Ascites is the most frequent complication in liver cirrhosis and it is associated with a marked worsening of prognosis; the 1-year survival after an episode of ascites has been reported to be 56% (1). Diuretics remain a cornerstone in the treatment of ascites due to advanced cirrhosis of liver. Diuretic therapy can be used for the treatment of patients with mild to moderate ascites and for the prevention of recurring ascites.

 

Treatment of ascites in cirrhosis is based on bed rest and low sodium diet. However, a restricted sodium and fluid diet may be sufficient to prevent excessive fluid accumulation in approximately only 10-20% of cirrhotic patients (2). Hence if ascites does not disappear, treatment is based upon the use of diuretics. Because of the role of hyperaldosteronism in salt retention, aldosterone antagonists are the first-choice drugs. When the aldosterone antagonists are ineffective, a diuretic response can be obtained by adding loop diuretics. Loop diuretics, like frusemide and torsemide and aldosterone antagonists, such as spironolactone and potassium canrenoate, are the most commonly used diuretics in patients with cirrhosis and ascites (3).

Bodyweight is an important parameter to assess the effectiveness of diuretic therapy. The objective of treatment is to achieve a weight loss of 350-500 g/day during the first 7 days of treatment. Patients not showing a reduction in body weight when on high doses of aldosterone antagonist and loop diuretics are considered to have ‘diuretic resistant' ascites. Such patients need invasive therapeutic procedures (3).

An algorithm summarizing the treatment of cirrhotic ascites is provided in the adjoining figure (4).

References:
1. Scand J Gastroenterol 2001; 36: 309-313
2. Aliment Pharmacol Ther 1994; 8: 397-402
3. Cardiovasc Drugs Ther 1993; 7: 81-85
4. Cardiology 1994; 84: 87-98

 

 

In cirrhotics, because of the activation of the renin angiotensin system and the role of angiotensin II in causing reabsorption of sodium and water, there is increased reabsorption of sodium ions in the proximal tubule. Hence, the amount of sodium ions reaching the loop of Henle (site of action of loop diuretics) in a liver cirrhosis patient is lesser compared to other patients. Also, there is diminished binding of loop diuretics to the plasma proteins. Hence the efficacy of loop diuretics is reduced in these patients. In fact, a reduced urinary excretion of frusemide has been found in diuretic-resistant patients with cirrhotic ascites, indicating that these patients have an impaired secretion of frusemide into the proximal tubule, leading to a reduced availability of frusemide at its active site on the luminal surface of the ascending limb of the loop of Henle (1).

Torsemide exhibits pharmacokinetic and pharmacodynamic profiles that make it a preferred compound in cirrhosis. The bioavailability, pharmacokinetics, and pharmacodynamics of torsemide (10 mg orally and intravenously) were determined in a randomized crossover clinical trial (2) involving 12 patients with ascites caused by cirrhosis. Torsemide was rapidly absorbed with a bioavailability of 96.3% (confidence interval, 84% to 109%). In healthy subjects, approximately 20% of an administered dose of torsemide is excreted unchanged in the urine and the remainder is metabolized by the liver, producing compounds that have little or no diuretic activity. Compared with healthy subjects, patients with cirrhosis exhibit a decrease in nonrenal clearance and increases in bioavailability, volume of distribution, renal clearance, elimination half-life, and percentage of the dose excreted into the urine. A greater proportion of the dose is delivered to the site of action over a more prolonged period of time. Hence, pharmacokinetic changes of torsemide in cirrhosis compensate for the pharmacodynamic abnormality associated with cirrhosis.

