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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

DIGOXIN Digoxin toxicity

DIGOXIN Digoxin toxicity is common in the elderly because of decreased renal elimination and reduced apparent volume of distribution. Confusion, nausea and vomiting, altered vision and an acute abdominal syndrome resembling mesenteric artery obstruction are all more common features of digoxin toxicity in the elderly than in the young. Hypokalaemia due to decreased potassium intake (potassium-rich foods are often expensive), faulty homeostatic mechanisms resulting in increased renal loss and the concomitant use of diuretics is more common in the elderly, and is a contributory factor in some patients. Digoxin is sometimes prescribed when there is no indication for it (e.g. for an irregular pulse which is due to multiple ectopic beats rather than atrial fibrillation). At other times, the indications for initiation of treatment are correct but the situation is never reviewed. In one series of geriatric patients on digoxin, the drug was withdrawn in 78% of cases without detrimental effects. DIURETICS Diuretics are more likely to cause adverse effects (e.g. postural hypotension, glucose intolerance and electrolyte disturbances) in elderly patients. Too vigorous a diuresis may result in urinary retention in an old man with an enlarged prostate, and necessitate bladder catheterization with its attendant risks. Brisk diuresis in patients with mental impairment or reduced mobility can result in incontinence. For many patients, a thiazide diuretic, such as bendroflumethiazide, is adequate. Loop diuretics, such as furosemide, should be used in acute heart failure or in the lowest effective dose for maintenance treatment of chronic heart failure. Clinically important hypokalaemia is uncommon with low doses of diuretics, but plasma potassium should be checked after starting treatment. If clinically important hypokalaemia develops, a thiazide plus potassium-retaining diuretic (amiloride or triamterene) can be considered, but there is a risk of hyperkalaemia due to renal impairment, especially if an ACE inhibitor and/or angiotensin receptor antagonist and aldosterone antagonist are given together with the diuretic for hypertension or heart failure. Thiazide-induced gout and glucose intolerance are important side effects. ISCHAEMIC HEART DISEASE This is covered in Chapter 29. ANGIOTENSIN CONVERTING ENZYME INHIBITORS (ACEI) AND ANGIOTENSIN RECEPTOR BLOCKERS (ARB) These drugs plays an important part in the treatment of chronic heart failure, as well as hypertension (see Chapters 28 and 31), and are effective and usually well tolerated in the elderly. However, hypotension, hyperkalaemia and renal failure are more common in this age group. The possibility of atheromatous renal artery stenosis should be borne in mind and serum creatinine levels checked before and after starting treatment. Potassium-retaining diuretics should be co-administered only with extreme caution, because of the reduced GFR and plasma potassium levels monitored. Despite differences in their pharmacology, ACEI and ARB appear similar in efficacy, but ARB do not cause the dry cough that is common with ACEI. The EFFECT OF DRUGS ON SOME MAJOR ORGAN SYSTEMS IN THE ELDERLY 59 question of whether co-administration of ACEI with ARB has much to add remains controversial; in elderly patients with reduced GFR, the safety of such combined therapy is an important consideration. ORAL HYPOGLYCAEMIC AGENTS Diabetes is common in the elderly and many patients are treated with oral hypoglycaemic drugs (see Chapter 37). It is best for elderly patients to be managed with diet if at all possible. In obese elderly diabetics who remain symptomatic on diet, metformin should be considered, but coexisting renal, heart or lung disease may preclude its use. Short-acting sulphonylureas (e.g. gliclazide) are preferred to longer-acting drugs because of the risk of hypoglycaemia: chlorpropamide (half-life 36 hours) can cause prolonged hypoglycaemia and is specifically contraindicated in this age group, glibenclamide should also be avoided. Insulin may be needed, but impaired visual and cognitive skills must be considered on an individual basis, and the potential need for dose reduction with advancing age and progressive renal impairment taken into account. ANTIBIOTICS The decline in renal function must be borne in mind when an antibiotic that is renally excreted is prescribed, especially if it is nephrotoxic (e.g. an aminoglycoside or tetracycline). Appendix 3 of the British National Formulary is an invaluable practical guide. Over-prescription of antibiotics is a threat to all age groups, but especially in the elderly. Broad-spectrum drugs including cephalosporins and other beta-lactams, and fluoroquinones are common precursors of Clostridium difficile infection which has a high mortality rate in the elderly. Amoxicillin is the most common cause of drug rash in the elderly. Flucloxacillin induced cholestatic jaundice and hepatitis is more common in the elderly. Case history An 80-year-old retired publican was referred with ‘congestive cardiac failure and acute retention of urine’. His wife said his symptoms of ankle swelling and breathlessness had gradually increased over a period of six months despite the GP doubling the water tablet (co-amilozide) which he was taking for high blood pressure. Over the previous week he had become mildly confused and restless at night, for which the GP had prescribed chlorpromazine. His other medication included ketoprofen for osteoarthritis and frequent magnesium trisilicate mixture for indigestion. He had been getting up nearly ten times most nights for a year to pass urine. During the day, he frequently passed small amounts of urine. Over the previous 24 hours, he had been unable to pass urine. His wife thought most of his problems were due to the fact that he drank two pints of beer each day since his retirement seven years previously. On physical examination he was clinically anaemic, but not cyanosed. Findings were consistent with congestive cardiac failure. His bladder was palpable up to his umbilicus. Rectal examination revealed an enlarged, symmetrical prostate and black tarry faeces. Fundoscopy revealed a grade II hypertensive retinopathy.

