Bumetanide

Bumetanide is a sulfonamide- type loop diuretic , used in the treatment of edema associated with congestive heart failure, cirrhosis, and kidney disease such as nephrotic syndrome. It is structurally related to furosemide, but its diuretic potency is approximately 40 times greater. Bumetanide may be particularly useful in patients who do not respond to other diuretics or who have severe renal impairment and require large doses of loop diuretics .

Mechanism of action

The exact mechanism of action of bumetanide is not well known, but it has been suggested that the drug interferes with renal failure of cyclic adenosine 3 ‘, 5’-monophosphate (c-AMP). Unlike ethacrynic acid, bumetanide does not bind to the sulfhydryl groups of kidney proteins. The drug blocks the active reabsorption of sodium chloride in the ascending loop of Henle and possibly impairs electrolyte transfer in the proximal tubule. These effects cause increased urinary excretion of sodium, chloride, and water, resulting in profound diuresis. Additionally, bumetanide causes increased excretion of potassium, hydrogen , calcium, magnesium , bicarbonate, ammonium, and phosphate.

Diuresis caused by bumetanide can lead to increased aldosterone production, resulting in increased sodium reabsorption and increased excretion of potassium and hydrogen. Excessive loss of these electrolytes can lead to metabolic alkalosis .

Bumetanide is not an aldosterone antagonist , and it does not interfere with the activity of carbonic anhydrase. Bumetanide greatly increases renal blood flow by dilating the renal vasculature. Diuretics, including bumetanide, lower blood pressure, causing hypovolemia (decreased plasma and extracellular fluid), temporarily increasing glomerular filtration rate, and decreased cardiac output.

Cardiac output eventually returns to normal, but a reduction in peripheral resistance remains, which lowers blood pressure . In general, diuretics worsen glucose tolerance, and exert detrimental effects on the lipid profile

Pharmacokinetics

Bumetanide is administered orally, intramuscularly, or intravenously. After oral administration, bumetanide is 85-95% absorbed. The food delayed oral absorption, but do not alter the diuretic response. Diuresis generally begins 30 to 60 minutes after oral administration, 40 minutes after IM administration, and within minutes after IV administration. Peak effect occurs 1-2 hours after oral administration and 15-30 minutes after IV administration. Duration of action of bumetanide is 3-6 hours.

Bumetanide is extensively bound (96%) to plasma proteins , but it is unknown whether it crosses the placenta , enters CSF, or appears in human milk.

Bumetanide is metabolized in the liver, giving rise to five metabolites. 80% of the administered dose is excreted in the urine (45% unchanged), and 10-20% is excreted in the faeces. The plasma half-life is 1-1.5 hours.

Toxicity

Bumetanide has no mutagenic activity in vitro , with or without metabolic activation .

In the 18-month chronic toxicity studies, an increase in mammary adenomas was observed in female rats treated with 60 mg / kg / day (2000 times the human dose).

In reproduction studies, doses of 10, 30, 60 or 100 mg / kg / day only caused a slight decrease in the number of pregnancies in treated animals .

Indications

Treatment of peripheral edema, or edema associated with heart failure or nephrotic syndrome:

Oral administration:

  • Adults and adolescents: Initially 0.5-2 mg orally once a day. Multiple daily doses can be administered at 4-5 hour intervals if the initial diuretic response is not adequate. The maximum daily dose is 10 mg / day. In the management of edema, doses of up to 20 mg / day PO have been administered to patients with renal failure.
  • Elderly: See adult dose. Elderly patients may be more sensitive to the effects of the usual adult dose.
  • Children and infants: Initially 0.015 to 0.1 mg / kg PO once a day or once every other day. The maximum daily dose is 0.1 mg / kg or 10 mg.
  • Neonates: Initially, 0.01-0.05 mg / kg PO every 24-48 hours.

