Drugs Affecting

Calcium Balance

Dr. CHANDANE R. D.
Professor
Dept. Of Pharmacology
Lady Hardinge Medical
College New Delhi
 Calcium
Physiological role:
• Excitability of nerves and muscles, regulates
permeability and integrity of cell membranes and cell
adhesion
• Excitation-contraction coupling of all types of muscles
• Excitation and secretion of endocrine and exocrine
glands, neurotransmitters release from nerve 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
• Hypoalbuminemia – no decrease in conc. Of
Ca++
• Acidosis – favours ionization
• Alkalosis – disfavours ionization
– hyperventilation precipitates tetany and
laryngospasm in Calcium deficiency
40-41% is bound to plasma protein – albumin,
9-10% - citrate, carbonate and phosphate and
50% is free ionized and important form-Responsible
for calcium function and Can be directly measured
 Absorption and Excretion
• Absorbed from entire small intestine including
duodenum – carrier mediated active transport under
the influence of Vit.D
• Phytates, phosphates, oxalates and tetracycline, also
Glucocorticoides and Phenytoin reduces absorption
• Filtered through glomerulus but mostly reabsorbed
• Vit. D increases and Calcitonin decreases reabsorption
in proximal tubule
• PTH -increases distal tubular reabsorption -thiazide
• 300 mg is excreted daily in urine and faeces
• Daily requirement: 800 -1500 mg per day (1/3rd
absorbed)
 Preparations of calcium
S.No Preparation Characteristic
1 Calcium 27 % calcium , highly irritant , not for IM
chloride use. Orally also irritable
2 Calcium 9 % calcium , non irritating Sense of
gluconate warmth produced on injection
3 Calcium 13 % calcium, orally well tolerated , non
lactate irritating
4 Calcium 23 % calcium , used as antacid and calcium
dibasic supplement
phosphate
5 Calcium 40 % calcium , tasteless, non irritating ,
carbonate used as antacid and calcium supplement
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. 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
Uses….

4. Empirically in dermatoses, parathesia and

weakness
5. Antacids
6. Hyperkalemia: Calcium gluconate iv life
saving and reduce cardiotoxic effects
7. Black widow spider envenomation: iv
8. Magnesium toxicity, cardiac arrest and
Hyperphosphataemia(CRF)
 Treatment of hypercalcemia
• Hydration & dietary calcium restriction < 400 mg/day
• Sodium chloride: Saline administration will cause renal
elimination of calcium
• Furosemide 20 -40 mg every 2-4 hrs
• Glucocorticoids: reduce intestinal absorption & tubular
reabsorption of calcium
• Calcitonin: 4 IU/kg SC OR IM twice or once daily can be
increased to 8 IU/kg IM 6 hrly
• Mithramycin (Plicamycin) : decrease bone resorption
low dose 10 μg/kg IV
• Inorganic phosphate: phosphosoda 5 ml TDS
- Biphosphonate
 PARATHYROID HORMONE
(Parathormone)
• Location : Posterior to thyroid gland , 4 in nos
Secreted by principal cells
• Preproparathyroid hormone → proparathyroid
hormone → PTH(84 AA polypeptide)
• Plasma Ca2+ is the major factor regulating PTH
secretion. Hypocalcemia stimulates PTH
secretion whereas hypercalcemia inhibits it.
• Calcium inhibits PTH secretion by stimulating
calcium sensing receptor on parathyroid cells.
 Mechanism of action
• PTH receptor - G protein coupled receptor on
activation increases cAMP formation & intracellular
Ca++ in target cells, in bone target cells are osteoblast

