CLINICAL PHARMACOLOGY 2003 (PART 38)

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The principally pharmacological aspects of vitamins are described here.The nutritional aspects, physiological function, sources, daily requirements and deficiency syndromes (primary and secondary) are to be found in any textbook of medicine. • • • • Vitamin A: retinol Vitamin B: complex Vitamin C: ascorbic acid Vitamin D, calcium, parathyroid hormone, calcitonin, bisphosphonates, bone • Treatment of calcium and bone disorders • Vitamin E:tocopherol that subclinical vitamin deficiencies are a cause of much chronic ill-health and liability to infections. This idea has led to enormous consumption of vitamin preparations, which, for most consumers, probably have no more than placebo value....

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38 Vitamins, calcium, bone SYNOPSIS that subclinical vitamin deficiencies are a cause of much chronic ill-health and liability to infections. The principally pharmacological aspects of This idea has led to enormous consumption of vitamins are described here.The nutritional vitamin preparations, which, for most consumers, aspects, physiological function, sources, daily probably have no more than placebo value. requirements and deficiency syndromes Fortunately most of the vitamins are comparatively (primary and secondary) are to be found in any nontoxic, but prolonged administration of vitamins textbook of medicine. A and D can have serious ill-effects. • Vitamin A: retinol Vitamins fall into two groups: • Vitamin B: complex • water-soluble vitamins: the B group and C • Vitamin C: ascorbic acid • fat-soluble vitamins: A, D, E and K • Vitamin D, calcium, parathyroid hormone, calcitonin, bisphosphonates, bone • Treatment of calcium and bone disorders • Vitamin E:tocopherol Vitamin A: retinol Vitamin A is a generic term embracing substances Vitamins are substances that are essential for normal having the biological actions of retinol and related metabolism and must be chiefly supplied in the diet. substances (which are called retinoids). The principal Humans cannot synthesise vitamins in the body functions of retinol are to: except some vitamin D in the skin and nicotinamide from tryptophan. Lack of a particular vitamin may • sustain normal epithelia • form retinal photochemicals lead to a specific deficiency syndrome. This may be primary (inadequate diet), or secondary, due to failure • enhance immune functions of absorption (intestinal abnormality or chronic • protect against infections and probably some diarrhoea), or to increased metabolic need (growth, cancers. pregnancy, lactation, hyperthyroidism). Deficiency of retinol leads to metaplasia and Vitamin deficiencies are commonly multiple, hyperkeratosis throughout the body. This metaplasia and complex clinical pictures occur. There are is reminiscent of the early stage of transformation of numerous single and multivitamin preparations to normal tissue to cancer. provide prophylaxis and therapy. Retinol and derivatives are used in doses above It has often been suggested, but never proved, those needed for nutrition, i.e. pharmacotherapy, in 735
38 VITAMINS, CALCIUM, BONE dyskeratotic skin diseases (psoriasis, acne) and in above physiological doses, i.e. with pharmacotherapy leukaemia. (for precautions, see use in acne and psoriasis, p. 313). Misguided pregnant health enthusiasts may Tretinoin is retinoic acid. It is used in acne by take enough self-prescribed supplements to hazard topical application, see page 313, and orally to a fetus. The Teratology Society advises that supple- induce remission in promyelocytic leukaemia. ments should not exceed 8000 IU (2400 micrograms) per day. Isotretinoin is a retinoic acid isomer (t1^ 20 h). It is used orally in acne (see p. 313). It is effective in Acute overdose: Travellers have been made ill by preventing second primary tumours in patients who eating the livers of Arctic carnivores: have been treated for squamous cell carcinoma of Eskimos never eat polar-bear liver, knowing it to the head and neck. be toxic, and husky dogs, with instinctive wisdom, also avoid it. Those who pooh-pooh the Eskimos' Acitretin is a retinoic acid derivative (t l / 2 48 h). It is fears of the husky dogs' instincts and are tempted used orally for psoriasis, see p. 313. to enjoy a man's portion of polar-bear liver — appetites get sharp near the North Pole — will Retinol itself is used in prevention and treatment consume anything up to 10 000 000 IU of vitamin A of deficiency (ta/2 7-14 d). (normal daily requirement is 5000 IU). This is too much of a good thing, and the diner will probably Adverse effects soon find himself drowsy then overcome by headache and vomiting, and finally losing the Toxic effects occur with prolonged high intake (in outer layer of his skin.2 children 25 000-500 000 IU daily). A diagnostic sign of chronic poisoning is the presence of painful tender swellings on the long bones. Anorexia, skin lesions, hair loss, hepatosplenomegaly, papilloedema, bleeding and general malaise also occur. Vitamin A Vitamin B complex is very cumulative (it is stored in liver and fat) and effects take weeks to wear off. Most cases of vitamin A number of widely differing substances are now, A poisoning have been due to mothers administering for convenience, classed the Vitamin B complex'. large amounts of fish-liver oils to their children in Those used for pharmacotherapy include the following: the belief that it was good for them. Chronic overdose also causes an increased liability Thiamine (B:) is used orally for nutritional pur- of biological membranes and of the outer layer of poses, but is given i.v. in serious emergencies, e.g. the skin to peel. An extreme example of this is the Wernicke-Korsakoff syndrome, when it can cause case of the hungry Antarctic explorer who in 1913 anaphylactic shock; the injection should be given ate the liver of his husky sledge dogs. His feet felt over 10 min (or i.m.). sore and Cobalamins (B12): see Chapter 29. the sight of my feet gave me quite a shock, for the thickened skin of the soles had separated in each Folic acid: see Chapter 29. case as a complete layer ... I did what appeared to be the best thing under the circumstances: smeared Pyridoxine (B6) is a coenzyme (including decar- the new skin with lanoline ... and with bandages boxylases) for transamination and is concerned bound the skin soles back in place.1 with many metabolic processes. Normal adult Vitamin A and its derivatives are teratogenic at requirements are about 2 mg/d. As pharmacotherapy, 1 Shearman J C 1978 Vitamin A and Sir Douglas Mawson. ; British Medical Journal 1: 283. Editorial 1962 British Medical Journal 1: 855. 736
VITAMIN C: A S C O R B I C ACID 38 pyridoxine is given to treat certain pyridoxine- the oranges and lemon recovered and were back on dependent inborn errors of metabolism, namely duty within a week; of the others, only the pair homocystinuria, hereditary sideroblastic anaemia taking cider was slightly improved. The efficacy of and primary hyperoxaluria. Deficiency may be oranges and lemons in the prevention and cure of induced by drugs such as isoniazid, hydralazine scurvy was repeatedly confirmed. Eventually the and penicillamine; pyridoxine 10 mg/day prevents British Navy provided a regular daily allowance of the development of peripheral neuritis without lemon juice, unfortunately later replaced by the interfering with therapeutic action. cheaper lime4 juice which contained insufficient Pyridoxine has also been used for a variety of ascorbic acid to prevent scurvy completely. conditions including premenstrual tension, vomiting in pregnancy and radiation sickness in doses some- times exceeding 100 mg/day. Concerns that pro- Function longed exposure to high doses may be harmful, e.g. Ascorbic acid is required for the synthesis of collagen. causing sensory neuropathy, have not been It is also a powerful reducing agent (antioxidant) resolved. and plays a part in intracellular oxidation-reduction systems, and in mopping up oxidants (free radicals) Niacin (nicotinic acid, nicotinamide) (B7) is an produced endogenously or in the environment, e.g. essential part of codehydrogenases I and II, and so cigarette smoke (see Vitamin E). it is present in every living cell. It is used in some hyperlipidaemias, see page 527. Adverse effects do not occur with standard doses Indications for ascorbic acid of nicotinamide. Nicotinic acid, which is converted • The prevention and cure of scurvy into nicotinamide, causes peripheral vasodilatation • Urinary acidification (rarely appropriate) accompanied by an unpleasant flushing and itching, • Methaemoglobinaemia, for its properties as and the patient may faint. reducing agent (see below) • Coryza: it is possible that large daily doses (1 g or more/d) of ascorbic acid (daily nutritional requirement 60 mg) may reduce the Vitamin C: ascorbic acid incidence and severity of coryza (common cold). Reliable trials in this disease are difficult and the Deficiency of ascorbic acid leads to scurvy,3 which results are inconclusive. To justify use of such is characterised by petechial haemorrhages, doses in populations, benefit must be shown to haematomas, bleeding gums (if teeth are present) be clinically, as well as statistically, significant; and anaemia. It has a memorable place in the and harm insignificant. This has not been history of therapeutic measurement. achieved. Scurvy had been a scourge for thousands of years, particularly amongst sailors on long voyages. In 1753, Dr James Lind performed a simple controlled Adverse effects therapeutic trial on 12 sailors with advanced scurvy. High doses may cause sleep disturbances, headaches They were all on the same basic diet and were and gut upsets. Ascorbic acid is partly eliminated in living in the same quarters on board ship at sea. He the urine unchanged and partly metabolised to divided them into pairs and dosed each pair oxalate. Doses above 4 g/d, which have been taken separately on cider, sulphuric acid, sea-water, vinegar, over long periods in the hope of preventing coryza, a concoction of garlic, mustard, balsam and myrrh, increase urinary oxalate concentration sufficiently and two oranges and a lemon. The pair receiving to from oxalate stones. Intravenous ascorbic acid 3 Only man (and other primates), guinea-pigs, the Indian 4 fruit bat and the red-vented bulbul (a bird) get scurvy; other Hence the term 'limey' for British sailors; generally used animals are able to synthesise ascorbic acid for themselves. pejoratively, but obsolete except in Australia. 737
