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Second, the adduct of ethacrynic Post Date: Tue, 14 Oct 2008 22:04:37 +0000 However, it is not possible to attribute diuretic action to this type of biochemical reaction, for at least three reasons. First, the other high-ceiling diuretics do not share the same reactiv-ity with thiols. Second, the adduct of ethacrynic acid with cysteine is a more potent inhibitor of electrolyte transport than ethacrynic acid itself (Burg and Green, 1973c). Autor of the post: Undefined Since ATPase is presumably directly Post Date: Tue, 14 Oct 2008 21:48:55 +0000 And third, if one considers the thiol-dependent reactions of either aerobic or anaerobic metabolism, it is still unknown to what extent the overall rates of metabolism can be correlated with either electrolyte transport or drug action (Baer and Beyer, 1972; Bowman et al, 1973; Klahr et al, 1973). Some of the high-ceiling diuretics inactivate the Na+,K+-dependent adenosine triphosphatase (ATPase) of the kidney, but attempts to implicate this as the mechanism of drug action have encoun-tered quantitative difficulties (Williamson, 1970; Epstein, 1973). Since ATPase is presumably directly related to cation transport, the problem is further compounded by the demonstration that ethacrynic acid acts on the primary transport of the chloride anion, as well as on that of the sodium cation. Autor of the post: Undefined From the available data Post Date: Tue, 14 Oct 2008 21:31:13 +0000 On an experimental basis, the metabolic actions of furosemide have been used to enhance the preser-vation of transplanted kidneys (Panijayanond et al, 1973).Comparative Diuretic Action. From the available data the drugs of this class have remarkably similar actions upon the kidney in most species. Autor of the post: Undefined The diuretic action Post Date: Tue, 14 Oct 2008 21:14:00 +0000 Ethacrynic acid and bumeta-nide are almost inactive in the rat, except at extremely high doses. In the dog and man, bumetanide is effective in a dose about 2% that of furosemide, but its maximal effect is the same. The diuretic action of this group of drugs may be additive to that of less effective agents, but the high-ceiling diuretics themselves are not additive to each other (Hook and Williamson, 1965a). Autor of the post: Undefined Effect on Composition of Extracellular Fluid Post Date: Tue, 14 Oct 2008 20:58:53 +0000 One of the major differences between furosemide and ethacrynic acid is that the former has a broader dose-response curve. Accordingly, the therapeutic regimen may be initiated with rather small doses and adjusted upward to meet the needs of the individual patient.Effect on Composition of Extracellular Fluid. Autor of the post: Undefined For all agents, potassium depletion Post Date: Tue, 14 Oct 2008 20:39:29 +0000 Metabolic alkalosis may result from the use of the high-ceiling diuretics for essentially the same reason as with the mercurials, namely, the negative balance of extracellular fluid accompanied by a chloride loss relatively greater than that of bicarbonate. In the case of ethacrynic acid, an increase in the rate of hydrogen ion excretionmay be a contributing factor (Cannon et al, 1965). For all agents, potassium depletion may contribute to extracellular alkalosis. Autor of the post: Undefined Clinical Toxicity Post Date: Tue, 14 Oct 2008 20:25:22 +0000 The degree of alkalosis depends on many factors, including the magnitude of diuresis and the intake of chloride salts, either as sodium chloride in the diet or as potassium or am-monium chloride as supplements. The sig-nificance of hypokalemia is discussed more fully at the end of the chapter.Clinical Toxicity. Autor of the post: Undefined In susceptible subjects, attacks Post Date: Tue, 14 Oct 2008 20:08:47 +0000 From the extensive ex-perience with ethacrynic acid and furosemide, two generalizations may be made: (1) fluid and electrolyte imbalance is the most common form of clinical toxicity, and (2) side reactions unrelated to primary drug action are quite rare. Hyperuricemia is relatively common, but in most patients it represents little more than a chemical abnormality. In susceptible subjects, attacks of gout may be precipitated. Autor of the post: Undefined Furosemide and thiazides have been Post Date: Tue, 14 Oct 2008 19:54:51 +0000 The other reactions include gastrointestinal disturbances (with or without bleeding), depression of formed elements in the blood, skin rashes, paresthesias, and hepatic dysfunction (see Kim et al, 1971). Gastrointestinal side effects may be more frequent with ethacrynic acid than with furosemide. Furosemide and thiazides have been implicated as a cause of allergic inter-stitial nephritis, leading to reversible renal failure (Lyons et al, 1973). Autor of the post: Undefined Transient deafness has been reported Post Date: Tue, 14 Oct 2008 19:42:06 +0000 A decrease in car-bohydrate tolerance may occur, but to a lesser extent than with the thiazides (Dollery, 1973). The development of deafness, either transient or permanent, is a serious and rare complication with ethacrynic acid. Transient deafness has been reported with furosemide. 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