Parenteral administration:

  • Adults and adolescents: Initially 0.5-1 mg IV or IM. If the desired response is not achieved, administer a second or third dose within 2-3 hours. IV doses should be given slowly over 2 minutes. The maximum parenteral dose is 10 mg per day. In the management of edema, parenteral doses of up to 20 mg / day have been administered to patients with renal failure.
  • Elderly: See adult dose. Elderly patients may be more sensitive to the effects of the usual adult dose.
  • Children and babies; Initially 0.015 to 0.1 mg / kg IV or IM once a day or once every other day. The maximum daily dose is 0.1 mg / kg or 10 mg.
  • Neonates †: Initially 0.01 to 0.05 mg / kg IV or IM every 24-48 hours.

Treatment of hypertension

Oral administration:

  • Adults and adolescents: Initially 0.5-2 mg orally once a day. Multiple daily doses can be given at 4-5 hour intervals if response is not adequate. The maximum daily dose is 10 mg per day divided into 2 doses.
  • Elderly: See adult dose. Elderly patients may be more sensitive to the effects of the usual adult dose.
  • Children and infants: Initially 0.015 to 0.1 mg / kg PO once a day (maximum: 10 mg / day).
  • Neonates: Initially, 0.01-0.05 mg / kg PO every 24-48 hours.

Treatment of acute hypercalcaemia associated with neoplastic disease in combination with intravenous saline:

Parenteral administration:

  • Adults: Initially, 1-2 mg IV every 1-4 hours to maintain a urine output of 200-250 ml / hour. Saline administration should begin before the first dose of bumetanide is administered to avoid volume contraction that can limit calciuria.
  • Elderly: See adult dose. Elderly patients may be more sensitive to the effects of the usual adult dose.

For the treatment of ascites

Oral administration:

  • Adults: loop diuretics, preferably in combination with spironolactone or amiloride, are used for the treatment of ascites. While most of the data refer to furosemide , bumetanide should provide a similar answer. Bumetanide 1 mg PO or IV once daily may be prescribed initially along with an aldosterone antagonist.or a potassium-sparing diuretic. If necessary, the dose of each agent can be doubled until a satisfactory diuretic response is achieved. Based on the recommendations for furosemide, the maximum equivalent dose of bumetanide should not exceed 4 mg / day in the treatment of ascites. However, doses of up to 6 mg orally once a day have been used long-term.
  • Elderly: See adult dose. Elderly patients may be more sensitive to the effects of the usual adult dose .

Maximum dosage limits:

• Adults: 10 mg / day PO, IV or IM. • Elderly: 10 mg / day PO, IV or IM. • Adolescents: 10 mg / day PO, IV or IM. • Children: 0.1 mg / kg / day or 10 mg / day PO, IV, or IM, whichever is less. • Infants: 0.1 mg / kg / day or 10 mg / day PO, IV, or IM, whichever is less. • Neonates: 0.05 mg / kg / day PO, IV or IM.

Patients with renal insufficiency: The dose should be modified depending on the clinical response and the degree of renal insufficiency, but there are no quantitative recommendations available.

Contraindications and precautions

Bumetanide is contraindicated when an electrolyte imbalance is present , such as hyponatraemia , hypokalaemia, hypocalcaemia , hypochloremia, and hypomagnesemia. Bumetanide-induced fluctuations in serum electrolyte concentrations can rapidly occur which can precipitate severe hepatic effects in susceptible patients, including hepatic encephalopathy and / or coma. Therefore, bumetanide should be used with caution in patients with liver disease, such as cirrhosis and ascites .

Blood and urine glucose levels should be closely monitored in patients with diabetes mellitus receiving bumetanide because loop diuretics can alter glucose tolerance resulting in hyperglycemia .

Bumetanide is classified in category C risk in pregnancy . The safety of bumetanide administration during pregnancy has not been established, therefore the drug should be administered to pregnant women only when absolutely necessary.

Bumetanide is contraindicated in anuria . It should be used with caution in any patient with severe kidney disease, such as severe kidney failure or end-stage renal failure. The hypovolemia induced by drugs may precipitate azotemia in these patients. However, bumetanide is an effective diuretic for many patients with kidney failure. The renal failure to reduce the clearance and requires the use of higher doses at intervals longer dosing. Bumetanide may be less effective in these patients, and delayed excretion of the drug may increase the risk of toxicity.

