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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

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and daytime sleeping should be discouraged. Increased daytime exercise improves sleep at night. • Alcohol should be avoided because it causes rebound restlessness and sleep disturbance after the initial sedation has worn off. Tolerance and dependence develop rapidly. It also causes dehydration (gueule de bois) and other unpleasant manifestations of hangover. SPECIAL PROBLEMS AND SPECIAL GROUPS JET LAG Jet lag consists of fatigue, sleep disturbances, headache and difficulty in concentrating. It is due to mismatching of the body clock (circadian dysrhythmia) against a new time environment with its own time cues (Zeitgebers). Resetting the internal clock is hastened by conforming to the new time regime. Thus, one should rest in a dark room at night, even if not tired, and eat, work and socialize during the day. Sufferers should not allow themselves to sleep during the day (easier said than done!). Taking hypnotics at night can make things worse if sleepiness is experienced the next day. However, short-acting benzodiazepines may be effective if taken before going to bed for two or three nights. Melatonin is of uncertain usefulness but may help sleep patterns, and improves daytime well-being if taken in the evening. It is not generally available in the UK, although it is in several other countries including the USA. NIGHT WORK Night work causes more serious sleep difficulties than jet lag because hypnotics cannot be used for long periods. Moreover, drug-induced sleep during the day precludes family and other non-work activities. A better strategy is to allow the subject to have a short, non-drug-induced sleep during the night shift. This improves efficiency towards the end of the night shift and reduces sleep needs during the day. CHILDREN The use of hypnotics in children is not recommended, except in unusual situations (e.g. on the night before an anticipated unpleasant procedure in hospital). Hypnotics are sometimes used for night terrors. Children are, however, prone to experience paradoxical excitement with these drugs. Promethazine, an antihistamine which is available without a prescription, is often used, but is of doubtful benefit. ELDERLY Anxiety and insomnia are prevalent in the elderly, for a variety of psychological and physical reasons. As a rule, elderly patients are more sensitive to the action of central nervous system (CNS) depressant drugs than younger patients, and the pharmacokinetics of these drugs are also altered such that their action is more prolonged with increasing age. Hypnotics increase the risk of falls and nocturnal confusion. Even shortacting drugs can lead to ataxia and hangover the next morning. In the treatment of insomnia, when short-term treatment with drugs is considered necessary, short-acting hypnotics should be used in preference to long-acting drugs but with ANXIETY 107 explanation from the outset that these will not be continued long term. (Short-acting benzodiazepines have the greatest abuse potential.) Insomnia occurring in the context of documented psychiatric disorders or dementia may be better treated with low doses of antipsychotic drugs. Case history A 42-year-old man with chronic depression presents to his general practitioner with a long history of difficulty in sleeping at night, associated with early morning waking. His general practitioner had made the diagnosis of depression and referred him some years previously for cognitive behavioural therapy, but this had not resulted in significant improvement of his symptoms. His difficulty in sleeping is now interfering with his life quite significantly, so that he feels tired most of the day and is having difficulty holding down his job as an insurance clerk. The GP decides that he would benefit from taking temazepam at night; he prescribes him this, but says that he will only give it for a maximum of a month, as he does not want his patient to become addicted. Question 1 Is this the correct management? Question 2 What would be a suitable alternative treatment? Answer 1 No. Although the benzodiazepine might help in the short term, it does not provide the patient with a long-term solution, and does not tackle the root cause of his insomnia. Answer 2 A more appropriate treatment would be with a regular dose of a sedating antidepressant drug, for example amitriptyline at night. ANXIETY Anxiety is fear and is usually a normal reaction. Pathological anxiety is fear that is sufficiently severe as to be disabling. Such a reaction may be a response to a threatening situation (e.g. having to make a speech) or to a non-threatening event (e.g. leaving one’s front door and going into the street). Episodes of paroxysmal severe anxiety associated with severe autonomic symptoms (e.g. chest pain, dyspnoea and palpitations) are termed panic attacks and often accompany a generalized anxiety disorder. GENERAL PRINCIPLES AND MANAGEMENT OF ANXIETY • Distinguish anxiety as a functional disturbance from a manifestation of organic brain disease or somatic illness (e.g. systemic lupus erythematosus). • Assess the severity of any accompanying depression, which may need treatment in itself. • Most patients are best treated with cognitive therapy, relaxation techniques and simple psychotherapy and without drugs. • Some patients are improved by taking regular exercise. • In severely anxious patients who are given anxiolytic drugs, these are only administered for a short period (up to two to four weeks) because of the risk of dependence.

