Notwithstanding, frusemide has adverse effects that limit its usefulness. The degree of kaliuresis that the drug induces can lead to potentially fatal consequences, especially in metabolically deranged states such as congestive heart failure and renal failure. Also, frusemide is a quick and short acting drug (owing to its short half-life 1 hour) and hence is more useful for intravenous administration in emergencies. However, this feature limits its usefulness in chronic therapy. Also, its bioavailability is erratic and this adds to unpredictability of response.

Added to this is the fact that frusemide is exclusively excreted by the kidneys. Hence any compromise in renal function impairs clearance of the drug. This leads to accumulation of metabolites in patients with severe renal impairment, which could lead to toxicity. Special caution must therefore be taken in patients with severe renal insufficiency.

Torsemide, a new pyridine-sulfonylurea loop diuretic, is the result of an endeavor to overcome the drawbacks of frusemide.

More potent diuresis and natriuresis
Torsemide produces intense diuresis and natriuresis comparable to that of frusemide. However, torsemide is more potent than frusemide on a weight per weight basis. 10-20 mg of torsemide produces effects equivalent to that of 40 mg of frusemide.

Torsemide also inhibits chloride conductance that occurs from the peritubular side of the nephron. The concentration of torsemide required to exert this activity is 100 times higher than the required luminal concentration.

Additional anti-aldosterone effects
Torsemide, and not frusemide, has been shown to inhibit aldosterone binding to its receptor in the rat kidney. Aldosterone activity has been shown to promote myocardial fibrosis, potassium and magnesium depletion, sympathetic activation, parasympathetic inhibition and baroreceptor dysfunction.

Lesser hypokalemia
Torsemide has been reported to have a weaker kaliuretic effect than other loop diuretics. Unlike other loop diuretics, torsemide has no activity at the proximal tubule because of its lack of effect on either phosphate or bicarbonate reabsorption, which occurs primarily at this site. Potassium reabsorption also occurs at the proximal tubule; therefore, less potassium excretion occurs with torsemide. It has also been attributed to the anti-aldosterone effects of torsemide.

Reduced kaliuresis is an important feature that distinguishes torsemide from frusemide; this feature results in better electrolyte balance and a lesser risk of hypokalemia.

Other effects on urinary excretion
The calciuric effect of torsemide 200-400 mg was compared with that of frusemide 500-1000 mg in 10 patients with advanced chronic renal failure (CRF) after 28 days of therapy. Frusemide induced a significant increase in calcium excretion and a corresponding decrease in serum calcium concentrations. Torsemide did not significantly change calcium excretion or serum calcium levels. Hence, unlike other diuretics which are calcium wasting, torsemide has calcium sparing effect.

Torsemide does not cause changes in lipid profile, glucose metabolism and serum uric acid and creatinine. Hence, unlike frusemide and other thiazide diuretics, torsemide can be used for chronic ailments like hypertension without the risk of changes in biochemical parameters.

References:
1. Clin Pharmacol Ther 1987; 42: 187-92
2. Drugs 1991; 41: 81-103
3. Am J Health-Syst Pharm 1995; 52: 1771-80

Safe in patients with renal failure
The drug is metabolized to a large extent in the liver (80%). Renal clearance of the parent drug accounts for approximately 20% of the total clearance. The plasma half-life is about 3-6 hours and has not been shown to increase with repeated doses. In elderly patients and patients with renal failure, the elimination half-life remains unchanged. In contrast, since frusemide has no alternative metabolic pathways, it has a prolonged half-life in patients with renal impairment, leading to accumulation of the parent drug, resulting in toxicity.

References
1. Clin Pharmacol Ther 1987; 42: 187-92

The RALES study has demonstrated that the aldosterone antagonist spironolactone, originally thought to act only as a potassium sparing diuretic, can significantly improve survival, reduce hospitalization rates and improve symptoms in CHF patients, by its interference with the neurohumoral system. The reported anti-aldosterone effect of torsemide may account for its ability to reduce mortality rate in CHF patients. The RALES and the TORIC study throw up the exciting possibility that torsemide, by its specific pharmacological profile, might provide additional benefits in CHF, which are beyond its pure diuretic effect.

