Dose Of Torasemide Research Articles

A Systematic Critical Review of Clinical Pharmacokinetics of Torasemide.

Torasemide is a potassium-sparing loop diuretic used to treat fluid retention associated with congestive heart failure and kidney and hepatic diseases. This systematic review was conducted to combine all accessible data on the pharmacokinetics (PK) of torasemide in healthy and diseased populations, which may help clinicians avert adverse drug reactions and determine the correct dosage regimen. Four databases were systematically searched to screen for studies associated with the PK of torasemide, and 21 studies met the eligibility criteria. The review protocol was registered in the PROSPERO database (CRD42023390178). A decrease in maximum plasma concentration (C max ) was observed for torasemide after administration of the prolonged-release formulation in comparison to that after administration of the immediate-release formulation, that is, 1.12 ± 0.17 versus 1.6 ± 0.2 mcg/mL. After administering an oral dose of torasemide, a 2-fold increase in the area under the concentration-time curve (AUC) was reported in patients with congestive heart failure compared with the healthy population. Moreover, the patients with renal failure (clearance < 30 mL/min) showed an increase in value of AUC 0-∞ that is, 42.9 versus 8.091 mcg.h -1 .mL -1 compared with healthy subjects. In addition, some studies have reported interactions with different drugs, in which irbesartan showed a slight increase in the AUC 0-∞ of torasemide, whereas losartan and empagliflozin did not. The current review summarizes all available PK parameters of torasemide that may be beneficial for avoiding drug-drug interactions in subjects with renal and hepatic dysfunction and for predicting doses in patients with different diseases.

Высокие дозы торасемида в практике врача: очевидные преимущества

Торасемид является на сегодня наиболее назначаемым петлевым диуретиком в клинической практике. Его высокие дозы используются преимущественно в двух клинических ситуациях, сопровождающихся гипергидратацией: при хронической сердечной недостаточности (ХСН) и хронической болезни почек (ХБП). Последние международные рекомендации по ХСН, 2019 г., определили четкий алгоритм применения больших доз торасемида с учетом того, что именно высокие дозы дают стойкий длительный диуретический эффект. Суточная доза находится в промежутке 50–300 мг торасемида, назначается непрерывно и длительно. Из клинической практики известно, что высокий уровень натрийуретического пептида В, как правило, сопровождается выраженным диурезом. При ХБП большие дозы торасемида находятся в диапазоне 40–100 мг (200 мг) в сутки. Учитывая ограничения водовыделительной функции почек, которая пропорционально снижается при увеличении степени ХБП, режим и эффективность назначения торасемида отличаются от таковых при ХСН. При ХБП торасемид назначается в дозе до 100 мг 6 дней в неделю, седьмой — перерыв. При применении доз 100–200 мг торасемид назначают в следующем режиме: два дня приема — два дня перерыва. Большие дозы торасемида демонстрируют высокую эффективность в уменьшении/ликвидации гипергидратации при ХСН и ХБП. Их длительное назначение снижает показатели общей и сердечно-сосудистой смертности. Усиление эффекта торасемида возможно за счет одновременного назначения ксипамида. Комбинация торасемида и фуросемида считается нецелесообразной.

The impact of torasemide on haemodynamic and neurohormonal stress, and cardiac remodelling in heart failure \u2013 TORNADO: a study protocol for a randomized controlled trial

