Drugs affecting ca++ regulation

This powerpoint presentation imparts some knowledge about drugs that affects the calcium regulation,bone related information.

1. Drugs Affecting Ca ++ Regulation Presented by Moh.Uzair M.Pharm(Pharmacology) II nd Semester SPER, Jamia Hamdard New Delhi 1 SEMINAR ON

2. Contents Physiological importance of Ca ++ Intake of Ca ++ Factors affecting Ca ++ absorption Bone Bone Homeostasis Regulators of bone mineral homeostasis Parathyroid hormone (PTH) Calcitonin 2

3. Estrogen & SERM Glucocorticoids Bisphosphonates Fluorides Calcimimetics Strontium Ranelate Rank Ligand (RANKL) Inhibitor References 3

4. Anatomical & Physiological importance of Ca ++ Ca ++ salts in bone provide structural integrity of the skeleton. Ca ++ is the most abundant mineral in the body. Ca ++  ions in extracellular and cellular fluids is essential to normal function of a host of biochemical processes— 1. Neuromuscular excitability and signal transduction. 2. Blood coagulation. 3 . Hormonal secretion. 4 . Enzymatic regulation & neuron excitation. 4

5. Intake of Ca ++  About 1000 mg of Ca ++ is ingested per day. About 200 mg of this Ca ++ is absorbed into the body. Absorption occurs in the small intestine, and requires vitamin D. Milk and dairy products-Egg yolk , Fish, beans. Cow’s milk 100mg/100ml Human milk 30mg/100ml 5 Mohd Uzair Ansari

6. Factors affecting Ca ++ absorption A) Factors favoring calcium absorption— An acidic pH. Presence of sugar acids, organic acids and citric acid. High protein diet- Lysine and Arginine cause absorption . Presence of vitamin D. State of health and intact mucosa- A healthy adult absorbs about 40% of dietary calcium.  PTH (Parathormone) stimulates the activation of vitamin D, thus indirectly increases absorption of vitamin D . 6

7. Cont… B) Factors inhibiting absorption of calcium— Alkaline pH High fat diet- Fatty acids form calcium soaps that can not be absorbed. Presence of Phytates and oxalates- Insoluble calcium salts are formed. Dietary fiber in excess inhibits absorption. Excess phosphates, magnesium and iron decrease absorption. 7

8. Glucocorticoids reduce intestinal absorption of calcium. Calcitonin reduces calcium absorption indirectly by inhibiting the activation of vitamin D. Advancing age and intestinal inflammatory disorders inhibit absorption of calcium. 8

9. Bone Bone is consist of minerals ( Ca ++ & PO 4 3- ) & collagen which is hydroxy prolin amino acid . Bones are covered with osteoblast cell which make membrane, within this membrane interstitial fluid are filled that is Ca ++ & PO 4 3- rich(unbound form). Bone contain two types of cells— Osteoblast Osteoclast 9

10. Bone Homeostasis Bone resorbtion and formation are two continuous process important to maintain the bone strength. In absence of any of these process bone becomes brittle. PTH, Calcitriol (Vit.D 3 ) & Fibroblast Growth Factor are primary hormone regulators of bone homeostasis. Secondary regulators of Ca ++ homeostasis include Calcitonin, glucocorticoids and estrogens. 10

11. These hormones, or drugs that mimic or suppress their actions, are used in the treatment of bone mineral disorders (e.g., osteoporosis, rickets, osteomalacia, Paget’s disease), as are several nonhormonal agents. 11 Mohd Uzair Ansari

12. Regulators of bone mineral homeostasis 12

13. Parathyroid hormone (PTH) Polypeptide hormone(84 AA),which is synthesized from chief cells of parathyroid gland. The synthesis and secretion of PTH is primarily regulated by the serum concentration of free ionized calcium. Low plasma Ca ++ stimulates PTH release. 13

14. Mechanism Of Action (PTH) 14

15. Actions of PTH 15

16. PTH Analogs Teriperatide Abaloparatide These above analogs that activate osteoblasts for bone matrix synthesis that augments bone formation. These are peptides and hence given by SC route in thigh or abdomen. Used for osteoporosis. 16

17. Adverse Effect & Contraindication A black box warning has been issued regarding risk of Osteosarcoma. Should be avoided in : Paget’s disease Prior radiotherapy to bone 17 Mohd Uzair Ansari

18. Vitamin D Vitamin D, a fat-soluble vitamin. Prohormone , which is converted in the body into a number of biologically active metabolites that function as true hormone. Synthesized in the skin from 7-dehydrocholesterol under the influence of ultraviolet light or absorbed from the diet in the natural form (vitamin D3, cholecalciferol) or the plant form(vitamin D2, ergocalciferol). 18

19. Pathways of Vitamin D production 19

20. Actions of Vitamin D 20

21. Vitamin D Preparations Cholecalciferol(inactive) derived from UV conversion of 7- dehydrocholesterol. Ergocalciferol(active vit.D 2 ) derived from yeast and fungal sterol. Calcitriol (active vit.D 3 ) Calcipotriol Doxercalciferol 21

22. Calcitonin Peptide hormone secreted by the parafollicular cell of thyroid gland. Decreases serum calcium and phosphate by inhibiting bone resorption and inhibiting renal excretion of these minerals. Calcitonin is approved for treatment of osteoporosis and has been shown to increase bone mass and to reduce spine fractures. 22

23. Actions of calcitonin (Opposite to that of PTH) 23

24. Calcitonin Preparations Synthetic salmon calcitonin( salcatonin ) used for— . Subcutaneous salcatonin is used to treat the Paget’s disease. . Intranasal salcatonin is used for prophylaxis of osteoporosis. It has analgesic effect on acute vertebral fractures caused osteoporosis 24

