists; (5) MAOI plus a TCA – but only in expert psychiatric hands; or (6) small doses of flupentixol (for short-term treatment only). Figures 20.1 and 20.2 show a treatment algorithm for management of depressive illness. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) These drugs are safer in overdose than the tricyclic group. Selective serotonin reuptake inhibitors (SSRIs) do not stimulate Table 20.1: Relative antidepressant side effects DEPRESSIVE ILLNESSES AND ANTIDEPRESSANTS 117 appetite and have much fewer antimuscarinic side effects than the tricyclics and other catecholamine-uptake inhibitors. They are also well tolerated in the elderly. Examples include fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram and escitalopram. Uses These include the following: 1. in depression (they have similar efficacy to tricyclics, but are much more expensive); 2. in chronic anxiety, and as prophylaxis for panic attacks; 3. obsessive-compulsive states; 4. bulimia nervosa; 5. seasonal affective disorder, especially if accompanied by carbohydrate craving and weight gain; 6. possibly effective as prophylactic agents in recurrent depression. Adverse effects 1. The most common adverse reactions to SSRIs are nausea, dyspepsia, diarrhoea, dry mouth, headache, insomnia and dizziness. Sweating, erectile dysfunction and delayed orgasm are well-recognized associations. These tend to become less severe after one to two months of treatment. 2. They have less anticholinergic and cardiotoxic actions than tricyclic drugs. Drug Anticholinergic Cardiac Nausea Sedation Overdose Pro-convulsant Tyramine Tricyclics and related antidepressants effects effects risk interaction Amitriptyline ��� ��� � ��� �� �� � Clomipramine ��� �� � �� � �� � Dothiepin �� �� � ��� ��� �� � Imipramine �� �� � � �� �� � Lofepramine �� � � � � � � Trazodone Selective serotonin reuptake inhibitors � � �� �� � � � Citalopram � � �� � � � � Fluoxetine � � �� � � ? � Paroxetine � � �� � � ? � Sertraline Monoamine oxidase inhibitors � � �� � � ? � Phenelzine � � �� � � � ��� Moclobemide Others � � � � � ? � Venlafaxine � �� �� � ? � � �, little or nothing reported; �, mild; ��, moderate; ���, high; ?, insufficient information available.

118 MOOD DISORDERS 3. Epilepsy can be precipitated. 4. They are usually non-sedating, but may cause insomnia and do not usually cause orthostatic hypotension. 5. All antidepressants can cause hyponatraemia, probably due to induction of inappropriate antidiuretic hormone secretion, but it is reported more frequently with SSRIs than with other antidepressants. Contraindications These include the following: • hepatic and renal failure; • epilepsy; • manic phase. Psychotherapy Significant symptoms persist after 6 weeks Add medication Continue same treatment Diagnosis of unipolar depression Psychotherapy and medication Evaluate response to medication after 3–4 weeks Evaluate response to medication after 6–8 weeks Medication Partial response No response Advance dose as tolerated Symptoms resolving Symptoms persist Go to second phase of treatment Figure 20.1: General algorithm for the initial phase of treatment of depression. When symptoms persist after first-line treatment, re-evaluate the accuracy of the diagnosis, the adequacy of the dose and the duration of treatment before moving to the second phase of treatment. (Redrawn with permission from Aronson SC and Ayres VE. ‘Depression: A Treatment Algorithm for the Family Physician’, Hospital Physician Vol 36 No 7, 2000. Copyright 2000 Turner White Communications, Inc.) Drug interactions • Combinations of SSRI with lithium, tryptophan or MAOIs may enhance efficacy, but are currently contraindicated because they increase the severity of 5HT-related toxicity. In the worst reactions, the life-threatening 5HT syndrome develops. This consists of hyperthermia, restlessness, tremor, myoclonus, hyperreflexia, coma and fits. After using MAOIs, it is recommended that two weeks should elapse before starting SSRIs. Avoid fluoxetine for at least five weeks before using MAOI because of its particularly long halflife (about two days). • The action of warfarin is probably enhanced by fluoxetine and paroxetine. • There is antagonism of anticonvulsants. • Fluoxetine raises blood concentrations of haloperidol. SEROTONIN-NORADRENALINE REUPTAKE INHIBITORS AND RELATED ANTIDEPRESSANTS Venlafaxine: A potent 5HT and NA uptake inhibitor that appears to be as effective as TCAs, but without anticholinergic effects. It may have a more rapid onset of therapeutic action than other antidepressants, but this has yet to be confirmed. It is associated with more cardiac toxicity than the SSRIs. Duloxetine inhibits NA and 5HT reuptake. TRICYCLICS AND RELATED ANTIDEPRESSANTS (TCAs) Uses These include the following: 1. depressive illnesses, especially major depressive episodes and melancholic depression; 2. atypical oral and facial pain; 3. prophylaxis of panic attacks; 4. phobic anxiety; 5. obsessive–compulsive disorders; 6. imipramine has some efficacy in nocturnal enuresis. Although these drugs share many properties, their profiles vary in some respects, and this may alter their use in different patients. The more sedative drugs include amitriptyline, dosulepin and doxepin. These are more appropriate for agitated or anxious patients than for withdrawn or apathetic patients, for whom imipramine or nortriptyline, which are less sedative, are preferred. Protriptyline is usually stimulant. Only 70% of depressed patients respond adequately to TCAs. One of the factors involved may be the wide variation in individual plasma concentrations of these drugs that is obtained with a given dose. However, the relationship between plasma concentration and response is not well defined. A multicentre collaborative study organized by the World Health Organization failed to demonstrate any relationship whatsoever between plasma amitriptyline concentration and clinical effect.

