Vitamins, calcium, bone

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Chapter 39 Vitamins, calcium, bone

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:

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:

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.

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.

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:

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

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.

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.

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.