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Drugs AffectingCalcium BalanceDr. D. K. BrahmaDepartment of PharmacologyNEIGRIHMS, Shillong
Calcium –Physiological Roles• Excitability of nerves and muscles and regulates permeability of cell membranes. Also integrity of cell menbanes• Ca++ essential for excitation and coupling of all types of muscles• Excitation and secretion of endocrine and exocrine glands and release of neurotransmitters from erve endings• Intracellular messenger for hormones, autacoids and transmitters• Impulse generation and conduction in heart• Coagulation of Blood• Structural function of Bone and Teeth - hydroxyapatite
Plasma Calcium Level• Regulated by 3 hormones Parathormone, calcitonin and Calcitriol (active vit. D)• Normal plasma level = 9-11 mg/dl• 40% is bound to plasma protein – albumin, 10% - citrate, carbonate and phosphate and 50% is free ionized and important form• Hypoalbuminemia – no decrease in conc. Of Ca++• Acidosis – favours ionization• Alkalosis – disfavours ionization – hyperventilation precipitates tetany and aryngospasm in Calcium deficiency
Pharmacokinetics• Absorbed from entire small intestine including duodenum – carrier mediated active transport under the influence of Vit.D• Phytates, phosphates, oxalates and tetracycline – reduces absorption • Glucocorticoides and Phenytoin reduces Ca absorption• Filtered through glomerulus but mostly reabsorbed• Vit. D increases and Calcitonin decreases reabsorption in proximal tuule• PTH increases distal tubular reabsorption• 300 mg is excreted daily in urine and faeces• Daily requirement: 800 -1500 mg per day (1/3rd absorbed)
CalciumPreparations• Calcium chloride (27% Ca): freely water soluble, but irritant - tissue necrosis on IM or IV (extravasation). Orally also irritant• Calcium gluconate (9 % Ca): 0.5 gm/1 gm tabs and 10% injections – non irritant (preferred)• Calcium lactate: orally non irritant• Calcium dibasic phosphate (23% Ca): Insoluble, but with HCl form soluble salts - antacids and replacement• Calcium chloride: Insoluble and no irritant – antacids
Calcium - Uses1. 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 therapy2. Dietary supplement: growing children, pregnant, lactating and meopausal etc. Also in men and women reduce the bone loss3. Osteoporosis: Prevention ant treatment of osteoporosis with HRT/raloxifene/Alendronate – to ensure Ca++ deficiency does not occur • Calcium and Vit. D3 used as adjuvant4. Empirically in dermatoses, parathesia and weakness5. Antacids
Vitamin D• Mainly D3 (cholecalciferol) and D2 (calciferol)• Both are equally active in man• Calcitriol (active form of D3) is more important physiologically• Released from liver in blood and binds to specific vit D binding globulin
Actions of calcitriol• 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• 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• Also enhances tubular reabsorption of Calcium
Pharmacokinetics• Absorbed fro intestine in presence of Bile salts mainly by lymphatics• D3 is better absorbed than D2• Binds to alpha-globulin and stored in fatty tissues for many months• Half life varies from 1 – 18 days
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
Vit D - Uses• Metabolic Rickets • Vit D resistant rickets: PO4 with high doses of calcitriol • Vit D dependent rickets • Renal rickets• Senile or postmenopausal osteoporosis• Hypoparathyroidism: calcitriol/alfacalcitriol• Fanconi like syndrome
Introduction• Non-hormonal agent in Ca++ homeostasis• Recently attracted considerable attention• Prevent osteoporosis and 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”• BPNs have selective affinity for Calcium phosphate – so calcified tissues
Classification –BPNsClassified in generations (chronological): BPNs Relative PotencyFirst generation: Simpler side chainEtidronate 1Tiludronate 102nd generation: amino or nitrogenous side chainPamidronate 100Aledronate 100-500Ibadronate 500-10003rd generation:Risedronate 1000Zoledronate 5000
BPNs - MOA • 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• 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 • Accelerated apoptosis of osteoclasts reducing their number • Disruption of the cytoskeleton of the ruffled boarder of osteoclasts
BPNs - MOAFigure 2. Osteoclastic membrane domains. 1) When an osteoclast is not resorbing bone, it shows nosigns of polarized membrane domains. 2) Once the osteoclast starts the resorbing, it quicklypolarizes its membrane into distinct domains. Ruffled border (RB) is a membrane domain facing thebone surface, where the actual resorption takes place. Sealing zone (SZ) forms a tight contact to thebone, sealing the proteolytic enzymes and acid into the forming resorption lacuna. Basolateralmembrane (BL) faces towards the bone marrow. 3) 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.
Therapeutic Uses1. 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 5 years protection2. Pagets disease: Honeycomb like bone architecture – arrest osteolytic lesions, reduce bone pain and improve secondary symptoms. Alendronate, Risedronate, Pami and Zole are used. Calcitonin combination better3. Hypercalcaemia of Malignancy: Medical emergency with altered consciousness – Pamidronate 60-90 mg IV 2-4 hours or Zoledronate 4 mg IV 15 minutes. Suplement with calcitonin IM 6-12 Hrly for 2 days4. Osteolytic Bone Metastasis
Individual Drugs1. Etidronate: Not used anymore2. Pamidronate: Only IV 60-90 mg for 2-4 Hrs, weekly or monthly in Pagets disease and hypercalcaemia3. 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 half- life 10.5 years
Individual Drugs – contd.4. Risedronate: Similar to Alendronate, but more potent • Used in osteoporosis and Paget`s disease5. Zolendronate: Prenterally 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