Vitamin D

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Chapter: Essential pharmacology : Drugs Affecting Calcium Balance

Vitamin D is the collective name given to antirachitic substances synthesized in the body and found in foods activated by UV radiation.


VITAMIN D

 

Vitamin D is the collective name given to antirachitic substances synthesized in the body and found in foods activated by UV radiation.

 

D3 : cholecalciferol — synthesized in the skin under the influence of UV rays.

D2 : calciferol—present in irradiated food— yeasts, fungi, bread, milk.

D1 : mixture of antirachitic substances found in food—only of historic interest.

 

In 1919 it was established that rickets was due to deficiency of a dietary factor as well as lack of exposure to sunlight. McCollum (1922) showed that this fat soluble dietary factor was different from vit A and its structure was determined in 1935. The interrelation between calciferol and cholecalciferol and their activation in the body has been fully understood only in the 1970s.

 

Activation of Vit D

 

It takes place in the following manner—

 

Ergosterol differs from 7dehydrocholesterol in having an extra double bond between C22–23 and a methyl group at C24. In man vit D2 and D3 are equally active and calcitriol (active form of D3) is more important physiologically; 25OH D3 is released in blood from the liver and binds loosely to a specific vit D binding globulin. The final hydroxylation in kidney is rate limiting and is controlled by many factors. This step is activated or induced by calcium/vit D deficiency as well as by PTH, estrogens and prolactin, while calcitriol inhibits it in a feedback manner.

 


 

Thus, vit D should be considered a hormone because:

 

a)  It is synthesized in the body (skin); under ideal conditions it is not required in the diet.

b)  It is transported by blood, activated and then acts on specific receptors in the target tissues.

c)   Feedback regulation of vit D activation occurs by plasma Ca2+ level and by the active form itself.

 

 

Actions

 

1. Calcitriol enhances absorption of calcium and phosphate from intestine. This is brought about by increasing the synthesis of calcium channels and a carrier protein for Ca2+ called ‘calcium binding protein’ (Ca BP) or Calbindin. The action of calcitriol is analogous to that of steroid hormones. It binds to a cytoplasmic vitamin D receptor (VDR) translocate to the nucleus increase synthesis of specific mRNA regulation of protein synthesis. Another line of evidence suggests that activation of VDR promotes endocytotic capture of calcium and transports it across the duodenal mucosal cell in vesicular form. At least part of vit D action is quick (within minutes) and, therefore, appears to be exerted by mechanisms not involving gene regulation.

 

2. Calcitriol enhances resorption of calcium and phosphate from bone by promoting recruitment and differentiation of osteoclast precursors in the bone remodeling units, but mature osteoclasts lack VDR. Like PTH, calcitriol induces RANKL in osteoblasts which may then activate the osteoclasts. Osteoblastic cells express VDR and respond to calcitriol by laying down osteoid, but it mainly appears to help bone mineralization indirectly by maintaining normal plasma calcium and phosphate concentration. Its action is independent of but facilitated by PTH.

 

3. Calcitriol enhances tubular reabsorption of calcium and phosphate in the kidney, but the action is less marked than that of PTH. However, in hypervitaminosis D, influence of hypercalcaemia overrides the direct action and more calcium is excreted in urine.

 

4. Other actions Actions of calcitriol on immunological cells, lymphokine production, proliferation and differentiation of epidermal and certain malignant cells, neuronal and skeletal muscle function have also been demonstrated.

 

Vit D Deficiency

 

Plasma calcium and phosphate tend to fall due to inadequate intestinal absorption. As a consequence, PTH is secreted calcium is mobilized from bone in order to restore plasma Ca2+. The bone fails to mineralize normally in the newly laid area, becomes soft rickets in children and osteomalacia in adults. However, in contrast to osteoporosis, the organic matrix (osteoid) is normal in these conditions.

 

Hypervitaminosis D

 

It may occur due to chronic ingestion of large doses (~50,000 IU/day) or due to increased sensitivity of tissues to vit D. Manifestations are due to elevated plasma calcium and its ectopic deposition.

 

Hypercalcaemia, weakness, fatigue, vomiting, diarrhoea, sluggishness, polyuria, albuminuria, ectopic Ca2+ deposition (in soft tissues, blood vessels, parenchymal organs), renal stones or nephrocalcinosis, hypertension, growth retardation in children. Even coma has been reported. Treatment: consists of withholding the vitamin, low calcium diet, plenty of fluids and corticosteroids. Recovery may be incomplete in many cases.

 

 

Pharmacokinetics

 

Vit D is well absorbed from the intestines in the presence of bile salts, mainly through lymphatics. Absorption of D3 form is somewhat better than that of D2. Malabsorption and steatorrhoea interfere with its absorption.

 

In the circulation, it is bound to a specific α globulin and is stored in the body, mostly in adipose tissues, for many months. It is hydroxylated in the liver to active and inactive metabolites. The t½ of different forms varies from 1–18 days: 25OHD 3, having the longest t½ , constitutes the primary circulating form. Calcitriol is cleared rapidly.

 

Metabolites of vit D are excreted mainly in bile.

 

Unitage  And  Preparations

 

1 μg of cholecalciferol = 40 IU of vit D.

