Pharmacology of calcium metabolism

Gyanendra Raj Joshi PharmD, RPh

Objectives:Function / Physiological roles of calcium.Calcium and salts as drugControl of calcium metabolism.Parathyroid hormone.Calcitonin.Vitamin D.Drugs affecting calcium metabolism.

Calcium is required for:• Muscle and nerve functional integrity.• Cardiac function.• Coagulation of blood.• Cementing substance of the bones.

Daily requirements: 0.5-0.75g/day. It increases duringpregnancy and lactation.

Normal serum calcium: 9 -11mg%. 6 - 6.5 mg% exists inionized form, which is the active form.

Absorption and Excretion

• Absorption- facilitated diffusion, carrier mediated active transport

• Filtration• Reabsorption• Excretion

Preparations 1) Calcium chloride 2) Calcium gluconate 3) Calcium lactate 4) Calcium dibasic

phosphate 5) Calcium carbonate

Adverse effects :GI side effects :

constipation, bloating , and excess gas

IrritationTissue necrosis

Uses: • As a supplement during pregnancy and lactation

or when dietary calcium is low.• Osteomalacia and osteoporosis.• Hypoparathyroidism.• Acute tetany: 10-20 ml calcium gluconate 10% i.v

in emergency.• Cal gluconate in dermatoses , paresthesias ,

weakness• As antacid

Control of Calcium Metabolism

• Vitamin D• Calcitonin• Parathyroid hormone.

Vitamin D• It is a fat-soluble vitamin.• Normally, adults do not require vitamin D.• Children and female during pregnancy and lactation require

400-800 units/day.Forms of vitamin D:• Vit.D2 (ergocalciferol): it is of plant origin & formed by

ultraviolet irradiation of ergosterol in plants.• Vit.D3 (cholecalciferol): it is made by ultraviolet irradiation of

7-dehydrocholesterol. It is the form presents in natural foods and is formed in the skin.

• Vitamin D1: mixture of antirachitic substances

Activation of vitamin D:• D2 & D3 are made active by two hydroxylation reactions:• 25-hydroxylation in the liver to 25-OH-cholecalciferol

(calcifediol).• 1α-hydroxylation in the kidney under the influence of

parathyroid hormone to 1α- 25(OH)2 cholecalciferol (calcitriol).

• Absence or deficiency of hydroxylase enzyme in the kidney causes renal rickets.

• Renal rickets is treated with (1α-hydroxycholecalciferol) = alfacalcidol (one alpha).

Functions of vitamin D:• Increases absorption of calcium & phosphate

from intestine.• Increases reabsorption of calcium &

phosphate from renal tubules.• It deposits calcium into bone.• It raises plasma calcium and phosphate.• Increases excretion of magnesium in the

urine.

Uses:• Rickets and osteomalacia. In renal failure & renal rickets use

1α-OH- cholecalciferol (alfacalcidol or one-alpha) that needs only hepatic hydroxylation to be more active (1α- 25(OH)2 cholecalciferol)

• Pregnancy and lactation• Hypoparathyroidism.• Hypophosphatemia.• Osteoporosis. • Fanconi Syndrome• Psoriasis: local vitamin D (creams or ointments) preparation is

available.Adverse reactions:Hypervitaminosis-D: hypercalcemia, hypercalciuria andsoft tissue calcification especially in the kidney & blood vessels

(calcinosis)

Forms available for clinical uses include

1. Natural forms:• D2 = ergocalciferol. It is of plant origin.• D3 = cholecalciferol. It is of an animal origin and

formed by sunrays in the skin.2. Active metabolites:• Calcitriol.• Alfacalcidol or one-alpha (1α- OH- cholecalciferol)3. Vit. D analogue• Dihydrotachysterol.

CalcitoninIt is a hormone secreted by C-cells of the thyroid gland.Mechanism:• GPCR, increase cAMP

Role :• It inhibits osteoclasts reduces bone resoption.• It reduces re-absorption of calcium & phosphorus in the kidney. • Lowering serum calcium.• It also has an analgesic effect in Paget’s disease, metastatic bone

cancer and after vertebral fracture due to osteoporosis.Source:• Natural sources (pork, salmon, eel).• Synthesizes.Preparation:It is available as solution for s.c, i.m injection and as nasalspray.

Uses:• Hypercalcemia

– Hyperparathyroidism – Hypervitaminosis– Malignancy

• Postmenopausal osteoporosis.• To promote healing of bones• Paget’s disease• Metastatic bone cancer pain.

Adverse effects: • Allergy, flushing, nausea, vomiting, and tingling of face & hands.• Bad taste • May interfere with action of Digoxin

Parathyroid hormone• Secreted by parathyroid glands – Rapid response to reduced calcium (minutes)

• Polypeptide – 84 amino acid residues– 9,500 daltons M.W.

• Peptide fragments can be active for periods measured in hours

• Operates in tissues via cAMP second messenger

Functions:• Increasing absorption of calcium from the intestine through

activation of vitamin D in the kidney. • Increasing reabsorption of calcium from the distal convoluted

tubule in the kidney.• Increasing mobilization of calcium from bones to blood through its

binding to osteoblast RANKL stimulation of osteoclasts enhance bone resorption (normal bone destruction)

• Increasing excretion of phosphates in the urine.

Uses: Parathyroid hormone has no valid use. For hypoparathyroidism vitamin D and calcium are quite effective.

Hypoparathyroidism• Low plasma Ca levels• Tetany• Convulsions • Laryngospasm• Paresthesia • Cataract• Psyciatric changes • Pseudohypoparathyroidism

Hyperparathyroidism• Hypercalcemia• Decalcification of bone • Renal stones • Muscle weakness• Constipation • Anorexia • Metastatic calcification

Bisphosphonates• Most effective antiresorptive drugs • 3 generations :– First generation: etidronate, tiludronate– Second generation: Pamidronate, alendronate – Third generation: risedronate, zoledronate

• Uses:– Osteoporosis – Pagets disease – Hypercalcemia of malignancy – Osteolytic bone metastasis

Other Drugs Affecting Calcium Metabolism

• Estrogen: inhibits PTH-stimulated bone resorption, so it can prevent or delay bone loss in postmenopausal women. It is used in postmenoposal osteoporosis (unless contraindicated).

• Glucocorticoids: chronic systemic use causes protein catabolism and increase calcium excretion leading to osteoporosis. It is of benefit in treatment of hypercalcemia.

• Fluoride: as additive in drinking water and in dentifrice, it prevents dental caries. Chronic ingested high concentration of the ion leading to new bone synthesis.

• Mithramycin(Plicamycin): decreases serum calcium in Paget's disease and reduces hypercalcemia associated with cancer. It inhibits bone resorption (inhibits the osteoclasts).

• Thiazides: inhibit excretion of calcium. Used to reduce kidney stone formation.

• Furosemide plus saline infusion: enhanceCalcium excretion Decreases serumcalcium and used in acute hypercalcemia.

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