Sevorane Mechanism of Action

Pharmacology: In a variety of animal species, including man, sevoflurane has been demonstrated to be a fast-acting, non-irritating agent. Administration has been associated with a smooth, rapid loss of consciousness during inhalational induction and a rapid recovery following discontinuation of anaesthesia.
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 that sevoflurane does not reduce collateral myocardial infarction perfusion. In clinical studies, the incidence of myocardial ischaemia and myocardial infarction in patients at risk for myocardial ischemia was comparable between sevoflurane and isoflurane.
Animal studies have shown that regional blood flow (eg, 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 9 hrs.
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. MAC equivalents for sevoflurane for various age groups are summarized in Table 1. (See Table 1.)

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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: Solubility: The low solubility of sevoflurane in blood would suggest that 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 and end-tidal concentrations (F₁ and F_A) were measured. The F_A/F₁ (wash-in) value at 30 min for sevoflurane was 0.85. The F_A/F_AO (wash-out) value at 5 min 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 anaesthetics 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 (eg, 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 P-450 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 trifluoroacetic 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.
Approximately 7% of adults evaluated for inorganic fluoride concentrations in the Abbott Clinical Program experienced concentrations >50 mcM; no clinically significant effect on renal function was observed in any of these individuals.
Toxicology: Sevoflurane has a low order of acute toxicity in rats, mice, rabbits, dogs and monkeys.
Anesthesia induction was smooth and rapid, with no struggling, signs of gasping or other undesirable reactions. Deaths from exposure to lethal concentrations were due to respiratory arrest. Exposure was not associated with any specific organ toxicity or developmental toxicity in laboratory animals.
Fischer 344 rats were anesthetized within 2-3 min after start of exposure to sevoflurane (1.4%) for up to 10 hrs. There were no functional or morphologic defects following administration of sevoflurane.
In a Segment I reproduction study, sevoflurane had no significant effects on male or female reproductive capabilities at exposure concentrations of up to 1 MAC (2.2%). Segment II and III studies in rats indicate that sevoflurane is not a selective developmental toxicant.
Compound A: In Wistar rats, the LC₅₀ of Compound A was 1050-1090 ppm in animals exposed for 1 hr and 400-420 ppm in animals exposed for 3 hrs (median lethal concentrations were approximately 1070 and 330-490 ppm, respectively). In rats exposed to 30, 60 or 120 ppm of Compound A in an 8-week chronic toxicity study (24 exposures, 3 hrs/exposure), no apparent evidence of toxicity was observed other than loss of body weight in females on the last study day.
Sprague-Dawley rats were administered with Compound A via nose-only inhalation exposure in an open system [25, 50, 100 or 200 ppm (0.0025-0.02%) of Compound A]. Control groups were exposed to air. The threshold, at which reversible alterations in urinary and clinical parameters indicative of renal changes (concentration-dependent increases in BUN, creatinine, glucose, protein/creatinine ratios and N-acetyl glucosamidase/creatinine ratios) were observed, was 114 ppm of Compound A. Histological lesions were also reversible.
Since the uptake of inhalational agents in small rodents is substantially higher than in humans, higher levels of drug, Compound A (degradant of sevoflurane) or 2-bromo-2-chloro-1, 1-difluoro ethylene (BCDFE) (degradant/metabolite of halothane) would be expected in rodents. Also, the activity of the key enzyme (β-lyase) involved in haloalkene nephrotoxicity is 10-fold greater in the rat than it is in humans.
Compound A concentrations are reported to increase with increasing absorber temperature, increasing sevoflurane concentrations and with decreasing fresh gas flow rates. In clinical situation, the highest concentration of Compound A in the anesthesia circuit with soda lime as the CO₂ absorbent was 15 ppm in pediatrics and 32 ppm in adults. However, concentrations up to 61 ppm have been observed in patients attached to systems with baralyme as the CO₂ absorbent. Although exposure to sevoflurane in low flow systems is limited, there has been no evidence of renal dysfunction attributable to Compound A.
Compound B: In clinical situation, the concentration of Compound B detected in the anesthesia circuit did not exceed 1.5 ppm. Inhalation exposure to Compound B at concentrations of up to 2400 ppm (0.24%) for 3 hrs resulted in no adverse effects on renal parameters or tissue histology in Wistar rats.
Clinical Safety and Efficacy Studies: Efficacy: Numerous clinical studies have been conducted with sevoflurane as the anesthetic agent for pediatric and adult patients. The results have shown that sevoflurane provides smooth, rapid induction of, as well as rapid emergence from anesthesia.
Sevoflurane was associated with faster times to induction and to such recovery events as emergence, response to command and orientation compared to reference drugs.
Adult Anesthesia: Mask Induction: In adult studies in which mask induction was performed, sevoflurane was demonstrated to provide smooth and rapid induction of anesthesia.
Maintenance: In 3 outpatient and 25 inpatient studies involving 3591 adult patients (2022 sevoflurane, 1196 isoflurane, 111 enflurane, 262 propofol) sevoflurane was demonstrated to be an effective agent for the maintenance of anesthesia.
Sevoflurane was demonstrated to be an appropriate agent for use in neurosurgery, cesarian section, patients undergoing coronary artery bypass surgery (CABG), and noncardiac patients at risk for myocardial ischemia.
Pediatric Anesthesia: In 2 outpatient and 3 inpatient studies involving 1498 pediatric patients (837 sevoflurane, 661 halothane), sevoflurane was demonstrated to be an effective agent for the induction and maintenance of anesthesia.
Mask Induction: In pediatric studies in which mask induction was performed, the induction time was statistically significantly shorter and the incidence of coughing was statistically significantly lower with sevoflurane than with halothane.
Safety: Clinical studies in a wide variety of patient populations (children, adults, elderly, renally impaired, hepatically impaired, obese, patients undergoing cardiac bypass surgery, patients treated with aminoglycosides or metabolic inducers, patients exposed to repeat surgeries, patients undergoing surgeries ≥6 hrs in duration), the results of evaluations of laboratory parameters (eg, SGPT, SGOT, alkaline phosphatase, total bilirubin, serum creatinine, BUN) as well as investigator-reported incidence of adverse events relating to hepatic and renal function, demonstrated that sevoflurane does not have a clinically significant effect on liver or kidney function, nor does it exacerbate preexisting renal or hepatic impairment. These studies also demonstrated that there were no statistically significant differences between sevoflurane and reference agents in the proportions of patients showing changes in any clinical chemistry parameter.
The impact on renal function was comparable among sevoflurane and the reference drugs, between types of anesthesia circuits, among flow rates and between patients with or without inorganic fluoride concentrations ≥50 mcm.
The incidence of renal dysfunction was <1% for both sevoflurane (0.17%) and reference drugs (0.22%; isoflurane, halothane, enflurane, propofol) in comparative studies. This overall incidence is consistent with that of a general surgical population. In all cases, an alternate cause or reasonable explanation existed for the renal dysfunction.
Hepatically Impaired: Sevoflurane is effective and well tolerated when used as the primary agent for the maintenance of anesthesia in patients with impaired hepatic function, Child-Pugh Class A and B. Sevoflurane did not exacerbate preexisting hepatic impairment.
Renally Impaired: Sevoflurane was evaluated in renally impaired patients with baseline serum creatinine ≥1.5 mg/dL (130 micromole/L). Based on the incidence and magnitude of changes in serum creatinine concentrations, sevoflurane did not further deteriorate renal function.