The diuretic effects of torsemide begin within 10 minutes of IV dosing and peak within the first hour. Hence, torsemide IV has a rapid onset of action, which is comparable to frusemide IV. In a comparative study (1) on the fluid and electrolyte excretion of 45 patients with chronic renal failure, single doses of torsemide (200 mg) or frusemide (200 mg) were administered intravenously. The urine was collected in 2 consecutive fractions of 6 hours, followed by one of 12 hours. The fractional excretion of volume and sodium within the first 6 hours were comparable for both the therapies. However, a higher excretion in the second 6-hour period or the subsequent 12 hr period was observed for torsemide IV as compared to frusemide IV. This demonstrates the longer duration of salidiuretic activity of torsemide. This difference reached significance in the third collection period between the two treatment groups (Figure 1).

In another study (2), the pharmacodynamic effects of torsemide IV 20 mg were compared with frusemide IV 40 mg in 6 healthy volunteers. The results showed that for the excretion of water, sodium, chloride and calcium, torsemide was significantly more active and for a longer time than frusemide, whereas, frusemide caused significantly greater kaliuresis than torsemide. Indeed, the effects of frusemide during the second fraction (1 to 2 hour fraction after administration) represent only 25% of those of fraction 0 to 1 hour compared to 50% for torsemide. Also, from this study, it appears that torsemide IV is twice as potent compared to frusemide by the intravenous route (Table 1).

There is a wide variability in bioavailability of oral frusemide. The oral dose of frusemide is twice that of IV doses because of incomplete absorption. On the other hand, because of the high bioavailability of torsemide, oral and IV doses are therapeutically equivalent, so patients may be switched to and from the IV form with no change in dose. Torsemide IV injection can be administered either slowly as a bolus over a period of 2 minutes or administered as a continuous infusion.

Diuretic therapy is a critical component in the management of acute cardiogenic pulmonary edema. In pulmonary edema, IV loop diuretics cause transient venodilation resulting in a fall in cardiac filling pressures and decrease pulmonary congestion prior to the onset of diuresis. Loop diuretics also increase the production of vasodilator prostaglandins (1). Hence, an effective and safe loop diuretic is an important option in this setting.

Stringer et al (2) evaluated the effectiveness and safety of intravenously administered torsemide as an adjunctive therapy in 19 patients with acute cardiogenic pulmonary edema. Frusemide IV was used as a positive control. Patients were randomized to receive 20 mg or 40 mg of torsemide or 40 mg or 80 mg of frusemide and the dose was titrated as necessary over the next 24 hours. In torsemide IV-treated patients, there was a significant increase in fractional sodium excretion (FeNa) from 2.88% at baseline to 6.76% at peak (p = 0.0342). Median baseline to peak urine volume was significantly increased in patients on torsemide IV, 134 ml to 375 ml (p = 0.0034).

At 24 hours, the number of torsemide-treated patients with pulmonary rales had decreased significantly (p<0.05). In addition, in the torsemide group but not in the frusemide group, the proportion of patients whose orthopnea improved was significantly greater than the proportion that worsened (p < 0.01). None of the patients experienced serious adverse events or required withdrawal from the study. These results suggest that IV torsemide is an effective and well-tolerated diuretic in patients with acute cardiogenic pulmonary edema.

References:
1. J Clin Pharmacol 1994; 34: 1083-1087 2. CHF 2002; 8 (6): 307-312

Intravenous loop diuretics have an important role in severe congestive heart failure with peripheral edema. They induce aggressive diuresis and natriuresis to relieve edema. Severe volume overload in CHF should be treated with IV diuretics to immediately reduce preload and symptoms of fluid congestion.

In a double-blind dose-response study (1), 49 patients with NYHA class III or IV heart failure were randomized to receive a single IV dose of 5, 10, or 20 mg torsemide or 40 mg frusemide. Torsemide produced dose-related increases in fractional and total sodium and chloride excretion and in urine volume but had no clear dose-related effect on fractional or total potassium excretion. The changes from baseline in 24-hour fractional and total sodium, chloride and potassium excretions were statistically significant in both the 20 mg torsemide and the 40 mg frusemide groups, whereas the changes in 24-hour urine volume were statistically significant in the groups receiving 10, 20 mg torsemide and 40 mg frusemide. The increase in total electrolyte excretion and urine volume were greater with 20 mg torsemide as compared to 40 mg frusemide (Figure 1).

