The supra-additive natriuretic effect addition of theophylline ethylenediamine and bumetanide in congestive heart failure: Permutation trial tests in patients in long-term treatment with bumetanide

Abstract

The additive natriuretic effect of oral theophylline ethylenediamine, 400 mg., and the potent diuretic bumetanide has been studied in patients with advanced congestive heart failure. Two permutation trial tests including six patients each were performed in subjects receiving long-term therapy with digoxin and bumetanide, 4 mg. daily. In the first trial, the response to supplementary theophylline ethylenediamine, 400 mg., was definitely superior to that of additional bumetanide, 2 mg., in terms of renal output of sodium, chloride, potassium, water and osmolal clearance. In the second trial the comparison was made of the effects of theophylline ethylenediamine, 400 mg. plus bumetanide, 4 mg., of theophylline ethylenediamine, 400 mg., and of bumetanide, 4 mg. In terms of natriuresis and chloruresis, the response to the combination of two drugs was significantly larger than the sum of the effects of other treatments. The third permutation trial test comprised six patients, who had not previously received bumetanide. In this group no additive natriuretic or diuretic effect could be demonstrated after administration of theophylline ethylenediamine. It is concluded that in patients receiving longterm treatment with the potent diuretic bumetanide the combined effects of oral theophylline ethylenediamine and bumetanide represent a supra-additive natriuretic and chloruretic effect addition. A tentative explanation for the mechanism of interaction of drugs in terms of inhibition of renal tubular sodium transport is given. Since the combined effects of the two drugs involve a tendency to development of increased kaliuresis, it is recommended that supplementary use of theophylline ethylenediamine in this setting is combined with the administration of potassium chloride. Apparently oral theophylline ethylenediamine represents an alternative possibility to thiazide diuretics when additional natriuresis and diuresis are required in patients with advanced heart failure on long-term treatment with potent diuretics like bumetanide.