Sodium and Fluid Excretion With Torsemide in Healthy Subjects is Limited by the Short Duration of Diuretic Action

Abstract

BackgroundLoop diuretics are highly natriuretic but their short duration of action permits postdiuretic sodium retention, which limits salt loss unless dietary salt is severely restricted. We tested the hypothesis that a more prolonged duration of action would enhance salt loss.Methods and ResultsTen healthy participants were crossed over between 20 mg of oral immediate‐release or extended‐release (ER) torsemide while consuming a fixed diet with 300 mmol·d−1 of Na+. Compared with immediate‐release, plasma torsemide after ER was 59% lower at 1 to 3 hours but 97% higher at 8 to 10 hours as a result of a >3‐fold prolongation of time to maximal plasma concentrations. The relationship of natriuresis to log torsemide excretion showed marked hysteresis, but participants spent twice as long with effective concentrations of torsemide after ER, thereby enhancing diuretic efficiency. Compared with immediate‐release, ER torsemide did not reduce creatinine clearance and increased fluid (1634±385 versus 728±445 mL, P<0.02) and Na+ output (98±15 versus 42±17 mmol, P<0.05) despite an 18% reduction in exposure. Neither formulation increased K+ excretion.ConclusionsTorsemide ER prolongs urine drug levels, thereby increasing the time spent with effective drug concentrations, reduces postdiuretic Na+ retention, and moderates a fall in glomerular filtration rate. It caused significant Na+ loss even during very high salt intake. Thus, a short duration of action limits salt loss with loop diuretics. These conclusions warrant testing in subjects with edema and heart failure.

Clinical Pharmacology in Diuretic Use

“…Although the advantages of this approach over high-dose bolus treatment remain largely speculative (46), the physiologic basis for this approach is appealing, and recent stepped care guidelines (see below) recommend continuous infusions (47). Along these lines, an investigational extended release formulation of torsemide that delivers torsemide to the circulation over 8-12 hours was reported recently to double salt and water losses in normal volunteers after a single dose, without increasing potassium excretion (48). If such a formulation, which should avoid some of the obvious pharmacokinetic limitations of short acting loop diuretics, works as well in patients with heart failure or nephrotic syndrome, it may change the standard approach to treatment.…”

Medical management of acute heart failure

“…Recently, the US Food and Drug Administration (FDA) approved extended-release torsemide (once-a-day formulation) for patients with HF and persistent edema 62 . The formulation results in prolonged drug levels in urine, which has been shown to improve natriuresis by preventing post-diuretic sodium retention 63 .…”

Association of rheumatoid arthritis and high sodium intake with major adverse cardiovascular events: a cross-sectional study from the seventh Korean National Health and Nutrition Examination Survey

“…Second, drugs such as antihypertensive agents, metformin and glucocorticoids could affect urinary sodium excretion or MACE. [46][47][48] However, we were not able to adjust for them because of the absence of information on medication in the KNHANES dataset. Third, Open access since definitions of main diseases were based on self-reported physician-diagnosed status, their prevalence might have been overestimated.…”