Vitamins, calcium, bone

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Chapter 39 Vitamins, calcium, bone

Chrysothemis Brown

Synopsis

In general, the pharmacological aspects of vitamins appear 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.

• Treatment of calcium and bone disorders.

• Vitamin E: tocopherol.

Vitamins1 are substances that are essential for normal metabolism but are supplied chiefly in the diet.

Humans cannot synthesise vitamins in the body except some vitamin D in the skin and nicotinamide from tryptophan. Lack of a particular vitamin may lead to a specific deficiency syndrome. This may be primary (inadequate diet) or secondary, due to failure of absorption (intestinal abnormality or chronic diarrhoea) or to increased metabolic need (growth, pregnancy, lactation, hyperthyroidism).

Vitamin deficiencies are commonly multiple, and complex clinical pictures occur. There are numerous single and multivitamin preparations available to provide prophylaxis and therapy.

Recently, there has been great interest in the suggestion that subclinical vitamin deficiencies may be a cause of chronic disease and liability to infection. This idea has prompted a number of clinical trials examining the potential benefit of vitamin supplementation in the prevention of cancer, cardiovascular disease and other common diseases. With the exception of vitamin D, there is little robust evidence to support this claim and, for most consumers, over-the-counter vitamin preparations are probably of little more than placebo value. Fortunately, most vitamins are comparatively non-toxic; however, prolonged administration of vitamin A and vitamin D can have serious ill-effects.

In addition to maintaining adequate nutritional levels, a number of vitamins can be used at pharmacological doses for therapy.

Vitamins fall into two groups:

• Water-soluble vitamins: the B group and vitamin C.

• Fat-soluble vitamins: A, D, E and K.

Vitamin A: retinol

Vitamin A is a generic term embracing substances having the biological actions of retinol and related substances (called retinoids). The principal functions of retinol are to:

• sustain normal epithelia

• promote corneal and conjunctival development

• form retinal photochemicals

• enhance immune functions

• protect against infections and probably some cancers.

Deficiency of retinol leads to xerophthalmia, squamous metaplasia, hyperkeratosis and impairment of the immune system.

Therapeutic uses

Retinol and derivatives provide therapeutic benefit in a number of clinical areas.

Psoriasis

Tazorotene, a topical retinoid, is effective in the treatment of chronic stable plaque psoriasis. Skin irritation is common, making it unsuitable for the treatment of inflammatory forms of psoriasis. The 0.05% cream is better tolerated than 0.1% although less effective. Acitretin is a retinoic acid derivative (t½ 48 h) that is used orally for severe psoriasis. Dose range 25 mg alternate days – 50 mg daily (see p. 262, as well as other disorders of keratinisation).

Acne

Tretinoin is retinoic acid and is used in acne by topical application (see p. 273). Isotretinoin is a retinoic acid isomer (t½ 20 h) given orally for acne (see p. 273). It is also effective for preventing second tumours in patients following treatment for primary squamous cell carcinoma of the head and neck.

Acute promyelocytic leukaemia

Tretinoin can be used to induce remission in conjunction with chemotherapy in acute promyelocytic leukaemia, a subgroup of acute myeloid leukaemia (AML) involving chromosomal translocation of the retinoic acid receptor-alpha gene. Initially, it proved remarkably successful, but the high doses given caused the fatal ‘differentiation syndrome’ (previously called ‘retinoic acid syndrome’; respiratory distress, fever and hypotension) and the duration of treatment is now shorter.

Vitamin A deficiency

Primary deficiency is common in developing countries. Retinol is used to prevent and treat deficiency; 1 microgram = 3.3 IU (t½ 7—14 days). For prevention of deficiency in susceptible individuals, supplements are given at 4–6-monthly intervals. Dosing is according to age. More frequent doses are required for treatment of xerophthalmia. Secondary deficiency resulting from fat malabsorption is seen with pancreatic insufficiency and disorders of the gastrointestinal tract. Vitamin A supplementation at pharmacological doses is standard for patients with cystic fibrosis. This can result in chronic toxicity and serum retinol levels should be monitored.

Adverse effects

Acute toxicity occurs in adults with a single dose of more than 600 000 IU/day. Symptoms include headache, nausea, vomiting and drowsiness. Travellers have become ill by eating the livers of Arctic carnivores.