• induces a factor ‘Receptor for activation of nuclear

factor-κB-ligand’ (RANKL) which diffuses and
combines with RANK on osteoclast precursors and
transforms them into osteoclasts as well as activates
osteoclasts
• Increase formation of the remodeling pit is f/b
osteoblastic deposition of new bone into it.
• PTH enhances proliferation and differentiation of
preosteoblasts and deposition of osteoid as well.
• ↑ Bone resorption with high conc of PTH
continuously, but intermittent exposure to low conc
↑bone formation.
• Rapidly metabolised in liver & kidney
• T1/2 is 2-5 min
Actions
• Bone: Resorption of calcium from bone increasing the
number of bone remodeling units and activating
osteoclasts
• Kidney: increases calcium reabsorption in the distal
tubule also promote phosphate excretion
• Intestine:increase absorption indirectly by increases
circulating calcitriol by two mechanisms 1) Directly by
stimulating 1α hydroxylase in kidney and 2) indirectly
by decreasing serum phosphate.
• Decrease ca level in milk saliva and ocular lens.
 rParathyroid hormone [rPTH(1-34),
teriparatide]
• Mechanism of action: Stimulates new bone formation on
trabecular and cortical bone surfaces by preferential
stimulation of osteoblastic activity over osteoclastic
activity.
• Daily SC injections of 40mcg of rPTH for 12-18 months ,
increased BMD by 9-13% and decreased risk of vertebral
fractures by 65 to 69 % T1/2-1hr, costly
• Use: severe osteoporosis with multiple risk of fracture
• Diagnostic use: teriparatide i.v.: if plasma calcium level
fails to rise, then it is pseudohypoparathyroidism.
• S/E:headache, nausea, dizziness and leg cramps
• C/I: Pagets disease and hypercalcaemia
 Hyperparathyroidism

