Drugs affecting calcium balance

Drugs affecting calcium balance

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  Drugs affecting calcium balance-1 Calcium& PTH Dr Naser Ashraf Tadvi Associate Professor Pharmacology Ayaan Institute of Medical Sciences
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  Objectives • Recall thephysiological functions of calcium • Describe the regulation of plasma calcium • Describe Pharmacokinetics of calcium • Enlist the oral and parenteral preparations of calcium • Describe therapeutic uses of Calcium salts • Explain the treatment of Hypercalcemia • Discuss the Pharmacology of Parathyroid hormone (MOA, actions, uses)
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  Case study • A28-year-old female presented to Medicine OPD with complains of numbness and tingling sensation in perioral area since past few days • She also had muscle cramps in back and lower extremities • The casualty doctor elicited Trosseu`s and Chvostek`s sign and found them to be positive
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  • ↑neuromuscular irritability •Paresthesia, tetany, seizures • Laryngeal spasm • Teeth hypoplasia • Skin & nails atrophy Hypocalcemia
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  Calcium • More than90 % stored in bones & teeth rest distributed to plasma & all tissues of cells • Normal levels = 9 to 11mg/dL Ionized Protein Bound Complexed to anions 50 % exerts the biological action 40 % to albumin 10 % phosphates, citrates
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  Physiological Functions of calcium Controls Excitability of Nervesand Muscle Essential for Muscular Contraction Formation of Bone and teeth Hormonal and neurotransmitter release Second messenger in some hormonal actions Blood clotting Maintains integrity of cell membrane and regulates cell adhesion
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  Regulation of plasmalevel of calcium
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  Influences affecting boneturnover ↑ Resorption • Corticosteroids • Parathormone • Hypervitaminosis D • PGE2, IL-1, IL-6 • Alcoholism • Loop diuretics ↓ Resorption • Androgens / Estrogen • Calcitonin • Bisphosphonates • Fluoride • Gallium nitrate • Mithramycin • Thiazide diuretics
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  Absorption of Calcium •Facilitated diffusion from entire small intestine • Carrier mediated active transport under influence of Vit-D in duodenum • Low calcium intake, • Vitamin D and PTH • Oxalates, phosphates & phytates • Glucocorticoids • Phenytoin Agents ↑ absorption: Agents ↓ absorption: Normally only 1/3 of ingested calcium is absorbed
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  Excretion of calcium •300 mg of endogenous calcium excreted daily • 150 mg in urine and 150 mg in feces • Recommended daily allowance – 800 mg to 1500 mg
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  Preparations of calcium Oral •Calcium carbonate (40 % Ca) • Calcium lactate (13 % Ca ) • Calcium citrate (21% Ca) • Calcium Dibasic Phosphate (23% Ca) • Calcium Gluconate Parenteral • Calcium gluconate (9 % Ca) • Calcium chloride (27 % ca) • Calcium laevulinate(13 %)
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  Preparations of calcium S.NPreparation Characteristic 1 Calcium Carbonate (40% Ca) Tasteless, non irritating, also used as antacid 2 Calcium lactate (13 % ) orally well tolerated, non irritating 3 Calcium Citrate (21%) Tasteless and non irritating 4 Calcium dibasic phosphate ( 23%) used as antacid and calcium supplement 5 Calcium gluconate (9%) non irritating, Sense of warmth produced on injection 6 Calcium chloride (27%) highly irritant , not for IM use.
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  Uses of CalciumPreparations 1. To prevent or correct calcium deficiency • Children 1-10 yr :0.8 – 1.2 g /day • Young adult, pregnant, lactating female: 1.2 -1.5 g • Men : 1 g • Women> 50 yr not taking HRT: 1.5 g
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  Uses of CalciumPreparations 2. Tetany (Hypocalcemia) : • 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. • Long term oral treatment to provide. 1- 1.5 g of calcium daily is instituted along with Vit D
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  Other uses ofcalcium 3. Osteoporosis: 4. As antacid 5. Placebo 6. Sometimes in treating dermatoses and urticaria 7. As Phosphate binder in CKD Uses of Calcium Preparations
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  Hypercalcemia • Lethargy, anorexia,weakness • Nausea, vomiting, constipation • Polyuria, dehydration • Irregularities in heart • Metastatic calcification • Mental changes indicate severe hypercalcemia
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  Treatment of hypercalcemia •Hydration & dietary calcium restriction < 400 mg • Sodium chloride:causes renal elimination of calcium • Furosemide 20 -40 mg every 6 to 12 hourly • Bisphosphonates • Glucocorticoids: • Calcitonin: 4 IU/kg SC OR IM twice or once daily • Mithramycin : 25 μg/kg IV over period of 4- 6 Hr • Inorganic phosphate: phosphosoda 5 ml TDS
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  Hypercalcemia • Vitamin D •Thiazide diuretics • Antacid with absorbable alkali Drugs causing Hypocalcemia • Furosemide • Insulin • Corticosteroids • Carbenoxolone • Degraded tetracycline • Laxative abuse
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  Parathyroid Hormone (PTH) •Polypeptide – 84 AA • 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 • PTH rapidly degraded in kidney & liver
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  Actions of PTH Increasesresorption of calcium from bone Increases number of bone remodelling units Activates the osteoclastsIncreases calcium resorption in distal tubule No direct effect increases calcium absorption by enhancing formation of calcitriol
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  precursor Mechanism of Actionof PTH PTH receptor : Gprotein coupled , activation ↑cAMP and ↑ calcium in target cells Target cell in bone ↑bone remodelling units with osteoclast recruitment . Proliferation & differentiation of pro- osteoblast & deposition of osteoid as well Secrete acid and proteolytic enzymes Resorb bone matrix
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  Cinacalcet • Activates CaSRin parathyroids and blocks PTH secretion • Indicated in secondary hyperparathyroidism (due to renal disease) & in parathyroid tumor Uses of PTH • Not used in hypoparathyroidism because Vitamin D can be used more conveniently Teriparatide • Recombinant preparation 1-34 residues of AA, duplicates all actions of PTH. Approved for severe osteoporosis
