CALCIPLEX 250 MG TABLETS

Indications

• Calcium deficiency states
• Osteoporosis prevention and treatment
• Psoriasis
• Hypoparathyroidism
• Renal osteodystrophy

Mechanism of action

Calcitriol exerts its effects primarily through its interaction with vitamin D receptors (VDRs), which are ligand-activated transcription factors. Upon binding to its receptor, calcitriol forms a heterodimeric complex with retinoic acid X receptor (RXR) that binds to vitamin D-responsive elements in DNA, leading to the regulation of gene transcription. This action accounts for its antiproliferative effects on keratinocytes in psoriasis, its immunomodulatory activities, and its potential anticarcinogenic effects through the modulation of VDR levels in cancer cells. Additionally, it may suppress pro-inflammatory responses by downregulating the expression of certain receptors in immune cells.

Pharmacodynamics

As a biologically active form of vitamin D, calcitriol enhances calcium absorption in the intestines, increases renal reabsorption of calcium, and influences bone metabolism. It is a potent immunomodulator, impacting the activity of T and B lymphocytes. The pharmacological effects extend to the regulation of various cellular processes, including proliferation and differentiation, particularly in keratinocytes and immune cells. Its duration of action is approximately 3 to 5 days following a single dose.

Pharmacokinetics

Calcitriol is well-absorbed from the gastrointestinal tract and is extensively metabolized in the liver and kidneys. It has a half-life that typically ranges from 5 to 8 hours, and its effects can last several days due to its pharmacodynamic properties. The metabolism involves hydroxylation processes and is influenced by the patient’s vitamin D status, renal function, and other factors such as age and body weight.

Contra-indications

• Hypercalcemia
• Vitamin D toxicity
• Severe renal impairment

Adverse effects

• Hypercalcemia
• Hyperphosphatemia
• Nausea
• Vomiting
• Constipation
• Weakness
• Headache
• Dizziness
• Dry mouth
• Metallic taste

Interactions

• Thiazide diuretics may enhance the risk of hypercalcemia
• High doses of magnesium-containing antacids may lead to increased magnesium levels
• Phenytoin and barbiturates may reduce calcitriol efficacy due to accelerated metabolism

Precautions

• Monitor calcium levels during therapy
• Use caution in patients with a history of kidney stones
• Caution in patients with cardiovascular disease
• Adjust dosage in renal impairment

Pregnancy

Calcitriol is classified as pregnancy category C. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Calcitriol is excreted in breast milk. Caution should be exercised when administering to a nursing mother.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Capsules
• Oral solution
• Injectable solution

Mechanism of action

Carbonate ions participate in buffering reactions that help maintain pH homeostasis in biological systems. They can react with acids to form bicarbonate and carbon dioxide, thus neutralizing excess acidity in the body. This mechanism is crucial in processes such as respiration and metabolism.

Pharmacodynamics

As a buffer, carbonate helps to stabilize pH levels in different biological environments, preventing excessive acidity or alkalinity that could impair cellular functions. It is involved in the transport of carbon dioxide in the blood and plays a role in maintaining the acid-base equilibrium necessary for physiological processes.

Pharmacokinetics

Carbonate ions are readily absorbed in the gastrointestinal tract when ingested and can be found in various body fluids. They are involved in the bicarbonate buffering system, where they are converted to bicarbonate (HCO3-) and carbon dioxide (CO2) through reactions with acids. The kidneys regulate the levels of bicarbonate and carbonate in the body, excreting or reabsorbing them as needed to maintain homeostasis.

Pregnancy

There is no specific information available regarding the use of carbonate compounds during pregnancy. Consult a healthcare provider for advice.

Breast-feeding

There is no specific information available regarding the use of carbonate compounds while breastfeeding. Consult a healthcare provider for advice.

Storage

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

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.