indication

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.

pharmacology

Torasemide (INN) or torsemide (USAN) 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

Torasemide 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, torasemide indirectly increases potassium excretion via the sodium-potassium exchange mechanism. Torasemide's effects in other segments of the nephron have not been demonstrated. Thus torasemide 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. Torasemide'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.

toxicity

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.

biotransformation

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 torasemide, and M3, equal in activity to torasemide. Overall, torasemide appears to account for 80% of the total diuretic activity, while metabolites M1 and M3 account for 9% and 11%, respectively.

absorption

Rapidly absorbed following oral administration. Absolute bioavailability is 80%. Food has no effect on absorption.

half life

3.5 hours

route of elimination

Torsemide is cleared from the circulation by both hepatic metabolism (approximately 80% of total clearance) and excretion into the urine (approximately 20% of total clearance in patients with normal renal function).

drug interactions

Amifostine: Torasemide may increase the hypotensive effect of Amifostine. At chemotherapeutic doses of Amifostine, Torasemide should be withheld for 24 hours prior to Amifostine administration. Use caution at lower doses of Amifostine.

Amikacin: Increased ototoxicity

Capecitabine: Capecitabine, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Capecitabine is initiated, discontinued or dose changed.

Cholestyramine: Cholestyramine may decrease the bioavailability of Torasemide by inhibiting Torasemide absorption. Monitor for changes in the therapeutic and adverse effects of Torasemide if Cholestyramine is initiated, discontinued or dose changed. Spacing administration by at least 2 hours may reduce the risk of interaction.

Colesevelam: Colesevelam may decrease the bioavailability of Torasemide by inhibiting Torasemide absorption. Monitor for changes in the therapeutic and adverse effects of Torasemide if Colesevelam is initiated, discontinued or dose changed. Spacing administration by at least 2 hours may reduce the risk of interaction.

Colestipol: Colestipol may decrease the bioavailability of Torasemide by inhibiting Torasemide absorption. Monitor for changes in the therapeutic and adverse effects of Torasemide if Colestipol is initiated, discontinued or dose changed. Spacing administration by at least 2 hours may reduce the risk of interaction.

Delavirdine: Delavirdine, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Delavirdine is initiated, discontinued or dose changed.

Floxuridine: Floxuridine, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Floxuridine is initiated, discontinued or dose changed.

Fluconazole: Fluconazole, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Fluconazole is initiated, discontinued or dose changed.

Fluorouracil: Fluorouracil, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Fluorouracil is initiated, discontinued or dose changed.

Flurbiprofen: Flurbiprofen, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Flurbiprofen is initiated, discontinued or dose changed.

Gemfibrozil: Gemfibrozil, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Gemfibrozil is initiated, discontinued or dose changed.

Gentamicin: Increased ototoxicity

Ibuprofen: The NSAID, ibuprofen, may decrease the diuretic and antihypertensive effect of the loop diuretic, torasemide.

Indomethacin: The NSAID, indomethacin, may decrease the diuretic and antihypertensive effects of the loop diuretic, torasemide.

Ketoconazole: Ketoconazole, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Ketoconazole is initiated, discontinued or dose changed.

Mefenamic acid: Mefanamic acid, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Mefanamic acid is initiated, discontinued or dose changed.

Miconazole: Miconazole, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Miconazole is initiated, discontinued or dose changed.

Netilmicin: Increased ototoxicity

Nicardipine: Nicardipine, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Nicardipine is initiated, discontinued or dose changed.

Piroxicam: Piroxicam, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Piroxicam is initiated, discontinued or dose changed.

Rituximab: Additive antihypertensive effects may occur. Increased risk of hypotension. Consider withholding Torasemide for 12 hours prior to administration of Rituximab.

Sitaxentan: Sitaxsentan, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Sitaxsentan is initiated, discontinued or dose changed.

Sulfadiazine: Sulfadiazine, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Sulfadiazine is initiated, discontinued or dose changed.

Sulfisoxazole: Sulfisoxazole, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing Torasemide metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Sulfisoxazole is initiated, discontinued or dose changed.

Tobramycin: Increased ototoxicity

Tolbutamide: Tolbutamide, a strong CYP2C9 inhibitor, may increase the serum concentration of Torasemide, a CYP2C9 substrate, by decreasing its metabolism and clearance. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of Torasemide if Tolbutamide is initiated, discontinued or dose changed.

Trandolapril: The loop diuretic, Torasemide, may increase the hypotensive effect of Trandolapril. Torasemide may also increase the nephrotoxicity of Trandolapril.

Treprostinil: Additive hypotensive effect. Monitor antihypertensive therapy during concomitant use.