Bumetanide

Bumetanide is an antihypertensive agent belonging to Loop Diuretics.

Bumetanide is used to treat the symptoms of fluid retention or edema in people with congestive heart failure, liver disease or kidney disorder. It is also used for treatment of hypertension and hypercalcemia.

Bumetanide is available in oral and injectable administrations (intravenous, intramuscular). Bumetanide is rapidly absorbed after the 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 litres. Plasma clearance is 225 to 228 ml/min.

Bumetanide shows common side effect like frequent urination, feeling thirsty, dry mouth, headache, feeling confused or dizzy, muscle cramps or weak muscles, etc.

Bumetanide is available in the dosage form of Tablets and Injectable solution.

Bumetanide is available in India, Japan, US, UK, Europe, and Canada.

Bumetanide belonging to the Loop Diuretics, acts as an antihypertensive agent.

Bumetanide interfere with renal cAMP and/or inhibits the sodium-potassium ATPase pump. Bumetanide appears to block the active reabsorption of chloride and possibly sodium in the ascending loop of Henle, altering electrolyte transfer in the proximal tubule. This result in excretion of sodium, chloride, and water and, hence, diuresis.

The Onset of action of Bumetanide occurs within 30-60min of its administration.

The Duration of Action for Bumetanide in the body is approximately 4-6 hours.

The Tmax was found within 1-2 hours following the administration of Bumetanide and the Cmax was about 176ng/mL.

Bumetanide is available in the form of Tablets and Injectable solution.

Bumetanide tablet taken by mouth. Usually once or twice a day but should not exceed a daily dose of 10mg.

Bumetanide Injectable solutions by Intramuscular and Intravenous route as single dose or several dose but should not exceed a daily dose of 10 mg.

Bumetanide is used to reduce extra fluid in the body (edema) caused by conditions such as congestive heart failure, liver disease, and kidney disease. Getting rid of the extra water helps to decrease fluid in the lungs so that you can breathe easier. It also helps to reduce swelling of the arms, legs, and stomach/abdomen.

Bumetanide is an antihypertensive agent belonging to Loop Diuretics. Bumetanide interferes with renal cAMP and/or inhibits the sodium-potassium ATPase pump, which alter the electrolyte transfer in the proximal tubule. Bumetanide is used to treat the symptoms of fluid retention or edema in people with congestive heart failure, liver disease or kidney disorder. Also used for treatment of hypertension and hypercalcemia.

Bumetanide is approved for use in the following clinical indications

• Edema

Bumetanide approved for managing various edematous conditions secondary to cardiac failure with or without ascites, or hepatic/renal disease, including nephrotic syndrome. It may also be indicated for refractory edema resistant to other loop diuretics.

Although not approved, there have been certain off-label indications. These include

• Hypertension

Bumetanide may be used alone or in conjunction with other antihypertensive agents in treating hypertension, although this is not an FDA-approved indication.

• Hypercalcemia

Treating acute hypercalcemia is also an off-label indication for the drug. Bumetanide may be an appropriate option for patients who have an allergic reaction to furosemide, another loop diuretic.

• Edema

Adults

Orally: 0.5-2 mg once; may be repeated in 4-5 hours for up to 2 doses; not to exceed 10 mg/day

Intramuscular: 0.5-1 mg once; may be repeated in 2-3 hours for up to 2 doses; not to exceed 10 mg/day

Intravenously: 1 mg initially, then 0.5-2 mg/hour.

Continuous Infusion: 1 mg/hour up to 12 mg/day.

Transitioning from IV to oral: Give the same IV dose orally (eg, total daily IV dose of 3 mg/day should be converted to an oral dose of 3 mg/day in 1 to 3 divided doses), then monitor urine output and adjust oral dose as needed.

Pediatric (off-label)

Infants under 6 months: 0.01-0.05 mg/kg once daily or every other day; the optimum diuretic effect is reported at 0.04 mg/kg; lower dosages have been shown to have greater efficacy

Infants 6 months and older: 0.01-0.1 mg/kg once daily or every other day; not to exceed 10 mg/day.

• Hypertension (off-label)

1mg Intravenous loading dose, then 0.5-2 mg/day orally divided every 12 hours

• 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.

Bumetanide is available in various strengths as Tablets (0.5mg, 1mg and 2mg) and Injectable

solution (0.25mg/ml).

Bumetanide is available in the form of Tablets and Injectable solution.

Avoid consumption of a high-salt or low-sodium diet while taking Bumetanide.

Bumetanide is contraindicated in following:

• Patients with anuria
• Patients with the history of hypersensitivity to Bumetanide.
• Patients with progressive renal disease
• In patient in hepatic coma or in states of severe electrolyte depletion

• Volume and Electrolyte Depletion

The dose of Bumetanide should be adjusted to the patient's need. Excessive doses or too frequent administration can lead to profound water loss, electrolyte depletion, dehydration, reduction in blood volume and circulatory collapse with the possibility of vascular thrombosis and embolism, particularly in elderly patients.

