TORSEMIDE- torsemide injection, solution
American Regent, Inc.
For IV InjectionRx Only
Torsemide Injection is a diuretic of the pyridine-sulfonylurea class. Its chemical name is 1-isopropyl-3-[(4-m-toluidino-3-pyridyl)sulfonyl] urea and its structural formula is:
Its molecular formula is C16 H20 N4 O3 S, its pKa is 6.42, and its molecular weight is 348.42.
Torsemide is a white to off-white crystalline powder. Torsemide vials for intravenous injection contain a sterile solution of torsemide (10 mg/mL), polyethylene glycol-400, tromethamine, and sodium hydroxide (as needed to adjust pH) in water for injection.
Micropuncture studies in animals have shown that torsemide acts from within the lumen of the thick ascending portion of the loop of Henle, where it inhibits the Na+/K+/2Cl–carrier system. Clinical pharmacology studies have confirmed this site of action in humans, and effects in other segments of the nephron have not been demonstrated. Diuretic activity thus correlates better with the rate of drug excretion in the urine than with the concentration in the blood.
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.
The volume of distribution of torsemide is 12 liters to 15 liters in normal adults or in patients with mild to moderate renal failure or congestive heart failure. In patients with hepatic cirrhosis, the volume of distribution is approximately doubled.
In normal subjects the elimination half-life of torsemide is approximately 3.5 hours. 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). The major metabolite in humans is the carboxylic acid derivative, which is biologically inactive. Two of the lesser metabolites possess some diuretic activity, but for practical purposes metabolism terminates the action of the drug.
Because torsemide is extensively bound to plasma protein (>99%), very little enters tubular urine via glomerular filtration. Most renal clearance of torsemide occurs via active secretion of the drug by the proximal tubules into tubular urine.
In patients with decompensated congestive heart failure, hepatic and renal clearance are both reduced, probably because of hepatic congestion and decreased renal plasma flow, respectively. The total clearance of torsemide is approximately 50% of that seen in healthy volunteers, and the plasma half-life and AUC are correspondingly increased. Because of reduced renal clearance, a smaller fraction of any given dose is delivered to the intraluminal site of action, so at any given dose there is less natriuresis in patients with congestive heart failure than in normal subjects.
In patients with renal failure, renal clearance of torsemide is markedly decreased but total plasma clearance is not significantly altered. A smaller fraction of the administered dose is delivered to the intraluminal site of action, and the natriuretic action of any given dose of diuretic is reduced. A diuretic response in renal failure may still be achieved if patients are given higher doses. The total plasma clearance and elimination half-life of torsemide remain normal under the conditions of impaired renal function because metabolic elimination by the liver remains intact.
In patients with hepatic cirrhosis, the volume of distribution, plasma half-life, and renal clearance are all increased, but total clearance is unchanged.
The pharmacokinetic profile of torsemide in healthy elderly subjects is similar to that in young subjects except for a decrease in renal clearance related to the decline in renal function that commonly occurs with aging. However, total plasma clearance and elimination half-life remain unchanged.
The diuretic effects of torsemide begin within 10 minutes of intravenous dosing and peak within the first hour. Diuresis lasts about 6 to 8 hours. In healthy subjects given single doses, the dose-response relationship for sodium excretion is linear over the dose range of 2.5 mg to 20 mg. The increase in potassium excretion is negligible after a single dose of up to 10 mg and only slight (5 mEq to 15 mEq) after a single dose of 20 mg.
Torsemide has been studied in controlled trials in patients with New York Heart Association Class II to Class IV congestive heart failure. Patients who received 10 mg to 20 mg of daily torsemide in these studies achieved significantly greater reductions in weight and edema than did patients who received placebo.
In single-dose studies in patients with nonanuric renal failure, high doses of torsemide (20 mg to 200 mg) caused marked increases in water and sodium excretion. In patients with nonanuric renal failure, severe enough to require hemodialysis, chronic treatment with up to 200 mg of daily torsemide has not been shown to change steady-state fluid retention. When patients in a study of acute renal failure received total daily doses of 520 mg to 1200 mg of torsemide, 19% experienced seizures. Ninety-six patients were treated in this study; 6/32 treated with torsemide experienced seizures, 6/32 treated with comparably high doses of furosemide experienced seizures, and 1/32 treated with placebo experienced a seizure.
When given with aldosterone antagonists, torsemide also caused increases in sodium and fluid excretion in patients with edema or ascites due to hepatic cirrhosis. Urinary sodium excretion rate relative to the urinary excretion rate of torsemide is less in cirrhotic patients than in healthy subjects (possibly because of the hyperaldosteronism and resultant sodium retention that are characteristic of portal hypertension and ascites). However, because of the increased renal clearance of torsemide in patients with hepatic cirrhosis, these factors tend to balance each other, and the result is an overall natriuretic response that is similar to that seen in healthy subjects. Chronic use of any diuretic in hepatic disease has not been studied in adequate and well-controlled trials.
In patients with essential hypertension, torsemide has been shown in controlled studies to lower blood pressure when administered once a day at doses of 5 mg to 10 mg. The antihypertensive effect is near maximal after 4 to 6 weeks of treatment, but it may continue to increase for up to 12 weeks. Systolic and diastolic supine and standing blood pressures are all reduced. There is no significant orthostatic effect, and there is only a minimal peak-trough difference in blood pressure reduction.
The antihypertensive effects of torsemide are, like those of other diuretics, on the average greater in black patients (a low-renin population) than in nonblack patients.
When torsemide is first administered, daily urinary sodium excretion increases for at least a week. With chronic administration, however, daily sodium loss comes into balance with dietary sodium intake. If the administration of torsemide is suddenly stopped, blood pressure returns to pretreatment levels over several days, without overshoot.
Torsemide has been administered together with β-adrenergic blocking agents, ACE inhibitors, and calcium-channel blockers. Adverse drug interactions have not been observed, and special dosage adjustment has not been necessary.
Torsemide Injection is indicated for the treatment of edema associated with congestive heart failure, renal disease, or hepatic disease. Use of torsemide has been found to be effective for the treatment of edema associated with chronic renal failure. Chronic use of any diuretic in hepatic disease has not been studied in adequate and well-controlled trials.
Torsemide Injection is indicated when a rapid onset of diuresis is desired or when oral administration is impractical.
Torsemide Injection is indicated for the treatment of hypertension alone or in combination with other antihypertensive agents.
Torsemide Injection is contraindicated in patients with known hypersensitivity to torsemide or to sulfonylureas.
Torsemide Injection is contraindicated in patients who are anuric.
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