Torsemide

Torsemide is an antihypertensive agent belonging to Loop Diuretics.

Torsemide is a loop diuretic used to treat edema in congestive heart failure, liver cirrhosis, renal disease, and hypertension.

The bioavailability of Torsemide tablets is approximately 80%. The drug is absorbed with little first-pass metabolism, and the serum concentration reaches its peak (Cmax) within 1 hour after oral administration. The volume of distribution of Torsemide is 12 to 15 liters in normal adults or patients with mild to moderate renal or congestive heart failure. Torsemide is extensively bound to plasma protein (>99%). Torsemide is metabolized by the hepatic cytochrome CYP2C9 and, to a minor extent, CYP2C8 and CYP2C18. In normal subjects, the elimination half-life of torsemide is approximately 3.5 hours. After a single oral dose, the amounts recovered in urine were: Torsemide 21%, metabolite M1 12%, metabolite M3 2%, and metabolite M5 34%.

Torsemide shows common side effects like Chest pain, decreased urination, diarrhea, dry mouth, increased thirst, irregular heartbeat, loss of appetite, mood changes, muscle pain or cramps, nausea or vomiting, numbness or tingling in the hands, feet, or lips, seizures, swelling of the hands, ankles, feet, or lower legs, trouble breathing, unusual tiredness or weakness, etc.

Torsemide is available in the dosage form of Tablets and Injectable solutions.

Torsemide is available in India, China, the US, the UK, England, Singapore, Canada, and Germany.

Torsemide belonging to Loop Diuretics acts as an antihypertensive agent.

Torsemide causes sodium chloride excretion and water by inhibiting the sodium and chloride reabsorption in the ascending loop of Henle and distal collecting tubule. The effect is caused by blocking the chloride-binding site of the Na+/K+/2Cl- cotransport mechanism. Torsemide does not affect the renal blood flow or glomerular filtration rate (GFR).

However, studies have also shown that genetics can play a role in the drug response of various loop diuretics, including Torsemide.

The onset of action of Torsemide occurs within 1 hour (by mouth), and 10min (Intravenous) administration.

The Duration of Action for Torsemide in the body is approximately 6-8 hours (by mouth) and 6-8 hours (Intravenous).

The Tmax was found within 1-2 hours (by mouth) and 1 hour (Intravenous) following the administration of Torsemide.

Torsemide is available in the form of Tablets and Injectable solutions.

Torsemide tablet is taken by mouth. Usually once a day.

Torsemide Injectable solutions by Intravenous once a day.

Torsemide is a loop diuretic used to treat edema in congestive heart failure, liver cirrhosis, renal disease, and hypertension. This medicine works by acting on the kidneys to increase urine flow. Torsemide is also used alone or with other medicines to treat high blood pressure (hypertension). High blood pressure adds to the workload of the heart and arteries.

Torsemide is an antihypertensive agent belonging to Loop Diuretics. Torsemide causes the excretion of sodium chloride and water by inhibiting sodium and chloride reabsorption in the ascending loop of Henle and distal collecting tubule. The effect is caused by blocking the chloride-binding site of the Na+/K+/2Cl- cotransport mechanism. Torsemide does not affect renal blood flow or glomerular filtration rate (GFR). Torsemide is a loop diuretic used to treat hypertension and edema in congestive heart failure, liver cirrhosis, renal disease, and hypertension.

Torsemide is approved for use in the following clinical indications

• Edema

Torsemide is indicated for the treatment of edema associated with heart failure, renal disease or hepatic disease.

• Hypertension

Torsemide is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with Torsemide.

The antihypertensive effects of Torsemide are on average more significant in black patients than in nonblack patients. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide the selection of therapy. Torsemide can be used alone or in combination with other antihypertensive agents.

• Edema

Edema associated with heart failure

The recommended initial dose is 10 or 20 mg of oral Torsemide once daily. If the diuretic response is inadequate, titrate upward by approximately doubling until the desired diuretic response is obtained. Doses higher than 200 mg have not been adequately studied.

Edema associated with chronic renal failure

The recommended initial dose is 20 mg oral Torsemide once daily. If the diuretic response is inadequate, titrate upward by approximately doubling until the desired diuretic response is obtained. Doses higher than 200 mg have not been adequately studied.

Edema associated with hepatic cirrhosis

The recommended initial dose is 5 mg or 10 mg oral Torsemide once daily, administered with an aldosterone antagonist or a potassium-sparing diuretic. If the diuretic response is inadequate, titrate upward by approximately doubling until the desired diuretic response is obtained. Doses higher than 40 mg have not been adequately studied in this population.

• Hypertension

The recommended initial dose is 5 mg once daily. If the 5 mg dose does not adequately reduce blood pressure within 4 to 6 weeks, increase it to 10 mg once daily. If the response to 10 mg is insufficient, add another antihypertensive agent to the treatment regimen.

Torsemide is available in various strengths as Tablets (5, 10, 20, and 100mg) and Injectable solution (10mg/ml).