38 VITAMINS, CALCIUM, BONE may precipitate a haemolytic attack in subjects with related sterol compounds having similar biological glucose-6-phosphate dehydrogenase deficiency. properties in that they prevent or cure the vitamin D deficiency diseases, rickets and osteomalacia. The METHAEMOGLOBINAEMIA important forms are: A reducing substance is needed to convert the • D2 or ergocalcif erol (calciferol) made by methaemoglobin (ferric iron) back to oxyhaemo- ultraviolet irradiation of ergosterol globin (ferrous iron) whenever enough has formed • D3 or colecalcif erol made by ultraviolet seriously to impair the oxygen-carrying capacity of irradiation of 7-dehydrocholesterol; it is the form the blood. Ascorbic acid is nontoxic (it acts by direct that occurs in natural foods and is formed in the reduction) but is less effective than methylene blue skin. (methylthioninium chloride). Both can be given Vitamins D2 and D3 are made more active by two orally, i.v. or i.m. Excessive doses of methylene blue hydroxylation reactions: (a) 25-hydroxylation in the can cause methaemoglobinaemia (by stimulating liver, and (b) la-hydroxylation in the kidney (under NADPH-dependent enzymes). the control of parathormone) to form, la-25- Methaemoglobinaemia may be induced by dihydroxycholecalciferol; this, the most active oxidising drugs: sulphonamides, nitrites, nitrates natural form of vitamin D, is available as calcitriol. (may also occur in drinking water), primaquine, In renal disease this final rate-limited renal a- -caine local anaesthetics, dapsone, nitrofurantoin, hydroxylation is inadequate, and administration of nitroprusside, vitamin K analogues, chlorates, aniline the less biologically active precursors is therefore and nitrobenzene. In the rare instance of there being liable to lack efficacy. urgency, methylene blue 1 mg/kg slowly i.v. benefits Subsequently there was introduced a loc- within 30 min. (Ascorbic acid competes directly hydroxylated form (loc-hydroxycholecalciferol) with the chemical cause but is inadequate in severe alf acalcidol (One-Alpha), that requires only hepatic cases, which are the only ones that need treatment.) hydroxylation to become the highly active lcx-25- In the congenital form, oral methylene blue with dihydroxycholecalciferol (calcitriol). Alf acalcidol or without ascorbic acid gives benefit in days to (and of course calcitriol) is therefore effective in weeks. renal failure since the defective renal hydroxylation Methylene blue turns the urine blue and high stage is bypassed. Its extraordinary potency and concentrations can irritate the urinary tract, so that efficacy is indicated by the usual adult maintenance fluid intake should be high when big doses are used. dose, often only 0.25-1 micrograms/d. In addition there is a structural variant of vitamins Sulphaemoglobinaemia cannot be treated by drugs. D2 and D3 dihydrotachysterol (ATIO, Tachyrol), It can be caused by sulphonamides, nitrites or nitrates. which is also biologically activated by hepatic 25- hydroxylation. Vitamin D, calcium, Advantages of alfacalcidol and dihydrotachysterol include a fast onset and short duration of clinical parathyroid hormone, effect (days) which renders them suitable for rapid calcitonin, adjustment of plasma calcium, e.g. in hypopara- thyroidism. Such factors are not relevant to the bisphosphonates, bone slower adjustment of plasma calcium (weeks) with vitamins D2 and D3 in the ordinary management of The agents are closely interrelated and will be vitamin D deficiency. discussed together. Actions are complex. Vitamin D promotes the active transport (absorption) of calcium and therefore VITAMIN D of phosphate from the gut, to control, with Vitamin D comprises a number of structurally parathormone, the mineralisation of bone and to 738
TREATMENT OF CALCIUM AND BONE DISORDERS 38 promote the renal tubular reabsorption of calcium calcitriol, are therefore preferred as their rapid onset and phosphate. The plasma calcium concentration and offset of action makes for easier control of rises. After a dose of D2 or D3 there is a lag of about plasma calcium. Supplementary calcium by mouth 21 h before the intestinal effect begins and this is may also be needed. probably due to the time needed for its metabolic Alfacalcidol or calcitriol, but not ergocalciferol, conversion to the more active forms. But with the should be prescribed if patients with severe renal biologically active calcitriol the lag is only 2 h. impairment require vitamin D therapy (see above). A large single dose of vitamin D has biological Calcipotriol and tacalcitol are vitamin D analogues effects for as long as 6 months (because of metabolism available as creams or ointments for the treatment and storage). Thus the agent is cumulative and of psoriasis (p. 313). overdose by a mother anxious that her child shall have strong bones can cause serious toxicity. Symptoms of overdose are due mainly to excessive rise in plasma calcium. General effects include: Indications for vitamin D are the prevention and malaise, drowsiness, nausea, abdominal pain, thirst, cure of rickets of all kinds and osteomalacia, and constipation and loss of appetite. Other long-term the symptomatic treatment of some cases of hypo- effects include ectopic calcification almost anywhere parathyroidism; also psoriasis. in the body, renal damage and an increased calcium Calcitriol is licensed for the management of output in the urine; renal calculi may be formed. It postmenopausal osteoporosis. is dangerous to exceed 10 000 units daily of vitamin In osteomalacia secondary to steatorrhoea or renal D in an adult for more than about 12 weeks. disease there is defective absorption of calcium Vitamin D toxicity may arise from well-meaning, from the gut and large amounts of vitamin D are but needless, administration by parents. The US often needed to enhance absorption. Food and Drug Administration warns that intake of Use of vitamin D as pharmacotherapy should in fortified diet supplements should not exceed 400 general be accompanied by monitoring of plasma units a day. calcium. Patients with sarcoidosis are intolerant of vitamin D possibly even to the tiny amount present in a Dose and preparations (1.0 microgram = 40 units). normal diet, and to that synthesised in their skin by Simple vitamin D deficiency can be prevented by sunlight. The intolerance may be due to over- taking an oral supplement of only 10 micrograms production of calcitriol (see above) by macrophages (400 units) of ergocalciferol daily. Vitamin D deficiency activated by interferon; the overproduction is is not uncommon in Asians consuming unleavened reversed by corticosteroid, which is also used in the bread and in the elderly living alone; it can be pre- treatment of severe hypervitaminosis D (see below). vented by taking an oral supplement of ergocalciferol Epileptic patients taking drugs that are enzyme 20 micrograms (800 units) daily. Vitamin D in inducers can develop osteomalacia (adults) or rickets deficiency caused by intestinal malabsorption or (children). This may be due to enzyme induction chronic liver disease usually requires vitamin D in increasing vitamin D metabolism and causing pharmacological doses, such as ergocalciferol tablets deficiency, or there may be inhibition of one of the up to 1 mg (40 000 units) daily. The maximum hydroxylations that increase biological activity. antirachitic effect of vitamin D is delayed for 1-2 months and the plasma calcium concentration reflects the dosage given days or weeks before. Frequent changes of dose are therefore not required. Treatment of calcium and The hypocalcaemia of hypoparathyroidism may require ergocalciferol in doses up to 2.5 mg bone disorders (100 000 units) daily to achieve normocalcaemia but the dose is difficult to titrate and hypercalcaemia HYPOCALCAEMIA from overdose may take weeks to resolve. The synthetic vitamin D derivatives, alfacalcidol and In acute hypocalcaemia requiring systemic therapy 739
