Continuing Education Activity

Bumetanide is FDA-approved for managing various edematous conditions secondary to cardiac failure or hepatic or renal disease, including nephrotic syndrome. It is a member of the loop diuretic class of drugs. This activity reviews bumetanide's indications, action, and contraindications as a valuable agent in treating and managing various edematous conditions secondary to cardiac failure or hepatic or renal disease. This activity will highlight the mechanism of action, adverse effects, and other key factors such as dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions pertinent for interprofessional team members in the treatment and care of patients with edematous conditions.

Objectives:

• Identify the mechanism of action of bumetanide.
• Describe the potential adverse effects of bumetanide.
• Review the appropriate monitoring of patients receiving bumetanide.
• Summarize interprofessional team strategies for improving care coordination and communication to advance bumetanide and improve outcomes.

Indications

Bumetanide has United States Food and Drug Administration (FDA) approval for managing various edematous conditions secondary to cardiac failure with or without ascites, or hepatic/renal disease, including nephrotic syndrome.[1] It may also be indicated for refractory edema resistant to other loop diuretics.

Bumetanide may be used alone or in conjunction with other antihypertensive agents in treating hypertension, although this is not an FDA-approved indication. Treating acute hypercalcemia is also an off-label indication for the drug.[2] Bumetanide may be an appropriate option for patients who have an allergic reaction to furosemide, another loop diuretic.

Recent studies show seizures and behavioral problems in patients with tuberous sclerosis may be treated by agents that enhance GABA-anergic transmission by influencing chloride regulation.[3] Using bumetanide for this purpose is also not FDA-approved. 

Mechanism of Action

Diuretics play a crucial role in treating edema and hypertension by causing the induction of a negative balance of solute and water. Loop diuretics are physiologically the most potent family of diuretics, as demonstrated by possessing natriuretic and chloriuretic potency of diuretic drug class. These agents potentially increase Na and Cl excretion to over 25% of the filtered load. Although they have no direct epithelial effect on segments such as the thin descending limb of Henle and the thick ascending limb of Henle, many diuretics decrease fluid reabsorption by abolishing the papillary osmotic gradient. Most of the loop diuretics have a direct inhibitory effect on the cotransport process, specifically by interfering with the active chloride transport secondary to the presence of sodium, located on the luminal membrane of the segment. Loop diuretics (furosemide, bumetanide, torsemide, ethacrynic acid) inhibit the concentrating mechanisms in the medullary segment, whereas diuretics such as thiazides are effective primarily in the cortical segment and inhibit the urinary diluting mechanism.[4][5]

Bumetanide inhibits the reabsorption of sodium and chloride in the ascending loop of Henle and proximal renal tubule, which interferes with the chloride-binding cotransport system. This mechanism increases the excretion of water, magnesium phosphate, sodium chloride, magnesium phosphate, and calcium. It decreases both free water clearance and solute free water reabsorption increases sodium chloride excretion to the distal tubule (natriuresis), calciuria, phosphaturia, and minimal bicarbonaturia. Studies have shown the onset of diuretic action occurs during 0 to 30 minutes following intravenous use and 30 to 60 min following oral administration. The diuretic effect and the total duration of action last for 3 to 4 hours (270 min) with similar net urine output between intravenous and oral administration.[6] The peak of the drug's action occurs at 90 minutes after oral administration.[1]

Administration

Bumetanide is available in oral and injectable administrations (intravenous, intramuscular). Bumetanide is rapidly absorbed after oral and intravenous formulations. 95% of the drug extensively bounds to plasma proteins and is eliminated by the metabolism of the butyl side chain and partially removed through urine excretion. The apparent half-life is 1.0 to 1.5 hours, and the volume of distribution is about 25 liters. Plasma clearance is 225 to 228 ml/min.

Bumetanide has high bioavailability, is between 80% to 100%; this means that oral and IV bioavailability are roughly equivalent, constructed to furosemide where oral doses should be roughly double IV doses.[7]

The different modes of administration of bumetanide with dosages are the following:

• Bumetanide oral tablet: 0.5 mg, 1 mg, 2 mg
• Bumetanide intramuscular/intravenous injection solution: 0.25 mg/1 mL

Dosing regimens based on the condition are as follows:

• Edema
  • Oral route of administration:
    • 0.5 to 10 mg per day orally divided once or twice daily. Initiate treatment 0.5 to 2.0 mg per day, repeating every 4 to 5 hours until obtaining the appropriate response. The maximum dosage is 10 mg per day.
  • Intramuscular/intravenous route of administration:
    • 0.5 to 10 mg per day IM/IV divided once or twice daily. Initiate treatment 0.5 to 1.0 mg per day over 1 to 2 minutes, repeating every 2 to 3 hours until obtaining the appropriate response. The maximum dosage is 10 mg per day.
      • An alternate day schedule or schedule of three to four days on with a one to two-day rest period may increase tolerability and effectiveness in continued edema control. Intravenous administration should be reserved for patients unable to take oral medications.
      • Bumetanide solution is not Y-site compatible with midazolam and is admixed incompatible with dobutamine and milrinone.
• Hypercalcemia (off-label):
  • 1 to 4 mg IV every 1 to 4 hours; administer with saline to maintain the patient's urine output at 200 to 250 mL/hour.
• Hypertension (off label):
  • 0.5 to 2.0 mg daily by mouth divided into one or two doses.

