16th May 2025

Prescribing in hepatic impairment

The liver plays an important role in the pharmacokinetic and pharmacodynamic properties of drugs. This can be directly through metabolism of medications or indirectly through impairment of other functions of the liver. Some of these will be discussed in turn:

Impairment of absorption

Lipophilic drugs require the presence of bile salts to aid their absorption from the gut e.g. fat soluble vitamins. In cholestatic liver disease there is impairment to bile production or flow, resulting in less bile reachin

Impairment of drug distribution

One of the synthetic functions of the liver is the production of plasma proteins, many drugs are bound to these proteins to allow for transport of drug molecules around the body. The proportion of a drug bound to plasma proteins is not free to bind to receptors and exert a pharmacological effect.

In liver disease this synthetic function can become impaired resulting in reduced circulating plasma proteins (hypoalbuminaemia). This can lead to an increase in the unbound fraction of drugs leading to more drugs to be available. In medications that are highly protein bound (e.g. phenytoin and prednisolone) this can result in increased adverse effects and a reduction in dose may be indicated.

Complications of oedema and ascites are driven by low levels of circulating plasma proteins. Medications which cause fluid retention may exacerbate this e.g. NSAIDs and corticosteroids.

g the gut, which in turn may reduce drug absorption.

Impairment of drug metabolism

The liver is the main site of drug metabolism in the body. Many drugs that are taken orally undergo a first pass metabolism, which reduces the concentration of the active drug reaching its site of action. In liver disease first pass metabolism is diminished which can result in increased circulating levels of active drugs in the body.

Other drugs are administered as a prodrug (e.g. clopidogrel, enalapril, and oxcarbazepine) which are inactive until they undergo metabolism in the liver. If the liver isn’t functioning correctly there may be decreased activity of these medications as less of the prodrug will be converted to its pharmacologically active form.

It is worth noting that routine liver function tests are not a reliable marker of the ability of the liver to metabolise drugs, it can be difficult to predict the extent that a drug’s metabolism may be impaired in an individual patient.

Impairment of drug elimination

Certain medications are excreted in bile and therefore their elimination from the body can be impaired in people with hepatic impairment e.g. rifampicin and fusidic acid.

Reduction in clotting factors

Another aspect of the liver’s synthetic function is the production of clotting factors, which will be shown by prolonged prothrombin time. This may exacerbate the effects of oral anticoagulant medications.

Hepatic encephalopathy

Hepatic encephalopathy is a reversible cause of impaired brain function which occurs in patients with severe liver disease. Drugs that cause sedation (e.g. opioid analgesics, benzodiazepines, Z-drugs) may exacerbate or precipitate hepatic encephalopathy.

Hepatotoxic drugs

Hepatotoxicity is the injury or damage to the liver caused by drug exposure and may be dose related or idiosyncratic. Patterns of idiosyncratic drug induced liver injury include hepatocellular, cholestatic, or mixed. Drug induced liver injury should be considered in acute liver injury or jaundice without any evidence of obstruction. In the presence of impaired liver function those drugs that cause dose-related damage may do so at lower doses, and those that produce idiosyncratic reactions may occur at an increased frequency. These drugs should be avoided or used with caution in patients with liver disease. Examples of hepatotoxic drugs include:

• Co-amoxiclav
• Nitrofurantoin
• Infliximab
• Azathioprine