Cholecalciferol

CHOLECALCIFEROL IS A VITAMIN D COMPOUND. IT IS WELL ABSORBED FROM THE G.I. TRACT. IT CIRCULATE IN THE BLOOD BOUND TO A SPECIFIC ALFA-GLOBULIN. IT CAN BE STORED IN ADIPOSE AND MUSCLE TISSUE FOR LONG PERIODS OF TIME. IT IS RELEASED FROM SUCH STORAGE SITES AND FROM THE SKIN WHERE IT IS FORMED IN THE PRESENCE OF SUNLIGHT OR ULTRAVIOLET LIGHT.

Dose :

ORALY - 10 MCG DAILY AS PREVENTIVE DOSE. DEFICIENCY STATES MAY REQUIRE HIGHER DOSES UPTO 1 MG(40,000 UNITS) DAILY. DOSES UPTO 2.5 MG MAY BE USED IN TREATMENT OF HYPOCALCAEMIA DUE TO HYPOPARATHYROIDISM.

Monograph

CHOLECALCIFEROL Stability. A review of the compatibility and stability of com- ponents of total parenteral solutions when mixed in I-or 3- litre flexible containers.' Vitamin D may bind strongly to plastic which can lead to significant losses to the bag and ad- ministration set. Vitamin D losses from paediatric TPN mix- tures have been estimated to be about 30 to 36% over a 24- hour administration period. The quantity of vitamin D deliv- ered depends on infusion rate, type of administration set, composition of mixture, and total volume infused. Units The Second International Standard Preparation (1949) of vitamin D consisted of bottles containing approximately 6 g of a solution ofcholecalciferol in vegetable oil (1000 units per g). This standard has now been discontinued. NOTE. One unit of vitamin D is contained in 25 ng of cholecalciferol or ergocalciferol (i.e. I mg of chole- calciferol or ergocalciferol is equivalent to 40 000 units of vitamin D). Adverse Effects and Treatment Excessive intake of vitamin D leads to the develop- ment of hypercalcaemja and its associated effects including hypercalciuria,ectopic calcification and renal and cardiovascular damage. Symptoms of overdosage include anorexia, lassitude, nausea and vomiting, diarrhoea, polyuna, sweating, headache, thirst, and vertigo. In- terindividual tolerance to vitamin D varies consider- ably; infants and children are generally more susceptible to its toxic effects. The vitamin should be withdrawn if toxicity occurs. It has been stated that vitamin D dietary supplementation may be det- rimental in persons already receiving an adequate intake through their diet and exposure to sunlight since the difference between therapeutic and toxic concentrations is relatively small. Calcitriol, which is more potent than the other forms of vitamin D, might reasonably be expected to pose a greater risk of toxicity: however, its effects are re- ported to be reversed more rapidly on withdrawal than when other derivatives are used. Hypersensitivity reactions have occurred. Vitamin D is the most likely of all vitamins to cause overt toxicity. Doses of 60 000 units per day can cause hypercalcae- mia. with muscle weakness, apathy, headache, anorexia, nau- sea and vomiting, bone pain, ectopic calcification, protcinuria, hypertension, and cardiac arrhythmias. Chronic hypeicalcaemia can lead to generalised vascular calcification. nephrocalcinosis, and rapid deterioration of renal function.' Hypercalcaemia has been reported in one person following brief industrial exposure to cholecalciferol.~ A study in children treated for renal osteodystrophy has pro- vided some evidence that hypercalcaemia may occur more frequently with calcitriol than with ergocalciferol.' Another such study has suggested that vitamin D has nephrotoxic properties independent of the degree of induced hypercalcae- mia. and thatthe decline in renal function may be more marked with calcitriol. Topical calcitriol may affect calcium homoeostasis, and hy- percalcaemia has been reported in some studies' For mention of the effect of other vitamin D analogues used in psoriasis on calcium homoeostasis. Precautions Vitamin D should not be administered to patients with hypercalcaemia. It should be administered with caution to infants as they may have increased sensi- tivity to its effects and should be used with care in patients with renal impairment or calculi, or heart 'disease who might be at increased risk of orgSn damage if hypercalcaemia occurred. Plasma phos- phate concentrations should be controlled during vi- tamin D therapy to reduce the risk of ectopic calcification. It is advised that patients receiving pharmacological