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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

DISTRIBUTION Drug

DISTRIBUTION Drug distribution is altered by cardiac failure. The apparent volume of distribution (V d) of, for example, quinidine and lidocaine in patients with congestive cardiac failure is markedly reduced because of decreased tissue perfusion and altered partition between blood and tissue components. Usual doses can therefore result in elevated plasma concentrations, producing toxicity. ELIMINATION Elimination of several drugs is diminished in heart failure. Decreased hepatic perfusion accompanies reduced cardiac output. Drugs such as lidocaine with a high hepatic extraction ratio of �70% show perfusion-limited clearance, and steadystate levels are inversely related to cardiac output (Figure 7.1). During lidocaine infusion, the steady-state concentrations are almost 50% higher in patients with cardiac failure than in healthy volunteers. The potential for lidocaine toxicity in heart failure is further increased by the accumulation of its polar metabolites, which have cardiodepressant and pro-convulsant properties. This occurs because renal blood flow and glomerular filtration rate are reduced in heart failure. Theophylline clearance is decreased and its half-life is doubled in patients with cardiac failure and pulmonary oedema, increasing the potential for accumulation and toxicity. The metabolic capacity of the liver is reduced in heart failure both by tissue hypoxia and by hepatocellular damage from hepatic congestion. Liver biopsy samples from patients with heart failure have reduced drug-metabolizing enzyme activity. Heart failure reduces renal elimination of drugs because of reduced glomerular filtration, predisposing to toxicity from drugs that are primarily cleared by the kidneys, e.g. aminoglycosides and digoxin. RENAL DISEASE RENAL IMPAIRMENT Renal excretion is a major route of elimination for many drugs (Chapter 6), and drugs and their metabolites that are excreted predominantly by the kidneys accumulate in renal failure. Renal disease also affects other pharmacokinetic processes (i.e. drug absorption, distribution and metabolism) in more subtle ways. ABSORPTION Gastric pH increases in chronic renal failure because urea is cleaved, yielding ammonia which buffers acid in the stomach. This reduces the absorption of ferrous iron and possibly also of other drugs. Nephrotic syndrome is associated with resistance RENAL DISEASE 35 to oral diuretics, and malabsorption of loop diuretics through the oedematous intestine may contribute to this. DISTRIBUTION Renal impairment causes accumulation of several acidic substances that compete with drugs for binding sites on albumin Lidocaine concentration (�g/ml) (a) Steady-state arterial concentration of lidocaine (�g/ml) 10 1 0.1 3.4 3.0 2.6 2.2 1.8 1.4 0 Heart failure Control 60 120 180 240 Time after injection (min) 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 1.6 1.4 1.2 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 Cardiac index (I/min/m 2 (b) ) Arterial lidocaine (�g/ml) 0 250 500 750 1000125015001750 Estimated hepatic blood flow (ml/min/m 2 1.0 (c) ) Figure 7.1: (a) Mean values (and standard deviations) of plasma lidocaine concentrations in seven heart failure patients and controls following a 50-mg intravenous bolus. (b) Relationship between arterial lidocaine level and cardiac index (dotted vertical line is lower limit of normal cardiac index, square is mean for low cardiac index patients, triangle is mean for patients with normal cardiac index). (c) Relationship of steady-state arterial lidocaine level following 50-mg bolus and infusion of 40 mg/kg/min (vertical line is lower limit of normal hepatic blood flow, square is mean for patients with low hepatic blood flow, triangle is mean for patients with normal flow). (Reproduced from: (a) Thompson PD et al. American Heart Journal 1971; 82, 417; (b,c) Stenson RE et al. Circulation 1971; 43: 205. With permission of the American Heart Association Inc.)