BackgroundApproximately 50% of heart failure patients are readmitted to hospital within 6 months, owing to deterioration of their condition. Thus, symptomatic treatment of heart failure requires significant improvement. The aim of this study is to compare the effects of torasemide and furosemide on biochemical parameters of haemodynamic and neurohormonal compensation, myocardial remodelling, clinical outcomes and quality of life in patients with chronic heart failure.MethodsThis is a multicentre, randomized, open, blinded endpoint phase-IV trial. The study includes 120 heart failure patients in NYHA (New York Heart Association) functional class II–IV, treated with optimal heart failure therapy, with indications for use of loop diuretics. At enrolment, patients are stable, with a fixed dose of loop diuretics. Patients are randomized to treatment with furosemide or torasemide (randomization 1:1). After randomization, the current fixed dose of furosemide is continued or is replaced by an equipotential dose of torasemide (4:1). The study consists of two control visits (3 and 6 months after enrolment) with minimal follow-up of 6 months. Assessment involves clinical examination, Quality of Life Questionnaire, laboratory tests, echocardiography, electrocardiography, 24 h Holter-electrocardiography monitoring, 6 -min walk test and assessment of fluid retention. Any need for dose adjustment is assessed during the observation. The primary objective is to compare the effects of torasemide and furosemide on clinical and biochemical parameters of haemodynamic and neurohormonal compensation and myocardial remodelling. Secondary objectives include monitoring of: changes in signs and symptoms of heart failure, NYHA functional class, quality of life, dosage changes, rate of readmissions and mortality.DiscussionDespite decades of the diuretic’s history, knowledge about diuretic therapy is still unsatisfactory. The most widely used diuretic, furosemide, has a stormy pharmacokinetics and pharmacodynamics, and is associated with a high risk of mortality and hospitalization for worsening heart failure. Reports are very encouraging and suggest beneficial effects of torasemide. Hence, there is a need for further studies of the overall effect of torasemide, compared with furosemide. This can translate into improved quality of life and better prognosis of patients with heart failure.Trial registrationClinicalTrials.gov, NCT01942109. Registered on 24 August 2013.

Comparison of the Effects on Ambulatory Blood Pressure of Awakening versus Bedtime Administration of Torasemide in Essential Hypertension

Torasemide is a high‐ceiling loop diuretic frequently used in the treatment of congestive heart failure, renal failure, and hypertension. Low doses of torasemide (2.5 to 5 mg/day) do not elevate 24 h natriuresis, and they constitute effective monotherapy for mild‐to‐moderate uncomplicated essential hypertension according to results based on clinic blood pressure (BP). However, there has yet to be a proper evaluation of its 24 h efficacy or potential dependency of effects according to the circadian time of treatment. Accordingly, this trial investigated the administration time‐dependent efficacy of torasemide in uncomplicated essential hypertensive patients. We studied a total of 113 grade 1 and 2 hypertensive patients, 51.7±10.6 yrs of age, randomly assigned to receive torasemide (5 mg/day) as a monotherapy either upon awakening or at bedtime. BP was measured by ambulatory monitoring for 48 consecutive hours before and after six weeks of treatment. The efficacy of torasemide was significantly greater with bedtime dosing (i.e., 14.8 and 9.5 mmHg reduction in the 24 h mean systolic and diastolic BP, respectively) as compared with morning dosing upon awakening (i.e., 6.4 and 3.4 mmHg reduction in mean systolic and diastolic BP; p<0.001 between the two treatment‐time groups). The percentage of patients with controlled ambulatory BP after treatment was also higher after bedtime treatment (64 vs. 23%; p<0.001). Safety and tolerability were comparable between the two treatment‐time groups. A dose of 5 mg/day torasemide is more effective for BP reduction for uncomplicated essential hypertensive patients when ingested at bedtime than in the morning upon arising. The difference in antihypertensive efficacy as a function of the circadian dosing‐time of torasemide here documented should be taken into account when prescribing this loop diuretic to treat essential hypertensive patients.

Administration time-dependent effects of torasemide on ambulatory blood pressure in patients with essential hypertension

Torasemide is a high ceiling loop diuretic frequently used for treatment of congestive heart failure and hypertension [Drug Saf. 1996;14:104–120]. Low doses of torasemide (2.5 to 5 mg/day) do not elevate 24h natriuresis, but they constitute effective once-daily monotherapy for mild-to-moderate uncomplicated essential hypertension [J Hum Hypertens. 2002;16:S78–S83). These results have been mainly based on clinic blood pressure (BP) measurements, without proper evaluation of the 24h efficacy of the drug. On the other hand, diuretics have not yet been studied in relation to possible circadian variation of effects. Accordingly, we investigated the administration time-dependent antihypertensive efficacy of torasemide in hypertensive patients. We studied 55 previously untreated patients with grade 1-2 essential hypertension (25 men), 48.7 ± 11.9 years of age, randomly assigned to receive torasemide (5 mg/d) as a monotherapy either upon awakening or at bedtime. BP was measured by ambulatory monitoring at 20-min intervals from 07:00 to 23:00 hours and at 30-min intervals at night for 48 hours before and after 6 weeks of therapy. Efficacy of torasemide was significantly higher after bedtime dosing (11.2 and 8.0 mm Hg reduction in the 24-hour mean of systolic and diastolic BP, respectively) as compared to the administration of the drug on awakening (6.2 and 3.7 mm Hg reduction in systolic and diastolic BP). The percentage of patients with controlled ambulatory BP after treatment was also higher after bedtime treatment (52 versus 28%, P=0.042). The time-response curves indicate a full 24h therapeutic coverage only when torasemide was administered before bedtime, with a significant higher efficacy of bedtime dosing as compared to morning treatment after the first 7 hours post-dosing. The 24h urinary secretion of sodium and potassium remained unchanged after treatment for both groups. A single dose of 5 mg/day torasemide is effective for BP reduction mainly after bedtime administration, The differences in efficacy and therapeutic coverage as a function of the circadian time of treatment with torasemide here documented should be taken into account when prescribing this loop diuretic for treatment of patients with essential hypertension.

