ANTIDIURETICS The drugs that decrease urine volume are called antidiuretics. Primary indication of antidiuretics is the treatment of diabetes insipidus (DI). ● Anti-Diuretic Hormone (ADH) Physiological antidiuretic is vasopressin (antidiuretic hormone or ADH) that is synthesized in the hypothalamus and secreted by the posterior pituitary. It is secreted in response to increased plasma osmolality or decreased volume of extracellular fluid (ECF). ADH acts via 3 receptors V1; V2 and V3 ◆ Actions of ADH • In the absence of ADH, collecting ducts (CD) of the nephron are impermeable to water. ADH increases the permeability of CD by its action on V2 receptors. Stimulation of these receptors elevates cAMP levels that increase aquaporins on the apical membrane of CD (by decreasing endocytosis and increasing exocytosis).V2 receptor activation also increases permeability of CD to urea by stimulating the urea transporter. • Vasopressin (ADH) as the name suggests is a potent pressor of blood vessels. Vasoconstrictor action is mediated by the activation of V1 (also called V1a) receptors. This action requires much higher concentration than V2 receptor activation. V2 receptor mediated vasodilatory action (due to the release of NO) has also been demonstrated. • ADH is also involved in the release of vWF and factor VIII from the endothelium. This action is also mediated by V2 receptors. • V3 receptors (previously known as V1b receptors) are involved in the release of ACTH. ●Thiazides These drugs are used as diuretics but, exert paradoxical effect (decrease urine formation) in DI. This paradoxical effect is believed to be due to increased formation of cAMP in the distal tubules. Another proposed mechanism is that thiazides cause dehydration that result in compensatory increase in reabsoprption of Na+ and water from the proximal portions of nephron. These are low efficacy antidiuretics but are beneficial in both central as well as nephrogenic DI. e.g. Chlorpropamide, Clofibrate and Carbamazepine ● Amiloride It is the agent of choice for the treatment of Lithium induced DI. ● VASOPRESSIN RECEPTOR ANTAGONISTS • V1receptor antagonists may be useful when total peripheral resistance is increased (e.g. CHF and hypertension) whereas V2 antagonists may be useful for the treatment of SIADH • Relcovaptan is selective V1 antagonist whereas lixivaptan, mozavaptan and tolvaptan are V2 selective antagonists. • Conivaptan is V1a/V2 receptor antagonist used as an aquaretic (increase water excretion without affecting electrolytes like sodium) in CHF.