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Calcium,vit d,osteoporosis
Calcium is an essential mineral that makes up 2% of total body weight. Over 99% is stored in bones and teeth, with the remainder distributed in tissues and plasma. Calcium levels are tightly regulated by parathyroid hormone (PTH), calcitonin, vitamin D, and calcium-sensing receptors. PTH increases calcium levels by promoting bone resorption and renal reabsorption, while calcitonin decreases them by inhibiting bone resorption and renal reabsorption. Vitamin D enhances intestinal calcium absorption and bone resorption. Bisphosphonates are effective anti-resorptive drugs used to treat osteoporosis and other bone diseases by inhibiting osteoclast activity and bone res
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Calcium,vit d,osteoporosis
- 2. Calcium • Calcium is5 th most common element of our body after C,O,H,N, making 2 % of our body weight- 1-1.5kg in an adult. • More than 99% stored in bones & teeth. • Rest distributed to plasma & all tissues of cells. • Normal levels = 9 to 11mg/dL
- 5. Calcium Ionized Protein Bound Complexed to anions 50% exerts the biological action 40 % to albumin 10 % phosphates, citrates
- 7. Calcium isabsorbed from entire intestine by carrier mediated active transport under influence of Vit – D. Phytates ,phosphates oxalates &tetracyclines complex calcium in insoluble form - interfere with absorption. Vit –D increases and calcitonin decreases proximal tubular reabsorption & PTH increases distal tubular reabsorption. Daily dietery allowance for calcium- 0.8-1.5 g per day.
- 8. Regulation of plasmalevel of calcium
- 10. Preparations of calcium S.N o PreparationCharacteristic 1 Calcium chloride 27 % calcium , highly irritant , not for IM use. Orally also irritable 2 Calcium gluconate 9 % calcium , non irritating Sense of warmth produced on injection 3 Calcium lactate 13 % calcium, orally well tolerated , non irritating 4 Calcium dibasic phosphate 23 % calcium , used as antacid and calcium supplement 5 Calcium carbonate 40 % calcium , tasteless, non irritating , used as antacid
- 11. Hypocalcemia • ↑neuromuscular irritability • Hyperactivereflexes • Paresthesia, tetany, seizures • Laryngeal spasm • Teeth hypoplasia • Bone fractures • Skin & nails atrophy
- 12. Uses of calcium •Tetany (Hypocalcemia) : • 10 -20 ml of calcium gluconate (90 –180mg) injected IV over 10 min, followed by slow IV infusion. • Total of 50-100 ml of 10 % calcium gluconate required to reverse the muscle spasms over 6 hrs. • Long term oral treatment to provide. 1- 1.5 g of calcium daily is instituted along with Vit D.
- 13. • As dietarysupplement: • Children 1-10 yr :0.8 – 1.2 g /day • Young adult, pregnant, lactating female: 1.2 -1.5 g • Men , women 25 -50 yrs : 1 g • Women> 50 yr not taking HRT: 1.5 g • Osteoporosis – with HRT/Raloxifene/alendronate • Placebo • As antacid • Cardiac arrest Other uses of calcium
- 14. Hypercalcemia • Lethargy, anorexia,weakness • Nausea, vomiting, constipation • Polyuria, dehydration • Irregularities in heart • Metastatic calcification • Mental changes indicate severe hypercalcemia
- 15. • Polypeptide –84 AA(1-34 biological action) • Mol. Wt = 9500 •Released by chief cells in the parathyroid gland. •Chief cells contain receptors for Ca2+ • Calcium-sensing receptor (CaSR) •↓ in plasma Ca2+ levels mediates the release of PTH by ↑ Camp and rise inhibits secretion. •PTH rapidly degraded in kidney & liver. Parathyroid Hormone (PTH)
- 16. Actions of PTH- Increasesplasma Ca+2 levels Increases resorption of calcium from bone Increases resorption of calcium from bone Increases number of bone remodelling units Increases number of bone remodelling units Activates the osteoclasts Activates the osteoclastsIncreases calcium reabsorption in distal tubule Increases calcium reabsorption in distal tubule No direct effect . Increases calcium absorption by enhancing formation of calcitriol in kidney by activating 1α hydroxylase..calcitriol promotes ca+2 absorption. No direct effect . Increases calcium absorption by enhancing formation of calcitriol in kidney by activating 1α hydroxylase..calcitriol promotes ca+2 absorption.
