PLD 401 Pharmacology III Parathyroid Hormones - PDF

PLD 401 Pharmacology III Parathyroid Hormones Dr. Zeinab M. Awwad Lecturer of Pharmacology, Faculty of Pharmacy, PUA  Learning Outcomes (LOs) By the end of this lecture students will be able to: 1. Identify agents affecting bone mineral homeostasis. 2. Describe the action, secretio...

PLD 401 Pharmacology III Parathyroid Hormones Dr. Zeinab M. Awwad Lecturer of Pharmacology, Faculty of Pharmacy, PUA  Learning Outcomes (LOs) By the end of this lecture students will be able to: 1. Identify agents affecting bone mineral homeostasis. 2. Describe the action, secretion, regulation, disorders and treatment of parathyroid hormone. 3. Explain the action & clinical significance of vitamin D. 4. Discuss the action & clinical significance of calcitonin.  AGENTS AFFECTING BONE MINERAL HOMEOSTASIS − The main bone minerals are “calcium” and “phosphorous”. − Approximately, 98% of body calcium and 85% of body phosphorous in the human adult are found in bone. − Calcium and phosphate enter the body from the intestine and are reabsorbed by the kidney. --The movement of calcium and phosphate across intestinal and renal epithelia is closely regulated so that any disease in the intestine or kidney disrupts bone mineral homeostasis. − Calcium phosphate crystals in the form of “hydroxyapatite”give the bone its hard matrix. -Calcium and phosphate play other roles in the body. Calcium is required for: Muscle contraction, nerve conduction, hormone release, enzyme regulation and blood clotting.  Phosphate is an integral component of : nucleic acids, phospholipids of cell membranes and energy metabolism. − Calcium and phosphate are also linked by their ability to chemically react with each other to form calcium phosphate so that the product (X) of their concentration in plasma is always constant and their plasma levels are opposite to each other. ►The normal level of plasma calcium is 8.8-10.4 mg/dl (2.2 -2.6 mmol/L) and that of phosphate is 2.5-4.5 mg/dl (0.81 -1.45 mmol/L). ►The main hormones involved in the regulation of bone mineral homeostasis are: Parathyroid hormone Vitamin D Calcitonin  PARATHYROID HORMONE Parathyroid hormone (parathormone, PTH) is a single chain peptide hormone composed of 84 amino acids (the 34 amino acid terminal is responsible for hormone activity).  Synthesis: Secretion and regulation of PTH: − The secretion of PTH is mainly controlled by the level of plasma calcium. − The parathyroid cell has a calcium sensor on its membrane so that : -Hypocalcemia stimulates PTH secretion. -Hypercalcemia inhibits PTH secretion.  N.B. Phosphate can also regulate PTH secretion indirectly by forming complexes with calcium leading to hypocalcemia which in turn enhances PTH secretion. Actions of PTH: ∙PTH regulates calcium and phosphate flux across cellular membranes in bone and kidney resulting in: Increased plasma calcium (hypercalcemia) and decreased plasma phosphate (hypophosphatemia). In bone: PTH increases the activity of “osteoclasts” and inhibits the activity of “osteoblasts” to stimulate bone resorption by mobilization of calcium and phosphate from bones to the blood. In kidney: 1. PTH increases the ability of the kidney tubules to reabsorb calcium but reduces their ability to reabsorb phosphate promoting its excretion.  2. PTH stimulates the production of 1,25 dihydroxy vitamin D3 (calcitriol) that stimulates: −Calcium and phosphate absorption from the intestine. −Calcium and phosphate mobilization from bones. −Calcium and phosphate reabsorption by the kidney tubules.  Disorders of PTH secretion Hypoparathyroidism Hyperparathyroidism I. Hypoparathyroidism: −Hypoparathyroidism results from deficiency or absence of PTH and is characterized by hypocalcemia and hyperphosphatemia. −It may be idiopathic or surgical due to accidental removal or damage of several parathyroid glands during thyroidectomy. −Pseudohypoparathyroidism is another condition characterized by a resistance to PTH and not a deficiency in its secretion.  Symptoms of hypocalcemia: ∙Neuromuscular irritability manifested as: Muscle cramps, tetany, paresthesia of lips and tongue, carpopedal spasm and spasm of facial muscles. ∙Arrhythmia. ∙Other symptoms include brittle nails, dry skin, and coarse hair.  Treatment of hypoparathyroidism 1. Teriparatide: −It is a synthetic polypeptide that consists of the biologically active 34- amino acid N-terminal region of human PTH. −It is also used in the differential diagnosis of hypoparathyroidism and pseudohypoparathyroidism. 2. Calcium and vitamin D supplement.  