References
1. Eur J Heart Failure 2002; 4: 507-13
2. Pharmacoeconomics 2001; 19: 679-703
3. Pharmacoeconomics 2000; 17: 429-40

Trials in chronic renal failure confirm that torsemide (100-200 mg) is a high ceiling diuretic and has effects on urine volume and electrolyte excretion similar to those of frusemide. Long-term use of torsemide has been found to be safe and effective. Torsemide, however, has a longer lasting diuretic effect and is free from the rebound decrease in electrolyte excretion found approximately 12 hours after a dose of frusemide. Torsemide has also been found to be effective in patients undergoing haemodialysis.

In patients with nephrotic syndrome, torsemide has been shown to be effective as monotherapy in oral dosages of up to 200 mg/day and in combination with spironolactone. Studies have also shown greater diuretic and natriuretic effect with torsemide as compared to frusemide.

References
1. J Cardiovasc Pharmacol 1993; 22 (suppl 3): S59-S70

Torsemide is metabolized mainly in the liver: severe hepatic dysfunction would therefore allow more of the active parent compound to reach its urinary site of action. Patients with cirrhosis exhibit an increase in renal clearance resulting in little increase in its half-life. The increased renal clearance offsets a decrease in pharmacodynamic responsiveness, so that the magnitude of natriuretic effect of torsemide in cirrhotic patients is similar to the effect observed in non-cirrhotic patients. Also, importantly, the anti-aldosterone and K+-sparing effects of torsemide are invaluable in the treatment of cirrhosis with ascites.

References
1. Life Sciences 1998; 63: 45-50
2. Cardiovasc Drug Ther 1993; 7: 81-5
3. Clin Investig 1993; 71: 579-84

Thiazides are recommended as first-line drugs for hypertension. Loop diuretics such as frusemide have proven to be less effective in controlling blood pressure than thiazides; an observation that has been attributed to their relatively short duration of action. In contrast, torsemide has been found to be as effective as thiazides (hydrochlorothiazide and a combination of hydrochlorothiazide and a potassium sparing diuretic) in small doses for the therapy of hypertension without changes in serum electrolytes or metabolic indicators.

The dosages of torsemide used in the treatment of hypertension, typically 2.5 or 5 mg/day, are described as non-diuretic. A significant natriuresis is seen 6 hours after the first administration, but rebound sodium retention occurs to such an extent that 24-hour sodium excretion is unchanged from pre-treatment values. dose torsemide treatment appear to be unrelated to net loss of extracellular volume. The mechanism of antihypertensive action may be due to its anti-aldosterone effect that may block some portion of the compensatory rebound, which is presumably mediated through the renin-angiotensin system. Additionally, torsemide has been found to block thromboxane A2-induced contraction of isolated canine coronary arteries.

References
1. Drugs 1991; 41 (suppl 3): 81-103
2. J Hum Hypertens 2002; 16 (Suppl 1): S78-S83
3. J Pharm Pharmacol 1992; 44: 64-5

1. Torsemide is more potent than frusemide on a weight per weight basis. 10-20 mg of torsemide produces effects equivalent to that of 40 mg of frusemide.
   
   
2. Torsemide has a fast onset of action and produces intense diuresis, which is comparable to that of frusemide. However, unlike frusemide, which is short acting, torsemide has a more sustained diuretic action.
   
   
3. Torsemide has a more predictable absorption profile and better bioavailability than frusemide. Frusemide has an erratic and highly variable bioavailability, which leads to unpredictability of response. This may affect the overall outcomes with frusemide.
   
   
4. Torsemide is potassium sparing in nature: this is attributable to its aldosterone-inhibiting property. Torsemide also prevents calcium loss.
   
   
5. Studies have shown that in congestive heart failure, torsemide-treated patients were less likely to be readmitted for heart failure and for all cardiovascular causes. Torsemide is also associated with decreased mortality rates. It also results in reduced overall costs.
   
   
6. Torsemide is excreted mainly via the hepatic route; hence high doses up to 100-200 mg in advanced chronic renal failure may be used. Frusemide, on the other hand, accumulates in renal failure and causes toxicity.
   
   
7. Torsemide has been used in combination with spironolactone in cirrhosis of liver with ascites. This decreases potassium loss and further imbalance of electrolytes. Frusemide on the other hand causes potassium loss and adds to imbalance of electrolytes.
   
   
8. Torsemide is the first loop diuretic indicated for the treatment of hypertension. Doses required are sub-diuretic doses (2.5 to 5 mg) and do not have any biochemical or electrolyte adverse effects. Torsemide may be used alone or in combination with other drugs for hypertension.