- 17. Cinacalcet- It activatesca+2 sensing receptor (CaR) I parathyroid and blocks PTH secretion .Indicated in secondary hyperparathyroidism and parathyroid tumour. Teriperatide- Recently approved recombinant preperation for treatment of severe osteoporosis.It stimulates new bone formation.
- 18. • A hypocalcemichormone discovered by Copp . • 32 AA , 3600 Mol.Wt . • Produced by para follicular- C-cells of thyroid gland. • Physiological effects are opposite to those of PTH. • Rapid acting, short term regulator of plasma Ca levels. Calcitonin
- 19. Calcitoni n Bone Kidney Directly inhibits theosteoclasts of bone Decreased bone resorption ↓↓ plasma calcium ↓↓ Plasma phosphate Inhibits the reabsorption of Ca & Po4 in proximal renal tubule Actions of calcitonin
- 20. Preparations of calcitonin •Porcine (Natural) calcitonin: • Antigenic • Synthetic salmon calcitonin: • More potent due to slower metabolism • Synthetic human calcitonin: • 1 IU = 4 μg of std preparation • Calcitonin is given by SC/IM routes. Salmon calcitonin is also available as nasal spray
- 21. Uses of calcitonin •Hypercalcemia states (e.g associated with neoplasia) :hyperthyroidism,hyper vitaminosis D,hyper calcemia of malignancy. • Pagets disease of bone: • Chronic use of calcitonin relieves pain & reduces some neurological complications , but biphosphonates T/t of choice. • Postmenopausal osteoporosis & corticosteroid induced osteoporosis: • Salmon calcitonin is used as nasal spray along with Vit D supplements 200 IU /day
- 22. Vitamin D • VitaminD: collective name given to antirachitic substances synthesized in body & found in foods activated by UV radiation • D2: calciferol- present in irradiated food- yeasts, fungi, bread, milk • D3: cholecalciferol- synthesized in skin under influence of UV rays.
- 23. Activation of VitD 7 dehydrocholester ol Ergosterol Cholecalciferol Vit D3 Calciferol Vit D2 Calcifediol (25 OH Vit D3) Calcitriol (1,25 (OH)2 Vit D3) 25 OH Vit D2 1,25 (OH)2 Vit D2 UV Light Liver microsomes Kidney mitochondria Active forms
- 25. Actions of VitD • Enhances absorption of calcium & phosphate from intestine • Enhances resorption of calcium & phosphate from bone , similar mechanism to PTH. • Calcitriol enhances the tubular resorption of calcium and phosphate in kidneys. • Cell differentiation: Particularly of collagen & skin epithelium. • Immunity: Important for Cell Mediated Immunity & coordination of the immune response.
- 26. Pharmacokinetics • Well absorbedfrom intestines in presence of bile salts • Absorption of D3 little better than D2 • In circulation bound to alpha globulin and stored mainly in adipose tissues for months. • Hyroxylated in liver to active & inactive compounds • Half life varies 1- 18 days , 25-OH D3 has longest half life Unitage • 1 μg of cholecalciferol = 40 IU of Vit D • RDA = 400 IU /day
- 27. Preparations • Ergocalciferol:Vit D2 •oral capsules • Cholecalciferol: Vit D3 • Oral/IM injection 3-6 lac IU every 2-6 month interval . • Calcitriol: • oral capsules & solution 0.25 - 1 μg daily or IV on alternate days . • Alfacalcidiol & dihydrotachysterol: • Prodrugs orally effective and rapidly biotransformed into calcitriol in liver. They are effective in renal bone disease,vit D resistant and dependent rickets & hypoparathyroidism. • Calcipotriol : Vitamin D analog used topically in
- 28. Uses of VitD 1. Prophylaxis: 400 IU/day and treatment of rickets & osteomalacia - 3000 -4000 IU/day or alternatively Oral/IM injection 3-6 lac IU every 2-6 month interval . 2. Metabolic rickets : 1. Vit D resistant rickets: high doses. 2. Vit D dependent rickets: calcitriol or alphacalcidiol 3. Renal rickets: calcitriol or alphacalcidiol . 3. Senile or post menopausal osteoporosis 4. Hypoparathyroidism : calcitriol or alphacalcidiol are better 5. Fanconis syndrome: Vit D can raise lowered phosphate levels that occur in this condition.