38 VITAMINS, CALCIUM, BONE calcium gluconate inj. is given as a 10% solution, 2-3 days and continued at a rate of 21/day until 10-20 ml at the rate of about 2 ml per min and plasma calcium falls below 3.0 mmol/1 and the followed by a continuous i.v. infusion containing oral intake is adequate. The regimen requires 40 ml (9 mmol) per day with monitoring of plasma careful attention to fluid and electrolyte balance, calcium. It must not be given i.m. as it is painful and including potassium. Furosemide may be added causes necrosis. Calcium glubionate (Calcium Sandoz) to the regimen once salt depletion has been can be given by deep i.m. injection in adults. corrected. For chronic use, e.g. hypoparathyroidism, alfa- • Bisphosphonates (see later). Pamidronate5 is calcidol or calcitriol are needed. Dietary calcium is infused according to the schedule in Table 38.1; it increased by giving calcium gluconate (an effer- is active in a wide variety of hypercalcaemic vescent tablet is available) or lactate. Aluminium disorders. Fall in serum calcium begins in 1-2 d, hydroxide binds phosphate in the gut causing hypo- reaches a nadir in 5-6 d and lasts 20-30 d. phosphataemia, which stimulates renal formation Etidronate may be given i.v. in hypercalcaemia of of the most active vitamin D metabolite and usefully malignant disease. It acts in 1-2 d and a dose enhances calcium absorption. lasts 3-4 weeks; it may also provide benefit for neoplastic metastatic disease in bone. Clodronate Adverse effects of intravenous calcium may be (oral or i.v.) or zoledonic acid (i.v.) are alternatives. very dangerous. An early sign is a tingling feeling • Calcitonin (see below). When the hypercalcaemia in the mouth and of warmth spreading over the is at least partly due to mobilisation from bone, body. Serious effects are those on the heart, which calcitonin can be used to inhibit bone resorption, mimic and synergise with digitalis (fatal cardiac and it may enhance urinary excretion of calcium. arrest may occur in digitalised animals) and it would The effect develops in a few hours, and seem advisable to avoid i.v. calcium in any patient responsiveness may be lost over a few days (but on a digitalis glycoside (except in severe symptomatic may sometimes be restored by an adrenal steroid). hypocalcaemia). The effect of calcium on the heart • An adrenocortical steroid, e.g. prednisolone is antagonised by potassium and similarly the toxic 20-40 mg/d orally, is effective in particular effects of a high serum potassium in acute renal failure situations; it reduces the hypercalcaemia of may be to some extent counteracted with calcium. vitamin D intoxication (which is due to excessive intestinal absorption of calcium) and of sarcoidosis (principally by its disease-modifying HYPERCALCAEMIA effect). Steroid may be effective in the Treatment of severe acute hypercalcaemia causing hypercalcaemia of malignancy where the disease symptoms is needed whether or not the cause can itself is responsive, e.g. myeloma of lymphoma. be removed; generally a plasma concentration of Most patients with hyperparathyroidism do not 3.0 mmol/1 (12 mg/100 ml) needs urgent treatment respond. if there is also clinical evidence of toxicity (individual tolerance varies greatly). TABLE 38.1 Treatment of hypercalcaemia with disodium pamidronate Temporary measures Calcium (mmol/1) Pamidronate (mg) After taking account of the patient's cardiac and 4.0 90 • Physiological saline solution is important, firstly to Infuse slowly, e.g. 30 mg in 250 ml 0.9% saline over I hour. Expect correct sodium and water deficit and secondly to response in 3-5 days. promote sodium-linked calcium diuresis in the proximal renal tubule. Initially, 0.9% saline 5 formerly called arninohydroxypropylidenediphosphonate 500 ml should be given i.v. every 4-6 h for disodium, APD. 740
TREATMENT OF CALCIUM AND BONE DISORDERS 38 • Phosphate i.v. is quickly effective but lowers centration (and fall in phosphate); but, at low doses, calcium by precipitating calcium phosphate in the balance favours bone formation (osteoblast bone and soft tissues and inhibiting osteoclastic activity). activity; it should be used only when other methods have failed. CALCITONIN • Trisodium edetate (therapeutically equivalent to disodium edetate) i.v. chelates calcium and the Calcitonin is a peptide hormone produced by the C inert complex is excreted by glomerular cells of the thyroid gland (in mammals). It acts on filtration. Although it is rapidly effective, it bone (inhibiting osteoclasis) to reduce the rate of causes pain in the limb receiving the infusion bone turnover, and on the kidney to reduce and may cause renal damage. reabsorption of calcium and phosphorus. It is • Dialysis is quick and effective and is likely to be obtained from natural sources (pork, salmon, eel), needed in severe cases or with renal failure. or synthesised. The t1/2 varies according to source; tl/2 human is 10 min. Antibodies develop particularly to The above measures are temporary only, giving pork calcitonin and neutralise its effect; synthetic time to tackle the cause. salmon calcitonin (salcatonin) is therefore preferred for prolonged use; loss of effect may also be due to Long-term use down-regulation of receptors. Calcitonin is used (s.c., i.m. or intranasally) to control hypercalcaemia To bind dietary calcium in the gut sodium cellulose (rapid effect), Paget's disease of bone (relief of pain, phosphate (Calcisorb) is an oral ion exchange substance and to relieve compression of nerves, e.g. auditory with a particular affinity for calcium. Bound calcium cranial), metastatic bone cancer pain, and post- is eliminated in the faeces. It is used particularly for menopausal osteoporosis. patients who overabsorb dietary calcium and who develop hypercalciuria and renal stones. Adverse effects include allergy, nausea, flushing Inorganic phosphate, e.g. sodium acid phosphate and tingling of the face and hands. (Phosphate Sandoz) taken orally also binds calcium in the gut. BISPHOSPHONATES HYPERCALCIURIA Bisphosphonates are synthetic, nonhydrolysable analogues of pyrophosphate in which the central In renal stone formers, in addition to general oxygen atom of the -P-O-P- structure is replaced measures (low calcium diet, high fluid intake), with a carbon atom to give the -P-C-P- group. urinary calcium may be diminished by a thiazide diuretic (with or without citrate to bind calcium) Actions. These compounds are effective calcium and oral phosphate (see above). See also chelators that rapidly target exposed bone mineral Nephrolithiasis (p. 543). surfaces in vivo, where they can be released by bone- resorbing osteoclasts, resulting in inhibition of osteoclast function and osteoclast apoptosis. The PARATHYROID HORMONE bisphosphonates (alendronate, clodronate, etidronate, Parathyroid hormone acts chiefly on kidney increasing pamidronate, risedronate, tiludronate and zoledronate) renal tubular resorption and bone resorption of inhibit the activation and function of osteoclasts and calcium; it increases calcium absorption from the possibly directly stimulate formation of bone by the gut, indirectly, by stimulating the renal synthesis of osteoblasts. They also bind strongly to hydrox- la-25-dihydroxycholecalciferol (see Vitamin D). It yapatite crystals and, in high doses, can inhibit the increases the rate of bone remodelling (mineral and mineralisation of bone. The doses at which effects on collagen) and osteocyte activity with, at high doses, mineralisation occur are not related to antiresorptive an overall balance in favour of resorption (osteoclast efficacy. There is wide variation between these activity) with a rise in plasma calcium con- compounds in terms of their capacity to inhibit 741
38 VITAMINS, CALCIUM, BONE U resorption relative to that of inhibiting mineralisation. density measurements. It occurs most commonly in Etidronate, for instance, must be administered postmenopausal women and patients taking cor- cyclically to prevent demineralisation whereas ticosteroid long-term. Underlying causes such as alendronate, more recently available, does not appear hyperthyroidism, hyperparathyroidism and hypo- to interfere with mineralisation at antiresorptive gonadism (in both sexes) should be excluded before doses and can be used continously. treatment is initiated. People at risk of osteoporosis, e.g. elderly Pharmacokinetics. Bisphosphonates are poorly housebound persons, must maintain an adequate absorbed after oral ingestion. Absorption is further intake of calcium and vitamin D. Calcium dietary impaired by food, drinks and drugs containing supplementation (Ca gluconate, carbonate, hyd- calcium, magnesium, iron or aluminium salts. A roxyapatite, citrate, maleate) reduces nett bone loss proportion of bisphosphonate that is absorbed is where intake may be inadequate, i.e. below 800 rapidly incorporated into bone; the remaining mg/d, and ergocalciferol 10 micrograms (400 units) fraction is excreted unchanged by the kidneys. by mouth corrects dietary vitamin D deficiency. Once incorporated into the skeleton, bisphosphonates Postmenopausal osteoporosis is due to gonadal are released only when the bone is resorbed during deficiency; it can be prevented. One in 4 women in turnover. They may be given orally or i.v. her 60s and one in 2 in her 70s in the UK experiences an osteoporotic fracture. Uses. Three bisphosphonates (alendronate, etidronate, • Oestrogen arrests the process by reducing bone risedronate) are currently licensed in the UK for the resorption. treatment of osteoporosis (zoledronate is also • Progestogen arrests the process by increasing effective), and the others are used in Paget's disease bone formation, but therapeutic benefit is less of bone, and hypercalcaemia due to cancer than with oestrogen. (pamidronate, clodronate, zoledronate). Bisphos- phonates may also provide benefit for neoplastic Oestrogen inhibits the age-related loss of bone disease that has spread to bone; evidence indicates that occurs in most women after menopause. that clodronate by mouth and pamidronate i.v. are Observational studies have indicated that the use of effective in the secondary prevention of bone oestrogen reduces the risk of vertebral fracture by metastases due to multiple myeloma and breast approximately 50% and the risk of hip fracture by cancer. 25-30%. Unopposed oestrogen increases by 10-fold the risk of endometrial cancer, which is diminished Adverse effects include gastrointestinal disturb- by added progestogen. Therefore combinations of ances, with oesophageal irritation being a particular oestrogen and progestogen are the mainstay of problem with alendronate. This should be given at treatment for postmenopausal osteoporosis; they least 30 minutes before food, with the patient inhibit the rapid bone loss that occurs immediately remaining erect during this period. Alendronate after the menopause and should be continued for 5 can be taken weekly (70 mg) instead of daily years. (10 mg). Disturbances of calcium and mineral Longer-term use is more problematic, given the metabolism (e.g. vitamin D deficiency, parathyroid probable increase (though < 2-fold) in the risk of hormone dysfunction) should be corrected before breast cancer associated with extended use. starting a bisphosphonate. Increased bone pain (as Reasonable candidates are the small proportion of well as relief), fractures (high dose, prolonged use postmenopausal women with documented osteo- only) can occur due to demineralisation of bone. porosis or osteopenia (decreased bone density) or those at increased risk for osteoporosis (personal or family history of nontraumatic fracture, current OSTEOPOROSIS smokers, or those with a body-mass index < 22) Osteoporosis is an abnormal decrease in amount of who do not have a personal or family history of bone, but what is there is of normal quality. Low breast cancer or other contraindications and who are bone mass is reflected in reduced bone mineral willing to try this therapy. With more long-term 742
