Metabolism of inhalational anaesthetic agents

[SH4:p75]

Metabolism and rate of change in MAC

• Metabolism may influence the rate of decrease in the inhalational anaesthetic agents at the end of anaesthetics
• Metabolism does not influence the rate of increase in inhalational anaesthetic agents during induction
  * The amount administered is in great excess to the amount metabolised

Difference between inhalational anaesthetic agentss

• For enflurane, isoflurane, desflurane, and sevoflurane, alveolar ventilation is the main route of elimination
• For halothane, both alveolar ventilation and metabolism are important
• For methoxyflurane, metabolism is the dominant route of elimination

Methods of measuring metabolism

Two methods of measuring metabolism

• Measurement of metabolites
• Mass balance
  * Advantage = no knowledge of metabolite is required
  * Disadvantage = losses through other routes (e.g. skin, faeces, wound) would be considered metabolised

Determinants of metabolism

Magnitude to metabolism depends on

1. Chemical structure
2. Hepatic enzyme activity
3. Blood concentration of inhalational anaesthetic agents
4. Genetic factors

1. Chemical structure

• Ether bond and carbon-halogen bond are sites most susceptible to oxidative metabolism

Terminal carbons

• Two halogen atoms on a terminal carbon
  --> Easiest for dehalogenation
• Terminal carbon with fluorine atoms
  --> Very resistant to oxidative metabolism
  * C-F bond is twice that of C-Br or C-Cl bond

Ether bonds

• Oxidation of ether bond less likely when hydrogen on the carbons surrounding the oxygen atom are replaced by halogen atoms
• Absence of ester bond
  --> Cannot be metabolised by hydrolysis

2. Hepatic enzyme activity

• Phenobarbital, phenytoin, isoniazid
  --> Increase hepatic P450 enzymes
  --> Increase defluorination of volatile inhalational anaesthetic agents (especially enflurane)
• Obesity increases defluorination of halothane, enflurane, and isoflurane

3. Blood concentration of inhalational anaesthetic agents

• At 1 MAC
  --> Hepatic enzymes saturated
  --> Fraction of inhalational anaesthetic agents metabolised is small
• At 0.1 MAC
  --> Fraction of inhalational anaesthetic agents metabolised is high
• Inhalational anaesthetic agents which are more soluble in blood and lipids (e.g. halothane, methoxyflurane)
  --> Reservoir
  --> Subanaesthetic concentration maintained
  --> Higher fraction metabolised

4. Genetic factors

• The MOST important determinant of enzyme activity

Metabolism of inhalational anaesthetic agents

Nitrous oxide

0.004% of the absorbed dose of N2O
--> Reductive metabolism (to N2) in GIT
* By anaerobic bacteria in GIT (e.g. Pseudomonas)

Halothane

• 15% to 20% metabolised
• Normally oxidative metabolism by P-450 system
• Reductive metabolism when pO2 decrease

Oxidative metabolism

• Main metabolites are
  * Trifluoroacetic acid
  * Chloride
  * Bromide
• Trifluoroacetyl halide (intermediate metabolite)
  --> Interact with surface proteins of hepatocytes
  --> Stimulate formation of antibody
  --> Hepatitis

Reductive metabolism

• Only in halothane (not other inhalational anaesthetic agentss)
• Most likely to occur with hepatocyte hypoxia and enzyme induction
• Main metabolites are
  * Fluoride
  * Others
• No evidence of hepatotoxicity or nephrotoxicity

Enflurane

• 3% metabolised (oxidative)
• Metabolites are:
  * Inorganic fluoride
  * Organic fluoride compounds
• Fluoride comes from dehalogenation of terminal carbon atom
• Ether bond is very stable

Isoflurane

• 0.2% metabolised (oxidative)
• Steps of metabolism [SH4:p79]
  1. Oxidation of C-H bond on alpha carbon
  2. Formation of acetyl halide + HCl
  3. Break into difluoromethanol + trifluoroacetic acid (main metabolite)
  4. Difluoromethanol + O ==> 2 HF + CO2
• Metabolites include:
  * Trifluoroacetic acid
  * HCl
  * HF
  * CO2
• Ether bond is fairly stable
• Enzyme induction with phenobarbital, phenytoin, and isoniazid
  --> Mild increase in metabolism and release of fluoride
  --> Still much lower level than enflurane

Desflurane

• 0.02% metabolised (oxidative)
  * C-F in desflurane (alpha carbon) is harder to break than C-Cl in isoflurane
  --> Less metabolism
  * Low blood and tissue solubility also contribute
• Steps of metabolism [SH4:p79]
  1. Oxidation of C-H bond on alpha carbon
  2. Formation of acetyl halide + HF
  3. Break into difluoromethanol + trifluoroacetic acid (main metabolite)
  4. Difluoromethanol + O ==> 2 HF + CO2
• Metabolites include:
  * Trifluoroacetic acid
  * HF
  * CO2
• Enzyme induction with phenobarbital or ethanol does not influence metabolism

Sevoflurane

• About 5% metabolised (oxidative)
• Steps of metabolism [SH4:p69]
  1. Hexafluoroisopropanol + CO2 + F-
  2. (catalysed by uridine diphosphate glucuronic acid) ==> Hexafluoroisopropanol glucuronide
• Intermediate metabolite hexafluoroisopropanol
  --> Conjugation wit glucuronic acid
  --> Urinary excretion
  * Not considered toxic
• Also degraded by desiccated carbon dioxide absorber
  --> Formation of compound A, etc
• Does not undergo metabolism to acetyl halide
  --> Does not lead to formation of trifluoroacetylated liver protein
  --> Does not stimulate formation of antitrifluoroacetylated protein antibodies
  --> Does not lead to hepatotoxicity
• Peak plasma fluoride level is higher than that from enflurane
  * Mostly produced by liver --> May be less nephrotoxic than intrarenal production of fluoride (in the case of enflurane)