The Mode of Action and Use of Chlorothiazide and Related Compounds

Abstract

Chlorothiazide acts to inhibit renal tubular reabsorption of electrolytes. Experimental data are presented which indicate that, under various conditions, anion reabsorption is depressed unselectively so that the pre-existing ratio (Cl/HCO₃) is not changed during chlorothiazide diuresis. The data suggest that chlorothiazide acts primarily to block sodium ion reabsorption. Chlorothiazide diuresis is potentiated experimentally by KHCO₃ and clinically by acetazoleamide, organomercurials, or spirolactone. The latter two can also operate to block the potassium wastage of chlorothiazide. Increased potassium excretion caused by chlorothiazide is viewed as a consequence of the activity of the drug in blocking sodium reabsorption proximal to the site of potassium secretion. According to this concept, all chlorothiazide-type compounds will cause potassium depletion in proportion to their capacity to block proximal sodium reabsorption by diverting more sodium distally to the site of potassium secretion. Unlike mercurial agents, chlorothiazide either depresser or does not change excretion of free water during a water diuresis. These data suggest that chlorothiazide acts both in the proximal and distal portions of the nephron, while mercurial agents may act largely in the proximal tubule. The different mode of action of chlorothiazide on tubular reabsorption of electrolytes, as compared with other diuretic agents (acetazoleamide, organomercurials, spirolactone), affords evidence that a number of discrete tubular transport mechanisms participate in the regulation of electrolyte and water balance and provide a rational basis for combined use of various types of diuretic agents in treating edematous patients. The nature of the antihypertensive action of chlorothiazide has not yet been elucidated. The effect may be related to electrolyte and fluid depletion, but evidence for a more direct action on the circulation is reviewed. Other aspects of the pharmacology of chlorothiazide and its derivatives are considered, and the application of this information in treatment of states of edema or hypertension is discussed.