In another controlled, double blind, randomized clinical trial (1), the pharmacokinetics of 20 mg torsemide (n=10) were compared with 40 mg frusemide (n=9) over 24 hours after single oral administration to patients with ascites due to liver cirrhosis. The fractional excretions of volume (FEVOL), sodium (FESOD) and chloride (FECHLOR) were similar and not significantly different in the 24 h urine collections between the two groups. After reaching peak fractional excretions, FEVOL, FESOD and FECHLOR in the torsemide group remained higher with time than those in the frusemide group until the 8-10 hour period urine fraction, but a significant level (p<0.05) was only reached for FEVOL (6-10 h). The median serum elimination half-life of torsemide was 4.8 hours and of frusemide 2.2 hours and also longer than healthy volunteers (3 hours). The duration of action, which is estimated by the time course of fractional excretions, was longer in the torsemide group than in frusemide group, because, after reaching peak salidiuresis, the fractional excretions declined more smoothly after administration of torsemide, whereas they dropped more markedly after administration of frusemide (Figure 1). From the clinical point of view, the prolonged action of torsemide may be advantageous especially in patients with liver disease, because disturbance in electrolytes and the risk of coma might be avoided.

Another study (3) evaluated the pharmacodynamic effects of single oral doses of frusemide (80 mg) and torsemide (20 mg) (which were equipotent in healthy subjects), in 14 patients with cirrhosis and ascites. The drugs were alternated following a randomized double-blind crossover design after a washout period of at least 2 days.

The results showed that in the first 6 hours, the diuretic effect of torsemide was similar to frusemide group. However, in the 6-24 hour interval, torsemide induced significantly higher natriuresis (38±11 vs. 17±4 mmol sodium) and diuresis. Also, the body weight 24 hours after administration was reduced by 0.49 ± 0.29 kg following frusemide and 0.73 ±0.35 kg following torsemide.

Another randomized, double-blind crossover study (4), evaluated the dose-response relationship of torsemide (5 mg, 10 mg or 20 mg) in 17 patients with ascites on a constant dose of spironolactone, during a 13-day hospitalization period. Torsemide produced statistically significant, dose-related 24 h diuresis, natriuresis and chloruresis compared to placebo (Figure 2). Most of the torsemide induced diuresis and natriuresis occurred during the first 6 h post-dose, with the greatest increase at 1-2 h post dose.

The diuretic effect of 5 mg dose of torsemide was similar to placebo. The 24 h volume collection with 10 and 20 mg doses was approximately 450 and 800 ml larger than that collected after placebo, respectively. The dose-response relationships were similar for the two spironolactone dose groups (patients who received spironolactone £100 mg daily and those patients who received >100 mg daily), indicating that torsemide was effective in both. Also, torsemide was effective in increasing fractional sodium excretion irrespective of the edema status. Torsemide 10 and 20 mg also showed statistically significant dose-related changes from the pre-dose control values in body weight. Hence the study concluded that torsemide increased sodium excretion substantially in patients with cirrhosis and ascites who were receiving spironolactone.

References:
1. Arzneim Forschung 1988; 38: 176-179
2. Clin Pharmacol Ther 1993; 54: 90-97
3. J of Hepatology 1993; 17: 353-358
4. Aliment Pharmacol Ther 1994; 8: 397-402

 

 

The effects of torsemide (20 mg/day) and frusemide (50 mg/day), each given over 4 days, were compared in a randomized and crossover study (1) carried out in seven patients with cirrhosis and tense ascites. Patients also received a low-sodium (40 mmol/day) diet and the aldosterone antagonist, potassium canrenoate (100 mg bid). Torsemide induced a remarkably higher natriuretic (120 ± 15 vs. 33 ± 6 mmol/day, p < 0.02) (Figure 1) and diuretic (1450 ± 63 vs. 900 ± 58 ml, p < 0.005) effect than frusemide. Reduction in body weight was also significantly higher (2.5 ± 1.6 vs. 0.2 ± 1.3 kg, p < 0.01) during the torsemide period. Kaliuresis was similar during the two treatment periods, despite the striking differences observed in natriuresis.

Neither torsemide nor frusemide induced any significant change in serum electrolyte or creatinine concentrations, or in ammonia levels. The results of this study indicate that torsemide is suitable for the treatment of sodium retention in patients with cirrhosis and ascites.

