Effects of Liver Disease on Drug Metabolism
Liver disease may have complex effects on drug clearance, biotransformation, and pharmacokinetics. Pathogenetic factors include alterations in intestinal absorption, plasma protein binding, hepatic extraction ratio, liver blood flow, portal-systemic shunting, biliary excretion, enterohepatic circulation, and renal clearance. Sometimes alterations increase levels of bioavailable drug, causing normal drug doses to have toxic effects. However, levels and effects for an individual drug are unpredictable and do not correlate well with the type of liver injury, its severity, or liver function test results. Thus, no general rules are available for modifying drug dosage in patients with liver disease.
Clinical effects can vary independent of drug bioavailability, especially in chronic liver disease; eg, cerebral sensitivity to opioids and sedatives is often enhanced in patients with chronic liver disease. Thus, seemingly small doses of these drugs given to cirrhotic patients may precipitate encephalopathy. The mechanism of this effect probably involves alterations in cerebral drug receptors.
Adverse drug reactions do not appear to be more likely in patients with advanced liver disease; however, such patients may tolerate any hepatic adverse effects of drugs less well.