Drugs in Hepatic Failure

Drugs in Hepatic Failure

1. Definition, scope & why the liver matters in pharmacology

• Hepatic failure / hepatic impairment in a pharmacological sense means a loss of the liver's drug-handling capacity sufficient to alter the disposition (and sometimes the action) of administered drugs, requiring dose modification or drug avoidance to prevent toxicity. The prototypical chronic form is cirrhosis, but the principles extend to acute liver failure, severe hepatitis and infiltrative/cholestatic disease (KDT 8e Ch.5, p.78).
• The liver is the body's dominant site of drug biotransformation: "The biotransformation of drugs occurs primarily in the liver" via phase 1 reactions (oxidation, reduction, hydrolysis — chiefly CYP enzymes) and phase 2 reactions (conjugations to polar, excretable metabolites) (G&G 14e Ch.2, p.30).
• It is also a major excretory organ (biliary secretion of drugs/metabolites by canalicular transporters, with possible enterohepatic recycling) and the organ responsible for the first-pass (presystemic) effect that limits the oral bioavailability of many drugs (G&G 14e Ch.2, pp.26, 30, 32).
• Because hepatic dysfunction simultaneously degrades metabolic clearance, first-pass extraction, plasma-protein synthesis (albumin, clotting factors) and biliary excretion, a single failing organ perturbs almost every pharmacokinetic parameter at once — making hepatic-failure prescribing inherently more complex than renal-failure prescribing (KDT 8e Ch.5, p.78).
• Crucial asymmetry vs. renal failure: "The changes in drug metabolism due to liver disease are complex and there is no simple test (like creatinine clearance for renal disease) to estimate the extent of alteration in drug disposition. Moreover, the kinetics of different drugs is affected to different extents." This is the single most examinable concept of the topic (KDT 8e Ch.5, p.78).