TREATMENT OF CALCIUM AND BONE D I S O R D E R S 38 evidence, raloxifene 60 mg daily where affordable TABLE 38.2 Anti-fracture efficacy of interventions in will become an attractive option. This selective post menopausal osteoporotic women: grades of oestrogen receptor agonist can be used unopposed recommendation without apparent increase in risk of breast or Spine Nonvertebral Hip endometrial cancer. Alendronate A A A Bisphosphonates increase bone mineral density in Calcitonin A B A osteoporosis. Calcitriol A A ND Calcium A B B A schema for the prevention of osteoporosis with Calcium plus vitamin D ND A A HRT beyond 5 years, or other options, appears in Cyclical etidronate A B B Figure 38.1 Hip protectors A HRT A A B Physical exercise ND B B Treatment of osteoporosis. It is usual to start with Raloxifene A ND ND HRT or a bisphosphonate and, if these are unsuitable, Risedronate A A A Tibolone ND ND ND calcitriol, calcitonin or raloxifene may be used. Vitamin D ND B B Calcitonin, additionally, is effective for relief of pain for up to 3 months after vertebral fracture where Grade A, meta-analysis of randomised, controlled trials or from at other analgesics fail. least one randomised, controlled trial, or from at least one well designed, controlled study without randomisation; grade B, from at Fracture is the only important outcome of least one other type of well designed, quasi-experimental study, or osteoporosis and the evidence to support the efficacy from well designed, nonexperimental studies (e.g. comparative of various interventions appears in Table 38.2. studies, correlation studies, case-control studies); grade C, from expert committee reports/opinions and/or clinical experience of authorities. ND, not demonstrated. Data from the Royal College of Corticosteroid-induced osteoporosis. The greatest Physicians and the Bone and Tooth Society. rate of bone loss occurs during the first 6-12 months of corticosteroid use. Patients taking the equivalent of prednisolone 7.5 mg or more each day for 3 months or longer should be considered for prophylactic treatment, and this is mandatory in those over 65 years. Treatment for osteoporosis should be given when a patient taking a cor- ticosteroid sustains a low-trauma fracture. Long- term use of inhaled corticosteroids may reduce bone mineral density and place patients at risk. The treatment options for both the prophylaxis and treatment are: hormone replacement (HRT in women, testosterone in men), a bisphosphonate and calcitriol. OSTEOMALACIA Osteomalacia is due to primary or secondary vitamin D deficiency. In secondary cases, e.g. malabsorption or renal disease, high doses of vitamin D are sometimes needed. Long-term therapy with some Fig. 38.1 The prevention of osteoporosis.With permission from J Manson, Harvard Medical School and the New England Journal of antiepilepsy drugs may cause osteomalacia see Medicine Vitamin D). 743
38 VITAMINS, CALCIUM, BONE PAGET'S DISEASE OF BONE GUIDETO FURTHER READING This disease is characterised by bone resorption and Bates C J 1995 Vitamin A. Lancet 345: 31-35 formation (bone turnover) being increased as much Bushinsky D A, Monk R D 1998 Calcium. Lancet as 50 times normal, the results of which are large, 352:306-311 vascular, deformed, painful bones which fracture. Cooper C, Eastell R 1993 Bone gain and loss in Bisphosphonates (etidronate, pamidronate, til- premenopausal women. British Medical Journal udronate) are effective because of their inhibition of 306:1357-1358 crystal formation, growth and dissolution, such as Delmas P D, Meunier P J 1997 The management of must occur in bone mineralisation and Paget's disease of bone. New England Journal of demineralisation. The response is dose-related and Medicine 336: 558-566. remission after a course may last up to two years. Editorial 1962 Arctic offal. British Medical Journal Calcition (which inhibits bone resorption) has been 1:855 largely superseded by the bisphosphonates but is Eastell R 1998 Treatment of postmenopausal useful to reduce bone blood flow before operation. osteoporosis. New England Journal of Medicine 338: 736-746. Eraser D R 1995 Vitamin D. Lancet 345:104-107 Greenberg E R, Sporn M B 1996 Antioxidant vitamins, Vitamin E: tocopherol cancer and cardiovascular disease. New England Journal of Medicine 334:1198-1190 The functions of vitamin E may be to take up Humphrey J H, Rice A L 2000 Vitamin A (scavenge) the free radicals generated by normal supplementation in young infants. Lancet metabolic process and by substances in the environ- 356:422-424 ment, e.g. hydrocarbons, and so to prevent them Manolagas S C et al 1995 Bone marrow, cytokines, and attacking polyunsaturated fats in cell membranes bone remodeling. New England Journal of with resultant cellular injury. A deficiency syndrome Medicine 332: 305-311 is now recognised, including peripheral neuropathy Manson J E, Martin K A 2001 Postmenopausal with spinocerebellar degeneration; and a haemolytic Hormone-Replacement Therapy. New England anaemia in premature infants. Journal of Medicine 345: 3 4 - 0 Alpha tocopheryl acetate (Ephynal) pharmaco- Meydani M 1995 Vitamin E. Lancet 345: 170-175 therapy may benefit the neuromuscular complications Relston S H 1992 Medical management of of congential cholestasis and abetalipoproteinaemia. hypercalcaemia. British Journal of Clinical Pharmacology 34:11-20 Seeman E 2002 Pathogenesis of bone fragility in women and men. Lancet 359:1841-1850 Vitamin K Spector T D, Sambrook P N 1993 Steroid osteoporosis. British Medical Journal 307: 519-520 see page 568. Willett W C, Stampfer M J 2001 What vitamins should I be taking, doctor? New England Journal of Medicine 345:1819-1824 744
Index Abbreviations; COPD, chronic Acetylation reactions, 113 Acidity, see pH obstructive pulmonary disease; MI, slow acetylator status, 123 Acidosis, metabolic, see Ketoacidosis; myocardial infarction. Acetylcholine, 434, 435 Lactic acidosis; Metabolic Alzheimer's disease and, 407-8 acidosis drugs opposing, 441 Acipimox, 527 Parkinson's disease and, 422 Acitretin, 736 Acetylcholine receptors psoriasis, 313, 736 A-delta fibres and nociception, 320 (cholinoceptors), 433 Acne, 308, 313-14, 714, 725 Abacavir, 260 agonists, 433-4 retinoids, 313-14, 736 Abbreviations antagonists Acrivastine, 555 prescriptions, 33, 34 CNS action, see Antimuscarinics Acromegaly, 711 weights and measures, 33, 34 as muscle relaxants, 356 Acrosoxacin, 233 Abciximab, 486, 587 muscarinic, see Muscarinic ACh ACTH, see Corticotrophin Abdominal paracentesis, ascites, 656 receptor Actinic keratoses, 311 Abortifacients, 629-30, 720-5, 732 nicotinic, see Nicotinic ACh Actinomycetes and actinomycosis, 254 Abscesses, 254 receptors antibiotic choice, 212 pulmonary, 241 Acetylcholinesterase (AChE; true Action (of drugs) Absence seizures, 418 cholinesterase), 124, 436 mode/mechanism of, 90-3 Absorption inhibition classification by, 83 cutaneous, see Skin; Topical route by drugs, see new drugs and knowledge of, GI tract, 104-5 Anticholinesterases 47 children, 125 by organophosphates, 92 prolonging, methods, 118 in disease, 128 reactivating drugs, 438 unwanted, see Adverse/unwanted elderly, 126 Acetylcysteine, 154 effects interactions at site of, 131 paracetamol overdose, 288 see also Interactions poisons, prevention, 152-3 Acetylsalicylic acid, see Aspirin Action potential, cardiac cells, 498, 499 pregnancy, 127 Achalasia, 633 antiarrhythmics (class III) reducing time, 118 Aciclovir, 257-8 prolonging, 499, 501, 503-4 zero-order, 101 adverse effects, 258 class I antiarrhythmics altering see also Malabsorption; monitoring for, 309 duration, 499, 500-2 Reabsorption herpes simplex virus, 258 Activated partial thromboplastin time, Abstinence syndrome, see Withdrawal topical, 258, 315 568 syndrome varicella-zoster virus, 258 Active transport, see Transport Abused drugs, see Substance misuse Acid(s), gastric, see Gastric acid Activity, biological, metabolism Acamprosate, 186 Acid-base balance, 539 altering, 112 Acarbose, 688, 689 disturbances, 539 Acyclovir, see Aciclovir ACE inhibitors, see aspirin-related, 289-90, 290 Addiction, 166 Angiotensin-converting essential drugs (WHO list) in, see also Dependence enzyme inhibitors 32 Addisonian anaemia, see Anaemia, Acenocoumarol, 573 see also pH pernicious Acetaminophen, see Paracetamol Acid-fast bacterial infections, see Addisonian crisis, 671 Acetazolamide, 539 Leprosy; Tuberculosis Addison's disease (chronic Acetic acids (NSAIDs), 286 Acidification, urinary, 540 adrenocortical insufficiency), adverse effects, 285-6 in poisoning, 156 663, 671, 671-4 745
