| There is no single marker for quantifying liver impairment (unlike renal excretion).
Drug metabolism is decreased in severe liver disease. |
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 |
| Pharmacodynamic Considerations |
- 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.