Importantly, torsemide IV 20 mg and frusemide IV 40 mg caused significant decreases in mean body weight, whereby the decrease in body weight was greater with torsemide IV than frusemide IV (0.94kg vs. 0.74 kg, respectively) Both were equally well tolerated. In conclusion, this study demonstrated that intravenous torsemide is effective and well tolerated in the treatment of sodium and fluid retention resulting from moderate to severe congestive heart failure.

Reference:
1. Am Heart J 1994; 128: 352-357

a) Chronic renal failure

In a single-dose multicentre study (1), torsemide IV 200 mg was compared with the same doses of frusemide IV in 90 patients (creatinine clearance <30 ml/24 hours). Urine volume, renal sodium, calcium and chloride excretion increased with both drugs. Potassium excretion was altered less by torsemide. A dose increase enhanced the diuretic effect of both drugs. However, the increase in fractional excretion was greater with torsemide than with frusemide when the dose was doubled, indicating a steeper dose-response relationship for torsemide compared with frusemide in this dose range.

Boesken et al (2) investigated the effects of torsemide IV 200 mg, both acute and after repeated dosing in comparison to baseline values on placebo, in an open uncontrolled multicentre study. Forty-four patients with advanced chronic renal failure (mean creatinine clearance 8.9+-9.6 ml/min, range 1.1-63.7 ml/min) were treated with a single placebo infusion (20 ml over 60 min) at day 1 followed by torsemide infusions once daily (200 mg in 20 ml over 60 min) for a further seven days. The increase versus placebo in the primary efficacy variable of 24 hr fractional volume excretion was statistically significant both acutely (from a mean 14.32% to 21.07%, p=0.0001) as well as after repeated dosing (from 14.32% to 18.10%, p = 0.0012). Similarly, the 24-hr fractional sodium excretion was increased significantly both acutely (from a mean 7.54% to 12.58%) and also after repeated dosing (from 7.54% to 10.05%, p<0.05).

A marked decrease in body weight was observed even after the first administration of torsemide (mean change: -1.1 kg). The total mean loss in body weight amounted to 2.6 kg after the last torsemide injection. Further, the percentage of patients who were free from edema rose from 58.1% at baseline to 83.3% at one week. The change in fractional potassium excretion was considerably smaller than that of sodium and chloride excretion after acute dosing of torsemide. After repeated dosing, however, this effect seemed to vanish. There was only a minor change in calcium excretion and on alteration in phosphate excretion, neither acutely nor with repeated dosing.

These results were similar to data from another study conducted by Russo et al who administered torsemide IV (mean initial daily dose 0.9 mg torsemide/kg body weight) for 7 days to 9 hospitalized patients with chronic renal failure (creatinine clearance 14+-3.7 ml/min) for the treatment of arterial hypertension and peripheral edema. The authors observed a distinct increase in diuresis on the first day of treatment (2500 ml vs. 1500 ml at baseline), which continued to remain increased after the seventh day of treatment (1800 ml). The above findings are also confirmed by results from studies with repeated oral dosing of 100/200 mg torsemide or 200/400 mg torsemide daily in patients with advanced chronic renal failure.

b) Dialysis patients

A subgroup of patients (n=18), in the study by Russo et al were on dialysis with a mean creatinine clearance of 5.1+-3.0 ml/min at baseline (residual dialysis of >300 ml). Torsemide was found to be efficacious even in patients on hemodialysis; after the first IV dose of 200 mg torsemide, the mean fractional volume excretion was increased from 16.22% at baseline by 3.42% to 18.99% (in absolute 24 hr urinary volume from 1044 ml at baseline by 563 ml to 1607 ml). In parallel, the mean fractional sodium excretion was increased from 8.67 % at baseline by 2.99% to 11.14% (in absolute 24 hr urinary sodium excretion from 83.8 mmol at baseline by 51.2 mmol to 128.0 mmol).

c) Acute renal failure

In clinical practice, high doses of loop diuretics are required to increase urine flow rate and thereby perhaps ameliorate the progress of acute renal failure (ARF) in patients with acute oliguria. Although controversial, some studies have suggested that this may be associated with reduced morbidity and mortality in ARF patients.

