Drug metabolism is decreased in liver disease especially in severe disease i.e. albumin < 27 g/L and/or INR > 1.2

General Advice

For general advice, see Individualising Drug Therapy, including: when prescribing ‘start low and go slow’; consider dose tapering after desired effects are achieved and discontinue unnecessary drugs.

Drug metabolism varies substantially between individuals.

There are several causes of decreased drug metabolism:

  • Irreversible:
    • Genetics – there is wide variability between individuals, only partly identified by individual genetic tests.
    • Age – drug metabolism decreases with age, at a rate of 1% per year after the age of forty.
    • Frailty – associated with decreased drug metabolism over and above the decrease associated with age.
    • Organ failure has been shown to reduce drug metabolism.
      • Liver disease – affects drug clearance only when severe (Child Pugh B or C).
      • Renal dysfunction – end-stage renal disease is associated with approximately 50% reduction in drug metabolism.
      • COPD – severe COPD is associated with approximately 50% reduction in drug metabolism.
      • Heart failure – the chronic effects are not quantified, but acute hepatic congestion decreased drug metabolism.
    • Reversible:
      • Enzyme inhibition by drugs.
      • Acute illness: hypo-perfusion and metabolic insult (e.g. acidosis)

Assessing metabolic function:

  • Drug metabolism is decreased in “severe” liver dysfunction (Child Pugh B or C).
  • There is no single marker for liver function (and therefore liver drug metabolism).
    • Clotting factors and albumin are useful surrogate markers of liver synthetic function. Note: tranaminases (ALT, AST, etc) do not reflect drug metabolism.
Pharmacokentic Considerations
  • Approximately 70% of drugs are cleared predominantly by metabolism, mostly in the liver.
  • Predicting doses for individuals is hard and doses are usually titrated to response (clinical or laboratory).
    • The patient’s dose requirements for other drugs metabolised by the same pathway provides some information. For example, bradycardia with moderate doses of metoprolol should prompt caution with other CYP2D6 substrates.
    • In severe liver disease reduce starting doses by 50%.
Common narrow therapeutic index drugs relevant in liver impairment (not exhaustive):
anti-arrhythmics antipsychotics NSAIDs
anticoagulants benzodiazepines Opioids
antiepileptics immunosuppressants paracetamol

For specialist advice about using a specific medicine contact the relevant specialty, or Medicines Information on 80900

  • Sensitivity to some drugs may be increased e.g. CNS agents (because encephalopathy may accompany severe liver disease) and anticoagulants (because clotting factors may be altered).
  • Some medicines are hepatotoxic. If you are investigating a patient with possible drug-induced liver injury (DILI), refer to Livertox, or contact Medicines Information (03 364 0900).