Another randomized double-blind study (2) compared the clinical effects of torsemide (10 mg/day) with frusemide (25 mg/day) in 24 nonazotemic cirrhotic patients with ascites during a 3-day period. Patients had not shown adequate diuretic response to a restricted sodium diet, bed rest and potassium canrenoate (200 mg/day). Torsemide induced significantly greater natriuresis than frusemide (p<0.02), with a two-fold greater percentage increase in basal values (day 1: 130% vs. 50%; day 2: 104% vs. 42% and day 3: 65% vs. 26% respectively). The extent of kaliuresis observed during the two treatments was almost identical despite the striking differences in the natriuretic response. Body weight loss was significantly higher during torsemide (p<0.02) administration, and the overall decrease at the end of the treatment was twice as high as frusemide (2.5 ± 0.6 kg vs. 1.3 ± 0.4 kg respectively) (Figure 2).

These short-term trials indicate that in the doses used, torsemide has a more potent effect on urinary volume, natriuresis and bodyweight loss in cirrhotics, but less effect on urinary potassium excretion than frusemide. The lack of pronounced kaliuresis with torsemide is of potential clinical importance because the increased blood ammonia concentration induced by a diuretic in hepatic cirrhosis is related to the serum potassium concentration. This is supported by the absence of any adverse effects on blood ammonia concentration in the studies reported.

References:
1. Cardiovasc Drugs Ther 1993; 7: 81-85
2. Hepatology 1991; 13: 1101-1105

 

 

A multicentre, double-blind, randomized, controlled clinical trial (1) investigated the efficacy and safety of torsemide in the dose ranges 5-20 mg/day and 10-40 mg/day in two parallel groups of 36 and 34 hospitalised patients, respectively, with hepatic cirrhosis complicated by ascites. Patients with hyponatremia, hypokalemia, serum creatinine concentration above 3 mg/dl and patients requiring paracentesis were excluded from the trial. Twelve patients were treated concomitantly with spironolactone. The mean duration of treatment with torsemide was 18 days. Body weight was decreased by averages of 3 kg and 4.3 kg respectively, in 61% of patients on the lower doses of torsemide and 85% of those taking the higher doses of the drug (Figure 1). These changes in body weight were accompanied by a reduction in abdominal girth in 64% of patients taking the low doses of torsemide and in 74% of those on the higher doses of the drug. In parallel with these changes, there was an improvement in edema status in 18 of the 36 patients (50%) taking the low doses of torsemide and an improvement in 19 of the 34 patients (56%) taking the higher doses of the drug (Figure 1).

The second long-term study (2) was a double-blind, randomized, comparative trial of torsemide 20 mg/day and frusemide 50 mg/day, on a background of spironolactone 200 mg/day in 28 nonazotemic cirrhotic patients with controlled ascites studied over a period of 10 weeks. Although no significant differences were observed in the effects of the two diuretics on urine volume or fractional excretion of sodium, torsemide exerted a significantly greater effect than frusemide on free water clearance (44%, p<0.02). Torsemide caused lesser fractional excretion of inorganic phosphate (-18246%, p<0.001), magnesium (-144%, p<0.05), potassium (-73%, NS), calcium (-260%, NS) and uric acid (-94%, NS) as compared to frusemide. Based on this data, torsemide is about 2-3.5 times more effective, on a weight basis, than frusemide on water output, free water clearance and fractional excretion of sodium and chloride. Hence, torsemide can represent an alternative tool for the long-term treatment of ascites in view of its effects on sodium and water excretion and on other urinary parameters.

Despite the evidence that the main effect of loop diuretics is the inhibition of sodium reabsorption at the site where urinary dilution occurs, torsemide, as with frusemide increased the excretion of dilute urine in cirrhotic patients. This may be explained by the inhibition of sodium chloride net transport in the thick ascending limb, which can decrease the interstitium hypertonicity, thus inhibiting the water reabsorption in the collecting duct. Remarkably, frusemide showed a strong scattering effect on fractional excretion of magnesium and inorganic phosphate. The remarkable scattering effect on inorganic phosphate is consistent with a direct action at the level of the proximal tubule. In contrast, the absence of an important action of torsemide at the same site may be indicated by the lack of significant changes in inorganic phosphate fractional excretion in the torsemide group.

