M & H Sevoflurane USP Mechanism of Action

Pharmacology: Pharmacodynamics: In a variety of animal species including man, sevoflurane has been demonstrated to be a fast-acting, nonirritating agent. Administration has been associated with a smooth, rapid loss of consciousness during inhalational Induction and a rapid recovery following discontinuation of anesthesia.
Induction is accomplished, with a minimum of excitement or signs of upper respiratory irritation, no evidence of excessive secretions within the tracheobronchial tree and no central nervous system stimulation. In pediatric studies in which mask induction was performed, the incidence of coughing was statistically significantly lower with sevoflurane than with halothane.
Like other potent inhalational anesthetics, sevoflurane depresses respiratory function and blood pressure in a dose-related manner.
In both dogs and humans, the epinephrine-induced arrhythmogenic threshold for sevoflurane was comparable to that of isoflurane and higher than that of halothane. Studies in dogs have demonstrated sevoflurane does not reduce collateral myocardial perfusion. In clinical studies, the incidence of myocardial ischemia was comparable between sevoflurane and isoflurane.
Animal studies have shown regional blood flow (e.g. hepatic, renal, cerebral circulations) is well-maintained with sevoflurane. In both animal studies (dogs, rabbits) and clinical studies, changes in neurohemodynamics (intracranial pressure, cerebral blood flow/blood flow velocity, cerebral metabolic rate for oxygen, and cerebral perfusion pressure) were comparable between sevoflurane and isoflurane. Sevoflurane has minimal effect on ICP (intracranial pressure) and preserves CO₂ responsiveness.
Sevoflurane does not affect renal concentrating ability, even after prolonged anesthetic exposure, up to approximately nine hours.
Minimum Alveolar Concentration: The minimum alveolar concentration (MAC) is the concentration at which 50% of the population tested does not move in response to a single stimulus of skin incision.
For MAC equivalents for sevoflurane for various age groups, see Dosage & Administration.
The MAC of sevoflurane in oxygen was determined to be 2.05% for a 40 year old adult. As with other halogenated agents, MAC decreases with age and with the addition of nitrous oxide.
Pharmacokinetics: Sevoflurane is absorbed on inhalation. The blood/gas partition coefficient is low. Up to 5% of the absorbed dose of sevoflurane is metabolized in the liver by the cytochrome P450 isoenzyme CYP2E1 and defluorinated to its major metabolites hexafluoroisopropanol (HFIP), inorganic fluoride, and carbon dioxide. HFIP is rapidly conjugated with glucuronic acid and eliminated in the urine. Sevoflurane crosses the placenta.
Solubility: The low solubility of sevoflurane in blood would suggest alveolar concentrations should rapidly increase upon induction and rapidly decrease upon cessation of the inhaled agent. This was confirmed in a clinical study where inspired concentrations (F_I), end-tidal concentrations (F_A) and F_A immediately before the beginning of elimination (F_A0) were measured. The F_A/F_I (wash in) value at 30 minutes for sevoflurane was 0.85. The F_A/F_A0 (wash out) value at five minutes was 0.15.
Distribution: 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: The rapid pulmonary elimination of sevoflurane minimizes the amount of anesthetic available for metabolism. In humans <5% sevoflurane absorbed is metabolized via cytochrome P450 2E1 isoform to hexafluorisopropanol (HFIP), with release of inorganic fluoride and carbon dioxide (or a one carbon fragment). Once formed HFIP is rapidly conjugated with glucuronic acid and eliminated as a urinary metabolite. No other metabolic pathways for sevoflurane have been identified. It is the only fluorinated volatile anesthetic which is not metabolized to trifluroacetic acid.
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. The defluorination of sevoflurane is not inducible by barbiturates.