TABLE 1 Pharmacokinetics of Mannitol
would appear that the potential risks of mannitol administration considerably outweigh any potential benefits in most patients with renal dysfunction.
The first loop diuretics were the mercurial agents, which are of historic interest only. The discovery of furosemide opened a new dimension to diuretic therapy, providing an effective agent in many conditions unresponsive to other available diuretics. Additional loop diuretics have since been developed with little if any difference from furosemide in terms of pharmacology. The tangible differences among loop diuretics are in their pharmacokinetics.
Numerous studies have assessed the pharmacokinetics of loop diuretics, the majority of which have been conducted in healthy subjects (Table 2) , Most of the studies in healthy volunteers assessed a young age group; importantly, healthy elderly subjects appear to differ from their young counterparts only insofar as would be predicted by their mildly diminished renal function.
Many studies have assessed concentrations of diuretic in only serum or plasma. Loop diuretics act from the lumen side of the nephron . hence, urinary rather than serum amounts of these diuretics are the major determinants of response . Since these diuretics are highly bound to serum proteins (namely, albumin), they cannot enter the tubular lumen by glomerular filtration and reach this site by active secretion by the organic acid transport pump at the straight segment of the proximal tubule. The relationship between amounts of diuretic at the site of action (urinary loop diuretic excretion rate) and response is shown in Fig. 1. This relationship is defined by a sigmoidally shaped curve. This relationship implies that a threshold concentration must be reached at the site of action before any response occurs. The relationship also allows definition of a maximal response (FENa- = 20-25%) and a dose that causes this response.
TABLE 2 Pharmacokinetics of Loop Diuretics in Healthy Volunteers
Volume of distribution (liters/kg)
Fraction of dose excreted in urine (%)
DIURETIC EXCRETION RATE (yg/min)
FIGURE 1. Relationship between urinary excretion rate of loop diuretics and diuretic response.
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