Another recent long-term trial (3) compared the efficacy of torsemide (20 mg/day) versus frusemide (40 mg/day) in 46 cirrhotic ascites patients receiving spironolactone (200 mg/day). The initial doses of diuretics were increased every 3 days upto 60, 120 and 400 mg/day, respectively, if the body weight loss was <300 mEq/day.

Torsemide induced a significantly greater diuretic response than frusemide at 24 hours and maximum diuresis during the entire study despite basal urinary volume being higher in frusemide group (Figure 2). Natriuresis was also higher with torsemide than with frusemide and kaliuresis was similar in both groups. Significantly more patients in frusemide group (n=9) required an increase in the loop diuretic dose as compared to torsemide (n=2) (Figure 3).

References:
1. Cardiology1994; 84(2): 80-86
2. Clin Investigator 1993; 71: 579-584
3. Scand J Gastroenterol 2001; 36: 309-313

These short- and long-term studies confirm the ability of torsemide to enhance diuresis, free water clearance and fractional excretion of sodium and chloride in patients with hepatic cirrhosis, resulting in loss of body weight and mobilization of ascites, and confirm the potassium-, magnesium-, and phosphate-sparing properties of the drug. They also reflect the superiority of torsemide over frusemide in patients with cirrhosis and ascites.

 

 

An open multicentre study (1) evaluated the therapeutic efficacy, safety and tolerability of the combination of a high ceiling diuretic torsemide (10-40 mg) and spironolactone (50-400 mg) in 117 cirrhotic patients with ascites for 6 months. At the end of 6 weeks, the mean dose of torsemide was 16 mg/day. Bodyweight decreased by a mean of 1.8 kg at 6 weeks, further decreased by a mean of 3.8 kg at week 14 and thereby remained relatively constant (Figure 1). Parallel to the decrease of body weight, reductions of ascites (Figure 2), edema, abdominal girth and ankle circumference were observed. In 92 patients at baseline, 42 had mild, 22 moderate and 8 severe edema; 20 patients were free from edema at baseline. Of the 68 patients who completed 6 months of treatment with spironolactone and torsemide, 38 were free from edema, 21 still had mild and 9 moderate residual edema. The decrease in serum potassium concentration from 4.44 to 4.23 mmol/l at the end of the study was not significant. Hence, torsemide in combination with spironolactone is safe and effective in the treatment of ascites and edema in patients with advanced hepatic cirrhosis.

 

 

 

Patients with cirrhosis and ascites may develop resistance to the diuretic and natriuretic effects of aldosterone antagonists and loop diuretics, the so-called 'refractory' or 'diuretic resistant' ascites. Several factors may account for this phenomenon the most important being alteration of intrarenal sodium handling, with increased sodium reabsorption in the proximal tubule, often in the setting of reduced glomerular filtration rate. Alterations in frusemide pharmacokinetics have also been suggested to contribute to diuretic resistance. Torsemide has been found to be useful in diuretic-resistant ascites as it differs from frusemide, both pharmacologically and pharmacodynamically.

In 18 patients with cirrhosis and diuretic resistant ascites in a study (1), torsemide 40 mg induced a significant, 2.5 fold greater increase in urinary sodium volume than frusemide 80 mg in the first hour after intravenous drug administration. Pharmacokinetics of frusemide and torsemide are altered in such patients. Both showed reduced elimination rate through renal and non-renal routes, and a larger distribution of body fluids. Torsemide remained in the body for a longer time than frusemide, mainly due to its lower clearance and longer terminal half-life. Pharmacokinetic alterations, however, were more marked for frusemide, since the urinary excretion pattern of pharmacologically active species was quantitatively unchanged after torsemide, whereas it was reduced after frusemide. The apparent half-life of torsemide (9.6 hours) was about two-fold longer than that of frusemide (4.87 hours, p<0.05). Torsemide induced a significant 2.5-fold greater increase in urinary excretion of sodium than frusemide in the first hour after drug administration, whereas the kaliuretic response was similar.

