Drugs affecting calcium balance

Useful for MBBS student Pharmacology PG and other interested health science students

1. Drugs Affecting Calcium Balance Dr. CHANDANE R. D. Associate Professor Dept. Of Pharmacology Lady Hardinge Medical College New Delhi

2. Calcium Physiological role: Excitability of nerves and muscles, regulates permeability and integrity of cell membranes and cell adhesion Excitation-contraction coupling of all types of muscles Excitation and secretion of endocrine and exocrine glands, neurotransmitters release from nerve endings Intracellular messenger for hormones, autacoids and transmitters Impulse generation and conduction in heart Coagulation of Blood Structural function of Bone and Teeth - hydroxyapatite

3. Plasma Calcium Level Regulated by 3 hormones Parathormone , calcitonin and Calcitriol (active vit . D) • Normal plasma level = 9-11 mg/dl • Hypoalbuminemia – no decrease in conc. Of Ca++ • Acidosis – favours ionization • Alkalosis – disfavours ionization – hyperventilation precipitates tetany and laryngospasm in Calcium deficiency

4. 40-41% is bound to plasma protein – albumin, 9-10% - citrate, carbonate and phosphate and 50% is free ionized and important form- Responsible for calcium function and Can be directly measured

5. Absorption and Excretion Absorbed from entire small intestine including duodenum – carrier mediated active transport under the influence of Vit.D • Phytates , phosphates, oxalates and tetracycline, also Glucocorticoides and Phenytoin reduces absorption • Filtered through glomerulus but mostly reabsorbed • Vit . D increases and Calcitonin decreases reabsorption in proximal tubule • PTH -increases distal tubular reabsorption - thiazide • 300 mg is excreted daily in urine and faeces • Daily requirement: 800 -1500 mg per day (1/3rd absorbed)

6. Preparations of calcium S.No Preparation Characteristic 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 and calcium supplement

7. USES 1. Tetany : Severe cases Calcium gluconate 10 to 20 ml IV over 10 minutes followed by 50 to 100 ml of Ca gluconate solution over 6 Hrs • Oxygen inhalation, IV fluids then oral therapy 2. Dietary supplement: growing children, pregnant, lactating and meopausal etc. In men and women reduce the bone loss 3. Osteoporosis: Prevention ant treatment of osteoporosis with HRT/ raloxifene / Alendronate – to ensure Ca++ deficiency does not occur • Calcium and Vit . D3 used as adjuvant

8. Uses…. 4. Empirically in dermatoses , parathesia and weakness 5. Antacids 6. Hyperkalemia : Calcium gluconate iv life saving and reduce cardiotoxic effects 7. Black widow spider envenomation : iv 8. Magnesium toxicity, cardiac arrest and Hyperphosphataemia (CRF )

9. 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 ( Plicamycin ) : decrease bone resorption low dose 10 μg /kg IV • Inorganic phosphate : phosphosoda 5 ml TDS - Biphosphonate

10. PARATHYROID HORMONE ( Parathormone ) Location : Posterior to thyroid gland , 4 in nos Secreted by principal cells Preproparathyroid hormone → proparathyroid hormone → PTH(84 AA polypeptide) Plasma Ca2+ is the major factor regulating PTH secretion. Hypocalcemia stimulates PTH secretion whereas hypercalcemia inhibits it. Calcium inhibits PTH secretion by stimulating calcium sensing receptor on parathyroid cells.

11. Mechanism of action PTH receptor - G protein coupled receptor on activation increases cAMP formation & intracellular Ca++ in target cells, in bone target cells are osteoblast induces a factor ‘Receptor for activation of nuclear factor- κB - ligand ’ (RANKL) which diffuses and combines with RANK on osteoclast precursors and transforms them into osteoclasts as well as activates osteoclasts

12. Increase formation of the remodeling pit is f/b osteoblastic deposition of new bone into it. PTH enhances proliferation and differentiation of preosteoblasts and deposition of osteoid as well. ↑ Bone resorption with high conc of PTH continuously, but intermittent exposure to low conc ↑bone formation.

