MEDITROL

Indications

• Hypoparathyroidism
• Vitamin D-dependent rickets
• Hypophosphataemic rickets
• Persistent hypocalcaemia due to hypoparathyroidism
• Prevention of vitamin D deficiency in renal or cholestatic liver disease

Dosage

Children: In neonates, the dose is typically 20 nanograms/kg once daily, while children aged 1 month to 11 years may receive 25-50 nanograms/kg once daily, adjusted as necessary. For children aged 12-17 years, the usual dose is 1 microgram once daily, also adjusted as needed.

Adults: The typical adult dose is 0.25 to 1 microgram per day, adjusted based on calcium and phosphate levels.

Mechanism of action

Calcitriol binds to vitamin D receptors in target tissues, which leads to increased intestinal absorption of calcium and phosphate, renal tubular reabsorption of calcium, and mobilization of calcium from the bones. This activity helps to maintain serum calcium levels, which is crucial for bone mineralization and overall skeletal health.

Pharmacodynamics

The pharmacodynamic effects of calcitriol include the regulation of calcium homeostasis and promotion of bone mineralization. By enhancing calcium absorption in the intestine and increasing renal reabsorption of calcium, calcitriol helps to prevent hypocalcemia. It also influences the activity of osteoblasts and osteoclasts, thus facilitating bone remodeling.

Pharmacokinetics

Calcitriol is well-absorbed from the gastrointestinal tract, with peak plasma concentrations occurring approximately 6 to 24 hours after oral administration. Its half-life is about 5 to 8 hours. It is metabolized in the liver and other tissues, and the metabolites are excreted primarily via the kidneys. Renal impairment can affect the metabolism and clearance of calcitriol, necessitating careful monitoring.

Contra-indications

• Hypercalcaemia
• Hypercalciuria
• Vitamin D toxicity
• Severe renal impairment

Adverse effects

• Hypercalcaemia
• Hypercalciuria
• Dizziness
• Weight decreased
• Confusion
• Renal impairment
• Muscle weakness
• Paralytic ileus
• Polydipsia
• Psychiatric disorder
• Sensory disorder
• Urinary disorders

Interactions

• Other vitamin D compounds
• Thiazide diuretics (may increase risk of hypercalcaemia)
• Anticonvulsants (may reduce vitamin D activity)

Precautions

• Monitor plasma calcium concentration, especially in renal impairment
• Careful dosing in infants
• Avoid excessive sun exposure and sunlamps
• Use with caution in patients with a history of nephrolithiasis

Pregnancy

Manufacturers advise avoiding unless essential due to potential risks.

Breast-feeding

No information available on safety during breastfeeding.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Calcitriol oral drops 1 microgram/mL
• Calcitriol capsules 250 nanograms
• Calcitriol capsules 500 nanograms
• Calcitriol capsules 1 microgram

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)₂-D3 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)₂-D3 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. A study suggests that calcitriol plays an immunoregulatry role by suppressing the aryl hydrocarbon receptor (AhR) expression in human Th9, a pro-inflammatory CD4 T cell subset. This suppression subsequently leads to repressed expression of BATF, a transcription factor essential for Th9. Calcitriol 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. Ergocalciferol and doxercalciferol (1-hydroxyergocalciferol); cholecalciferol and calcifediol (25-hydroxycholecalciferol); and dihydrotachysterol in their activated forms (1,25-dihydroxyergocalciferol; 1,25-dihydroxycholecalciferol [calcitriol]; and 25-hydroxydihydrotachysterol; respectively), along with parathyroid hormone and calcitonin, regulate serum calcium concentrations; in addition to conversion to the active 1,25-dihydroxycholecalciferol, calcifediol also has intrinsic activity. Calcitriol (activated vitamin D) enhances the efficiency of intestinal calcium absorption along the entire small intestine, but principally in the duodenum and jejunum. Calcitriol also enhances phosphorus absorption along the entire small intestine, but principally in the jejunum and ileum. The activated forms of ergocalciferol, doxercalciferol, and cholecalciferol may have a negative feedback effect on parathyroid hormone (PTH) production. Calcitriol appears to act in intestine in manner that is analogous to the way steroid hormones such as estrogens act on target tissues. ... Cytosol of chicken intestinal cells contains a 3.7 S protein that binds calcitriol specifically and with high affinity. Formation of complex with this receptor facilitates transfer of calcitriol to nuclear chromatin. ... Calcitriol stimulates synthesis of RNA and at least two proteins in intestinal mucosa, alkaline phosphatase and a calcium-binding protein. ... It was proposed that the calcium-binding protein is involved in transport of calcium. ... /However/, it has been reported that calcitriol-induced stimulation of intestinal transport of phosphate precedes that of calcium, and it is possible that primary effect of the vitamin is on phosphate rather than calcium transport. The effects of 1,25-dihydroxyvitamin D3 (I) on the human promyelocytic leukemia cell line HL-60 were investigated. I induces the differentiation of HL-60 into mono- and multinucleated macrophage-like cells. Phenotypic change is evident within 24 hours and reaches a plateau at 72-96 hours of incubation. The changes are metabolite-specific and include adherence to substrate, acquisition of the morphological features

Pharmacodynamics

Calcitriol is a biologically active calcitrophic hormone with anti-osteoporotic, immunomodulatory, anticarcinogenic, antipsoriatic, antioxidant, and mood-modulatory activities. Its main sites of action are the intestine, bone, kidney and parathyroid hormone. Calcitriol is a ligand for the vitamin D nuclear receptor, which is expressed in, but not limited to, gastrointestinal (GI) tissues, bones, and kidneys. As an active form of vitamin D₃, calcitriol elevates the plasma levels of calcium by stimulating intestinal calcium uptake, increasing reabsorption of calcium by the kidneys, and possibly increasing the release of calcium from skeletal stores. The duration of pharmacologic activity of a single dose of exogenous calcitriol is expected to be about 3 to 5 days. In addition to its important role in calcium metabolism, other pharmacological effects of calcitriol have been studied in various conditions including cancer models. Various studies demonstrated expression of vitamin D receptors in cancer cell lines, including mouse myeloid leukemia cells. Calcitriol has been found to induce differentiation and/or inhibit cell proliferation _in vitro_ and _in vivo_ in many cell types, such as malignant cell lines carcinomas of the breast, prostate, colon, skin, and brain, myeloid leukemia cells, and others. In early human prostate cancer trials, administration of 1.5 µg/d calcitriol in male participants resulted in a reduction in the rate of PSA rise in most participants, however it was coincided with dose-limiting hypercalcemia in most participants. Hypercalcemia and hypercalcuria were evident in numerous initial trials, and this may be due to these trials not testing the drug at concentrations that are active in preclinical systems. Findings from preclinical data show an additive or synergistic antineoplastic action of calcitriol when combined with agents including dexamethasone, retinoids, and radiation, as well as several cytotoxic chemotherapy drugs such as platinum compounds. Vitamin D deficiency has long been suspected to increase the susceptibility to tuberculosis. The active form of calcitriol, 1,25-(OH)₂-D3, has been found to enhance the ability of mononuclear phagocytes to suppress the intracellular growth of <i>Mycobacterium tuberculosis</i>. 1,25-(OH)₂-D3 has demonstrated beneficial effects in animal models of such autoimmune diseases as rheumatoid arthritis. Vitamin D appears to demonstrate both immune-enhancing and immunosuppressive effects.