• Hypercalcaemia, decalcification of bone—deformities and

fractures, metastatic calcification, renal stones,
constipation
T/T: 1) surgical removal of the parathyroid tumour
2) low calcium, high phosphate diet with plenty of fluids is
advised.
3) Cinacalcet: It activates the Ca2+ sensing receptor (CaSR)
in the parathyroids and blocks PTH secretion. Use:
secondary hyperparathyroidism due to renal disease and in
parathyroid tumour.
 Calcitonin
• Calcitonin, 32-amino acid peptide hormone
(Mol Wt 3600) secreted by the thyroid
gland, tends to decrease plasma Ca conc and
has effects opposite to those of PTH
• Parafollicular cells, or C cells, lying in the
interstitial fluid between the follicles of the
thyroid gland
• rise in plasma Ca2+ increases, while fall in
plasma Ca2+ decreases calcitonin release.
Actions:
• Inhibit bone resorption by direct action on
Osteoclasts- decrease their ruffled surface
• inhibits the proximal tubular reabsorption of
calcium and phosphate by direct action on
kidney. But hypocalcemic action reduce
calcium glom filtration so reduce urinary ca
• Action is mediated through G- protein coupled
calcitonin receptor & increased cAMP
formation but target cells are different from
that of PTH
Calcitonin : Preparations: SC/IM routes
• Porcine (Natural) calcitonin: Antigenic
• Synthetic salmon calcitonin: More potent
due to slower metabolism. also as nasal spray
• Synthetic human calcitonin:
• 1 IU = 4 μg of std preparation
S/E: Nausea, flushing and tingling of fingers
Bad taste, flu-like symptoms, allergic reactions
and joint pain
Uses:
1) Hypercalcemia states: Hyperparathyroidism,
hypervitaminosis D, osteolytic bony metastasis and
hypercalcaemia of malignancy; used only to supplement
BPNs as weak hypocalcemic
2) Pagets disease of bone:Bisphosphonates are preferred
calcitonin 2nd line
3) Postmenopausal osteoporosis & corticosteroid induced
osteoporosis: It is less effective than BPNs/HRT. Salmon
calcitonin as nasal spray along with Vit D supplements 200 IU
/day increase bone mineral density in menopausal women and
to reduce vertebral, but not nonvertebral, fractures.
4) Diagnosis of medullary carcinoma of thyroid:
 Vitamin D
• Mainly D3 (cholecalciferol) and D2
(calciferol)
• Both are equally active in human
• Calcitriol (active form of D3) is more
important physiologically
• Released from liver in blood and binds to
specific vit D binding globulin
vit D should be considered a hormone because:
(a) It is synthesized in the body (skin); under
ideal conditions it is not required in the diet.
(b) It is transported by blood, activated and then
acts on specific receptors in the target tissues.
(c) Feedback regulation of vit D activation
occurs by plasma Ca2+ level and by the active
form of vit D itself.
 Actions of calcitriol
1) 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
2) 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
3) enhances tubular reabsorption of Calcium and phosphate
4) Apart from effects on Ca2+ and phosphate–, calcitriol also
affects maturation and differentiation of mononuclear
cells (possibility of use in cancers), inhibits epidermal
proliferation and promotes epidermal differentiation
(potential t/t of psoriasis ).
 Pharmacokinetics
A) Absorbed from intestine in presence of Bile
salts mainly by lymphatics D3 is better
absorbed than D2
D) Binds to alpha-globulin and stored in fatty
tissues for many months
M) It is hydroxylated in the liver to active and
inactive metabolites
E) Half life varies from 1 – 18 days. Metabolites
of vit D are excreted mainly in bile
 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
• Dihydrotachysterol: Vit D2 analogue HypoPTH and
Renal bone disease
 Vit D - Uses
1) Prophylaxis (400 IU/day ) and treatment(3000 -4000
IU/day) of rickets & osteomalacia : alternatively Oral/IM
injection 3-6 lac IU every 2-6 month interval
2) Metabolic Rickets
a)Vit D resistant rickets: PO4 with high doses of calcitriol
b)Vit D dependent rickets:deficiency of renal hydoxylating
mechanism which converts 25-OHD3 into calcitriol. T/T:
calcitriol or alfacalcidol
c) Renal rickets: Calcitriol/alfacalcidol or dihydrotachysterol
3) Senile or postmenopausal osteoporosis:
4) Hypoparathyroidism: calcitriol/alfacalcitriol
dihydrotachysterol
5) Doxercalciferol and Paricalcitol have been approved
for treatment of secondary hyperparathyroidism in patients
with chronic renal disease. These are less likely to cause
hypercalcemia than calcitriol
6) Fanconi like syndrome: can raise lowered phosphate
7) Calcipotriol : Vitamin D analog used topically in
psoriasis. slightly more effective than glucocorticoids.
Systemically tried for skin cancer and immunological
disorder
Drug Interactions:
1. Cholestyramine and chronic use of liquid
paraffine can reduce vit D absorption.
2. Phenytoin and phenobarbitone reduce the
responsiveness of target tissues to calcitriol;
their prolonged use (for epilepsy) can cause
rickets/ osteomalacia. It was believed earlier
that these drugs enhance degradation of vit D.
level of calcitriol is normal, but its effect on
intestine and bone is diminished.
 Vitamin D deficiency
Rickets in small children
1. Osseous changes:
a) Head: craniotabes, frontal bossing, box like skull,
delayed closure of anterior fontanelle
b) Teeth: delayed eruption, with abnormal order
c) Chest: rachitic rosary, pigeon chest, funnel-shaped chest
d) Spinal column: scoliosis,kyphosis, and lordosis
e) Extremities: bowlegs
f) Rachitic dwarfism
2. Muscular system: potbelly, late in standing and walking
3. Motor development: delayed
4. Other nervous and mental symptoms
 Treatment
1. Food and nursing care
2. Prevention of complications
3. Special therapy
Vitamin D therapy
A. General daily Vitamin D 2000-4000IU/day for 2-
4 weeks, then change to preventive dosage (400IU).
B. A single large dose: For severe case, or Rickets
with complication, or those who can’t bear oral
therapy. Vitamin D3 3 LAC -6 LAC IU, im,
• preventive dosage can be used after 2-6 months.
 Prevention