• Hypokalemia

Hypokalemia can occur as a consequence of Bumetanide administration. Prevention of hypokalemia requires particular attention in the following conditions: patients receiving digitalis and diuretics for congestive heart failure, hepatic cirrhosis and ascites, states of aldosterone excess with normal renal function, potassium-losing nephropathy, certain diarrheal states, or other states where hypokalemia is thought to represent particular added risks to the patient, i.e., history of ventricular arrhythmias. In patients with hepatic cirrhosis and ascites, sudden alterations of electrolyte balance may precipitate hepatic encephalopathy and coma. Treatment in such patients is best initiated in the hospital with small doses and careful monitoring of the patient's clinical status and electrolyte balance. Supplemental potassium and/or spironolactone may prevent hypokalemia and metabolic alkalosis in these patients.

• Ototoxicity

In cats, dogs and guinea pigs, bumetanide has been shown to produce ototoxicity. In these test animals’ bumetanide was 5 to 6 times more potent than furosemide and, since the diuretic potency of bumetanide is about 40 to 60 times of furosemide, it is anticipated that blood levels necessary to produce ototoxicity will rarely be achieved. The potential exists, however, and must be considered a risk of intravenous therapy, especially at high doses, repeated frequently in the face of renal excretory function impairment. Potentiation of aminoglycoside ototoxicity has not been tested for bumetanide. Like other members of this class of diuretics, bumetanide probably shares this risk.

• Allergy to Sulfonamides

Patients allergic to sulfonamides may show hypersensitivity to Bumetanide.

• Thrombocytopenia

Since there have been rare spontaneous reports of thrombocytopenia from postmarketing experience, patients should be observed regularly for possible occurrence of thrombocytopenia.

• Hyperuricemia

Hyperuricemia may occur; it has been asymptomatic in cases reported till date. Reversible elevations of the BUN and creatinine may also occur, especially in association with dehydration and particularly in patients with renal insufficiency. Bumetanide may increase urinary calcium excretion with resultant hypocalcemia.

• Hypomagnesemia

Diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Consumption of alcohol is not recommended while you are taking this medicine due to increased risk of severe adverse effects. These side effects may include dizziness and fainting.

It is not known whether this drug is excreted in human milk. As a general rule, nursing should not be undertaken while the patient is on Bumetanide since it may be excreted in human milk.

Bumetanide has been assigned to pregnancy category C by the FDA. Animal studies have failed to reveal evidence of teratogenicity. A dose-related reduce in litter size and an increase in resorption rate were noted in the rabbits at doses between 3.4 and 10 times the maximum recommended therapeutic human dose (on a per kg basis). There are no data from human pregnancy studies. Bumetanide should only be given during pregnancy when benefit outweighs risk.

Avoid consumption of a high-salt or high-sodium diet while taking Bumetanide.

The adverse reactions related to Bumetanide can be categorized as

Common Adverse effects

• Hyperuricemia (characteristic of all loop diuretics), hypochloremia, hypokalemia, azotemia, and hyponatremia.

Less Common Adverse effects

• Hyperglycemia and increased serum creatinine, muscle weakness, and hearing impairment.

Rare Adverse effects

• Hypotension (including orthostatic hypotension), encephalopathy (in instances of pre-existing hepatic disease), and renal failure.

• Drugs With Ototoxic Potential

Especially in the presence of impaired renal function, the use of parenterally administered bumetanide in patients to whom aminoglycoside antibiotics are also being given should be avoided, except in life-threatening conditions.

• Drugs With Nephrotoxic Potential

There has been no experience with the concurrent use of Bumetanide with drugs known to have a nephrotoxic potential. Therefore, the simultaneous administration of these drugs should be avoided.

• Lithium

Lithium should generally not be given with diuretics (such as Bumetanide) because they reduce its renal clearance and add a high risk of lithium toxicity.

• Probenecid

Pretreatment with probenecid reduces both the natriuresis and hyperreninemia produced by Bumetanide. This antagonistic effect of probenecid on Bumetanide natriuresis is not due to a direct action on sodium excretion but is probably secondary to its inhibitory effect on renal tubular secretion of bumetanide. Thus, probenecid should not be administered concurrently with Bumetanide.

• Indomethacin

Indomethacin blunts the increases in urine volume and sodium excretion seen during Bumetanide treatment and inhibits the bumetanide-induced increase in plasma renin activity. Concurrent therapy with Bumetanide is thus not recommended.

• Antihypertensives

Bumetanide may potentiate the effect of various antihypertensive drugs, necessitating a reduction in the dosage of these drugs.

• Digoxin

Interaction studies in humans have shown no effect on digoxin blood levels.

• Anticoagulants

Interaction studies in humans have shown Bumetanide to have no effect on warfarin metabolism or on plasma prothrombin activity.

