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Drug Information for Sevoflurane (Halocarbon Products Corporation): DESCRIPTION
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Sevoflurane, volatile liquid for inhalation, a nonflammable and nonexplosive liquid administered by vaporization, is a halogenated general inhalation anesthetic drug. Sevoflurane is fluoromethyl 2,2,2,-trifluoro-1(trifluoromethyl) ethyl ether and its structural formula is:
Sevoflurane, Physical Constants are
Molecular weight 200.05 Boiling point at 760 mm Hg 58.6°C Specific gravity at 20°C 1.520 to 1.525 Vapor pressure in mm Hg 157 mm Hg at 20°C197 mm Hg at 25°C317 mm Hg at 36°C
Distribution Partition Coefficients at 37°C
Blood/Gas 0.63 to 0.69 Water/Gas 0.36 Olive Oil/Gas 47 to 54 Brain/Gas 1.15
Mean component/Gas Partition Coefficients at 25°C for Polymers Used Commonly in Medical Applications
Conductive Rubber 14.0 Butyl Rubber 7.7 Polyvinylchloride 17.4 Polyethylene 1.3
Sevoflurane is nonflammable and nonexplosive as defined by the requirements of International Electrotechnical Commission 601-2-13.
Sevoflurane is a clear, colorless, liquid containing no additives. Sevoflurane is not corrosive to stainless steel, brass, aluminum, nickel-plated brass, chrome-plated brass or copper beryllium. Sevoflurane is nonpungent. It is miscible with ethanol, ether, chloroform, and benzene, and it is slightly soluble in water. Sevoflurane is stable when stored under normal room lighting conditions according to instructions. No discernible degradation of sevoflurane occurs in the presence of strong acids or heat. When in contact with alkaline CO2 absorbents (e.g Baralyme® and to a lesser extent soda lime) within the anesthesia machine, sevoflurane can undergo degradation under certain conditions. Degradation of sevoflurane is minimal, and degradants are either undetectable or present in non-toxic amounts when used as directed with fresh absorbents. Sevoflurane degradation and subsequent degradant formation are enhanced by increasing absorbent temperature increased sevoflurane concentration, decreased fresh gas flow and desiccated CO2 absorbents (especially with potassium hydroxide containing absorbents e.g. Baralyme).
Sevoflurane alkaline degradation occurs by two pathways. The first results from the loss of hydrogen fluoride with the formation of pentafluoroisopropenyl fluoromethyl ether, (PIFE, C4H2F6O), also known as Compound A, and trace amounts of pentafluoromethoxy isopropyl fluoromethyl ether, (PMFE, C5H6F6O), also known as Compound B. The second pathway for degradation of sevoflurane, which occurs primarily in the presence of desiccated CO2 absorbents, is discussed later.
In the first pathway, the defluorination pathway, the production of degradants in the anesthesia circuit from the extraction of the acidic proton in the presence of a strong base (KOH and/or NaOH) forming an alkene (Compound A) from sevoflurane similar to formation of 2-bromo-2-chloro-1,1-difluoro ethylene (BCDFE) from halothane. Laboratory simulations have shown that the concentration of these degradants is inversely correlated with the fresh gas flow rate (See Figure 1).
Since the reaction of carbon dioxide with absorbents is exothermic, the temperature increase will be determined by quantities of CO2 absorbed, which in turn will depend on fresh gas flow in the anesthesia circle system, metabolic status of the patient, and ventilation. The relationship of temperature produced by varying levels of CO2 and Compound A production is illustrated in the following in vitro simulation where CO2 was added to a circle absorber system.
Compound A concentration in a circle absorber system increases as a function of increasing CO2 absorbent temperature and composition (Baralyme producing higher levels than soda lime), increased body temperature, and increased minute ventilation, and decreasing fresh gas flow rates.It has been reported that the concentration of Compound A increases significantly with prolonged dehydration of Baralyme. Compound A exposure in patients also has been shown to rise with increased sevoflurane concentrations and duration of anesthesia. In a clinical study in which sevoflurane was administered to patients under low flow conditions for ≥2 hours at flow rates of 1 Liter/minute, Compound A levels were measured in an effort to determine the relationship between MAC hours and Compound A levels produced. The relationship between Compound A levels and sevoflurane exposure are shown in Figure 2a.
Compound A has been shown to be nephrotoxic in rats after exposures that have varied in duration from one to three hours. No histopathologic change was seen at a concentration of up to 270 ppm for one hour. Sporadic single cell necrosis of proximal tubule cells has been reported at a concentration of 114 ppm after a 3-hour exposure to Compound A in rats. The LC50 reported at 1 hour is 1050 to 1090 ppm (male-female) and, at 3 hours, 350 to 490 ppm (male-female).
An experiment was performed comparing sevoflurane plus 75 or 100 ppm Compound A with an active control to evaluate the potential nephrotoxicity of Compound A in non-human primates. A single 8-hour exposure of Sevoflurane in the presence of Compound A produced single-cell renal tubular degeneration and single-cell necrosis in cynomolgus monkeys. These changes are consistent with the increased urinary protein, glucose level and enzymic activity noted on days one and three on the clinical pathology evaluation. This nephrotoxicity produced by Compound A is dose and duration of exposure dependent.
At a fresh gas flow rate of 1 L/min, mean maximum concentrations of Compound A in the anesthesia circuit in clinical settings are approximately 20 ppm (0.002%) with soda lime and 30 ppm (0.003%) with Baralyme in adult patients; mean maximum concentrations in pediatric patients with soda lime are about half those found in adults. The highest concentration observed in a single patient with Baralyme was 61 ppm (0.0061%) and 32 ppm (0.0032%) with soda lime. The levels of Compound A at which toxicity occurs in humans is not known.
The second pathway for degradation of sevoflurane occurs primarily in the presence of desiccated CO2 absorbents and leads to the dissociation of sevoflurane into hexafluoroisopropanol (HFIP) and formaldehyde. HFIP is inactive, nongenotoxic, rapidly glucuronidated and cleared by the liver. Formaldehyde is present during normal metabolic processes. Upon exposure to a highly desiccated absorbent, formaldehyde can further degrade into methanol and formate. Formate can contribute to the formation of carbon monoxide in the presence of high temperature that can be associated with desiccated Baralyme®. Methanol can react with Compound A to form the methoxy addition product Compound B. Compound B can undergo further HF elimination to form Compounds C, D, and E.
Sevoflurane degradants were observed in the respiratory circuit of an experimental anesthesia machine using desiccated CO2 absorbents and maximum sevoflurane concentrations (8%) for extended periods of time (> 2 hours). Concentrations of formaldehyde observed with desiccated soda lime in this experimental anesthesia respiratory circuit were consistent with levels that could potentially result in respiratory irritation. Although KOH containing CO2 absorbents are no longer commercially available, in the laboratory experiments, exposure of sevoflurane to the desiccated KOH contained CO2 absorbent, Baralyme, resulted in the detection of substantially greater degradant levels.
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