1. pregnant and lactating women should take adequate

amount of vitamin D.
2. Advocate sunbathing
3.Advocate breast feeding, give supplementary food on time
4. Vitamin D supplementation:
• In prematures, twins & weak babies: 800 IU/day
• For term babies and infants : 400 IU per day,
• For those babies who can’t maintain a daily
supplementation: Vitamin D3 1-2L IU IM.
5. Calcium supplementation:
 Vitamin D - Sources
• Sunlight is the most important source
• Not found naturally in many foods
• Synthesized in body
• Plants (ergosterol) – Sun-cured forages
• Fluid milk products are fortified with vitamin D
• Oily fish & Fish liver oil
• Egg yolk
• Butter
• Liver
• Difficult for vegetarians
 Hypervitaminosis D
• chronic ingestion of large doses (~50,000 IU/day) or due to
increased sensitivity of tissues to vit D.
• causes hypercalcemia, which manifest as:
Nausea & vomiting • Excessive thirst , polyuria & anorexia
• Severe itching • Joint & muscle pains • Disorientation &
coma. • Calcification of soft tissue– Lungs, heart, blood
vessels ,
• Hypercalcemia - formation in renal stone
• Treatment: withholding the vitamin, low calcium diet,
plenty of fluids and corticosteroids
 Calcium Homeostasis
• Calcium and phosphate homeostasis is
maintained by the action of vitamin D (active
form is calcitriol), parathyroid hormone
(PTH), and FGF-23 (Fibroblast growth
factor-23).
• Secondary regulators of Ca2+ homeostasis
include calcitonin, glucocorticoids and
estrogens.
 TES
O NA
S P H
PH O
BI S
Introduction

• Non-hormonal agent in Ca++ homeostasis

• Recently in attention due to Prevention of
osteoporosis, 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”
 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
Alendronate 100-500
Ibadronate 500-1000
3rd generation: nitrogen atom within a
heterocyclic ring
Risedronate 1000
Zoledronate 5000
 MECHANISM OF ACTION
• 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:
A) Accelerated apoptosis of osteoclasts reducing their no.
B) Disruption of the cytoskeleton of the ruffled boarder of
osteoclasts
C) Also affect osteoclast precursors and inhibit their
differentiation by suppressing IL-6.
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.
• Reduction in cholesterol synthesis via inhibition of
farnesyl pyrophosphate synthase by bisphosphonates
• BPN esp 2nd and 3rd generation : Metabolic effects in
the mevalonate pathway for isoprenoid lipid synthesis.
They inhibit prenylation of certain GTP-binding
proteins involved in cytoskeletal organization,
membrane ruffling and vesicle movement. The net
result is inactivation of osteoclasts, impaired vesicle
fusion and enhanced apoptosis.
• Interference with mevalonate pathway may also impart
antitumor action on bony metastasis
 Pharmacokinetics
• Highly polar so less poorly absorbed through
GIT
• Part of absorbed drug is incorporated into bone
& remains for long periods years to months
• The free drug is excreted unchanged in urine
 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 > effective
than calcitonin 5 years protection on cont use. t½ of
alendronate in bone is ~ 10 years, treatment beyond 5 years is
considered unnecessary.
• first choice drugs now for osteoporosis.
2. Osteolytic Bone Metastasis: Parenteral
pamidronate/zoledronate
3. Pagets disease: abnormal osteoclast function - Honeycomb like
bone architecture – arrest osteolytic lesions, reduce bone pain
and improve secondary symptoms. Alendronate, Risedronate,
Pami and Zole are used. Calcitonin combination better.
4. Hypercalcaemia of Malignancy: Medical emergency with
altered consciousness – Pamidronate 60-90 mg IV 2-4 hours or
Zoledronate 4 mg IV 15 minutes. Supplement with calcitonin
IM 6-12 Hrly for 2 days, i.v. hydration, furosemide,
Corticosteroids.
5. Breast Prostate cancer and multiple myeloma: zolendronate
anticancer effect and prevent bony metastasis
6. Philadelphia-chromosome positive CML: Zolendronate as
adjunctive
 Adverse effects

