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|Systematic (IUPAC) name|
|Trade names||Sojourn, Ultane, Sevorane|
|Legal status||POM (UK) ℞-only (US)|
|Mol. mass||200.055 g/mol|
|(what is this?)|
Sevoflurane (1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane; synonym, fluoromethyl hexafluoroisopropyl ether), is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used for induction and maintenance of general anesthesia. This anesthetic's name derives from having its from having seven fluorine atoms in its substituents, alongside a standard suffix for such agents.
It is one of the most commonly used volatile anesthetic agents, particularly for outpatient anesthesia, and including in anesthesia of children and infants, and in veterinary medicine. Together with desflurane, sevoflurne is replacing isoflurane and halothane in modern anesthesiology. It is often administered in a mixture of nitrous oxide and oxygen.
After desflurane, it is the volatile anesthetic with the fastest onset and offset. Though desflurane has the lowest blood/gas coefficient of the currently used volatile anesthetics, sevoflurane is the preferred agent for mask induction due to its lesser irritation to mucous membranes.
Sevoflurane "has an excellent safety record", but is under review for potential neurotoxicity especially relevant to administration in infants and children, and rare case reports akin to halothane hepatitis have made clear that low frequency liver injury may occur.
Sevoflurane was discovered by Ross Terrell. First reports on the use of sevoflurane appeared in the literature in 1971; it was introduced into clinical practice initially in Japan in 1990. The rights for sevoflurane in the US and other countries were held by Abbott Laboratories; it is now available as a generic drug.[when?]
Toxic breakdown products
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Studies examining a current significant health concern, anesthetic-induced neurotoxicity (including with sevoflurane, and especially with children and infants) are "fraught with confounders, and many are underpowered statistically", and so are argued to need "further data... to either support or refute the potential connection".
In vitro studies related to this and other important drug safety questions have focused on chemical degradation products, and on metabolic products relevant to sevoflurane administration. Sevoflurane forms a range of degradation products, compound A [fluoromethyl-2,2-difluoro-1-(trifluoromethyl)vinyl ether][non-primary source needed] also called PIFE (pentafluoroisopropenyl fluoromethyl ether) and Compound B [1,1,1,3,3-pentafluoro-2-(fluoromethoxy)-3-methoxypropane],[non-primary source needed] also called PMFE (pentafluoromethoxy isopropyl fluoromethyl ether) on contact with the soda lime in a rebreathing apparatus, which absorbs exhaled carbon dioxide, especially at higher temperatures and when the soda lime is desiccated.[excessive detail?] Compound A is formed by an elimination reaction which is likely to be the E2 reaction as for an E1 reaction a carbocation centred on a primary carbon bearing two fluorine atoms would have to form.[excessive detail?] Compound A reacts with methanol to form compound B by nucelophilic attack on the difluoroalkene group in compound A; a further elimination reaction forms compounds C, D and E.[excessive detail?][non-primary source needed] Hydrofluoric acid is formed in the same reaction as compound A, but as soda-lime is alkaline and contains calcium the hydrogen fluoride is likely to converted into insoluble calcium fluoride.[excessive detail?] Compound A has been shown to cause renal necrosis in rats.
Compound A reacts with the thiol groups in glutathione to form S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-L-cysteine, which then undergoes an enzymic reaction to form ammonium ions, pyruvate and 2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropanethiolate; this ultimate fluorinated product is then converted to 2-(fluoromethoxy)-3,3,3-trifluorothiopropanoyl fluoride, an electrophile that can react with tissues, causing damage.[non-primary source needed]
In humans, direct histological evidence of renal toxicity has not been demonstrated, although there is dose-related proteinuria, glycosuria and enzymuria. During low-flow anaesthesia, when the lower fresh gas flow leads to decreased flushing of the circuit and increased temperature of the soda lime, compound A may build up to clinically significant levels, although there have never been any reports of adverse events in humans.
Sevoflurane also reacts with hydroxide anions to form fluoride anions and ((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)methanol, the ((1,1,1,3,3,3-hexafluoropropan-2-yl)oxy)methanol (a hemiacetal) breaks down to form formaldehyde and 1,1,1,3,3,3-hexafluoropropan-2-ol.[relevant? ] The formaldehyde forms formic acid and methanol in a Cannizzaro reaction; the methanol then reacts to form compound B.[relevant? ]
As a result, sevoflurane is sometimes administered with a minimum fresh gas flow of 2 liters per minute, making it a relatively expensive choice for maintaining general anesthesia. Only two countries currently have recommended minimum flow rates of 2L/min; Canada and Australia. Recent generic competition in select markets has also significantly lowered the unit cost of sevoflurane, making it more cost effective.
Concern regarding the safety of anaesthesia is especially acute with regard to children and infants, where preclinical evidence from relevant animal models suggest that common clinically important agents, including sevoflurane, may be neurotoxic to the developing brain, and so cause neurobehavioural abnormalities in the long term; two large-scale clinical studies (PANDA and GAS) were ongoing as of 2010, in hope of supplying "significant [further] information" on neurodevelopmental effects of general anaesthesia in infants and young children, including where sevoflurane is used.
Sevoflurane has been implicated in neuronal degeneration in infant mice. This activity is thought to occur via blockade of NMDA receptors or hyperactivity of GABA neurotransmission. In one study, the researchers showed exposure of infant mice to inhaled sevoflurane resulted in learning deficits and abnormal social behaviour.
|Boiling point:||58.6 °C||(at 101.325 kPa)|
|Density:||1.517–1.522 g/cm³||(at 20 °C)|
|MAC :||2.1 vol %|
|Molecular weight:||200 u|
|Vapor pressure:||157 mmHg (22.9 kPa)||(at 20 °C)|
|197 mmHg (26.3 kPa)||(at 25 °C)|
|317 mmHg (42.3 kPa)||(at 36 °C)|
|Blood:Gas partition coefficient:||0.68|
|Oil:Gas partition coefficient:||47|
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