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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

analgesic. Following its

analgesic. Following its release, there were spontaneous reports to the CSM of photosensitivity and onycholysis. Further reports appeared in the elderly, in whom its half-life is prolonged, of cholestatic jaundice and hepatorenal failure, which was fatal in eight cases. Benoxaprofen was subsequently taken off the market when 3500 adverse drug reaction reports were received with 61 fatalities. The yellow card/black triangle scheme was also instrumental in the early identification of urticaria and cough as adverse effects of angiotensin-converting enzyme inhibitors. Although potentially the population under study by this system consists of all the patients using a drug, in fact under-reporting yields a population that is not uniformly sampled. Such data can be unrepresentative and difficult to work with statistically, contributing to the paucity of accurate incidence data for adverse drug reactions. Systems such as the yellow card scheme (e.g. FDA MedWatch in the USA) are relatively inexpensive and easy to manage, and facilitate ongoing monitoring of all drugs, all consumers and all types of adverse reaction. Reports from the drug regulatory bodies of 22 countries are collated by the World Health Organization (WHO) Unit of Drug Evaluation and Monitoring in Geneva. Rapid access to reports from other countries should be of great value in detecting rare adverse reactions, although the same reservations apply to this register as apply to national systems. In addition, this database could reveal geographical differences in the pattern of untoward drug effects. CASE–CONTROL STUDIES A very large number of patients have to be monitored to detect a rare type B adverse effect. An alternative approach is to identify patients with a disorder which it is postulated could be caused by an adverse reaction to a drug, and to compare the frequency of exposure to possible aetiological agents with a control group. A prior suspicion (hypothesis) must exist to prompt the setting up of such a study – examples are the possible connection between irradiation or environmental pollution and certain malignancies, especially where they are observed in clusters. Artefacts can occur as a result of unrecognized bias from faulty selection of patients and controls, and the approach remains controversial among epidemiologists, public health physicians and statisticians. Despite this, there is really no practicable alternative for investigating a biologically plausible hypothesis relating to a disease which is so uncommon that it is unlikely to be represented even in large trial or cohort populations. This methodology has had notable successes: the association of stilboestrol with vaginal adenocarcinoma, gatifloxacin with hypo- and hyperglycaemia, and salmeterol or fenoterol use with increased fatality in asthmatics. INTENSIVE MONITORING Several hospital-based intensive monitoring programmes are currently in progress. The Aberdeen–Dundee system abstracts data from some 70 000 hospital admissions each year, storing ADVERSE DRUG REACTION MONITORING/SURVEILLANCE (PHARMACOVIGILANCE) 65 these on a computer file before analysis. The Boston Collaborative Drug Surveillance Program (BCDSP), involving selected hospitals in several countries, is even more comprehensive. In the BCDSP, all patients admitted to specially designated general wards are included in the analysis. Specially trained personnel obtain the following information from hospital patients and records: 1. background information (i.e. age, weight, height, etc.); 2. medical history; 3. drug exposure; 4. side effects; 5. outcome of treatment and changes in laboratory tests during hospital admission. A unique feature of comprehensive drug-monitoring systems lies in their potential to follow up and investigate adverse reactions suggested by less sophisticated detection systems, or by isolated case reports in medical journals. Furthermore, the frequency of side effects can be determined more cheaply than by a specially mounted trial to investigate a simple adverse effect. Thus, for example, the risk of developing a rash with ampicillin was found to be around 7% both by clinical trial and by the BCDSP, which can quantify such associations almost automatically from data on its files. New adverse reactions or drug interactions are sought by multiple correlation analysis. Thus, when an unexpected relationship arises, such as the 20% incidence of gastro-intestinal bleeding in severely ill patients treated with ethacrynic acid compared to 4.3% among similar patients treated with other diuretics, this cannot be attributed to bias arising from awareness of the hypothesis during data collection, since the data were collected before the hypothesis was proposed. Conversely, there is a possibility of chance associations arising from multiple comparisons (‘type I’ statistical error), and such associations must be reviewed critically before accepting a causal relationship. It is possible to identify predisposing risk factors. In the association between ethacrynic acid and gastro-intestinal bleeding, these were female sex, a high blood urea concentration, previous heparin administration and intravenous administration of the drug. An important aspect of this type of approach is that lack of clinically important associations can also be investigated. Thus, no significant association between aspirin and renal disease was found, whereas long-term aspirin consumption is associated with a decreased incidence of myocardial infarction, an association which has been shown to be of therapeutic importance in randomized clinical trials (Chapter 29). There are plans to extend intensive drug monitoring to cover other areas of medical practice. However, in terms of new but uncommon adverse reactions, the numbers of patients undergoing intensive monitoring while taking a particular drug will inevitably be too small for the effect to be detectable. Such monitoring can therefore only provide information about relatively common, early reactions to drugs used under hospital conditions. Patients are not in hospital long enough for detection of delayed effects, which are among the reactions least likely to be recognized as such even by an astute clinician.

