Pharmacology of Calcium

Metabolism



Calcium Metabolism
[Calcium & Phosphate homeostasis]

Basic pharmacology
Principal Hormonal
Regulators of Bone
Mineral Homeostasis
PTHCaPO4
Vit D Both Interaction
FGF 23 PO4
Secondary Hormonal
Regulators
Calcitonin [Both],
Glucocorticoids, Estrogen, insulin, GH

Non- Hormonal
Regulators
Bisphosphonates
Cinacalcet
Plicamycin
Thiazides
Fluoride
Strontium Ranelate
Calcium turnover
Principal regulators of
calcium and phosphate
homeostasis: (PTH), (FGF23),
and vitamin D
Remodeling
_
_
Interaction of principal
regulators of calcium/Po4 homeostasis
The hormonal interactions controlling bone mineral homeostasis. In the body (A),
1,25(OH)
2
D is produced by the kidney under the control of parathyroid hormone
(PTH), which stimulates its production, and fibroblast growth factor 23 (FGF23),
which inhibits its production. 1,25(OH)
2
D in turn inhibits the production of PTH by
the parathyroid glands and stimulates FGF23 release from bone. 1,25(OH)
2
D is the
principal regulator of intestinal calcium and phosphate absorption. At the level of
the bone (B), both PTH and 1,25(OH)
2
D regulate bone formation and resorption,
with each capable of stimulating both processes. This is accomplished by their
stimulation of preosteoblast proliferation and differentiation into osteoblasts, the
bone forming cell. PTH and 1,25(OH)
2
D stimulate the expression of RANKL by
the osteoblast, which, with MCSF, stimulates the differentiation and subsequent
activation of osteoclasts, the bone resorbing cell. FGF23 in excess leads to
osteomalacia by inhibiting 1,25(OH)
2
D3 production and lowering phosphate levels.
MCSF, macrophage colony-stimulating factor; OPG, osteoprotegerin; RANKL,
ligand for receptor for activation of nuclear factor- B.

Calcium
[9-11mg/dl]
Physiological functions

Excitability of nerve and muscles
Permeability
Muscle contraction
Neurotransmitter release
Blood coagulation
As second messenger

Calcium
Preparations
Ca chloride-irritant-only
i.v
Ca gluconate-0.5g tab &
10% i.v. amp.-sense of
warmth during
injection[less irritant]
Ca lactate-oral non
irritating
Ca dibasic phosphate and
carbonate-Antacids
Uses
Tetany-10ml/10% i.v.
10mts [Ca chloride]
Followed by oral calcium
and Vit D
Supplement-children ,
pregnancy,
Osteoporosis-with other
drugs.[Only Ca and Vit D
not effective]
Antacids

PTH
Principal regulators of calcium and phosphate
homeostasis:
PARATHYROID HORMONE (PTH)
Increases serum calcium and decreases serum phosphate.
Bone formation-
Stimulate proliferation and differentiation of Preosteoblasts to osteoblasts
Bone resorption-
PTH acts on the osteoblast to induce a membrane-bound protein
called RANK ligand (RANK-L). This factor acts on osteoclasts and
osteoclast precursors to increase both the numbers and the activity of
osteoclasts.
These actions increase bone turnover or bone remodeling, -
osteoclastic bone resorption and followed by osteoblastic bone
formation.
The net effect of excess PTH is to increase bone resorption.
Principal regulators of calcium and phosphate
homeostasis:
PARATHYROID HORMONE (PTH),
PTH in low and intermittent doses increases bone formation
without first stimulating bone resorption.
Clinical use- recombinant PTH (teriparatide) for the
treatment of osteoporosis.
Kidney
1. Stimulation of 1,25-dihydroxyvitamin D (1,25[OH]
2
D)
production.
2. I ncreases reabsorption of calcium and magnesium
3. Reduces reabsorption of phosphate, amino acids, bicarbonate,
sodium, chloride, and sulfate.
PTH and 1,25(OH)
2
D regulate bone
formation and resorption
[remodeling]
Stimulate
proliferation and
differentiation of
Preosteoblasts
Stimulate
Expression of
RANK-L by
Osteoblasts
RANK-L
[Receptor Activator of Nuclear factor for KB-Ligand]
PTH
Uses: Clinically not used to treat hypocalcimia
Expensive.
Parenteral administration
Calcium with Vit D can be used for the same
purpose.
Teriparatide[1-34 PTH]-Recombinant
Stimulates bone density[low and intermittent
doses]
Used in Osteoporosis


FIBROBLAST GROWTH FACTOR 23
[FGF23]