Theoretically, administration of loop diuretics should also reduce the energy requirements of the cells of the thick limb of the loop of Henle. These drugs act by inhibiting the Na+/2Cl-/K+ pump in the luminal cell membrane resulting in a fall in transcellular sodium transport. Basal Na+/K+ ATPase activity becomes unnecessary and the requirement of the cell for oxygen falls. A study (3) has shown that reducing active transport with loop diuretics significantly reduces the damage to the thick ascending limb of Henle's loop in the isolated perfused kidney. It is therefore possible that loop diuretics might 'protect' the cells of the thick ascending limb during the hypoxia which accompanies hypotension and sepsis, frequent predisposing factors in ARF, by reducing the need for energy consumption.

A prospective, randomized, placebo-controlled, double-blind study (4) evaluated the effect of loop diuretics in 92 patients with ARF. All patients received intravenous dopamine, 2 µg/kg body weight/min throughout 20% mannitol, 100 ml every 6 hr for the first 3 days, and in a double-blind manner, either torsemide, frusemide or placebo, 3 mg/kg body weight IV every 6 hr for 21 days or until renal recovery or death. The proportion of patients who showed significant increase in urine volume in the first 24 hours were 57% in torsemide group, 48% in frusemide group and 23% in placebo group

Further, torsemide IV 250 mg (4 to 13 days) has caused significant diuresis (increase in urine output to 1780 ml/day) in various case studies (n = 5) (5).

References:
1. Drugs 1991; 41 (Suppl 3): 69-79
2. Clinical Nephrology 1997; 48: 22-28
3. Kidney Int 1984; 25: 65-72
4. Nephrol Dial Transplant 1997; 12: 2592-2596
5. Drugs 1995; 49: 121-142

Loop diuretics, especially frusemide, and aldosterone antagonists are the most commonly used drugs in the treatment of ascites in cirrhosis. However, there is development of diuretic resistance in these patients possibly due to alterations in the pharmacokinetics of frusemide.

Intravenous torsemide and frusemide were evaluated pharmacologically (1) in 18 patients with cirrhosis and diuretic-resistant ascites who were administered an IV bolus of torsemide (40 mg) or frusemide (80 mg). Torsemide induced a greater increase, about 2.5 fold higher urinary excretion of sodium (p < 0.01) and about 1.5 fold higher urine flow rate (p < 0.01) at 1 hour than frusemide (Figure 1). No significant difference in serum potassium was observed between torsemide and frusemide. Hence, torsemide is effective in increasing sodium excretion in patients with cirrhosis and ascites.

Reference:
1. Journal of Hepatology 1996; 25: 481-490

• In heart failure as well as cirrhosis/ascites, the ratio of equipotency of IV formulations of torsemide and frusemide is 1:2.
• In renal failure, the ratio of equipotency of IV torsemide and frusemide is 1:1.

Drugs 1991; 41(Suppl 3): 69-79

Diuretic resistance is a frequently faced clinical problem. There have been different approaches to alleviating this problem, such as switching loop diuretics, administering diuretics acting at other sites (e.g. thiazides), in combination with the loop diuretics (sequential nephron blockade) or using IV or continuous infusion of loop diuretics. Potential advantages of continuous infusion over oral or intermittent bolus are production of a more consistent urine flow, fewer alterations in fluid balance, and less severe urinary losses of sodium and chloride while using a lower dosage of loop diuretics.

Due to their short duration of action, intermittent doses of loop diuretics can produce rebound sodium retention amid dosing intervals. Similar to sequential blocking, continuous infusion of loop diuretic (CILT) may curtail rebound sodium reabsorption. A study has concluded that preceding a bolus dose, continuous infusion of frusemide produced constant and significant diuresis and natriuresis, as compared to intermittent administration.

