Clinical Pharmacokinetics of Frusemide

Frusemide is an anthranilic acid derivative that is pharmacologically more potent than organomercurial agents in producing natriuresis and is effective when taken orally even in acid-base disorders or advanced renal failure. The bioavailability of commercially prepared tablets is comparable to an aqueous solution of frusemide. In healthy subjects the range of oral absorption is 60 to 69%. In patients with end-stage renal disease (ESRD), absorption is reduced to values between 43 and 46%. Food decreases the rate of absorption but does not affect bioavailability. Chronic phenytoin therapy, however, does reduce bioavailability to about the level of ESRD. Plasma protein binding in healthy subjects has been demonstrated to be between 91 and 99%. Frusemide is almost exclusively bound to albumin and it competes for binding sites with other acidic drugs. In patients with reduced plasma albumin concentration or azotaemia, frusemide binding is reduced. The mean apparent volume of distribution in the steady-state ranges from 0.07 to 0.18L/kg body weight in healthy adults. It may be modestly increased in adults with cardiac failure, but is very large in neonates with fluid overload. After intravenous injection, intact frusemide is the major urinary product in the first 4 hours. After this time, frusemide glucuronide and the free amine metabolite are also found. In healthy subjects, between 6 and 18% of an intravenous dose is found in the faeces. However, in renal failure, this is increased to 60% of the injected dose. Although apparently secreted by proximal portions of the nephron, frusemide has its principal action on the luminal surface of the ascending limb of Henle’s loop. In this segment it exerts an inhibitory action on active chloride, thus producing a saluresis of both sodium and chloride. Probenecid substantially reduces the renal secretion of frusemide and the plasma clearance, and prolongs the half-life of the drug without impairing its natriuretic effect. Frusemide plasma clearance is greater than the creatinine clearance except in ESRD where it tends to be about 50% of the measured value. Elimination half-lives of 19 to 100 minutes are reported in healthy subjects but may be 8 to 15 hours in ESRD. In patients with both hepatic and renal insufficiency, reported half-lives were 11 to 20 hours. In neonates elimination half-lives of 7 to 8 hours have been reported apparently due to very large distribution volumes as well as low renal and hepatic clearance. Although the natriuretic effect of frusemide is variable and apparently dependent on the state of sodium reabsorption at the site of drug action, it appears that the saluretic response is more closely correlated with the urinary concentration of frusemide than with the plasma level. If the salt and water balance is maintained, a sigmoid-shaped dose-response curve is observed. From a therapeutic viewpoint, the maximum response with the least amount of drug would occur if the urinary excretion of frusemide were on the ‘steep’ portion of the curve. This concept has been applied in several clinical studies and probably explains the greater natriuresis seen when a divided oral dose regimen is given or small continuous infusions have been used.