Primary site of production- osteoblasts and
osteocytes
Inhibits 1,25(OH)
2
D3 production and phosphate
reabsorption in the kidney,
Leading to hypophosphatemia and inappropriately
low levels of circulating 1,25(OH)
2
D
3

Vit D
Vit D is a hormone?
1. Prohormone
2. Synthesized in body
3. Carried in the blood
4. Acts on target tissues
5. Feedback regulation exists
Vit D
Source:
Natural-D3 Cholecalciferol
Plant- D2 Ergocalciferol

Vit D[Natural or Plant]

25[OH]D

1-25[OH]D[Calcitriol]
Liver
Kidney
Vit D
Preparations
Calciferol[D2]
Cholecalciferol[D3]
Calcitriol[Active form]
Alfacalcidol[1 OHD
3
]
Analogs of 1,25(OH)
2
D
Calcipotriol [Psoriasis]
Doxercalciferol and Paricalcitol

Uses
Prophylaxis and treatment of
Vit D deficiency

Metabolic rickets
Renal rickets[Alfacalcidol]
Osteoporosis
Hypoparathyroidism

Drug interactions
Cholestyramine
Phenytoin & Phenobarbitone-
Reduce action on target tissues

Prophylaxis -(400 IU/day)
Treatment-(4000IU/ day)
Alfacalcidol
[1 OHD
3
INTERACTION OF PTH, FGF23, & VITAMIN D
Secondary hormone regulators
-Calcitonin
Secreted by the parafollicular cells of the thyroid
Lowers serum calcium and phosphate by actions on bone and kidney. Calcitonin
inhibits osteoclastic bone resorption.

In the kidney-reduces both calcium and phosphate reabsorption as well as
reabsorption of -Na, K, and Mg.

Decreases gastrin secretion and reduces gastric acid output while increasing secretion of
sodium, potassium, chloride, and water in the gut.

In the adult human, no readily demonstrable problem develops in cases of calcitonin
deficiency (thyroidectomy) or excess (medullary carcinoma of the thyroid).
Useful drug for the treatment of Paget's disease, hypercalcemia, and osteoporosis.
Non- Hormonal Regulators
of Bone mineral homeostasis
Bisphosphonates
Cinacalcet
Plicamycin
Thiazides
Fluoride
Strontium Ranelate

WHAT ARE BISPHOSPHONATES?




Bisphosphonates are small inorganic molecules
Bind to a substance called hydroxyapatite on the
surface of bones.
Osteoclasts are inhibited and destroyed.
Bisphosphonates reduce bone resorption
Bisphosphonates
Non-Nitrogenous
[I Gen]
Etidronate- 1
Clodronate 10
Tiludronate - 10

Nitrogenous
[II Gen]
Pamidronate [i.v.only] 100
Neridronate - 100
Olpadronate - 500
Alendronate - 500
[5-10mg daily/35-70 mg weekly]
Ibandronate - 1000

[III Gen]
Risedronate 2000
Zoledronate -[i.v.] 10000

Bisphosphonates
MOA
Non-Nitrogenous
Structure-similar to
pyrophosphate
Accumulates within the
osteoclasts and promote their
apoptosis.
Prevents bone
resorption


Nitrogenous
Inhibit farnesyl diphosphate synthase,
an enzyme in the mevalonate pathway.
Inhibition of this enzyme prevents the
synthesis signalling proteins necessary
in the formation of the ruffled border
Prevents attachment of osteoclasts to
bone-
Prevents bone
resorption


Bisphosphonates
PK

Oral absorption is poor[5-10%]
Affected by milk
Excreted by kidney
Highly concentrated in bones and remains for years

Bisphosphonates
ADE

Oesophagitis-
Prevented by remaining seated upright for 30 to 60
minutes after taking the medication with a glass of
water
Intravenous bisphosphonates -fever and flu-like
symptoms
Associated with osteo-necrosis of the jaw
Rarely # of long bones
Clinical uses of bisphosphonates
Prevention or treatment of postmenopausal
osteoporosis
Paget's disease of bone.
Hypercalcaemia caused by malignant disease.
Prevention or treatment of glucocorticoid-
induced osteoporosis.
Under investigation for the treatment of cancer
metastases in bone




Osteoporosis
Abnormal loss of bone predisposing to fractures.
Most common in postmenopausal women but also occurs in men

Regular ex
Diet
Ca and Vit D
supplements
Bisphosphonates-
Oral/i.v.
Teriparatide
SERM-Raloxifene
Calcitonin
Strontium
Denosumab[Anti
RANKL antibody]
HRT not recommended