Citrol

Uses

Calcitriol & Calcium combination is used for Osteoporosis, Hypoparathyroidism, Hypocalcaemia, Osteomalacia rickets, Renal osteodystrophy.

Citrol is also used to associated treatment for these conditions: Hypocalcemia, Osteodystrophy, Psoriasis Vulgaris (Plaque Psoriasis), Secondary Hyperparathyroidism (SHPT), Vitamin D Resistant RicketsCalcium Deficiency, Deficiency of Vitamin D3, Deficiency, Vitamin D, Folate deficiency, Hypocalcemia, Iron Deficiency (ID), Osteoporosis

How Citrol works

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.

Calcium citrate increases plasma calcium levels. This reduces calcium flux from osteocyte activity by reducing the secretion of parathyroid hormone (PTH) . Calcium does this by stimulating a G-protein coupled calcium receptor on the surface of parathyroid cells. The reduction in calcium flux increases the amount of calcium deposited in bone resulting in an increase in bone mineral density. The reduction in PTH secretion also reduces the amount of vitamin D metabolized to its active form, calcidiol. Since calcidiol increases the expression of calcium dependent ATPases and transient receptor potential cation channel subfamily V member 6 (TRPV6) both of which are involved in calcium uptake from the gut, a reduction in calcidiol results in less calcium absorption. Additionally, TRPV5, the channel responsible for calcium reabsorption in the kidney, is downregulated when PTH secretion is reduced thus increasing calcium excretion via the kidneys. Another hormone, calitonin, is likely involved in the reduction of bone resorption during periods of high plasma calcium.

Dosage

Citrol dosage

Hyperparathyroidism in renal failure: 0.25 mcg/day or alternate day. May increase slowly.

Hypoparathyroidism or pseudohypoparathyroidism: 0.5-2 mcg once daily.

Vitamin D dependent rickets: 0.015-0.02 mcg/kg/day. Maintenance: 0.03-0.06 mcg/kg/day. Max: 2 mcg/day.

Hyperparathyroidism in dialysis patients: 0.5-4 mcg 3 times/wk. Max: 8 mcg 3 times/wk.

Hyperparathyroidism in renal failure: 0.5 mcg 3 times/wk, may increase by 0.25-0.5 mcg at 2-4 wk intervals. Maintenance: 0.5-3 mcg 3 times/wk.

Side Effects

Weakness; headache; somnolence; nausea; vomiting; dry mouth; constipation; muscle pain; bone pain; metallic taste; polyuria; polydipsia; anorexia; irritability; weight loss; nocturia; mild acidosis; reversible azotemia; generalized vascular calcification; nephrocalcinosis; conjunctivitis (calcific); pancreatitis; photophobia; rhinorrhoea; pruritus; hyperthermia; decreased libido; elevated BUN; albuminuria; hypercholesterolaemia; elevated AST and ALT; ectopic calcification; hypertension; cardiac arrhythmias.

Toxicity

LD₅₀ (oral, rat) = 620 μg/kg; LD₅₀ (intraperitoneal, rat) > 5 mg/kg .

Symptoms of calcitriol toxicity mirrors the early and late signs and symptoms of vitamin D intoxication associated with hypercalcemia . Early signs include weakness, headache, somnolence, nausea, vomiting, dry mouth, constipation, muscle pain, bone pain and metallic taste. Late signs are characterized by polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis (calcific), pancreatitis, photophobia, rhinorrhea, pruritus, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated SGOT and SGPT, ectopic calcification, hypertension, cardiac arrhythmias and, rarely, overt psychosis .

Patients taking more than 4g of calcium a day are at risk of hypercalcemia and metabolic alkalosis . Chronic intake of calcium supplements is associated with adverse gastrointestinal symptoms such as constipation and flatulence .

Precaution

Idiopathic hypercalcaemia. Pediatric doses must be individualised and monitored under close medical supervision. Coronary disease, renal function impairment and arteriosclerosis, especially in the elderly. Hypoparathyroidism.

Interaction

Calcium: Co-administration with thiazide diuretics or vit D may lead to milk-alkali syndrome and hypercalcaemia. Decreased absorption with corticosteroids. Decreases absorption of tetracyclines, atenolol, iron, quinolones, alendronate, Na fluoride, Zn and calcium-channel blockers. Enhances cardiac effects of digitalis glycosides and may precipitate digitalis intoxication.

Calcitriol: Hypermagnesaemia may develop in patients on chronic renal dialysis. Hypercalcaemia in patients on digitalis may precipitate cardiac arrhythmias. Intestinal absorption of calcitriol may be reduced by cholestyramine and colestipol. Phenytoin, barbiturates may decrease the T1/2 of calcitriol. May develop hypercalcaemia with thiazide diuretics.

Volume of Distribution

Upon intravenous administration, the volume of distribution of calcitriol was 0.49±0.14 L/kg in healthy male volunteers and 0.27±0.06 l/kg in uraemic male patients participating in a pharmacokinetic study . There is some evidence that calcitriol is transferred into human milk at low levels (ie, 2.2±0.1 pg/mL) in mothers . Calcitriol from maternal circulation may also enter the fetal circulation .

Elimination Route

Upon administration, calcitriol is rapidly absorbed from the intestines. When a single oral dose of 0.5 mcg of calcitriol was administered, the mean serum concentrations of calcitriol rose from a baseline value of 40.0±4.4 (SD) pg/mL to 60.0±4.4 pg/mL at 2 hours, and declined to 53.0±6.9 at 4 hours, 50±7.0 at 8 hours, 44±4.6 at 12 hours and 41.5±5.1 at 24 hours . Following administration of single doses of 0.25 to 1.0 mcg of calcitriol, the peak plasma concentrations were reached within 3 to 6 hours . In a pharmacokinetic study, the oral bioavailability was 70.6±5.8% in healthy male volunteers and 72.2±4.8% in male patients with uraemia .

The percentage of calcium absorbed varies inversely with intake . Tmax of about 3.5-5h varying with formulation .

Half Life

After administration of single oral doses, the elimination half life was 5-8 hours .

Clearance

The metabolic clearance rate was 23.5±4.34 ml/min in healthy male volunteers and 10.1±1.35 ml/min in male patients with uraemia . In the pediatric patients undergoing peritoneal dialysis receiving dose of 10.2 ng/kg (SD 5.5 ng/kg) for 2 months, the clearance rate was 15.3 mL/hr/kg .

Elimination Route

In normal subjects, approximately 27% and 7% of the radioactivity appeared in the feces and urine, respectively, within 24 hours . Calcitriol undergoes enterohepatic recycling and biliary excretion. The metabolites of calcitriol are excreted primarily in feces. Cumulative excretion of radioactivity on the sixth day following intravenous administration of radiolabeled calcitriol averaged 16% in urine and 49% in feces .

Cleared via the kidneys but largely reabsorbed (98-99%) under normal conditions .

Pregnancy & Breastfeeding use

Pregnancy Category-C. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks

Contraindication

Hypercalcaemia; evidence of vitamin D toxicity, pregnancy & lactation.

Special Warning

Elderly patients: No specific dosage modifications are required in elderly patients.

Acute Overdose

Administration of Calcitriol to patients in excess of their daily requirements can cause hypercalcaemia, hypercalciuria and hyperphospatemia. Since Calcitriol is a derivative of vitamin D, the signs and symptoms of overdose are the same as for an overdose of vitamin D.

Storage Condition

Store between 15-30° C. Protect from moisture, heat and light. Do not freeze.

Innovators Monograph

You find simplified version here Citrol