doses of vitamin D should have their plasma-calci- um concentration monitored at regular intervals, es- pecially initially and if symptoms suggest toxicity (see above). Similar monitoring is recommended in infants if they are breast fed by mothers receiving vitamin D. Pregnancy. Hypercalcaemia during pregnancy may produce congenital disorders in the offspring, and neonatal hypopar- athyroidism. However, the risks to the fetus of unticated ma- ternal hypoparathyroidism are considered greater than the risks of hypercalcaemia due to vitamin D therapy. Indeed, one report noted increased requirements for vitamin D prepara- tions during pregnancy for the treatment of hypoparathy- roidism;' the doses tended to need increasing during the second half of pregnancy. In one woman in whom the dose of calcitriol was kept at the increased level after delivery (in an attempt to allow for the calcium loss involved in breast feed- ing) hypercalcaemia developed; this did not occur in 2 wom- en who did not breast feed and in whom the dose of the vitamin D preparations was reduced soon after delivery. ' Interactions There is an increased risk of hypercalcaemia if vita- min D is coadministered with thiazide diuretics and calcium. Plasma-calcium concentrations should be monitored in patients receiving the drugs concur- rently. Some antiepileptics may increase vitamin D requirements (e.g. carbamazepine, phenobarbitone, phenytoin, and primidone). Danazol. A report of hypercalcaemia associated with dana- zol in a patient maintained on alfacalcidol therapy for hy- poparathyroidism.' Introduction of danazoi appeared to reduce the maintenance requirement for alfacalcidol. Thyroxine. Three patients receiving dihydrotachysterol and calcium for postoperative hypoparathyroidism, following thyroidectomy, developed hypercalcaemia when their con- comitant thyroxine therapy was discontinued before a radio- iodine scan.' The dose of dihydrotachysterol should be re- duced and serum-calcium concentrations should be moni- tored when thyroid treatment is interrupted, since elimination of dihydrotachysterol may be delayed in hypothyroidism. Pharmacokinetics Vitamin D substances are well absorbed from the gastro-intestinal tract. The presence of bile is essen- tial for adequate intestinal absorption; absorption may be decreased in patients with decreased fat ab- sorption. Vitamin D and its metabolites circulate in the blood bound to a specific a-globulin. Vitamin D can be stored in adipose and muscle tissue for long periods of time. It is slowly released from such storage sites and from the skin where it is formed in the presence of sunlight or ultraviolet light. Ergocalciferol and cholecalciferol have a slow onset and a long dura- tion of action; calcitriol and its analogue alfacaici- dol, however, have a more rapid action and shorter half-lives. Cholecalciferol and ergocalciferol are hydroxylated in the liver by the enzyme vitamin D 25-hydroxylase to form 25-hydroxycholecalciferol (calcifediol) and 25-hydroxyergocalciferol respectively. These com- pounds undergo further hydroxylation in the kid- neys by the enzyme vitamin D I-hydroxylase to form the active metabolites 1.25-dihydroxychole- calciferol (calcitriol) and 1,25-dihydroxyergocalcif- erol respectively. Further metabolism also occurs in the kidneys, including the formation of the 1,24,25- trihydroxy derivatives. Of the synthetic analogues, alfacalcidol is converted rapidly in the liver to calci- triol, and dihydrotachysterol is hydroxylated, also in the liver, to its active form 25-hydroxydihydrotachy- sterol. Vitamin D compounds and their metabolites are ex- creted mainly in the bile and faeces with only small amounts appearing in urine; there is some enterohe- patic recycling but it is considered to have a negligi- ble contribution to vitamin D status. Certain vitamin D substances may be distributed into breast milk. Human Requirements The daily requirements of vitamin D in adults are small and may be met mainly by exposure to sun- light and/or obtained from the diet. A daily dietary intake of about 200 to 400 units (5 to 10mcg of chole- calciferol or ergocalciferol) of vitamin D is general- ly considered adequate for healthy adults. In comparison with older adults in the age range of 