A CLOSER LOOK AT PHARMACOLOGY OF PARATHYROID HORMONE, VITAMIN D AND CALCITONIN

Pharmacology of Parathyroid Hormone (PTH), Vitamin D, and Calcitonin

(a) Parathyroid Hormone (PTH)

PTH is a peptide hormone secreted by the parathyroid glands that plays a critical role in calcium and phosphate homeostasis. It acts primarily on three target organs: bone, kidneys, and the intestine.

• Mechanism of Action: PTH increases serum calcium levels by stimulating osteoclast-mediated bone resorption, enhancing renal tubular reabsorption of calcium, and promoting the activation of vitamin D in the kidneys. Activated vitamin D (calcitriol) subsequently increases intestinal absorption of calcium.
• Pharmacological Effects:
  • Increases serum calcium levels.
  • Decreases serum phosphate levels by reducing renal tubular phosphate reabsorption.
  • Stimulates production of calcitriol in the kidneys.

Synthetic Analogs

1. Teriparatide (recombinant human PTH 1-34):
   • Route of Administration: Subcutaneous injection.
   • Clinical Uses: Treatment of osteoporosis in postmenopausal women and men at high risk for fractures; also used for glucocorticoid-induced osteoporosis.
   • Adverse Reactions: Hypercalcemia, nausea, dizziness, leg cramps, and potential risk of osteosarcoma with prolonged use.

2. Abaloparatide:
   • Route of Administration: Subcutaneous injection.
   • Clinical Uses: Similar to teriparatide; used for osteoporosis treatment in postmenopausal women at high fracture risk.
   • Adverse Reactions: Hypercalcemia, hypercalciuria, orthostatic hypotension, and increased uric acid levels.

(b) Vitamin D

Vitamin D is a fat-soluble prohormone that undergoes two hydroxylation steps to become biologically active as calcitriol (1,25-dihydroxyvitamin D). It regulates calcium and phosphate metabolism by increasing intestinal absorption and maintaining bone mineralization.

• Mechanism of Action: Calcitriol binds to the vitamin D receptor (VDR) in target tissues such as intestines, bones, kidneys, and parathyroid glands. This interaction modulates gene transcription to enhance calcium absorption from the gut and promote bone remodeling.
• Pharmacological Effects:
  • Increases intestinal absorption of calcium and phosphorus.
  • Promotes bone mineralization.
  • Suppresses parathyroid hormone secretion.

Synthetic Analogs

1. Calcitriol (1,25-dihydroxyvitamin D):
   • Route of Administration: Oral or intravenous administration.
   • Clinical Uses: Management of hypocalcemia in chronic kidney disease (CKD), hypoparathyroidism, rickets, and osteomalacia.
   • Adverse Reactions: Hypercalcemia leading to symptoms such as nausea, vomiting, weakness, polyuria, polydipsia; hyperphosphatemia.

2. Alfacalcidol (1α-hydroxyvitamin D3):
   • Route of Administration: Oral or intravenous administration.
   • Clinical Uses: Used in CKD patients to manage secondary hyperparathyroidism; also used for osteoporosis treatment.
   • Adverse Reactions: Hypercalcemia and hyperphosphatemia.

3. Doxercalciferol (synthetic vitamin D2 analog):
   • Route of Administration: Oral or intravenous administration.
   • Clinical Uses: Secondary hyperparathyroidism in CKD patients undergoing dialysis.
   • Adverse Reactions: Hypercalcemia and oversuppression of PTH leading to adynamic bone disease.

4. Ergocalciferol (Vitamin D2) & Cholecalciferol (Vitamin D3):
   • These are precursors converted into active metabolites within the body. They are administered orally for vitamin D deficiency or insufficiency but are less potent compared to calcitriol or alfacalcidol.

(c) Calcitonin

Calcitonin is a peptide hormone secreted by parafollicular cells (“C cells”) of the thyroid gland that lowers blood calcium levels by inhibiting osteoclastic activity in bones and reducing renal reabsorption of calcium.

• Mechanism of Action: Calcitonin binds directly to receptors on osteoclasts to inhibit their activity. It also reduces renal tubular reabsorption of both calcium and phosphate ions.
• Pharmacological Effects:
  • Decreases serum calcium levels by inhibiting bone resorption.
  • Promotes urinary excretion of calcium and phosphate.

Synthetic Analogs

1. Salmon Calcitonin:
   • More potent than human calcitonin due to higher receptor affinity.
   • Routes:
     1. Intranasal spray – commonly used for ease of administration.
     2. Subcutaneous or intramuscular injection – used when rapid action is required.
   • Clinical Uses:
     1. Treatment for Paget’s disease of bone,
     2. Postmenopausal osteoporosis,
     3. Hypercalcemia associated with malignancy,
     4. Bone pain relief from metastatic cancer lesions or fractures due to osteoporosis/Paget’s disease.
   • Adverse Reactions: Nasal irritation with intranasal use; nausea/vomiting; flushing; hypersensitivity reactions including anaphylaxis; long-term use may lead to antibody formation reducing efficacy.