Div: How does liver failure affect pharmacology of drugs

Definition & Types of Liver Failure

• Liver failure = impaired metabolic & synthetic function of liver
• CLD = associated with more predictably impaired metabolism
• ALD (acute liver failure) = associated with severely impaired drug metabolism
• Alcoholic liver disease → may result in ↑metabolism due to enzyme induction

Pharmacokinetics

Absorption

• ↓abs 2° portal HTN & interstitial oedema
• ↓abs fat soluble drugs (Vit K) 2° ↓ bile salts
• ↑OBA (morphine) 2° ↓1^st pass metabolism

Distribution

• • ↓plasma protein synthesis = ↑free drug
    • ↑V_D for lipophilic drugs (PPF)
  • ↑ECF volume 2° ascites = ↑V_D hydrophilic drug (NDMR)
  • ↓pH = alters ionisation of acid/base
  • ↑free drug → normally matched by ↑drug clearance because unbound drug metabolised, but unbound drug may be affected by ↓metabolic capacity of liver

Metabolism

• ↓BF 2° portal shunts = ↓metabolism of drugs with high HER
• ↓biotransformation phase 1 & 2 reactions = ↓metabolism of drugs with low HER
• ↓plasma cholinesterase synthesis = prolonged actions of sux, mivacurium

Elimination

• ↓biliary drug clearance
• ↓renal drug clearance 2° hepatorenal syndrome
• ↓PPB = ↑renal clearance

Pharmacodynamics

Encephalopathy

• ↑effect of BZD, M, PPF

Coagulopathy

• ↑effect of anticoagulants
• ↓platelet production 2 ° splenomegaly

↑Hepatotoxicity

• ↓Hepatic enzyme = ↑risk paracetamol toxicity + ↑risk of moving to zero order kinetics

Fluid Balance/Electrolytes

• Ascites → ↑aldosterone 2° intravascular depletion → ↑Na/↓K

Drug Monitoring/Dosing

PPB

• ↑V_D → alters loading dose
• ↓Clearance → alters maintenance dose
• Drug monitoring → measures bound + unbound [drug] ∴may underestimate [drug]