PARATHYROID HORMONE AND DRUGS AFFECTING CALCIUM METABOLISM

Question 1

Discuss functions of calcium

Answer 1

1.Current flow across excitable membranes.
2.Fusion and release of storage vesicles.
3.Muscular contraction.
4.Second messenger.
5.Blood coagulation.
6.Involved in formation and remodeling of the skeleton.

Question 2

What is the calcium ion body store?

Answer 2

Body store of ion is about 1300g in men and 1000g in women.

Question 3

The normal serum calcium concentration in adults range from
What percentage is ionized, protein bound and complexed?

Answer 3

8.5 to 10.4mg/dl.
This exist as ionized (50%), protein bound (40%), complexed (10%).

40% is bound to plasma protein with albumin making up 90% of the proteins.

Question 4

Which type of calcium is responsible for hypo hypo calcium?
concentration of calcium controlled by what?
what regulates calcium?

Answer 4

Ionized calcium is responsible for exerting physiological effects and its disturbances produces signs and symptoms of hypo or hypercalcemia.

Concentration is controlled by hormones, mainly PTH and 1,25-dihydroxyvitamin D (calcitriol).

Regulation is at the intestine, kidney and bone.

Question 5

Most important sources of calcium?

Describe the absorption of calcium

The effect of glucocorticoids calcium transport?

how much is the obligatory daily intestinal loss of calcium?

Answer 5

Milk and dairy products consitute important sources of calcium.

Absorption is by facilitated diffusion throughout the small intestine and fractionally by vit. D dependent transport in the proximal jejunum.
Intestinal ca2+ absorption is inversely related to calcium intake.

Glucocorticoids and phenytoin depress intestinal ca2+ transport.

Obligatory daily intestinal loss is about 150mg/day.

Question 6

Disgust the excretion and tubular absorption of calcium

Answer 6

Calcium is excreted by the kidneys but more than 98% of filtered ca2+ is reabsorbed.
Tubular reabsorption of ca2+ is regulated by by PTH.
Other influences on tubular reabsorption include filtered Na+, nonreabsorbed ions and diuretics.

Question 7

Discuss the parathyroid hormone and its chemistry

Answer 7

PTH
Polypeptide hormone.
Regulates plasma ca2+ by affecting bone resorption/formation, renal ca2+ excretion/reabsorption and GIT ca2+ reabsorption via calcitriol synthesis.

Chemistry:
Single chain polypeptide with 84 aas.
Biological activity associated with the N-terminal portion.
aas 1-27 essential for optimal binding to PTH receptors.

Question 8

Discuss the synthesis of parathyroid hormone

Answer 8

Synthesis:
Synthesis commences from a 115aa preprohormone .
Cleavage of 25aas converts it to prohormone.
Above is converted in the Golgi apparatus to PTH by cleavage of 6 aas (PTH 1-84).
PTH (7-84) is a major proteolytic product of PTH.
PTH has a plasma t1/2 0f 2-5 minutes.
Clearance is mainly by liver and kidneys.

Question 9

What is the mechanism of action of PTH?

Answer 9

Mechanism of action:
Mediated through PTH-1 receptor and PTH-2 receptors.
PTH1R also binds PTHrP.
PTH2R binds only PTH.
Both are G-protein coupled receptors acting thru Gs and Gq.
Regulation of secretion is mainly by ca2+

Question 10

Discuss vitamin D

Answer 10

Vitamin D
Actually a hormone.
Receptors for the activated form expressed in many cells that are not involved in calcium homeostasis eg erythropoietic cells, lymphocytes etc.
Cholecalciferol and ergocalciferol.

Question 11

Discuss the chemistry of vitamin D

Answer 11

Chemistry:
7-dehydrocholesterol synthesized in the skin.
Exposure of skin to sunlight converts 7-dehydrocholesterol to cholecalciferol (vit D3).
The provitmin for vit D2 is ergosterol.
Ergosterol and vit D2 differ from 7-dehydrocholesterol and vit. D3 resp. by presence of a double bond between C22 and C23 and a methyl group at C24.

Question 12

Discuss the pharmacokinetics of vitamin D

Answer 12

Chemistry:
7-dehydrocholesterol synthesized in the skin.
Exposure of skin to sunlight converts 7-dehydrocholesterol to cholecalciferol (vit D3).
The provitmin for vit D2 is ergosterol.
Ergosterol and vit D2 differ from 7-dehydrocholesterol and vit. D3 resp. by presence of a double bond between C22 and C23 and a methyl group at C24.

Question 13

Discuss the metabolic activation of vitamin D

Answer 13

Metabolic activation:
Primary active metabolite is calcitriol (1α,25-dihydroxyvitamin D, 1,25(OH)2D).
1,25(OH)2D) is a product of two successive hydoxylations of vit.D.
Initial 25-hydroxylation occurs in the liver to generate 25-OH-cholecalciferol (25-OHD or calcifediol) and 25-OH-ergocalciferol.
Major circulating form of vit D3 is 25-OHD with a t1/2 of 19 days.
Reduced EC Ca2+ stimulates 1α-hydroxylation of 25-OHD increasing formation of 1,25(OH)2D.
Elevated Ca2+ levels to 24-hydroxylation of 25-OHD .

The second step in the metabolic activation is 1α-hydroxylation of 25-OHD primarily in the kidney but also in other sites.
1α-hydroxylase, CYP1α, 25-hydroxyvitaminD3-1α-hydroxylase is the responsible enzyme.
24-hydroxylase expressed in the kidneys hydroxylates calcitriol and 25-OHD to 1,25(OH)2D and 24,25(OH)2D respectively.

