see also:

• Pharmacokinetics
• Metabolism of drugs
• assessment of hepatic function
• liver diseases
• cirrhosis
• hepatic encephalopathy

• decreased hepatic blood flow (eg. portosystemic shunts) will decrease metabolism rates of high extraction ratio drugs (see below)
• liver cirrhosis with moderate to severe liver dysfunction may reduce rates of drug metabolism by as much as 50%
  • presumably due to spatial separation of blood from hepatocyte by fibrosis along the hepatic sinusoids
• certain drugs may risk hepatic decompensation
  • patients with liver cirrhosis:
    • pegylated interreron alfa-2a with ribavarin for Rx of chronic active hepatitis due to hepatitis C infection
  • antiretroviral Rx in patients with HIV / AIDS and co-existent hepatitis B or C, even in absence of cirrhosis
• liver damage may reduce production of normal proteins (eg. vitamin K-dependent clotting factors) and thus increase toxicity of warfarin
• hepatic enzyme inhibition or induction due to concomitant drugs or ethanol intake
  • risk of paracetamol toxicity, etc
• cholestatic jaundice (icterus) may impair elimination of drugs and their active metabolites that are dependent on biliary excretion
  • further impairment will occur if the drug is excreted as a glucuronide and is subject to enterohepatic circulation
• drugs with a narrow therapeutic range that are extensively metabolised by the liver (> 20% by hepatic metabolism) should be avoided or used with extreme caution (eg. morphine, theophylline) in patients with significant liver disease.

• ascertain how much the drug depends on hepatic metabolism
  • if > 90% of the drug is excreted unchanged in the urine, then hepatic impairment is unlikely to play a significant role in accumulation of the drug.
• determine the degree of hepatic impairment, hepatic enzyme levels and possibly as ultrasound of the liver with portal vein Doppler study
• if there is doubt about the degree of hepatic impairment or the drug has a narrow therapeutic index¹⁾, then lower the recommended starting dose by 50% and titrate to effect under careful supervision - 'start low and go slow'.
• determine possible interactions between the new drug and any drugs the patient is already taking.

• high 1st pass effect drugs eg. morphine 0.67; verapamil (Isoptin), propranolol, antidepressants, chlorpromazine, GTN, levodopa
  • ⇒ oral bioavailability = extent of absorption x (1 - ER)
• clearance limited by blood flow (normal hepatic blood flow is 90L/hr)
  • eg. portosystemic shunts (eg. portal hypertension in liver disease) will decrease hepatic blood flow and lower hepatic clearance of high extraction ratio drugs thus risk toxicity.
  • ⇒ change in intrinsic clearance has little effect
  • ⇒ change in plasma protein binding or other competitive binding has little effect

• eg. anticonvulsants, non-steroidal anti-inflammatory drugs (NSAIDs), diazepam, warfarin
• ⇒ changes in intrinsic clearance or concentration of unbound drug has significant effect on clearance
• ⇒ but changes in blood flow has little effect

• Australian Prescriber April 2009 - Prescribing in liver disease