Carbonic anhydrase inhibitors as diuretics

Several human carbonic anhydrase (CA) isoforms, namely hCA II, IV, VB, XII, and XIV, are expressed in many segments of the human nephron, the functional unit of the kidney. Acetazolamide and structurally related sulfonamides act as diuretics, inhibiting CAs in the proximal convoluted tubule, being used for the treatment of edema due to congestive heart failure (HF), and for drug-induced edema, in addition to their application as systemic antiglaucoma agents. Among loop and thiazide diuretics that are used to treat HF, hypertension, and other related diseases, a number of these drugs contain a primary sulfonamide group in their molecule. Their diuretic effects are associated with mechanisms of action different than renal CA inhibition, as they scarcely inhibit hCA II, the isoform to which most roles related to kidney physiopathology among the various CA isoforms were ascribed at the time of the discovery of these diuretics. Wider and more complex CA inhibition profiles have been successively proved against the entire panel of hCAs, opening new horizons regarding their possible polypharmacology. This chapter focuses on old and innovative therapeutic applications of the sulfonamide diuretics.