Intrinsic hepatic clearance of drugs depends on metabolic enzyme capacity and activity of sinusoidal and canalicular transporters. In chronic liver disease, metabolism of drugs is decreased due to reduction in absolute cell mass, decrease in enzyme activity and impaired uptake of drugs across the endothelium. Drug doses should be reduced and interval between doses prolonged. In addition to impairment of biliary excretion, renal excretion of drugs may also be affected as advanced liver disease is often associated with hepatorenal syndrome and impaired renal function.

Acetaminophen overdose is one of the commonest causes of acute liver failure. It is metabolized mainly in the liver into acetaminophen glucuronide (55 %) and acetaminophen sulfate (33 %). Five to ten percent is metabolized by hepatic P450 enzymes to N-acetyl-p-benzoquinoneimine (NAPQI), which is a highly reactive metabolite. Under normal circumstances NAPQI is detoxified by conjugation with glutathione and then excreted in urine.

In acetaminophen overdose, hepatic stores of glutathione may be depleted. Accumulation of NAPQI then leads to liver cellular necrosis. Factors increasing the risk of hepatotoxicity are poor nutritional status, increased age, certain genetic variations, chronic alcohol use, drugs which inhibit glucuronidation and drugs which induce liver P450 enzymes.

Patients are usually asymptomatic for the first 24 h. Subsequently they present with abdominal pain, nausea, and signs of liver failure. Treatment is by administration of N-acetylcysteine, which serves as a glutathione precursor, ideally within the first 16 h. N-acetylcysteine neutralizes NAPQI and prevents it from reacting with liver cells. Activated charcoal can be given to reduce acetaminophen absorption from the stomach if patients present within one hour of acetaminophen ingestion.

Opioids are used in the acutely ill for analgesia and sedation. The liver is the main site of metabolism for most opioids with the exception of remifentanil, which is cleared by ester hydrolysis. Opioids that are metabolized by glucuronidation (e.g., morphine, oxymorphone, buprenorphine) are mostly highly extracted and have increased oral bioavailability in liver dysfunction, leading to higher drug levels. Most other opioids are metabolized by oxidation and their clearance is reduced to a variable extent. Scoring systems for severity of liver disease, such as Child-Pugh Score and Model for End-Stage Liver Disease (MELD), lack sensitivity and correlation with liver drug metabolizing capacity. In severe liver failure, the concentration of opioids in the central nervous system may be increased, due to increased cerebral blood flow, increased permeability of the blood brain barrier and altered transporter function. This increases the risk of adverse effects such as respiratory depression and hepatic encephalopathy. Dosages of opioids have to be reduced, dosing intervals prolonged and sustained-release forms avoided in severe liver disease to reduce the risk of drug accumulation.