The common side of Bumetanide include the following

• Common
  

Frequent urination, feeling thirsty, dry mouth, headache, feeling confused or dizzy, muscle cramps or weak muscles.

• Rare

Unexplained bruising or bleeding, a high temperature, sore throat and mouth ulcers, ringing in ear (tinnitus) or loss of hearing.

• Pregnancy

Teratogenic Effects Pregnancy Category C

Bumetanide is neither teratogenic nor embryocidal in mice when given in doses up to 3400 times the maximum human therapeutic dose. Bumetanide has been shown to be nonteratogenic, but it has a slight embryocidal effect in rats when given in doses of 3400 times the maximum human therapeutic dose and in rabbits at doses of 3.4 times the maximum human therapeutic dose. In one study, moderate growth retardation and increased incidence of delayed ossification of sternebrae were observed in rats at oral doses of 100 mg/kg/day, 3400 times the maximum human therapeutic dose. These effects were associated with maternal weight reductions noted during dosing. No such adverse effects were observed at 30 mg/kg/day (1000 times the maximum human therapeutic dose). No fetotoxicity was observed at 1000 to 2000 times the human therapeutic dose. In rabbits, a dose-related decrease in litter size and an increase in resorption rate were noted at oral doses of 0.1 and 0.3 mg/kg/day (3.4 and 10 times the maximum human therapeutic dose). A slightly increased incidence of delayed ossification of sternebrae occurred at 0.3 mg/kg/day; however, no such adverse effects were observed at the dose of 0.03 mg/kg/day. The sensitivity of the rabbit to Bumetanide parallels the marked pharmacologic and toxicologic effects of the drug in this species. Bumetanide was not teratogenic in the hamster at an oral dose of 0.5 mg/kg/day (17 times the maximum human therapeutic dose). Bumetanide was not teratogenic when given intravenously to mice and rats at doses up to 140 times the maximum human therapeutic dose. There are no adequate and well-controlled studies in pregnant women. A small investigational experience in the United States and marketing experience in other countries to date have not indicated any evidence of adverse effects on the fetus, but these data do not rule out the possibility of harmful effects. Bumetanide should be given to a pregnant woman only if the potential benefit justifies the potential risk to the fetus.

• Nursing Mothers

It is not known whether this drug is excreted in human milk. As a general rule, nursing should not be undertaken while the patient is on Bumetanide since it may be excreted in human milk.

• Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 have not been established. In vitro studies using pooled sera from critically ill neonates have shown bumetanide to be a potent displacer of bilirubin. The administration of bumetanide could present a particular concern if given to critically ill or jaundiced neonates at risk for kernicterus.

• Geriatric Use

Clinical studies of Bumetanide did not include sufficient numbers of subjects aged 65 and over to determine whether they responded differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Overdosage can lead to acute profound water loss, volume and electrolyte depletion, dehydration, reduction of blood volume and circulatory collapse with a possibility of vascular thrombosis and embolism. Electrolyte depletion may be manifested by weakness, dizziness, mental confusion, anorexia, lethargy, vomiting and cramps. Treatment consists of replacement of fluid and electrolyte losses by careful monitoring of the urine and electrolyte output and serum electrolyte levels.

Pharmacodynamic

Bumetanide is a loop diuretic of the sulfamyl category to treat heart failure. It is often used in patients in whom high doses of furosemide are ineffective. There is however no reason not to use bumetanide as a first choice drug. The main difference between the two substances is in bioavailability. Bumetanide has more predictable pharmacokinetic properties as well as clinical effect. In patients with normal renal function, bumetanide is 40 times more effective than furosemide.

Pharmacokinetics

• Absorption

Bumetanide is a loop diuretic with a rapid onset and short duration of action. Following oral administration of Bumetanide the onset of diuresis occurs in 30 to 60 minutes. Peak activity is reached between 1 and 2 hours. At usual doses (1 mg to 2 mg) diuresis is largely complete within 4 hours; with higher doses, the diuretic action lasts for 4 to 6 hours. Diuresis starts within minutes following an intravenous injection and reaches maximum levels within 15 to 30 minutes.

• Distribution

In healthy individuals, greater than 95% of Bumetanide is bound to plasma protein, mainly albumin.

• Metabolism and Excretion

Oral administration of Bumetanide to human volunteers revealed that 81% of the administered radioactivity was excreted in the urine, 45% of it as unchanged drug. Urinary and biliary metabolites identified in this study were formed by oxidation of the N-butyl side chain. Biliary excretion of Bumetanide amounted to only 2% of the administered dose.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/018225s024lbl.pdf
• https://www.rxlist.com/Bumetanide-drug.htm#description
• https://www.drugs.com/dosage/bumetanide.html#Precautions
• https://go.drugbank.com/drugs/DB00887
• https://www.rxlist.com/consumer_bumetanide_bumex/drugs-condition.htm