Pharmacokinetic Changes of Psychotropic Drugs in Patients with Liver Disease

Abstract

Dose adjustment of psychotropic drugs in patients with liver cirrhosis may be important as most of these drugs are predominantly eliminated by the liver and many of them are associated with dose-dependent adverse reactions. As no surrogate parameter is available to predict hepatic metabolism of drugs, dose adjustment according to pharmacokinetic properties of the drugs is proposed. Psychotropic drugs (antiepileptics, antiparkinsonian drugs, psycholeptics such as antipsychotics, anxiolytics, sedatives and hypnosedatives, and psychoanaleptics such as antidepressants, psychostimulants and antidementia drugs) marketed in Switzerland in 2006 were therefore classified according to their hepatic extraction and/or bioavailability to predict their kinetic behaviour in patients with cirrhosis. The expected changes in hepatic metabolism predicted by pharmacokinetic properties were compared with the results from kinetic studies carried out in patients with liver disease. These studies were identified using MEDLINE searches. Of the 116 psychotropic drugs available on the Swiss market by the year 2006, only 12 were predominantly eliminated through the kidney. For five substances, no Q(0) value (the dose fraction metabolized or excreted extra-renally) could be determined because of lack of pharmacokinetic data. Of 99 drugs with predominant hepatic metabolism, 29.3% were categorized as high, 25.2% as intermediate and 38.4% as low extraction drugs, while seven substances could not be classified. Pharmacokinetic studies in patients with liver disease were available for 55 of these 99 drugs eliminated predominantly by the liver (Q(0)-value > or = 0.5). Only a few kinetic studies in patients with liver disease were found for antipsychotics, antiparkinsonian drugs and antidepressants, except for selective serotonin reuptake inhibitors and some newer antidepressants. The expected changes in pharmacokinetics were generally in good agreement with the changes reported in pharmacokinetic studies. For 12 drugs, the observed changes in pharmacokinetics from clinical studies were different from the changes expected based on their classification. However, for low extraction drugs metabolized by cytochrome P450 isozymes, clearance may be reduced by up to 50%. In conclusion, the classification of drugs according to their hepatic extraction and/or bioavailability is a useful tool for dose adjustment, if information from clinical studies is lacking. There is a gap in information about pharmacokinetic changes in patients with liver cirrhosis for a large number of centrally acting drugs. Kinetic studies for centrally acting drugs with predominant hepatic metabolism should be carried out in patients with liver disease to allow precise dose recommendations for enhanced patient safety.

Drug dosage recommendations in patients with chronic liver disease

“…The Child-Pugh score is mostly used in the review articles which include drug dosage recommendations in patients with chronic liver disease through the application of an explicit methodological procedure (8,(15)(16)(17)(18)(19). The bulletin written by Shapiro (20) compared the Child-Pugh scores with the Cockcroft-Gault equation used in the adjustment for renal insufficiency.…”

“…Accordingly, Shlatter et al (16) agree in the dosage recommendations based on E H and/or pharmacological bioavailability, justifying adjustments of initial doses and maintenance.…”

“…Moreover, no guidelines in case of concomitant renal insufficiency or hepato-renal syndrome have been developed which could show one of its own limitations. Despite the existence of theoretical general recommendations in the medical literature about drug dosage in patients with hepatic insufficiency taking into account the pharmacokinetic parameters of E H , plasma protein binding and bioavailability (1,(15)(16)(17)(18)(19)21,22), it has been considered more useful to individualize the recommendations for each drug and adjust them to adult patients with liver diseases. We wonder if the recommendations can be applied to all patients with hepatic disease or if, on the contrary, a limit between acute, chronic or multiorganic failure hepatic diseases should be established.…”

Review article: depression and the use of antidepressants in patients with chronic liver disease or liver transplantation

“…68 There are no published trials of nortriptyline, clomipramine, dibenzepin, imipramine or trimipramine use in patients with liver disease, and only occasional reports of DILI associated with their use. 95 Consensus advice is for initial doses of TCAs to not exceed 50% of standard starting doses, with subsequent titration dependent upon the balance of efficacy and adverse effects. Particular caution must be given in their prescription to patients with hepatic encephalopathy given their potentially sedative effects.…”

“…67,95 There are also a number of other antidepressants that are established in clinical use that may be of use in this population (see Table 1 for further details). Reboxetine has altered pharmacokinetics in those with CLD compared to healthy controls, but there are no reports of DILI in association with its use at present.…”