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Studies on the mechanism and characteristics of action of a new phthalimidine diuretic, clorexolone
Author(s) -
Baba Walten I.,
Lant Ariel F.,
Wilson Graham M.
Publication year - 1966
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt196672212
Subject(s) - diuretic , nephron , chemistry , reabsorption , endocrinology , aldosterone , mineralocorticoid , renal sodium reabsorption , medicine , mechanism of action , bicarbonate , sodium , diuresis , stimulation , tubular fluid , kidney , pharmacology , biochemistry , in vitro , organic chemistry
A study aimed at investigating the mechanism and characteristics of action of a new phthalimidine diuretic, clorexolone, has been undertaken in rats and in a group of twenty‐three normal human subiects under various experimental conditions. Hydroflumethiazide, a typical benzothiadiazine analogue, has been used as a standard of comparison. The pharmacological properties of clorexolone have been found to resemble closely those of hydroflumethiazide. Duration of clorexolone‐induced diuresis is, however, longer. At maximally effective doses, the natriuretic responses achieved by both drugs are not statistically different. Orally administered clorexolone is without effect on GFR and its action upon the nephron appears to be directed primarily at a tubular level. The cellular mechanism of clorexolone action does not involve significant inhibition of renal carbonic anhydrase in vivo since urinary bicarbonate excretion and pH remain unchanged after its administration. The natriuretic effect occurs independently of aldosterone antagonism and is, at least in part, due to selective inhibition of sodium reabsorption without water at the urinary diluting sites in the distal part of the nephron. The data do nat exclude the possibility of an additional interference with proximal processes of isoosmotic sodium reabsorption. The extent of the urinary potassium loss induced by clorexolone is linked to the degree of mineralocorticoid stimulation of the distal nephron K + ‐H/Na + competitive exchange system. In addition, significant increase in potassium excretion also occurs after clorexolone administration in adrenalectomized animals, a finding which implicates a direct action upon tubular handling of potassium ion independent of mineralocorticoid participation.