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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

Detailed recommendations

Detailed recommendations on dosage reduction can be found in textbooks of nephrology. These are useful for getting treatment under way but, although precise, such recommendations are inevitably based only on the effects of reduced renal function on drug elimination in ‘average’ populations. Individual variation is substantial, and therapeutic monitoring of efficacy, toxicity and sometimes of drug concentrations is essential in patients with impaired renal function. There are two ways of reducing the total dose to compensate for impaired renal function. Either each dose can be reduced, or the interval between each dose can be lengthened. The latter method is useful when a drug must achieve some threshold concentration to produce its desired effect, but does not need to remain at this level throughout the dose interval. This is the case with aminoglycoside antibiotics. Therapy with these drugs is appropriately monitored by measuring ‘peak’ concentrations (in blood sampled at a fixed brief interval after dosing, sufficient to permit at least partial tissue distribution), which indicate whether the dose is large enough to achieve a therapeutic plasma concentration, and ’trough’ concentrations immediately before the next dose (see Chapter 8). If the peak concentration is satisfactory but the trough concentration is higher than desired (i.e. toxicity is present or imminent), the dose is not reduced but the interval between doses is extended. This type of therapeutic drug monitoring is modified to a single time point (after dosing and beyond the distribution phase) when extended interval dosing of aminoglycosides is used to treat patients (Chapter 43). RENAL HAEMODYNAMICS Patients with mild renal impairment depend on vasodilator prostaglandin biosynthesis to preserve renal blood flow and GFR. The same is true of patients with heart failure, nephrotic syndrome, cirrhosis or ascites. Such patients develop acute reversible renal impairment, often accompanied by salt and water retention and hypertension if treated with non-steroidal anti-inflammatory drugs (NSAIDs, see Chapter 26), because these inhibit cyclo-oxygenase and hence the synthesis of vasodilator prostaglandins, notably prostaglandin I2 (prostacyclin) and prostaglandin E2. Sulindac is a partial exception because it inhibits cyclo-oxygenase less in kidneys than in other tissues, although this specificity is incomplete and dose dependent. Angiotensin converting enzyme inhibitors (e.g. ramipril) can also cause reversible renal failure due to altered renal haemodynamics. This occurs predictably in patients with bilateral renal artery stenosis (or with renal artery stenosis involving a single functioning kidney). The explanation is that in such patients GFR is preserved in the face of the fixed proximal obstruction by angiotensin-II-mediated efferent arteriolar vasoconstriction. Inhibition of angiotensin converting enzyme disables this homeostatic mechanism and precipitates renal failure. NEPHROTIC SYNDROME Plasma albumin in patients with nephrotic syndrome is low, resulting in increased fluctuations of free drug concentration LIVER DISEASE 37 following each dose. This could cause adverse effects, although in practice this is seldom clinically important. The high albumin concentration in tubular fluid contributes to the resistance to diuretics that accompanies nephrotic syndrome. This is because both loop diuretics and thiazides act on ion-transport processes in the luminal membranes of tubular cells (see Chapter 36). Protein binding of such diuretics within the tubular lumen therefore reduces the concentration of free (active) drug in tubular fluid in contact with the ion transporters on which they act. PRESCRIBING FOR PATIENTS WITH RENAL DISEASE 1. Consider the possibility of renal impairment before drugs are prescribed and use available data to estimate GFR. 2. Check how drugs are eliminated before prescribing them. If renal elimination accounts for more than 50% of total elimination, then dose reduction will probably be necessary after the first dose, i.e. for maintenance doses. 3. Monitor therapeutic and adverse effects and, where appropriate, plasma drug concentrations. 4. If possible avoid potentially nephrotoxic drugs (e.g. aminoglycosides, NSAIDs); if such drugs are essential use them with great care. Once a potential renal problem necessitating dose modification has been identified, there are a number of accepted reference sources that provide guidance for dose adjustment. These are useful approximations to get treatment under way, but their mathematical precision is illusory, and must not lull the inexperienced into a false sense of security – they do not permit a full ‘course’ of treatment to be prescribed safely. The patient must be monitored and treatment modified in the light of individual responses. The British National Formulary has a useful appendix which is concise, simple and accessible. LIVER DISEASE The liver is the main site of drug metabolism (Chapter 5). Liver disease has major but unpredictable effects on drug handling. Pharmacokinetic factors that are affected include absorption and distribution, as well as the metabolism of drugs. Attempts to correlate changes in the pharmacokinetics of drugs with biochemical tests of liver function have been unsuccessful (in contrast to the use of plasma creatinine in chronic renal impairment described above). In chronic liver disease, serum albumin is the most useful index of hepatic drug-metabolizing activity, possibly because a low albumin level reflects depressed synthesis of hepatic proteins, including those involved in drug metabolism. Prothrombin time also shows a moderate correlation with drug clearance by the liver. However, in neither case has a continuous relationship been