Torsemide is available in the form of Tablets and Injectable solutions.

Avoid consumption of a high-salt or high-sodium diet while taking Torsemide.

Torsemide is contraindicated in the following:

• In patients with known hypersensitivity to Torsemide or to povidone.
• In patients who are anuric.
• In patients with hepatic coma.

• Hypotension and Worsening Renal Function

Excessive diuresis may cause potentially symptomatic dehydration, blood volume reduction, hypotension, and worsening renal function, including acute renal failure, particularly in salt-depleted patients or those taking renin-angiotensin-aldosterone inhibitors. Worsening of renal function can also occur with the concomitant use of nephrotoxic drugs (e.g., aminoglycosides, cisplatin, and NSAIDs). Monitor volume status and renal function periodically.

• Electrolyte and Metabolic Abnormalities

Torsemide can cause potentially symptomatic hypokalemia, hyponatremia, hypomagnesemia, hypocalcemia, and hypochloremic alkalosis. Treatment with Torsemide can cause an increase in blood glucose levels and hyperglycemia Asymptomatic hyperuricemia can occur and gout may rarely be precipitated. Monitor serum electrolytes and blood glucose periodically.

• Ototoxicity

Tinnitus and hearing loss (usually reversible) have been observed with loop diuretics, including Torsemide. Higher than recommended doses, severe renal impairment, and hypoproteinemia, appear to increase the risk of ototoxicity.

Consumption of alcohol is not recommended while you are taking this medicine due to the increased risk of severe adverse effects. These side effects may include dizziness and fainting.

There are no data regarding the presence of Torsemide in human milk or the effects of Torsemide on the breastfed child. Diuretics can suppress lactation.

There are no available data on the use of Torsemide in pregnant women and the risk of major birth defects or miscarriage. In pregnant rats and rabbits dosed, on an mg/m2 basis, with 10 and 1.7 times a human dose of 20 mg/day, respectively, there was no fetotoxicity or teratogenicity. However, in pregnant rats and rabbits administered 50 and 6.8 times the human dose, respectively, decreases in body weight, decreased fetal resorption, and delayed fetal ossification was observed. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major malformations and miscarriage in clinically recognized pregnancies is 2-4%, and 15-20%, respectively.

Avoid consumption of a high-salt or high-sodium diet while taking Torsemide.

• Common Adverse effects

Nausea, Rash, Restlessness, Increases urinary frequency, Urticaria, Vertigo, Weakness, Diarrhea, Dizziness, and Headache.

• Rare Adverse effects

Pancreatitis, abdominal pain, paresthesia, confusion, visual impairment, loss of appetite, Increase in liver transaminases, photosensitivity reaction, pruritus, Acute urinary retention, anemia, Leucopenia, thrombocytopenia, Stevens-Johnson syndrome, Thiamine (vitamin B1) deficiency, toxic epidermal necrolysis.

• Nonsteroidal Anti-inflammatory Drugs

Because Torsemide and salicylates compete for secretion by renal tubules, patients receiving high doses of salicylates may experience salicylate toxicity when Torsemide is concomitantly administered. Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) and Torsemide has been associated with the development of acute renal failure. The antihypertensive and diuretic effects of Torsemide can be reduced by NSAIDs. Partial inhibition of the natriuretic effect of Torsemide by concomitant administration of indomethacin has been demonstrated for Torsemide under conditions of dietary sodium restriction (50 mEq/day) but not in the presence of normal sodium intake (150 mEq/day).

• Cytochrome P450 2C9 Inhibitors and Inducers

Torsemide is a substrate of CYP2C9. Concomitant use of CYP2C9 inhibitors (e.g., amiodarone, fluconazole, miconazole, oxandrolone) can decrease Torsemide clearance and increase Torsemide plasma concentrations. Concomitant use of CYP2C9 inducers (e.g., rifampin) increases Torsemide clearance and decreases plasma Torsemide concentrations. Monitor diuretic effect and blood pressure when used in combination with CYP2C9 inhibitor or inducer. Adjust the Torsemide dose if necessary. Because of its inhibition of CYP2C9 metabolism, Torsemide may affect the efficacy and safety of sensitive CYP2C9 substrates, such as celecoxib, or of substrates with a narrow therapeutic range, such as warfarin or phenytoin. Monitor patients and adjust dosages if necessary.

• Cholestyramine

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 Torsemide and cholestyramine should be coadministered, administer Torsemide at least one hour before or 4 to 6 h after cholestyramine administration.

• Organic Anion Drugs

Coadministration of organic anion drugs (e.g., probenecid) that undergo significant renal tubular secretion has the potential to reduce the secretion of Torsemide into the proximal tubule and thereby decrease the diuretic activity of Torsemide. Monitor diuretic effect and blood pressure during coadministration.

• Lithium

Like other diuretics, Torsemide reduces the renal clearance of lithium, inducing a high risk of lithium toxicity. Monitor lithium levels periodically when Torsemide is coadministered.

