Torsemide

Overview

Torsemide is a loop diuretic used as an adjunctive treatment for congestive heart failure (CHF) in dogs and cats, particularly in patients that have become refractory to furosemide. Compared with furosemide, torsemide is approximately 10–20 times more potent and its diuretic effect persists for about 12 hours, allowing lower starting doses and less frequent administration. Because the injectable formulation has been discontinued in the United States, torsemide is currently used only as an oral medication.

Mechanism of Action (MOA): Torsemide inhibits sodium and chloride reabsorption in the ascending loop of Henle by interfering with the Na+-K+-2Cl− cotransporter. This increases the renal excretion of water, sodium, potassium, chloride, calcium, magnesium, hydrogen, ammonium, and bicarbonate, producing a potent and prolonged diuretic effect.

Indications

Torsemide is used as an adjunctive loop diuretic for the management of congestive heart failure (CHF) in dogs and cats, particularly when response to furosemide is inadequate.

• Congestive heart failure (dogs and cats): Adjunctive treatment, especially in patients that have become refractory to furosemide; in cats this use is unlicensed and not all references give a feline dose.
• Myxomatous mitral valve disease (dogs): Management of pulmonary edema associated with Stage C or D congestive heart failure that is no longer adequately controlled with furosemide. In the US, it is licensed only for use with pimobendan, spironolactone, and an angiotensin-converting enzyme inhibitor.
• Edema from other causes (dogs and cats): May be considered for edema associated with pulmonary, hepatic, cardiac, or vascular disease; use in hepatic cirrhosis or renal failure is based mainly on human experience.

Dosage (Reference)

Dog

Cat

Warnings & Precautions

Torsemide should be used cautiously because excessive diuresis may result in dehydration, hypotension, electrolyte abnormalities, and worsening renal function. Careful patient selection and monitoring are recommended throughout therapy.

• Do not use in patients with anuria or renal failure, dehydration, hypovolemia, hypotension, known hypersensitivity to torsemide or other sulfonylureas, or concurrently with other loop diuretics.
• Use cautiously in patients with severe electrolyte depletion, significant hepatic dysfunction, diabetes mellitus, hyperuricemia, or other sulfonamide hypersensitivities; correct pre-existing electrolyte abnormalities and dehydration before starting treatment.
• Excessive diuresis may cause symptomatic dehydration, decreased blood volume, hypotension, and worsening renal function. Acute renal failure is possible.
• Electrolyte abnormalities (especially sodium, potassium, calcium, and magnesium) may occur and should be monitored.
• Ototoxicity may occur at higher-than-recommended doses or in patients with severe renal impairment or hyponatremia.
• Concurrent nephrotoxic drugs may increase the risk of renal injury.
• Pregnancy & lactation: Safety has not been established in animals. Use only when the maternal benefits outweigh the potential risks to the offspring.
• Reproductive studies: no effect on fertility in rats at up to 25 mg/kg/day, and no teratogenic effect in rats or rabbits at up to 15 and 5 times the human dose respectively; larger doses increased fetal resorptions, lowered fetal body weight and delayed ossification. It is not known whether torsemide enters milk, although furosemide does.
• Not for an animal in acute crisis: Torsemide is an oral drug for stable patients; where pulmonary edema, pleural effusion or ascites needs emergency treatment, injectable diuretic therapy should be given first.
• A marked fall in cardiac output can occur where output is already impaired – severe pulmonary hypertension, low-output heart failure, hypertrophic cardiomyopathy, pericardial or myocardial disease and cardiac tamponade.

Drug Interactions

The following drug interactions have been reported or are considered theoretical. Concurrent use is not necessarily contraindicated unless otherwise stated, but additional monitoring may be required.

• ACE inhibitors (e.g., enalapril, benazepril): Slightly increased risk of hypotension, particularly in patients that are volume- or sodium-depleted secondary to diuretic therapy.
• Aminoglycosides (e.g., gentamicin, amikacin): May increase the risk of ototoxicity or nephrotoxicity.
• Amphotericin B: Loop diuretics may increase the risk of nephrotoxicity.
• Cholestyramine: May decrease torsemide absorption; administer separately.
• Cisplatin: May increase the risk of worsening renal function or renal failure.
• Corticosteroids (e.g., dexamethasone, prednisolone): Increased risk of hypokalemia.
• Digoxin: Torsemide-induced hypokalemia may increase the risk of digoxin toxicity; digoxin also increases torsemide exposure, and the torsemide dose may need to be adjusted when the two are given together.
• Iohexol: Increased risk of nephrotoxicity.
• NSAIDs (e.g., carprofen, flunixin): May reduce the natriuretic effect of torsemide and increase the risk of worsening renal function or renal failure.
• Probenecid: May reduce the diuretic efficacy of torsemide.
• Salicylates (e.g., aspirin): Torsemide may reduce salicylate excretion.
• Clopidogrel: May interfere with the metabolism of torsemide; the two are listed as a combination to avoid.
• Cephalosporins: Concurrent use may increase the risk of nephrotoxicity and ototoxicity, as with aminoglycosides.

