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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

Response Therapeutic

Response Therapeutic range Toxic range Steep dose–response curve Narrow therapeutic index PLASMA AND TISSUE BINDING SITE INTERACTIONS Dose One large group of potential drug interactions that are seldom clinically important consists of drugs that displace one another from binding sites on plasma albumin or α-1 acid glycoprotein (AAG) or within tissues. This is a common occurrence and can readily be demonstrated in plasma or solutions of albumin/AAG in vitro. However, the simple expectation that the displacing drug will increase the effects of the displaced drug by increasing its free (unbound) concentration is seldom evident in clinical practice. This is because drug clearance (renal or metabolic) also depends directly on the concentration of free drug. Consider a patient receiving a regular maintenance dose of a drug. When a second displacing drug is commenced, the free concentration of the first drug rises only transiently before increased renal or hepatic elimination reduces total (bound plus free) drug, and restores the free concentration to that which prevailed before the second drug was started. Consequently, any increased effect of the displaced drug is transient, and is seldom important in practice. It must, however, be taken into account if therapy is being guided by measurements of plasma drug concentrations, as most such determinations are of total (bound plus free) rather than just free concentration (Chapter 8). An exception, where a transient increase in free concentration of a circulating substance (albeit not a drug) can have devastating consequences, is provided by bilirubin in premature babies whose ability to metabolize bile pigments is limited. Unconjugated bilirubin is bound by plasma albumin, and injudicious treatment with drugs, such as sulphonamides, that displace it from these binding sites permits diffusion of free Response Therapeutic range Toxic range Shallow dose–response curve Wide therapeutic index bilirubin across the immature blood–brain barrier, consequent staining of and damage to basal ganglia (‘kernicterus’) and subsequent choreoathetosis in the child. Instances where clinically important consequences do occur on introducing a drug that displaces another from tissue binding sites are in fact often due to additional actions of the second drug on elimination of the first. For instance, quinidine displaces digoxin from tissue binding sites, and can cause digoxin toxicity, but only because it simultaneously reduces the renal clearance of digoxin by a separate mechanism. Phenylbutazone (an NSAID currently reserved for ankylosing spondylitis unresponsive to other drugs, Chapter 26) displaces warfarin from binding sites on albumin, and causes excessive anticoagulation, but only because it also inhibits the metabolism of the active isomer of warfarin (S-warfarin), causing this to accumulate at the expense of the inactive isomer. Indometacin (another NSAID) also displaces warfarin from binding sites on albumin, but does not inhibit its metabolism and does not further prolong prothrombin time in patients treated with warfarin, although it can cause bleeding by causing peptic ulceration and interfering with platelet function. HARMFUL INTERACTIONS HARMFUL INTERACTIONS 73 Adverse effect likely Adverse effect unlikely Figure 13.2: Drug dose–response curves illustrating likelihood of adverse effect if an interaction increases its blood level. Dose It is impossible to memorize reliably the many clinically important drug interactions, and prescribers should use suitable references (e.g. the British National Formulary) to check for potentially harmful interactions. There are certain drugs with steep dose–response curves and serious dose-related toxicities for which drug interactions are especially liable to cause