INDEX Additive effects (drug interaction), 130 in hypercalcaemia, 740 breast-feeding and, 116 Adenosine, 506 in inflammatory bowel disease, classification, 476-7 adverse effects, 506 645, 646 interactions, 132, 466, 479-80, 503, antiarrhythmic action, 501, 506, in prostatic cancer, 617 504, 692 508, 510 in rheumatic fever, 295 overdose, 479 see also ADP; AMP in rheumatoid arthritis, 294 as partial agonists, 475, 477 Adenylate/adenylyl cyclase topical, see subheading above pharmacodynamics, 476, 480 p-adrenoceptors and, 91,448 in tuberculosis, 251 pharmacokinetics, 476, 503 platelet, 582 withdrawal, see Withdrawal in pregnancy, 480, 492 ADH, see Antidiuretic hormone Adrenal virilism, 672 selectivity, 475-6 Adherence, see Compliance Adrenaline (epinephrine), 447, 450, sexual intercourse and, 493 Adjuvant analgesics, 319 452-3 uses, 477 palliative care, 331 drugs blocking (3-adrenoceptor angina, 484, 486 Adjuvant therapy (cancer), 604 effects, 474 arrhythmias, 499, 501, 502-3, chemotherapy, 604 drugs depleting stores, 482 506 endocrine therapy, 617 glucose-elevating effects, 686 heart failure, 475,477, 516, 517 Administration, routes of, see Routes overdose, 453 hypertension, 477, 489, 491, 492, of administration phaeochromocytomas secreting, 494, 495 ADP and platelets, 581 495 hyperthyroidism, 477, 703 Adrenal gland, see uses, 452-3 MI, 477, 485, 486 Hypothalamic-pituitary- allergy (severe incl. migraine prophylaxis, 328,477 adrenal axis and entries anaphylactic shock), 143, phaeochromocytoma, 494, 495 under Adrenocortical 452-3, 558 varices, 656 Adrenal neuron blockade, 481 haemostasis, 584 P-Adrenoceptor agonists, 450 Adrenal steroids (corticosteroids - with local anaesthetics, 359 P-Adrenoceptor antagonists/blockers, commonly called shock, 457 477, 480 glucocorticoids), 294, 303-5, Adrenergic mechanisms, 447 P-Adrenoceptor agonists, 450 663-75 complexity, 448-50 asthma, 450, 558, 560, 562 actions (and mechanism of action), Adrenoceptor(s), 448 overuse, 564 280, 664, 664-5 activation, consequences, 448 hypokalaemic effects, 451 glucocorticoid / anti- selectivity of drugs for, 450-2 in premature labour, 450, 451, 686, inflammatory, see Adrenoceptor agonists (in general), 732 Anti-inflammatory effects 447-8 as uterine relaxants, 450, 732 immunosuppressive effects, see Adrenoceptor antagonists /blockers Adrenocortical function, steroids Immunosuppression (in general), 472-81 suppressing, 672 in insulin, 687 -Adrenoceptor(s), 448 Adrenocortical insufficiency, 671-2 mineralocorticoid, 664, 665 agonists, 450 acute, 671 adverse effects, 667-8, 670-1 effects, 449 chronic (Addison's disease), 663, osteoporosis, 668, 743 -Adrenoceptor antagonists/blockers, 672, 672-3 topical preparations, 304-5 472-4 chronic secondary, 672 analgesic effects, 323 phaeochromocytoma, 494, 495 Adrenocorticotrophic hormone, see chronic use (and precautions), -Adrenoceptor agonists, 450 Corticotrophin 669-70 effects, 449 Adrenogenital syndrome, 672 children, 670-1 -Adrenoceptor Adsorbent agents, poisoning, 152-3 contraindications, 670 antagonists/blockers, 472, Advanced cardiac life support, 514 dosage, 670 472-3, 473 Ad verse/unwanted effects schedules, 667 benign prostatic hyperplasia, 544 (toxicity / side-effects / essential (WHO list), 31 -Adrenoceptor agonists, CNS harmful effects), 5,135-50 interactions with anaesthetics, 362 effects, 450, 482-3 capacity for, 11 pharmacokinetics, 667 - Adrenoceptor cause/causation, 136-7,139-42 in pregnancy, 669 antagonists/blockers, 472 classification, 138-9 routes of administration, 670 p-Adrenoceptor(s), 448 type A (augmented) effects, 139, topical, see subheading below p-Adrenoceptor agonists, 450 653 synthesis, inhibition, 675 in beta-blocker overdose, 479 type B (bizarre) effects, 139, 658 synthetic analogues, 666-7 effects, 449 type C (chronic) effects, 139, 658 topical (for skin conditions), 303-5, in hyperkalaemia, 537 type D (delayed) effects, 139 667, 670, 674 P-Adrenoceptor antagonists/blockers, type E (ending of use) effects, adverse effects, 304-5 474-81 see Discontinuation pruritus, 302 action and effects, 474-5 syndrome psoriasis, 309-13 hyperkalaemic, 451-2 cutaneous, see Skin uses, 664, 671-4 peripheral vascular, 472, 474 definitions, 136 in anaphylactic shock, 143-4 adverse effects, 478-9, 501 dose-response curves and, 94, 95 in asthma, 557, 561, 562 asthma precipitation, 128, 478, drug interactions causing, 129 in COPD, 563 564 minimisation with fixed-dose drug in hay fever, 556 anaesthesia and, 363 combinations, 119 746
INDEX monitoring for, 309 in poisoning, 156 as antacid, 626, 627 recognition and diagnosis, 136-7 Alkalinity, see pH in hypocalcaemia, 740 rare effects, 138 Alkaloids Aluminium silicate, 153 see also reporting (subheading cholinergic, 434, 436, 437 Alveolar concentration, minimal, below) ergot, see Ergot alkaloids and anaesthetics, 349 reporting, 77 derivatives Alzheimer's disease, 407-8, 437 voluntary, 69-70, 74, 77 plant, 609 Amanita muscaria, 436 see also Pharmacovigilance Alkalosis, respiratory, see Respiratory Amantadine specific cell injury, 121 alkalosis influenza, 261 see also Carcinogenicity; Alkylating agents (and related drugs), Parkinson's disease, 426, 427 Hypersensitivity reactions; 605, 606-8 Amblyopia, tobacco, 594 Mutagenicity; Poisoning; polycythaemia rubra vera, 600 Ambulatory blood pressure Risk; Safety; Teratogen; Allergens monitoring, 490 Toxicology and specific drugs in asthma causation, 556-7 Amenorrhoea, 729 Aerosol formulations, 108 preventing exposure, 557 American trypanosomiasis (Chagas' asthma, 560 desensitisation, see Desensitisation disease), 275 Aerosol sprays, volatile, 302 treatment essential drugs (WHO list), 29 Affective disorders, see Mood Allergic interstitial nephritis, 541 Amethocaine (tetracaine), 302, 359 disorders Allergic vasculitis, 308 Amfebutamone, 177, 372 Affinity, albumin for drugs, 111 Allergy, 142-5, 553-6 Amide compounds, local anaesthetic, see also Binding adrenal steroids in, 665, 674 260-1, 359 African trypanosomiasis (sleeping drug choice, 657 Amikacin, 225 sickness), 275 contact, see Contact allergy Amiloride, 490,532, 535 essential drugs (WHO list), 29 to drugs, 142-5 [gamma]-Aminobutyric acid, see Afterload, 510 aspirin, 289 GABA drugs reducing, 462,484 cephalosporin, 221 Aminoglutethamide, 617, 675 Age clinical manifestations, 143-5 adverse effects, 614 drug abuse and, 168 corticosteroids, 304-5 Aminoglycosides, 215, 223-5 effects (on response), 125-6 cross-allergy, see Cross-allergy adverse effects, 224-5 adverse reactions, 139 diagnosis, 145 interactions, 132 Agonists, 91 distinctive features, 143 neuromuscular blocking agents, inverse, 91 insulin (or to added 362 partial, 91 components), 683, 685 mode of action, 223-4 surmountable, 92 penicillin, 217, 221 pharmacokinetics, 224 see also specific receptors photoallergy, 306 range of activity and uses, 224 AIDS, see HIV prevention, 145-6 5-Aminolaevulinic acid synthase, 140 AIRE study, 487 sulphonamides, 232 Aminophylline, 195 Airways thrombolytics, 580 uses, 195 chronic/persistent inflammation in treatment, 143-5,145 asthma, 195, 558, 562 asthma, 556 essential drug used in (WHO list), beta-blocker overdose, 479 reduction, 557-8, 561 28 heart failure, 518 maintenance, poisoning, 157 severe, adrenaline use, 143, 452-3 respiratory stimulation, 552 resistance increase, smokers, 174-5 see also Hypersensitivity reactions Aminoquinolones see also Respiratory tract Allopurinol, 296 4-aminoquinolones, 269 Akathisia, 386 adverse effects, 296 8-aminoquinolones, 269 Albendazole, 276 interactions, 133, 292 interactions, 285 Albumin uses 5-Aminosalicylic acid, 645-6 binding to, 111 nephrolithiasis, 543 alone, see Mesalazine low levels (hypoalbuminaemia), in tumour lysis syndrome in Crohn's disease, 647 disease states, 111, 128, 652 prevention, 541 dimer of, see Olsalazine Alcohol, see Ethanol; Methanol uses gout, 296, 297 prodrug, see Balsalazide Alcohol dehydrogenase, 179 Allylamine, 267 sulfapyridine and, see Sulfasalazine Aldosterone, 666 Alomifene (clomiphene), 719 in ulcerative colitis, 645-6 antagonist, see Spironolactone Alopecia, see Hair loss Amiodarone, 501, 503-4, 510 elevated, see also Alpha-adrenoceptors /receptors and adverse effects, 503 Hyperaldosteronism blockers, see Adrenoceptors atrial fibrillation, 508 Alendronate, 741, 742 Alprazolam, panic disorder, 393 interactions, 503-4 Alfacalcidol, 738, 739, 740 Alprostadil, 281, 471 pharmacokinetics, 503 Alfentanil, 342 erectile dysfunction, 471, 545 Amitriptyline Alfuzosin, 473 Alteplase, see Tissue plasminogen mode of use, 373 Alginic acid, 627 activator overdose, 376 Alimentary tract, see Gastrointestinal Altitude sickness, 539, 673 therapeutic efficacy, 373 tract Aluminium-containing antacids, use (other than depression) Alimenzamine, 555 626-7, 627 antispasmodic, 649 Alkalinisation, urinary, 540 Aluminium hydroxide neuralgia, 325 747