Simple and Sensitive Assay of Torasemide in Human Plasma by High-Performance Liquid Chromatography Using a Monolithic Silica Column

A rapid and sensitive method to assay torasemide in plasma was developed using a simple liquid-liquid extraction technique followed by high-performance liquid chromatography. Torasemide and the internal standard furosemide were extracted from 0.5 mL of plasma using ethyl acetate in the presence of 0.1M HCl. The analysis of the extracts was performed on a monolithic silica column with ultraviolet spectrophotometric detection. The calibration curve was linear over the concentration range of 0.05-5 μg mL−1 in plasma. Recoveries were reasonable for routine analyses (>80%); the limit of quantification was 0.05 μg mL−1 with a signal-to-noise ratio of 5. The coefficient of variation of the assay precision was less than 6.1%, and the accuracy exceeded 98%. This method was used to measure the torasemide concentration in plasma from healthy subjects after a single 20-mg oral dose of torasemide. This method provides a very simple, sensitive, and accurate way to determine torasemide concentrations in plasma.

Dose torasemide have an aldosterone receptor antagonist ?

Background: We reported that mineralocorticoid receptor antagonist spironolactone inhibits the transcardiac extraction of aldosterone (ALD) in patients with congestive heart failure (CHF). In the TORIC study, torasemide had more beneficial effect on mortality and morbidity of CHF patients than furosemide. However, the mechanism of the beneficial effect of torasemide remains unknown. Method: To evaluate whether the torasemide has an ALD receptor antagonist, we studied 50 CHF patients who had been randomly administered furosemide (n = 25) or torasemide (n = 25). Results: There was no difference of patients characteristics, other treatments, left ventricular ejection fraction, and plasma levels of BNP in the aortic root (AO) between the two groups. In the furosemide group, plasma ALD was significantly lower in the coronary sinus (CS) than in the AO (96 ± 11 vs. 75 ± 12 pg/mL, p < 0.001), suggesting that ALD is extracted through the heart. In contrast, there was no difference of plasma ALD between the AO and CS in the torasemide group (83 ± 11 vs. 78 ± 12 pg/mL, p = 0.17), suggesting that the extraction of ALD through the heart is inhibited by torasemide. In addition, there was a significant negative correlation between dose of torasemide and the transcardiac gradient (Ao-CS) of ALD in the torasemide group (r = -0.56, p < 0.01). Conclusion: These findings suggest that torasemide has an ALD receptor antagonist in the failing heart in patients with CHF.

Failure of the loop diuretic torasemide to improve renal function of hypoxemic vasomotor nephropathy in the newborn rabbit.