• Ototoxic Drugs

Loop diuretics increase the ototoxic potential of other ototoxic drugs, including aminoglycoside antibiotics and ethacrynic acid. This effect has been reported with the concomitant use of Torsemide and gentamycin. Avoid concomitant use of Torsemide and aminoglycoside antibiotics, if possible.

• Renin-angiotensin Inhibitors

Coadministration of Torsemide with ACE inhibitors or angiotensin receptor blockers can increase the risk of hypotension and renal impairment.

• Radiocontrast Agents

Torsemide can increase the risk of renal toxicity related to the administration of radiocontrast agents.

• Corticosteroids and ACTH

Concomitant use of Torsemide may increase the risk of hypokalemia.

The common side of Torsemide includes the following

• Common
  

Chest pain, decreased urination, diarrhea, dry mouth, increased thirst, irregular heartbeat, loss of appetite, mood changes, muscle pain or cramps, nausea or vomiting, numbness or tingling in the hands, feet, or lips, seizures, swelling of the hands, ankles, feet, or lower legs, trouble breathing, unusual tiredness or weakness.

• Rare

Black, tarry stools, dizziness, faintness, or lightheadedness when getting up from a suddenly sitting or lying position, ringing or buzzing in the ears or any hearing loss, or skin rash.

Pregnancy

• Pregnancy Category B

There are no available data on the use of Torsemide in pregnant women and the risk of major birth defects or miscarriage. In pregnant rats and rabbits dosed, on an mg/m2 basis, with 10 and 1.7 times a human dose of 20 mg/day, respectively, there was no fetotoxicity or teratogenicity. However, in pregnant rats and rabbits administered 50 and 6.8 times the human dose, respectively, decreases in body weight, decreased fetal resorption, and delayed fetal ossification was observed. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major malformations and miscarriage in clinically recognized pregnancies is 2-4%, and 15-20%, respectively.

• Nursing Mothers

There are no data regarding the presence of Torsemide in human milk or the effects of Torsemide on the breastfed child. Diuretics can suppress lactation.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Administration of another loop diuretic to premature infants has been associated with the precipitation of nephrocalcinosis/nephrolithiasis. Nephrocalcinosis/nephrolithiasis has also been observed in children under 4 years of age with no history of prematurity who have been treated chronically with the other loop diuretic. The other loop diuretic, when administered during the first weeks of life, has also been reported to increase the risk of persistent patent ductus arteriosus. The use of Torsemide in such patients has not been studied.

• Geriatric Use

Of the total number of patients who received Torsemide 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.

• The signs and symptoms of overdosage can be anticipated to include those of excessive pharmacologic effect: dehydration, hypovolemia, hypotension, hyponatremia, hypokalemia, hypochloremic alkalosis, and hemoconcentration. Treatment of overdosage should consist of fluid and electrolyte replacement. Laboratory determinations of serum levels of Torsemide and its metabolites are not widely available.
• No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate the elimination of Torsemide and its metabolites. Torsemide is not dialyzable, so hemodialysis will not accelerate elimination.

Pharmacodynamic

With oral dosing, the onset of diuresis occurs within 1 hour and the peak effect occurs during the first or second hour and the 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.

• Edema

Torsemide has been studied in controlled trials in patients with New York Heart Association Class II to Class IV 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.

• Hypertension

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 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.

Pharmacokinetics

• Absorption

The bioavailability of Torsemide tablets is approximately 80%, with small inter-subject variation; the 90% confidence interval is 75% to 89%. The drug is absorbed with little first-pass metabolism, and the serum concentration reaches its peak (Cmax) within 1 hour after oral administration. Cmax and area under the serum concentration-time curve (AUC) after oral administration are proportional to the dose over the range of 2.5 mg to 200 mg. Simultaneous food intake delays the time to Cmax by about 30 minutes, but overall bioavailability (AUC) and diuretic activity are unchanged.

• Distribution

The volume of distribution of Torsemide is 12 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. Torsemide is extensively bound to plasma protein (>99%).

• Metabolism

Torsemide is metabolized by the hepatic cytochrome CYP2C9 and, to a minor extent, CYP2C8 and CYP2C18. Three main metabolites have been identified in humans. Metabolite M1 is formed by methyl-hydroxylation of Torsemide, metabolite M3 is formed by ring hydroxylation of Torsemide, and metabolite M5 is formed by oxidation of M1. The major metabolite in humans is the carboxylic acid derivative M5, which is biologically inactive. Metabolites M1 and M3 possess some pharmacological activity; however, their systemic exposures are much lower when compared to Torsemide.

• Excretion

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). 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. After a single oral dose, the amounts recovered in urine were: Torsemide 21%, metabolite M1 12%, metabolite M3 2%, and metabolite M5 34%.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020136s027lbl.pdf
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020136s023lbl.pdf
• https://www.rxlist.com/consumer_torsemide_demadex/drugs-condition.htm
• https://www.drugs.com/dosage/torsemide.html
• https://www.ncbi.nlm.nih.gov/books/NBK559175/