About Torasemide

Description: Torasemide (Torsemide), a high-ceiling loop diuretic, acts on the thick ascending limb of the loop of Henle to promote rapid and marked excretion of water, sodium and chloride. It is a N-sulfonylurea, an aminopyridine and a secondary amino compound. It is functionally related to a 4-aminopyridine.
Systematic [IUPAC} Name: 1-[4-(3-methylanilino)pyridin-3-yl]sulfonyl-3-propan-2-ylurea
Formula: C16H20N4O3S
Pharmacotherapeutic group: High-ceiling diuretics
ATC Vet Code: QC03CA04
ATC Code: C03CA04
Action: Diuretic and Antihypertensive
Therapeutic Uses: torasemide is a potent loop diuretic used for the treatment of hypertension and oedema in patients with congestive heart failure. It has a role as a loop diuretic and an antihypertensive agent.

Clinical Applications

Canine MMVD: Torasemide is generally deployed in MMVD (Stages C and D) as a secondary savage diuretic when cases destabilise and appear refractory to the primary diuretic agent, Furosemide (Besche et al., 2020; Chetboul et al., 2017; Keene et al., 2019).
Diuretic: Torasmide is a potent diuretic in all situations, and its use may be beneficial at any stage of MMVD or other situations where diuresis is required (Besche et al., 2020).
Hypertension: Torsemide can be used alone or with other medicines to treat high blood pressure (hypertension).

Mechanism of Action

Torasemide acts by reducing the oxygen demand in the medullary thick ascending loop of Henle by inhibiting the Na+/K+/Cl- pump on the luminal cell membrane surface. This action is obtained by binding torasemide to a chloride ion-binding site of the transport molecule.
Torasemide affects the renin-angiotensin-aldosterone system by inhibiting the downstream cascade after activating angiotensin II. This inhibition will produce a secondary effect marked by the reduction of the expression of aldosterone synthase, TGF-B1, and thromboxane A2 and a decrease in the binding of the aldosterone receptor.

Metabolism

Hepatic: Torasemide is extensively metabolised in the liver via the hepatic CYP2C8 and CYP2C9 mainly by hydroxylation reactions, oxidation and reduction to 5 metabolites.

Elimination

Mixed (Faeces and Urine): Hepatic metabolites are generally excreted in the faeces, from which about 70-80% of the administered dose is excreted by this pathway. 20-30% of the administered dose remains unchanged and is excreted in urine.

Adverse Effects

Azotaemia: An increase in renal blood parameters and insufficiency are commonly observed during treatment (CEVA Animal Health, 2019; Vetoquinol, 2015)).
Electrolyte derangements: In cases of prolonged treatment, electrolyte deficiency (including hypokalaemia, hypochloraemia, and hypomagnesaemia) and dehydration may occur (CEVA Animal Health, 2019; Vetoquinol, 2015).
Gastrointestinal signs: Possible signs include nausea, emesis, and reduced or absent faeces. In rare cases, transient and mild episodes of soft faeces occur, but withdrawal of the treatment is not usually necessary (Vetoquinol, 2015).
Skin Changes: Erythema of the inner pinnae may occur (Vetoquinol, 2015).
Ototoxicity: High doses in laboratory animals have induced cytotoxicity, but this was reduced compared to Furosemide equivalence.

Contraindications

Renal Failure: Avoid use (CEVA Animal Health, 2019; Vetoquinol, 2015).
Severe Dehydration: Avoid use (CEVA Animal Health, 2019; Vetoquinol, 2015).
Hypovolaemia: Avoid use (CEVA Animal Health, 2019; Vetoquinol, 2015).
Hypotension: Avoid use (CEVA Animal Health, 2019; Vetoquinol, 2015).
Furosemide: Do not use concomitantly with other loop diuretics (CEVA Animal Health, 2019; Vetoquinol, 2015).
Hypersensitivity: Do not use in case of hypersensitivity to the active substance or any of the excipients (CEVA Animal Health, 2019; Vetoquinol, 2015).

Reproductive Safety

Pregnancy: Use is not recommended (CEVA Animal Health, 2019; Vetoquinol, 2015).
Lactation: Use is not recommended (CEVA Animal Health, 2019; Vetoquinol, 2015).
Male Fertility: Use is not recommended (CEVA Animal Health, 2019; Vetoquinol, 2015).
Female Fertility: Use is not recommended (CEVA Animal Health, 2019; Vetoquinol, 2015).
Neonates: Use is not recommended (CEVA Animal Health, 2019; Vetoquinol, 2015).

Interactions

Antibacterial interactions: Concomitant use with aminoglycosides or cephalosporins may increase the risk of nephrotoxicity and ototoxicity. Torasemide may increase the risk of sulfonamide allergy (CEVA Animal Health, 2019; Vetoquinol, 2015).
Antihypertensive Medicines: The effect of antihypertensive drugs, especially angiotensin-converting enzyme (ACE)-inhibitors, may be potentiated when co-administered with torasemide (CEVA Animal Health, 2019; Vetoquinol, 2015).
Cardiac Support Medicines: When combined with cardiac treatments (e.g. ACE inhibitors, digoxin), the dose regimen may need to be modified depending on the animal’s response to therapy (CEVA Animal Health, 2019; Vetoquinol, 2015).
Electrolyte Disruptors: Use alongside additional medicines that influence electrolyte balance (corticosteroids, amphotericin B, cardiac glycosides, and other diuretics), which requires careful monitoring (CEVA Animal Health, 2019; Vetoquinol, 2015).
Loop Diuretics: Co-administration can decrease natriuretic response (CEVA Animal Health, 2019; Vetoquinol, 2015).
Metabolism, Competitors: Concomitant administration of torasemide with other drugs metabolised by cytochrome P450 families 3A4 (e.g., enalapril, buprenorphine, doxycycline, cyclosporine) and 2E1 (isoflurane, sevoflurane, theophylline) may decrease their clearance from the systemic circulation (CEVA Animal Health, 2019; Vetoquinol, 2015).
NSAIDs: Co-administration can decrease natriuretic response.
Concurrent use of drugs that increase the risk of renal injury or renal insufficiency should be avoided (Vetoquinol, 2015).
Protein-Bound Medicines: Since protein binding facilitates the renal secretion of torasemide, a decrease in binding due to displacement by another drug may cause diuretic resistance. Exercise care when administering torasemide with other highly plasma protein-bound drugs (CEVA Animal Health, 2019; Vetoquinol, 2015).
Salicylates: Torasemide can reduce the renal excretion of salicylates, leading to an increased risk of toxicity (CEVA Animal Health, 2019; Vetoquinol, 2015).

UK Formulations

UpCard: 0.75, 3.0 and 7.5 mg tablets for dogs (Vetoquinol, 2015).
Isemid: 1mg, 2mg and 4mg chewable tablets for dogs (CEVA Animal Health, 2019).