Sevoflurane

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Sevoflurane
Sevoflurane.svg
Sevoflurane-3D-balls.png
Systematic (IUPAC) name
1,1,1,3,3,3-hexafluoro-2-(fluoromethoxy)propane
Clinical data
Trade names Sojourn, Ultane, Sevorane
AHFS/Drugs.com Consumer Drug Information
Legal status POM (UK) -only (US)
Routes inhaled
Identifiers
CAS number 28523-86-6 YesY
ATC code N01AB08
PubChem CID 5206
DrugBank DB01236
ChemSpider 5017 YesY
UNII 38LVP0K73A YesY
KEGG D00547 YesY
ChEBI CHEBI:9130 YesY
ChEMBL CHEMBL1200694 N
Chemical data
Formula C4H3F7O 
Mol. mass 200.055 g/mol
 N (what is this?)  (verify)

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.[citation needed]

It is one of the most commonly used volatile anesthetic agents, particularly for outpatient anesthesia,[1] and including in anesthesia of children and infants, and in veterinary medicine.[citation needed] Together with desflurane, sevoflurne is replacing isoflurane and halothane in modern anesthesiology.[citation needed] It is often administered in a mixture of nitrous oxide and oxygen.[citation needed]

After desflurane, it is the volatile anesthetic with the fastest onset and offset.[2] 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.[citation needed]

Sevoflurane "has an excellent safety record",[1] 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.[1]

Sevoflurane was discovered by Ross Terrell.[3] First reports on the use of sevoflurane appeared in the literature in 1971;[citation needed] it was introduced into clinical practice initially in Japan in 1990.[citation needed] The rights for sevoflurane in the US and other countries were held by Abbott Laboratories; it is now available as a generic drug.[when?][citation needed]

Toxic breakdown products[edit]

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".[4]

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][5][non-primary source needed] also called PIFE (pentafluoroisopropenyl fluoromethyl ether) and Compound B [1,1,1,3,3-pentafluoro-2-(fluoromethoxy)-3-methoxypropane],[6][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?][7][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.[citation needed]

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][8]

In humans, direct histological evidence of renal toxicity has not been demonstrated, although there is dose-related proteinuria, glycosuria and enzymuria.[citation needed] 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.[citation needed]

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.[citation needed][relevant? ] The formaldehyde forms formic acid and methanol in a Cannizzaro reaction; the methanol then reacts to form compound B.[citation needed][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.[citation needed] Only two countries currently have recommended minimum flow rates of 2L/min; Canada and Australia.[citation needed] Recent generic competition in select markets has also significantly lowered the unit cost of sevoflurane, making it more cost effective.[citation needed]

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.[9]

Animal studies[edit]

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.[10]

Sevoflurane raises intracranial pressure and can cause respiratory depression.[11]

Sevoflurane induces apoptosis in A549 cells (lung alveolar epithelial cells). [12]

Physical properties[edit]

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

Bispectral index[edit]

Sevoflurane has lower values of controversial bispectral index than desflurane.[13][14]

References[edit]

  1. ^ a b c Livertox: Clinical and Research Information on Drug-Induced Liver Injury (2014) "Drug Record: Sevoflurane", U.S. National Library of Medicine, 2 July 2014 update, see [1], accessed 15 August, 2014.
  2. ^ Sakai EM, Connolly LA, Klauck JA (December 2005). "Inhalation anesthesiology and volatile liquid anesthetics: focus on isoflurane, desflurane, and sevoflurane". Pharmacotherapy 25 (12): 1773–88. doi:10.1592/phco.2005.25.12.1773. PMID 16305297. 
  3. ^ Burns, William; Edmond I Eger II (August 2011). "Ross C. Terrell, PhD, an Anesthetic Pioneer". Anesth. Analg. 2 113 (113): 387–9. doi:10.1213/ane.0b013e3182222b8a. 
  4. ^ P. Vlisides P & Z. Xie (2012) Neurotoxicity of general anesthetics: an update., Curr Pharm Design, 18(38):6232-40, see [2], accessed 15 August 2015.
  5. ^ Stabernack CR, Eger EI 2nd, Warnken UH, Förster H, Hanks DK, Ferrell LD (2003). "Sevoflurane degradation by carbon dioxide absorbents may produce more than one compound nephrotoxic in rats". Can J Anaesth 50 (3): 249–52. doi:10.1007/BF03017793. PMID 12620947. 
  6. ^ Schmidt, R.; Roeder, M.; Oeckler, O.; Simon, A.; Schurig, V. (2000). "Separation and absolute configuration of the enantiomers of a degradation product of the new inhalation anesthetic sevoflurane". Chirality 12 (10): 751–5. doi:10.1002/1520-636X(2000)12:10<751::AID-CHIR8>3.0.CO;2-H. PMID 11054834. 
  7. ^ J.A. Ruzicka and M.T. Baker, Journal of Fluorine Chemistry, 1995, volume 71, issue 1, pages 55-58
  8. ^ R.A. Iyer, R.B. Baggs and M.W. Anders, Nephrotoxicity of the glutathione and cysteine S-conjugates of the sevoflurane degradation product 2-(fluoromethoxy)-1,1,3,3, 3-pentafluoro-1-propene (Compound A) in male Fischer 344 rats, J. Pharmacol. Exper. Therap., 1997, 283, 1544-1551
  9. ^ L. Sun (2010) Early childhood general anaesthesia exposure and neurocognitive development, Br J Anaesth. 105 Suppl 1:i61-8, DOI 10.1093/bja/aeq302, see [3], accessed 15 August 2015.
  10. ^ Satomoto M, Satoh Y, Terui K, et al. (March 2009). "Neonatal exposure to sevoflurane induces abnormal social behaviors and deficits in fear conditioning in mice". Anesthesiology 110 (3): 628–37. doi:10.1097/ALN.0b013e3181974fa2. PMID 19212262. 
  11. ^ Sevoflurane. 
  12. ^ Wei GH (Jan 2014). "The common anesthetic, sevoflurane, induces apoptosis in A549 lung alveolar epithelial cells". J Mol Med Rep 9 (1): 197–203. doi:10.3892/mmr.2013.1806. PMID 24248633. 
  13. ^ Kim JK (Feb 2014). "Relationship of bispectral index to minimum alveolar concentration during isoflurane, sevoflurane or desflurane anaesthesia.". J Int Med Res 42 (1): 130–7. doi:10.1177/0300060513505525. PMID 24366495. 
  14. ^ Kreuer S (Oct 2009). "Comparative pharmacodynamic modeling of desflurane, sevoflurane and isoflurane.". J Clin Monit Comput. 23 (8). doi:10.1007/s10877-009-9196-6. PMID 19711188. 

Further reading[edit]

External links[edit]