Chronic toxicity occurs with prolonged high intake (in children 25 000–50 000 IU/day, 10 times the recommended daily allowance, RDA). A diagnostic sign is the presence of painful tender swellings on long bones. Anorexia, skin lesions, hair loss, hepatosplenomegaly, papilloedema, bleeding and general malaise also occur. Vitamin A accumulates in liver and fat, and effects take weeks to wear off. Chronic overdose also makes the biological membranes and the outer layer of the skin more liable to peel.

Teratogenicity

Vitamin A and its derivatives are teratogenic at pharmacological doses (for precautions, see use in acne and psoriasis, p. 273). Supplements should not exceed 8000 IU (2400 micrograms) per day.

Vitamin B complex

A number of widely differing substances are now, for convenience, classed as the ‘vitamin B complex’. Those used for pharmacotherapy include the following:

Thiamine (B1)

Deficiency is associated with three distinct conditions: Wernicke–Korsakoff syndrome, beriberi, and Leigh’s syndrome. The UK RDA of thiamine is 1 mg for men and 0.8 mg for women. It is given orally for nutritional purposes, but intravenously in serious emergencies, e.g. Wernicke–Korsakoff syndrome. Give the injection over 10 min (or intramuscularly); note that it can cause anaphylactic shock.

Cobalamins (B12)

See Chapter 20.

Folic acid

See Chapter 20.

Pyridoxine (B6)

is a coenzyme in the metabolic transformation of many amino acids, including decarboxylation and transamination. The UK RDA of vitamin B6 is 1.4 mg for men and 1.2 mg for women. As pharmacotherapy, pyridoxine is given to treat certain pyridoxine-dependent inborn errors of metabolism, e.g. homocystinuria, hereditary sideroblastic anaemia and primary hyperoxaluria. Deficiency may be induced by drugs such as isoniazid, hydralazine and penicillamine; pyridoxine 10 mg/day prevents the development of peripheral neuritis without interfering with therapeutic action.

Pyridoxine, in doses sometimes exceeding 100 mg/day, has found use for a variety of conditions including premenstrual syndrome and nausea in pregnancy.

Niacin (nicotinic acid, B3)

is converted to nicotinamide, and subsequently to nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADPH), the cofactors that are essential for the oxidation–reduction reactions that comprise tissue respiration. Nicotinamide is used for nutritional purposes. Pellagra resulting from dietary deficiency of niacin is rarely seen in developed countries. Causes other than dietary include alcoholism, carcinoid syndrome and Hartnup disease. Nicotinic acid at pharmacological doses is used for the treatment of some hyperlipidaemias (see p. 444). Adverse effects include peripheral vasodilatation, unpleasant flushing, itching and fainting.

Vitamin C: ascorbic acid

Vitamin C is a powerful reducing agent (antioxidant) and is an essential cofactor and substrate in a number of enzymatic reactions, including collagen synthesis and noradrenaline synthesis. It also functions as an antioxidant, mopping up free radicals produced endogenously or in the environment, e.g. cigarette smoke (see vitamin E). There has been considerable interest in using vitamin C as an antioxidative agent to reduce oxidation of low-density lipoproteins (LDL) in atherosclerosis and prevent formation of carcinogens to reduce risk of cancer. However, randomised trials have not shown any beneficial effect thus far of vitamin C on either cancer incidence or primary or secondary prevention of coronary heart disease.

Indications

• The prevention and cure of scurvy.

• Methaemoglobinaemia.

Scurvy

Deficiency of ascorbic acid leads to scurvy, which is characterised by petechial haemorrhages, haematomas, bleeding gums (if teeth are present) and anaemia.

Methaemoglobinaemia

A reducing substance is needed to convert the methaemoglobin (ferric iron) back to oxyhaemoglobin (ferrous iron) whenever enough has formed seriously to impair the oxygen-carrying capacity of the blood. Ascorbic acid is non-toxic (it acts by direct reduction) but is less effective than methylene blue (methylthioninium chloride). Both can be given orally, intravenously or intramuscularly. Excessive doses of methylene blue can cause methaemoglobinaemia (by stimulating NADPH-dependent enzymes).

