Diuretic resistance: reduced bioavailability and effect of oral frusemide.
چکیده
A 42-year-old woman was admitted to hospital on 25 occasions from 1971 to 1979 severely overhydrated. Idiopathic oedemal was diagnosed after exclusion of other possible causes. She was treated with salt restriction, frusemide intermittently (20-40 mg/day, higher doses when necessary), and potassium chloride. Periodically spironolactone or amiloride was added. Indomethacin 50 mg thrice daily had no effect. After a three-week remission without treatment in 1978 she was readmitted free of oedema and put on a diet containing 20 mmol (mEq) sodium a day. The results of routine serum and urine tests, chest radiographs, cortisol excretion, and creatinine clearance were all normal. There was no orthostatic change in glomerular filtration rate or renin and aldosterone concentrations (the last two were uniformly high). Free water clearance was normal in the supine position after a 1-5 litre water load (51, 309, 305, and 109 ml/min respectively at hourly intervals) but severely diminished when the patient was standing (2, 2, 7, and 15 ml/min). Surprisingly, when she was oedematous frusemide 250-500 mg by mouth had a minimal effect, whereas 40 mg intravenously resulted in a brisk diuresis. We therefore determined the bioavailability and effect of the diuretic (80 mg by mouth and intravenously on two consecutive days) while she was recumbent on two separate occasions-when she was oedematous and when she was free of oedema. No other medication was allowed and food was withheld overnight. Plasma frusemide concentrations were measured2 repeatedly over an eight-hour period and recorded according to a two-compartment open model. Pharmacokinetic values were calculated by conventional methods. The pharmacokinetics and pharmacodynamics of frusemide in the oedematous and the oedema-free states are summarised in the table. The most striking finding was the low bioavailability (17-3%) of the diuretic in the oedematous compared with 74-7 % in the oedema-free state. Intravenous frusemide induced over three times as much diuresis in the oedematous as in the oedema-free state. Frusemide by mouth was less effective in the oedematous than in the oedema-free state, though the difference was less pronounced than would be expected from the differences in bioavailability. This discrepancy might be explained by the fact that the apparent volume of distribution of frusemide in the oedematous state was only half what it was in the oedema-free state, which led to higher plasma concentrations than expected from the bioavailability. This mechanism is shown when the bioavailability is estimated from the effect. Bioavailability in the oedematous and in the oedema-free state would then be 30 % and 90% respectively. Thus the relation is roughly the same as when the bioavailability is calculated from the plasma concentrations of frusemide.