INDEX Amlodipine, 466 Anaesthesia, local, 358-62 Androgen-dependent carcinoma, 718 Ammonia and hepatic dental procedures using, Angina/anginal pain, 462-84 encephalopathy, 656-7 chemoprophylaxis, 243 drugs, see Antianginal drugs Ammonium chloride, 540 local anaesthetics, 302, 358-62 sexual intercourse and, 493 Amnesia adrenaline with, 359, 452 unstable, 484, 486, 576 anterograde, 348 adverse effects, 360 variant/Prinzmetal, 484 premedication-induced, 346-7 as antitussives, 550 Angioedema, 314 Amoebiasis (E. histolytica), 275-6 desired properties, 358 drug-induced, 143, 308,469 essential drugs (WHO list), 29 essential (WHO list), 28 hereditary, 314, 715 Amotivational state, see Motivation mode of action, 358 Angiogenesis inhibitors, 618 Amoxicillin (amoxycillin), 219 peri-/postoperative use, 347 Angiotensin II, 467 clavulanic acid and, see pharmacokinetics, 358 Angiotensin II receptor antagonists Co-amoxiclav topical effect, 358-9, 361 (=AT1-receptor blockers), H. pylori, 630 Anagrelide, 600 467-9 cAMP (cyclic AMP) Anal problems, see Anus adverse effects, 469, 493 p-adrenoceptors and, 91, 448 Analeptics, see Central nervous system individual drugs, 469 platelets and, 581-2 stimulants; Respiratory interactions, 285 Amphetamines (amphetamine and stimulants in pregnancy, 492 related drugs), 193-4, 454-5 Analgesia, 319-43 uses, 467-8 dependence, 169, 193 mechanisms, 322-3 heart failure, 468 in mixtures with barbiturates, opioid addict, 171, 343 hypertension, 467-8, 489, 490, 170 patient-controlled, 328-9 492 msuse, postoperative, 348 MI, 468, 486 pharmacokinetics, 193 preoperative, 347 Angiotensin-converting enzyme poisoning/overdose, 193—1 Analgesic drugs, 319—13 (ACE) inhibitors, 467-9 therapeutic use adjuvant, see Adjuvant analgesics cautions and adverse effects, attention deficit/hyperactivity anticoagulants interacting with, 468-9, 493 disorder, 409 572 individual drugs, 469 narcolepsy, 405-6 choice and ranking interactions, 285, 469, 537 Amphotericin B, 264-5 (mild / moderate / severe / uses, 467-8 Ampicillin, 219-20 overwhelming pain), 324-5 diabetic nephropathy, 695 adverse effects, 219-20 clinical evaluation, 323-4 heart failure, 468, 488, 514, Amputation, chemoprophylaxis, 208 combining, 324 515-6, 516 Amylobarbitone, 385 definition, 319 hypertension, 467-8, 489 Anabolic effects of androgens, 713, 715 mechanisms of action, 322-3 MI, 486 Anabolic steroids, 715-6 essential (WHO list), 28 Animals abuse, 172-3, 715 in liver disease, 653 as disease models, 45 Anaemia narcotic, see Opioids preclinical studies, 45-7 aplastic, see Aplastic anaemia new, 323 transgenic, 44 essential drugs (WHO list), 30 NSAIDs as, 283, 322-3 Anion-exchange (bile acid-binding) haemolytic, see Haemolysis pancreatitis (acute), 659 resins, 523, 526-7 pernicious/Addisonian, 593, 594 topical, 302 Anistreplase, see APSAC iron therapy, 589 Analgesic nephropathy, 284, 540, 541 Ankle jerk relation time, P2-blockers, in pregnancy, 596 Anaphylactoid reactions, 146, 553 476 sickle-cell, 364, 599 local anaesthetics, 360 Anorectic drugs, see Weight-reducing Anaerobic microbes, pneumonia due muscle relaxants, 358 drugs to, 241 Anaphylaxis (anaphylactic reactions; Anorexia in palliative care, 331 Anaesthesia, 345-65 type I hypersensitivity), 142, Antacids, 626, 626-7 disease and, 363^1 143 adverse effects, 627 dissociative, 348, 353 anaphylactic shock, 143, 453, 554 in liver disease, 653 interactions with other drugs, 362-3 drug-induced, 143, 308 gastro-oesophageal reflux, 632 surgical, see Surgical anaesthesia muscle relaxants, 358 magnesium-containing, 626, 627, Anaesthesia, general, 345-55 essential drugs (WHO list), 28 645 Caesarean section, 362 mimicking reactions, see peptic ulcers, 626, 626-7 dental procedures using, Anaphylactoid reactions Antagonism, 130 chemoprophylaxis, 243 Ancylostoma spp., 277 antimicrobial combinations, 207 general anaesthetics, 346-8 Androgen(s), 713-4 competitive, 92 assessment, 349 adrenal, suppressing secretion, 672 insurmountable, 92 choice /available forms, 346-8 adverse effects, 714 physiological/functional, 92,130 essential (WHO list), 28 anabolic effects, 713, 715 sympathomimetics-anti- mode of action, 348 see also Anabolic steroids hypertensives, 492 uses, 359 antagonists (antiandrogens), 617, Antagonists, 91 history, 345-6 714-5 see also specific receptors stages of, 346 uses, 713-4 Anthelmintic drugs, 233, 276-7 vomiting after, 348, 636 see also Anabolic steroids essential (WHO list), 29 748
INDEX Anthraquinone laxatives, 641 see also Autoantibodies; overdose, 376 Antiandrogens, 617, 714-5 Immunoglobulins; pharmacokinetics, 372-3 Antianginal drugs, 462-84 Monoclonal antibodies selection, 373 essential drugs (WHO list), 30 Antibody-dependent cytotoxic (type tricyclic, see Tricyclic mode of action, 462 II) hypersensitivity, 142 antidepressants Antiangiogenic agents, 618 drug-induced, 143, 144,145 Antidiabetic drugs (oral), 687-9 Antiarrhythmic drugs, 477 mimicking reactions, 146 adverse effects /precautions, 688-9 classification, 498-500 Anticancer drugs, see Chemotherapy, essential (WHO list), 31 class I, 499, 500-1 cytotoxic interactions, 285, 692-3 class II, 499, 501, 502-3 Anticholinergics, see Antimuscarinics Antidiarrhoeal drugs, 643-4 class III, 499-500, 501, 503-1 Anticholinesterases (cholinesterase essential (WHO list), 31 class IV, 500, 501, 504 inhibitors), 434, 436-9 Antidiuretic effects of opioids, 334 essential (WHO list), 30 Alzheimer's disease, 407-8, 437 Antidiuretic hormone (ADH; interactions essential (WHO list), 32 vasopressin), 532, 711-2 with other antiarrhythmics, 480 interactions, 362 syndrome of inappropriate with warfarin, 572 poisoning, 92, 160, 437-9 secretion, 226, 535, 713 objectives with, 497-8 reversing neuromuscular blocking varices, 655 proarrhythmic effects, 502, 507 agent effects, 356, 356-7 Antidiuretic hormone analogues Antiasthma drugs, 195,450,454,557-63 Anticoagulants, 570-8 local anaesthetic action prolonged in breast milk, 116 adverse effects, 541 by, 359 essential drugs (WHO list), 32 contraindications, 577 uses, 712 inhaled, see Inhalation essential (WHO list), 30 diabetes insipidus, 712 Antibacterial drugs (commonly called indirect-acting, see Oral varices, 655 antibiotics), 215-55 anticoagulants von Willebrand's disease, 585 asthmatics, chest infections, 561-2 injectable, see Heparin Antidotes, 153-5 choice, 211-13 liver disease altering effects, 651 essential (WHO list), 29 classification, 202-3 long-term prophylaxis, 576-7 nerve gas, 438 in Crohn's disease, 647 new, 577-8 Antidysrhythmic drugs, see diarrhoea (and uses, 575-8 Antiarrhythmic drugs pseudomembranous colitis) Anticonvulsants, see Antiepileptics Antiemetic drugs, 334, 633-6 with, 210, 217, 228, 644-5 Antidepressants, 368-80, 410 antimuscarinics as, 442, 634, 636 in diarrhoea, see Diarrhoea adverse effects, 375-7, 395 cannabinoids as, 191, 635 essential (WHO list), 29 augmentation with another drug, in chemotherapy, 611 first and alternative choice, 211-13 374-5, 390 postoperative, 348 H. pylori eradication, 630-1 breast-feeding and, 116 Antiepileptics (anticonvulsants), historical aspects, 202 changing and stopping, 374 413-22 interactions classes, 368 anaesthesia and, 363 with anaesthetics, 362 novel/new, see subheading below blood concentration, monitoring, with oral contraceptives, 728 see also specific classes 415 in malaria, 269 essential (WHO list), 32 breast-feeding and, 116 mode of action, 215-34 historical development, 368-9 children, 416-17, 418 classification by, 203, 215-16 indications (other than dosage and administration, 414-15 nephrotoxicity, 540 depression), 375,410 essential (WHO list), 29 neuromuscular adverse effects, 441 antispasmodic, 649 first line, 414 reference data on drugs of choice, attention deficit/hyperactivity interactions 211-13 disorder, 409 with alcohol, 188 resistance to, 124, 209-10 generalised anxiety disorder, with antidepressants, 377-8, alternatives in, 229-30 396, 397 378 animals feed use implicated, hypersomnia, 406 with folate, 597 142 insomnia, 405 with NSAIDs, 285 gentamicin, 224 migraine prophylaxis, 328 with oral contraceptives, 416, H. pylori, 630-1 neuralgias, 325 727-8 mechanisms, 209-10 palliative care, 331 with warfarin, 572 mycobacteria (incl. panic disorder, 393, 394 mode of action, 413-14 tuberculosis), 250 social anxiety, 395 in pregnancy, 415-16 skin infections, 314 interactions, 363, 377-80, 572 second line, 414, 539 vancomycin, 223 between antidepressants, 379 uses (other than seizures) topical (for skin infections) mechanisms of action, 369-71 bipolar affective disorder, 391 in acne, 313 classification based on, 368 neuralgias, 325, 326, 419 secondary infections, 309 mode of use, 373-4 vitamin D deficiency with, 114, Antibiotics novel/new, 368, 369, 370 739, 743-4 cytotoxic, 608 adverse effects, 377 withdrawal, 415 for infections, see Antibacterial available drugs, 369 Antifibrinolytics, 578, 580, 729 drugs; Antifungal drugs etc. mode of action, 370 Antifolates, see Folic acid/folate Antibody, insulin, 683 mode of use, 374 antagonists 749
INDEX Antifungal drugs, 233, 263-7 development, 201 essential (WHO list), 30 classification, 264 interactions, 272 Antipseudomonal penicillins, 220-1 cutaneous infections, 30, 315 in malaria, 267-75 Antipsychotic drugs essential (WHO list), 29, 30 in acute attack, 269-70 (antischizophrenic / interactions, 285 essential (WHO list), 29 neuroleptic drugs; major Antihelminthic drugs, see prophylactic, 29, 269, 271-2 tranquillisers), 380-9,410 Anthelmintic drugs resistance, 269 adverse effects, 385-8, 654 Antihistamines (conventional term), in pregnancy, 272 Parkinsonism, 385-6, 423, 428 see Histamine H1 receptor in rheumatoid arthritis, 293 atypical, 381, 387-8 antagonists Antimetabolites, 605, 608 classical vs, 388-9 Antihypertensive drugs, 462-83 Antimicrobials, see Anti-infective mode of action, 382-3 aim of treatment, 487-8 drugs breast-feeding and, 116 anaesthesia and, 363 Antimitotic agents classical, 381 diuretics, see Diuretics in psoriasis, 309 atypical vs, 388-9 essential (WHO list), 30 topical corticosteroids as, 303 development, 380-1 interactions, 492 Antimony compounds, pentavalent, elderly, intolerance, 127 antidepressants, 378 276 essential (WHO list), 32 NSAIDs, 285, 492 Antimotility drugs, 643-4 interactions, 469 with other antihypertensive opioids as, 131, 342, 643-4 with SSRIs, 378 drugs, 480 Antimuscarinics (anticholinergics; mode of action, 381-3 mode of action, 461 muscarinic ACh receptor mode of use, 384-5 phaeochromocytoma, 494-5 antagonists), 427, 433, 441-4 P450 enzymes and, 372 problems with, 209-13 antipsychotics acting as, 386, 388 pharmacokinetics, 383 adverse effects, 488,492 dose, 444 uses / indications resistance, see Resistance extrapyramidal effects of attention deficit/hyperactivity threshold and targets for antipsychotics treated with, disorder, 409 treatment, 488 386 insomnia, 405 tolerance, 120 pharmacokinetics, 443-4 psychoses, 381 Antihypertensive therapy, non-drug, poisoning by, 444 Antipyretic drugs, NSAIDs as, 283 488 poisons acting as (antimuscarinic Antiretroviral drugs, 258, 259-61 Anti-infective drugs/antimicrobials/ syndrome), 158,161 