36 EFFECTS OF DISEASE ON DRUG DISPOSITION and other plasma proteins. This alters the pharmacokinetics of many drugs, but is seldom clinically important. Phenytoin is an exception, because therapy is guided by plasma concentration and routine analytical methods detect total (bound and free) drug. In renal impairment, phenytoin protein binding is reduced by competition with accumulated molecules normally cleared by the kidney and which bind to the same albumin drug-binding site as phenytoin. Thus, for any measured phenytoin concentration, free (active) drug is increased compared to a subject with normal renal function and the same measured total concentration. The therapeutic range therefore has to be adjusted to lower values in patients with renal impairment, as otherwise doses will be selected that cause toxicity. Tissue binding of digoxin is reduced in patients with impaired renal function, resulting in a lower volume of distribution than in healthy subjects. A reduced loading dose of digoxin is therefore appropriate in such patients, although the effect of reduced glomerular filtration on digoxin clearance is even more important, necessitating a reduced maintenance dose, as described below. The blood–brain barrier is more permeable to drugs in uraemia. This can result in increased access of drugs to the central nervous system, an effect that is believed to contribute to the increased incidence of confusion caused by cimetidine, ranitidine and famotidine in patients with renal failure. METABOLISM Metabolism of several drugs is reduced in renal failure. These include drugs that undergo phase I metabolism by CYP3A4. Drugs that are mainly metabolized by phase II drug metabolism are less affected, although conversion of sulindac to its active sulphide metabolite is impaired in renal failure, as is the hepatic conjugation of metoclopramide with glucuronide and sulphate. RENAL EXCRETION Glomerular filtration and tubular secretion of drugs usually fall in step with one another in patients with renal impairment. Drug excretion is directly related to glomerular filtration rate (GFR). Some estimate of GFR (eGFR) is therefore essential when deciding on an appropriate dose regimen. Serum creatinine concentration adjusted for age permits calculation of an estimate of GFR per 1.73 m2 body surface area. This is now provided by most chemical pathology laboratories, and is useful in many situations. Alternatively, Figure 7.2 shows a nomogram given plasma creatinine, age, sex and body weight and is useful when a patient is markedly over- or underweight. The main limitation of such estimates is that they are misleading if GFR is changing rapidly as in acute renal failure. (Imagine that a patient with normal serum creatinine undergoes bilateral nephrectomy: an hour later, his serum creatinine would still be normal, but his GFR would be zero. Creatinine would rise gradually over the next few days as it continued to be produced in his body but was not cleared.) A normal creatinine level therefore does not mean that usual doses can be assumed to be safe in a patient who is acutely unwell. eGFR is used to adjust the dose regimen in patients with some degree of chronic renal impairment for drugs with a low therapeutic index that are eliminated mainly by renal excretion. Dose adjustment must be considered for drugs for which there is �50% elimination by renal excretion. The British National Formulary tabulates drugs to be avoided or used with caution in patients with renal failure. Common examples are shown in Table 7.2. Clearance (ml/min) Weight 150 (kg) 130 110 100 90 80 70 60 50 40 30 20 120 110 100 90 80 70 60 50 40 30 R Age (years) 25 35 45 25 55 65 45 35 55 75 65 85 75 95 85 95 Serum creatinine (mg/100 ml) 5.0 4.0 3.0 2.0 1.7 1.5 1.2 1.3 1.0 0.9 0.8 0.7 0.6 0.5 0.4 10 Figure 7.2: Nomogram for rapid evaluation of endogenous creatinine clearance – with a ruler joining weight to age. Keep ruler at crossing point on R, then move the right-hand side of the ruler to the appropriate serum creatinine value and read off clearance from the left-hand scale. To convert serum creatinine in �mol/L to mg/100mL, as is used on this scale, simply divide by 88.4. (Reproduced with permission from Siersbaek-Nielson K et al. Lancet 1971; 1: 1133. © The Lancet Ltd.) Table 7.2: Examples of drugs to be used with particular caution or avoided in renal failure Angiotensin-converting enzyme Angiotensin receptor inhibitorsa blockersa Aldosterone antagonists Aminoglycosides Amphotericin Atenolol Ciprofloxacin Cytotoxics Digoxin Lithium Low molecular weight heparin Metformin NSAIDs Methotrexate aACEI and ARB must be used with caution, but can slow progressive renal impairment (see Chapter 28).

