Continuing Education Activity
Bumetanide is FDA approved for the management of various edematous conditions secondary to cardiac failure or hepatic or renal disease, including nephrotic syndrome. It falls under the loop diuretic class. This activity reviews the indications, action, and contraindications for bumetanide 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, relevant interactions pertinent for members of the interprofessional team in the treatment and care of patients with edematous conditions.
- 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.
Bumetanide has United States Food and Drug Administration (FDA) approval for the management of various edematous conditions secondary to cardiac failure with or without ascites, hepatic or renal disease, including nephrotic syndrome. It may also be indicated for refractory edema due to other loop diuretics. Bumetanide may be an appropriate option for a medical history of an allergic reaction due to furosemide, another loop diuretic.
Based on recent studies, seizures and behavioral problems in patients with tuberous sclerosis may be treated by agents that enhance GABA-anergic transmission by influencing chloride regulation. Using bumetanide for this purpose is non-FDA approved. Loop diuretics, such as bumetanide may also be therapeutic for the initial treatment of hypertension and acute hypercalcemia.
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. 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 of the 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, 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.
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. The peak of the drug's action occurs at 90 minutes after oral administration.
To control edema, a staggered dosing schedule or a 3 to 4 times daily dosing schedule with half-day rest intervals in between is recommended to increase tolerability and efficacy. It is the safest and most effective method for the continued control of edema. Oral and injectable administrations (intravenous, intramuscular) are available. 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 1.2 to 1.5 hours, and the volume of distribution is about 25 liters. Plasma clearance is 225 to 228 ml/min. The different modes of administration of bumetanide with dosages are the following:
- Bumetanide intramuscular injection solution: 0.25 mg/1 mL
- Bumetanide intravenous injection solution: 0.25 mg/1mL
- Bumetanide oral tablet: 0.5 mg, 1 mg, 2 mg
Oral Administration: The total daily dosage of bumetanide is 0.5 mg to 2 mg, usually given as a single dose. If the diuretic response after the initial dose of bumetanide is not adequate, a second or third dose is possible at 4- to 5-hour intervals, with a maximum daily dose of 10 mg. In patients with hepatic failure, dosing should remain at a minimum level and, if necessary, should be increased very carefully.
The primary adverse effects of bumetanide include hypocalcemia, azotemia, metabolic alkalosis, hyperglycemia, hypomagnesemia, hyponatremia, hypokalemia, tenderness, and myalgia. All loop diuretics decrease urate excretion, which can lead to hyperuricemia. Bumetanide may potentially cause ototoxicity, but there have been very few recorded instances. The most frequent clinical adverse reactions related to bumetanide are muscle cramps.
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.
Blood pressure, uric acid, jugular venous pressure, blood glucose, electrolytes, blood urea nitrogen/serum creatinine, and urine output must all need monitoring 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. Caution is also necessary for geriatric patients who have greater sensitivity to the hypotensive and diuretic effects of bumetanide.
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.
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.
Enhancing Healthcare Team Outcomes
Managing drug overdose requires an interprofessional team of healthcare professionals, including nurses, pharmacists, and several clinicians (potentially including mid-level practitioners) in different specialties. 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.
- Physicians 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 sometimes lifesaving. It is critical to follow up on serum electrolyte levels. Proper dose adjustments can be revolutionary 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 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 clinical expertise will provide the best patient outcomes while minimizing adverse events. [Level 5]