II. Hyperparathyroidism Hyperparathyroidism results from excessive secretion of PTH and is characterized by hypercalcemia and hypophosphatemia. Causes: It may be primary (due to age, post menopause, neck irradiation, parathyroid hyperplasia or adenoma) or secondary to chronic hypocalcemia which stimulates PTH. Severe hyperparathyroidism can lead to: Osteitis fibrosa cystica (bone lesions due to excessive bone resorption). Osteoporosis. Symptoms of hypercalcemia − In mild conditions (>12 mg/dl): skeletal muscle weakness, flatulence, constipation, nausea, vomiting, anorexia and confusion. − In severe conditions (>18 mg/dl): cardiac arrhythmia, shock and renal failure due to precipitation of calcium in the kidney with the formation of renal calculi. Treatment of hyperparathyroidism 1. Surgical parathyroidectomy. 2. Control hypercalcemia by: – Saline diuresis (i.v. saline and furosemide). – Calcitonin which decreases mobilization of calcium from the bones (by inhibiting osteoclasts) and by decreasing calcium reabsorption from the kidney tubules. – Biphosphonates which decrease mobilization of calcium from the bones by inhibiting osteoclasts and stimulating osteoblasts. –Glucocorticoids which reduce intestinal calcium absorption and promote renal calcium excretion. –Estrogens which reduce bone turnover and lower plasma calcium. –I.V. phosphate (only in life-threatening hypercalcemia because of the risk of renal failure and soft tissue calcification). –Calcimimetic agent (Cinacalcet). *The first representative of a new class of drugs that act through the calcium sensing receptors on parathyroid cells. *Cinacalcet blocks PTH secretion *It is approved for treatment of : secondary hyperthyroidism in chronic kidney diseases and for the treatment of parathyroid carcinoma.  VITAMIN D Vitamin D is a steroid hormone that acts on intracellular receptors affecting DNA transcription and protein synthesis. Vitamin D exists in 2 forms: Vitamin D2 (ergocalciferol) which is a plant-derived form. Vitamin D3 (cholecalciferol) which is generated in the skin from 7 dehydrocholesterol by UV irradiation.  Main actions of calcitriol Calcitriol stimulates: −Calcium and phosphate absorption from the intestine. −Calcium and phosphate mobilization from bones. −Calcium and phosphate reabsorption by the kidney tubules.  Deficiency of vitamin D Deficiency of vitamin D inadequate intestinal absorption of ca and ph Stimulates PTH secretion plasma calcium level is to restore Ca in plasma at reduced the expense of bone Rickets in children Osteomalacia in adults.  Hypervitaminosis D It results from vitamin D over treatment of patients with hypoparathyroidism. It is characterized by hypercalcemia which may lead to renal and cardiovascular damage.  Clinical uses of vitamin D Prophylaxis and treatment of: Rickets, osteomalacia, osteoporosis, hypoparathyroidism and hypophosphatemia.  CALCITONIN Secreted from the parafollicular C-cells of the thyroid gland in response to hypercalcemia.  Actions The main action of calcitonin is: To lower plasma calcium and phosphate concentration by an effect on bone and kidney without affecting their intestinal absorption. In kidney: calcitonin reduces reabsorption of both calcium and phosphate by the kidney tubules. In bone: calcitonin inhibits mobilization of calcium and phosphate by inhibiting osteoclasts.  Clinical uses Synthetic human calcitonin or salmon calcitonin (salcalcitonin) is used as subcutaneous injections / nasal spray in: 1.Control of hypercalcemia in hyperparathyroidism, vitamin D intoxication and bone neoplasia. 2.Treatment of Paget’s disease of bone. 3.Treatment of osteoporosis as in menopausal women.  Paget’s disease of bone: It is a localized bone disease characterized by uncontrolled osteoclastic bone resorption together with a secondary hyperactive osteoblastic repair leading to replacement of the normal bone matrix with softened enlarged defective bone. The cause of the disease is obscure mostly involving a viral infection. Bones particularly affected are those of pelvis, lower vertebrae, skull and lower limbs. Diagnosis: Elevation of serum alkaline phosphatase and urinary hydroxy proline together with radiological findings.  Treatment of Paget’s disease: 1.Calcitonin 2.Biphosphonates (osteoclast inhibitors) : −Biphosphonates are analogues of pyrophosphate. −Biphosphonates reduce bone resorption by promoting apoptosis of osteoclasts; they may also stimulate osteoblasts. −E.g: ▪Alendronate (Fosamax) ▪Etidronate ▪Pamidronate (Aredia)  Osteoporosis Osteoporosis is an abnormal loss of bone that occurs due to an increased bone resorption relative to bone formation. Causes It is mainly caused by inadequate estrogen production in post menopausal women; it also occurs in men. It can be also caused by chronic administration of: Glucocorticoids Thyrotoxicosis Hyperparathyroidism Malabsorption syndrome Or it can be idiopathic  Management of osteoporosis 1.Estrogen replacement therapy in postmenopausal women shortly after the onset of menopause. 2.Calcium and vitamin D supplement. 3.Calcitonin 4.Biphosphonates 5.SERMS (selective estrogen receptor modulators); Raloxifene Thank You