Elderly patients show increased sensitivity to the hypotensive and diuretic effects of bumetanide.Although the risk is extremely low, bumetanide should be used with caution in patients with hypersensitivity to sulfonamides or hypersensitivity to thiazide diuretics due to possible sensitivity. crusade.

Since loop diuretics can reduce uric acid clearance , patients with gout or hyperuricemia may have exacerbations of their disease .

Patients with ventricular arrhythmias, heart failure, excess aldosterone, or diarrhea should be carefully monitored because bumetanide-induced hypokalemia can exacerbate these conditions. Excessive diuresis with bumetanide should be avoided in patients with acute myocardial infarction, due to the risk of precipitating shock.

High doses and accumulation of bumetanide can cause ototoxicity . Bumetanide should be used with caution in patients with hearing impairment.

Cases of pancreatitis caused by bumetanide have been reported , so it should be used with caution in patients with a history of pancreatitis.

Interactions

Bumetanide-induced electrolyte disturbances such as hypokalaemia and / or hypomagnesemia can predispose patients to digitalis toxicity, with possible fatal arrhythmias. Electrolyte imbalances must be corrected before initiating cardiac glycoside therapy . In the absence of electrolyte imbalances, bumetanide and cardiac glycosides can be used safely together.

The hypokalemia also power blocking neuromuscular non depolarizing neuromuscular blockers. The use of metolazone with a concomitant loop diuretic can cause severe electrolyte loss. The metolazone only be used in combination with bumetanide in patients who are refractory to loop diuretics alone. Careful monitoring of serum electrolytes and cardiac function is recommended. In patients with creatinine clearance> 30 ml / min, the combination of a loop diuretic with a thiazide diuretic can also lead to a profound loss of fluids and electrolytes. Therefore, bumetanide should be used with great caution in combination with metolazone or any other thiazidic diuretic. In contrast, amiloride , spironolactone, and triamterene can counteract bumetanide-induced hypokalemia. In addition, amiloride and triamterene can counteract the loss of magnesium induced by loop diuretics. Lastly, bumetanide can produce additive hypotension if used in combination with other antihypertensive agents .

Hyponatraemia or hypovolaemia predisposes patients to episodes of acute hypotension after initiation of ACE inhibitor therapy. ACE inhibitors and loop diuretics are routinely administered together in the treatment of heart failure. If an ACE inhibitor is to be administered to a patient receiving bumetanide, the initial dose should be conservative.

Ethanol, since it also has diuretic properties, should be consumed in small amounts by patients receiving loop diuretics. The diuretic properties can be additive, leading to dehydration in some patients.

Fludrocortisone and glucocorticoids with mineralocorticoid activity (eg, cortisone , hydrocortisone, etc.) can cause sodium retention and hypokalemia . Similarly, amphotericin B, cisplatin, and other loop diuretics or thiazides can cause hypokalemia and hypomagnesemia. Loss of [electrolytes] can be severe and prolonged with amphotericin B or cisplatin. Concomitant administration of bumetanide with any of these agents can lead to significant hypokalemia and / or hypomagnesemia. Although it is possible to use bumetanide with these agents safely, it is necessary to closely monitor serum potassium and magnesium levels in these patients. The doctors they should be aware, however, that loop diuretics and cisplatin produce permanent ototoxicity in guinea pigs.

Lithium clearance may be decreased in patients treated with bumetanide. Careful monitoring of serum lithium concentrations is recommended when these drugs are administered together. Likewise, the concomitant administration of both agents can cause lithium toxicity .

Indomethacin has been shown to reduce the antihypertensive and diuretic effects of bumetanide in both normal and hypertensive patients. Other NSAIDs can interact in a similar way. Sulindac appears to interact with loop diuretics than other NSAIDs. NSAIDs inhibit renal prostaglandin synthesis, which can lead to fluid retention and increased peripheral vascular resistance. The risk of kidney failure may be increased in patients treated with an NSAID and a diuretic at the same time, due to the decrease in renal blood flow caused by inhibition of renal prostaglandin synthesis.

