Insights into intrarenal sites and mechanisms of action of diuretic agents.

Effective diuresis requires both sufficient glomerular filtrate and adequate delivery of the diuretic drug to the lumen of the renal tubule. Diuretics will not "force open" the kidney. Diuretics that work primarily in the proximal tubule include osmotic diuretics (e.g., mannitol), diuretics that interfere with the adenyl cyclase system (e.g., xanthines), and those which inhibit carbonic anhydrase (e.g., acetazolamide). Some thiazide and thiazide-like diuretics have a secondary site of action in the proximal tubule based on either carbonic anhydrase inhibition or other mechanisms, such as inhibition of sodium phosphate reabsorption. The diuretics that work primarily in the medullary diluting segment of the loop of Henle, furosemide and ethacrynic acid, block the active reabsorption of chloride and interfere with the tubular reabsorption of free water. The exact mechanism remains unknown. These diuretics tend to have a "high ceiling," to be potent and rapidly acting, and to have a short duration of effect. They are excellent for the treatment of severe fluid overload or pulmonary edema but are not ideal for the treatment of uncomplicated hypertension. Furosemide is a sulfonamide derivative; ethacrynic acid can be used in patients who are allergic to sulfa drugs. Diuretics that work primarily in the cortical diluting segment include the thiazides and thiazide-like drugs. They inhibit sodium transport by an undetermined mechanism. Most of them seem to reach a dose-response plateau beyond which little additional effect is gained by increasing the dose. Most of them appear to lose efficacy as the glomerular filtration rate decreases, except for metolazone and indapamide. The thiazides are most commonly used to treat hypertension. Diuretics that work primarily in the distal tubule and collecting tubule include the aldosterone inhibitor spironolactone and two drugs that impair tubular reabsorption of sodium by direct action, triamterene and amiloride. These drugs are primarily used for their potassium-sparing effect.