The use of diuretic therapy in vasomotor nephropathy is a controversial topic. It is generally agreed that diuretics in this situation enhance urinary output, reduce the degree of volume expansion, and improve cardiac and especially the compromised lung function. It is less clear whether diuretic therapy improves kidney function. The present study evaluates the effects of intravenous torasemide on renal function in 25 anesthetized ventilated hypoxemic newborn New Zealand White rabbits with vasomotor nephropathy. This well-established animal model mimics the renal physiology of the human newborn and, in particular, that of the premature infant. Three groups of hypoxemic rabbits were studied. The animals of group 1 (n = 8) received no diuretic therapy (hypoxemic control), and those of group 2 (n = 9) were given a single intravenous dose of torasemide (1 mg/kg) in a curative fashion 2 h after hypoxemia was induced. In the third group of animals (n = 8), torasemide was given preventively; a bolus intravenous dose of torasemide (0.2 mg/kg) was given before the induction of hypoxemia and sustained by the addition of 0.2 mg x kg(-1) x h(-1) of the drug to the continuous intravenous infusion given throughout the entire 3-h hypoxemic period. Hypoxemia alone (group 1) caused acute renal insufficiency with a significant fall in mean arterial blood pressure, GFR, and renal blood flow; the renal vascular resistance increased, and the filtration fraction was unchanged. The curative dose of torasemide (group 2) induced a significant diuresis and natriuresis with minimal augmentation of urinary potassium excretion, converting mildly oliguric to nonoliguric acute renal insufficiency. In this group of animals, torasemide did not improve the glomerular dysfunction. The preventive dose of torasemide (group 3) even somewhat worsened the already impaired renal functions without further increasing the diuretic effect of the drug. We conclude that in hypoxemic newborn animals with renal dysfunction, torasemide is an effective potassium-sparing diuretic that unfortunately does not improve renal blood flow and GFR. The failure of torasemide to attenuate the glomerular dysfunction of hypoxemic vasomotor nephropathy in the newborn rabbit is disturbing. These data certainly caution against the overzealous use of loop diuretics in hypoxemic oliguric neonates.

Gas chromatographic-mass spectrometric analysis of the loop diuretic torasemide in human urine

A fast and reliable gas chromatographic-mass spectrometric (GC-MS) method for the identification and determination of the loop diuretic torasemide in human urine is described. The usefulness of different derivatization procedures and reagents was studied. Flash methylation using trimethylanilinium hydroxide was the most convenient and appropriate procedure. The optimal urine isolation method comprised alkaline liquid-liquid extraction with ethyl acetate. After evaporation of the organic layer to dryness, the solid residue was reconstituted in the derivatizing reagent and was directly injected into the GC-MS system. Samples were analysed in the multiple ion detection mode using electron impact ionization. No interferences from other urinary compounds were found. Torasemide gave rise to a derivative that was identified by GC with Fourier transform infrared detection. There was a 70 +/- 5% recovery of torasemide. The coefficient of variation was 5% at a concentration of 0.05 microgram/ml. The method was used for the determination of torasemide in urine samples obtained from a healthy volunteer that had received a single, 10 mg dose of torasemide.

E8 - Non-diuretic doses of torasemide are as effective as regular diuretic doses of chlorthalidone for the treatment of arterial hypertension

E8 - Non-diuretic doses of torasemide are as effective as regular diuretic doses of chlorthalidone for the treatment of arterial hypertension

Renal excretory responses to single and repeated administration of diuretics in healthy subjects: Clinical connotations

Administration of an initial oral dose of hydrochlorothiazide 25 mg to healthy subjects is followed by increased 24-hour urinary outputs of sodium, chloride, and potassium. On the fourth day of once-daily dosing with hydrochlorothiazide 25 mg, 24-hour natriuresis and chloriuresis are no longer augmented, but the elevation in 24-hour kaliuresis that follows the first dose remains unchanged. Twenty-four-hour urinary calcium output is consistently reduced during repeated once-daily administration of hydrochlorothiazide 25 mg. The first oral dose of the loop diuretic torasemide augments the average natriuresis and kaliuresis in the 6 hours immediately after dosing in healthy subjects, in a dose-dependent fashion, within the 2.5 to 10-mg range. These increased urinary outputs are followed by rebounds below postplacebo values between 6 and 24 hours after dosing. As a result of this biphasic response, torasemide 2.5 mg qualifies as a nondiuretic formulation (it does not elevate 24-hour natriuresis), whereas torasemide 5 and 10 mg qualify as diuretic formulations. After the seventh dose of torasemide 5 or 10 mg during a regimen of once-daily therapy, 24-hour urinary sodium and chloride outputs no longer differ from their postplacebo counterparts. Twenty-four-hour kaliuresis tends to increase in a dose-dependent fashion after the first dose of torasemide (torasemide 2.5 and 5 mg do not augment it significantly), but this tendency is no longer present after the seventh once-daily dose, when torasemide (2.5, 5, or 10 mg) does not elevate the mean 24-hour kaliuresis. Twenty-four-hour calciuresis tends to increase in a dose-dependent manner (torasemide 2.5 mg does not elevate it significantly) after the first dose of torasemide; this calciuretic effect does not change in intensity after 7 days of once-daily treatment. The time course of natriuresis over the 24 hours following the administration of any given formulation of a loop or of an early distal tubular diuretic to healthy subjects is alike after the first and after the nth once-daily dose; therefore, it constitutes a definite characteristic of any given oral formulation. In the case of torasemide, lower doses have more protracted effects on natriuresis, to the extent that the time course of natriuresis over the 24 hours after administration of torasemide 2.5 mg to healthy subjects resembles the time course after administration of hydrochlorothiazide 25 mg, rather than the time course after administration of the overtly diuretic formulation torasemide 10 mg.