108 HYPNOTICS AND ANXIOLYTICS • Desensitization can be useful when severe anxiety develops in well-recognized situations (e.g. agoraphobia, arachnophobia, etc.). Anxiolytic drugs are sometimes given intermittently and with a flexible-dose scheme in such situations. • Benzodiazepines are the anxiolytics normally used where pharmacological therapy is indicated. Buspirone is as effective as and less hypnotic than the benzodiazepines, but has slower onset. • β-Blockers are sometimes useful in patients with prominent symptoms, such as palpitations or tremor. • Tricyclic antidepressants may be effective in anxiety and in preventing panic attacks. • Monoamine oxidase inhibitors (used only by specialists) can be useful for treating anxiety with depression, phobic anxiety, recurrent panic attacks and obsessive-compulsive disorders. • Individual panic attacks are usually terminated by benzodiazepines, which may have to be supplemented with short-term treatment with phenothiazines (e.g. chlorpromazine). • If hyperventilation is the principal ‘trigger’, advice on controlled breathing exercises can be curative. DRUGS USED TO TREAT SLEEP DISTURBANCES AND ANXIETY The distinction between hypnotics and anxiolytics is rather arbitrary, and the same classes of drugs are used for both purposes. Compounds with a short half-life tend to be used as hypnotics, because they cause less ‘hangover’ effects; longer half-life drugs tend to be used as anxiolytics, since a longer duration of action is generally desirable in this setting. Benzodiazepines are used for the short-term alleviation of anxiety, but should not be used long term, where antidepressants (Chapter 20) are usually the treatment of choice. BENZODIAZEPINES These drugs are anxiolytic, anticonvulsant muscle relaxants that induce sleepiness; they remain drugs of choice for the pharmacological treatment of insomnia and anxiety. Clonazepam is believed to be more anticonvulsant than other members of the group at equi-sedating doses. Benzodiazepines bind to specific binding sites in the GABAA receptor–chloride channel complex in the brain, and facilitate the opening of the channel in the presence of GABA; this increases hyperpolarization-induced neuronal inhibition. Examples • Diazepam – used as an anxiolytic, because of its long half-life. • Temazepam – used as a hypnotic, because of its short half-life. • Lorazepam – potent short half-life benzodiazepine. Should generally be avoided for more than very short-term use, as it causes intense withdrawal phenomena and dependence. • Diazepam or midazolam i.v. before procedures such as endoscopy, cardioversion and operations under local anaesthesia. Early short-lived high peak blood levels are accompanied by anterograde amnesia. Cautions • respiratory failure; • breast-feeding; • previous addiction. Adverse effects • drowsiness; • confusion; • paradoxical disinhibition and aggression. Adverse effects of intravenous diazepam include: 1. Cardiovascular and respiratory depression (uncommon). Patients with chronic lung disease, and those who have been previously given other central depressant drugs are at risk. 2. Local pain following i.v. injection. An emulsion of diazepam in intralipid is less irritating to the vein. Intra-arterial benzodiazepine can cause arterial spasm and gangrene. Drug dependence, tolerance and withdrawal Benzodiazepine dependence is usually caused by large doses taken for prolonged periods, but withdrawal states have arisen even after limited drug exposure. Pharmacological evidence of tolerance may develop within three to 14 days. The full withdrawal picture can manifest within hours of the last dose for the shorter-acting drugs, or may develop over up to three weeks with the longer-duration benzodiazepines. Withdrawal syndrome includes a cluster of features including frank anxiety and panic attacks. Perceptual distortions (e.g. feelings of being surrounded by cotton wool), visual and auditory hallucinations, paranoia, feelings of unreality, depersonalization, paraesthesiae, sweating, headaches, blurring of vision, dyspepsia and influenza-like symptoms can occur. Depression and agoraphobia are also common. The syndrome may persist for weeks. Withdrawal from benzodiazepines in patients who have become dependent should be gradual. If this proves difficult, then an equivalent dose of a long-acting benzodiazepine should be given as a single night-time dose instead of shorter-acting drugs. The dose should then be reduced in small fortnightly steps. Psychological support is important. Drug interactions Pharmacodynamic interactions with other centrally acting drugs are common, whereas pharmacokinetic interactions are not. Pharmacodynamic interactions include potentiation of the sedative actions of alcohol, histamine (H1) antagonists and other hypnotics.

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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

  • Page 68 and 69: DISTRIBUTION Ageing is associated w
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  • Page 72 and 73: FURTHER READING Dhesi JK, Allain TJ
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  • Page 84 and 85: Response Therapeutic range Toxic ra
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  • Page 110 and 111: A case report has suggested a possi
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  • Page 150 and 151: FURTHER ANTI-EPILEPTICS Other drugs
  • Page 152 and 153: Case history A 24-year-old woman wh
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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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    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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