Hypokalemia or hypomagnesemia can occur with the administration of potassium-lowering drugs such as loop diuretics and thiazide diuretics, increasing the chances of torsade de pointes induced by dofetilide. Potassium levels should be within the normal range before and during administration of dofetilide .

Hawthorn, Crataegus laevigata can reduce peripheral vascular resistance. The use of this plant in combination with antihypertensive agents can lead to further reductions in blood pressure in some people. Patients receiving hawthorn concomitantly with antihypertensive medications should receive regular blood pressure monitoring .

Ginseng can decrease the effectiveness of loop diuretics . A temporal relationship between ginseng use and resistance to furosemide therapy has been described , resulting in edema , hypertension, and hospitalization.

Aescin, an active saponin in horse chestnut seed, appears to have weak diuretic activity, but the exact mechanism is unclear. The effect appears to be dose dependent and may be additive with traditional diuretics.

Adverse reactions

Patients receiving bumetanide should be closely monitored for signs of electrolyte imbalances including hyponatraemia, hypokalaemia, hypocalcaemia, hypochloremia, and hypophosphataemia. Patients should be aware of the symptoms of these disorders (eg, tiredness , mental confusion, fatigue , weakness, dizziness, muscle cramps, headache, paraesthesia , thirst, anorexia , nausea, or vomiting), and report these signs immediately.

Hypokalemia is a particular problem with bumetanide administration, and additional treatment with potassium chloride or potassium-sparing diuretics may be necessary. Hypovolaemia and dehydration may occur during bumetanide treatment due to polyuria and excessive electrolyte loss. The risk of such events is increased when large doses are administered or when the drug is administered to patients with restricted sodium intake . Dehydration and the resulting hypovolemia can cause orthostatic hypotension and hemoconcentration, which could lead to circulatory collapse or thromboembolic events, particularly in chronic cardiac patients or the elderly..

Abrupt decreases in glomerular filtration rates and renal blood flow have been observed in patients treated with bumetanide. Similarly, reversible azotemia and increased serum creatinine have occurred in dehydrated patients.Only rare occasions, bumetanide-induced renal failure has been reported (for example, interstitial nephritis). Other adverse reactions are muscle cramps , encephalopathy (in patients with disease preexisting liver), dizziness , hypotension, sore head and nausea / vomiting. Hyperaldosteronism secondary to cirrhosis or nephrosis may predispose patients to develop potassium loss when bumetanide is administered. Potassium depletion is especially detrimental in cirrhotic, digitized, and nephrotic patients . Bumetanide-induced metabolic alkalosis can be exacerbated in patients with other disorders that cause potassium loss including vomiting, diarrhea , paracentesis, GI drainage, or excessive sweating.

Bumetanide can occasionally cause transient elevations in uric acid levels. Cases have been reported in which bumetanide therapy has resulted in reversible hyperuricaemia, which is usually asymptomatic.

Ototoxicity, manifested as reversible or permanent tinnitus or hearing loss, rarely occurs during bumetanide treatment and is usually associated with rapid administration of large doses of the drug. These adverse effects on hearing are more common in patients who also receive other ototoxic drugs or who have severe kidney failure.

Bumetanide has been associated with hyperglycemia , possibly due to loss of potassium, and glycosuria has been reported on rare occasions.

The diuretics thiazide and loop diuretics, have proven to cause hypercholesterolemia, hypertriglyceridemia, and increased plasma concentrations of LDL. Some studies have suggested that these effects may decrease or stop with long-term therapy, and are not clinically important.

Adverse nervous system effects associated with bumetanide therapy include fatigue, headache, weakness, and vertigo. On rare occasions, adverse haematological effects have been reported during bumetanide treatment and include thrombocytopenia and leukopenia .

Adverse gastrointestinal effects occur infrequently during bumetanide treatment and include anorexia, abdominal pain, diarrhea, dyspepsia, stomach pain, and xerostomia.

The effects musculoskeletal adverse are rare and include pain , musculoskeletal pain, arthritis , and asterixis .

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