Hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and disorders such as congestive heart failure and cirrhosis represents a common problem often encountered in the care of medical patients. Available treatment modalities for disorders of excess arginine vasopressin (AVP) secretion, or action, include fluid restriction, demeclocycline and NaCl administration, but all of these therapies have significant drawbacks and are suboptimal. Over the last decade, both peptide and nonpeptide antagonists of the AVP V2 receptor (V2R), which is responsible for antidiuresis in the collecting ducts of the kidney, have been developed. Initial clinical trials using peptide antagonists failed because of partial agonist effects of these compounds in humans. However, the recently synthesized nonpeptide AVP V2R antagonists have not shown this effect. These compounds therefore represent a promising treatment option to directly antagonize the effects of elevated plasma AVP levels directly at the receptor level, thereby increasing the water permeability of the renal collecting tubules by preventing insertion of the aquaporin-2 water channel into the apical membranes of collecting duct epithelial cells. In patients with SIADH, these agents have been shown to promote excretion of retained water with subsequent improvement of hyponatremia. As opposed to standard diuretics, the AVP V2R antagonists do not cause natriuresis or kaliuresis, so the resulting effect to increase free water excretion is more aptly designated as an 'aquaresis.' In this talk, SIADH and other water retaining disorders will be briefly reviewed, after which both preclinical and clinical studies of several nonpeptide AVP V2R antagonists currently under development will be summarized. The likely therapeutic indications for use of these compounds will be discussed, as will possible complications including vascular effects and effects on drug metabolism. Despite some potential limitations, this class of agents will likely revolutionize the treatment of disorders of water homeostasis.
03 - 04 Dec 2001
Society for Endocrinology