References:
1. CHF 2002; 8(2): 80-85 2. Annals of Pharmacotherapy 1995; 29: 1010-1014

• Patients with drug overdose and poisoning

• Hypertensive crisis (DBP > 120 mm Hg)

• Hypercalcemia (given along with isotonic saline)

• Life-threatening hyponatremia, hypoalbuminemia,

  hypochloremia (given along with hypertonic saline)

References:
1. In: The Pharmacological Basis of Therapeutics. Ed. Goodman & Gilman, 10th ed: 757-789
2. In: Pharmacology and Pharmacotherapeutics. Ed. RS Satoskar, 6th ed: 520-544
3. In: The Science and Practice of Pharmacy. Ed. Remington, 20th ed: 1344-1353

The tolerance of torsemide in 8 healthy volunteers was studied after administration of ascending IV doses, ranging from 2.5 to 80 mg on alternate days, with a washout period of 48 hours between successive doses (1). Torsemide was well tolerated at all doses investigated after IV administration. Side effects reported were mild. No adverse effects were reported after any of the IV doses. The incremental increases in potassium excretion with increasing doses of torsemide were significantly less marked.

In a dose-response study (2) in 49 patients with NYHA class III or IV heart failure, a single IV dose of 5, 10 or 20 mg of torsemide or 40 mg of frusemide were given. Both torsemide and frusemide were equally well tolerated. Minor adverse events, most of which probably were related to the patient's disease rather than to diuretic treatment, included dizziness, mild arrhythmias, dyspnoea, abdominal pain and pleural effusion. None of the patients had serum potassium concentration < 3.5 mEq/L after treatment. Minor, transient changes in other clinical laboratory values were observed in this single-dose study.

The side effects commonly reported with torsemide include dizziness, headache, nausea, weakness, vomiting, hyperglycemia, excessive urination, hyperuricemia, hypokalemia, excessive thirst, hypovolemia and dyspepsia (3).

There have been no reported cases of ototoxicity with torsemide IV. However, tinnitus and hearing loss (usually reversible) have been observed after rapid IV injection of other loop diuretics. Hence, when administered intravenously, torsemide should be injected slowly over 2 minutes, and single doses should not exceed 200 mg (3).

References :
1. Eur J Clin Pharmacol 1986; 31: 9-14
2. Am Heart J 1994; 128: 352-357
3. Physicians' Desk Reference 2004

Torsemide IV injection should be administered either slowly as a bolus over a period of 2 minutes or administered as a continuous infusion. Because of the high bioavailability of torsemide, oral and IV doses are therapeutically equivalent, so patients may be switched to and from the IV form with no change in dose.

Congestive Heart Failure

The usual initial dose is 10 mg or 20 mg of once daily IV torsemide. If the diuretic response is inadequate, the dose should be titrated upward by approximately doubling until the desired diuretic response is obtained. Single doses higher than 200 mg have not been adequately studied.

Chronic Renal Failure

The usual initial dose of torsemide is 20 mg of once daily IV torsemide. If the diuretic response is inadequate, the dose should be titrated upward by approximately doubling until the desired diuretic response is obtained. Single doses higher than 200 mg have not been adequately studied.

Hepatic Cirrhosis

The usual initial dose is 5 mg or 10 mg of once daily IV torsemide, administered together with an aldosterone antagonist or a potassium-sparing diuretic. If the diuretic response is inadequate, the dose should be titrated upward by approximately doubling until the desired diuretic response is obtained. Single doses higher than 40 mg have not been adequately studied.

Reference:
1. Physicians' Desk Reference 2004

Torsemide IV has a rapid onset of effect observed within 10 minutes and the peak effect is seen within 1 hour. It has a longer duration of action as compared to frusemide. Also, patients can be shifted from intravenous to oral of torsemide on the same dose, unlike frusemide.

In pulmonary edema, intravenous torsemide causes significant diuresis and natriuresis and improves symptoms.

Torsemide IV results in a greater 24-hour diuresis and natriuresis as compared to frusemide in CHF. It also decreases mean body weight significantly.

In chronic renal failure, torsemide IV causes a greater increase in fractional sodium excretion than frusemide along with a marked decrease in body weight (even after a single dose). Similar benefits were also obtained in advanced chronic renal failure patients on hemodialysis.

In acute renal failure, torsemide IV has been shown to convert oliguric to non-oliguric patients.

In cirrhosis, greater diuresis and natriuresis was observed with torsemide IV than frusemide IV.