  • Page 2 and 3: A Textbook of Clinical Pharmacology
  • Page 4 and 5: A Textbook of Clinical Pharmacology
  • Page 6 and 7: This fifth edition is dedicated to
  • Page 8 and 9: FOREWORD viii PREFACE ix ACKNOWLEDG
  • Page 10 and 11: PREFACE Clinical pharmacology is th
  • Page 12 and 13: PART I GENERAL PRINCIPLES
  • Page 14 and 15: ● Use of drugs 3 ● Adverse effe
  • Page 16 and 17: and acquired factors, notably disea
  • Page 18 and 19: 100 Effect (%) 0 0 5 10 1 10 100 (a
  • Page 20 and 21: Dose ratio -1 100 50 The relationsh
  • Page 22 and 23: ● Introduction 11 ● Constant-ra
  • Page 24 and 25: 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 48 and 49: Detailed recommendations on dosage
  • Page 50 and 51: DIGOXIN Myxoedematous patients are
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  • 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
  • Page 84 and 85: Response Therapeutic range Toxic ra
  • Page 86 and 87: Table 13.1: Interactions outside th
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    Key points • Genetic differences

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    • Discovery • • Screening Pre

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    Too many statistical comparisons pe

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    ETHICS COMMITTEES Protocols for all

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    Table 16.1: Recombinant proteins/en

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    duration and benefit. Adenoviral ve

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    ● Introduction 97 ● Garlic 97

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    A case report has suggested a possi

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    including hypericin and pseudohyper

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    PART II THE NERVOUS SYSTEM

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    ● Introduction 105 ● Sleep diff

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    and daytime sleeping should be disc

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    Key points • Insomnia and anxiety

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    Box 19.1: Dopamine theory of schizo

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    The Boston Collaborative Survey ind

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    Oral medication, especially in liqu

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    e.g. interpersonal difficulties or

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    Partial response to first-line trea

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    Key points Drug treatment of depres

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    Case history A 45-year-old man with

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    Levodopa PRINCIPLES OF TREATMENT IN

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    • pulmonary, retroperitoneal and

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    CHOREA The γ-aminobutyric acid con

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    Cholinergic crisis Treatment of mya

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    ● Introduction 133 ● Mechanisms

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    absolute arbiter. The availability

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    Table 22.2: Metabolic interactions

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    FURTHER ANTI-EPILEPTICS Other drugs

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    Case history A 24-year-old woman wh

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    Assessment of migraine severity and

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    ● General anaesthetics 145 ● In

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    is the theoretical concern of a ‘

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    • Respiratory system - apnoea fol

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    Competitive antagonists (vecuronium

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    have also proved useful in combinat

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    ● Introduction 155 ● Pathophysi

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    ASPIRIN (ACETYLSALICYLATE) Use Anti

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    Key points Drugs for mild pain •

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    increases, correlating with the hig

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    • If possible, use oral medicatio

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    PART III THE MUSCULOSKELETAL SYSTEM

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    ● Introduction: inflammation 167

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    Chapter 33). All NSAIDs cause wheez

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    • Stomatitis suggests the possibi

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    Pharmacokinetics Allopurinol is wel

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    PART IV THE CARDIOVASCULAR SYSTEM

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    ● Introduction 177 ● Pathophysi

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    esponsible for the strong predilect

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    Ezetimibe Fat Muscle Dietary fat In

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    educed). The risk of muscle damage

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    ● Introduction 185 ● Pathophysi

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    Each of these classes of drug reduc

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    AT 1 receptor) produce good 24-hour

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    Table 28.2: Examples of calcium-cha

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    Key points Drugs used in essential

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    Case history A 72-year-old woman se

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    Assess risk factors Investigations:

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    Persistent ST segment elevation Thr

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    Mechanism of action GTN works by re

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    Because of the risks of haemorrhage

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    Intrinsic pathway XIIa XIa the acti

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    that the pharmacodynamic response i

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    used with apparent benefit in acute

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    ● Introduction 211 ● Pathophysi

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    The drugs that are most effective i

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    therapeutic plasma concentration ca

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    ● Common dysrhythmias 217 ● Gen

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    BASIC LIFE SUPPORT CARDIOPULMONARY

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    arrest. The electrocardiogram is li

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    should be given to insertion of an

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    Drug interactions Amiodarone potent

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    effect when treating sinus bradycar

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    Case history A 24-year-old medical

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    PART V THE RESPIRATORY SYSTEM

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    CHAPTER 33 THERAPY OF ASTHMA, CHRON

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    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

  • Page 448 and 449:

    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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