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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

  • Page 78 and 79: antibiotics, such as penicillin or
  • Page 80 and 81: predisposes to non-immune haemolysi
  • Page 82 and 83: ● Introduction 71 ● Useful inte
  • Page 84 and 85: Response Therapeutic range Toxic ra
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  • Page 90 and 91: ● Introduction: ‘personalized m
  • Page 92 and 93: Table 14.2: Variations in drug resp
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  • Page 96 and 97: Key points • Genetic differences
  • Page 98 and 99: • Discovery • • Screening Pre
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  • Page 102 and 103: ETHICS COMMITTEES Protocols for all
  • Page 104 and 105: Table 16.1: Recombinant proteins/en
  • Page 106 and 107: duration and benefit. Adenoviral ve
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  • Page 110 and 111: A case report has suggested a possi
  • Page 112 and 113: including hypericin and pseudohyper
  • Page 114 and 115: PART II THE NERVOUS SYSTEM
  • Page 116 and 117: ● Introduction 105 ● Sleep diff
  • Page 118 and 119: and daytime sleeping should be disc
  • Page 120 and 121: Key points • Insomnia and anxiety
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  • Page 130 and 131: Partial response to first-line trea
  • Page 132 and 133: Key points Drug treatment of depres
  • Page 134 and 135: Case history A 45-year-old man with
  • Page 136 and 137: Levodopa PRINCIPLES OF TREATMENT IN
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  • Page 140 and 141: CHOREA The γ-aminobutyric acid con
  • Page 142 and 143: Cholinergic crisis Treatment of mya
  • Page 144 and 145: ● Introduction 133 ● Mechanisms
  • Page 146 and 147: absolute arbiter. The availability
  • Page 148 and 149: Table 22.2: Metabolic interactions
  • Page 150 and 151: FURTHER ANTI-EPILEPTICS Other drugs
  • Page 152 and 153: Case history A 24-year-old woman wh
  • Page 154 and 155: Assessment of migraine severity and
  • Page 156 and 157: ● General anaesthetics 145 ● In
  • Page 158 and 159: is the theoretical concern of a ‘
  • Page 160 and 161: • Respiratory system - apnoea fol
  • Page 162 and 163: Competitive antagonists (vecuronium
  • Page 164 and 165: have also proved useful in combinat
  • Page 166 and 167: ● Introduction 155 ● Pathophysi
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  • Page 170 and 171: Key points Drugs for mild pain •
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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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    STEP 5: CONTINUOUS OR FREQUENT USE

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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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