KEY POINTS

1. The liver is the major site of endogenous and exogenous drug metabolism. The primary result of drug metabolism is the production of more water-soluble and therefore more easily excreted drug metabolites. Drugs are sometimes biotransformed into more reactive metabolites, which may lead to toxicity.
2. Most drug metabolism is catalyzed by phase 1 or phase 2 enzymes. The predominant phase 1 enzymes are the cytochrome P450 (CYP) monooxygenases. Approximately 50 of the more than 1000 CYPs are functionally active in humans. The predominant isoform catalyzing metabolism of the inhaled anesthetics is CYP2E1. The major phase 2 enzyme is uridine diphosphate glucuronosyltransferase (UGT).
3. Many factors affect drug metabolism. Perhaps the most important are pharmacogenetic factors. Genetic status ultimately determines absorption, distribution, metabolism, and excretion. Other important determinants are environmental factors, age, gender disease states, and other drugs or medications.
4. Pharmacogenomics, or the influence of DNA sequence variation on the effect of a drug, provide a basis for understanding the variations observed in drug responses among patients.
5. N₂ O and xenon are nonhalogenated anesthetics. Xenon is not currently approved for clinical use. Other than the expense associated with its use, it may be the most ideal anesthetic agent.
6. Halothane, enflurane, isoflurane, and desflurane are all metabolized to trifluoroacylated hepatic protein adducts, which have been reported to induce liver injury in susceptible patients. The propensity to produce liver injury appears to parallel metabolism of the parent drug: halothane (20%) ≫≫ enflurane (2.5%) ≫ isoflurane (0.2%) > desflurane (0.02%). The incidence of halothane hepatitis in the adult population is roughly 1 in 10,000. Sevoflurane does not produce acylated protein adducts.
7. Halothane hepatitis has been reported in the pediatric population. The incidence appears to be approximately 1 in 200,000.
8. Toxicity and liver injury have been reported after repeated exposure on subsequent occasions to different fluorinated anesthetics. This phenomenon of cross-sensitization has also been reported with the chlorofluorocarbon (CFC) replacement agents, the hydrochlorofluorocarbons (HCFCs).
9. Sevoflurane is metabolized to hexafluoroisopropanol, formaldehyde, inorganic fluoride, and carbon dioxide. Although very high fluoride levels have been reported after sevoflurane anesthesia, fluoride-associated renal injury has not been reported.
10. The major base-catalyzed breakdown product of sevoflurane is compound A. Compound A is a nephrotoxic vinyl ether and induces a renal injury that is dose and time dependent. The threshold for renal injury in rats and humans appears to be approximately 150 ppm-hours of compound A exposure (i.e., 50 ppm for 3 hours). The toxic threshold appears to be reached only under clinical conditions of prolonged sevoflurane anesthesia, and observed changes occur in glucosuria and enzymuria. BUN and creatinine levels remain unchanged.
11. Desiccated carbon dioxide absorbents and inhaled anesthetics interactions can lead to the production of CO in the anesthesia circuit (desflurane ⋙ enflurane > isoflurane). Negligible amounts of CO are formed from halothane and sevoflurane.
12. There appears to be no risk associated with brief periods of low-level occupational exposure to waste anesthetic gases in the operating room, PACU, or ICU. Occupational exposure to high concentrations (10³ ppm) may be correlated with an increased incidence of abortions and decreased fertility. Individuals with vitamin B₁₂ deficiencies may be at risk of neurologic injury from N₂ O.