25. Estrogen & SERM Estrogen produced by ovaries. Natural estrogens include estradiol (Principal & most potent). Estrogen plays an important role in the growth and maturation of bone as well as in the regulation of bone turnover in adult bone. In young skeleton estrogen deficiency leads to increased osteoclast formation and enhanced bone resorption. Directly inhibits the osteoclast. 25

26. SERM(Selective Estrogen Receptor Modulators) Nonsteroidal synthetic agents that act as estrogen agonist in some tissues and antagonists in other tissues. Agonistic action is beneficial in tissues like bone( es resorption ) and blood ( better lipid profile ) . Antagonistic effects on breast and endometrial tissue. MOA is same as estrogen. Example— Raloxifene,Tamoxifene , Ospemifene , Lasoxifene & Arzoxifene . Used for treatment & prophylaxis of Postmenopausal osteoporosis, Breast cancer etc. 26

27. Glucocorticoids Glucocorticoids lower serum calcium levels by inhibiting osteoclast formation and activity, but over long periods they cause osteoporosis by decreasing bone formation and increasing bone resorption. They also decrease the absorption of calcium from the intestine by an anti-vitamin D action and increased its renal excretion. The decrease in serum calcium concentration increases the secretion of parathyroid hormone, and bone resorption is facilitated. 27 Mohd Uzair Ansari

28. 28

29. Bisphosphonates 29

30. Classification of BNPs BNPs are classified into 3 rd generations based on the sequence on discovery(chronology) as well as potency. 30 The II nd & III rd Gen BNPs are also called “aminobisphosph-onates” because they have ‘N’ atom in their structure. The amino BNPs inhibit farnesyl pyrophosphate synthase in cholesterol synthesis pathway that is required for osteoclast survival.

31. Cont… 31 All are given by Oral route Except Zolendronate & Pamidronate

32. Cont… Bisphosphonates are usually given orally and are poorly absorbed. Absorption is impaired by food, particularly milk, so the drugs must be taken on an empty stomach. Unwanted effects include gastrointestinal disturbances including peptic ulcers and oesophagitis. Uses- Paget’s disease of bone Osteoporosis (decrease risk of fracture) Malignant disease involving bone (e.g. metastatic breast cancer, multiple myeloma) 32 Advice Patient don’t lying down for 30 min & take large amt. of water.

33. Fluorides Well known for prophylaxis of dental caries, its efficacy to prevent osteoporosis. Sodium fluoride enhances osteoblasts activity and increase bone volume. These effects may be dose dependent— In low doses stimulate the osteoblasts. In higher doses suppress the osteoblasts . 33

34. Calcimimetics( Cinacalcet ) Also called Calcium Sensing Receptor Agonist. Calcimimetics are drugs that mimic the stimulatory effect of calcium on the calcium sensing receptor( CaSR ). CaSR are present on the Parathyroid gland . MOA Binds to receptor on parathyroid gland PTH secretion serum Ca ++ level Used for hypercalcemia associated with parathyroid carcinoma. Used for in the treatment of secondary hyperthyroidism (due to chronic renal failure). 34

35. Strontium Ranelate Strontium ranelate is composed of two atoms of strontium bound to an organic ion, ranelic acid. 35 MOA

36. Therapeutic Uses & ADR Osteoporosis (“bone thinning”). Fractures (broken bones). ADR— V enous thrombosis Seizures Cognition impairment 36

37. Rank Ligand (RANKL) Inhibitor Denosumab is a human monoclonal antibody that binds to and prevents the action of RANKL. Denosumab inhibits osteoclast formation and activity. It is at least as effective as the potent bisphosphonates in inhibiting bone resorption and can be used for treatment of postmenopausal osteoporosis. ADR— Osteonecrosis of jaw. Femoral fractures. Flu like symptoms 37

38. References 38 Marius E. Kraenzlin,Christian Meier., 2011.Parathyroid hormone analogues in the treatment of osteoporosis. NATURE REVIEWS | ENDOCRINOLOGY, Macmillan Publishers Limited.7,647-649. H. Kalervo Vaananen , Pirkko L. Harkonen.,1996. Estrogen anti bone metabolism. ELSEVIER| MATURITAS JOURNAL OF THE CLIMACTERIC & POSTMENOPAUSE. S 65. Management of glucocorticoids -induced osteoporosis: Role of teriparatide - Scientific Figure on ResearchGate . Available from: https://www.researchgate.net/figure/Synthesis-of-glucocorticoids-effects-on-bone-cells-Abbreviation-CSF-colony-stimulating_fig1_26301234

39. Peacock, M., Bilezikian , J.P., Klassen , P.S., et al., 2005. Cinacalcet hydrochloride maintains long-term normocalcaemia in patients with primary hyperparathyroidism. J. Clin . Endocrinol . Metab . 90, 135–141. https://link.springer.com/article/10.1007%2Fs00198-004-1753-8 https://www.endocrine.org/search#q=bisphosphonates Daniel D. Bikle . A gents That Affect Bone Mineral Homeostasis. Bertram G. Katzung, Basic & clinical Pharmacology 12 th edition. The McGraw-Hill Companies. San Francisco 2012.Page No.769-777 39

40. Peter A. Friedman. Agents Affecting Mineral Ion Homeostasis and Bone Turnover. Goodman & Gilman’s The Pharmacological Basis Of Therapeutics 12 th edition . Editor Laurence L.Brunton . The McGraw-Hill Companies.New York 2011.Page No. 1287-1302. Drugs used in bone disorders. Rang and Dale’s Pharmacology 7 Th edition. ELSEVIER CHURCHILL LIVINGSTONE. Edinburg 2012.Page No.438-439 40