Table of Contents
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
- 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:
- ⇒ changes in intrinsic clearance or concentration of unbound drug has significant effect on clearance
- ⇒ but changes in blood flow has little effect
references and other resources
ie. upper dose range for efficacy is close to the lower concentration range of toxicity
pk_liverdisease.txt · Last modified: 2009/04/09 03:41 by 127.0.0.1