Brands, Medical Use, Clinical Data
- Antihypertensive Agents
Brands / Synonyms
Demadex; Luprac; Torasemida [INN-Spanish]; Torasemide; Torasemidum [INN-Latin]; Torsemide; Torsemide [USAN]
For the treatment of edema associated with congestive heart failure, renal disease, or hepatic disease. Also for the treatment of hypertension alone or in combination with other antihypertensive agents.
Torsemide is a novel loop diuretic belonging to pridine sulphonyl urea. It differs form other thiazide diuretics in that a double ring system is incorporated into its structure. Like thiazides, loop diuretics must be secreted into the tubular fluid by proximal tubule cells. In the thick ascending loop Na+ and Cl- reabsorption is accomplished by a Na+/K+/2Cl- symporter. The thick ascending limb has a high reabsorptive capacity and is responsible for reabsorbing 25% of the filtered load of Na+. The loop diuretics act by blocking this symporter. Because of the large absorptive capacity and the amount of Na+ delivered to the ascending limb, loop diuretics have a profound diuretic action. In addition, more distal nephron segments do not have the reabsorptive capacity to compensate for this increased load. The osmotic gradient for water reabsorption is also reduced resulting in an increase in the amount of water excreted.
Mechanism of Action
Torsemide inhibits the Na+/K+/2Cl--carrier system (via interference of the chloride binding site) in the lumen of the thick ascending portion of the loop of Henle, resulting in a decrease in reabsorption of sodium and chloride. This results in an increase in the rate of delivery of tubular fluid and electrolytes to the distal sites of hydrogen and potassium ion secretion, while plasma volume contraction increases aldosterone production. The increased delivery and high aldosterone levels promote sodium reabsorption at the distal tubules, and By increasing the delivery of sodium to the distal renal tubule, torsemide indirectly increases potassium excretion via the sodium-potassium exchange mechanism. Torsemide's effects in other segments of the nephron have not been demonstrated. Thus torsemide increases the urinary excretion of sodium, chloride, and water, but it does not significantly alter glomerular filtration rate, renal plasma flow, or acid-base balance. Torsemide's effects as a antihypertensive are due to its diuretic actions. By reducing extracellular and plasma fluid volume, blood pressure is reduced temporarily, and cardiac output also decreases.
Rapidly absorbed following oral administration. Absolute bioavailability is 80%. Food has no effect on absorption.
Symptoms of overdose include dehydration, hypovolemia, hypotension, hyponatremia, hypokalemia, hypochloremic alkalosis, and hemoconcentration. Oral LD50 in rat is 5 g/kg, and intravenous LD50 in rat is 500 mg/kg.
Biotrnasformation / Drug Metabolism
Metabolized via the hepatic CYP2C8 to 5 metabolites. The major metabolite, M5, is pharmacologically inactive. There are 2 minor metabolites, M1, possessing one-tenth the activity of torsemide, and M3, equal in activity to torsemide. Overall, torsemide appears to account for 80% of the total diuretic activity, while metabolites M1 and M3 account for 9% and 11%, respectively
DEMADEX is contraindicated in patients with known hypersensitivity to DEMADEX or to sulfonylureas.
DEMADEX is contraindicated in patients who are anuric.
In patients with essential hypertension, DEMADEX has been administered together with beta-blockers, ACE
inhibitors, and calcium-channel blockers. In patients with congestive heart failure, DEMADEX has been administered
together with digitalis glycosides, ACE inhibitors, and organic nitrates. None of these combined uses was associated
with new or unexpected adverse events.
Torsemide does not affect the protein binding of glyburide or of warfarin, the anticoagulant effect of
phenprocoumon (a related coumarin derivative), or the pharmacokinetics of digoxin or carvedilol (a
vasodilator/beta-blocker). In healthy subjects, coadministration of DEMADEX was associated with significant reduction
in the renal clearance of spironolactone, with corresponding increases in the AUC. However, clinical experience
indicates that dosage adjustment of either agent is not required.
Because DEMADEX and salicylates compete for secretion by renal tubules, patients receiving high doses of
salicylates may experience salicylate toxicity when DEMADEX is concomitantly administered. Also, although possible
interactions between torsemide and nonsteroidal anti-inflammatory agents (including aspirin) have not been studied,
coadministration of these agents with another loop diuretic (furosemide) has occasionally been associated with renal
The natriuretic effect of DEMADEX (like that of many other diuretics) is partially inhibited by the concomitant
administration of indomethacin. This effect has been demonstrated for DEMADEX under conditions of dietary sodium
restriction (50 mEq/day) but not in the presence of normal sodium intake (150 mEq/day).