60 DRUGS IN THE ELDERLY Initial laboratory results revealed that the patient had acute on chronic renal failure, dangerously high potassium levels (7.6 mmol/L) and anaemia (Hb 7.4 g/dL). Emergency treatment included calcium chloride, dextrose and insulin, urinary catheterization, furosemide and haemodialysis. Gastroscopy revealed a bleeding gastric ulcer. The patient was discharged two weeks later, when he was symptomatically well. His discharge medication consisted of regular doxazosin and ranitidine, and paracetamol as required. Question Describe how each of this patient’s drugs prescribed before admission may have contributed to his clinical condition. Answer Co-amilozide – hyperkalaemia: amiloride, exacerbation of prostatic symptoms: thiazide Chlorpromazine – urinary retention Ketoprofen – gastric ulcer, antagonism of thiazide diuretic, salt retention, possibly interstitial nephritis Magnesium trisilicate mixture – additional sodium load (6 mmol Na � /10 mL). Comment Iatrogenic disease due to multiple drug therapy is common in the elderly. The use of amiloride in renal impairment leads to hyperkalaemia. This patient’s confusion and restlessness were most probably related to his renal failure. Chlorpromazine may mask some of the symptoms/signs and delay treatment of the reversible organic disease. The analgesic of choice in osteoarthritis is paracetamol, due to its much better tolerance than NSAID. The sodium content of some antacids can adversely affect cardiac and renal failure. NON-STEROIDAL ANTI-INFLAMMATORY DRUGS The elderly are particularly susceptible to non-steroidal antiinflammatory drug (NSAID)-induced peptic ulceration, gastrointestinal irritation and fluid retention. An NSAID is frequently prescribed inappropriately for osteoarthritis before physical and functional interventions and oral paracetamol have been adequately utilized. If an NSAID is required as adjunctive therapy, the lowest effective dose should be used. Ibuprofen is probably the NSAID of choice in terms of minimizing gastro-intestinal side effects. A proton pump inhibitor should be considered as prophylaxis against upper gastro-intestinal complications in those most at risk. PRACTICAL ASPECTS OF PRESCRIBING FOR THE ELDERLY Improper prescription of drugs is a common cause of morbidity in elderly people. Common-sense rules for prescribing do not apply only to the elderly, but are especially important in this vulnerable group. 1. Take a full drug history (see Chapter 1), which should include any adverse reactions and use of over-the-counter drugs. 2. Know the pharmacological action of the drug employed. 3. Use the lowest effective dose. 4.Use the fewest possible number of drugs the patient needs. 5. Consider the potential for drug interactions and co-morbidity on drug response. 6. Drugs should seldom be used to treat symptoms without first discovering the cause of the symptoms (i.e. first diagnosis, then treatment). 7. Drugs should not be withheld because of old age, but it should be remembered that there is no cure for old age either. 8. A drug should not be continued if it is no longer necessary. 9. Do not use a drug if the symptoms it causes are worse than those it is intended to relieve. 10. It is seldom sensible to treat the side effects of one drug by prescribing another. In the elderly, it is often important to pay attention to matters such as the formulation of the drug to be used – many old people tolerate elixirs and liquid medicines better than tablets or capsules. Supervision of drug taking may be necessary, as an elderly person with a serious physical or mental disability cannot be expected to comply with any but the simplest drug regimen. Containers require especially clear labelling, and should be easy to open – child-proof containers are often also grandparent-proof! RESEARCH Despite their disproportionate consumption of medicines, the elderly are often under-represented in clinical trials. This may result in the data being extrapolated to an elderly population inappropriately, or the exclusion of elderly patients from new treatments from which they might benefit. It is essential that, both during a drug’s development and after it has been licensed, subgroup analysis of elderly populations is carefully examined both for efficacy and for predisposition to adverse effects. Case history A previously mentally alert and well-orientated 90-year-old woman became acutely confused two nights after hospital admission for bronchial asthma which, on the basis of peak flow and blood gases, had responded well to inhaled salbutamol and oral prednisolone. Her other medication was cimetidine (for dyspepsia), digoxin (for an isolated episode of atrial fibrillation two years earlier) and nitrazepam (for night sedation). Question Which drugs may be related to the acute confusion? Answer Prednisolone, cimetidine, digoxin and nitrazepam. Comment If an H 2-antagonist is necessary, ranitidine is preferred in the elderly. It is likely that the patient no longer requires digoxin (which accumulates in the elderly). Benzodiazepines should not be used for sedation in elderly (or young) asthmatics. They may also accumulate in the elderly. The elderly tend to be more sensitive to adverse drug effects on the central nervous system (CNS).

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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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  • Page 32 and 33: Transdermal absorption is sufficien
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  • Page 36 and 37: and thromboxanes are CYP450 enzymes
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  • Page 64 and 65: METABOLISM At birth, the hepatic mi
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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

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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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