Metabolism of AA

[Ref: SH4:p75]

Metabolism and change in AA

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

Difference between AAs

For ENF, ISO, DES, and SEVO, alveolar ventilation is the main route of elimination

For HAL, 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 of mass balance

No knowledge of metabolite is required

Disadvantage of mass balance

Loss of AA through skin, wound, urine, and faeces would be considered as metabolised

Determinants of metabolism

Magnitude to metabolism depends on

1. Chemical structure
2. Hepatic enzyme activity
3. Blood concentration of AA
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 ether bond
--> Cannot be metabolised by hydrolysis

2. Hepatic enzyme activity

Phenobarbital, phenytoin, isoniazid
--> Increase hepatic P450 enzymes
--> Increase defluorination of volatile AA (especially ENF)

Obesity increases defluorination of HAL, ENF, and ISO

3. Blood concentration of AA

At 1 MAC
--> Hepatic enzymes saturated
--> Fraction of AA metabolised is small

At 0.1 MAC
--> Fraction of AA metabolised is high

AAs which are more soluble in blood and lipids (e.g. HAL, METHO)
--> Reservoir
--> Subanaesthetic concentration maintained
--> Higher fraction metabolised

4. Genetic factors

The MOST important determinant of enzyme activity

Metabolism of AA

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 HAL (not other AAs)
• Most likely to occur with low 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)
• Metabolism starts with oxidation of C-H bond on alpha carbon
  --> Difluoromethanol + trifluoroacetic acid (main metabolite)
• Metabolites include:
  * Trifluoroacetic acid
  * HCl
  * HF
  * CO2
• Ether bond is fairly stable also
• Enzyme induction with phenobarbital, phenytoin, and isoniazid
  --> Mild increase in metabolism and release of fluoride
  --> Still much lower level than ENF

Desflurane

• 0.02% metabolised (oxidative)
  * C-F in DES (alpha carbon) is harder to break than C-Cl in ISO
  --> Less metabolism
  * Low blood and tissue solubility also contribute
• Metabolism starts with oxidation of C-H bond on alpha carbon
  --> Difluoromethanol + trifluoroacetic acid
• Metabolites include:
  * Trifluoroacetic acid
  * HF
  * CO2
• Enzyme induction with phenobarbital or ethanol does not influence metabolism

Sevoflurane

• About 5% metabolised (oxidative)
• 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
• Intermediate metabolite hexafluoroisopropanol
  --> Conjugation wit glucuronic acid
  --> Urinary excretion
  * Not considered toxic
• Peak plasma fluoride level is higher than that from ENF
  * Mostly produced by liver --> May be less nephrotoxic than intrarenal production of fluoride (in the case of ENF)