[Mechanism of action of xipamide and its classification as a "low ceiling diuretic". Pharmacodynamic-pharmacokinetic studies in healthy volunteers and in kidney and liver patients].

Xipamide (CAS 14293-44-8) shows structural features comparable with the thiazide- as well as the class of loop diuretics. According to earlier findings this diuretic, in contrast to the thiazides, should not decrease the glomerular filtration rate (GFR) and be effective even in patients with advanced renal failure. Therefore recently the question, which class of diuretics xipamide should be related to, has been increasingly discussed. In order to solve this issue, the diuretic effect of xipamide was assessed in healthy volunteers once without and once under strict water and salt restriction. Additionally, changes in GFR were monitored by means of measurement of the creatinine clearance. Kinetic parameters were determined in plasma and urine; further, in patients with liver cirrhosis, renal elimination kinetics of the diuretic were correlated with the concentration of direct plasma bilirubin, as a marker of cholestasis, at the beginning of a treatment with xipamide, 40 mg qd. The investigations proved that xipamide, like a typical thiazide diuretic, gives rise to a temporary decrease in GFR of about 30 %, provided the renin-angiotensin-aldosterone system of the volunteer is activated by previous salt and water restriction. Xipamide leads to an increase of K+ and Mg2+ excretion, but to a decrease of Ca2+ excretion in urine, a charactaristical feature of the thiazide-like diuretics. The correlation between Na+ excretion and drug excreted in urine over time showed a functional graph that is characteristic for a "low ceiling" thiazide diuretic. In patients with renal failure FE(Na) was increased when related to the GFR-adjusted drug excretion rate, whereas it was diminished in conditions with decreased effective circulating volume like in liver cirrhosis with ascites. It could be shown that the elimination kinetics of xipamide are determined by renal drug clearance, which proportionally decreases with GFR. In patients with liver failure, a decrease of non-renal drug clearance went along with an increase in urinary drug excretion. The amount of drug excreted in urine (Ae) proportionally increased with the concentration of the patients' direct plasma bilirubin. Thus, from a pharmacological as well as clinical point of view xipamide acts like a thiazide diuretic. As could be shown for other thiazides some time ago, xipamide is effective not only in patients with cardiovascular diseases, but also in those with advanced renal failure.