Hepatic effects of AA

[Ref: SH4:p64]

Hepatic blood flow

• ISO, SEV, DES causes vasodilation in hepatic circulation
  * Hepatic blood flow is maintained
  * Portal vein blood flow is increased
• HAL causes vasoconstriction in hepatic circulation

Drug clearance

AA causes decrease in hepatic metabolic clearance of drugs such as propranolol
* By >50%

Liver function tets

• ENF and DES cause transient increases in plasma alanine aminotransferase
• ISO and DES cause transient increases in plasma alpha glutathione transferase

Hepatic dysfunction is most likely to be due to inadequate hepatocyte oxygenation
* Enzyme induction increases O2 demand and increases risk of inadequate oxygenation

Hepatotoxicity

Centrilobular necrosis

Halothane

Two types of hepatotoxicity:

• Mild, self-limited form
• Severe, rare form

Mild form of halothane hepatotoxicity

• Incidence
  = ~20% of postop patients
• Nonspecific drug effect
  * Due to decrease in hepatic blood flow
  --> Reduced hepatic oxygenation
• Symptoms and signs
  * Nausea
  * Lethargy
  * Fever
  * Minor increase in liver transaminase

Halothane hepatitis

• Incidence
  = 1 in 10,000 to 30,000
• Immune-mediated
• Symptoms and signs
  * Eosinophilia
  * Fever
  * Rash
  * Arthralgia
• Risk factors
  * Female gender
  * Middle age
  * Obesity
  * Prior exposure to HAL
  * Family history

Mechanism

• Formation of reactive oxidative trifluoroacetyl halide metabolite
  --> Covalently bound to liver microsomal proteins on hepatocyte surfaces
  --> Neoantigens
  --> Triggers immune response
• Metabolism of HAL is genetically determined

Evidence of immunogenic basis

Presence of IgG antibodies in at least 70% of patients
* Directed against liver microsomal proteins

ENF, ISO, and DES

Mild self-limited hepatic dysfunction can also happen with ENF, ISO, and DES
* Related to inadequate hepatocyte oxygenation

Immune-mediated hepatitis can also occur.

• Much lower incidence due to lower metabolism
• Risk is increased when patient has previously been sensitized against trifluoroacetyl proteins
• Overall risk (after previous exposure to HAL) is probably less than overall risk of anaesthetics

SEVO

Due to chemical structure of SEVO, metabolism of SEVO cannot lead to production of acetyl halide
--> Cannot form trifluoroacetylated liver protein
--> Cannot cause immune-mediated hepatitis or cross-reaction

Compound A is hepatotoxic in animals
* But concentration in circuit is far lower than toxic level in animals