Calcitriol
Calcitriol
Generic Name
Calcitriol
Mechanism
- Receptor binding – Binds intracellular vitamin D‑receptor (VDR) in target cells (enterocytes, osteoblasts, immune cells).
- Gene transcription – The VDR‑calcitriol complex heterodimerizes with the retinoid‑X receptor (RXR), translocates to the nucleus, and binds vitamin‑D‑response elements (VDREs) in promoter regions.
- Intestinal absorption – Upregulates *calbindin D₉k*, *transepithelial calcium transport proteins*, and intestinal epithelial uptake of Ca²⁺ and PO₄³⁻.
- Bone modulation – Enhances osteoblast commitment and bone matrix mineralization while indirectly inhibiting excessive osteoclast activity through RANKL/RANK signaling.
- Immune modulation – Induces differentiation of macrophages and dendritic cells, shifts T‑cell profiles toward anti‑inflammatory Th2 responses, and enhances antimicrobial peptide production (e.g., cathelicidin).
---
Pharmacokinetics
| Parameter | Details |
| Absorption | Oral, fat‑soluble; best absorbed when taken with meals. Bioavailability ~ 30–50 %. |
| Distribution | Widely distributed; bound primarily to plasma vitamin‑D‑binding protein (≈ 85 %) and albumin. Volume‑of‑distribution ~ 10 L/kg. |
| Metabolism | Hepatic 1‑α‑hydroxylation (CYP27B1) → active; catabolized by CYP24A1 to inactive 24‑hydroxylated metabolites. |
| Elimination | Renally excreted; half‑life (steady‑state) ~ 2–3 days. |
| Protein Binding | High; saturable in hyper‑vitamin‑D states. |
--
•
Indications
- Hypocalcemia
- *Post‑thyroidectomy hypoparathyroidism* (primary replacement).
- *Dialysis‑dependent renal osteodystrophy* and secondary hyperparathyroidism.
- *Vitamin‑D‑responsive rickets (radioducent, vitamin‑D‑resistant)* in pediatric patients.
- Bone disease in end‑stage renal disease (prevent bone loss, biochemical control of hyperphosphatemia).
- Certain cancers – Immunomodulation in chronic lymphocytic leukemia, T‑cell lymphoma, and metastatic breast/colon cancers (off‑label).
- Hypercalcemia of malignancy – As an adjunctive agent in select cases.
---
Contraindications
| Category | Details |
| Absolute | |
| • Hypercalcemia (serum Ca > 12 mg/dL). | |
| • Hyperphosphatemia (> 5.5 mg/dL) in renal failure. | |
| • Uncontrolled G‑banded malignant hypercalcemia. | |
| Relative | |
| • Acute kidney injury (risk of nephrolithiasis). | |
| • Vitamin D intoxication syndrome. | |
| • Pregnancy and lactation – use only if benefits outweigh risks. | |
| Warnings | Monitor serum Ca, phosphate, and creatinine in all patients. |
| • Potential for arrhythmias with severe hypercalcemia. | |
| • Interaction with glucocorticoids – reduces efficacy. |
--
•
Dosing
| Indication | Adult Dose | Pediatric Dose (≈ Age) | Notes |
| Hypoparathyroidism | 0.25–4 µg PO daily (titrated) | 0.25–1 µg/day (adjusted for weight) | Initiate low dose; adjust to maintain 8–10 mg/dL Ca. |
| Dialysis‑dependent renal osteodystrophy | 0.5 µg PO daily (oral or NP) | 0.5–1 µg PO daily | Start with 0.5 µg; titrate based on Ca/P, PTH, and bone markers. |
| Vitamin‑D‑resistant rickets (Pediatric) | 0.1–1 µg/kg/day (sublingual) | 0.1–0.5 µg/kg/day | Usually 5–7 days/week; monitor growth. |
| Hypercalcemia of malignancy | 0.25–0.5 µg/kg IV q24h (up to 4 µg) | 0.1–0.25 µg/kg IV | Short‑term rescue; combine with bisphosphonates. |
| Caution with steroids | If concomitant prednisolone > 5 mg/d, increase calcitriol requirement by ~ 50 %. |
• Formulations – Oral tablets (0.25–4 µg), sublingual gel (0.25–1 µg), IV (0.10–0.25 µg). NP (Nipple‑pad) for dialysis patients.
