Torasemide

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Abstract
The pharmacological properties and therapeutic use of the high-ceiling loop diuretic torasemide (torsemide) were previously reviewed in Drugs in 1991, the following being a re-examination of the role of the drug in the light of data that have subsequently become available (particularly in the management of oedematous disorders). Torasemide produces a more prolonged water and electrolyte excretion than equipotent diuretic doses of furosemide (frusemide), but does not increase kaliuresis to the same extent. Dosages of torasemide of 2.5 to 5 mg/day do not affect plasma renin activity or aldosterone release to a clinically significant extent, although torasemide 20mg increases plasma renin levels, angiotensin II activity and urinary dopamine and prostaglandin E excretion. Studies published since the previous review have confirmed the efficacy of low dosages of torasemide (2.5 to 5 mg/day) in the treatment of hypertension, and have shown it to be effective when administered orally at a dosage of 5 to 20 mg/day in the management of congestive heart failure. Dosages of up to 400 mg/day increased urinary volume excretion and natriuresis in patients with chronic renal failure. Bodyweight and peripheral oedema were reduced by torasemide 10 to 200 mg/day as monotherapy, and 5 to 20 mg/day when coadministered with spironolactone, in patients with nephrotic syndrome. Dosages of 10 to 40 mg/day, either as monotherapy or in conjunction with an aldosterone antagonist, reduced ascites, oedema and bodyweight in patients with hydropically decompensated liver failure. Adverse effects due to torasemide are usually mild and transient in nature. No evidence of ototoxicity has been demonstrated in humans, and torasemide does not appear to affect blood glucose levels, serum uric acid concentrations, or serum potassium levels at dosages below 5 mg/day. Thus, additional evidence has accumulated for the clinical efficacy of torasemide in the management of mild to moderate essential hypertension and oedematous conditions which require diuretic therapy. Further studies are now required to confirm the long term efficacy and tolerability of torasemide, and to investigate the place of the drug in therapy relative to cardiovascular agents other than furosemide and the thiazide diuretics. Torasemide is a high-ceiling loop diuretic which inhibits renal tubular reabsorption of sodium and chloride in the thick ascending limb of the loop of Henle, resulting in a pronounced saluresis and diuresis. Urinary volume excretion and saluresis increase linearly with the logarithm of increasing torasemide dose, with a dose of torasemide between 10 and 20mg being equivalent in diuretic and saluretic potency over 24 hours to furosemide (frusemide) 40mg. Torasemide produces a more prolonged water and electrolyte excretion than furosemide, but does not increase kaliuresis to the same extent. At a dosage of 2.5 mg/day, torasemide does not cause any overall increase in 24-hour natriuresis and is therefore nondiuretic. The effective use of torasemide at this dosage for the treatment of hypertension has been associated with the suggestion that increased natriuresis due to diuretic therapy does not play a part in the reduction of raised blood pressure. In patients with chronic congestive heart failure (CHF) torasemide 10 to 20mg appears to produce greater saluresis and diuresis than furosemide 40mg, but urinary potassium excretion does not follow the dose-related increase seen with sodium and chloride excretion after single doses of torasemide of up to 20mg. Torasemide 200mg, given intravenously, increased fractional urinary volume excretion to a greater extent than either intravenous furosemide 250mg or oral furosemide 500mg in patients with severe chronic renal impairment, and intravenous torasemide 60 to 100mg was superior in terms of fractional urinary volume excretion and fractional sodium excretion to intravenous furosemide 60mg in patients with moderate renal failure. Single-dose oral torasemide 20mg showed equivalent saluretic and diuretic potency to furosemide 40mg in a group of patients with liver cirrhosis and ascites. Torasemide 20mg increased cumulative 24-hour natriuresis and diuresis to a greater extent than furosemide 80mg, and torasemide 50mg exhibited a longer duration of action than furosemide 100mg in further studies of patients with hepatic cirrhosis. Neither glomerular filtration rate nor creatinine clearance is affected by torasemide at dosages of up to 20 mg/day, although plasma renin levels, angiotensin II activity, urinary dopamine excretion and urinary prostaglandin E excretion are similarly increased by torasemide 20mg and furosemide 40mg. Torasemide 2.5 to 5 mg/day has no significant effect, however, on plasma renin activity or aldosterone release. Intravenous torasemide 10 to 20mg is at least as effective as furosemide 20mg in reducing haemodynamic parameters of cardiac workload in patients with CHF, and single intravenous doses of torasemide 5 to 10mg reduced mean diastolic blood pressure by up to 25% in hypertensive patients. Torasemide may increase fasting plasma glucose levels at dosages above 5 mg/day, but no effects on serum triglycerides or serum total cholesterol levels are seen at dosages below 20 mg/day and 10 mg/day, respectively. Torasemide is rapidly absorbed following oral administration, with the peak plasma concentration achieved within the first hour. Plasma protein binding is 97 to 99%, and the volume of distribution (calculated after intravenous administration) is 0.09 to 0.31 L/kg. Metabolism of torasemide involves hepatic biotransformation, with up to 25% of an intravenous dose being excreted unchanged in the urine. Three major metabolites occur in humans, but are not considered to exert clinically significant diuretic effects. The mean plasma elimination half-life of torasemide in