Improvement in Diuretic Delivery

Loop diui :tics as well as thiazides are highly bound to albumin in the plasma. This bind .ng confines the drug to the vascular space and facilitates diuretic delivery t > the peritubular space surrounding the proximal tubule. From this location t re diuretics are secreted into the proximal tubule lumen. Albumin also plays a role in regulating the rate of secretion of anionic loop diuretics into the proximal tubule. This effect is independent of its function as a carrier molecule. Thus albumin is essential in determining the concentration of loop diuretic reaching its active site. The importance of these events in determining diuretic response has been shown by Inoue and associates using an analbumi-nemic rat model [7]. Thirty minutes following furosemide administration, these rats had a ninefold greater increase in the volume of furosemide distribution and a urinary furosemide excretion that was 74% less than that found in normal rats. Mixing furosemide with an equimolar concentration in albumin prior to administration reduced furosemide volume of distribution in analbu-minic rats to twofold that of normal rats while increasing urinary furosemide excretion to 69% of that seen in normal animals. These changes were associated with significant increases in diuretic response. Likewise, patients with hypoal-buminemia from a variety of causes demonstrated a significantly greater diuretic response following administration of 30 mg of furosemide bound to 6 g of albumin than to 30 mg of furosemide alone (see Fig. 1). This effect could not be attributed to increases in plasma albumin concentration or oncotic pressure. The extent to which this mechanism contributes to attenuated diuretic response in nephrotic syndrome or cirrhosis is unclear. Several investigators have noted that nephrotic patients with well preserved glomerular filtration rates have renal clearances of loop diuretics and total amount of diuretic reaching the urine that are not different from normal subjects when examined over long time intervals. However, as diuretic response depends on both duration of exposure of the tubule to the diurectic and tubule fluid diuretic concentration, the observations of Inoue and associates and the findings from pharmacokinetic studies of others need not be contradictory. In fact several investigators have attributed part of the impaired diuretic or natriuretic response to loop diuretics observed in nephrotics to alterations in diuretic secretion.

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