Bumetanide

Summary

Synopsis: Bumetanide¹ is a potent ‘loop’ diuretic for the treatment of oedema associated with congestive heart failure, hepatic and renal diseases, acute pulmonary congestion and premenstrual syndrome and in forced diuresis during and after surgery. Bumetanide may be given orally, intravenously or intramuscularly and produces a rapid and marked diuresis, and increased urinary excretion of sodium, chloride and other electrolytes (within 30 minutes) which persists for 3 to 6 hours. Its principal site of action is on the ascending limb of the loop of Henle, with a secondary action on the proximal tubule.

Pharmacologically, bumetanide is about 40- fold more potent thanfrusemide (furosemide), with the exception of its effects on urinary potassium excretion where its potency is lower. Studies in patients with oedema due to congestive heart failure, pulmonary oedema or hepatic disease show that oral or intravenous bumetanide 0.5 to 2 mg/day produces results comparable to those with frusemide 20 to 80 mg/day. In acute pulmonary oedema, intravenous bumetanide produces a very rapid diuresis. Higher doses of bumetanide may be required (up to 15 mg/day) in patients with chronic renal failure or nephrotic syndrome. In these patients muscle cramps are not uncommon with bumetanide, but glomerular filtration rates are unaffected. In most studies, diuretic effects were accompanied by decreased bodyweight, abdominal girth and improvements in a variety of haemodynamic parameters.

Comparison of bumetanide with frusemide at a dose ratio of 1: 40 reveals no significant differences in clinical response with the exception of renal disease, where patients with oedema appear to respond better to bumetanide.

Combination with thiazide diuretics enhances the clinical response to bumetanide. Potassium supplements and spironolactone may be beneficial additions to bumetanide where patients at risk of hypokalaemia can be identified. Clinically important side effects are infrequent, with audiological impairment occurring to a lesser extent than with frusemide. Bumetanide thus offers an important alternative to frusemide when a ‘loop’ diuretic is indicated.

Pharmacodynamic Studies: Bumetanide is a potent ‘loop’ diuretic, which produces a marked dose-related diuresis and urinary excretion of sodium and chloride in man over a dose range of 0.5 to 3.0mg. On a milligram-for-milligram basis bumetanide is 40-fold more potent than frusemide, although the dose-response curves for the two drugs are not parallel outside this dose range, and in cases such as renal impairment, where high doses may be used, a ratio of 40: 1 may be misleading. Total maximal diuresis increases by about 5- to 10-fold in healthy volunteers and patients, and urinary sodium and chloride excretion by about 10- to 20-fold, after both oral and intravenous doses of bumetanide. The fractional excretion rate of sodium is increased from less than 3% to up to 25%. The comparability of the total effects of these 2 dose routes reflects almost complete gastrointestinal absorption of oral doses. Bumetanide produces marked diuresis in states of hydropenia as well as in states of aqueous diuresis. Onset of diuresis in patients with oedematous states given oral bumetanide occurs within 30 minutes, reaches peak activity at 60 to 180 minutes and has a duration of 5 to 6 hours. Intravenous doses elicit effects within 10 minutes, and reach peak effects at 15 to 45 minutes.

The increase in total potassium excretion is about 3-fold, therefore the sodium/potassium excretion ratio is increased with bumetanide. This occurs to a greater extent with bumetanide than with frusemide or hydrochlorothiazide, thereby giving it a lesser theoretical kaliuretic potential than the latter 2 drugs. Increases in urinary calcium, magnesium and phosphate excretion also parallel those of sodium and water excretion, but may be greater than with frusemide. Urine osmolality is decreased with bumetanide. Excretion of titratable acid, bicarbonate, and ammonium ions are all increased, with negligible effects on urine pH - although renal tubular fluid may be acidified. Hyperuricaemia is commonly observed.

Bumetanide enhances renal blood flow and increases kidney volume. This precedes diuresis and is probably subject to control or mediation by local prostaglandin, kinin and kallikrein activity. Altered renal haemodynamics are probably responsible for increased plasma renin activity but are not essential for the diuretic effects of bumetanide. Glomerular filtration rate is usually unaffected, even in patients with renal insufficiency. Probenecid has been shown to inhibit the effects of bumetanide, despite raised plasma concentrations of the diuretic, but probably only after repeated or high doses. It is unlikely that bumetanide has any effect on carbonic anhydrase. Bumetanide has been shown to directly inhibit the electrolyte transport in the ascending limb of the loop of Henle. Furthermore, indirect evidence is suggestive of an additional proximal tubular site of action. Bumetanide directly inhibits the sodium-potassium-chloride cation co-transport systems in a number of cellular models and is about 60 to 100 times more potent than frusemide in such studies.

Pharmacokinetic Studies: Peak plasma concentrations of bumetanide following oral doses of 0.5 to 2mg occur after 0.5 to 2 hours and are dose related (30 to 80 Mg/L) in healthy volunteers. Absorption of bumetanide is rapid and almost complete (bioavailability up to 95%) in contrast to some commercially available frusemide formulations. A widely varying volume of distribution of 12 to 35L has been reported. Bumetanide is 93 to 95% protein bound in plasma with no appreciable binding to erythrocytes.

In man, renal elimination accounts for about half the total plasma clearance rate of 200 to 250 ml/min, the rest being cleared by hepatic metabolism or via the biliary route. Urinary recovery of 80% at 48 hours is composed primarily of unchanged drug, with unconjugated alcohols being the principal urinary metabolites. The elimination half-life of bumetanide is about 1 to 1.5 hours in healthy volunteers.

