THE SUPRA‐ADDITIVE NATRIURETIC EFFECT ADDITION OF QUINETHAZONE OR BENDROFLUMETHIAZIDE DURING LONG‐TERM TREATMENT WITH FUROSEMIDE AND SPIRONOLACTONE

Abstract

Abstract. The additive natriuretic effects of single doses of quinethazone (50 mg) or bendroflumethiazide (5 mg) have been studied in patients with advanced congestive heart failure receiving longterm treatment with furosemide (160 mg) and spironolactone (100 mg) daily. Three permutation trial tests were performed. In the first trial including 12 patients a significant increase of renal sodium, chloride, potassium and water excretion and osmolal clearance was found after supplementary administration of quinethazone or bendroflumethiazide. In the second trial including 6 patients the response to supplementary quinethazone (50 mg) was definitely superior to that of additional furosemide (80 mg). Accordingly the response to supplementary quinethazone cannot be explained as a dose addition effect of drugs acting on the same renal tubular receptors, but must represent an effect addition of diuretics acting by different mechanisms or at different sites in the nephron. The third trial compared in 6 patients the effects of quinethazone (50 mg) + spironolactone (100 mg), of furosemide (160 mg) + spironolactone (100 mg), and of quinethazone (50 mg) + furosemide (160 mg) + spironolactone (100 mg). In terms of natriuresis, chloruresis, cation excretion and weight loss the responses to the combination of all three drugs were significantly larger than the sums of the effects of other treatments. It is concluded that the combined effects of the drugs represent a supra‐additive effect addition (or a supra‐additive summation). A tentative explanation of the mechanism of this effect in terms of inhibition of renal tubular sodium transport is given. Since the combined effects of all three drugs involve a tendency to development of hypokalaemia, hypochloraemia and alkalosis, it is recommended that the supplementary use of quinethazone or bendroflumethiazide in this setting is combined with the administration of potassium chloride.