Liver — Drug PK

Pharmacodynamics

• Altered receptor binding
  • Postulated for relative resistance to non-depolarizing NMB in liver failure

Pharmacokinetics

• Absorption
  • Portal hypertension and interstitial oedema reduce absorption of drugs
  • Hepatic dysfunction
    • Increased bioavailability of drugs susceptible to hepatic first pass metabolism (diazepam)
    • Decreased activation of pro-drug (clopidogrel requires CYP2C19 activation)

• Distribution
  • Decreased synthesis of plasma proteins
    • Increases free fraction of protein bound drugs
      → Unbound drug more permeable → increased volume of distribution (amiodarone)
      → Unbound drug more active
  • Hypervolaemia secondary to renal Na⁺ and H₂O retention
    • Increased V_d for drugs distributed to extracellular volume
  • Decreased pH alteres ionization of acids and bases (acids ionized when pH above pKa and bases ionized when pH below pKa)

• Metabolism
  • Decreased hepatic metabolism
    • Increases T_1/2b of hepatically metabolized drug → Accumulation of drug if no alteration
  • Decreased butylcholinesterase production → Decreased metabolism for drugs metabolised by plasma esterases (suxamethonium – however clinically not significant for this drug) – red cell esterases remain therefore no effect for remifentanyl
• Elimination
  • Hepatorenal syndrome → decreased renal clearance
  • However renal drug clearance tends to decrease even in absence of renal impariment (drugs not hepatically converted to more water soluble metabolites)
  • Biliary clearance of drug is reduced

Sakurai 2016

Answer by Sakurai