2011A03 Outline the effects of liver failure on drug kinetics and dynamics.

· Liver failure

· Absorption

· Distribution

· Metabolism

· Excretion

· Dynamics

Definition

Failure of the liver to perform its functions:

· Metabolise energy substrates, drugs, toxins

· Synthesise albumin, α₁ acid glycoprotein (AAG), coag proteins, bile

· Store energy substrates, metals

Associated features

· Portal hypertension

· Portosystemic shunt

Oral

↓First pass metabolism + ↑Portosystemic shunt

· ↑Bioavailability

· ↑Toxicity (e.g. lignocaine airway topicalization)

↓Bile secretion

· ↓Absorption of Vitamins A, D, E, K

Rectal

Same factors -> improved rectal bioavailability

↑ECF volume

↑V_D hydrophilic drugs -> ↑loading dose required (e.g. rocuronium)

↓Albumin

↓α₁ acid glycoprotein

↑Unbound drug

· If highly bound and poorly metabolized -> ↑risk toxicity

· e.g. phenytoin -> arrhythmia

	Hepatic extraction ratio (HER) = [drug] in hepatic artery – [drug] in hepatic vein / [drug] in hepatic artery
↓Phase 1&2 reaction	↓Clearance if metabolism-limited drugs (HER <0.3) · e.g. thiopentone -> prolonged hypnosis · Phase 1 affected before phase 2
↓Hepatic blood flow (if cirrhosis)	↓Clearance if flow-limited (HER >0.7) · e.g. lignocaine -> seizure, arrhythmia, arrest
↓Plasma cholinesterase production	↓Clearance of suxamethonium, mivacurium, ester local anaesthetics

Bile

↓Production

· ↓Excretion of large and/or lipophilic drugs and metabolites -> ↑toxicity

· e.g. vecuronium -> prolonged paralysis

Urine

Hepatorenal syndrome

· ↓Excretion of small and/or hydrophilic drugs and metabolites -> ↑toxicity

· E.g. morphine-3-glucuronide -> seizure

Brain	Altered CNS receptor response · ↑Sensitivity to opioids, benzodiazepines Hyperammonaemia -> hepatic encephalopathy
Blood	↓Clotting factors, ↓anticoagulant factors, platelet sequestration · Unpredictable clotting status · Unpredictable effect of anticoagulants
Kidney	↑Sensitivity to nephrotoxins (e.g. gentamicin) -> hepatorenal syndrome
Liver	↑Sensitivity to hepatotoxins (e.g. paracetamol) -> worsening failure