A randomized, double-blind study (2) investigated the effect of single oral doses of frusemide 80 mg and torsemide 20 mg in 14 cirrhotic patients. All the patients in torsemide group responded to it, whereas in the frusemide group, five patients exhibited a weak response to frusemide (0-36 mmol/24 h, median 24; 690-1460 ml urinary volume, median 325). These patients showed significantly higher natriuresis and diuresis following torsemide median 24 h sodium excretion 24 vs. 78 mmol (p<0.05), median 24 h urinary volume 1325 vs. 2200 ml (p<0.05)]. In these patients, bodyweight was reduced by 0.2 ± 0.77 kg in torsemide but increased 24 h after frusemide by 0.12 ± 0.67 kg.

The findings that the 5 patients with the weakest response to frusemide showed a marked and significantly better natriuresis after torsemide is of particular interest. This is probably not due to crossover effects, since torsemide was given as the first drug in 3 patients and frusemide in 2 of these patients. It has been shown that the renal effect of frusemide is related to a stimulation of renal prostaglandin production. In the poor responders of frusemide in the study, prostaglandin production was possibly increased more by torsemide than by frusemide. The study concluded that the present data suggested advantages of torsemide over frusemide particularly in patients with cirrhosis and ascites who respond poorly to frusemide. Torsemide might be more advantageous than frusemide in the treatment of ascites due to cirrhosis.

References:
1. J of Hepatology 1996; 25: 481-490
2. J of Hepatology 1993; 17: 353-358

 

 

Torsemide has been shown to be generally well tolerated in patients of cirrhotic ascites. The safety of torsemide (10-40 mg) in combination with spironolactone (50-400 mg) was evaluated in a 6-month trial (1) in 117 cirrhotic ascites patients. There were no untoward adverse reactions with torsemide and no significant changes in serum electrolytes, liver, renal or hematological variables. Adverse events documented during the study were consistent with the underlying disease, e.g. oesophageal bleeding, gastrointestinal bleeding, hepatic coma and none were judged to be causally related to the drug treatment. The decrease in serum potassium concentration from 4.44 to 4.23 mmol/l at the end of the study was not significant.

In a long-term study (70 days) (2) in 28 cirrhotics, two patients on torsemide (20 mg/day) developed an episode of hepatic encephalopathy (grade I according to Kurtz's classification) that promptly resolved after a short period of diuretic withdrawal (3 and 4 days, respectively). The treatment was started again at the same dose, without further complications until the end of the study. Also, cramps were recorded in one patient in the torsemide group and two in the frusemide group. The fractional excretion of potassium, calcium, phosphate, magnesium and uric acid, however, was significantly lower in the torsemide-treated group compared with the frusemide treated patients.

In another study (3) comparing torsemide (n=22) with frusemide (n=24), seven patients in torsemide group (31%) as compared to 12 patients in frusemide group (50%) developed more than one complication during diuretic treatment. The incidence of renal failure was similar in both groups (four patients in torsemide group and five patients in frusemide group), irrespective of the presence of peripheral edema. Hyponatremia occurred in two patients in torsemide group (9%) and in six patients in frusemide group (25%).

References:
1. Cardiology 1994; 84: 87-98
2. Clin Invest 1993; 71: 579-584
3. Scand J Gastroenterol 2001; 36: 309-313

 

• The efficacy of frusemide is compromised in cirrhotics due to reduced bioavailability of the drug at the site of action. On the other hand, torsemide has a longer duration of action in cirrhotics as compared to frusemide, which may help to reduce the electrolyte disturbances and risk of coma. Also, it has a high and predictable bioavailability.

• Torsemide causes significantly greater diuresis, natriuresis, lesser kaliuresis, greater reduction in bodyweight and improvement in edema and ascites as compared to frusemide.

• It has been shown to be effective even in poor responders to frusemide.

• Torsemide is an effective, safe and well-tolerated option as compared to frusemide in cirrhotic ascites and also in diuretic-resistant ascites.