Question 14

Discuss the physiological function of vitamin D

Answer 14

Physiological functions
Augments absorption and retention of Ca2+ and phosphate.
1.Facilitates absorption of Ca2+ and phosphate from the small intestine.
2.Interacts with PTH to enhance Ca2+ and phosphate mobilization from bone.
3.Decreasing their renal excretion.

Question 15

Discuss the mechanism of action of vitamin D

Answer 15

Mechanism of action:
Interaction of calcitriol with VDRs.
Binding to cytosolic VDR in target cells is followed by translocation of receptor-hormone complex to the nucleus.
Interaction with DNA to modify gene transcription.
VDR belong to the steroid and thyroid hormone receptor supergene family.
Calcitriol is available for oral administration or injections.

Question 16

Doxercalciferol

Answer 16

Prodrug
Activated by hepatic 25-hydroxylation to generate the biologically active compound 1α,25-(OH)2D2.
Used in treating secondary hyperparathyroidism.

Question 17

Dihydrotachysterol (DHT, ROXANE).

Answer 17

Reduced form of vit D2.
Prodrug converted in the liver to 25-dihyroxytachysterol.
Mobilises bone minerals at high doses.
Good oral absorption.
Used in treating hypoparathyroidism.

Question 18

Other forms of vitamin D are

Answer 18

1α-hydroxycholecalciferol (1-OHD3, alphacalcidol, ONE-ALPHA).
Ergocalciferol (calciferol, DRISDOL

Question 19

Calcitriol analogs

Answer 19

1.Calcipotriol (calcipotriene)
Synthetic derivative of calcitriol.
Comparable affinity with calcitriol for VDR.
Less than 1% as active as calcitriol in regulating calcium metabolism.
Used in treatment of psoriasis.

2. Paricalcitol
   Synthetic calcitriol derivative.
   Reduces serum PTH levels without producing hypercalcemia or altering serum phosphorus.
   Approved for tx of secondary hyperparathyroidism in patients with CRF.
3. 22-Oxacalcitriol
   Potent suppressor of PTH gene expression.
   Limited activity on bone and intestine.
   Used in tx of patients with overproduction of PTH in CRF or in primary hyperparathyroisism.

Question 20

Indications for vitamin D therapy

Answer 20

Prophylaxis and treatment of Nutritional rickets.
Treatment of osteomalacia and renal osteodystrophy.
Treatment of hypoparathyroidism.
Prevention and treatment of osteoporosis.

Question 21

Calcitonin

Answer 21

Hypocalcemic hormone whose actions generally oppose those of PTH.
Produced and secreted by the thyroid parafollicular C cells.
It is a 32aa single-chain peptide.
It has a t1/2 of about 10 minutes.
Metabolic clearance is by the kidney.
Acts to reduce serum calcium and phosphate levels by:
Reducing the reabsorption of both as well as those of sodium, potassium and magnesium in the kidneys.
Inhibiting osteoclastic bone resorption.

Question 22

Hormones with effects on bone:

Answer 22

Glucocorticoids :
Stimulates calcium excretion by the kidneys.
Blocks bone formation.
Inhibiting intestinal absorption of calcium.
Estrogens
Reduce rate of bone loss in postmenopausal women.
Acts by reducing the bone resorbing effects of PTH

Question 23

Nonhormonal agents affecting bone

Answer 23

Bisphosphonates (alendronate, pamidronate, etidronate, risedronate, tiludronate, ibandronate and zoledronate).
These are analogs of pyrophosphate.
They have a strong affinity for bone, especially bone surfaces undergoing remodelling.
They are used in extensively in conditions xterized by osteoclast-mediated bone resorption.
They act by directly inhibition of osteoclasts.

Question 24

Pharmacokinetics

Answer 24

Poor intestinal absorption with limited oral absorption for all.
They should be adimistered with a full glass of water following an overnight fast at least 30 mins b4 breakfast.
Renal excretion.
Adverse effects include oesophagitis, renal toxicity with zoledronate.

Question 25

Uses

Answer 25

Hypercalcemia. Zoledronate appears to be more effective than pamidronate for this indication and is at least as safe.
Postmenopausal osteoporosis. Increased bone mineral density and reduced fracture incidences.
Cancer.

Question 26

Calcium sensor mimetics (calcimimetics)

Answer 26

They mimic the effect of calcium inhibition of PTH secretion by the parathyroid gland.
Prototype drug is Cinacalcet.
It is approved for:
1. the tx of secondary hyperparathyroidism owing to chronic renal disease
2.For patients with hypercalcemia associated with parathyroid Ca.

Question 27

Pharmacokinetics

Answer 27

Oral administration.
Exhibits first order absorption after oral admin
Peak plasma conc. Is achieved in 2-6 hours.
Maximal effect occurs 2-4 hours after admin.
T1/2 is 30-40 hours.
Eliminated primarily by renal excretion.
Available in 30, 60 and 90mg tablets.
Main side effect is hypocalcemia.

Question 28

Plicamycin

Answer 28

Cytotoxic antibiotic.
Also decreases plasma calcium concentration by inhibiting bone resorption.
Effect is noticeable within 24-48 hours of administration.
Used in treatment of Paget’s disease and hypercalcemia.

Question 29

Thiazides

Answer 29

Used in reducing renal calcium excretion.
Increases the effectiveness of PTH in stimulating reabsorption of calcium by the renal tubules.
Reduces hypercalciuria and stone formation in patients with idiopathic hypercalciuria..
They reduce urine oxalate excretion and increase urine magnessium and zinc levels.

Answer 30

SERMs: raloxifene stabilizes and increase bone mass density, reduces risk of vertebral compression fracture