13. Rapidly metabolised in liver & kidney T1/2 is 2-5 min Actions Bone: Resorption of calcium from bone increasing the number of bone remodeling units and activating osteoclasts Kidney: increases calcium reabsorption in the distal tubule also promote phosphate excretion Intestine: increase absorption indirectly by increases circulating calcitriol by two mechanisms 1) Directly by stimulating 1α hydroxylase in kidney and 2) indirectly by decreasing serum phosphate. Decrease ca level in milk saliva and ocular lens.

14. rParathyroid hormone [ rPTH (1-34), teriparatide ] Mechanism of action : Stimulates new bone formation on trabecular and cortical bone surfaces by preferential stimulation of osteoblastic activity over osteoclastic activity. Daily SC injections of 40mcg of rPTH for 12-18 months , increased BMD by 9-13% and decreased risk of vertebral fractures by 65 to 69 % T1/2-1hr, costly Use: severe osteoporosis with multiple risk of fracture Diagnostic use: teriparatide i.v .: if plasma calcium level fails to rise, then it is pseudohypoparathyroidism . S/E: headache, nausea, dizziness and leg cramps C/I: Pagets disease and hypercalcaemia

15. Hyperparathyroidism Hypercalcaemia , decalcification of bone—deformities and fractures, metastatic calcification, renal stones, constipation T/T : 1) surgical removal of the parathyroid tumour 2) low calcium, high phosphate diet with plenty of fluids is advised. 3) Cinacalcet : It activates the Ca2+ sensing receptor ( CaSR ) in the parathyroids and blocks PTH secretion. Use: secondary hyperparathyroidism due to renal disease and in parathyroid tumour .

16. Calcitonin Calcitonin , 32-amino acid peptide hormone (Mol Wt 3600) secreted by the thyroid gland, tends to decrease plasma Ca conc and has effects opposite to those of PTH Parafollicular cells, or C cells, lying in the interstitial fluid between the follicles of the thyroid gland rise in plasma Ca2+ increases, while fall in plasma Ca2+ decreases calcitonin release.

17. Actions: Inhibit bone resorption by direct action on Osteoclasts - decrease their ruffled surface inhibits the proximal tubular reabsorption of calcium and phosphate by direct action on kidney. But hypocalcemic action reduce calcium glom filtration so reduce urinary ca Action is mediated through G- protein coupled calcitonin receptor & increased cAMP formation but target cells are different from that of PTH

18. Calcitonin : Preparations : SC/IM routes Porcine (Natural) calcitonin : Antigenic Synthetic salmon calcitonin : More potent due to slower metabolism. also as nasal spray Synthetic human calcitonin : 1 IU = 4 μg of std preparation S/E: Nausea, flushing and tingling of fingers Bad taste, flu-like symptoms, allergic reactions and joint pain

19. Uses: 1) Hypercalcemia states: Hyperparathyroidism, hypervitaminosis D, osteolytic bony metastasis and hypercalcaemia of malignancy; used only to supplement BPNs as weak hypocalcemic 2) Pagets disease of bone: Bisphosphonates are preferred calcitonin 2 nd line 3) Postmenopausal osteoporosis & corticosteroid induced osteoporosis: It is less effective than BPNs/HRT. Salmon calcitonin as nasal spray along with Vit D supplements 200 IU /day increase bone mineral density in menopausal women and to reduce vertebral, but not nonvertebral , fractures. 4) Diagnosis of medullary carcinoma of thyroid:

20. Vitamin D Mainly D3 ( cholecalciferol ) and D2 ( calciferol ) Both are equally active in human Calcitriol (active form of D3) is more important physiologically Released from liver in blood and binds to specific vit D binding globulin

21. vit D should be considered a hormone because: (a) It is synthesized in the body (skin); under ideal conditions it is not required in the diet. (b) It is transported by blood, activated and then acts on specific receptors in the target tissues. (c) Feedback regulation of vit D activation occurs by plasma Ca2+ level and by the active form of vit D itself.

