Bumetanide

Bumetanide is a potent loop diuretic with a rapid onset and a short duration of action. The primary site of action is the ascending limb of the loop of Henle where it exerts inhibiting effects on electrolyte reabsorption, causing its diuretic and natriuretic action.

After oral administration, the diuretic effect is seen within 30 minutes with the peak effect seen between 1 and 2 hours. The diuretic effect is practically complete in 3 hours after a 1mg dose.

Absorption

Following oral administration, bumetanide is rapidly and almost completely absorbed from the gastro-intestinal tract with the bioavailability reported as between 80 and 95%.

Distribution

It is 95% bound to plasma proteins. It has a plasma elimination half-life of 0.75 to 2.6 hours.

Highest concentrations of the drug are achieved in the plasma, kidney and liver. It is not yet clear whether the drug crosses the placenta or passes into the cerebrospinal fluid.

Biotransformation and elimination

Bumetanide is cleared from the circulation at a rate of 120-250 ml/min with approximately half of an oral dose excreted unchanged via the kidneys with the remainder excreted via the bile into the faeces.

No active metabolites are known. The primary urinary metabolite is the 3' alcohol of the N-butyl chain and the primary biliary metabolite is the 2' alcohol.

In neonates and infants, elimination appears slower than in older paediatric patients and adults, possibly because of immature renal and hepatobiliary functions.

Mean serum elimination half-life decreases during the first month of life from 6 hours in neonates to 2.4 hours in infants 1 month of age.

Mean serum elimination half-life is 2.5 and 1.5 hours in infants younger than 2 months of age and in those 2–6 months of age, respectively. The apparent elimination half-life may be prolonged to approximately 6 hours (with a range up to 15 hours) after IV administration in premature or full-term neonates with respiratory disorders. Data for younger children, including neonates and infants, is not sufficient to allow for dosing recommendations.

Renal and hepatic impairment

There is an increase in half-life and a reduced plasma clearance in the presence of renal or hepatic impairment.

Chronic renal impairment

In patients with chronic renal failure, the liver takes more importance as an excretory pathway although the duration of action is not markedly prolonged.

Bumetanide has been extensively evaluated in a wide range of animal toxicity tests. Studies in rats and mice have shown it to have a relatively low acute toxicity. No toxic effects were seen in rats at doses of up to 50 mg/kg/day over a 26 week period. In thirteen and 26 week studies at doses of up to 100 mg/kg/day, haematological and clinical chemistry values were generally unaffected; other effects seen were generally related to the diuretic effects of the drug.

Reproductive studies have shown no teratogenic or embryotoxic effects at oral doses up to 50 mg/kg/day in rats and 100 mg/kg/day in mice. But at 3400 times the standard human dose embryocidal effects (growth retardation and decreased foetal weight) were observed in rats. Although no foetal abnormalities occurred foetal toxicity was greater in rabbits: increased resorption rate was observed at doses of 0.25 and 0.5 mg/kg/day.

Bumetanide showed no evidence of mutagenicity on Ames testing. Seventy-eight week studies in rats do not suggest that bumetanide has a significant carcinogenic potential although damage to kidneys, testes and the auditory system were observed in post mortem examinations. In common with other ‘loop’ diuretics, diuretics, intravenous bumetanide caused ototoxicity in cats.

Overall, these studies provide satisfactory evidence for the likely safety of bumetanide when administered to humans.