Determinants of access of diuretics to their site of action

For consideration of the determinants of access of diuretics to their site of action to be meaningful, one must understand molecular modes of action of diuretics and the anatomic site of effect along the nephron in addition to determinants of the renal handling of diuretics. Although the molecular mode of action is known for a number of drugs, such as the inhibition of carbonic anhydrase by acetazolamide, that for loop diuretics remains obscure. Sites of diuretic action along the nephron have been well delineated through collation of results from in vitro and in vivo techniques in a variety of species. Loop diuretics clearly block chloride reabsorption throughout the thick ascending limb of the loop of Henle. Access of diuretics to their renal tubular sites of action varies among drugs. Important determinants are plasma protein binding, active tubular secretion, nonionic diffusion, and intrarenal metabolism.