Drug Information for Sevoflurane (Halocarbon Products Corporation): CLINICAL PHARMACOLOGY

  • Sevoflurane is an inhalational anesthetic agent for use in induction and maintenance of general anesthesia. Minimum alveolar concentration (MAC) of sevoflurane in oxygen for a 40 year old adult is 2.1%. The MAC of sevoflurane decreases with age (See DOSAGE AND ADMINISTRATION for details).

  • Solubility

  • Because of the low solubility of sevoflurane in blood (blood/gas partition coefficient @ 37°C = 0.63 to 0.69), a minimal amount of sevoflurane is required to be dissolved in the blood before the alveolar partial pressure is in equilibrium with the arterial partial pressure. Therefore there is a rapid rate of increase in the alveolar (end-tidal) concentration (FA) toward the inspired concentration (FI) during induction.

  • Induction of Anesthesia

  • In a study in which seven healthy male volunteers were administered 70% N2O/30%O2 for 30 minutes followed by 1.0% sevoflurane and 0.6% isoflurane for another 30 minutes the FA/FI ratio was greater for sevoflurane than isoflurane at all time points. The time for the concentration in the alveoli to reach 50% of the inspired concentration was 4 to 8 minutes for isoflurane and approximately 1 minute for sevoflurane.

    FA/FI data from this study were compared with FA/FI data of other halogenated anesthetic agents from another study. When all data were normalized to isoflurane, the uptake and distribution of sevoflurane was shown to be faster than isoflurane and halothane, but slower than desflurane. The results are depicted in Figure 3.

  • Recovery from Anesthesia

  • The low solubility of sevoflurane facilitates rapid elimination via the lungs. The rate of elimination is quantified as the rate of change of the alveolar (end-tidal) concentration following termination of anesthesia (FA), relative to the last alveolar concentration (Fa0) measured immediately before discontinuance of the anesthetic. In the healthy volunteer study described above, rate of elimination of sevoflurane was similar compared with desflurane, but faster compared with either halothane or isoflurane. These results are depicted in Figure 4.

    Yasuda N, Lockhart S, Eger El II, et al: Comparison of Kinetics of sevoflurane and isoflurane in humans. Anesth Analg 72:316, 1991.

  • Protein Binding

  • The effects of sevoflurane on the displacement of drugs from serum and tissue proteins have not been investigated. Other fluorinated volatile anesthetics have been shown to displace drugs from serum and tissue proteins in vitro. The clinical significance of this is unknown. Clinical studies have shown no untoward effects when sevoflurane is administered to patients taking drugs that are highly bound and have a small volume of distribution (e.g., phenytoin).

  • Metabolism

  • Sevoflurane is metabolized by cytochrome P450 2E1, to hexafluoroisopropanol (HFIP) with release of inorganic fluoride and CO2. Once formed HFIP is rapidly conjugated with glucuronic acid and eliminated as a urinary metabolite. No other metabolic pathways for sevoflurane have been identified. In vivo metabolism studies suggest that approximately 5% of the sevoflurane dose may be metabolized.

    Cytochrome P450 2E1 is the principal isoform identified for sevoflurane metabolism and this may be induced by chronic exposure to isoniazid and ethanol. This is similar to the metabolism of isoflurane and enflurane and is distinct from that of methoxyflurane, which is metabolized via a variety of cytochrome 450 isoforms. The metabolism of sevoflurane is not inducible by barbiturates. As shown in Figure 5, inorganic fluoride concentrations peak within 2 hours of the end of sevoflurane anesthesia and return to baseline concentrations with in 48 hours postanesthesia in the majority of cases (67%). The rapid and extensive pulmonary elimination of sevoflurane minimizes the amount of anesthetic available for metabolism.

    Cousins M.J., Greenstein L.R., Hitt B.A., et al: Metabolism and renal effects of enflurane in man. Anesthesiology 44:44; 1976* and Sevo-93-044+.Legend:Pre-Anesth. = Pre-anesthesia

  • Elimination

  • Up to 3.5% of the sevoflurane dose appears in the urine as inorganic fluoride. Studies on fluoride indicate that up to 50% of fluoride clearance is nonrenal (via fluoride being taken up into the bone).

  • Pharmacokinetics of Fluoride Ion

  • Fluoride ion concentrations are influenced by the duration of anesthesia, the concentration of sevoflurane administered, and the composition of the anesthetic gas mixture. In studies where anesthesia was maintained purely with sevoflurane for periods ranging from 1 to 6 hours, peak fluoride concentrations ranged between 12 µM and 90 µM. As shown in Figure 6, peak concentrations occur within 2 hours of the end of anesthesia and are less than 25 µM (475 ng/mL) for the majority of the population after 10 hours. The half-life is in the range of 15 to 23 hours.

    It has been reported that following administration of methoxyflurane, serum inorganic fluoride concentration >50 µM were correlated with the development of vasopressin-resistant, polyuric, renal failure. In clinical trials with sevoflurane, there were no reports of toxicity associated with elevated fluoride ion levels.

  • Fluoride Concentrations After Repeat Exposure and in Special Populations

  • Fluoride concentrations have been measured after single, extended, and repeat exposure to sevoflurane in normal surgical and special patient populations, and pharmacokinetic parameters were determined.

    Compared with healthy individuals, the fluoride ion half-life was prolonged in patients with renal impairment, but not in the elderly. A study in 8 patients with hepatic impairment suggests a slight prolongation of the half-life. The mean half-life in patients with renal impairment averaged approximately 33 hours (range 21 to 61 hours) as compared to a mean of approximately 21 hours (range 10 to 48 hours) in normal healthy individuals. The mean half-life in the elderly (greater than 65 years) approximated 24 hours (range 18 to 72) hours). The mean half-life in individuals with hepatic impairment was 23 hours (range 16 to 47 hours). Mean maximal fluoride values (Cmax) determined in individual studies of special populations are displayed below.

    Table 1. Fluoride Ion Estimates in Special Populations Following Administration of Sevoflurane
    n Age (yr) Duration (yr) Dose (MAC∙hr) Cmax (µM)
    n = number of patients studied.
    Sevoflurane-O2 76 0 to 11 0.8 1.1 12.6
    Sevoflurane-O2 40 1 to 11 2.2 3.0 16.0
    Sevoflurane/N2O 25 5 to 13 1.9 2.4 21.3
    Sevoflurane/N2O 42 0 to 18 2.4 2.2 18.4
    Sevoflurane/N2O 40 1 to 11 2.0 2.6 15.5
    ELDERLY 33 65 to 93 2.6 1.4 25.6
    RENAL 21 29 to 83 2.5 1.0 26.1
    HEPATIC 8 42 to 79 3.6 2.2 30.6
    OBESE 5 3.0