A power point presentation on “Drugs Affecting Calcium Balance and Bisphosphonates” suitable for undergraduate level MBBS students

1. Drugs Affecting
Calcium Balance
Dr. D. K. Brahma
Department of Pharmacology
NEIGRIHMS, Shillong

2. 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

3. 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

4. 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)

5. 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

6. 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 weakness
5. Antacids

7. 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

8. 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

9. 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

10. 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

11. 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

13. 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

14. Classification –
BPNs
Classified in generations (chronological):
BPNs Relative Potency
First generation: Simpler side chain
Etidronate 1
Tiludronate 10
2nd generation: amino or nitrogenous side chain
Pamidronate 100
Aledronate 100-500
Ibadronate 500-1000
3rd generation:
Risedronate 1000
Zoledronate 5000

15. 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

16. 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.

17. Therapeutic 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 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

18. 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 half-
life 10.5 years

19. 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

20. Thank you