Renal dosing: in patients with anuria, bumetanide is contraindicated. In patients with hepatic failure, dosing should remain at a minimum level and, if necessary, should be increased very carefully.[1][6]

Data is lacking for the use of bumetanide in pregnancy and breastfeeding. No teratogenicity is expected based on data from other loop diuretics, although there is a potential risk for decreased placental perfusion based on the drug's mechanism of action. Clinicians should consider alternative therapy in patients breastfeeding high-risk infants.

Adverse Effects

The most common adverse events associated with bumetanide include hyperuricemia (characteristic of all loop diuretics), hypochloremia, hypokalemia, azotemia, and hyponatremia. Other, less common adverse effects include hyperglycemia and increased serum creatinine. muscle weakness, and hearing impairment.[8][9]

Rare but significant or potentially life-threatening adverse reactions include hypotension (including orthostatic hypotension), encephalopathy (in instances of pre-existing hepatic disease), and renal failure.[10]

All loop diuretics exhibit potent diuresis capabilities, and excessive amounts can lead to significant diuresis with fluid and electrolyte loss; close medical supervision is necessary when administering these agents.

Contraindications

Bumetanide is contraindicated in patients with hypersensitivity to the drug or components of the formulation. It is also contraindicated in patients with hypersensitivity to loop diuretics, hepatic disease, hepatic encephalopathy, severe electrolyte depletion, and anuria. Bumetanide is in the FDA pregnancy risk category C classification. The safety and efficacy of bumetanide use have not been established in neonates, infants, children, and adolescents under age 18 years.[11]

Complete medication reconciliation should be performed on all patients when adding any drug therapy, and bumetanide is no exception. Loop diuretics might enhance the hypotensive effect (specifically postural hypotension) and increase nephrotoxicity of ACE inhibtors.[12] Other significant interactions also exist; the pharmacist should check for potential interactions and report any concerns to the prescriber, so alternative therapy can be undertaken if necessary.

Monitoring

Blood pressure, uric acid, jugular venous pressure, blood glucose, electrolytes, blood urea nitrogen/serum creatinine, and urine output must be monitored in patients taking bumetanide. Bumetanide is a potent diuretic; it can precipitate electrolyte and acid-base imbalances such as hypokalemia, hypocalcemia, hypochloremia, hyponatremia, hypomagnesemia, metabolic alkalosis. It is essential to monitor urine output and serum electrolyte levels frequently. Dosage adjustments may be necessary, especially in patients treated for prolonged periods or with high doses; it is crucial that patients are monitored for hypokalemia, hypomagnesemia, and volume depletion resulting from excessive diuresis. Caution is also necessary for geriatric patients who have greater sensitivity to the hypotensive and diuretic effects of bumetanide.[13]

The development of oliguria during therapy for patients with progressive renal disease is a sign to discontinue treatment with bumetanide. Blood and/or urine glucose levels should be monitored closely in diabetes mellitus patients taking bumetanide because loop diuretics can impair glucose tolerance leading to hyperglycemia. Signs and symptoms of hearing impairment and tinnitus require attention from the clinician as bumetanide may cause ototoxicity, with the dose adjusted accordingly. The cardiac function also requires monitoring as it may worsen heart failure and ventricular arrhythmias in patients with preexisting conditions.[14]

Toxicity

Extensive or too frequent dosage can lead to acute volume and electrolyte depletion, low circulatory volume with a possibility of vascular thrombosis, and embolism. Symptoms such as weakness, mental confusion, anorexia, lethargy, vomiting, and cramps may occur because of electrolyte depletion. Treatment is with the adequate replacement of fluids and electrolytes such as add potassium supplements or potassium-sparing diuretics in case of potassium depletion. Asymptomatic hyperuricemia and slight reversible elevations of BUN and creatinine may also occur, particularly associated with dehydration or patients with renal insufficiency. Bumetanide has shown an increase in urinary calcium with resultant hypocalcemia. Similarly, hypomagnesemia should be measured periodically.[15]

Enhancing Healthcare Team Outcomes

Managing bumetanide therapy requires an interprofessional team of healthcare professionals, including clinicians (MDs, DOs, NPs, PAs) in multiple specialties, nurses, and pharmacists. Ensuring the proper management of patients using bumetanide may require consideration of some of the following by health professionals:

• There may be a need to involve specialty consultation depending on the reason for diuretic therapy and the patient's associated comorbidities.
• Ordering/prescribing clinicians should order serum electrolyte levels periodically and check for any fluid or electrolyte imbalance.
• Monitor the patient for signs of dehydration frequently, such as low urine output, etc. Taking prompt action can be beneficial and even lifesaving. It is critical to follow up on serum electrolyte levels. Proper dose adjustments can be crucial in improving the various conditions discussed above in the indications section.
• Hypokalemia must be ruled out, as it can be an alarming sign of impending cardiac arrhythmia, especially for those patients with a history of ventricular arrhythmia.
• Discuss and consult with a toxicologist and nephrologist if an overdose is suspected.
• Provide reassurance for asymptomatic hyperuricemia and azotemia in patients with signs of dehydration as they are likely to resolve after fluid replacement. 

Utilizing an interprofessional approach with each discipline sharing patient information and their particular clinical expertise will provide the best patient outcomes while minimizing adverse events. [Level 5]