10th July 2026

Pharmacokinetic alterations in hepatic impairment

Absorption 

• In patients with hepatic impairment, it is important to consider whether a drug is lipid-soluble. Lipid-soluble drugs, e.g. propranolol may be less well absorbed in a patient with cholestasis, as they rely on bile salts to aid their absorption. This can result in reduced concentrations of the drug in the plasma and, therefore, reduced efficacy. 
• In patients with cirrhosis and ascites, the absorption of some drugs, e.g. furosemide, is delayed. 
• In portal hypertension, there is a decreased first-pass metabolism. First pass metabolism creates a high extraction ratio, which reduces bioavailability. 

Distribution 

• In patients with hepatic impairment, it is important to consider whether a drug is water-soluble, as it may distribute into the ascitic fluid, which can reduce the drug concentration, as the drug distributes into the ascitic fluid, leading to lower blood concentrations. Larger loading doses may therefore be required. 
• Chronic liver disease can also result in low albumin levels. Drugs which are largely protein-bound, e.g. phenytoin and prednisolone are affected by hypoalbuminaemia, as the proportion of unbound drug increases, resulting in potentially increased adverse effects. 

Metabolism 

• Liver disease can reduce the capacity of the liver to metabolise certain drugs, leading to toxicity. This can be caused by a reduction in the metabolic capacity of the liver (i.e. reducing hepatic cell mass due to cirrhosis) and changes in liver blood flow. Reduced hepatic metabolism of drugs is most likely to be significant in patients with decompensated cirrhosis, cholestasis, and acute liver failure, but often restricted to patients with severe disease. 
• Drugs which have a high first-pass metabolism (high extraction ratio) are particularly problematic. Advanced cirrhosis can lead to the development of varices (collateral circulation) between the portal and venous system. This can subsequently increase the proportion of absorbed oral drug entering systemic circulation, as they are metabolised less. This increases bioavailability and the potential for adverse effects. Doses of these drugs need to be reduced. 
• If the drug is a pro-drug and requires liver activation, poor liver metabolism can reduce the rate of activation and therapeutic effect of these drugs. 
• The hepatic reserve is large, and liver disease must be severe before drug metabolism is affected. 
• Whilst impaired metabolism can be indicated by a high INR (international normalised ratio), reduced albumin level, and encephalopathy, unlike renal impairment, it is not possible to predict an individual’s capacity for drug metabolism depending on liver function tests. 

Excretion 

• In cholestatic patients, the elimination of drugs through the biliary route can be reduced, resulting in accumulation. Drugs which undergo significant biliary excretion, e.g. rifampicin and fusidic acid would be particularly affected. 
• Renal impairment can occur as a result of liver disease, and if the drug is renally excreted, dose reduction may be required. 

• Drugs which cause constipation, sedation or hypokalaemia are contraindicated in severe liver disease as these can further impair cerebral function and cause encephalopathy. 
• Drugs which cause fluid retention, e.g. non-steroidal anti-inflammatory drugs and corticosteroids can worsen ascites by causing fluid retention and should be avoided in these patients. 
• Reduced hepatic synthesis of blood clotting factors, causing a prolonged prothrombin time, increases the sensitivity to oral anticoagulants, e.g. warfarin and phenindione.