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Torasemide Pharmacology

Pharmacology

Clinical Particulars

Pharmacodynamics

Pharmacokinetics

Torasemide (Torsemide), a potent 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. Torasemide is used for the treatment of hypertension and oedema in patients with congestive heart failure. 


Torasemide has a role as a loop diuretic and an antihypertensive agent.

 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.

Applications

  • Pharmacology 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).

Pharmacodynamics

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.

Pharmacokinetics

Precautions

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).

Potentially Significant 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).

Precautions

Availability

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).

Availability

Identifiers

  • 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

Identifiers

Evidence Base

  1. Besche, B., Blondel, T., Guillot, E., Garelli-Paar, C., Oyama, M.A., 2020. Efficacy of oral torasemide in dogs with degenerative mitral valve disease and new onset congestive heart failure: The CARPODIEM study. J Vet Intern Med 34, 1746–1758. https://doi.org/10.1111/jvim.15864

  2. Bikdeli, B., Strait, K.M., Dharmarajan, K., Partovian, C., Coca, S.G., Kim, N., Li, S.-X., Testani, J.M., Khan, U., Krumholz, H.M., 2013. Dominance of furosemide for loop diuretic therapy in heart failure: time to revisit the alternatives? J Am Coll Cardiol 61, 1549–1550. https://doi.org/10.1016/j.jacc.2012.12.043

  3. Caro-Vadillo, A., Ynaraja-Ramírez, E., Montoya-Alonso, J.A., 2007. Effect of torsemide on serum and urine electrolyte levels in dogs with congestive heart failure. Vet Rec 160, 847–848. https://doi.org/10.1136/vr.160.24.847

  4. CEVA Animal Health, S., 2019. Isemid | European Medicines Agency [WWW Document]. URL https://www.ema.europa.eu/en/medicines/veterinary/EPAR/isemid (accessed 12.7.23).

  5. Chetboul, V., Pouchelon, J.-L., Menard, J., Blanc, J., Desquilbet, L., Petit, A., Rougier, S., Lucats, L., Woehrle, F., Investigators,  the T. study, 2017. Short-Term Efficacy and Safety of Torasemide and Furosemide in 366 Dogs with Degenerative Mitral Valve Disease: The TEST Study. Journal of Veterinary Internal Medicine 31, 1629–1642. https://doi.org/10.1111/jvim.14841

  6. Cosín, J., Díez, J., Investigators,  on behalf of the T., 2002. Torasemide in chronic heart failure: results of the TORIC study. European Journal of Heart Failure 4, 507–513. https://doi.org/10.1016/S1388-9842(02)00122-8

  7. Dubourg, L., Drukker, A., Guignard, J.P., 2000a. Failure of the loop diuretic torasemide to improve renal function of hypoxemic vasomotor nephropathy in the newborn rabbit. Pediatr Res 47, 504–508. https://doi.org/10.1203/00006450-200004000-00015

  8. Dubourg, L., Mosig, D., Drukker, A., Guignard, J.P., 2000b. Torasemide is an effective diuretic in the newborn rabbit. Pediatr Nephrol 14, 476–479. https://doi.org/10.1007/s004670050796

  9. Friedel, H.A., Buckley, M.M.-T., 1991. Torasemide. Drugs 41, 81–103. https://doi.org/10.2165/00003495-199141010-00008

  10. Ghys, A., Denef, J., Delarge, J., Georges, A., 1985. Renal effects of the high ceiling diuretic torasemide in rats and dogs. Arzneimittelforschung 35, 1527–1531.

  11. Greger, R., 1988. Inhibition of active NaCl reabsorption in the thick ascending limb of the loop of Henle by torasemide. Arzneimittelforschung 38, 151–152.