Side Effects & Overdose

Side Effects

Adverse effects in cats have not been fully established because of the limited veterinary use of torsemide. In dogs, a European field study of 251 dogs recorded a greater overall frequency of adverse reactions with torsemide than with furosemide. Gastrointestinal and renal effects are the most commonly reported adverse reactions.

• Gastrointestinal effects: Vomiting, diarrhea, and anorexia.
• Renal effects: Polyuria, increased renal values, renal insufficiency, or renal failure.
• Fluid and electrolyte abnormalities: Dehydration, prerenal azotemia, hyponatremia, hypokalemia, hypochloremia, hypocalcemia, and hypomagnesemia may occur; hyponatremia is probably the greatest concern.
• Dose-dependent effects: Dry oral mucosa, decreased food intake, increased water intake, increased urine pH, decreased urine specific gravity, and increased serum aldosterone concentrations.
• Other reported effects: Anemia, leukopenia, weakness, and restlessness.
• Ototoxicity: In humans, significant ototoxic effects appear to occur only rarely; high doses in laboratory animals have induced ototoxicity.
• Renal risk relative to furosemide: In the field study the risk of serious adverse events from renal insufficiency – raised BUN, raised creatinine and renal failure – was higher with torsemide than with furosemide, and median BUN and creatinine were higher at every time point, still raised at day 84.
• Urinary system effects: The commonest reactions on the US label involve the urinary system – polyuria and polydipsia, renal insufficiency, raised BUN and creatinine, and urinary incontinence – all reported more often than with furosemide.

Overdose

Fluid and electrolyte imbalance is the primary concern following torsemide overdose.

• Clinical concern: Fluid, electrolyte, and acid-base disturbances.
• Management: Consider gastrointestinal decontamination after very large or unknown ingestions.
• Supportive care: Observe the patient and monitor fluid status, electrolytes, and acid-base balance; institute supportive therapy as needed.
• Poison consultation: Consultation with a veterinary poison center is recommended for known or suspected overdoses.
• Margin of safety: The oral median lethal dose in dogs is greater than 2 g/kg, so the margin between a therapeutic dose and a lethal one is wide; the risk from an overdose is fluid and electrolyte loss rather than direct toxicity.

Key Notes

Practical clinical points for the use of torsemide in dogs and cats:

• Reduced diuretic resistance: In healthy dogs, diuretic resistance developed after 14 days of furosemide but not with torsemide; both drugs, however, raised blood urea nitrogen and creatinine compared with pre-treatment values.
• Water availability: Animals receiving torsemide should always have free access to fresh water because increased drinking and urination are expected during treatment.
• Follow-up monitoring: Recheck examinations detect complications early. Assess physical examination findings, hydration, blood urea nitrogen, creatinine and electrolytes before starting or changing the dose, again at 24 and 48 hours, and then monthly until stable; in both cats and dogs, renal parameters and electrolytes should be rechecked about a week after starting torsemide or increasing the dose.
• A veterinary product is now available in the US: UpCard-CA1, a torsemide oral solution containing 2 mg per mL, in 32 mL and 96 mL bottles, conditionally approved in May 2024 for dogs. A conditional approval is granted on a reasonable expectation of effectiveness and requires renewal, so the label may change.
• Torsemide and torasemide are the same drug – torsemide is the US name and torasemide the international one. European veterinary products are labeled torasemide (UpCard, tablets of 0.75, 3 and 7.5 mg); human trade names include Demadex, Isemid, Torem and Unat.
• Pharmacokinetics: Oral bioavailability is 80–100% in dogs and cats and torsemide is more than 98% protein bound. Diuresis begins within an hour, peaks at about 2 hours in dogs and 4 hours in cats, and persists for about 12 hours in both. The elimination half-life is about 10 hours in dogs and 13 hours in cats.
• Electrolyte pattern: Potassium is lost proportionally much less than sodium – about twice the sodium-to-potassium ratio seen with furosemide – so hyponatremia is probably the greater concern rather than hypokalemia. Part of the difference is attributed to a dose-dependent anti-aldosterone effect, although torsemide also raises plasma aldosterone while inhibiting receptor-bound aldosterone and the clinical significance of that is not established.
• Outcome evidence versus furosemide: Two larger studies found torsemide given every 24 hours noninferior to furosemide in dogs with congestive heart failure from myxomatous mitral valve disease. In dogs with first-time heart failure that had not previously received a diuretic it was associated with a 64% reduction in the risk of cardiac death, euthanasia for worsening heart failure or withdrawal for worsening heart failure; another study reported a two-fold reduction in the risk of reaching a composite endpoint of spontaneous cardiac death, euthanasia for heart failure or worsening heart-failure class within the first 12 weeks.
• Racing and performance animals: The Association of Racing Commissioners International designates torsemide a class 3 substance.
• Storage: Store tablets below 40°C (104°F), preferably between 15°C and 30°C (59°F and 86°F). Store the oral solution at or below 30°C (86°F) and discard it 90 days after the bottle is opened.