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  Summary • Calcium – Functions –Preparations – Uses • Treatment of hypercalcemia • PTH – Actions – Mechanism – Uses
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  Drugs affecting calcium balance-2 Calcitonin,Vitamin D Dr Naser Ashraf Tadvi Associate Professor Pharmacology Ayaan Institute of Medical Sciences
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  Objectives • Describe thepharmacological actions and therapeutic uses of calcitonin • Recall the steps in activation of Vitamin D, its mechanism of action and Physiological actions • Enlist Vit D preparations and describe their salient pharmacokinetic features, ADR and Therapeutic uses • Describe the mechanism of action, salient pharmacokinetic features, ADR and therapeutic uses of bisphosphonates • Explain the management of osteoporosis
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  • A hypocalcemichormone discovered by Copp • 32 AA, 3600 Mol.Wt • Produced by C-cells • Physiological effects are opposite to those of PTH • Plasma t ½ of calcitonin is 10 minutes but its action last for several hours Calcitonin
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  Calcitonin Bone Kidney Directly inhibitsthe osteoclasts of bone Decreased bone resorption ↓↓ plasma calcium ↓↓ Plasma phosphate Inhibits the reabsorption of Ca & Po4 in proximal renal tubule Actions of calcitonin
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  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 also available as nasal spray
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  Uses of calcitonin •Hypercalcemic states • Pagets disease of bone • Adjuvant second line drug • Postmenopausal osteoporosis – Salmon calcitonin is used as nasal spray along with Vit D supplements 200 IU /day
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  Vitamin D • VitaminD1: – Mixture of antirachitic substances found in the food- only of historic interest • Vitamin D2: – calciferol- present in irradiated food- yeasts, fungi, bread, milk • Vitamin D3: – cholecalciferol- synthesized in skin under influence of UV rays
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  Activation of VitD 7 dehydrocholesterol Ergosterol Cholecalciferol (Vit D3) Calciferol (Vit D2) (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
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  Actions of VitD • ↑absorption of calcium & phosphate from intestine • ↑ resorption of calcium & phosphate from bone • ↑ tubular resorption of calcium and phosphate in kidneys • Cell differentiation: particularly of collagen & skin epithelium • Important for Cell Mediated Immunity & coordination of the immune response.
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  Actions of VitD Groff & Gropper, 2000 • 1,25-(OH)2 D binds to vitamin D receptor (VDR) in cytoplasm • ↑ in calbindin (Ca-binding protein) • Net effect is ↑ absorption of calcium & phosphorus from intestine
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  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
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  Preparations • Calciferol (VitD2): Gelatin filled capsules 25000 to 50000 IU • Cholecalciferol (Vit D3): Oral/IM injection • 60000 IU capsules & 3-6 lac IU / ml inj • Calcitriol: oral capsules & solution • 0.25-1 μg daily or IV on alternate days • Alfacalcidiol & dihydrotachysterol: • Effective in renal bone disease & hypoparathyroidism • Calcipotriol : Vitamin D analog used topically in psoriasis
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  Uses of VitaminD 1. Prophylaxis and treatment of nutritional Vitamin D deficiency – For prevention or treatment of rickets in children and osteomalacia in adults – Prophylactic dose is 400 IU/ day, therapeutic dose is 3000 to 4000 IU/day – Alternatively 3 lac to 6 lac IU can be given orally / IM once in 2 to 6 months
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  Uses of VitD 2. Metabolic rickets : 3. Senile or post menopausal osteoporosis 4. Hypoparathyroidism : calcitriol or alphacalcidiol are better 5. Fanconis syndrome: – ↑es phosphate levels 6. Calcipotriol : Vitamin D analog used topically in psoriasis
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  Vitamin D deficiency •Deficiencyof vitamin D leads to: ➢ Rickets in small children. ➢ Osteoporosis
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  Treatment of rickets 1.Food and nursing care 2. Prevention of complications 3. Special therapy 1) Vitamin D therapy A. General method 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 300000-600000IU, im, preventive dosage can be used after 2-6 months.
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  Prevention 1. pregnant andlactating 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 1L-2L IU IM. 5. Calcium supplementation:
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  TOXICITY •Hypervitaminosis 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 ,
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  Biphosphonates • Analogs ofpyrophosphate • First generation: • Etidronate • Second generation: • Pamidronate • Alendronate • Third generation : • Risedronate • Zoledronate
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  • Mechanism ofaction Protect dissolution of hydroxyapatite from bone Accelerates apoptosis of osteoclasts Inhibits release of IL-6
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  • Highly polarso less poorly absorbed through GIT • Alendronate, ibandronate and risedronate administered orally • Pamidronate and Zoledronate administered IV • Part of absorbed drug is incorporated into bone & remains for long periods years to months • The free drug is excreted unchanged in urine • Pharmacokinetics
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  Biphosphonates uses andadverse effects • Uses • Pagets disease of bone: treatment of choice • prevention & treatment of post-menopausal osteoporosis • prevent corticosteroid induced osteoporosis • 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
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  Pro’s and Con’sof Available Osteoporosis Therapies Agent Pro’s Con’s Calcium/Vit D Cheap, accessible Partial efficacy HRT Effective breast ca, DVT, MI, CVA Raloxifene  vert Fx,  breast ca Less effect on BMD Bisphosphonates  vert and nonvert Fx GI intolerance Strontium Bulky, daily dosing ? Mechanism Teriparatide Effective Expensive, daily injections