In vitro hepatotoxicity of drugs using for analgosedation in ICU-patients

Question: A variety of medications can cause a wide range of toxic liver injuries. Most drugs using for analgosedation such as opioids are metabolized in the liver. Are the side effects of the most commonly used sedatives, hypnotics and opioids more problematic in patients with liver disease or acute liver dysfunction? Initially, we evaluated the hepatotoxic potential with healthy human liver cells. Methods: In a standardised mikrotiterplate assay the toxicity of different concentrations of sedativa, hypnotics and opioids such as fentanyl, ketamin, midazolam, propofol, remifentanyl, sufentanil and thiopental were tested with human liver cells (HepG2/C3A, medium, plasma). The lowest test concentration was the mean plasma levels after induction of an i.v. therapy (Cmax), as well as the 5-times and 10-times concentrations of Cmax were analyzed. As control groups (CG) served plasma and medium without agents. After incubation time of 2x3 days the viability of cells (LDH release, XTT test, trypan blue staining), the cytochrome 1A2 activity (CYP1A2, metabolism of ethoxyresorufin) and the synthesis of albumin were measured. Results: All opioids showed a decreased vitality in medium and plasma at Cmax compared with the CG; corresponding increased LDH release in remifentanil and sufentanil-treated cells. The CYP1A2 activity of the cells compared with the CG was significant decreased after incubation with fentanyl, remifentanyl and ketamin. Treatment with midazolam, propofol and sufentanil in the medium resulted in an increased cytochrome1A2 activity. A decreased mitochondrial dehydrogenases activity demonstrated midazolam, ketamin and sufentanil compared to the CG. The remifentanyl and sufentanil treated cells in the medium and plasma showed significantly reduced microalbumin synthesis; the other drugs caused an increase. Only ketamine, remifentanyl and sufentanil showed a dose dependent hepatotoxicity (data not shown). Conclusion: Ketamine, sufentanil and remifentanil in the Cmax concentration are associated with higher hepatotoxic potential than thiopental, propofol, fentanyl and midazolam (see rating in table 1 with number of stars in relation to the impairments compared to the CG). Liver function should be assessed prior to treatment and after initiation of analgosedation in patients with hepatic dysfunction.