22. Actions of calcitriol 1) Enhancement of absorption of Ca and PO4 from intestine By increasing the synthesis of calcium channels and a carrier “calcium binding protein ( CaBP )” or calbindin Analogous to stroid hormones – binds to cytoplasmic vit D receptor (VDR)-translocation-increased synthesis of mRNA-regulation of protein synthesis But, why quick? - Activation of VDR also promotes endocytotic capture of Calcium and transport across the duodenal mucosa

23. 2) Calcitriol also enhances recruitment and differentiation of osteoclast precursor for remodelling – resorption of Calcium and PO4 from bone Mature osteoclasts lack VDR, induces “receptor for acivaton of nuclear factor- kB - ligand (RAANKL)” in osteoblasts and activates osteoclasts indirectly Laying down and mineralization of osteoids 3) enhances tubular reabsorption of Calcium and phosphate 4) Apart from effects on Ca2+ and phosphate–, calcitriol also affects maturation and differentiation of mononuclear cells (possibility of use in cancers), inhibits epidermal proliferation and promotes epidermal differentiation (potential t/t of psoriasis ).

24. Pharmacokinetics A) Absorbed from intestine in presence of Bile salts mainly by lymphatics D3 is better absorbed than D2 D) Binds to alpha-globulin and stored in fatty tissues for many months M) It is hydroxylated in the liver to active and inactive metabolites E) Half life varies from 1 – 18 days. Metabolites of vit D are excreted mainly in bile

25. Unitage and preparation 1mcg of Cholecalciferol = 40 IU of vit.D Calciferol (D2): oily solutions in gelatin capsules – 25000/50000 IU caps Cholecalciferol (D3): oral and IM injections – given 3 to 4 weeks intervals Calcitriol : 0.25 to 1 mcg orally on altenate days Alfacalcidol : Prodrug – rapidly hydrolysed to calcitriol in liver. Equally active to calitriol on long term use. Dose – 1-2 mcg/day Dihydrotachysterol : Vit D2 analogue HypoPTH and Renal bone disease

26. Vit D - Uses 1) Prophylaxis (400 IU/day ) and treatment (3000 -4000 IU/day) of rickets & osteomalacia : alternatively Oral/IM injection 3-6 lac IU every 2-6 month interval 2) Metabolic Rickets a) Vit D resistant rickets : PO4 with high doses of calcitriol b) Vit D dependent rickets :deficiency of renal hydoxylating mechanism which converts 25-OHD3 into calcitriol . T/T: calcitriol or alfacalcidol c) Renal rickets : Calcitriol / alfacalcidol or dihydrotachysterol 3) Senile or postmenopausal osteoporosis:

27. 4) Hypoparathyroidism : calcitriol / alfacalcitriol dihydrotachysterol 5) Doxercalciferol and Paricalcitol have been approved for treatment of secondary hyperparathyroidism in patients with chronic renal disease. These are less likely to cause hypercalcemia than calcitriol 6) Fanconi like syndrome: can raise lowered phosphate 7) Calcipotriol : Vitamin D analog used topically in psoriasis . slightly more effective than glucocorticoids . Systemically tried for skin cancer and immunological disorder

28. Drug Interactions: 1. Cholestyramine and chronic use of liquid paraffine can reduce vit D absorption. 2. Phenytoin and phenobarbitone reduce the responsiveness of target tissues to calcitriol ; their prolonged use (for epilepsy) can cause rickets/ osteomalacia . It was believed earlier that these drugs enhance degradation of vit D. level of calcitriol is normal, but its effect on intestine and bone is diminished.