The pharmacokinetic profile and diuretic activity of torsemide are not altered by cimetidine or spironolactone.
Coadministration of digoxin is reported to increase the area under the curve for torsemide by 50%, but dose
adjustment of DEMADEX is not necessary.
Concomitant use of torsemide and cholestyramine has not been studied in humans but, in a study in animals,
coadministration of cholestyramine decreased the absorption of orally administered torsemide. If DEMADEX and
cholestyramine are used concomitantly, simultaneous administration is not recommended.
Coadministration of probenecid reduces secretion of DEMADEX into the proximal tubule and thereby decreases the
diuretic activity of DEMADEX.
Other diuretics are known to reduce the renal clearance of lithium, inducing a high risk of lithium toxicity, so
coadministration of lithium and diuretics should be undertaken with great caution, if at all. Coadministration of
lithium and DEMADEX has not been studied.
Other diuretics have been reported to increase the ototoxic potential of aminoglycoside antibiotics and of
ethacrynic acid, especially in the presence of impaired renal function. These potential interactions with DEMADEX
have not been studied.
Carcinogenesis, Mutagenesis and Impairment of Fertility: No overall increase in tumor
incidence was found when torsemide was given to rats and mice throughout their lives at doses up to 9 mg/kg/day
(rats) and 32 mg/kg/day (mice). On a body-weight basis, these doses are 27 to 96 times a human dose of 20 mg; on a
body-surface-area basis, they are 5 to 8 times this dose. In the rat study, the high-dose female group demonstrated
renal tubular injury, interstitial inflammation, and a statistically significant increase in renal adenomas and
carcinomas. The tumor incidence in this group was, however, not much higher than the incidence sometimes seen in
historical controls. Similar signs of chronic non-neoplastic renal injury have been reported in high-dose animal
studies of other diuretics such as furosemide and hydrochlorothiazide.
No mutagenic activity was detected in any of a variety of in vivo and in vitro tests of torsemide and its major
human metabolite. The tests included the Ames test in bacteria (with and without metabolic activation), tests for
chromosome aberrations and sister-chromatid exchanges in human lymphocytes, tests for various nuclear anomalies in
cells found in hamster and murine bone marrow, tests for unscheduled DNA synthesis in mice and rats, and others.
In doses up to 25 mg/kg/day (75 times a human dose of 20 mg on a body-weight basis; 13 times this dose on a
body-surface-area basis), torsemide had no adverse effect on the reproductive performance of male or female rats.
Pregnancy: Pregnancy Category B. There was no fetotoxicity or teratogenicity in rats
treated with up to 5 mg/kg/day of torsemide (on a mg/kg basis, this is 15 times a human dose of 20 mg/day; on a
mg/m2 basis, the animal dose is 10 times the human dose), or in rabbits, treated with 1.6 mg/kg/day (on a
mg/kg basis, 5 times the human dose of 20 mg/kg/day; on a mg/m2 basis, 1.7 times this dose). Fetal and
maternal toxicity (decrease in average body weight, increase in fetal resorption and delayed fetal ossification)
occurred in rabbits and rats given doses 4 (rabbits) and 5 (rats) times larger. Adequate and well-controlled studies
have not been carried out in pregnant women. Because animal reproduction studies are not always predictive of human
response, this drug should be used during pregnancy only if clearly needed.
Labor and Delivery: The effect of DEMADEX on labor and delivery is unknown.
Nursing Mothers: It is not known whether DEMADEX is excreted in human milk. Because many
drugs are excreted in human milk, caution should be exercised when DEMADEX is administered to a nursing woman.
Pediatric Use: Safety and effectiveness in pediatric patients have not been
Administration of another loop diuretic to severely premature infants with edema due to patent ductus arteriosus
and hyaline membrane disease has occasionally been associated with renal calcifications, sometimes barely visible on
X-ray but sometimes in staghorn form, filling the renal pelves. Some of these calculi have been dissolved, and
hypercalciuria has been reported to have decreased, when chlorothiazide has been coadministered along with the loop
diuretic. In other premature neonates with hyaline membrane disease, another loop diuretic has been reported to
increase the risk of persistent patent ductus arteriosus, possibly through a prostaglandin-E-mediated process. The
use of DEMADEX in such patients has not been studied.
Geriatric Use: Of the total number of patients who received DEMADEX in United States
clinical studies, 24% were 65 or older while about 4% were 75 or older. No specific age-related differences in
effectiveness or safety were observed between younger patients and elderly patients.