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Active ingredient: Calcitriol - Brands, Medical Use, Clinical Data

Brands, Medical Use, Clinical Data

Drug Category

  • Antihypocalcemic Agents
  • Antihypoparathyroid Agents
  • Essential Vitamin
  • Vitamins (Vitamin D)

Dosage Forms

  • Capsules
  • Solution

Brands / Synonyms

Calcijex; Calcitriol; Calcitriol (JAN/USP); Rocaltrol; Rocaltrol (TN)

Indications

Used to treat vitamin D deficiency or insufficiency, refractory rickets (vitamin D resistant rickets), familial hypophosphatemia and hypoparathyroidism, and in the management of hypocalcemia and renal osteodystrophy in patients with chronic renal failure undergoing dialysis. Also used in conjunction with calcium in the management and prevention of primary or corticosteroid-induced osteoporosis.

Pharmacology

Calcitriol, a pharmaceutical form of vitamin D, has anti-osteoporotic, immunomodulatory, anticarcinogenic, antipsoriatic, antioxidant, and mood-modulatory activities. Calcitriol has been found to be effective in the treatment of psoriasis when applied topically. Calcitriol has been found to induce differentiation and/or inhibit cell proliferation in a number of malignant cell lines including human prostate cancer cells. Vitamin D deficiency has long been suspected to increase the susceptibility to tuberculosis. The active form of Calcitriol, 1,25 (OH)2 D, has been found to enhance the ability of mononuclear phagocytes to suppress the intracellular growth of Mycobacterium tuberculosis. 1,25(OH)2D has demonstrated beneficial effects in animal models of such autoimmune diseases as rheumatoid arthritis. It has also been found to induce monocyte differentiation and to inhibit lymphocyte proliferation and production of cytokines, including interleukin IL-1 and IL-2, as well as to suppress immunoglobulin secretion by B lymphocytes. Vitamin D appears to demonstrate both immune-enhancing and immunosuppressive effects.

Mechanism of Action

The mechanism of action of Calcitriol in the treatment of psoriasis is accounted for by their antiproliferative activity for keratinocytes and their stimulation of epidermal cell differentiation. The anticarcinogenic activity of the active form of Calcitriol appears to be correlated with cellular vitamin D receptor (VDR) levels. Vitamin D receptors belong to the superfamily of steroid-hormone zinc-finger receptors. VDRs selectively bind 1,25(OH)2D and retinoic acid X receptor (RXR) to form a heterodimeric complex that interacts with specific DNA sequences known as vitamin D-responsive elements. VDRs are ligand-activated transcription factors. The receptors activate or repress the transcription of target genes upon binding their respective ligands. It is thought that the anticarcinogenic effect of Calcitriol is mediated via VDRs in cancer cells. The immunomodulatory activity of Calcitriol is thought to be mediated by vitamin D receptors (VDRs) which are expressed constitutively in monocytes but induced upon activation of T and B lymphocytes. 1,25(OH)2D has also been found to enhance the activity of some vitamin D-receptor positive immune cells and to enhance the sensitivity of certain target cells to various cytokines secreted by immune cells.

Absorption

Rapidly absorbed from the intestine.

Toxicity

LD50 (oral, rat) = 620 μg/kg; LD50 (intraperitoneal, rat) > 5 mg/kg; Overdose evident in elevated blood calcium levels causing symptoms of anorexia, nausea and vomiting, polyuria, polydipsia, weakness, pruritus, and nervousness, potentially with irreversible calcification of soft tissue in the kidney and liver.

Biotrnasformation / Drug Metabolism

The first pathway involves 24-hydroxylase activity in the kidney; this enzyme is also present in many target tissues which possess the vitamin D receptor such as the intestine. The end product of this pathway is a side chain shortened metabolite, calcitroic acid. The second pathway involves the conversion of calcitriol via the stepwise hydroxylation of carbon-26 and carbon-23, and cyclization to yield ultimately 1a,25R(OH)2-26,23S-lactone D3. The lactone appears to be the major metabolite circulating in humans.

Contraindications

Contraindications for vitamin D analogues (Vitamin D2, Vitamin D3, Calcitriol, and Calcidiol):

Vitamin D should not be given to patients with hypercalcemia or evidence of vitamin D toxicity. Use of vitamin D in patients with known hypersensitivity to vitamin D (or drugs of the same class) or any of the inactive ingredients is contraindicated.

Drug Interactions

Interactions for vitamin D analogues (Vitamin D2, Vitamin D3, Calcitriol, and Calcidiol):

Cholestyramine:

Cholestyramine has been reported to reduce intestinal absorption of fat soluble vitamins; as such it may impair intestinal absorption of any of vitamin D.

Phenytoin/Phenobarbital:

The coadministration of phenytoin or phenobarbital will not affect plasma concentrations of vitamin D, but may reduce endogenous plasma levels of calcitriol/ergocalcitriol by accelerating metabolism. Since blood level of calcitriol/ergocalcitriol will be reduced, higher doses of Rocaltrol may be necessary if these drugs are administered simultaneously.

Thiazides:

Thiazides are known to induce hypercalcemia by the reduction of calcium excretion in urine. Some reports have shown that the concomitant administration of thiazides with vitamin D causes hypercalcemia. Therefore, precaution should be taken when coadministration is necessary.

Digitalis:

Vitamin D dosage must be determined with care in patients undergoing treatment with digitalis, as hypercalcemia in such patients may precipitate cardiac arrhythmias.

Ketoconazole:

Ketoconazole may inhibit both synthetic and catabolic enzymes of vitamin D. Reductions in serum endogenous vitamin D concentrations have been observed following the administration of 300 mg/day to 1200 mg/day ketoconazole for a week to healthy men. However, in vivo drug interaction studies of ketoconazole with vitamin D have not been investigated.

Corticosteroids:

A relationship of functional antagonism exists between vitamin D analogues, which promote calcium absorption, and corticosteroids, which inhibit calcium absorption.

Phosphate-Binding Agents:

Since vitamin D also has an effect on phosphate transport in the intestine, kidneys and bones, the dosage of phosphate-binding agents must be adjusted in accordance with the serum phosphate concentration.

Vitamin D:

The coadministration of any of the vitamin D analogues should be avoided as this could create possible additive effects and hypercalcemia.

Calcium Supplements:

Uncontrolled intake of additional calcium-containing preparations should be avoided.

Magnesium:

Magnesium-containing preparations (eg, antacids) may cause hypermagnesemia and should therefore not be taken during therapy with vitamin D by patients on chronic renal dialysis.

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