Continuing Education Activity

Torsemide is a loop diuretic extensively used in the management of heart failure, renal disease, and cirrhosis. Torsemide acts on electrolyte channels in the renal tubules. Significant adverse events include electrolyte abnormalities, photosensitive reactions, and hypotension. Contraindications to use are sulfa allergy, anuria, and hepatic coma. This activity reviews the clinical use, monitoring, and toxicity of torsemide, in addition to a brief overview of clinical trials and the need for further research.

Objectives:

• Outline the clinical indications of torsemide.
• Describe in detail the mechanism of action of torsemide.
• Summarize the dosage adjustment of torsemide in patients with different degrees of chronic kidney disease.
• Review how interprofessional care coordination can improve therapy in patients receiving torsemide.

Indications

Torsemide is a loop diuretic that belongs to the pyridine -sulfonylurea class.[1] It received approval for use in the united states in 1993. The effect of torsemide is dose-dependent. The maximum effective dose is the dose required to attain maximum sodium excretion. Torsemide is available in oral and IV form. The bioavailability of oral torsemide is high, so the efficacy of oral and IV forms is equivocal.[1]

Indications of torsemide are: 

1. Edema secondary to the following
   • Heart failure: Diuretics are the mainstay of treatment in edema due to heart failure.[2] The initial dose is 5 to 10 mg once daily; the dose can be double until reaching the desired diuretic effect. The maximum daily dose is 200 mg /day.[3]
   • Chronic renal disease: Initial oral dose is 20 mg once daily, and the dose can double until obtaining the desired diuretic effect. The maximum dose is 200 mg/day. Doses over 200 mg have not been adequately studied.[1]
   • Hepatic cirrhosis: Initial oral dose is 5 to 10 mg once daily. The dose may be increased slowly by doubling the doses until achieving the desired diuretic effect. The maximum recommended daily dose is 40 mg. The usual recommendation is to administer with an aldosterone antagonist or a potassium-sparing diuretic.[1][4]
2. Hypertension (not a first-line agent)[5]: Initial oral dose is 5 mg once daily, and the dose may increase to 10 mg daily after 4 to 6 weeks. The maximum daily dose is 10 mg.[5][1] Usually used in combination with other oral antihypertensives.

Mechanism of Action

Torsemide causes 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).

However, studies have also shown that genetics can play a role in the drug response of various loop diuretics, including torsemide.[6]

Administration

Torsemide is available in two forms. IV form and oral form. 

Patients may take the oral form with or without food. IV administration is the recommendation for inpatient settings and when rapid action of the drug is needed.

The bioavailability of torsemide is approximately 80%, which allows equivalency between oral and IV to 1 to 1, unlike furosemide (oral to IV is 2 to 1 ).

The onset of diuresis occurs within 1 hr with a peak in 1 to 2 hours after oral administration. With IV administration, the onset of action is within 10 mins with a peak in one hour. The duration of action of the drug is around 6 to 8 hours, irrespective of the route of administration. The drug is primarily metabolized by the liver (80%) and excreted in the urine. Half-life elimination is approximately 3.5 hours.

Although torsemide does not offer significant advantages over other loop diuretics, it may benefit patients who show an inadequate response to or do not tolerate other agents.[4]

