Drugs Affecting

Calcium Balance
Dr. D. K. Brahma
Department of Pharmacology
NEIGRIHMS, 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 (1/3 rd
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 weakness

5. 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 mRNAregulation 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

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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
Classified in generations (chronological):
BPNs
First generation: Simpler side chain
Etidronate
Tiludronate
2nd generation: amino or nitrogenous
side chain
Pamidronate
Aledronate
Ibadronate
3rd generation:
Risedronate
Zoledronate

Relative Potency
1
10

100
100-500
500-1000

1000
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 - 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 raloxifene
I.
II.

Prevention and treatment of post-manaupasal osteoporosis

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 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.
b.

c.
d.

In empty stomach with glass of water

Do not allow to lie down or eat till 30 minutes
oesophagitis; Tea, coffee, mineral water, Juice,
NSAIDs
ADRs: Gastric errosion, retrosternal pain, flatulence
Bioavailability 1%, 50% goes to Bone, terminal
elimination half-life 10.5 years

Individual Drugs contd.

4. Risedronate: Similar to Alendronate, but
potent

more

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