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

 

General Advice

  • When prescribing, ‘start low and go slow’; consider dose tapering after desired effects are achieved and discontinue unnecessary drugs.
  • Causes of decreased metabolic function:
    • Age – metabolic function decreases with age at a rate of 1% per year after the age of forty.
    • Renal dysfunction – Severe, chronic renal impairment (creatinine clearance < 30 mL/minute) is associated with approximately a 50% reduction in metabolic clearance.
    • Drug interactions i.e. metabolising enzyme inhibitors.
  • Assess liver metabolic function (albumin concentration, INR, age and frailty) – see below.
  • There is no single marker for the degree of liver dysfunction. Standard liver function tests (e.g. ALT, ALP) do not accurately reflect liver dysfunction, however, severe liver dysfunction is indicated by an albumin of < 27 g/L and/or INR of > 1.2.
  • Consider using drugs cleared renally rather than metabolically.
  • Consider reducing doses of drugs that are predominantly metabolised (those with fe < 0.5) in relation to impairment of liver metabolic function – see below.

 

Approximately 70% of drugs are cleared predominantly by metabolism, mostly in the liver.Pharmacokinetic Problems

  • Dose reductions should be considered for all metabolised drugs:
    • For severe liver disease reduce the dose by 50%.
    • For non-severe liver disease consider reducing the dose (e.g. by 25%).
  • For low therapeutic index drugs it is more important to dose-reduce

 

Common metabolised low therapeutic index drugs

·                antidepressants ·                statins ·                calcium channel blockers
·                antipsychotics ·                paracetamol ·                lidocaine
·                opioids ·                anticonvulsants ·                NSAIDs
·                lipophilic betablockers   e.g. metoprolol ·                nitrates ·                warfarin

 

Pharmacodynamic Problems

  • Sensitivity to many drugs may be increased e.g. CNS agents (because encephalopathy may accompany severe liver disease) and anticoagulants (because clotting factors may be altered).
  • Hepatotoxic drugs may aggravate the already impaired liver.