Drugs Affecting Calcium 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)

Calcium Preparations

• 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 - 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. Also 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

4. 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

Bisphophonates (BPNs)

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 – BPNs

BPNs Relative Potency

First generation: Simpler side chainEtidronateTiludronate

110

2nd generation: amino or nitrogenous side chainPamidronateAledronateIbadronate

100100-500

500-1000

3rd generation:RisedronateZoledronate

10005000

Classified in generations (chronological):

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 - MOA

Figure 2. Osteoclastic membrane domains. 1) When an osteoclast is not resorbing bone, it shows no signs of polarized membrane domains. 2) 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. 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 Uses

1. Osteoporosis: Alendronate>HRT or raloxifeneI. Prevention and treatment of post-manaupasal osteoporosisII. Both Men and Women – age related, steroid induced and

idiopathic osteoporosis Oestrogen prevents only vertebral fracture, BNPs 5 years protection

2. 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 better

3. 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 days

4. Osteolytic Bone Metastasis

Individual Drugs

1. 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 waterb. Do not allow to lie down or eat till 30 minutes – oesophagitis;

Tea, coffee, mineral water, Juice, NSAIDsc. ADRs: Gastric errosion, retrosternal pain, flatulenced. 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 disease

5. 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

Thank you