Lecture pharmacology of calcium metabolism

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Lecture pharmacology of calcium metabolism

  1. 1. Pharmacology of calcium metabolism Gyanendra Raj Joshi PharmD, RPh
  2. 2. Objectives: Function / Physiological roles of calcium. Calcium and salts as drug Control of calcium metabolism. Parathyroid hormone. Calcitonin. Vitamin D. Drugs affecting calcium metabolism.
  3. 3. Calcium is required for: • Muscle and nerve functional integrity. • Cardiac function. • Coagulation of blood. • Cementing substance of the bones. Daily requirements: 0.5-0.75g/day. It increases during pregnancy and lactation. Normal serum calcium: 9 -11mg%. 6 - 6.5 mg% exists in ionized form, which is the active form.
  4. 4. Absorption and Excretion • Absorption- facilitated diffusion, carrier mediated active transport • Filtration • Reabsorption • Excretion
  5. 5. Preparations 1) Calcium chloride 2) Calcium gluconate 3) Calcium lactate 4) Calcium dibasic phosphate 5) Calcium carbonate Adverse effects : GI side effects : constipation, bloating , and excess gas Irritation Tissue necrosis
  6. 6. Uses: • As a supplement during pregnancy and lactation or when dietary calcium is low. • Osteomalacia and osteoporosis. • Hypoparathyroidism. • Acute tetany: 10-20 ml calcium gluconate 10% i.v in emergency. • Cal gluconate in dermatoses , paresthesias , weakness • As antacid
  7. 7. Control of Calcium Metabolism • Vitamin D • Calcitonin • Parathyroid hormone.
  8. 8. Vitamin D • It is a fat-soluble vitamin. • Normally, adults do not require vitamin D. • Children and female during pregnancy and lactation require 400-800 units/day. Forms of vitamin D: • Vit.D2 (ergocalciferol): it is of plant origin & formed by ultraviolet irradiation of ergosterol in plants. • Vit.D3 (cholecalciferol): it is made by ultraviolet irradiation of 7-dehydrocholesterol. It is the form presents in natural foods and is formed in the skin. • Vitamin D1: mixture of antirachitic substances
  9. 9. Activation of vitamin D: • D2 & D3 are made active by two hydroxylation reactions: • 25-hydroxylation in the liver to 25-OH-cholecalciferol (calcifediol). • 1α-hydroxylation in the kidney under the influence of parathyroid hormone to 1α- 25(OH)2 cholecalciferol (calcitriol). • Absence or deficiency of hydroxylase enzyme in the kidney causes renal rickets. • Renal rickets is treated with (1α-hydroxycholecalciferol) = alfacalcidol (one alpha).
  10. 10. Functions of vitamin D: • Increases absorption of calcium & phosphate from intestine. • Increases reabsorption of calcium & phosphate from renal tubules. • It deposits calcium into bone. • It raises plasma calcium and phosphate. • Increases excretion of magnesium in the urine.
  11. 11. Uses: • Rickets and osteomalacia. In renal failure & renal rickets use 1α-OH- cholecalciferol (alfacalcidol or one-alpha) that needs only hepatic hydroxylation to be more active (1α- 25(OH)2 cholecalciferol) • Pregnancy and lactation • Hypoparathyroidism. • Hypophosphatemia. • Osteoporosis. • Fanconi Syndrome • Psoriasis: local vitamin D (creams or ointments) preparation is available. Adverse reactions: Hypervitaminosis-D: hypercalcemia, hypercalciuria and soft tissue calcification especially in the kidney & blood vessels (calcinosis)
  12. 12. Forms available for clinical uses include 1. Natural forms: • D2 = ergocalciferol. It is of plant origin. • D3 = cholecalciferol. It is of an animal origin and formed by sunrays in the skin. 2. Active metabolites: • Calcitriol. • Alfacalcidol or one-alpha (1α- OH- cholecalciferol) 3. Vit. D analogue • Dihydrotachysterol.
  13. 13. Calcitonin It is a hormone secreted by C-cells of the thyroid gland. Mechanism: • GPCR, increase cAMP Role : • It inhibits osteoclasts  reduces bone resoption. • It reduces re-absorption of calcium & phosphorus in the kidney. • Lowering serum calcium. • It also has an analgesic effect in Paget’s disease, metastatic bone cancer and after vertebral fracture due to osteoporosis. Source: • Natural sources (pork, salmon, eel). • Synthesizes. Preparation: It is available as solution for s.c, i.m injection and as nasal spray.
  14. 14. Uses: • Hypercalcemia • • • • – Hyperparathyroidism – Hypervitaminosis – Malignancy Postmenopausal osteoporosis. To promote healing of bones Paget’s disease Metastatic bone cancer pain. Adverse effects: • Allergy, flushing, nausea, vomiting, and tingling of face & hands. • Bad taste • May interfere with action of Digoxin
  15. 15. Parathyroid hormone • Secreted by parathyroid glands – Rapid response to reduced calcium (minutes) • Polypeptide – 84 amino acid residues – 9,500 daltons M.W. • Peptide fragments can be active for periods measured in hours • Operates in tissues via cAMP second messenger
  16. 16. Functions: • Increasing absorption of calcium from the intestine through activation of vitamin D in the kidney. • Increasing reabsorption of calcium from the distal convoluted tubule in the kidney. • Increasing mobilization of calcium from bones to blood through its binding to osteoblast  RANKL  stimulation of osteoclasts  enhance bone resorption (normal bone destruction) • Increasing excretion of phosphates in the urine. Uses: Parathyroid hormone has no valid use. For hypoparathyroidism vitamin D and calcium are quite effective.
  17. 17. Hypoparathyroidism • Low plasma Ca levels • Tetany • Convulsions • Laryngospasm • Paresthesia • Cataract • Psyciatric changes • Pseudohypoparathyroidism Hyperparathyroidism • Hypercalcemia • Decalcification of bone • Renal stones • Muscle weakness • Constipation • Anorexia • Metastatic calcification
  18. 18. Bisphosphonates • Most effective antiresorptive drugs • 3 generations : – First generation: etidronate, tiludronate – Second generation: Pamidronate, alendronate – Third generation: risedronate, zoledronate • Uses: – Osteoporosis – Pagets disease – Hypercalcemia of malignancy – Osteolytic bone metastasis
  19. 19. Other Drugs Affecting Calcium Metabolism • Estrogen: inhibits PTH-stimulated bone resorption, so it can prevent or delay bone loss in postmenopausal women. It is used in postmenoposal osteoporosis (unless contraindicated). • Glucocorticoids: chronic systemic use causes protein catabolism and increase calcium excretion leading to osteoporosis. It is of benefit in treatment of hypercalcemia.
  20. 20. • Fluoride: as additive in drinking water and in dentifrice, it prevents dental caries. Chronic ingested high concentration of the ion leading to new bone synthesis. • Mithramycin(Plicamycin): decreases serum calcium in Paget's disease and reduces hypercalcemia associated with cancer. It inhibits bone resorption (inhibits the osteoclasts).
  21. 21. • Thiazides: inhibit excretion of calcium. Used to reduce kidney stone formation. • Furosemide plus saline infusion: enhance Calcium excretion  Decreases serum calcium and used in acute hypercalcemia.
  22. 22. Probable questions :

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