Abstract

Ethacrynic acid [2,3-dichloro-4-(2-methylenebutyryl) phenoxy]acetic acid, a structurally unique saluretic-diuretic agent in the dog and in man, contains an α,β-unsaturated ketone structure that combines readily with sulfhydryl groups. Although organomercurials likewise will combine with sulfhydryl groups (and they may both act in this manner), the two categories of compounds are dissimilar in many aspects of their pharmacology. Ethacrynic acid differs even more fundamentally from other categories of diuretic agents.

Its characteristics include excellent oral absorption and extremely rapid onset of action when administered orally or intravenously, a dose-response curve that has a somewhat greater threshold (mg/kg), a steeper slope, and a maximal ceiling in terms of salt or water output per unit time that is several-fold the response to hydrochlorothiazide. It has a short duration of action. Because of its profound magnitude of effect, ethacrynic acid can produce a more substantial reduction in plasma volume and electrolytes than can be induced by the thiazides, but it does not differ qualitatively from them in this respect except that it increases chloride rather than bicarbonate excretion under conditions of sodium bicarbonate-induced alkalosis in the dog. The maximal saluretic-diuretic response to ethacrynic acid by the dog is at least as great as to an organomercurial under conditions of acidosis which are optimal for the mercurial, but, unlike the mercurial, its maximal effect is not influenced by acid-base balance or urinary pH. Unlike the organomercurial, ethacrynic acid does not seem to inhibit the exchange of sodium for potassium across the distal portion of the nephron. Characteristically, ethacrynic acid causes the osmolar concentration of urine to approach that of plasma water by increasing incommensurately salt or water output, depending on the conditions of hydration and salt-loading of the animal.

The sites of action of ethacrynic acid on sodium transport are interpreted to be the ascending limb of the loop of Henle in addition to the inhibition of sodium transport in both the proximal and distal portions of the nephron. In addition to glomerular filtration of the small portion of unbound drug, it is secreted by the probenecid-sensitive proximal secretory mechanism and is reabsorbed more distally. Ethacrynic acid is eliminated in bile and urine as such and as metabolites including the cysteine adduct.