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Bumetanide


Bumetanide

Article Author:
Gursharan Sidhu
Article Editor:
Yana Puckett
Updated:
6/21/2020 8:24:28 PM
For CME on this topic:
Bumetanide CME
PubMed Link:
Bumetanide

Indications

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 the nephrotic syndrome. It may also be indicated for refractory edema due to other loop diuretics. Bumetanide may be an appropriate option in case of 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.[1][2][3]

Mechanism of Action

Diuretics play a crucial role in the treatment of 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 thin descending limb of Henle and 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.[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 excretion of sodium chloride to the distal tubule (natriuresis), calciuria, phosphaturia, and minimal bicarbonaturia. Studies have shown the onset of diuretic action to occur 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

To control edema, a staggered dosing schedule or a 3 to 4 times daily dosing schedule with half-day rest intervals 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.[1][6]

Adverse Effects

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.[7][8][9]

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.[10]

Monitoring

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.[11]

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.[12]

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.[13]

Enhancing Healthcare Team Outcomes

Managing drug overdose requires an interprofessional team of healthcare professionals that includes a nurse, a pharmacist, and several physicians 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 associated co-morbidities of a patient.
  • 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 electrolytes levels. Proper dose adjustments can be revolutionary in improving the various conditions discussed above in the indications section.
  • Hypokalemia is essential to rule out, which can be an alarming sign of impending cardiac arrhythmia, especially 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. 

References

[1] Flamenbaum W,Friedman R, Pharmacology, therapeutic efficacy, and adverse effects of bumetanide, a new     [PubMed PMID: 6763204]
[2] Pacifici GM, Clinical pharmacology of the loop diuretics furosemide and bumetanide in neonates and infants. Paediatric drugs. 2012 Aug 1     [PubMed PMID: 22702741]
[3] Navas A,Jannus F,Fernández B,Cepeda J,Medina O'Donnell M,Díaz-Ruiz L,Sánchez-González C,Llopis J,Seco JM,Rufino-Palomares E,Lupiáñez JA,Gómez-Ruiz S,Quiles JL,Battino M,Choquesillo-Lazarte D,Ruiz-Muelle AB,Fernández I,Reyes-Zurita F,Rodríguez-Diéguez A, Designing Single-Molecule Magnets as Drugs with Dual Anti-Inflammatory and Anti-Diabetic Effects. International journal of molecular sciences. 2020 Apr 29     [PubMed PMID: 32365648]
[4] Kokko JP, Site and mechanism of action of diuretics. The American journal of medicine. 1984 Nov 5     [PubMed PMID: 6496555]
[5] Jayakumar S,Puschett JB, Study of the sites and mechanisms of action of bumetanide in man. The Journal of pharmacology and experimental therapeutics. 1977 Apr     [PubMed PMID: 850144]
[6] Pentikäinen PJ,Penttilä A,Neuvonen PJ,Gothoni G, Fate of [14C]-bumetanide in man. British journal of clinical pharmacology. 1977 Feb     [PubMed PMID: 843423]
[7] Roberts CJ,Homeida M,Roberts F,Bogie W, Effects of piretanide, bumetanide and frusemide on electrolyte and urate excretion in normal subjects. British journal of clinical pharmacology. 1978 Aug     [PubMed PMID: 678389]
[8] Davies DL,Wilson GM, Diuretics: mechanism of action and clinical application. Drugs. 1975     [PubMed PMID: 1092541]
[9] Ward A,Heel RC, Bumetanide. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use. Drugs. 1984 Nov     [PubMed PMID: 6391889]
[10] Sung KW,Kirby M,McDonald MP,Lovinger DM,Delpire E, Abnormal GABAA receptor-mediated currents in dorsal root ganglion neurons isolated from Na-K-2Cl cotransporter null mice. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2000 Oct 15     [PubMed PMID: 11027211]
[11] Vardeny O,Claggett B,Kachadourian J,Desai AS,Packer M,Rouleau J,Zile MR,Swedberg K,Lefkowitz M,Shi V,McMurray JJV,Solomon SD, Reduced loop diuretic use in patients taking sacubitril/valsartan compared with enalapril: the PARADIGM-HF trial. European journal of heart failure. 2019 Mar     [PubMed PMID: 30741494]
[12] Allegaert K,Lahav A,van den Anker JN, Erratum to: A Mechanism to Explain Ototoxicity in Neonates Exposed to Bumetanide: Lessons to Help Improve Future Product Development in Neonates. Paediatric drugs. 2016 Dec     [PubMed PMID: 27665286]
[13] Hung CM,Peng CK,Wu CP,Huang KL, Bumetanide attenuates acute lung injury by suppressing macrophage activation. Biochemical pharmacology. 2018 Oct     [PubMed PMID: 30102895]