 

The daily requirement varies, depending on exposure to sunlight. It is estimated that if no vit D3 is synthesized in the body, a dietary allowance of 400 IU/day will prevent deficiency symptoms. The forms in which vit D is supplied are—

 

1. Calciferol (Ergocalciferol, vit D2) As solution in oil, filled in gelatin capsules 25,000 and 50,000 IU caps.

 

2. Cholecalciferol (vit D3) As granules for oral ingestion and oily solution for i.m. injection.

 

ARACHITOL 300,000 IU (7.5 mg) and 600,000 IU (15 mg) per ml inj.

 

CALCIROL 60,000 IU in 1 g granules—given at 3–4 weeks intervals, and then every 2–6 months.

 

3. Calcitriol 0.25–1 μg orally daily or on alternate days; CALTROL, ROLSICAL, ROCALTROL 0.25 μg cap. CALCIBEST 1 μg in 1 ml aqueous inj; 0.5–1 μg i.v. on alternate days.

 

Hypercalcaemia is the main adverse effect; must be watched for and therapy promptly stopped if plasma Ca2+ rises.

 

4. Alfacalcidol It is 1 αOHD3—a prodrug that is rapidly hydroxylated in the liver to 1, 25 (OH)2 D3 or calcitriol. Therefore, it does not require hydroxylation at position 1 which is the limiting step in the generation of the active form of vit D, and which takes place in the kidney. As such, it is effective in renal bone disease, vit D dependent rickets, vit D resistant rickets, hypoparathyroidism, etc.— indications for which calcitriol is needed. It is also being used in osteoporosis.

 

Alfacalcidol is orally active and clinically equally effective on long term basis to calcitriol. Its metabolic activation in liver does not pose a problem even in severe liver disease.

 

Dose: 1–2 μg/day, children < 20 kg 0.5 μg/day. Repeated serum calcium measurements are essential for regulation of maintenance dose. Hypercalcaemia should be watched for and therapy promptly interrupted for few days when it develops.

 

ONE ALPHA, ALPHA D3, ALPHADOL 0.25 and 1 μg caps, ALFACAL 0.25, 0.5 μg caps.

 

a)   Dihydrotachysterol (DHT) A synthetic analogue of vit D2—less active in antirachitic tests, but directly mobilizes calcium from bone: does not require PTH dependent activation in the kidney—particularly useful in hypoparathyroidism and renal bone disease.

Dose:  0.25–0.5 mg/day.

 

Combination preparations of vit D are listed in Table 67.2.

 

Use

 

1. Prophylaxis (400 IU/day) and treatment (3000–4000 IU/day) of nutritional vit D deficiency which causes rickets in children and osteomalacia in adults. Alternatively 300,000–600,000 IU can be given orally or i.m. once in 2–6 months. Prophylactic treatment may be given in obstructive jaundice, steatorrhoea and other conditions which predispose to vit D deficiency.

 

2. Metabolic rickets These are a group of conditions in which tissues do not respond to normal doses of vit D.

 

(a) Vit D resistant rickets: Xlinked hereditary disease in which vit D metabolism is normal but calcium and phosphate metabolism is deranged. Administration of phosphate with high dose of calcitriol or alfacalcidol is beneficial.

 

(b) Vit D dependent rickets: Another genetic disorder due to deficiency of renal hydroxylating mechanism which converts 25OHD3 into calcitriol. Administration of calcitriol or alfacalcidol is effective in normal doses.

 

(c) Renal rickets: Conversion of 25OHD3 into calcitriol does not occur due to chronic renal disease. Calcitriol/alfacalcidol or dihydrotachysterol are needed in usual doses.

 

3. Senile Or Postmenopausal Osteoporosis Agerelated decrease in calcium absorption from gut has been noted. Vit D3 + calcium have been shown to improve calcium balance in osteoporotic females and elderly males. However, benefit in terms of improved bone mass or reduced fracture risk is controversial or marginal (see p. 327). But this does not apply to active therapy with calcitriol/alfacalcidol for patients with established osteoporosis, because it suppresses parathyroids and reduces bone remodeling. Vit D deficiency results in secondary hyperparathyroidism which contributes to osteoporosis. Though bone mineral density may be improved, calcitriol therapy carries the risk of hypercalcaemia, calcium stones and metastatic calcification.

 

4. Hypoparathyroidism Dihydrotachysterol or calcitriol/alfacalcidol are more effective than vit D2 or D3 because they act quickly and directly without the need for hydroxylation in kidney which needs PTH. Alternatively, conventional preparations of vit D3 may be given in high doses (25000100,000 IU/day).

 

5. Fanconi Syndrome Vit D can raise the lowered phosphate levels that occur in this condition.

 

6. A nonhypercalcaemic analogue of vit D Calcipotriol (DAIVONEX 0.005% oint) is used locally in plaque type psoriasis, and has yielded good results (see Ch. No. 64). Systemically it has been tried in skin cancer and immunological disorders.

 

Interactions

 

1. Cholestyramine and chronic use of liquid paraffine can reduce vit D absorption.

 

2. Phenytoin and phenobarbitone reduce the responsiveness of target tissues to calcitriol; their prolonged use (for epilepsy) can cause rickets/ osteomalacia. It was believed earlier that these drugs enhance degradation of vit D. However, now it has been shown that plasma level of calcitriol is normal, but its effect on intestine and bone is diminished.

 

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