• Oral bisphosphonates causes Gastrointestinal

complications such as gastritis or esophagitis, abdominal
pain, nausea, vomiting, diarrhea, and constipation.
• Bisphosphonate-related osteonecrosis of the jaw- Phossy
jaw so regular dental care and avoid dental extraction.
• Zoledronate - associated with renal toxicity and first
generation bisphosphonates - osteomalacia.
• Long-term bisphosphonates -increases the risk of atypical
‘chalkstick’ fracture of femur (subtrochantric or shaft).
Risk increases with concurrent high dose steroid therapy.
• increase the risk of esophageal cancer.
Contraindication: renal dysfunction, esophageal motility
disorders and peptic ulcer
 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 halflife 10.5 years
4. Risedronate: Similar to Alendronate, but more
potent • Used in osteoporosis and Paget`s disease
5. Zolendronate: Parenterally 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
 Osteoporosis
A systemic skeletal disease characterized by low
bone mass & micro-architectural deterioration
of bone tissue, with a consequent increase in
bone fragility and susceptibility to fracture
Primary osteoporosis
• Postmenopausal:↓ estrogen results in ↑ osteoclastic activity
without ↑osteoblastic activity
Bone loss – 2-3% per year of total bone mass
Most common fx: vertebral, distal forearm
• Age related – 3rd decade of life starts slow decline in bone
mass at rate of 0.5-1% per year
Most common types of fx: hip and radius, F>M
Secondary Osteoporosis
Acromegaly, Addison’s disease, Amyloidosis, Anorexia, COPD,
Hemochromatosis, Hyperparathyroidism, Lymphoma and
leukemia, Malabsorption states, Multiple myeloma, Multiple
sclerosis, Rheumatoid arthritis, Sarcoidosis, Severe liver dz,
esp. PBC, Thalessemia, Thyrotoxicosis
 Drugs causing osteoporosis
• Aluminum
• Anticonvulsants
• Excessive thyroxine
• Glucocorticoids
• GnRH agonists
• Heparin
• Lithium
 Drugs used in osteoporosis

• Other: Androgen, Androgenic progestin,

thiazide diuretics
 Selective Estrogen Receptor Modulators (SERM) & Estrogen

• Estrogens inhibit bone resorption directly by inhibiting

osteoclasts activity,
• Acts on osteoblast to ↓ pro-resorptive [IL-1, IL-6,
TNF-α and osteocalcin] and ↑ anti-resorptive [IGF-1
and TGF-β]
• Raloxifene is a selective estrogen receptor modulator
with estrogen agonistic action on bone and antagonistic
action on breast and endometrium(Carcinoma risk↓) . So
preferred drug for the treatment and prevention of post-
menopausal osteoporosis.
Risk of thromboembolism.
 Denosumab
• monoclonal antibody against RANK-L
• Osteoclasts express a receptor called receptor for
activated nuclear factor k B (RANK) When this
receptor is stimulated by RANK-L, bone resorption
results due to activation of osteoclasts
• Treatment and Prevention of osteoporosis.
• Also used for unresectable giant cell tumor of bone
• decrease serum calcium therefore avoided in
patients with hypocalcemia
 Strontium ranelate
• It has a novel mechanism of action as it inhibits
bone resorption as well as stimulates bone
formation.
• Blocks osteoclastic differentiation and promote
their apoptosis so inhibit bone resorption.
• Strontium is incorporated into hydroxyapatite,
replacing calcium.
• Small increased risk of venous thrombosis,
seizures and abnormal cognition
• Gallium nitrate: inhibits bone resorption and is
useful in the management of Paget’s disease and
hypercalcemia of malignancy but nephrotoxicity
limits its use
• Fluorides are used to prevent dental caries,
osteoporosis?
• Thiazides inhibit the renal excretion of Ca2+ so
used in osteoporosis ( use in recurrent calcium stones
due to hypercalciurea).
• Romosozumab is an investigational bone-forming
agent that is designed to work by inhibiting the
protein sclerostin, thereby increasing bone formation
and decreasing bone breakdown.
 Relative efficacy of drugs on BMD of
lumbar spine
• Most to least effective
Teriparatide 40mcg
PTH 25mcg+ estradiol
Allendronate 10mg
Estradiol 0.625mg
Raloxifene 120mg
Calcitonin 200IU