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pk_liverdisease

prescribing drugs in patients with liver impairment

liver disease and drug Rx

  • 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.

factors to consider when prescribing drugs dependent on hepatic elimination

  • 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 extraction ratio drugs:

  • 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

low extraction ratio drugs:

references and other resources

1)
ie. upper dose range for efficacy is close to the lower concentration range of toxicity
pk_liverdisease.txt · Last modified: 2009/04/09 13:41 (external edit)