In patients with chronic hepatic or renal disease both the plasma protein-bound fraction and clearance rates may be decreased, and the half-life of bumetanide increased. There appear to be no important pharmacokinetic interactions between bumetanide and either digoxin or warfarin, or when potassium is added to or combined with bumetanide.

Therapeutic Trials: Clinical trials with bumetanide have been extensively carried out in patients with oedematous states due to congestive heart failure, liver and renal disease. However, these studies suffer from inadequate standardisation of disease severity and of the subjective and objective measurements used to gauge clinical respose to bumetanide. Overall there appears to be no significant difference between the effects of bumetanide and frusemide (in a dose ratio of 1:40), with the effects of both drugs being somewhat attenuated upon repeated doses but stabilising at above basal levels of diuresis and saliuresis. Continued efficacy for periods up to 18 months has been shown with bumetanide.

In patients with congestive heart failure, oral and intravenous bumetanide 0.5 to 2 mg/day produces a rapid increase in urinary water and electrolyte excretion, along with decreased abdominal girth, bodyweight and hepatomegaly. Where congestive heart failure is complicated by hypertension, ischaemic or valvular heart disease or non-obstructive hypertrophic cardiomyopathy, bumetanide may reduce mean arterial blood pressure, pulmonary and systemic arterial resistance, right atrial pressure, pulmonary capillary venous pressure, left ventricular end-diastolic pressure and heart rate without affecting cardiac work indexes or blood gases. At higher doses bumetanide is also effective in most congestive heart failure patients where renal insufficiency is present. In infants, a suboptimal dose of 0.015 mg/kg given as an oral solution produced both short and long term diuresis and saliuresis with no significant adverse effects.

Patients with acute pulmonary oedema or hypertension experience the necessarily rapid and intense diuresis and electrolyte excretion following intravenous and intra-arterial administration of bumetanide 1 to 3mg. However, very severely diseased patients may be resistant to clinical improvements.

Advanced liver disease of various aetiology accompanied by oedema or ascites has been successfully treated with bumetanide 1 to 4 mg/day, with the elimination of ascites and oedema, and decreases in bodyweight and abdominal girth. A successful response may be achieved in patients with both hepatic disease and renal insufficiency but, in such patients, only data on intra-arterial administration are currently available. Addition of spironolactone in patients with advanced liver disease prevents the plasma potassium decreases seen during bumetanide therapy but may not increase the diuretic response.

Bumetanide is usually an effective diuretic in patients with oedema associated with chronic renal failure and nephrotic syndrome, especially where other diuretic therapy has failed or aggravated the renal impairment. However, higher doses (up to 15 mg/day) may be necessary. In cases of severe renal insufficiency, bumetanide may not produce adequate diuresis, although natriuresis may be pronounced. Overall, comparative studies indicate an advantage in favour of bumetanide over frusemide in both short and long term use in these patients. Such high doses are more commonly associated with muscle cramps than in patients with other oedematous conditions, but glomerular filtration rate is usually unaffected and may even increase with bumetanide. However, there is some evidence to suggest that in these patients the relative potency of frusemide compared with bumetanide may be greater than the 1:40 ratio reported in other patients.

Other conditions in which bumetanide has proven useful include forced diuresis after surgery (cardiac, urological, and for Dupuytren’s contracture) and reduction of oedema in premenstrual tension, although experience in these fields is limited.

The few controlled studies where potassium was given either as a supplement to or in combination with bumetanide therapy do not indicate any advantages for potassium replacement. However, in studying this controversial area little attempt has been made to identify those patients particularly ‘at risk’ of hypokalaemia.

When bumetanide is combined with the thiazide diuretics there is a distinct supraadditive effect without affecting glomerular filtration rate. Further addition of spirono-lactone does not confer any clinical advantages, but helps allay the increased hypokalaemic effect of combined ‘loop’ and thiazide diuretic therapy.

Side Effects: The incidence of clinical side effects during treatment with bumetanide is relatively low and is approximately equivalent to that observed with frusemide (8.8% vs 7.4%, respectively). Impaired hearing and vertigo occur to a lesser extent than with frusemide (1.7% vs 3.0%) and audiometric studies have confirmed this difference between the ototoxic potential of the drugs. Muscle cramps occur in some patients treated with high doses of bumetanide, and mammary ‘abnormalities’, encephalopathy and hepatic oedema have occasionally been reported.

Abnormal laboratory results occur in 45 to 50% of patients treated with bumetanide and frusemide, but may be pre-existent in these patients and are rarely of clinical or statistical significance. Changes in serum electrolyte, creatinine and uric acid concentrations reflect the basic pharmacological activity of the drugs. Liver function test and haematological abnormalities are infrequent, although hyperglycaemia occurs in 6.6% and 10.1% of patients treated with bumetanide or frusemide, respectively. However, the possibility of a direct association between altered carbohydrate metabolism and bumetanide administration remains speculative. Despite a lesser kaliuretic effect than frusemide, bumetanide is not associated with a lower incidence of hypokalaemia.

Dosage and Administration: Bumetanide is usually administered as an oral dose of 0.5 to 2 mg/day to patients with oedematous states although this may be exceeded, especially in cases of renal oedema where doses of up to 15 mg/day may be necessary. Intravenous or intramuscular bumetanide 0.5 to 2 mg/day is usually reserved for those patients in whom oral administration is impractical, or where a very prompt onset of action is necessary, as in cases of acute pulmonary oedema.