Calcimimetics

The extracellular calcium Ca -sensing receptor plays a central role in maintaining a nearly constant level of extracellular calcium by sensing small changes in Ca and directly and/or indirectly altering the translocation of calcium ions into or out of the extracellular fluid so as to normalize CaQ+. Changes in the level of expression and/or function of the CaR reset the level of CaQ+. Recently developed activators (calcimimetics)... 

A class of allosteric activators of the Ca2+-sensing receptor that sensitizes the receptor to extracellular calcium and acts only in the presence but not in the absence of calcium. Calcimimetics can be used to treat various forms of hyperparathyroidism, although they are only approved for use in patients with end stage renal disease receiving dialysis treatment. 

Cinacalcet is a calcimimetic that increases the sensitivity of receptors on the parathyroid gland to serum calcium levels to reduce PTH secretion. Cinacalcet maybe beneficial in patients with an increased Ca-P product who have elevated PTH levels and cannot use vitamin D therapy. Because the effects of cinacalcet on PTH can reduce serum calcium levels and result in hypocalcemia, cinacalcet should not be used if serum calcium levels are below normal. 

By the time ESRD develops, most patients require a combination of phosphate-binding agents, vitamin D, and calcimimetic therapy to achieve K/DOQI goals. 

Paricalcitol is a synthetically manufactured analogue of calcitriol. It is indicated for the prevention and treatment of secondary hyperparathyroidism in chronic kidney disease. Cinacalcet, a drug that acts as a calcimimetic, can be added if the effects on PTH levels are isufficient. 

Cinacalcet is a calcimimetic agent that modulates the response of the calciumsensing receptor on the parathyroid gland, and thus may lead to a reduction in the levels of calcium. It is marketed to treat hypercalcemia (Figure 8.83). 

This rather common disease, if associated with symptoms and significant hypercalcemia, is best treated surgically. Oral phosphate and bisphosphonates have been tried but cannot be recommended. Asymptomatic patients with mild disease often do not get worse and may be left untreated. The calcimimetic agent cinacalcet, discussed previously, has been approved for secondary hyperparathyroidism and is in clinical trials for the treatment of primary hyperparathyroidism. If such drugs prove efficacious, medical management of this disease will need to be reconsidered. 

Steddon SJ, Cunningham J Calcimimetics and calcilytics—fooling the calcium receptor. Lancet 2005 365 2237. [PMID 15978932]... 

Cinacalcet (Sensipar) [Hyperparathyroidism Agent/ Calcimimetic] Uses Secondary hyperparathyroidism in CRF T Ca2+ in parathyroid carcinoma Action 4- PTH by T Ca-sensing receptor sensitivity Dose ... 

Ray, K., and Northup, J. (2002). Evidence for distinct cation and calcimimetic compound (NPS 568) recognition domains in the transmembrane regions of the human Ca2+ receptor. J. Biol. Chem. 277, 18908-18913. 

While FHH most commonly presents as an asymptomatic form of hypercalcemia, a few kindreds exhibit more severe hypercalcemia. Nevertheless, even in these cases the natural history of the disorder is usually so benign that the great majority of these patients should be followed without intervention, with a few exceptions (see above). In the unusual individual with FHH and symptomatic hypercalcemia, the new calcimimetics-described in more detail below—could potentially provide a useful form of treatment indeed the use of this treatment was recently described in this setting. 

Fox, J, Fowe, SH, Petty, BA and Nemeth, EF, 1999, NPS R-568 a type II calcimimetic compound that acts on parathyroid cell calcium receptor of rats to reduce plasma levels of parathyroid hormone and... 

Nemeth, EF, Steffey, ME, Hammerland, LG, Hung, BC, Van Wagenen, BC, DelMar, EG and Balandrin, MF, 1998b, Calcimimetics with potent and selective activity on the parathyroid calcium receptor, Proc Natl Acad Sci U S A 95 4040-4045... 

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