Medical brain notes 47

  CALCIUM HOMEOSTASIS   Calcium is the principal extracellular electrolyte regu-lated by PTH, calcitonin, and D 3 .  Extracellular calcium  is a critical component of signal transduction across the plasma membrane, which regulates a wide spectrum of physiological events including muscle contraction, se-cretion of neurotransmitters and hormones, and the action of growth factors, cytokines, and protein hormones.  Intracellular calcium  is an important cofactor in many   enzymatic reactions. Plasma calcium exists in three forms:  ionized  (50%),  protein bound  (46%), and  com-plexed  to organic ions (4%). Total plasma calcium con-centration is normally tightly maintained within the range of 4.5 to 5.7 mEq/L, primarily by the actions of PTH and D 3 , which regulate bone resorption and cal-cium absorption from the intestine and kidney. The calcium-lowering actions of calcitonin may regulate postprandial plasma calcium depositi...

  PARATHYROID HORMONE   PTH is secreted from the parathyroid glands in response to a low plasma concentration of ionized (free) calcium. PTH immediately causes the transfer of labile calcium stores from bone into the bloodstream. PTH increases rates of dietary calcium absorption by the intestine indi-rectly via the vitamin D 3  system activation of enterocyte activity. Within the kidney, PTH directly stimulates cal-cium reabsorption and a phosphate diuresis.     Chemistry   PTH is a single-chain polypeptide composed of 84 amino acid residues that is devoid of disulfide bonds and has a molecular weight of 9500. Biological activity of the human hormone resides primarily in the amino terminal end of the protein (i.e., amino acids 1–34). This portion of PTH has full biological activity both in vivo and in vitro. Synthetic fragments of the 1-34 portion of the PTH molecule have been synthesized. A paraneo-plastic hormone,  PTH related peptide  ( PTHrP )...

  CALCITONIN   Calcitonin release is normally stimulated by rising serum calcium levels and suppressed by hypocalcemia. The major physiological effects of calcitonin are inhibi-tion of bone resorption and deposition of postabsorp-tive calcium into bone following a meal, which prevents postprandial hypercalcemia.   Chemistry   C alcitonin  is a single-chain polypeptide composed of 32 amino acid residues having a molecular weight of ap-proximately 3600. A cysteine disulfide bridge at the 1-7 position of the amino terminal end of the peptide is es-sential for biological activity; however, the entire amino acid sequence is required for optimal activity.     Synthesis and Secretion   The regulation of calcitonin synthesis and release from the parafollicular C cells of the thyroid gland is cal-cium dependent.  Rising serum calcium is the principal   stimulus responsible for calcitonin synthesis and re-lease.  Other hormones, such as gluca...

  VITAMIN D 3   (CHOLECALCIFEROL)   Vitamin D 3 , through its active metabolite, 1,25-(OH) 2 D 3 , also plays an important role in maintaining calcium homeostasis by enhancing intestinal calcium absorption, PTH-induced mobilization of calcium from bone, and calcium reabsorption in the kidney.   Synthesis and Activation   The primary supply of vitamin D 3  in humans is not ob-tained from the diet but rather is derived from the ultravi-olet photoconversion of 7-dehydrocholesterol to vitamin D 3  in skin.  Thus, vitamin D 3   synthesis varies with the sea-sons. D 3  is a prohormone and requires further metabolic conversion to exert biological activity in its target organs (Fig. 66.2). The liver and the kidney are the major sites of metabolic activation of this endogenous sterol hor-mone. The initial transformation of D 3  occurs in the liver and is catalyzed by the enzyme 25-OH-D 3 -hydroxylase to form 25-(OH)D 3 ; this is the primary ...

  BISPHOSPHONATES   The bisphosphonates are synthetic organic compounds that are incorporated directly into the hydroxyapatite of bone and then inhibit osteoclastic bone resorption. This antiresorptive action makes them useful in the pharmacological treatment of hypercalcemia, osteo-porosis, and Paget’s disease.   Chemistry   The bisphosphonates have a common structure, P-C-P, which is similar to the structure of the native pyrophos-phate P-O-P found in bone hydroxyapatite. The differ-ent compounds in clinical use vary by the attachments to the R component of the native molecule. Mechanism of Action   The bisphosphonates inhibit osteoclastic resorption of bone by binding to the hydroxyapatite crystals of bone. When osteoclasts first attach to bone in the active resorp-tive sites, the bisphosphonates are released from that bone. The release of these compounds locally prevents further osteoclastic attachment to those resorptive sur-faces. The bisphosphonates also ...

  CLINICAL USES OF PARATHYROID HORMONE, CALCITONIN, VITAMIN D, AND BISPHOSPHONATES   These hormones and drugs are used most commonly for disorders of calcium and bone metabolism rather than to correct specific hormone deficiencies. For example, the use of PTH replacement in hypoparathyroidism in the past was not practical because of the difficulty in obtaining purified hormone and the fact that it is injected subcutaneously. With the recent ability to produce large quantities of recombinant PTH (rPTH), its use will be more common, especially for severe osteoporosis.   Hypercalcemia of Malignancy   Hypercalcemia is a common clinical condition that can accompany a variety of other medical conditions, such as sarcoidosis, vitamin D toxicity, hyperparathyroidism, and malignancy. When calcium levels are exceptionally high, adjunctive measures for the control of plasma cal-cium levels are necessary, as this is a medical emergency. Various modalities in combination are used...

  ADVERSE EFFECTS   With the exception of the possible development of a hypervitaminosis associated with high-dose administra-tion of vitamin D 2  or D 3 ,. Allergic reactions to the injection of calcitonin and PTH have occurred and chronic use of some bisphosphonates has been associ-ated with the development of osteomalacia. The princi-pal side effects of intravenous bisphosphonates are mild and include low-grade fever and transient increases in serum creatinine and phosphate levels. Oral bisphos-phonates are poorly absorbed and can cause esophageal and gastric ulceration. They should be taken on an empty stomach; the individual must remain upright for 30 minutes after ingestion. Human Parathyroid Hormone   Human rPTH (1-34) has been produced by recombinant technologies, is now approved, and will soon be available for the treatment of osteoporosis. It is given subcuta-neously, 25 g/day cyclically for 12 to 18 months, to in-crease bone density in individuals with a h...