  12. Hori, Y., Takusagawa, F., Ikadai, H., Uechi, M., Hoshi, F., Higuchi, S., 2007. Effects of oral administration of furosemide and torsemide in healthy dogs. Am J Vet Res 68, 1058–1063. https://doi.org/10.2460/ajvr.68.10.1058

  13. Hosseini, F., Mahmoudi Filabadi, Z., Hill, P.B., Hosseininejad, M., 2023. Evaluation of the short-term echocardiographic effects of two loop diuretics, furosemide and torsemide, in a group of dogs. Veterinary Medicine and Science 9, 1508–1512. https://doi.org/10.1002/vms3.1129

  14. Iwanaga, K., Araki, R., Isaka, M., 2021. A retrospective study of 14 dogs with advanced heart failure treated with loop diuretics and hydrochlorothiazide. Open Vet J 11, 342–345. https://doi.org/10.5455/OVJ.2021.v11.i3.2

  15. Keene, B.W., Atkins, C.E., Bonagura, J.D., Fox, P.R., Häggström, J., Fuentes, V.L., Oyama, M.A., Rush, J.E., Stepien, R., Uechi, M., 2019. ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs. J Vet Intern Med 33, 1127–1140. https://doi.org/10.1111/jvim.15488

  16. Kim, Y.C., Lee, M.G., Ko, S.-H., Kim, S.H., 2004. Effect of intravenous infusion time on the pharmacokinetics and pharmacodynamics of the same total dose of torasemide in rabbits. Biopharmaceutics & Drug Disposition 25, 211–218. https://doi.org/10.1002/bdd.401

  17. Kim, Y.C., Lee, M.G., Ko, S.-H., Kim, S.H., 2003. Effects of the rate and composition of fluid replacement on the pharmacokinetics and pharmacodynamics of intravenous torasemide. J Pharm Pharmacol 55, 1515–1522. https://doi.org/10.1211/0022357022034

  18. Mentz, R.J., Hasselblad, V., DeVore, A.D., Metra, M., Voors, A.A., Armstrong, P.W., Ezekowitz, J.A., Tang, W.H.W., Schulte, P.J., Anstrom, K.J., Hernandez, A.F., Velazquez, E.J., O’Connor, C.M., 2016. Torsemide versus Furosemide in Patients with Acute Heart Failure (From the ASCEND-HF Trial). Am J Cardiol 117, 404–411. https://doi.org/10.1016/j.amjcard.2015.10.059

  19. Müller, K., Gamba, G., Jaquet, F., Hess, B., 2003. Torasemide vs. furosemide in primary care patients with chronic heart failure NYHA II to IV--efficacy and quality of life. Eur J Heart Fail 5, 793–801. https://doi.org/10.1016/s1388-9842(03)00150-8

  20. Oyama, M.A., Peddle, G.D., Reynolds, C.A., Singletary, G.E., 2011. Use of the loop diuretic torsemide in three dogs with advanced heart failure. Journal of Veterinary Cardiology 13, 287–292. https://doi.org/10.1016/j.jvc.2011.10.001

  21. Peddle, G.D., Singletary, G.E., Reynolds, C.A., Trafny, D.J., Machen, M.C., Oyama, M.A., 2012. Effect of torsemide and furosemide on clinical, laboratory, radiographic and quality of life variables in dogs with heart failure secondary to mitral valve disease. Journal of Veterinary Cardiology, The Mitral Valve 14, 253–259. https://doi.org/10.1016/j.jvc.2012.01.003

  22. Potter, B.M., Ames, M.K., Hess, A., Poglitsch, M., 2019. Comparison between the effects of torsemide and furosemide on the renin-angiotensin-aldosterone system of normal dogs. Journal of Veterinary Cardiology 26, 51–62. https://doi.org/10.1016/j.jvc.2019.11.003

  23. Sogame, Y., Okano, K., Hayashi, K., Uchida, T., Tsuda, Y., 1996. Urinary excretion profile of torasemide and its diuretic action in dogs. J Pharm Pharmacol 48, 375–379. https://doi.org/10.1111/j.2042-7158.1996.tb05936.x

  24. Uechi, M., Matsuoka, M., Kuwajima, E., Kaneko, T., Yamashita, K., Fukushima, U., Ishikawa, Y., 2003. The effects of the loop diuretics furosemide and torasemide on diuresis in dogs and cats. J Vet Med Sci 65, 1057–1061. https://doi.org/10.1292/jvms.65.1057

  25. Vargo, D.L., Kramer, W.G., Black, P.K., Smith, W.B., Serpas, T., Brater, D.C., 1995. Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide and furosemide in patients with congestive heart failure. Clinical Pharmacology & Therapeutics 57, 601–609. https://doi.org/10.1016/0009-9236(95)90222-8

  26. Vetoquinol, S., 2015. UpCard | European Medicines Agency [WWW Document]. URL https://www.ema.europa.eu/en/medicines/veterinary/EPAR/upcard (accessed 12.6.23).

Evidence
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