29. Vitamin D deficiency Rickets in small children 1. Osseous changes: a ) Head: craniotabes , frontal bossing, box like skull, delayed closure of anterior fontanelle b ) Teeth: delayed eruption, with abnormal order c ) Chest: rachitic rosary, pigeon chest, funnel-shaped chest d ) Spinal column: scoliosis,kyphosis , and lordosis e ) Extremities: bowlegs f ) Rachitic dwarfism 2. Muscular system: potbelly, late in standing and walking 3. Motor development: delayed 4. Other nervous and mental symptoms

30. Treatment 1. Food and nursing care 2. Prevention of complications 3. Special therapy Vitamin D therapy A. General daily Vitamin D 2000-4000IU/day for 2-4 weeks, then change to preventive dosage (400IU). B. A single large dose : For severe case, or Rickets with complication, or those who can’t bear oral therapy. Vitamin D3 3 LAC -6 LAC IU, im , preventive dosage can be used after 2-6 months.

31. Prevention 1. pregnant and lactating women should take adequate amount of vitamin D. 2. Advocate sunbathing 3.Advocate breast feeding , give supplementary food on time 4. Vitamin D supplementation : • In prematures , twins & weak babies: 800 IU/day • For term babies and infants : 400 IU per day, • For those babies who can’t maintain a daily supplementation : Vitamin D3 1-2L IU IM. 5. Calcium supplementation:

32. Vitamin D - Sources • Sunlight is the most important source • Not found naturally in many foods • Synthesized in body • Plants ( ergosterol ) – Sun-cured forages • Fluid milk products are fortified with vitamin D • Oily fish & Fish liver oil • Egg yolk • Butter • Liver • Difficult for vegetarians

33. Hypervitaminosis D chronic ingestion of large doses (~50,000 IU/day) or due to increased sensitivity of tissues to vit D. causes hypercalcemia , which manifest as: Nausea & vomiting • Excessive thirst , polyuria & anorexia • Severe itching • Joint & muscle pains • Disorientation & coma. • Calcification of soft tissue– Lungs, heart, blood vessels , • Hypercalcemia - formation in renal stone Treatment: withholding the vitamin, low calcium diet, plenty of fluids and corticosteroids

34. Calcium Homeostasis Calcium and phosphate homeostasis is maintained by the action of vitamin D (active form is calcitriol ), parathyroid hormone (PTH), and FGF-23 (Fibroblast growth factor-23). Secondary regulators of Ca2+ homeostasis include calcitonin , glucocorticoids and estrogens.

35. BIPHOSPHONATES

36. Introduction Non-hormonal agent in Ca ++ homeostasis Recently in attention due to Prevention of osteoporosis, useful in metabolic bone diseases and hypercalcaemia Most effective “ antiresorptive ” drug at present BPNs are analogous of pyrophosphates – Carbon atom replacing “P-O-P skeleton”

37. Classification – BPNs Classified in generations (chronological): BPNs Relative Potency First generation: Simpler side chain Etidronate Tiludronate 1 10 2nd generation: amino or nitrogenous side chain Pamidronate Alendronate Ibadronate 100 100-500 500-1000 3rd generation: nitrogen atom within a heterocyclic ring Risedronate Zoledronate 1000 5000

38. MECHANISM OF ACTION BPNs have selective affinity for Calcium phosphate – so calcified tissues 2 main component of Bone – Bone matrix and Solid mineral phase (hydroxyapatite ) Normally, The non-mineralized osteoid covers the mineralized bone matrix preventing its resorption by osteoclasts For resorption – osteoids must get dissolved or mineralized (solubilized ) such that osteoclasts can attach to the mineralized matrix

39. In resorptive pits – acidic zone is created at ruffled boarders of osteoclasts followed by resorption of matrix by acid hydrolases BPNs localize in the acidic zone due to high affinity for Ca ++ ions Ca ++ ions released from bone surface due to high acidity BPNs also released – internalized into osteoclasts by endocytosis Results in: A) Accelerated apoptosis of osteoclasts reducing their no. B) Disruption of the cytoskeleton of the ruffled boarder of osteoclasts C) Also affect osteoclast precursors and inhibit their differentiation by suppressing IL-6.

