Background: Loop diuretics have outstanding acute natriuretic and diuretic actions. However, their therapeutic efficacy is limited by a modest depletion of body salt or water due to the compensatory increase in renal sodium reabsorption after diuretic effects wear off. We tested the hypothesis that a more prolonged duration of action would enhance salt and water loss. Methods: Ten normal subjects received 20 mg of oral torsemide on two occasions while consuming a fixed diet with 300 mmol.day-1 of Na+. They were randomized to an immediate release (IR) or to an Extended Release (ER) formulation. The ER formulation delivered torsemide into solution over 12 hours. Results: Compared to IR, the plasma levels of torsemide in the subjects given ER were 59% lower 1-3 hours after dosing, accompanied by a lower naturieses, but were 97% higher 8-10 hours after dosing, leading to a 2-fold increased naturiesis. This resulted in a 2.4-fold prolongation of time to maximal levels and a >2-fold increase in excreted fluid (1634 + 385 versus 728 + 445 mL; P < 0.02) and Na+ (98 + 15 versus 42 + 17 mmol; P < 0.05) despite an 18% reduction in torsemide bioavailability. Only after ER was there a reduction on mean blood pressure (-2.9 + 1.8 vs +1.3+ 1.2 mmHg; P<0.05) and weight (-0.5 + 0.2 kg; P < 0.05) but only after IR was there a significant reduction in creatinine clearance (CCR; -24.5 + 6.6 ml*min-1 per 1.73 m-2; P < 0.005). The higher Na+ excretion and relatively well preserved CCR after ER resulted in a similar increase in fractional excretion of Na+ after ER and IR. Neither drug led to a significant loss of potassium. Conclusion: An ER formulation of torsemide led to a doubling of the time to peak plasma levels and loss of salt and water without reducing GFR resulting in significant reductions in weight and mean BP despite a high salt intake.
Shen, W., Khwaja, F., Feig, P. U., Shah, S., & Wilcox, C. (2014). A NOVEL EXTENDED RELEASE FORMULATION OF TORSEMIDE ENHANCES NATRIURESIS WITHOUT LOWERING GFR IN NORMAL HUMAN SUBJECTS. Journal of the American College of Cardiology, 63(12), A1401. https://doi.org/10.1016/s0735-1097(14)61401-7