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

 

List:

·     Liver failure

·     Absorption

·     Distribution

·     Metabolism

·     Excretion

·     Dynamics

 

Liver failure:

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

 

Absorption:

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

 

Distribution:

↑ECF volume

↑VD 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

 

Metabolism:

 

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

 

Excretion:

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

 

Dynamics:

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