Drug metabolism in liver disease

• First pass metabolism: the concentration of the drug when administered orally is greatly reduced before it reaches the systemic circulation, largely due to metabolism by the liver
  • If liver function is reduced, plasma concentrations of these drugs will increase due to first pass metabolism and also porto-systemic shunting
  • Need much lower doses to achieve therapeutic effect
• Phase I metabolism is affected early
  • Affects metabolism of fat-soluble drugs - opiates, calcium blockers, cyclosporin, metronidazole and others
• Phase II metabolism affected late - explains why some drugs are better than others for patients with liver disease

Prescribing NSAIDs - AVOID

• Avoid if possible
  • Prostaglandin synthesis will be decreased
    • Worsen renal impairment - PGEs act against the renal vasoconstriction caused by liver disease via RAAS and ADH
    • Further sodium retention
    • Risk of hepato-renal syndrome
    • Worsening of CHF
  • People with cirrhosis are at increased risk of peptic ulcers – risk of GI bleed or perforation
• If unavoidable give standard NSAID or COX-2 inhibitor
• Always co-prescribe a PPI

Prescribing opiates - AVOID OR USE SPARINGLY

• Can cause confusion and respiratory depression - give low dose and watch out for sedation/encephalopathy

Paracetamol - ANALGESIA OF CHOICE

• Safer option than NSAIDS and opiates but use lowest possible dose to avoid toxicity
• Half-life prolonged in patients with liver dysfunction
• Increased P450 can be stimulated by alcoholism

Antibiotics in established liver disease

• Mostly safe
• Notable exceptions:
  • Aminoglycosides - nephrotoxic
  • Quinolones - epileptogenic
  • Metronidazole metabolism reduced