Antirheumatoid drugs, essential chemotherapy (in general), tricyclic antidepressants acting as, (WHO list), 28 201-14 375, 376, 377 Antisense strategies, 44 breast-feeding and, 116 unwanted effects, 427 Antiseptics, 703 classification, 202-3 urinary tract problems, 442, 543-4 essential (WHO list), 31 combinations of, 207 uses, 442 Antispasmodics, see Smooth muscle essential (WHO list), 29 antiemetic, 442, 634, 638 relaxants eye, 32 asthma, 559 Antithrombotic drugs, essential (WHO skin, 30 gastric acid suppression, 629 list), 30 history, 201-2 Parkinsonism, 423, 427, 442 see also Anticoagulants; Antiplatelet metabolic processes altered by, 90 preoperative, 347,442 drugs; Thrombolytic drugs mode of action, 203 smooth muscle relaxants, 443, Antithymocyte immunoglobulin, 600 principles of therapy, 203-5 649 Antithyroid drugs, 701-6 selection/choice, 205, 205-7, Antimycobacterial drugs, see essential (WHO list), 31 211-13 Antileprotics; Antituberculosis drugs, 212, 250-3 Anti-inflammatory drugs Antituberculosis drugs chemoprophylaxis, 250-1 asthma, 557, 561 Antimycotic drugs, see Antifungal essential (WHO list), 29 breast-feeding and, 116 drugs principles of use, 250 non-steroidal, see Non-steroidal Antioestrogens, 719-20 special problems, 250 anti-inflammatory drugs Antioxytocics (tocolytics; uterine Antitussives, 549-52 skin, essential (WHO list), 30 relaxants), 450, 732-3 essential (WHO list), 32 steroidal, see Adrenal steroids P-agonists as, 450, 732 opioids as, 334, 554 Anti-inflammatory effects essential (WHO list), 32 Antiviral drugs, 257-63 adrenal steroids (=glucocorticoid Antiplatelet drugs, 92-3,582-6 essential (WHO list), 29 effect), 303, 664, 665, 672-4 adverse effects, 583-4 interactions, 285 choice for anti-inflammatory aspirin as, 92-3, 289, 484, 582, 586 Anus effect, 667 interactions, 285 fissure, 649 contraindications, 670 uses, 584 pruritus, 303 mechanism, 280 angina (unstable), 484 Anxiety disorders, 392-7 NSAIDs, 283 MI, 485, 486, 576, 583, 584 antidepressants in, 375 Antileprotics, 212, 253-4 stroke prevention, 579 beta-blockers, 477 essential (WHO list), 29 Antiprogestogens, 720-1 classification, 393-6 Antilymphocyte immunoglobulin, Antiprotozoal drugs, 267-75 insomnia in, 400 600, 620 essential (WHO list), 29 Anxiolytic drugs (minor tranquillisers) Antimalarial drugs Antipruritics, 302-3 breast-feeding and, 116 750
INDEX indications, 410 septic, 249 Atropine, 441-4 insomnia, 401, 402 Arthroplasty (prosthetic joint adverse effects of/poisoning by, P40 enzymes and, 372 insertion), 161, 444, 507 preoperative, 346-7 chemoprophylaxis, 208-9 in bradycardia, 442, 507 warfarin interactions, 573 Arylaminoalcohols, 269 in poisoning/overdose, 154, 438 see also Hypnotics; Sedatives Ascaris lumbricoides, 277 by beta-blockers, 479 Aortic dissection, 477 Ascites, 536, 656-7 Attention deficit/hyperactivity Aortic stenosis, 468 Ascorbic acid, see Vitamin C disorder, 409 Apathy in schizophrenia, 383 Asparaginase, 609 Aura of migraine, 326 Aplastic anaemia (anaemia of bone adverse effects, 612 Auranofin, 292 marrow failure), 600, 714 Aspergillosis, 264 Aurothiomalate, sodium, 292 drug-induced, 144 Aspirin (acetylsalicylic acid), 92-3, Autoantibodies, nicotinic ACh chloramphenicol, 229 286, 288-9 receptors, 439, 440 Apnoea adverse effects and overdose, Autoimmune active chronic hepatitis, obstructive sleep, 405 289-90 657, 673 premature infants, 552 doses, 289 Autonomic ganglion-blocking drugs, Apolipoprotein E defect, 522 gout and, see Gout 441, 450, 482 Apomorphine mode of action, 288-9 Autonomic nervous system, 434 erectile dysfunction, 546 pharmacokinetics, 289 cardiac effects of, 507-8 Parkinson's disease, 425, 428 surgery and, 577 cholinergic drug action, 434 Apoptosis-promoting drugs, 605, 618 uses, 582 poisons affecting, 158 Appetite suppressants, see angina (unstable), 484, 576 tetanus toxin affecting, 430 Weight-reducing drugs as antiplatelet agent, 92-3, 289, see also Parasympathetic nervous Aprotinin, 580 484, 582, 586 system; Sympathetic APSAC (anistreplase; anisoylated atrial fibrillation, 508 nervous system plasminogen streptokinase MI, 485, 576, 584 Autonomic neuropathy, 666 activator complex), 578-9, pre-eclampsia reduction, 492 Autonomy, consumers, 579 rheumatic fever, 295 self-medication and, 25-6 allergy to, 580 stroke prevention, 579 Azapropazone, 286, 287 Arachidonic acid cascade, 280-1 Assays, biological, 95 Azatadine, 555 see also Eicosanoids Astemizole, 555 Azathioprine, 292, 608, 619-20 Arecoline, 436 Asthma, 556-63 adverse effects, 292 Argatroban, 577 P-agonists in, see P2-Adrenoceptor monitoring for, 309 Aromatase inhibitors, 617, 675 agonists indications Arrhythmias, cardiac, 497-513 acute severe, 562-3 autoimmune active chronic drug-induced, 157 drug-induced, 144 hepatitis, 657 antiarrhythmic, 502, 507 p-blockers, 128, 478,563 Crohn's disease, 647, 647-8 halofantrine, 273 drug therapy, see Antiasthma drugs myasthenia gravis, 440 thrombolytics, 579 opioid effects, 334 rheumatoid arthritis, 292 drug therapy, see Antiarrhythmic pathophysiology, 556 ulcerative colitis, 646 drugs types, 556 interactions, 133 objectives of treatment, 497-8 Astringents, 302 Azidothymidine (zidovudine), 258-9 physiology/pathophysiology, 498 Atenolol, 480 Azithromycin, 228 protocol for treatment, 510-4 Atherosclerotic disease, 522 tuberculosis, 253 see also Bradycardia; Tachycardia hypotension, 457 Azlocillin, 220-1 Arsenic overdose, 154 smoking and, 177 Azoles / imidazoles Artemesinin, 274-5 Atonic seizures, 418 antibacterial, 216, 233-4 Artemether, 274-5 Atorvastatin, 525 antifungal, 233, 265-6 Arterial occlusion Atovaquone candidiasis, 263 coronary, see Coronary artery in amoebiasis, 275 dermatophytes, 263 disease proguanil and (Malarone), in antihelminthic, 233, 276, 277 peripheral, see Peripheral malaria, 270 antimalarial, 275 vasculature ATPase, drugs inhibiting, 90 AZT (zidovudine), 259-60 Arterioles Atracurium, 356 Aztreonam, 220 adrenoceptor function and agonist Atrial ectopic beats, 507-8 actions, 449 Atrial fibrillation, 505, 508 Bacille Calmette-Guerin (BCG) dilatation, drugs causing, 461, 470 Atrial flutter, 505, 508 adverse effects, 615 Artesunate, 274-5 Atrial natriuretic peptide, 510 in cancer, 617-8 Arthritis (and arthropathies), 282, 290-5 Atrial tachycardia, 508, 508-9 Bacilli crystal-associated, 282, 295-8 Atrioventricular block, variable, 508 antibiotic choice, 211-12 degenerative (osteoarthritis), 282, Atrioventricular node, 498, 504 gram-negative, see Gram-negative 295 beta-blockers and, 502 organisms inflammatory, 282 calcium channel blockers and, 500 Baclofen, 357 rheumatoid, see Rheumatoid Atrioventricular re-entrant Bacteria, 215-55 arthritis tachycardia, 502, 508 as biological weapons, 161-2 751
INDEX Bacteria (cont'd) uses, 401, 410 Bipolar (manic-depressive) disorder, drugs acting against, see acute stress disorder, 395-6 389-92 Antibacterial drugs epilepsy, 421 drugs used, see Mood-stabilising infections caused by, 215-55 insomnia, 400-1 drugs blood, see Septicaemia panic disorder, 393, 394 insomnia in, 400 endocardial, see Endocarditis post-traumatic stress disorder, Bisacodyl, 641 genital tract, 247-9 395 Bishydroxycoumarin, 570 intestinal, 247-9 psychotic disorders, for rapid Bismuth chelate/bismuth salts, 629, meningeal, 243-5 tranquillisation with, 385 630 opportunistic, 210, 213, 621 withdrawal, 402 Bisoprolol, 480, 516, 517 respiratory, see Respiratory tract Benzthiazepines, 465 Bisphosphonates (biphosphonates), sexually-transmitted, 247-8 Benztropine, 154, 427 741-2 skin, superficial and deep, Benzylpenicillin (penicillin G), 216, actions, 741-2 314-15 217-18 adverse effects, 742 urinary tract, see Urinary tract adverse effects, 218 pharmacokinetics, 742 metabolism, antimicrobials preparations and dosage, 218 uses, 742 affecting, 90, 203 uses, 218 hypercalcaemia, 740 types, and antibiotic choice, 211-13 Beta-adrenoceptors/receptors and osteoporosis, 742, 743 Bactericidal drugs, 202-3 blockers, see Adrenoceptors Paget's disease, 744 combinations, 207 Beta-lactam antibiotics, 215 Bitters, 634 endocarditis, 241 essential (WHO list), 29, 216-23 see also Tonics Bacteriophages and antibiotics Betahistine, 636 Bivalirudin, 577 resistance, 209 Betamethasone, 666 Bladder Bacteriostatic drugs, 202, 203 Bethanecol, 433, 435 cholinergic drug effects, 434 combinations, 207 Bethanidine, 481 functional problems, 543-4 Bacteriuria, asymptomatic, 247 Bezafibrate, 526 physiology, 543 Balsalazide Bias in trials, avoidance, 61-2 Blastomycosis, 264 Crohn's disease, 647 Bicalutamide, 715 Bleomycin, 608 ulcerative colitis, 646 Bicarbonate, sodium Blepharitis, marginal, 311 Barbiturates, 404,421 as antacid, 627 Blinding in trials, 62-3 dependence, 169 in hyperkalaemia, 537 Blood, 567-601 in mixtures with Bicarbonate ion, 539 concentration in, see Concentration amphetamines, 170 Biguanides, see Metformin drug-induced dyscrasias / disorders Baroreceptor reflexes, 489 Bile acid-binding resins, 523, 526-7 with antipsychotics, 386, 387 Barrier contraceptives, 728 Bile salt malabsorption, 648 with thionamides, 703 Barrier preparations, 301 Biliary cirrhosis, primary, 657 essential (WHO list) list of drugs BCG, see Bacille Calmette-Guerin Biliary system affecting, 30 BCNU, see Carmustine excretion, 115 infections, 237-8 Beclomethasone, 666-7 obstruction, 714, 715 pH, aspirin effects, 289-90 asthma, 557, 561 pressure, opioid effects, 335 Blood-brain barrier, 98 Beliefs, false, 12-13 stones, 658-9 Blood flow Bendrofluazide, 534 Bilirubin metabolism/excretion, drugs beta-blocker effects, 474, 478 Beneficence, ethical principle of, 53 interfering with, 653 liver, see Liver Beneficial effects of drugs, 5, 6 Binding (of drugs), 111-12 in shock, 455-6 see also Cost-benefit analysis to plasma proteins, see Proteins Blood pressure Benoxaprofen, 75 to receptors, 91-2 abnormal, see Hypertension; Benserazide, levodopa with, 119, 424 to tissue, see Tissue Hypotension Bentonite, 153 Bioassays, 95 clonidine effects, 482-3 Benzhexol, 427, 444 Bioavailability, 105-7 monitoring, 490 Benznidazole, 275 Bioequivalence, 56, 61 targets in antihypertensive therapy, Benzocaine, 302, 359 Biological activity, metabolism 488 Benzodiazepine(s), 392, 395, 401-3, 410 altering, 112 Blood products, essential (WHO list), adverse effects, 395, 402 Biological agents 30 antagonist, see Flumazenil cancer, 615, 618 Blood transfusion, iron overload, 592 dose, 402 rheumatoid arthritis, 293-4 Blood vessels, see Vascular system generalised anxiety disorder, 396 Biological substances, poisoning by, Blood volume interactions, 403 161 antihypertensives increasing, 489 overdose, 403 Biological variation (in response), expansion in orthostatic perioperative use, 346, 348 122-4 hypotension, 458 pharmacokinetics, 401 Biological weapons, 161-2 reduced, see Hypovolaemia in pregnancy, 403 Biotechnology-derived Body surface area and dose receptors, see Pharmaceuticals, 44 calculation, 117-18 GABAA-benzodiazepine toxicology testing, 46 Body weight, see Weight receptor complex Biperiden, 427 Bone, 739-44 tolerance and dependence, 402 Biphosphonates, see Bisphosphonates infections, 249 752
