Psychiatric patients commonly have comorbid medical problems that may affect response and tolerability to psychiatric medications. Below we provide some important concepts to remember when prescribing psychiatric medications in patients with liver disease.
Pharmacokinetic and Pharmacodynamic Considerations in Liver Disease
- The Bioavailability (BA) of a drug is the proportion of drug that makes its way to the systemic circulation
- For drugs given by mouth (PO), bioavailability (i.e., how much of the drug makes it to the systemic circulation) is influenced by gastrointestinal functioning and first pass metabolism
- Recall that the small intestine is the major site of absorption for most orally administered drugs
- Many patients with liver disease suffer from gastroparesis or impaired GI motility, which delays drug delivery to the intestine
- Patients with cirrhosis, portal hypertension, and vascular congestion usually absorb drugs from the intestine much slower
- Hepatic insufficiency typically decreases first pass metabolism which can result in increased plasma drug levels
- Quantitative changes in plasma protein levels due to hepatic insufficiency alters protein binding and free drug levels (but this is probably clinically insignificant)
- Ascites and peripheral edema increase the volume of distribution of hydrophilic (i.e., water soluble) drugs which may result in overall decreased plasma drug concentrations
- Therapeutic drug monitoring may be valuable but should be interpreted with caution because changes in protein binding may lead to falsely low estimates (always try to measure free drug levels!)
- Drugs with a small therapeutic window (lithium) should be used with caution
- Drugs with multi step biotransformation or those with active metabolites (amitriptyline, imipramine, venlafaxine, bupropion) are more complicated to dose
- Generally avoid drugs with long half-lives (e.g., fluoxetine) or extended/slow-release formulations due to unpredictable pharmacokinetics in hepatic insufficiency
- Caution with hydrophilic drugs and/or active metabolites that distribute in total body water as paracentesis, diuresis, and fluid loss can cause rapid changes in drug concentration (due to rapid fluid shifts)
Adjust dose according to the Child-Pugh Score
(See Bottom of The Page)
Score A (5-6 points): use 75-100% regular dose
Score B (7-9 points): use 50% regular dose
Score C (10-15 points): CAUTION/AVOID USE
Medications Requiring Dose Adjustments in Liver Disease
|SSRIs||Extensively metabolized; decreased clearance and prolonged half-life. Initial dose should be reduced by 50%, with potentially longer dosing intervals between doses. Target doses are typically substantially lower than usual|
|MAOIs||Potentially hepatotoxic. No dosing guidelines.|
|TCAs||Extensively metabolized. Potentially serious hepatic effects. No dosing guidelines.|
|Bupropion||Extensively metabolized; decreased clearance. Reduce dose/frequency. In severe Cirrhosis, do not exceed 75mg/day for conventional tablets or 100mg/day for sustained release formulations|
|Desvenlafaxine||Primarily metabolized by conjugation. No adjustment in starting dose needed in HI. Do not exceed 100mg/day in severe HI.|
|Venlafaxine||Decreased clearance of venlafaxine and its active metabolite. Reduce dosage by 50% in mild to moderate HI, per manufacturer.|
|Duloxetine||Extensively metabolized; reduced metabolism and elimination. Do not use in patients with any HI.|
|Mirtazapine||Extensively metabolized; decreased clearance. No dosing guidelines.|
|Trazodone||Extensively metabolized. No dosing guidelines.|
|Clozapine||Extensively metabolized. Discontinue in patients with marked transaminase elevations or jaundice. No dosing guidelines.|
|Paliperidone||Primarily renally excreted. No dosage adjustment needed.|
|Risperidone||Extensively metabolized. Free fraction increased 35%. Starting dosage and dose increments not to exceed 0.5mg twice daily. Increases >1.5mg twice daily should be made at intervals of > 1 week.|
|Quetiapine||Extensively metabolized. Clearance decreased 30%. Start at 25mg/day and increase by 25-50mg/day.|
|Ziprasidone||Extensively metabolized; increased half-life and serum level in mild to moderate HI. In spite of this, manufacturer recommends no dosage adjustment.|
|Typicals||All metabolized in liver. No specific dosing recommendations. Avoid phenothiazines (thioridazine, trifluoperazine, thorazine) due to cholestatic hepatotoxicity. Reduce starting dose of all typicals and titrate slowly.|
|Alprazolam||Decreased metabolism and increased half-life. Reduce dosage by 50%. Avoid use in patients with cirrhosis.|
|Chlordiazepoxide, clonazepam, diazepam||Extensively metabolized. Reduced clearance and prolonged half-life. Avoid use if possible.|
|Buspirone||Extensively metabolized. Half-life may be prolonged. Reduce dosage and frequency in mild to moderate cirrhosis. Do not use in patients with severe HI.|
|Valproate||Extensively metabolized; reduced clearance and increased half-life. Reduce dosage; monitor liver function tests frequently, especially in first 6 months of therapy. Avoid in severe HI if possible.|
|Lamotrigine||Initial, escalation, and maintenance dosages should be reduced by 50% in moderate HI (Child-Pugh B) and by 75% in severe HI (Child-Pugh C).|
Hepatotoxic Potential has been documented with the following medications:
Monoamine Oxidase Inhibitors (MAOIs)
Elevated Transaminases (AST, ALT) seen with
Benzodiazepines and Liver Impairment
Benzodiazepines are usually avoided in patients with encephalopathy, but when needed (e.g., delirium tremens) use benzodiazepines that bypass phase I metabolism such as Lorazepam, Oxazepam, and Temazepam. These agents primarily undergo glucuronidation and are preferred in patients with hepatic insufficiency.
- Stern, T. A., Freudenreich, O., Fricchione, G., Rosenbaum, J. F., & Smith, F. A. (2018). Massachusetts General Hospital handbook of general hospital psychiatry. Edinburgh: Elsevier.
- S. J. Ferrando, J. L. Levenson, & J. A. Owen (Eds.), Clinical manual of psychopharmacology in the medically ill (pp. 3-38). Arlington, VA, US: American Psychiatric Publishing, Inc.
- Levenson, J. L. (2019). The American Psychiatric Association Publishing textbook of psychosomatic medicine and consultation-liaison psychiatry. Washington, D.C.: American Psychiatric Association Publishing.
- McCarron, Robert M., et al. Lippincotts Primary Care Psychiatry: for Primary Care Clinicians and Trainees, Medical Specialists, Neurologists, Emergency Medical Professionals, Mental Health Providers, and Trainees. Wolters Kluwer Health/Lippincott Williams & Wilkins, 2009.
- Schatzberg, A. F., & DeBattista, C. (2015). Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing.
- Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
- Hales et al. The American Psychiatric Association Publishing Textbook of Psychiatry. 6th Ed.
- Goldberg & Ernst. Managing Side Effects of Psychotropic Medications. 1st Ed. 2012. APP.