ETHACRYNIC ACID: SITE AND MODE OF ACTION *

In 1962, Schultz et al.' reported a new class of diuretic compounds, the a,-Punsaturated ketone derivative? of aryloxyacetic acids. These were developed in the Merck, Sharp & Dohme Research Laboratories during a search for nonmercurial inhibitors of sulfhydryl-catalyzed systems. In FIGURE 1 is shown the chemical structure of one of the more potent of these compounds, ethacrynic acid, which is 2,3-dichloro-4( 2 methylenebutry1)-phenoxyacetic acid. It is this substance which has had the most extensive experimental and clinical evaluation. Chemically, it is different from all previously known diuretic agents. The uniqueness of its biological activity was first appreciated by Baer and his associates2 in their preliminary studies with ethacrynic acid in dogs. In TABLE 1, I have summarized the observations made with intravenous ethacrynic acid and other conventional diuretics on the electrolyte excretion patterns in the dog. The data on ethacrynic acid are a composite of the studies of Byer and his associate^,^ Earley & Friedler,4 and our own group,5 and the data on the other diuretic agents are a summary of the available data in the literature modified slightly by our own observations. Like organomercurials, ethacrynic acid produces a marked increase in the excretion of sodium and chloride. Bicarbonate excretion is unchanged or may actually decrease in contrast to acetazolamide and chlorothiazide, which increase the excretion of bicarbonate. The magnitude of the natriuresis with ethacrynic acid is equal to or greater than the mercurials, the average peak fractional excretion of sodium achieving a mean value of approximately 18%. Unlike mercurials, however, ethacrynic acid can also be administered orally, and its effects are not inhibited by alkalosis or hypochloremia. Unlike carbonic anhydrase inhibitors, ethacrynic acid is effective in the presence of acidosis. Acute diuresis is always associated with an increase in potassium excretion, an effect similar to that of thiazides and acetazolamide, but different from mercurials. Other differences from mercurials are the rapidity of onset of peak effects (i,e., 20 minutes) with ethacrynic acid, in contrast to 1-2 hours with mercurials. Finally, during maximal effects of either organomercurials or thiazides or both, ethacrynic acid produces a further increase in both absolute and fractional sodium excretion. All of these observations, therefore, indicate the novelty of ethacrynic acid compared to conventional diuretics and imply that it has a different site and/or mode of action in the kidney. The important clinical implication of these experimental obscrvations, namely, that it would be a very potent agent in the therapy of edema and that it would be effective in conditions refractory to other diuretics, has always been substantiated by many different investigators in the United States and in Europe. For example, its successful use in the treatment of congestive heart failure, cirrhosis and nephrotic syndrome has been well documented by the studies of Foltq6 C a n n ~ n , ~ Melvin,6 and Maher,g and their respective colleagues. Ethacrynic acid has been shown to be effective in the presence of hyponatremia,