healthy volunteers ranges from 2.2 to 5.1 hours. Torasemide exhibits similar pharmacokinetic properties in both young and elderly healthy volunteers, and no significant accumulation of the parent drug or its metabolites has occurred following oral administration of torasemide to patients with chronic renal failure at dosages of up to 200 mg/day for up to 11 days. Linear pharmacokinetics of torasemide have been observed after intravenous and oral administration of 20 to 200mg, and oral doses of 50 to 200mg to patients with renal failure and CHF, respectively. Torasemide 2.5 to 5 mg/day has shown equivalent antihypertensive efficacy to hydrochlorothiazide 25 mg/day, and lacks the adverse metabolic and kaliuretic effects seen with natriuretic dosages of thiazide diuretics. Monotherapy with torasemide at the subdiuretic dosage of 2.5 mg/day normalised diastolic blood pressure in 60 to 76% of patients with mild to moderate essential hypertension, compared with 72 to 82% of patients receiving hydrochlorothiazide 25 to 50 mg/day, respectively, in combination with a potassium-sparing diuretic. Torasemide 2.5 mg/day has not been associated with any impairment of quality of life, based on assessments of daily activity and well-being. Short term studies have shown orally administered torasemide 5 to 20 mg/day to decrease the severity of oedema and mean bodyweight to a greater extent than placebo or furosemide 40mg in patients with chronic CHF. Torasemide 20 mg/day also achieved a greater reduction in pre-existing oedema than furosemide 40 mg/day in patients with chronic CHF. Efficacy appeared to be maintained for 11 months in a longer term dose-ranging study using torasemide 5 to 20 mg/day. Intravenous torasemide 400 to 800mg has shown equivalent diuretic efficacy to furosemide 1000mg in patients with acute renal failure, whereas oral administration of torasemide 200 to 400 mg/day increased urine volume and natriuresis similarly to furosemide 250 to 1000 mg/day in patients with chronic renal failure. Oral torasemide 50 to 200 mg/day appears to be at least as effective as furosemide 125 to 500 mg/day in reducing interdialysis weight gain and increasing diuresis and saluresis in patients with advanced renal impairment. Both torasemide 10 to 200 mg/day as monotherapy, and torasemide 5 to 20 mg/day plus spironolactone 50 to 200 mg/day, significantly reduced bodyweight and peripheral oedema after up to 13 weeks’ treatment in patients with nephrotic syndrome. Monotherapy with torasemide up to 40 mg/day reduced abdominal girth due to ascites in patients with hydropically decompensated liver failure by up to 5.9%; furthermore, torasemide 10 to 20 mg/day coadministered with spironolactone 100 to 200 mg/day effectively reduced oedema, ascites and bodyweight in these patients. Torasemide 10 to 20 mg/day plus potassium canrenoate 200 mg/day decreased ascites and oedema in cirrhotic patients to a greater extent than either monotherapy with potassium canrenoate 400 mg/day for up to 7 days, or furosemide 25 to 50 mg/day plus potassium canrenoate 200 mg/day for 3 to 4 days. Addition of torasemide 10 to 40 mg/day to pre-existing therapy with spironolactone 50 to 400 mg/day improved ascites and oedema in 73% and 67% of patients, respectively, after 6 months’ treatment. The adverse effects attributable to torasemide are usually mild and transient in nature and include fatigue, dizziness, headache, muscle cramps, lower back pain, skin rash, nausea and orthostatic hypotension. Although other adverse reactions, including pruritus, paraesthesia and chest pain have been noted after 48 weeks’ therapy with torasemide 2.5 to 5 mg/day, these are rare, and withdrawal from treatment due to torasemide-related drug reactions is seldom necessary. Analysis of pooled clinical trial data has shown the rate of occurrence of adverse events to be significantly less with torasemide than with combinations of hydrochlorothiazide and potassium-sparing diuretics in patients with hypertension. No evidence of ototoxicity has been detected in humans after 4 weeks’ oral administration of torasemide at dosages of up to 400 mg/day. Torasemide does not appear to affect blood glucose levels, serum uric acid concentrations, or serum potassium levels at dosages below 5 mg/day. Probenecid has been shown to reduce the diuretic and natriuretic effects, and to increase the plasma elimination half-life, of torasemide. Nonsteroidal anti-inflammatory drugs are also known to decrease the diuretic and natriuretic response to loop diuretics; indomethacin pretreatment appears to reduce diuresis and natriuresis due to torasemide under conditions of sodium restriction. No pharmacokinetic interactions have been reported following coadministration of torasemide with digoxin, spironolactone, carvedilol or cimetidine. Torasemide does not appear to interfere with serum protein binding of either warfarin or phenprocoumon. An oral dosage of torasemide 2.5 mg/day, increasing to 5 mg/day if necessary after 12 weeks is recommended for the management of mild to moderate essential hypertension. Oral dosages of torasemide 5 mg/day, increasing to 20 mg/day (the maximum recommended dosage being 40 mg/day), are recommended for patients with chronic CHF, and torasemide 5 to 40 mg/day may also be used in conjunction with an aldosterone antagonist such as spironolactone for the management of ascites secondary to hepatic cirrhosis. Oedema associated with nephrotic syndrome may be treated with torasemide 100mg coadministered with an aldosterone antagonist. Intravenous administration of torasemide 20 to 200 mg/day is recommended in advanced chronic renal failure, and no dosage adjustment appears necessary in patients undergoing haemofiltration or haemodialysis. High-dosage intravenous torasemide (up to 800 mg/day) appears to be effective in converting oliguric acute renal failure to the polyuric form.
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