66 ADVERSE DRUG REACTIONS MONITORING FROM NATIONAL STATISTICS A great deal of information is available from death certificates, hospital discharge diagnoses and similar records. From these data, it may be possible to detect a change in disease trends and relate this to drug therapy. Perhaps the best-known example of this is the increased death rate in young asthmatics noted in the mid-1960s, which was associated with overuse of bronchodilator inhalers containing non-specific β-adrenoceptor agonists (e.g. adrenaline and/or isoprenaline). Although relatively inexpensive, the shortcomings of this method are obvious, particularly in diseases with an appreciable mortality, since large numbers of patients must suffer before the change is detectable. Data interpretation is particularly difficult when hospital discharges are used as a source of information, since discharge diagnosis is often provisional or incomplete, and may be revised during follow up. Key points • Rare (and often severe) adverse drug events may not be detected in early drug development but only defined in the first few years post marketing (phase IV of drug development). • Be aware of and participate in the MHRA yellow card system for reporting suspected adverse drug reactions. • Use of any recently marketed drug, which is identified with a black triangle on its data sheet or in the British National Formulary, indicates the need to be particularly suspicious about adverse drug reactions and to report any suspected adverse drug reaction via the yellow card system. • Constant vigilance by physicians for drug-induced disease, particularly for new drugs, but also for more established agents, is needed. FEEDBACK There is no point in collecting vast amounts of data on adverse reactions unless they are analysed and conclusions reported back to prescribing doctors. In addition to articles in the medical journals and media, the Current Problems in Pharmacovigilance series deals with important and recently identified adverse drug reactions. If an acute and serious problem is recognized, doctors will usually receive notification from the MHRA/Commission on Human Medicines, and often from the pharmaceutical company marketing the product. ALLERGIC ADVERSE DRUG REACTIONS Immune mechanisms are involved in a number of adverse effects caused by drugs (see below and Chapter 50). The development of allergy implies previous exposure to the drug or to some closely related substance. Most drugs are of low molecular weight (300–500 Da) and thus are not antigenic. However, they can combine with high molecular weight entities, usually proteins, to form an antigenic hapten conjugate. The factors that determine the development of allergy to a drug are not fully understood. Some drugs (e.g. penicillin) are more likely to cause allergic reactions than others, and type I (immediate anaphylactic) reactions are more common in patients with a history of atopy. A correlation between allergic reactions involving immunoglobulin E (IgE) and human leukocyte antigen (HLA) serotypes has been reported, so genetic factors may also be important. There is some evidence that drug allergies are more common in older people, in women and in those with a previous history of drug reaction. However, this may merely represent increased frequencies of drug exposure in these patient groups. TYPES OF ALLERGY Drugs cause a variety of allergic responses (Figure 12.1) and sometimes a single drug can be responsible for more than one type of allergic response. TYPE I REACTIONS Type I reactions are due to the production of reaginic (IgE) antibodies to an antigen (e.g. penicillins and cephalosporins). The antigen binds to surface bound IgE on mast cells causing degranulation and release of histamine, eicosanoids and cytokines. It commonly occurs in response to a foreign serum or penicillin, but may also occur with streptomycin and some local anaesthetics. With penicillin, it is believed that the penicilloyl moiety of the penicillin molecule is responsible for the production of antibodies. Treatment of anaphylactic shock is detailed in Chapter 50. TYPE II REACTIONS These are due to antibodies of class IgG and IgM which, on contact with antibodies on the surface of cells, bind complement, causing cell lysis (e.g. penicillin, cephalosporins, methyldopa or quinine) causing, for example, Coombs’ positive haemolytic anaemia. TYPE III IMMUNE COMPLEX ARTHUS REACTIONS Circulating immune complexes can produce several clinical allergic states, including serum sickness and immune complex glomerulonephritis, and a syndrome resembling systemic lupus erythematosus. The onset of serum sickness is delayed for several days until features develop such as fever, urticaria, arthropathy, lymphadenopathy, proteinuria and eosinophilia. Recovery takes a few days. Examples of causative agents include serum, penicillin, sulfamethoxazole/trimethoprim, streptomycin and propylthiouracil. Amiodarone lung and hydralazine-induced systemic lupus syndrome are also possibly mediated by immune complex-related mechanisms, although these reactions are less well understood. TYPE IV DELAYED HYPERSENSITIVITY REACTIONS Type IV reactions are delayed hypersensitivity reactions, the classical example of which is contact dermatitis (e.g. to topical

