sulindac and Ascites

The ability of the kidneys to excrete sodium and free water is often impaired in patients with cirrhosis. Sodium retention is a sine qua non for ascites formation. The impairment of water excretion causes hyponatremia and hypo-osmolality. In addition, these patients frequently have functional renal failure caused by intense renal vasoconstriction. The renin-angiotensin-aldosterone system and the sympathetic nervous system, which are activated in most cirrhotic patients with ascites, and a nonosmotic hypersecretion of antidiuretic hormone are important mechanisms of sodium and water retention. Angiotensin II and sympathetic nervous activity may also be involved in the pathogenesis of functional renal failure. The renal production of prostaglandins is increased in cirrhotic patients with ascites as a homeostatic response to antagonize the vascular effect of endogenous vasoconstrictors and the tubular action of antidiuretic hormone. Nonsteroidal anti-inflammatory drugs should, therefore, be administered with caution in these patients because they may induce acute renal failure and water retention. Although sulindac inhibits the renal synthesis of prostaglandins in cirrhotic patients with ascites, it appears to have less effect on renal function than do other nonsteroidal anti-inflammatory drugs administered to these patients.

Topics: Anti-Inflammatory Agents; Ascites; Atrial Natriuretic Factor; Body Water; Diuretics; Hemodynamics; Humans; Kidney; Liver Cirrhosis; Prostaglandins; Renin-Angiotensin System; Sodium; Sulindac; Sympathetic Nervous System; Vasopressins

Nonsteroidal anti-inflammatory drugs (NSAID) suppress prostaglandin-dependent renal blood flow and furosemide-induced diuresis in patients with cirrhosis and ascites. Since sulindac may selectively spare inhibition of renal prostaglandins, we evaluated the interactions of acute administration of sulindac or indomethacin with furosemide in 15 patients with cirrhosis and ascites. Prior to furosemide, indomethacin reduced creatinine clearance (by 55%), urinary volume (by 82%), sodium (by 93%), and prostaglandin E2 (by 87%) (all P less than 0.05), whereas sulindac had no effect. However, both drugs reduced furosemide-induced diuresis. Indomethacin appeared slightly more potent in reducing the diuresis (55% v 38%), natriuresis (67% v 52%), and prostaglandin E2 (PGE2) release (81% v 74%). In a similar protocol in healthy subjects, furosemide-induced diuresis and natriuresis were also blunted by both drugs. Thus, under conditions of enhanced prostaglandin activity from furosemide, sulindac does affect renal function. These data suggest that renal function should be monitored in patients with cirrhosis and ascites who receive sulindac as well as other NSAID.

Topics: Anti-Inflammatory Agents; Ascites; Clinical Trials as Topic; Creatinine; Dinoprostone; Diuresis; Drug Evaluation; Furosemide; Humans; Indenes; Indomethacin; Liver Cirrhosis; Natriuresis; Potassium; Prostaglandin Antagonists; Prostaglandins E; Sodium; Sulindac

Urinary excretion of two prostacyclin metabolites was investigated in 48 subjects: 8 controls and 40 cirrhotics (9 without ascites, 22 with ascites and preserved renal function, and 9 with functional renal failure). Urinary 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), believed to reflect renal prostacyclin production, was significantly increased in patients without ascites and in ascitic patients with preserved renal function, but cirrhotics with renal failure showed rates similar to controls. Excretion of 2,3-dinor-6-keto-PGF1 alpha (PGI-M), the major urinary metabolite of systemic prostacyclin, was increased in all groups of patients, including those with renal failure. A single dose of sulindac, a renal-sparing prostaglandin synthesis inhibitor, reduced PGI-M but not 6-keto-PGF1 alpha in 5 cirrhotic patients. This would be consistent with the predicted renal origin of the latter and the systemic origin of the former. Ascitic patients with high urinary excretion of PGI-M (above the median value) showed significantly lower mean arterial pressure and higher plasma renin activity and aldosterone than patients with excretion below the median. Urinary 6-keto-PGF1 alpha was higher in patients with low PGI-M. Finally, creatinine clearance corrected excretion of PGI-M, as an estimation of relative plasma levels correlates both with plasma renin activity and plasma aldosterone in the 31 subjects who presented with ascites. It is suggested that enhanced synthesis of systemic prostacyclin may influence hemodynamic changes in patients with liver cirrhosis. Overproduction of systemic prostacyclin in the absence of increased renal prostacyclin synthesis appears to be characteristic of patients with functional renal failure.

Topics: 6-Ketoprostaglandin F1 alpha; Ascites; Chromatography, High Pressure Liquid; Epoprostenol; Humans; Kidney; Kidney Failure, Chronic; Liver Cirrhosis; Radioimmunoassay; Sulindac

In 5 patients with cirrhosis and ascites the glomerular filtration rate (GFR), free water clearance (CH2O) and urinary excretion of prostaglandin E2(PGE2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) were measured before and after a 3-day treatment with sulindac (400 mg/day). The administration of sulindac induced a marked fall of urinary excretion of PGE2 (from 24.2 +/- 5.5 to 3.8 +/- 1.1 ng/h; p less than 0.05), 6-keto-PGF1 alpha (from 19.9 +/- 2.9 to 5.6 +/- 1.1 ng/h; p less than 0.02) GFR (from 111 +/- 15 to 67 +/- 10 ml/min; p less than 0.01) and CH2O (from 7 +/- 1.5 to 3.7 +/- 1.3 ml/min; p less than 0.02) in all patients studied. The plasma concentration of the active metabolite sulindac sulfide in cirrhotics was 400% of that found in 6 healthy volunteers (9.6 +/- 1.7 vs. 2.4 +/- 0.6 ng/ml). Our results indicate that sulindac, at a dose of 400 mg/day, inhibits the renal synthesis of prostaglandins and impairs renal function in cirrhotics with ascites. These effects are probably related to the marked alteration of sulindac kinetics that occurs in these patients.

Topics: 6-Ketoprostaglandin F1 alpha; Ascites; Body Water; Dinoprostone; Glomerular Filtration Rate; Humans; Indenes; Kidney; Kinetics; Liver Cirrhosis; Norepinephrine; Prostaglandins E; Renin; Sulindac; Vasopressins

The effect of sulindac, a nonsteroidal anti-inflammatory drug, on renal prostaglandin synthesis and renal function variables was investigated in six cirrhotic patients with tense ascites and marked sodium retention. We studied serum thromboxane (TXB2) production, urinary prostaglandin excretion (6-keto-prostaglandin F1 alpha and TXB2) and renal function before and after administration of a therapeutic dose of sulindac (400 mg). After treatment, no significant changes were observed in urinary prostaglandin excretion, serum creatinine concentration, urine volume, or urinary sodium and creatinine clearance, whereas the serum TXB2 concentration was reduced in 89%. In five patients systemic prostaglandins were inhibited, but renal excretion remained unchallenged. However, one patient showed marked reduction of urinary prostaglandins associated with a depression of renal function. The study suggests that sulindac could be a safe substitute for other nonsteroidal anti-inflammatory drugs in cirrhotic patients with ascites. Further pharmacological trials seem to be warranted.

Topics: Ascites; Humans; Indenes; Kidney; Liver Cirrhosis; Liver Function Tests; Prostaglandins; Risk; Sulindac