Adverse Effects

1. Electrolyte disturbances: As a result of diuresis, torsemide can cause electrolyte abnormalities, including hypokalemia, hypocalcemia, acid-base imbalance, etc., causing fatal cardiac arrhythmias. It is more common with IV administration and with higher doses. 
2. Hypotension due to excessive diuresis. So diuretics are not recommended to start or be given on the day of any surgical procedure as they can severely affect blood pressure when compounded with anesthesia.
3. Renal failure due to aggressive diuresis, especially in cases of hypovolemia or infection/sepsis
4. Ototoxicity, especially with concomitant ototoxic drugs
5. Hyperuricemia may occur, including asymptomatic hyperuricemia or gout especially when used with other drugs that can cause hyperuricemia (like Thiazide diuretics)
6. Pancreatitis[7]
7. Sulfa allergy, causing Stevens-Johnson syndrome or toxic epidermal necrolysis[7]
8. Photosensitivity reaction[8]
9. Gastrointestinal symptoms like nausea, dyspepsia, diarrhea, constipation
10. Central nervous system manifestations like nervousness or anxiety
11. Diuretic resistance: Sometimes, an adequate diuretic response is unattainable despite using higher doses of loop diuretics. The diuretic response can be improved by IV administration or using torsemide with other diuretics (e.g., another loop diuretic or thiazide diuretic). Serum electrolytes require very close monitoring if using the diuretic combination.

Contraindications

Contraindications for using torsemide can classify as either absolute or relative.

Absolute contraindications

1. Hypersensitivity reactions/sulfa allergy

Relative contraindications

1. Elderly patients, especially if hypotensive 
2. Patients with hepatic coma
3. Anuric acute renal failure
4. Electrolyte abnormalities or arrhythmias at baseline
5. Patients with diabetes, as torsemide can cause hyperglycemia in high-risk individuals.

Monitoring

• Periodic monitoring of blood pressure and volume status is recommended.
• Lab monitoring includes BUN/Cr, Serum Co2, Electrolytes, and blood glucose periodically.

Toxicity

Toxicity usually occurs with medications that can increase serum concentrations of torsemide like methotrexate etc. No antidote is available for the treatment of toxicity. In instances of toxicity, close monitoring of kidney function and electrolytes are essential to promptly identify and treat acute kidney injury and severe electrolyte abnormalities.

Ototoxicity and nephrotoxicity occur with concomitant use of nephro or ototoxic medications. Animal studies have shown temporary ototoxicity with no permanent effect.[9] Further research is necessary for confirmation of temporary vs. permanent ototoxic effects in humans.

Enhancing Healthcare Team Outcomes

In patients with decompensated heart failure, both renal and hepatic clearance becomes reduced due to decreased renal plasma flow and hepatic congestion, respectively. As a result of reduced renal clearance, only a fraction of the given dose is delivered to the site of action in the kidney, causing less natriuresis in patients with heart failure than in normal subjects at any given dose.

A meta-analysis, including randomized clinical trials (RCTs) and observational studies, including heart failure patients, has shown that torsemide is associated with significant improvement in functional status and reduced cardiac mortality compared to furosemide. Findings also denote that there is no statistically significant difference in all-cause mortality or side effects experienced among the two diuretics.[10] However, further research in the future is needed to implement the findings in clinical practice. 

• In chronic kidney disease, dose adjustment of diuretics inversely relates to GFR.
• In moderate chronic kidney disease (CKD) (estimated GFR >30 mL/min/1.73 m), the maximum effective dose of torsemide is approximately 20 to 50 mg.
• In severe CKD (estimated GFR <30 mL/min/1.73 m), the maximum effective dose of torsemide is approximately 50 to 100 mg.
• In cases of acute kidney injury with oliguria, a higher dose is necessary for a diuretic response.
• It is important to note that torsemide does not get removed by hemodialysis, so no dosing adjustment is necessary for dialysis patients.
• In clinical practice, it is essential to note the oral dose equivalency of different loop diuretics, which is as follows: torsemide 20 mg = bumetanide 1 mg = furosemide 40 mg.

Torsemide therapy is best administered under the guidance of an interprofessional team approach, with clinicians (MDs, DOs, PAs, MDs), nurses, and pharmacists all contributing from their individual areas of expertise and engaging in open communication with other team members to monitor the patient's reaction to therapy. The pharmacist can also check for drug-drug interactions; nursing staff can counsel patients and serve as the initial contact point for the prescribing clinician. These are but a few examples of how interprofessional teamwork can improve outcomes with torsemide therapy when indicated and limit adverse events. [Level 5]