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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

  • Page 26 and 27: lood (from which samples are taken
  • Page 28 and 29: ● Introduction 17 ● Bioavailabi
  • Page 30 and 31: ROUTES OF ADMINISTRATION ORAL ROUTE
  • Page 32 and 33: Transdermal absorption is sufficien
  • Page 34 and 35: FURTHER READING Fix JA. Strategies
  • Page 36 and 37: and thromboxanes are CYP450 enzymes
  • Page 38 and 39: and lorazepam. Some patients inheri
  • Page 40 and 41: Orally administered drug Parenteral
  • Page 42 and 43: ● Introduction 31 ● Glomerular
  • Page 44 and 45: ACTIVE TUBULAR REABSORPTION This is
  • Page 46 and 47: DISTRIBUTION Drug distribution is a
  • Page 48 and 49: Detailed recommendations on dosage
  • Page 50 and 51: DIGOXIN Myxoedematous patients are
  • Page 52 and 53: ● Introduction 41 ● Role of dru
  • Page 54 and 55: 25 20 10 Life-threatening toxicity
  • Page 56 and 57: ● Introduction 45 ● Harmful eff
  • Page 58 and 59: vagina in girls in their late teens
  • Page 60 and 61: an anti-analgesic effect when combi
  • Page 62 and 63: Case history A 20-year-old female m
  • Page 64 and 65: METABOLISM At birth, the hepatic mi
  • Page 66 and 67: lifelong effects as a result of tox
  • Page 68 and 69: DISTRIBUTION Ageing is associated w
  • Page 70 and 71: DIGOXIN Digoxin toxicity is common
  • Page 72 and 73: FURTHER READING Dhesi JK, Allain TJ
  • Page 74 and 75: Factors involved in the aetiology o
  • 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 88 and 89: Table 13.5: Competitive interaction
  • Page 90 and 91: ● Introduction: ‘personalized m
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  • Page 96 and 97: Key points • Genetic differences
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  • Page 106 and 107: duration and benefit. Adenoviral ve
  • Page 108 and 109: ● Introduction 97 ● Garlic 97
  • Page 110 and 111: A case report has suggested a possi
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  • Page 114 and 115: PART II THE NERVOUS SYSTEM
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  • Page 120 and 121: Key points • Insomnia and anxiety
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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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    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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