The new loop diuretic torasemide belongs to the pyridine sulfonylurea class. It is well absorbed and yields a bioavailablity of about 80% in healthy individuals, even higher in patients with oedema. This is roughly double that of the 'classical' loop diuretic furosemide (frusemide) [26 to 65%]. Torasemide is highly bound to protein (99%) as is furosemide. The volume of distribution of torasemide was determined as 0.2 L/kg as compared with 0.11 to 0.18 L/kg for furosemide. Torasemide undergoes extensive hepatic metabolism; only 20% of the parent drug is recovered unchanged in the urine. For comparison only 10 to 20% of furosemide undergoes phase II metabolisation (to the glucuronide). In chronic renal failure the renal clearance of torasemide decreased in proportion to the decrease of the patients' glomerular filtration rate, whereas the total plasma clearance (3 times that of the renal clearance) appeared to be independent of renal function. As expected, the renal excretion of torasemide metabolites is significantly retarded in renal disease. The pharmacokinetics of torasemide are significantly influenced by liver disease. Total plasma clearance of torasemide was reduced to about half of that found in the control group, yielding an increase in elimination half-life. A greater than normal fraction of torasemide was recovered in the urine of patients with cirrhosis. In contrast, the kinetics of furosemide appeared to depend more on kidney function than on liver disease. The pharmacodynamics of torasemide are principally the same as those reported from conventional loop diuretics due to their interference with one binding site in the thick ascending limb of Henle's loop, the Na+:K+:2Cl- carrier. The maximum natriuretic effect of all loop diuretics amounts to about 3 mmol Na+/min. Members of this class differ, however, with respect to their intravenous potency or affinity for the receptor, respectively: bumetanide > piretanide > torasemide > furosemide. So far, the only loop diuretic which has been shown to effectively lower high blood pressure is torasemide. This effect occurs at the low dose of 2.5 mg/day.
Diuretic therapy in edematous diseases often yields an inadequate natriuretic response ("diuretic resistance"). To study the functional changes in patients with congestive heart failure, liver cirrhosis with ascites, and nephrotic syndrome, characterized by a reduced effective arterial blood volume (EABV), different diuretic strategies were studied. It was shown that monotherapy with hydrochlorothiazide or furosemide was followed by an inadequate natriuretic response. Correlation of diuretic response with pretreatment fractional sodium excretion of the patient revealed a clear-cut interdependency: Those patients were resistant whose FENa+ was greatly below normal (<0.2%). In addition, it was found that the coadministration of the carboanhydrase inhibitor acetazolamide to diuretic therapy was very effective. We therefore conclude that an increase in proximal-tubular Na+ reabsorption is the major ("pharmacodynamic") determinant for diuretic resistance in edematous diseases with functional "underfilling" of the vascular tree. This alteration of the kidney can easily be overcome by coadministration of a carboanhydrase inhibitor (e.g., acetazolamide).
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