- 29. Bisphosphonates(BPNs) • Analogs ofpyrophosphate • Most effective anti resorptivedrugs. • 3 generaions according to potency • First generation: • Etidronate • Second generation: • Pamidronate • Alendronate 2nd and 3rd generations more potent,highly efficacious with additional modes of action. • Third generation : • Risedronate • Zoledronate
- 30. Have stronger affinityfor calcium phosphate. Have selective action on calcified tissues. 2 main components of bone are protein matrix and solid mineral phase (hydroxyapatite)
- 31. • Mechanism ofaction Protect dissolution of hydroxyapatite from bone Accelerates apoptosis of osteoclasts Inhibits release of IL-6 to supress differentiation of osteoclast precursors.
- 32. Bisphosphonates uses andadverse effects• Uses • Pagets disease of bone: Treatment of choice • For prevention and treatment of post- menopausal osteoporosis . • To prevent corticosteroid induced osteoporosis along with calcium carbonate . • Hypercalcemia of malignancy : Zolendronate • Control hypercalcemia of hyperparathyroidism. • To relieve pain of lytic bone lesions. • Nausea, vomiting diarrhoea, esophagitis, peptic ulcer, fever, myalgia, hypocalcemia, headache & skin rashes • osteonecrosis , renal impairment . • Adverse effects
- 34. Actions of VitD Groff & Gropper, 2000 • 1,25-(OH)2 D binds to vitamin D receptor (VDR) in nucleus • ↑ in calbindin (Ca-binding protein) • Net effect is ↑ absorption of calcium & phosphorus from intestine
- 35. • Highly polarso less poorly absorbed through GIT • Part of absorbed drug is incorporated into bone & remains for long periods years to months • The free drug is excreted unchanged in urine • Pharmacokinetics (BP)
- 36. Treatment of hypercalcemia •Hydration & dietary calcium restriction < 400 mg/day • Sodium chloride: • Saline administration will cause renal elimination of calcium • Furosemide : 20 -40 mg every 2-4 hrs • Glucocorticoids: reduce intestinal absorption & tubular reabsorption of calcium • Calcitonin: 4 IU/kg SC OR IM twice or once daily can be increased to 8 IU/kg IM 6 hrly • Mithramycin : 25 μg/kg IV over period of 4- 6 Hrs • Inorganic phosphate: phosphosoda 5 ml TDS
Editor's Notes
- #3 Calcium is 5 th most common element of our body after COHN making 2 % of our body Acidosis favours & alkalosis disfavours the ionization of calcium : hyperventilation precipitates the tetany and laryngospasm in calcium deficiency by reducing ionization.
- #6 Calcium is 5 th most common element of our body after COHN making 2 % of our body Acidosis favours & alkalosis disfavours the ionization of calcium : hyperventilation precipitates the tetany and laryngospasm in calcium deficiency by reducing ionization.
- #11 Calcium chloride
- #13 Tetany: for immediate treatment of severe cases: 10 -20 ml of calcium gluconate 90 – 180 mg injected iv over 10 min. followed by slow IV infusion. Total of 50-100 ml of 10 % calcium gluconate required to reverse the muscle spasms over 6 hrs. Supportive treatment with IV fluids and oxygen inhalation maybe required. Long term oral treatment to provide. 1- 1.5 g of calcium daily is instituted along with Vit D. MILD cases only oral therapy. Osteoporosis: HRT/Raloxifene /alendronate prefered but imp that calcium deficiency does not develop. Calcium + vitamin D3 have adjuvant role. But their use alone is controversial. Side effects: calcium supplements are usually well tolerated. Only GI side effects like, constipation, bloating, and excess gas especially with calcium carbonate have been reported As dietary supplement: Children 1-10 yr :0.8 – 1.2 g /day Young adult, pregnant, lactating female: 1.2 -1.5 g Men , women 25 -50 yrs : 1 g Women&gt; 50 yr not taking HRT: 1.5 g
- #16 a peptide hormone: increases plasma Ca2+
- #17 PTH decreases the calcium levels in milk , saliva and occular lens – hypoparathyroidism – cataract
- #19 Parathyroid, cells of thymus cells, and medullary carcinoma of thyroid also posses cacitonin Physiological role of calcitonin in maintaining the plasma cacium appears to be minor Plasma half life of calcitonin is 10 min but its action lasts for several hours.