40. Osteoclastic membrane domains. When an osteoclast is not resorbing bone, it shows no signs of polarized membrane domains. Once the osteoclast starts the resorbing, it quickly polarizes its membrane into distinct domains. Ruffled border (RB ) is a membrane domain facing the bone surface, where the actual resorption takes place. Sealing zone (SZ) forms a tight contact to the bone , sealing the proteolytic enzymes and acid into the forming resorption lacuna. Basolateral membrane (BL ) faces towards the bone marrow. When the osteoclast is actively resorbing bone, a fourth domain arises into the basolateral membrane, the functional secretory domain (FSD ) , which acts as a route of osteoclasts to exocytose the resorbed material.

41. Reduction in cholesterol synthesis via inhibition of farnesyl pyrophosphate synthase by bisphosphonates BPN esp 2 nd and 3 rd generation : Metabolic effects in the mevalonate pathway for isoprenoid lipid synthesis. They inhibit prenylation of certain GTP-binding proteins involved in cytoskeletal organization, membrane ruffling and vesicle movement. The net result is inactivation of osteoclasts, impaired vesicle fusion and enhanced apoptosis . Interference with mevalonate pathway may also impart antitumor action on bony metastasis

42. Pharmacokinetics Highly polar so 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

43. USES 1. Osteoporosis : Alendronate>HRT or raloxifene I . Prevention and treatment of post- manaupasal osteoporosis II . Both Men and Women – age related, steroid induced and idiopathic osteoporosis Oestrogen prevents only vertebral fracture, BNPs > effective than calcitonin 5 years protection on cont use. t½ of alendronate in bone is ~ 10 years , treatment beyond 5 years is considered unnecessary. first choice drugs now for osteoporosis. 2. Osteolytic Bone Metastasis: Parenteral pamidronate / zoledronate

44. 3. Pagets disease: abnormal osteoclast function - Honeycomb like bone architecture – arrest osteolytic lesions, reduce bone pain and improve secondary symptoms. Alendronate , Risedronate , Pami and Zole are used. Calcitonin combination better. 4. Hypercalcaemia of Malignancy: Medical emergency with altered consciousness – Pamidronate 60-90 mg IV 2-4 hours or Zoledronate 4 mg IV 15 minutes. Supplement with calcitonin IM 6-12 Hrly for 2 days, i.v . hydration, furosemide , Corticosteroids . 5. Breast Prostate cancer and multiple myeloma: zolendronate anticancer effect and prevent bony metastasis 6. Philadelphia-chromosome positive CML: Zolendronate as adjunctive

45. Adverse effects Oral bisphosphonates causes Gastrointestinal complications such as gastritis or esophagitis , abdominal pain, nausea, vomiting, diarrhea, and constipation. Bisphosphonate -related osteonecrosis of the jaw- Phossy jaw so regular dental care and avoid dental extraction. Zoledronate - associated with renal toxicity and first generation bisphosphonates - osteomalacia . Long-term bisphosphonates -increases the risk of atypical ‘ chalkstick ’ fracture of femur ( subtrochantric or shaft). Risk increases with concurrent high dose steroid therapy. increase the risk of esophageal cancer. Contraindication: renal dysfunction, esophageal motility disorders and peptic ulcer

46. Individual Drugs 1. Etidronate : Not used anymore 2. Pamidronate : Only IV 60-90 mg for 2-4 Hrs, weekly or monthly in Pagets disease and hypercalcaemia 3. Alendronate : Available in oral form 5, 10, 35, 70 mg tabs. Prevention of osteoporosis in man and woman. a. In empty stomach with glass of water b. Do not allow to lie down or eat till 30 minutes – oesophagitis ; Tea, coffee, mineral water, Juice, NSAIDs c. ADRs: Gastric errosion , retrosternal pain, flatulence d. Bioavailability 1% , 50% goes to Bone, terminal elimination halflife 10.5 years