38 EFFECTS OF DISEASE ON DRUG DISPOSITION demonstrated, and such indices of hepatic function serve mainly to distinguish the severely affected from the milder cases. Clearances of indocyanine green, antipyrine and lidocaine have also been disappointing. Currently, therefore, cautious empiricism coupled with an awareness of an increased likelihood of adverse drug effects and close clinical monitoring is the best way for a prescriber to approach a patient with liver disease. Drugs should be used only if necessary, and the risks weighed against potential benefit. If possible, drugs that are eliminated by routes other than the liver should be employed. EFFECTS OF LIVER DISEASE ON DRUG ABSORPTION Absorption of drugs is altered in liver disease because of portal hypertension, and because hypoalbuminaemia causes mucosal oedema. Portal/systemic anastomoses allow the passage of orally administered drug directly into the systemic circulation, bypassing hepatic presystemic metabolism and markedly increasing the bioavailability of drugs with high presystemic metabolism such as propranolol, morphine, verapamil and ciclosporin, which must therefore be started in low doses in such patients and titrated according to effect. DISTRIBUTION OF DRUGS IN PATIENTS WITH LIVER DISEASE Drug distribution is altered in liver disease. Reduced plasma albumin reduces plasma protein binding. This is also influenced by bilirubin and other endogenous substances that accumulate in liver disease and may displace drugs from binding sites. The free fraction of tolbutamide is increased by 115% in cirrhosis, and that of phenytoin is increased by up to 40%. It is particularly important to appreciate this when plasma concentrations of phenytoin are being used to monitor therapy, as unless the therapeutic range is adjusted downward, toxicity will be induced, as explained above in the section on drug distribution in renal disease. Reduced plasma protein binding increases the apparent V d if other factors remain unchanged. Increased V d of several drugs (e.g. theophylline) is indeed observed in patients with liver disease. Disease-induced alterations in clearance and V d often act in opposite directions with regard to their effect on t 1/2. Data on t 1/2 in isolation provide little information about the extent of changes in metabolism or drug distribution which result from liver disease. DRUG METABOLISM IN LIVER DISEASE CYP450-mediated phase I drug metabolism is generally reduced in patients with very severe liver disease, but drug metabolism is surprisingly little impaired in patients with moderate to severe disease. There is a poor correlation between microsomal enzyme activity from liver biopsy specimens in vitro and drug clearance measurements in vivo. Even in very severe disease, the metabolism of different drugs is not affected to the same extent. It is therefore hazardous to extrapolate from knowledge of the handling of one drug to effects on another in an individual patient with liver disease. Prescribing for patients with liver disease 1. Weigh risks against hoped for benefit, and minimize nonessential drug use. 2. If possible, use drugs that are eliminated by routes other than the liver (i.e. in general, renally cleared drugs). 3. Monitor response, including adverse effects (and occasionally drug concentrations), and adjust therapy accordingly. 4. Avoid sedatives and analgesics if possible: they are common precipitants of hepatic coma. 5. Predictable hepatotoxins (e.g. cytotoxic drugs) should only be used for the strongest of indications, and then only with close clinical and biochemical monitoring. 6. Drugs that are known to cause idiosyncratic liver disease (e.g. isoniazid, phenytoin, methyldopa) are not necessarily contraindicated in stable chronic disease, as there is no evidence of increased susceptibility. Oral contraceptives are not advisable if there is active liver disease or a history of jaundice of pregnancy. 7. Constipation favours bacterial production of false neurotransmitter amines in the bowel: avoid drugs that cause constipation (e.g. verapamil, tricyclic antidepressants) if possible. 8. Drugs that inhibit catabolism of amines (e.g. monoamine oxidase inhibitors) also provoke coma and should be avoided. 9. Low plasma potassium provokes encephalopathy: avoid drugs that cause this if possible. Potassium-sparing drugs, such as spironolactone, are useful. 10. Avoid drugs that cause fluid overload or renal failure (e.g. NSAID) and beware those containing sodium (e.g. sodium-containing antacids and high-dose carbenicillin). 11. Avoid drugs that interfere with haemostasis (e.g. aspirin, anticoagulants and fibrinolytics) whenever possible, because of the increased risk of bleeding (especially in the presence of varices!). THYROID DISEASE Thyroid dysfunction affects drug disposition partly as a result of effects on drug metabolism and partly via changes in renal elimination. Existing data refer to only a few drugs, but it is prudent to anticipate the possibility of increased sensitivity of hypothyroid patients to many drugs when prescribing. Information is available for the following drugs.

  • 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 46 and 47: DISTRIBUTION Drug distribution is a
  • 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
  • Page 84 and 85: Response Therapeutic range Toxic ra
  • Page 86 and 87: Table 13.1: Interactions outside th
  • 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
  • Page 94 and 95: lipoprotein (LDL) is impaired. LDL
  • Page 96 and 97: 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

  • Page 402 and 403:

    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

  • Page 422 and 423:

    ● Introduction 411 ● Acne 411

  • Page 424 and 425:

    DERMATITIS (ECZEMA) PRINCIPLES OF T

  • Page 426 and 427:

    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

  • Page 432 and 433:

    PART XIII THE EYE

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    ● Introduction: ocular anatomy, p

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    to cause pupillary dilatation, name

  • Page 438 and 439:

    Table 52.3: Antibacterial agents us

  • Page 440 and 441:

    Table 52.6: Common drug-induced pro

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    PART XIV CLINICAL TOXICOLOGY

  • Page 444 and 445:

    ● 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

  • Page 474 and 475:

    puberty (male), delay 314 puerperiu

  • Page 476:

    tolerance 9, 433 benzodiazepines 10

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