- #20 Generally opposite to that of PTH IT DECREASES THE RUFFLED SURFACE OF OSTEOCLASTS WHICH FORMS CONTACT WITH RESORPTIVE PIT PLASMA HALFR LIFE IS 10 MIN BUT ITS HYPOCALCEMIC ACTION LASTS FOR 8 HRS Calcitonin is made by the C cells of the thyroid gland A large peptide &quot;prohormone&quot; is made and then cut down to the 32 amino acid calcitonin Stimulates osteoblasts, inhibits osteoclasts Causes removal of Ca from plasma to calcify new bone Lowers plasma Ca (opposes PTH) Minor role in adult due to PTH feedback Major role in children due to the rapid nature of bone remodeling and its effect on osteoclastic activity
- #21 Adverse events experienced are nausea, flushing, tingling of fingers, bad taste allergic reactions By lowering plasma calcium calcitonin may interfere with action of digoxin.
- #22 Hypercalcemia: hyperparathyroidism , hypervitaminosos, osteolytic bony metatsis : 4-8IU/Kg im 6 -12 hrly for 2 days acts rapidly within 4 hrs the response peaks at 48 hrs Weak hypocalcemic so only used to supplement BPN generally. Pagets disease 100 units daily or on alternate days
- #24 7 dehydro cholesterol synthesized in skin The final step of hydroxylation is rate limiting step it is induced by Calcium/ Vit D deficiency, as well as by PTH, ESTROGENS & PROLACTIN WHLE CALCITRIOL INHIBITS IT IN FEED BACK MANNER Skin (UV light) 7-dehydro cholesterol Vitamin D3 Ergosterol Vitamin D2 Liver OH-group added 25-Hydroxy vitamin D3 Storage form of vitamin (~3 months storage in liver) Kidney OH-group added by 1-hydroxylase 1,25-dihydroxy vitamin D3 Active form of vitamin D, a “steroid hormone” OH-group added by 24-hydroxylase 24,25-dihydroxy vitamin D3 Inactive form of vitamin D, ready for excretion
- #26 OSTEOBLASTIC CELLS ALSO HAVE VDR and respond to cacitriol by laying down osteoid but it mainly appears to help bone mineralizaton indirectly by maintaining calcium & po4 levels Calcitriol enhances the tubular resorption of calcium and phosphate in kidneys : but action is less marked than that of PTH
- #27 Well absorbed from intestines in presence of bile salts mainly through the lymphatics Absorption of D3 little better than D2 Malabsorption and steathorrhea interfere with its absorption Calcitriol is excreted rapidly The metabolites of Vit d ARE excreted in bile
- #28 Alfacalcidiol :1 alpha hydroxyD3 DOSE 1-2 MICROGRAM /DAY & dihydrotachysterol: SYNTHETIC ANALOG OF VIT D2 LESS EFFECTIVE IN ANTIRACHITIC TESTS BUT DIRECTLY MOBILIZES CALCIUM FROM BONE : DOES NOT REQUIRE PTH dependent activation in kidney dose = 0.25 -0.5 mg/day
- #29 Hypervitaminosos D: m ay occur because of chronic ingestion of large doses of vit D &gt; 50000 IU/DAY MANIFESTATIONS ARE DUE TO INCREASED CALCIUM LEVELS & ECTOPIC DEPOSITION HYPERCALCEMIA , weakness, fatigue, vomiting , diarrhoea, sluggishness, poluria, albuminuria, ectopic calcium deposition, renal stones, hypertension, growth retardation in children, . Coma T/t = no vitamin D , low calcium diet, plenty of fluids & glucocorticoids recovery may be incomplete in many cases.
- #37 Mild hypercalcemia Control of underlying causative factor Hydration Oral glucocorticoids