Torasemide in comparison with thiazides in the treatment of hypertension

There are a number of clinically relevant differences between torasemide and the thiazide diuretics in the treatment of hypertension. Only 2.5-5 mg torasemide once daily is sufficient for antihypertensive treatment; these low doses of torasemide exert comparable antihypertensive effects to those of the overtly natriuretic doses of thiazides (e.g., hydrochlorothiazide 25 mg) that are currently used once daily for the treatment of hypertension. Whereas natriuretic thiazide doses reduce blood pressure rapidly, the blood pressure-lowering effect of low-dose torasemide appears to occur more gradually during the first weeks of treatment. The diurnal blood pressure rhythm is not altered by either drug. In contrast to the thiazides, torasemide does not cause significant renal potassium loss in doses recommended to treat hypertension. Long-term antihypertensive treatment with torasemide has not resulted in undesired metabolic side effects, such as hypomagnesemia, alterations in glucose and lipid metabolism, or hyperuricemia. As compared with the thiazides, torasemide appears to be a safer and equally effective alternative for antihypertensive treatment when subdiuretic doses of this loop diuretic are used.

Anti-aldosteronergic effect of torasemide

The diuretic actions of torasemide and furosemide were studied in normotensive rats and in deoxycorticosterone acetate (DOCA)-saline-loaded hypertensive rats. Torasemide (0.3 ~ 3 mg/kg) and furosemide (3 ~ 30 mg/kg) had a dose-dependent and significant diuretic action in normotensive rats. Potassium retention was only observed in the case of torasemide. Torasemide also had a dose-dependent and significant diuretic action in DOCA-saline-loaded hypertensive rats, whereas furosemide did not. Higher doses of torasemide (10 mg/kg) and furosemide (100 mg/kg) increased both plasma renin activity and aldosterone concentration in normotensive rats in a similar manner. In vivo aldosterone receptor binding was determined to test the possible anti-aldosteronergic effect of torasemide. Torasemide inhibited the binding of aldosterone to its receptor in the cytoplasmic fraction of rat kidney in a dose-dependent manner, while furosemide produced no effect. These results suggest strongly that an anti-aldosteronergic action of torasemide contributes to producing less kaliuresis.

The Loop Diuretic Torasemide in Chronic Renal Failure

The pharmacodynamic effect of a diuretic agent is essentially dependent on its renal elimination characteristics. The influence of renal function on the pharmacodynamic and pharmacokinetic characteristics of a diuretic should therefore be considered. The results of a study with torasemide given intravenously in healthy subjects and in patients with stable chronic renal failure of various degrees are reported and discussed. After a single dose of torasemide 20mg, a marked diuresis was observed and electrolyte excretion was increased, whereas the glomerular filtration rate was unchanged. Throughout the duration of action (tau) of torasemide, drug-induced excretion of Cl-, Na+, K+, Ca++ and Mg++ was linearly related to the creatinine clearance (CLcr), and excretion of K+ and Ca++ were closely related to that of Na+ over the entire range of CLcr. Similarly, excretion of Mg++ was related to that of K+. As occurs with furosemide (frusemide), torasemide induced a kaliuresis which amounted to 12% of natriuresis. This kaliuretic effect of loop diuretics is less than that of thiazides. Beyond tau, e.g. over a 24-hour period, kaliuresis was no longer correlated with natriuresis. The extent to which a rebound effect occurred was diminished with increasing renal impairment. tau averaged 6 hours and was independent of CLcr. The mean half-life (t1/2) of torasemide was approximately 5 hours and was independent of renal function, since renal clearance accounted for only around 25% of total body clearance. In contrast to the parent drug, however, the active minor metabolite M1 and the inactive main metabolite, M5, were found to accumulate in patients with chronic renal failure.