INDEX pain (metastases etc.) analgesia, premenstrual tension, 730 Calcitriol (la-25-dihydroxy- 328 Brompheniramine, 555 cholecalciferol), 738, 739 steroid adverse effects, 668 Bronchi uses, 739, 740 Bone marrow cholinergic drug effects, 434 psoriasis, 313 failure, anaemia of, see Aplastic decongestion, 455 Calcium anaemia secretions, see Mucus secretion cardiac cells and, 504 suppression see also Airway homeostasis, disturbances, 739-44 with chloramphenicol, 229 Bronchial muscle, opioid effects, 335 diuretic-induced, 538 with cytotoxic drugs, 611, 612, Bronchitis, 239-40 see also Hypercalcaemia; 613, 614, 615 Bronchoconstriction/bronchial Hypercalciuria; therapeutic, polycythaemia hyperreactivity Hypocalcaemia; rubra vera, 599-600 beta-blocker-induced, 478, 479 Hypocalciuria transplantation drugs reducing, 557-8 supplementation in aplastic anaemia, 600 Bronchodilators, asthma, 558-9 intravenous, adverse effects, 740 CSFs, 598, 599 Brugia spp., 277 oral, 742 Bordetella pertussis, 239 Buccal absorption, 105 Calcium channel blockers, 464-7 Borrelia burgdorferi, 254 advantages/disadvantages, 107 adverse effects, 465, 494 Botulinum toxin, 429 Budesonide, 666-7 indications, 465 Bovine insulin, 680 asthma, 557, 561 angina, 465, 484 Bowel, see Intestine primary biliary cirrhosis, 657 arrhythmias (class IV Bowen's disease, 311 Bulimia nervosa, 375 antiarrhythmics), 500, 504 Bradycardia, 456 Bulk-forming laxatives hypertension, 465, 489, 491-2 sinus, 507 constipation, 639-40 migraine prophylaxis, 328 treatment diarrhoea, 644 interactions, 466, 504 atropine, 442, 507 Bullous pemphigoid, 308 pharmacokinetics, 465 isoprenaline, 506 Bumetanide, 530, 534, 536 in pregnancy, 492 Bradykinesia, Parkinson's disease, 422 Bupivacaine, 359, 361 Calcium glubionate, 740 Bradykinin, 467 Buprenorphine in opioid dependence, Calcium gluconate, 154, 541, 740 Brain 338 Calcium pyrophosphate arthropathy, drug passage into, 98 Bupropion, 177, 372 298 oedema, 674 Burns, infected, 254, 315 Calculi, see Stones see also Central nervous system and Buserelin, 617, 714 Calymmatobacterium gmnulomatis, 248 specific parts of brain Buspirone, 395, 396 Camouflaging preparations, 301 Brain-derived neurotrophic factors adverse effects, 395, 396 Campylobader jejuni, 227, 245 and mood, 371 generalised anxiety disorder, 396 Cancer (malignant tumours/ Brain natriuretic peptide, 514 Busulphan, 606 neoplasms), 604-19 Bran, 640 adverse effects, 612 adjuvant therapy, see Adjuvant Brand name, see Proprietary name polycythaemia rubra vera, 599 therapy Branhamella catarrhalis, 241 chemoprevention, 618-9 Breast C-fibres, pain and, 320 chemotherapy, see Chemotherapy, cancer neuropathic, 321 cytotoxic chemotherapy, 607, 608, 617, 675 Cj-esterase deficiency, 314, 719 'cures', 619 endocrine therapy, 617, 714, Cabergoline, 425 fungating, 332 718, 719 Caesarean section oral contraceptives and risk of, 147, HRT and risk of, 719, 742-3 ketamine use, 354 723 oral contraceptives and risk of, spinal anaesthesia, 362 pain relief, 328 724 Caffeine, 194,195,195-6 smoking and (lung and other enlargement, digoxin-induced, 505 actions, 194-5 sites), 176-7 pain (mastalgia), 328, 731 mode of, 194 specific sites and types Breast milk and breast-feeding, 116 physical performance drugs used, 607 antiepileptics, 416 enhancement, 173 skin (and precancer), 311 antiretroviral drugs, 259 in drinks, 195-6 treatment and outcome, 603-4 caffeine, 196 orthostatic hypotension, 458 see also Carcinogenicity; Tumour cell propylthiouracil, 702 overdose, 196 Candesartan, 469 see also Lactation pharmacokinetics, 194 Candidiasis, 263-4 Breast pain (mastalgia), 328, 731 preparations and uses, 195 Cannabis (and cannabinoids), 192-4 Brinzolamide, 539 tolerance and dependence, 195-6 dependence, 169 British Anti-Lewisite, see Dimercaprol Calamine, 302, 307 pharmacology, 189-91 British Approved Name, 84 Calciferol, see Ergocalciferol therapeutic use, 191 British Hypertension Society Calcipotriol, 739 antiemetic, 191, 635 guidelines, 488, 490 psoriasis, 313 Capreomycin, tuberculosis, 253 British Thoracic Society guidelines, Calcitonin, 741 Capsules, 105 asthma, 560 uses, 741 Captopril, 469 Bromocriptine hypercalcaemia, 740 heart failure, 515-6 Parkinson's disease, 425, 562 Paget's disease, 744 MI, 486 753
INDEX Car driving, see Driving HRT, 717, 718 intravenous anaesthetics, 353 Carbachol, 433, 435 oral contraceptives, 723, 724, local anaesthetics, 359 Carbamazepine, 417-19 725 methyldopa, 483 adverse effects, 419 opioid effects, 334, 335 opioids (incl. morphine), 333-4, teratogenicity, 416 poisons affecting, 161 334 oral contraceptive interactions, 727 sexual intercourse and, 493 poisons, 158 pharmacokinetics, 419 smoking and steroids, 668 uses, 419 long-term effects (disease), 177 withdrawal syndrome, 121 bipolar affective disorder, 391 nicotine effects, 176 see also Neurological complications diabetes insipidus, 712 xanthine effects, 195 Central nervous system depressants epilepsy, 414 see also Vascular system (cerebral depressants) trigeminal neuralgia, 326, 419 Cardioversion alcohol as, 180 Carbapenems, 221-3 electrical, see Electroconversion alcohol interacting with other, 187 Carbaryl, 437 pharmacological, see interactions, 132 Carbidopa, levodopa with, 92,119, 424 Antiarrhythmic drugs in liver disease, 653 Carbimazole, 701-2 Carmustine (BCNU), 606 opioids as, 333-4 Carbocisteine, 551 adverse effects, 612 shock caused by poisoning with, Carbohydrate Carotid sinus massage, 507 456 dietary, in diabetes, 690 Carrier-mediated transport, 99 Central nervous system stimulants, intolerance, 538 Carvedilol, 516, 517 192-7 metabolism, hydrocortisone effects, Case-control studies, 77 misuse, 192-7 664 CAST study, 507 sports, 172 Carbon monoxide Cataplexy, 405, 406 therapeutic use poisoning, 159 Cataracts, steroid-related, 668 attention deficit/hyperactivity in tobacco smoke, 173 Catecholamines, 452-3 disorder, 409 absorption, 175 blockade, antiarrhythmics, 499 narcolepsy, 405-6 Carbon tetrachloride, 160, 657 G-proteins coupled receptors and, Centrilobular necrosis, 654 Carbonic anhydrase, 539 91 Cephalosporins and cephamycins, inhibitors, 539 pharmacokinetics, 451 215, 221 Carboplatin, 608 thyroid hormones and, 700 adverse effects, 221 adverse effects, 612 Catechol-O-methyl transferase classification and uses, 221, 222 Carboprost, obstetrics, 732 (COMT) inhibitors, 426, 428 mode of actions, 221 Carboxypenicillins, 220 Cathartics, see Laxatives pharmacokinetics, 221 Carcinogenicity Cathinine/cathine/cathidine, 196 Cerebrospinal fluid, drug passage drugs, 46, 146-7 Cation-exchange resins, 537, 539-40 into, 98 cytotoxic and Causation (of injury), proof, 11 Cerebrovascular accident, see Stroke immunosuppressive, CCNU, see Lomustine Cerebrum, see Brain; Central nervous 615-6, 621 CD20, monoclonal antibody, 618 system radioiodine, 705 Cef-, cephalosporins beginning with, Cervix tobacco smoke, 173-4 215 cancer, oral contraceptives and risk Carcinoid tumours, 481 cefamandole, 221 of, 723 Cardiac function/disorders etc., see ceftriaxone, 221 ectropion, oral contraceptives and Heart Celecoxib, 283, 286, 632 risk of, 724 Cardiogenic shock, 456 Cell(s) ripening/softening, drugs aiding, Cardiomyocytes, see Myocytes drugs causing specific injuries to, 732-3 Cardioprotection, beta-blocker, 477 121 Cestodes, see Tapeworms Cardiovascular drugs, 461-96 membrane, see Membrane Cetirizine, 555 atropine as, 442 metabolic processes within, drugs Chagas' disease, see American essential (WHO list), 30 acting on, 90 trypanosomiasis in liver disease, 653 in microbes, 90, 203 Chancroid, 248 neuromuscular adverse effects, 441 wall, antibacterials acting on, 203, Charcoal, activated, 152 sexual function, 478, 492-3 215, 216-23 aspirin overdose, 290 Cardiovascular system, 461-528 Cell cycle (cancer cells) and cytotoxic paracetamol overdose, 288 anaesthetics drugs, 605-6 repeated doses, 155 halogenated (inhaled), 350, 351 Central nervous system, drugs acting Cheese reaction, MAO inhibitors, 379, intravenous, 353 on 425 local, adverse effects reactions, 2-adrenoceptor agonists, 450, Chelated forms of iron, 590 360 482-3 Chelating agents, 154-5 antidepressant effects, 377 alcohol, 180-1,184 iron excess, 591-2, 592-3 antimuscarinic drug effects, 442, anticholinergic, 443 Chemical(s) (non-drug) 443 antidepressants (toxic effects), 377 poisoning by, 158-60 antipsychotic effects, 386, 387 antitussives, 550, 550-1 as weapons, 437-8 beta-blocker effects, 474 cholinergic, 434-5 Chemical interactions, direct, 131 diabetes-related disease, 695 elderly, pharmacodynamic Chemical name, full, 84 oestrogens and responses, 126-7 Chemistry, combinatorial, 44 754