Calcium metabolism [Pharmacology]

8/12/2019 Calcium metabolism [Pharmacology]

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Pharmacology of CalciumMetabolism


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Calcium Metabolism[Calcium & Phosphate homeostasis]

Basic pharmacology Principal Hormonal

Regulators of Bone

Mineral Homeostasis PTH CaPO4

Vit D Both InteractionFGF 23 PO4

Secondary HormonalRegulatorsCalcitonin [ Both ],Glucocorticoids, Estrogen, insulin, GH

Non- HormonalRegulatorsBisphosphonates

CinacalcetPlicamycinThiazides

FluorideStrontium Ranelate


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Calcium turnover


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Principal regulators ofcalcium and phosphate

homeostasis: (PTH), (FGF23),and vitamin D

Remodeling

_


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_

Interaction of principalregulators of calcium/Po4 homeostasis


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The hormonal interactions controlling bone mineral homeostasis. In the body ( A),1,25(OH) 2D 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) 2D in turn inhibits the production of PTH bythe parathyroid glands and stimulates FGF23 release from bone. 1,25(OH) 2D is the

principal regulator of intestinal calcium and phosphate absorption. At the level ofthe bone ( B), both PTH and 1,25(OH) 2D regulate bone formation and resorption,with each capable of stimulating both processes. This is accomplished by theirstimulation of preosteoblast proliferation and differentiation into osteoblasts, the

bone forming cell. PTH and 1,25(OH) 2D stimulate the expression of RANKL bythe osteoblast, which, with MCSF, stimulates the differentiation and subsequent

activation of osteoclasts, the bone resorbing cell. FGF23 in excess leads toosteomalacia by inhibiting 1,25(OH) 2D3 production and lowering phosphate levels.MCSF, macrophage colony-stimulating factor; OPG, osteoprotegerin; RANKL,ligand for receptor for activation of nuclear factor- B.


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CalciumPreparations

Ca chloride-irritant-onlyi.v

Ca gluconate-0.5g tab &

10% i.v. amp.-sense ofwarmth duringinjection[less irritant]

Ca lactate-oral nonirritating

Ca dibasic phosphate andcarbonate-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 Dnot effective]

Antacids


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PTH


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Principal regulators of calcium and phosphatehomeostasis:

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 proteincalled RANK ligand (RANK-L ). This factor acts on osteoclasts andosteoclast precursors to increase both the numbers and the activity ofosteoclasts.

These actions increase bone turnover or bone remodeling, -osteoclastic bone resorption and followed by osteoblastic boneformation.

The net effect of excess PTH is to increase bone resorption.


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Principal regulators of calcium and phosphatehomeostasis:

PARATHYROID HORMONE (PTH),

PTH in low and intermittent doses increases bone formationwithout first stimulating bone resorption.

Cli ni cal use- r ecombinant PTH (ter iparatide) for the

tr eatment of osteoporosis. Kidney

1. Stimulation of 1,25-dihydroxyvitamin D (1,25[OH] 2D)production .

2. I ncreases reabsorption of calcium and magnesium3. Reduces reabsorption of phosphate , amino acids, bicarbonate,

sodium, chloride, and sulfate.


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PTH and 1,25(OH) 2D regulate boneformation and resorption

[remodeling]

Stimulateproliferation anddifferentiation ofPreosteoblasts

StimulateExpression ofRANK-L byOsteoblasts

RANK-L

[R eceptor Activator of Nuclear factor for KB-Ligand]


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PTH

Uses: Clinically not used to treat hypocalcimiaExpensive.Parenteral administrationCalcium with Vit D can be used for the same

purpose. Teriparatide[1-34 PTH]-Recombinant

Stimulates bone density[ low and intermittentdoses]

Used in Osteoporosis


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FIBROBLAST GROWTH FACTOR 23

[FGF23]

Primary site of production- osteoblasts andosteocytes

Inhibits 1,25(OH) 2D3 production and phosphatereabsorption in the kidney,

Leading to hypophosphatemia and inappropriatelylow levels of circulating 1,25(OH) 2D3


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Vit D

Vit D is a hormone?1. Prohormone2. Synthesized in body3. Carried in the blood

4. Acts on target tissues5. Feedback regulation exists


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Vit D

Source: Natural-D3 CholecalciferolPlant- D2 Ergocalciferol

Vit D[Natural or Plant]

25[OH]D

1-25[OH]D[Calcitriol]

Liver

Kidney


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Vit D

Preparations

Calciferol[D2] Cholecalciferol[D3] Calcitriol[Active form]

Alfacalcidol[1

OHD 3] Analogs of 1,25(OH) 2D

Calcipotriol [Psoriasis]Doxercalciferol and Paricalcitol

Uses

Prophylaxis and treatment ofVit 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


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INTERACTION OF PTH, FGF23, & VITAMIN D


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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 asreabsorption of -Na, K, and Mg.

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

In the adult human, no readily demonstrable problem develops in cases of calcitonindeficiency (thyroidectomy) or excess (medullary carcinoma of the thyroid).

Useful drug for the treatment of Paget's disease, hypercalcemia, and osteoporosis.


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Non- Hormonal Regulatorsof Bone mineral homeostasis

BisphosphonatesCinacalcet

PlicamycinThiazidesFluoride

Strontium Ranelate


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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


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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


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BisphosphonatesMOA

Non-Nitrogenous Structure-similar to

pyrophosphate Accumulates within the

osteoclasts and promote theirapoptosis.

Prevents bone

resorption

Nitrogenous Inhibit farnesyl diphosphate synthase,

an enzyme in the mevalonate pathway. Inhibition of this enzyme prevents the

synthesis signalling proteins necessaryin the formation of the ruffled border

Prevents attachment of osteoclasts to bone-

Prevents bone

resorption


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i h h


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BisphosphonatesPK

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

Bi h h


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BisphosphonatesADE

Oesophagitis- Prevented by remaining seated upright for 30 to 60

minutes after taking the medication with a glass ofwater

Intravenous bisphosphonates -fever and flu-likesymptoms

Associated with osteo-necrosis of the jaw Rarely # of long bones


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Clinical uses of bisphosphonates

Prevention or treatment of postmenopausalosteoporosis

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


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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

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Calcium metabolism [Pharmacology]

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