Effects of Liver Disease on the Renal Elimination of Drugs

Kidney Function Restoration Program

How To Cure Kidney Damage Naturally

Get Instant Access

Drug therapy in patients with advanced cirrhosis is further complicated by the fact that renal blood flow and glomerular filtration rate are frequently depressed in these patients in the absence of other known causes of renal failure. This condition, termed the hepatorenal syndrome, occurs in a setting of vasodilation of the splanchnic circulation that results in underfilling of the systemic circulation. This activates pressor responses, causing marked vasoconstriction of the renal circulation (44). The functional nature of this syndrome is indicated by the observations that it reverses following successful liver transplantation and is not accompanied by significant histological evidence of kidney damage.

Ginès et al. (45) monitored 234 patients with cirrhosis, ascites, and a glomerular filtration rate (GFR) of more than 50 mL/min. These authors found that the hepatorenal syndrome developed within 1 year in 18%, and within 5 years in 39%, of these

FIGURE 7.5 Schematic diagram showing the relationship between Child-Pugh stages of liver disease severity and the intrinsic clearance of drugs mediated by specific cytochrome P450 metabolic pathways. Estimates for glucuronidation (30), CYP2D6 (29), CYP1A2 (38), CYP3A4 (40), and CYP2C19 (29) pathways are based on the literature sources. The ery-thromycin breath test was used to assess hepatic CYP3A in a study in which no patients with mild liver disease were included, and results in patients with moderate and severe liver disease were combined.

Threpyomycin

FIGURE 7.5 Schematic diagram showing the relationship between Child-Pugh stages of liver disease severity and the intrinsic clearance of drugs mediated by specific cytochrome P450 metabolic pathways. Estimates for glucuronidation (30), CYP2D6 (29), CYP1A2 (38), CYP3A4 (40), and CYP2C19 (29) pathways are based on the literature sources. The ery-thromycin breath test was used to assess hepatic CYP3A in a study in which no patients with mild liver disease were included, and results in patients with moderate and severe liver disease were combined.

patients. Although the Pugh score was of no predictive value, high plasma renin activity, low serum sodium concentrations, and small liver size were independent predictors of the onset of this syndrome. Baseline GFR also was of predictive value, but serum creatinine and creatinine clearance, either measured or calculated from the Cockcroft and Gault equation (Chapter 1), overestimated renal function in this group of patients (46). This overestimation reflects the fact that the rate of creatinine synthesis is depressed in these patients, so serum creatinine concentrations may remain within the normal range even when inulin clearance decreases to as low as 10 mL/min. As a result, many patients with cirrhosis and ascites have a normal serum creatinine concentration but a GFR of less than 60 mL/min.

The need for caution in estimating drug dosage for patients with the hepatorenal syndrome is exemplified by carbenicillin, an antipseudomonal, semisyn-thetic penicillin that is excreted primarily by the kidneys, with biliary excretion normally accounting for less than 20% of total elimination. The decline in renal function that is associated with severe liver disease prolongs the elimination half-life of this drug from 1 hour in subjects with normal renal and liver function to approximately 24 hours (47). Although studies in patients with hepatorenal syndrome were not reported, similar half-life prolongations have been described in patients with combined renal and hepatic functional impairment who were treated with the newer but pharmacokinetically similar antipseudomonal penicillins piperacillin (48) and mezlocillin (49). Consequently, it is advisable to consider reducing doses even for drugs that are eliminated to a significant extent by renal excretion when treating patients with cirrhosis that is severe enough to be accompanied by ascites.

Was this article helpful?

0 0
Diabetes Sustenance

Diabetes Sustenance

Get All The Support And Guidance You Need To Be A Success At Dealing With Diabetes The Healthy Way. This Book Is One Of The Most Valuable Resources In The World When It Comes To Learning How Nutritional Supplements Can Control Sugar Levels.

Get My Free Ebook


Post a comment