25 years upwards the requirements per kg body-weight are greater in infants, children, and young adults and during pregnancy and lactation. Requirements may also be higher in people who are not exposed to ad- equate sunlight such as the elderly or housebound. Vitamin D is present in few foods. Fish-liver oils. especially cod-liver oil, are good sources of vitamin D. Other sources, which contain much smaller amounts, include butter, eggs. and liver. Some foods are often fortified with vitamin D and milk and mar- garine will therefore also provide a supply of vitamin D. Cooking processes do not appear to af- fect the activity of vitamin D. In the United Kingdom dietary reference values (see p. 1332) for vitamin D have only been published for selected groups of the population.' In the US Recommended Dietary Allowanc- es had been set, and have recently been replaced by Dietary Reference Intakes (see p. 1332). Differing amounts are recom- mended for infants and children of varying ages, for adults. and for pregnant and lactating women. In the UK a dietary intake was considered unnecessary for adults living a normal lifestyle who were being exposed to solar radiation: for those confined indoors a Reference Nutrient Intake (RNI) of 10 ng [as cholecalciferol or ergocalciferol] daily was set. This RNI of 10 ng daily was also considered to be applicable to all per- sons aged 65 years or more and to pregnant and lactating women. RNIs were set for children up to the age of 3 years: dietary intake was considered unnecessary for older children. Mention was made that in order to achieve the above refer- ence nutrient intakes, supplementation of the diet may actual- ly be required and supplementation was also recommended for Asian women and children in the UK. In the USA the tra- ditional Recommended Dietary Allowances were: 7.5mcg dur- ing the first 6 months of life but if infants were breast fed and not exposed to sunlight it was recommended that a supple- ment of 5 to 7.5mcg daily should be given: 10 ng for all per- sons up to the age of 24 years; 5mcg for all persons over the age of 24 years: and 10mcg for all pregnant or lactating wom- en. Under the new Dietary Reference Intakes, Adequate In- takes have been set for vitamin D.' These are: 5 ng per day (as cholecalciferol) for all persons from birth through to age 50 years including pregnant or lactating women: 10 mcgDer dav for adults aged 51 to 70 years: and 15mcg per day for those aged greater than 70 years. Uses and Administration Vitamin D compounds are fat-soluble sterols, some- times considered to be hormones or hormone pre- cursors, which are essential for the proper regulation of calcium and phosphate homoeoStasis and bone mineralisation. Vitamin D deficiency develops when there is inade- quate exposure to sunlight or a lack of the vitamin in the diet. Deficiency generally takes a prolonged pe- riod of time to develop due to slow release of the vitamin from body stores. Deficiency may occur in some infants who are breast fed without supplemen- tal vitamin D or exposure to sunlight, in the elderly whose mobility and thus exposure to light may be impaired, and in persons with fat malabsorption syndromes; certain disease states such qs renal fail- ure may also affect the metabolism of vitamin D substances to metabolically active forms and thus result in deficiency. Deficiency leads to the develop- ment of a syndrome characterised by hypocalcae- mia. hypophosphataemia, undermineralisation or demineralisation of bone. bone pain, bone fractures, and muscle weakness, known in adults as osteoma- lacia (see below). In children, in whom there may be growth retardation and skeletal deformity, especial- ly of the long bones, it is known as rickets. Vitamin D compounds are used in the treatment and prevention of vitamin D deficiency states and hy- pocalcaemia associated with disorders such as hy- poparathyroidism, and renal osteodystrophy. as indicated by the cross-references given below. A variety of forms and analogues of vitamin D are available, and the choice of agent depends on the cause of the condition to be treated and the relative properties of the available agents. Cholecalciferol and ergocalciferol are equal in potency, and have a slow onset and relatively prolonged duration of ac- tion. Dihydrotachysterol has relatively weak anti- rachitic activity, but its actions are faster in onset and less persistent than those of the calciferols and it does not require renal hydroxylation. Calcifediol, an intermediate metabolite, has some action of its own but is also converted to the more potent 1,25-dihy- droxycholecalciferol (calcitriol); calcitriol and its analogue alfacalcidol are the most potent and rapid- ly acting of the vitamin D substances.  