Site and mechanism of the action of diuretics.

The mechanism of action of diuretics can be established by studying the molecular mechanism of action, the site of action within the nephron, and the relationship between the pharmacokinetics of the diuretic and its effect. The molecular mechanism of action is known for diuretic agents such as acetazolamide (carbonic anhydrase), theophylline (phosphodiesterase), digitalis glucosides (Na-K-ATPase), spironolactone (aldosterone antagonism) and dopamine (specific receptors?). The "receptor" for the clinically most important diuretics, i.e. loop diuretics, thiazides, and other potassium-sparing diuretics is, however, unknown. It appears from recent studies of the ion transport in the diluting segment that there probably is a sodium-chloride co-transport in this segment and that loop diuretics specifically inhibit the active chloride transport. The main site of diuretic action is well established for the different groups of diuretics: carbonic anhydrase inhibitors act on the proximal tubulus, loop diuretics on the diluting segment, thiazides on the cortical diluting segment/distal tubulus, and potassium-sparing agents on distal tubulus/collecting ducts. Moreover, some diuretics have additional tubular sites of action. It is also important to realize that other effects of diuretics, e.g. inhibition of the tubuloglomerular feedback mechanism or renal and extra-renal hemodynamic effects, can modify the tubular diuretic effect. Finally, the renal handling of diuretics is of importance to the diuretic effect by determining the concentration of the drug at the "receptor" sit (s). It is emphasized that knowledge of the different aspects of the mechanisms of action of diuretics is a prerequisite for rational use of diuretics, clinically as well as experimentally.