Diuretics: mechanism of action and therapy.

Abstract

T HE CLINICAL USE of diuretics is unsurpassed by the use of any class of drugs. with the possible exception of minor tranquilizers. There is little question that most of the readers of a monograph such as this are adept at the normal use of these agents. Therefore, this review will concentrate on some of the newer information about the action of diuretics and concentrate on some specific usages of the drugs in a variety of conditions. Drugs with weak diuretic activity (methylxanthines, digitalis preparations, indapamide) have been consciously excluded, as have drugs no longer in the active pharmaceutical armamentarium (organic mercurials, ticrynafen). With the exception of the addition of new drugs to the map (Fig l), little has changed with regard to the site of action of most diuretics. Major effects on the proximal tubule are restricted to carbonic anhydrase inhibitors, inhibition of reabsorption in the loop of Henle is achieved with “loop diuretics” including bumetenide and muzolimine. thiazides act along portions of the distal tubule, and potassium-sparing diuretics act in the corticalcollecting tubule. r * This map represents predominant sites of useful clinical effects. If all detectable effects of the various drugs are added, the clearcut boundaries of areas of influence smudge a great deal. This smudging will be discussed as each group of agents is considered in turn. dehydrogenase. 74 The effect in the proximal tubule, whether due to action on cellular proton secretion or on H&O1 degradation, is to stop absorption of bicarbonate. The diminished reabsorption of bicarbonate can alter volume reabsorption in several ways. First, the action of the drug on the generation of carbonic acid or the formation of bicarbonate results in decreased availability of protons to the apical sodium proton exchanger, and less sodium enters the cells while less bicarbonate is reabsorbed.5 lo Second. it is known that up to one third of proximal reabsorption. mostly in the late proximal tubule. is a passive reabsorptive process that occurs because of the generation of chloride concentration gradients between urine and blood.” I5 Inhibition of carbonic anhydrase results in the loss of these gradients and. therefore, the absence of this driving force. Finally, in this situation bicarbonate becomes a non-reabsorbable anion, and contributes to an osmotic diuretic effect. Diuresis is limited by the occurrence of carbonic anhydrase independent bicarbonate reabsorption, the effects of acidosis to reduce the relative importance of bicarbonate reabsorption on proximal sodium handling, the effects of volume contraction, and the effects of the drug to reduce glomerular filtration rate (GFR). Ih ”