For the treatment of simple nutritional deficiencies cholecalciferol or ergocalciferol are generally pre- ferred. They are usually given by mouth, but may also be administered by intramuscular injection. A dose of 10 ng (400 units) daily is generally sufficient in adults for the prevention of simple deficiency states. Deficiency due to malabsorption states or liver disease often requires high- er doses for treatment, of up to I mg (40 (XX) units) daily. Doses of up to 2.5 mg (100 (XX) units) daily may be used in the treatment of hypocalcaemia due to hypoparathy- roidism.  Where large doses are required it may be preferable to use one of the more potent derivatives. In particular. when renal function is impaired as in renal osteodystro- phy, with consequent reduction in the conversion of cal- ciferols to their active metabolites, then alfacalcidol or calcitriol. which do not require renal hydroxylation, should be given. Calcitriol is given by mouth or by intra- venous injection. Usual initial adult doses of 0.25 mcg dai- ly or on alternate days are given by mouth, increase if necessary, in steps of 0.25 mcg at intervals of 2 to 4 weeks, to a usual dose of 0.5 to I ug daily. Initial doses intrave- nously are usually 0.5 ng three times a week increased if necessary in steps of 0.25 to 0.5 mcg at intervals of 2 to 4 weeks, to a usual dose of 0.5 to 3 mcg three times a week. Alternatively, alfacalcidol is given in initial doses of I ng daily by mouth, or 0.5 ng for elderly patients. Doses of 0.25 to I ng daily may be given for maintenance. Sug- gested doses for children under 20 kg'are 0.05 ng (50 ng) per kg body-weight daily -and for premature infants and neonates a dose of 0.05 to O.I ng (50 to 100 ng) per kg daily. Doses of alfacalcidol may also be given by intrave- nous injection over 30 seconds.  Of the other available forms, cakifediol. the 25-hydrox- ylated metabolite of cholecalciferol. is given inusual adult doses of 50 to 100 ng daily or 100 to 200 ng on alternate days by mouth. For hypocalcaemic tetany due to hypoparathyroidism, dibydrotachysterol is given in initial adult doses of 0.25 to 2.5 mg daily by mouth, de- pending on severity. Maintenance doses have ranged from 0.25 mg per week to I mg daily. Paricalcitol is an- other vitamin D analogue which is used to treat the sec- ondary hyperparathyroidism associated with chronic renal failure. When vitamin D substances are given in pharmaco- logical doses, dosage must be individualised for each patient, and should be based on regular moni- toring of plasma-calcium concentrations (initially weekly, and then every 2 to 4 weeks), to optimise clinical response and avoid hypercalcaemia. Vitamin D, usually in the form of calcitriol. may be used in the treatment ofosteoporosis (see below). In established postmenopausal osteoporosis, calcitriol 0.25 ng twice daily is recommended. Vitamin D and calcium supplements are often given as adjuncts to other therapies in osteoporosis. Calcitriol has been used in the management of psor- iasis (see below). Calciferol derivatives are used as a rodenticide. Hyperparathyroidism. Vitamin D has been employed for certain forms of hyperparathyroidism. The secondary hyper- parathyroidism of renal osteodystrophy may respond to oral or intravenous treatment with calcitriol. or its analogue alfacalcidol. which do not require renal hydroxylation tor activation. However, doses capable of suppressing parathy- roid hormone secretion may lead to hvpercalcaemia3 and a decline in renal function (see also under Adverse Effects. above), which may limit their value. Hypoparathyroidism. Although parenteral calcium salts may be given acutely for hypocalcaemic tetany. long-term treatment of hypoparathyroidism usually aims at cor- rection of associated