• Administration – Provide with high‑fat meals to maximize absorption; avoid concurrent calcium carbonate supplements on same dose to reduce *first‑pass* absorption of calcitriol.
--
•
Adverse Effects
| Category | Adverse Effect | Details |
| Common | Hypercalcemia | 1–2 mg/dL rise within 7–14 days. |
| Polyuria / polydipsia | Due to nephrogenic DI. | |
| Hypomagnesemia (indirect) | Secondary to calcium‑driven PTH suppression. | |
| GI upset | Nausea, constipation, abdominal pain. | |
| Serious | Hypercalcemia‑induced arrhythmias | Elevated QTc, atrial fibrillation. |
| Nephrolithiasis / nephropathy | Calcium stone formation, reduced creatinine clearance. | |
| Osteoporosis / bone loss | Paradoxical bone resorption with overdosing. | |
| Hormone suppression | Suppression of PTH leading to hypoparathyroidism. |
--
•
Monitoring
| Parameter | Target | Frequency |
| Serum calcium (total and ionized) | 8.5–10.5 mg/dL | Baseline ➜ 2–3 weeks ➜ monthly (or per protocol). |
| Serum phosphate | 2.5–4.5 mg/dL | As for calcium. |
| Creatinine / eGFR | ≤ 20 mL/min/1.73 m² (dialysis) | Every 4 wk; sooner if clinical changes. |
| PTH (intact) | 150–300 pg/mL (dialysis) | 1–3 mo; adjust dose accordingly. |
| Urea or 24‑h urinary calcium (in pts with stones) | ≤ 250 mg/day | Baseline, then every 6–12 mo. |
| Alkaline phosphatase | Normalization | Every 3–6 mo. |
| 25‑OH vitamin D (for compliance) | > 20 ng/mL | Baseline; repeats per specialty. |
• Electrocardiogram if symptomatic or Ca > 12 mg/dL.
--
•
Clinical Pearls
1. Calcitriol → the “active” D – Unlike ergocalciferol (vitamin D₂), calcitriol bypasses hepatic 25‑hydroxylation, making it preferable in patients with liver disease or absorption issues.
2. Dialysis synergy – When combined with high‑phosphorus binders (sevelamer) and phosphate‑restricted diet, calcitriol effectively lowers PTH and stabilizes Ca/P.
3. Sublingual route superior in children – Avoids first‑pass hepatic metabolism; especially useful in kids with malabsorption.
4. Avoid simultaneous high‑dose calcium supplement – Calcium can precipitate with calcitriol in the gut, reducing bioavailability; space them by at least 2 h.
5. Add‑on to glucocorticoids – Steroid therapy reduces endogenous 1‑α‑hydroxylase activity; clinicians should anticipate a 30–50 % increase in calcitriol dose to maintain normocalcemia.
6. Watch for neuromuscular irritability – High serum calcium can cause paresthesias, cramps, and even seizures; consider early dose reduction if symptoms arise.
7. Bone salvage paradox – Over‑supplementation can trigger bone resorption; titrate slowly and confirm with bone turnover markers.
8. Renal stone risk – Implement low‑calcium diet and low‑P intake to mitigate nephrolithiasis in long‑term users.
9. Treatment of vitamin‑D‑resistant rickets – In children < 5 yr, use 0.1 µg/kg/day sublingual; start at 2 mg serum Ca for 4–6 wk before titration.
10. Use with caution in obstructions – Congestive heart failure can amplify the serum‑Ca rise; consider alternate agents like cinacalcet if persistent hypercalcemia.
--
• Calcitriol remains a cornerstone for managing hypocalcemia, renal osteodystrophy, and certain immune‑mediated conditions. Early recognition of its pharmacodynamic profile, vigilant monitoring, and individualized dosing are essential for optimal patient safety and therapeutic efficacy.