74 DRUG INTERACTIONS harm (Figure 13.2), and where special caution is required with concurrent therapy. These include: • warfarin and other anticoagulants; • anticonvulsants; • cytotoxic drugs; • drugs for HIV/AIDS; • immunosuppressants; • digoxin and other anti-dysrhythmic drugs; • oral hypoglycaemic agents; • xanthine alkaloids (e.g. theophylline); • monoamine oxidase inhibitors. The frequency and consequences of an adverse interaction when two drugs are used together are seldom known precisely. Every individual has a peculiar set of characteristics that determine their response to therapy. RISK OF ADVERSE DRUG INTERACTIONS In the Boston Collaborative Drug Surveillance Program, 234 of 3600 (about 7%) adverse drug reactions in acute-care hospitals were identified as being due to drug interactions. In a smaller study in a chronic-care setting, the prevalence of adverse interactions was much higher (22%), probably because of the more frequent use of multiple drugs in elderly patients with multiple pathologies. The same problems exist for the detection of adverse drug interactions as for adverse drug reactions (Chapter 12). The frequency of such interactions will be underestimated by attribution of poor therapeutic outcome to an underlying disease. For example, graft rejection following renal transplantation is not uncommon. Historically, it took several years for nephrologists to appreciate that epileptic patients suffered much greater rejection rates than did nonepileptic subjects. These adverse events proved to be due to an interaction between anticonvulsant medication and immunosuppressant cortico-steroid therapy, which was rendered ineffective because of increased drug metabolism. In future, a better understanding of the potential mechanisms of such interactions should lead to their prediction and prevention by study in early-phase drug evaluation. SEVERITY OF ADVERSE DRUG INTERACTIONS Adverse drug interactions are diverse, including unwanted pregnancy (from failure of the contraceptive pill due to concomitant medication), hypertensive stroke (from hypertensive crisis in patients on monoamine oxidase inhibitors), gastrointestinal or cerebral haemorrhage (in patients receiving warfarin), cardiac arrhythmias (e.g. secondary to interactions leading to electrolyte disturbance or prolongation of the QTc) and blood dyscrasias (e.g. from interactions between allopurinol and azathioprine). Adverse interactions can be severe. In one study, nine of 27 fatal drug reactions were caused by drug interactions. Key points • Drug interactions may be clinically useful, trivial or adverse. • Useful interactions include those that enable efficacy to be maximized, such as the addition of an angiotensin converting enzyme inhibitor to a thiazide diuretic in a patient with hypertension inadequately controlled on diuretic alone (see Chapter 28). They may also enable toxic effects to be minimized, as in the use of pyridoxine to prevent neuropathy in malnourished patients treated with isoniazid for tuberculosis, and may prevent the emergence of resistant organisms (e.g. multi-drug regimens for treating tuberculosis, see Chapter 44). • Many interactions that occur in vitro (e.g. competition for albumin) are unimportant in vivo because displacement of drug from binding sites leads to increased elimination by metabolism or excretion and hence to a new steady state where the total concentration of displaced drug in plasma is reduced, but the concentration of active, free (unbound) drug is the same as before the interacting drug was introduced. Interactions involving drugs with a wide safety margin (e.g. penicillin) are also seldom clinically important. • Adverse drug interactions are not uncommon, and can have profound consequences, including death from hyperkalaemia and other causes of cardiac dysrhythmia, unwanted pregnancy, transplanted organ rejection, etc. ADVERSE INTERACTIONS GROUPED BY MECHANISM PHARMACEUTICAL INTERACTIONS Inactivation can occur when drugs (e.g. heparin with gentamicin) are mixed. Examples are listed in Table 13.1. Drugs may also interact in the lumen of the gut (e.g. tetracycline with iron, and colestyramine with digoxin). PHARMACODYNAMIC INTERACTIONS These are common. Most have a simple mechanism consisting of summation or opposition of the effects of drugs with, respectively, similar or opposing actions. Since this type of interaction depends broadly on the effect of a drug, rather than on its specific chemical structure, such interactions are non-specific. Drowsiness caused by an H1-blocking antihistamine and by alcohol provides an example. It occurs to a greater or lesser degree with all H1-blockers irrespective of the chemical structure of the particular drug used. Patients must be warned of the dangers of consuming alcohol concurrently when such antihistamines are prescribed, especially if they drive or operate machinery. Non-steroidal anti-inflammatory agents and antihypertensive drugs provide another clinically important example. Antihypertensive drugs are rendered less effective by concurrent use of non-steroidal anti-inflammatory drugs, irrespective of the chemical group to which they belong, because of inhibition of biosynthesis of vasodilator prostaglandins in the kidney (Chapter 26).

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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

  • 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
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  • 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 76 and 77: 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
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  • Page 88 and 89: Table 13.5: Competitive interaction
  • 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
  • Page 108 and 109: ● Introduction 97 ● Garlic 97
  • 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
  • Page 122 and 123: Box 19.1: Dopamine theory of schizo
  • Page 124 and 125: The Boston Collaborative Survey ind
  • Page 126 and 127: Oral medication, especially in liqu
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  • Page 130 and 131: Partial response to first-line trea
  • Page 132 and 133: 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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