47. 4. Risedronate : Similar to Alendronate , but more potent • Used in osteoporosis and Paget`s disease 5. Zolendronate : Parenterally effective, highly potent • Suppression of osteoclastic activity and additional antitumor effect ( mevalonate pathway) • Proliferation of bony metastasis of Prostate and breast cancer cells are suppressed • Can be infused in 15 minutes • ADR : Flu-like symptoms due to cytokine release

48. Osteoporosis A systemic skeletal disease characterized by low bone mass & micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture

49. Primary osteoporosis Postmenopausal: ↓ estrogen results in ↑ osteoclastic activity without ↑ osteoblastic activity Bone loss – 2-3% per year of total bone mass Most common fx : vertebral, distal forearm Age related – 3rd decade of life starts slow decline in bone mass at rate of 0.5-1% per year Most common types of fx : hip and radius, F>M Secondary Osteoporosis Acromegaly , Addison’s disease, Amyloidosis , Anorexia, COPD, Hemochromatosis , Hyperparathyroidism, Lymphoma and leukemia, Malabsorption states, Multiple myeloma, Multiple sclerosis, Rheumatoid arthritis, Sarcoidosis , Severe liver dz , esp. PBC, Thalessemia , Thyrotoxicosis

50. Drugs causing osteoporosis Aluminum Anticonvulsants Excessive thyroxine Glucocorticoids GnRH agonists Heparin Lithium

51. Drugs used in osteoporosis Other: Androgen, Androgenic progestin, thiazide diuretics

52. Selective Estrogen Receptor Modulators (SERM) & Estrogen Estrogens inhibit bone resorption directly by inhibiting osteoclasts activity, Acts on osteoblast to ↓ pro-resorptive [IL-1, IL-6, TNF-α and osteocalcin] and ↑ anti- resorptive [IGF-1 and TGF-β] Raloxifene is a selective estrogen receptor modulator with estrogen agonistic action on bone and antagonistic action on breast and endometrium (Carcinoma risk↓) . So preferred drug for the treatment and prevention of post-menopausal osteoporosis. Risk of thromboembolism .

53. Denosumab monoclonal antibody against RANK-L Osteoclasts express a receptor called receptor for activated nuclear factor k B (RANK) When this receptor is stimulated by RANK-L, bone resorption results due to activation of osteoclasts Treatment and Prevention of osteoporosis . Also used for unresectable giant cell tumor of bone decrease serum calcium therefore avoided in patients with hypocalcemia

54. Strontium ranelate It has a novel mechanism of action as it inhibits bone resorption as well as stimulates bone formation. Blocks osteoclastic differentiation and promote their apoptosis so inhibit bone resorption . Strontium is incorporated into hydroxyapatite , replacing calcium. Small increased risk of venous thrombosis, seizures and abnormal cognition

55. Gallium nitrate: inhibits bone resorption and is useful in the management of Paget’s disease and hypercalcemia of malignancy but nephrotoxicity limits its use Fluorides are used to prevent dental caries , osteoporosis? Thiazides inhibit the renal excretion of Ca2+ so used in osteoporosis ( use in recurrent calcium stones due to hypercalciurea ). Romosozumab is an investigational bone-forming agent that is designed to work by inhibiting the protein sclerostin , thereby increasing bone formation and decreasing bone breakdown.

56. Relative efficacy of drugs on BMD of lumbar spine Most to least effective Teriparatide 40mcg PTH 25mcg+ estradiol Allendronate 10mg Estradiol 0.625mg Raloxifene 120mg Calcitonin 200IU

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