hypocalcaemia with oral vitamin D compounds, which increase the intestinal absorption of calci- um. If dietary calcium is inadequate these may be combined with calcium supplementation. Hypoparathyroidism in pregnancy poses severe risks of fetal hyperparathyroidism with neonatal hypocalcaemic rickets, which may be fatal. Treatment with calcium and either chole- calciferol or ergocalciferol in doses of 1.25 to 2.5 mg daily, or dihydrotachysterol 0.25 to 1.0 mg daily is essentiaV Malignant neoplasms. The active form of vitamin D, cal- citriol (1,25-dihydroxycholecalciferol) has been found to pro- mote tissue differentiation and to inhibit cellular proliferation in vitm. These findings have prompted workers to investigate the potential role and efficacy of vitamin D metabolites or an- alogues (sometimes referred to as deltanoids) in malignant neoplasms and in other disorders of cell growth such as psor- iasis (see below). Animal and in vitro studies with alfacalcidol have led to the suggestion that evaluation should be undertaken in malignant disease of the human breast.' A study in humans has been performed with the calcitriol derivative calcipotriol in this trial calcipotriol used topically in advanced or cutane- ous metastatic breast cancer was considered to exert some positive effects and further investigation was considered war- ranted.' Regression of T-cell lymphoma of the skin (mycosis fungoides, has been reported following application of calcipotriol.' and following systemic treatment with calcitriol and a retinoid in a patient who failed to respond to topical calcipotriol.* However. 3 other patients with cutaneous T-cell lymphoma failed to respond to calcitriol and isotretinoin, which may have been because of the phenotype orstage of the disease. Systemic treatment, again with calcitriol and a retin- oid. has also been reported to produce regression of actinic keratoses and non-melanoma skin cancers in 4 patients Osteornalacia. Treatment of osteomalacia primari- ly aims at correcting any underlying deficiency states, and vi- tamin D substances, calcium* or phosphate supplements may be given by mouth as necessary. Where rickets is due to im- paired symhesis of calcitriol (type I pseudodeficiency) or re- ceptor resistance (type II pseudodeficiency) replacement therapy with calcitriol may be indicated (in the latter case with very high dose calcium),' while X-linked hypophospha- taemic rickets is generally treated with phosphate supplemen- tation and calcitriol. although vitamin D alone is also effective.' The use of single large doses of a vitamin D sub- stance (stosstherapie), for the prophylaxis of rickets, is highly controversial because of problems with toxicity, although it may be effective in patients with rickets due to proven vitamin D deficiency.-' PREGNANCY AND THE NEONATE. Most infants receive adequate calci- um and vitamin D during pregnancy and during breast feeding or bottle feeding to prevent the development of rick- ets.However, it is considered that there are certain groups of women whose infants may be at special risk of neonatal rick- ets and these include those suffering economic deprivation. those living at high latitudes, and Asian immigrants in north- ern Europe, especially in winter. It is therefore suggested that pregnant women in such circumstances should receive sup- plements as the diet and sunshine exposure may not be providing adequate calcium ( I to 1.2 g daily) or vitamin D (400 units daily).' Rickets may be more problematical in the premature infant as vitamin D requirements may be increased. Although there is no evidence that routine administration is necessary or desir- able, healing of illness as a result of rickets may be achieved rapidly by the use of alfacalcidol 100 to 200 ng per kg body- weight daily.' Oiteopetrosis. For mention of the use of high-dose calcitri- ol in the management of juvenile osteopetrosis, see under Corticosteroids, p. 1024. Osteoporosis. Studies using vitamin D for the treatment of osteoporosis have produced conflicting results. However, in patients over 75 years of age, in whom dietary deficiencies are common, calcium and vitamin D supplements are recommended. Vitamin D may be used in the prevention of corticosteroid induced osteoporosis.