Parathyroid Hormone

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Chapter: Essential pharmacology : Drugs Affecting Calcium Balance

Vassale and Generali (1900) were the first to perform selective parathyroidectomy (without removing thyroids) and found that it produced tetany and death. MacCallum and Voegtlin in 1909 established this to be due to decrease in plasma calcium levels; parathormone (PTH) was isolated in 1925.


PARATHYROID HORMONE

(Parathormone)

 

Vassale and Generali (1900) were the first to perform selective parathyroidectomy (without removing thyroids) and found that it produced tetany and death. MacCallum and Voegtlin in 1909 established this to be due to decrease in plasma calcium levels; parathormone (PTH) was isolated in 1925.

 

PTH is a single chain 84 amino acid polypeptide, MW 9500. It is synthesized as prepro-PTH, the excess amino acids are split off in two steps and it is then stored in intracellular vesicles. Secretion of PTH is regulated by plasma Ca2+ concentration through a calcium-sensing receptor (CaSR), that is a G-protein coupled receptor on the surface of parathyroid cells. There is no trophic hormone for it. Fall in plasma Ca2+ induces PTH release and rise inhibits secretion by decreasing cAMP in the parathyroid cells. Agents that increase cAMP cause PTH release, but direct activation of protein kinase C by fall in Ca2+ concentration is more important physiologically. Prolonged hypocalcaemia causes hypertrophy and hyperplasia of parathyroids, while sustained hypercalcaemia has the opposite effect. Changes in phosphate concentration in plasma affect PTH secretion indirectly by altering Ca2+ concentration. The active form of vit. D calcitriol inhibits expression of PTH gene in parathyroid cells. PTH is rapidly degraded in liver and kidney; its plasma t½ is 2–5 min.

 

 

Actions

 

PTH increases plasma calcium levels by:

 

Bone

 

PTH promptly increases resorption of calcium from bone. This is the most prominent action of PTH—exerted by increasing the number of bone remodeling units and activating osteoclasts when high concentrations are present continuously. Since bone resorption is followed by new bone deposition, this is also promoted by PTH: increased bone formation occurs when PTH is given intermittently and in low doses.

 

Kidney

 

PTH increases calcium reabsorption in the distal tubule and provides moment to moment regulation of calcium excretion. It also promotes phosphate excretion which tends to supplement the hypercalcaemic effect. However, grossly increased plasma calcium level occurring in hyperparathyroidism overrides the direct

action on tubules and calcium excretion in urine is actually increased. The converse occurs in hypoparathyroidism.

 

Intestines

 

PTH has no direct effect on calcium absorption but increases it indirectly by enhancing the formation of calcitriol (active form of vit D) in the kidney by activating 1αhydroxylase. Calcitriol then promotes intestinal absorption of calcium.

 

PTH decreases calcium levels in milk, saliva and ocular lens—may be responsible for development of cataract in hypoparathyroidism.


 

Mechanism Of Action

 

The PTH receptor is a G protein coupled receptor which on activation increases cAMP formation and intracellular Ca2+ in target cells. In bone, the target cell is the osteoblast because PTH receptors are not expressed on the surface of osteoclasts. Acting on the osteoblast, PTH induces a factor ‘Receptor for activation of nuclear facto-rκ-Bligand’ (RANKL) which diffuses and combines with RANK on osteoclast precursors and transforms them into osteoclasts as well as activates osteoclasts (Fig. 24.2). Moreover, birth rate of bone remodeling units into which osteoclasts are recruited is enhanced. Formation of the remodeling pit is followed by osteoblastic deposition of new bone into it. PTH enhances proliferation and differentiation of preosteoblasts and deposition of osteoid as well. Bone resorption predominates when high concentrations of PTH are present continuously, but intermittent exposure to low concentrations has the opposite effect.



 

Hypoparathyroidism  

  

Manifestations are:

Low plasma calcium levels, tetany, convulsions, laryngospasm, paresthesias, cataract and psychiatric changes. Pseudohypoparathyroidism occurs due to reduced sensitivity of target cells to PTH caused by a mutant G protein that couples PTH receptor activation to cAMP generation in target cells.

 

Hyperparathyroidism


It is mostly due to parathyroid tumour. It produces— 

Hypercalcaemia, decalcification of bone—deformities and fractures (osteitis fibrosa generalisata), metastatic calcification, renal stones, muscle weakness, constipation and anorexia.

 

Treatment is surgical removal of the parathyroid tumour. When this is not possible—low calcium, high phosphate diet with plenty of fluids is advised.

 

Cinacalcet

 

It activates the Ca2+ sensing receptor (CaR) in the parathyroids and blocks PTH secretion. It is indicated in secondary hyperparathyroidism due to renal disease and in parathyroid tumour.

 

Use

 

PTH is not used in hypoparathyroidism because plasma calcium can be elevated and kept in the normal range more conveniently by vit D therapy. PTH has to be given parenterally, while vit D can be given orally. Vit D is cheap. However, recombinant human PTH (1–84 amino acid) has been produced and is being clinically tested.

 

Teriparatide

 

This recombinant preparation of 1–34 residues of amino terminal of human PTH has been recently approved for the treatment of severe osteoporosis. It duplicates all the actions of long (1–84) PTH. Injected s.c. once daily, it has been found to increase bone mineral density in osteoporotic women. The effect was faster and more marked than that produced by estrogens and bisphosphonates (BPNs). Teriparatide is the only agent which stimulates bone formation, whereas the other two only check bone resorption. In clinical trials it was found to be equally or more effective than estrogens and BPNs in reducing risk of vertebral as well as nonvertebral fractures. Its plasma t½ is 1 hr; given once daily only intermittent action is produced and bone forming action predominates over bone resorbing action. High cost and need for daily s.c. injections are the limitations.

 

Diagnostic use To differentiate pseudo from true hypoparathyroidism: teriparatide is given i.v.: if plasma calcium level fails to rise, then it is pseudohypoparathyroidism.

 

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