Methaemoglobinaemia may be induced by oxidising drugs: sulphonamides, nitrites, nitrates (may also occur in drinking water), primaquine, -caine local anaesthetics, dapsone, nitrofurantoin, nitroprusside, vitamin K analogues, chlorates, aniline and nitrobenzene. Where symptoms are severe enough to warrant urgent treatment, methylene blue given intravenously at 1–2 mg/kg gives response within 30 min. Patients should be monitored for rebound methaemoglobinaemia. Methylene blue turns the urine blue and high concentrations can irritate the urinary tract, so that fluid intake should be high when large doses are used. Methlyene blue should not be administered to patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency since its action is dependent on NADPH produced by G6PD. In addition to being ineffective in this circumstance it may induce haemolysis. Ascorbic acid is inadequate for the treatment of acute methaemoglobinaemia requiring treatment.

Congenital methaemogobinaemia can be treated long term with either oral methylene blue or ascorbic acid with partial effect.

Adverse effects

High doses may cause sleep disturbances, headaches and gut upsets. Ascorbic acid is eliminated partly in the urine unchanged and partly metabolised to oxalate. Doses above 4 g/day increase urinary oxalate concentration and there is a potential risk of renal oxalate stones with chronic ascorbic acid administration. Intravenous ascorbic acid may precipitate a haemolytic attack in subjects with G6PD deficiency.

Vitamin D, calcium, parathyroid hormone, calcitonin, bisphosphonates, bone

Vitmain D is closely interrelated with calcium homeostasis and bone metabolism and these topics are therefore discussed together.

Vitamin D

Vitamin D comprises a number of structurally related sterol compounds having similar biological properties (but different potencies) in that they prevent or cure the vitamin D-deficiency diseases, rickets and osteomalacia. The most relevant form of vitamin D is vitamin D3 (colecaciferol). This is made by ultraviolet irradiation of 7-dehydrocholesterol in the skin. It is also absorbed in the intestinal tract; however, few foods contain significant levels of vitamin D (Fig. 39.1). Vitamin D2 (ergocalciferol) is made by ultraviolet irradiation of ergosterol in plants. This is not the naturally occurring form.

image

Fig. 39.1 Metabolism of vitamin D. D3, Vitamin D3 (cholecalciferol); pre-D3, pre-vitamin D3; DBP, vitamin D-binding protein; 25-OHase, liver 25-hydroxylase; 25(OH)D3, 25-hydroxycholecalciferol (25(OH)D3; 1-OHase, 25-hydroxyvitamin D3-1-hydroxylase; 1,25(OH)2D3, calcitriol; PTH, parathyroid hormone.

(From Deeb K K, Trump D L, Johnson C S 2007 Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nature Reviews Cancer 7(9): 684.)

Vitamin D3 (and D2) undergo two successive hydroxylations: first in the liver to form 25-hydroxyvitamin D and second in the proximal tubules of the kidney (under the control of parathyroid hormone, PTH) to form 1α,25-dihydroxyvitamin D3 (calcitriol), the most physiologically active form of vitamin D.

There exist also a variety of synthetic vitamin D analogues, developed to treat vitamin D deficiency and hypoparathyroidism. The vitamin D derivative 1α-hydroxycolecalciferol (alfacalcidol) requires only hepatic hydroxylation to become calcitriol. The usual adult maintenance dose, 0.25–1 micrograms/day, indicates its potency.

Other 1α-hydroxylated vitamin D analogues include paricalcitol. In addition, a structural variant of vitamins D2 and D3, dihydrotachysterol (ATIO, Tachyrol), is also biologically activated by hepatic 25-hydroxylation. All are effective in renal failure as they bypass the defective renal hydroxylation stage.

Pharmacokinetics

Alfacalcidol and dihydrotachysterol have a fast onset and short duration of clinical effect (days) which renders them suitable for rapid adjustment of plasma calcium, e.g. in hypoparathyroidism. Such factors are not relevant to the slower adjustment of plasma calcium (weeks) with vitamins D2 and D3 in the ordinary management of vitamin D deficiency.

Actions

are complex. Vitamin D promotes the active transport of calcium and phosphate in the gut (increased absorption) and renal tubule (reduced excretion), and thus controls, with PTH, the plasma calcium concentration and the mineralisation of bone (see Fig. 39.1). After a dose of D2 or D3 there is a lag of about 21 h before the intestinal effect begins; this is probably due to the time needed for its metabolic conversion to the more active forms. With the biologically more active calcitriol, the lag is only 2 h.

A large single dose of vitamin D has biological effects for as long as 6 months (because of metabolism and storage). Thus, the agent is cumulative (see toxicity).

Indications

• The prevention and cure of rickets of all kinds and osteomalacia (vitamin D deficiency).

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