Diuretic dose schedules: is twice daily more effective?

A certain amount of controversy surrounds the question of the relative efficacy of diuretic therapy given once daily or twice daily. The observation (British Medical Journal, 1979) that 'any dose given once daily is likely to be more than twice as effective as half the dose given twice daily' is countered by reports (Hunter & Underwood, 1975; Wilson et al., 1975) that the total effect of loop diuretics is enhanced by dividing the dosage. An attempt was made to clarify this controversy in the course of our evaluation of the recently introduced loop diuretic, piretanide (comparable in diuretic potency to frusemide and bumetanide (Roberts et al., 1978) by comparison of natriuretic and diuretic responses to three different schedules of diuretic administration(a) full dosage in the morning; (b) full dosage in the aftemoon; (c) half dosage given twice daily. Nine patients, 5 male and 4 female, ages 43-76 years, admitted to hospital with congestive cardiac failure were started on oral therapy with the 'loop' diuretic, piretanide. No patient had received any diuretic for at least 24 h prior to the study but any other concomitant medication was continued, unchanged. Diuretic therapy was administered on alternate days with the treatment sequence allocated in accordance with a Latin square design involving piretanide 12 mg at 08.00 h, piretanide 12 mg at 16.00 h or piretanide 6 mg at 08.00 h and 16.00 h. Thus days 1, 3, 5 contained diuretic therapy and days 2, 4 were control periods. Daily estimation were made of weight, pulse and blood pressure, routine serum biochemistry, and 24 h collections of urine for volume and electrolyte analysis. Daily fluid intake was restricted to 1500 ml. Over the 5 days the mean weight loss was 3.1 kg. There were no significant changes in resting heart rate or blood pressure. Serum urea, creatinine, urate and electrolyte concentrations were not significantly altered. The results for daily urine volume and sodium output are summarised in Table 1. Statistical evaluation was by analysis of variance. There was no significant different in diuresis or natriuresis for the three treatment schedules, but all treatments produced a highly significant (P < 0.001) increase in urine volume and sodium output compared to the mean for control days. The most important finding was that the total diuretic and natriuretic effects of piretanide did not significantly differ with respect to the dosage schedule. Thus, in terms of 24 h urinary volume and sodium output, the diuretic was equally effective whether full dosage was administered once daily (either a.m. or p.m.) or half dosage was given twice daily. We were not able to confirm, therefore, that a twice daily diuretic regimen significantly increased the natriuresis/diuresis, as has been reported for 4-