Comparison of loop diuretics in patients with chronic renal insufficiency

Comparison of loop diuretics in patients with chronic renal insufficiency. Furosemide and bumetanide share a number of characteristics including reduced natriuretic effects in azotemic patients. It has been presumed that this condition affects each drug equally. Previous studies, however, suggest dissimilar pathways of delivery to their sites of action. Though not rigorously tested, this potential disparity might cause them to differ when used in azotemia. We, therefore, assessed the pharmacokinetic and pharmacodynamic characteristics of intravenously administered furosemide and bumetanide in ten adult patients with stable, chronic renal insufficiency (mean creatinine clearance = 14.1 ± 2.0 ml/min/1,73 m2) in a randomized, cross–over study during controlled sodium intake. Our goals were to assess differences in diuretic effectiveness and in so doing to determine the dose required to produce a maximal response. The mean diuretic doses of 172 and 4.3 mg for furosemide and bumetanide, respectively (ratio = 40:1) were sufficient to produce a maximum response. Despite similarities in maximal fractional excretion of sodium (18.2 ± 2.6% with furosemide vs. 19.4 ± 4.5% with bumetanide, P = 0.687) demonstrating an equal tubular responsiveness to both drugs, overall response as quantified by cumulative natriuresis in the initial eight hour period was 52% greater with furosemide (108 ± 17 vs. 71 ± 7 mEq; P = 0.042). The difference in total excreted sodium was accounted for by a preserved nonrenal clearance of bumetanide (113 ± 12 compared to 53 ± 5 ml/min for furosemide, P -0.001) which resulted in relatively less bumetanide in serum available to be delivered into the urine. Thus, while renal clearances were numerically similar (6 ± 1 vs. 7 ± 1 ml/min for furosemide and bumetanide, respectively, P = 0.549), the percentage of the bumetanide dose excreted in the urine during the initial eight hours was 42% less than furosemide (5.2 ± 1.0% vs. 9.0 ± 1.8%, P = 0.021). In summary, patients with stable, severe chronic renal insufficiency have a greater cumulative sodium excretion after intravenous furosemide compared to a dose of bumetanide determined to be equipotent in patients with normal renal function. The mechanism of the disparity between the two diuretics was explained by differences in nonrenal clearance. The clinical implications of these findings are that comparable patients require a dose ratio of furosemide to bumetanide of 20:1 to attain equal effects in cont