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Agents Affecting Calcium balance

Agents Affecting Calcium balance

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Agents Affecting Calcium balance

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  1. Agents Affecting Calcium balance

  2. Calcium • 99% of total body calcium in the bone which serve as a reservoir for Ca++ storage. • 10% of total adult bone mass turns over each year during remodeling process • Normal plasma conc. : 9-11mg/dl • 40% bound to plasma proteins :10% complexed with citrate, phosphate & carbonate: remaining 50% ionized form.

  3. Physiological roles • Controls excitability of nerves and muscles & regulates permeability of cell membranes • Essential for excitation-contraction coupling • Intracellular messenger for hormones, autacoids & transmitters. • Impulse generation in the heart • Coagulation of blood • Structural function in bone and teeth

  4. Absorption • By facilitated diffusion from SI, carrier mediated active transport under influence by vit D • Filtered at glomerulus, reabsorbed in tubules

  5. Preparations • Calcium chloride • Calcium gluconate • Calcium lactate • Calcium dibasic phosphate • Calcium carbonate

  6. Adverse effects • Constipation, bloating, excess gas Uses : • As dietary supplement • Tetany • Osteoporosis • Antacid

  7. Calcium, bones and osteoporosis • Reduced bone density and mass: osteoporosis • Susceptibility to fracture. • Earlier in life for women than men but eventually both genders succumb. • Reduced risk: • Calcium in the diet • habitual exercise • avoidance of smoking and alcohol intake • avoid drinking carbonated soft drinks

  8. Ca++ homeostasis. • Three principal hormones regulate Ca++ and. • Parathyroid hormone (PTH), • 1,25-dihydroxy Vitamin D3 (Vitamin D3), • Calcitonin

  9. Parathyroid hormone (PTH) • Preproparathyroid hormone – proparathyroid- parathyroid. • The dominant regulator of PTH is plasma Ca2+. • Secretion of PTH is inversely related to [Ca2+]. • Rapidly degraded in liver, kidney • Plasma t½ - 2-5min

  10. PTH –Actions • Bone –↑ resorption of Ca from bone • Kidney – ↑Ca reabsorption in distal tubule Promote phosphate excretion • Intestines –↑ Ca absorption – enhancing calcitriol

  11. PTH • Teriparatide -Human recombinant PTH - osteoporosis

  12. Calcitonin • Parafollicular C cells of thyroid gland • Synthesis & secretion regulated by plasma Ca++ conc. • Calcitonin acts to decrease plasma Ca++ levels • Calcitonin is a physiological antagonist to PTH with regard to Ca++ homeostasis • Plasma t½ -10min

  13. Calcitonin • Inhibits bone resorption by direct action on osteoclasts -↓ ruffled surface which forms contact with resorptive pit • Inhibits PCT Ca & PO4 reabsorption.

  14. Calcitonin • Synthetic salmon calcitonin • Uses - Hypercalcemic states, pagets disease • A/E – nausea, flushing, altered taste, allergic rtns

  15. Vitamin D • Humans acquire vitamin D from two sources • Cholecalciferol & ergocalciferol. • skin by ultraviolet radiation and ingested in the diet. • Vitamin D, after its activation to the hormone 1,25-dihydroxy Vitamin D3 is a principal regulator of Ca++.

  16. Vitamin D • 7-dehydrocholesterol – cholecalciferol : UV light • Cholecalciferol - 25-hydroxy vit D :liver • 1a-hydroxylase converts it to 1,25-dihydroxy-D, the most potent metabolite of Vitamin D - kidney • The 1a-hydroxylase enzyme is the point of regulation of D synthesis. • PTH stimulates 1a-hydroxylase and increases 1,25-dihydroxy D.

  17. Vitamin D • increase Ca & PO4 absorption from intestine

  18. Vitamin D • increase Ca & PO4 absorption from intestine Calcium binding protein /calbindin • increase bone resorption from old bone &mineralize new bone • increase renal reabsorption of Ca &PO4. • Overall effect :increase serum Ca & PO4

  19. Vitamin D • Osteoblasts, but not osteoclasts have vitamin D receptors. • 1,25-(OH)2-D acts on osteoblasts which produce a paracrine signal that activates osteoclasts to resorb Ca++ from the bone matrix.

  20. Vitamin D • Cholecalciferol • Ergocalciferol • Calcitriol • Alfacalcidiol • Calcipotriol • Doxercalciferol

  21. Uses • Prophylaxis & treatment of nutritional vit D deficiency • Metabolic rickets • Senile/postmenopausal osteoporosis • Hypoparathyroidism

  22. Bisphosphonates (BPNs) • Etidronate, tiludronate, pamidronate, alendronate, risedronate,, and zoledronate • Inhibit osteoclast mediated bone resorption • Structural resemblance to pyrophosphate found in bone hydroxyapatite. • retard formation and dissolution of hydroxyapatite crystals within and outside the skeletal system

  23. Binds to hydroxyapatite crystals • When osteoclasts attach to bone matrix, during resorption, BPNs internalize into osteoclasts – apoptosis of osteoclasts & disruption of cytoskeleton and ruffled border of osteoclasts • Inhibition of osteoclast mediated resorption and promotion of bone remodelling • Block mevalonate synthesis

  24. Uses • Osteoporosis • Paget’s disease • Osteolytic bone metastasis • Hypercalcemia of malignancy

  25. A/E –esophagitis, gastric erosion, flatulance, headache, bodyache, • C/I – decreased renal function, GERD, peptic ulcer