Isoflurane

Isoflurane, sold under the brand name Forane among others, is a general anesthetic.[3] It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia rather than isoflurane, due to airway irritation with isoflurane.[2][4] Isoflurane is given via inhalation.[3]

Isoflurane
Clinical data
Trade namesForane, others
AHFS/Drugs.comFDA Professional Drug Information
License data
Pregnancy
category
Routes of
administration		Inhalation
ATC code
Legal status
Legal status
Identifiers
IUPAC name
  • (RS)-2-Chloro-2-(difluoromethoxy)-1,1,1-trifluoro-ethane
    OR
    (RS)-1-chloro-2,2,2-trifluoroethyl difluoromethyl ether
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.043.528
Chemical and physical data
FormulaC3H2ClF5O
Molar mass184.49 g·mol−1
3D model (JSmol)
SMILES
  • FC(F)(F)C(Cl)OC(F)F
InChI
  • InChI=1S/C3H2ClF5O/c4-1(3(7,8)9)10-2(5)6/h1-2H Y
  • Key:PIWKPBJCKXDKJR-UHFFFAOYSA-N Y
 NY (what is this?)  (verify)

Side effects of isoflurane include a decreased ability to breathe (respiratory depression), low blood pressure, and an irregular heartbeat.[2] Serious side effects can include malignant hyperthermia or high blood potassium.[3] It should not be used in patients with a history of malignant hyperthermia in either themselves or their family members.[2] It is unknown if its use during pregnancy is safe for the fetus, but use during a cesarean section appears to be safe.[2][3] Isoflurane is a halogenated ether.[5]

Isoflurane was approved for medical use in the United States in 1979.[3][6] It is on the World Health Organization's List of Essential Medicines.[7][8]

Medical uses

Isoflurane is always administered in conjunction with air or pure oxygen. Often, nitrous oxide is also used. Although its physical properties imply that anaesthesia can be induced more rapidly than with halothane,[9] its pungency can irritate the respiratory system, negating any possible advantage conferred by its physical properties. It is used in general anesthesia in tandem with or alternatively to other anesthetic drugs, such as thiopentone or propofol.[10][11]

Adverse effects

Animal studies have raised safety concerns of certain general anesthetics, in particular ketamine and isoflurane, in young children. The risk of neurodegeneration was increased in combination of these agents with nitrous oxide and benzodiazepines such as midazolam.[12] Whether these concerns occur in humans is unclear.[12]

Elderly

Biophysical studies using NMR spectroscopy has provided molecular details of how inhaled anesthetics interact with three amino acid residues (G29, A30 and I31) of amyloid beta peptide and induce aggregation. This area is important as "some of the commonly used inhaled anesthetics may cause brain damage that accelerates the onset of Alzheimer's disease".[13]

Physical properties
Molecular weight184.5g/mol[14]
Boiling point (at 1 atm):48.5 °C[14]
Density (at 25 °C):1.496 g/mL[14]
MAC :1.15 vol %
Vapor pressure:238 mmHg31.7 kPa(at 20 °C)
295 mmHg39.3 kPa(at 25 °C)
367 mmHg48.9 kPa(at 30 °C)
450 mmHg60.0 kPa(at 35 °C)[14]
Water solubility13.5 mM(at 25 °C)[15]
Blood:gas partition coefficient:1.4
Oil:gas partition coefficient:98

It is administered as a racemic mixture of (R)- and (S)-optical isomers.[16][17] Isoflurane has a melting point of 48 - 48.5°Celsius (118 - 119°Fahrenheit) and a boiling point of 48.5 - 49 °C (119 - 120 °F).[14] It is non-combustible but can give off irritable and toxic fumes when exposed to flame.[14]

Mechanism of action

Similar to many general anesthetics, the exact mechanism of the action has not been clearly delineated.[18] Isoflurane reduces pain sensitivity (analgesia) and relaxes muscles. Isoflurane likely binds to GABA, glutamate and glycine receptors, but has different effects on each receptor. Isoflurane acts as a positive allosteric modulator of the GABAA receptor in electrophysiology studies of neurons and recombinant receptors.[19][20][21][22] It potentiates glycine receptor activity, which decreases motor function.[23] It inhibits receptor activity in the NMDA glutamate receptor subtypes. Isoflurane inhibits conduction in activated potassium channels.[24] Isoflurane also affects intracellular molecules. It inhibits plasma membrane calcium ATPases (PMCAs) which affects membrane fluidity by hindering the flow of Ca2+ (calcium ions) out across the membrane, this in turn affects neuron depolarization.[25][26] It binds to the D subunit of ATP synthase and NADH dehydrogenase.

General anaesthesia with isoflurane reduces plasma endocannabinoid AEA concentrations, and this could be a consequence of stress reduction after loss of consciousness.[27]

History

Together with enflurane and halothane, Isoflurane began to replace the flammable ethers used in the pioneer days of surgery; this shift began in the 1940s to the 1950s.[28] Its name comes from being a structural isomer of enflurane, hence they have the same empirical formula.[29]

Environment

The average lifetime of isoflurane in the atmosphere is 3.2 years, its global warming potential is 510 and the yearly emissions add up to 880 tons.[30]

Veterinary use

Isoflurane is frequently used for veterinary anaesthesia.[31][32][33]

References
  1. "Isoflurane Use During Pregnancy". Drugs.com. 2 September 2020. Retrieved 9 September 2020.
  2. "Isoflurane 100% Inhalation Vapour, Liquid - Summary of Product Characteristics (SmPC)". (emc). 29 October 2019. Retrieved 9 September 2020.
  3. "Forane- isoflurane inhalant". DailyMed. Retrieved 11 February 2022.
  4. Kliegman RM, Stanton BM, Geme JS, Schor NF (2015). Nelson Textbook of Pediatrics (20 ed.). Elsevier Health Sciences. p. 420. ISBN 9780323263528. Archived from the original on 2016-12-20.
  5. Aglio LS, Lekowski RW, Urman RD (2015). Essential Clinical Anesthesia Review: Keywords, Questions and Answers for the Boards. Cambridge University Press. p. 115. ISBN 9781107681309. Archived from the original on 2016-12-20.
  6. "Forane: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 11 February 2022.
  7. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  8. World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
  9. Niedermeyer E, da Silva FH (2005). Electroencephalography: Basic Principles, Clinical Applications, and Related Fields. Lippincott Williams & Wilkins. p. 1156. ISBN 978-0-7817-5126-1. Archived from the original on 2016-05-09.
  10. PAUCA, A. L.; DRIPPS, R. D. (1973-07-01). "CLINICAL EXPERIENCE WITH ISOFLURANE (FORANE*): Preliminary Communication". BJA: British Journal of Anaesthesia. 45 (7): 697–703. doi:10.1093/bja/45.7.697. ISSN 0007-0912. PMID 4730162.
  11. Chen, Zhengyong (2004-08-01). "The effects of isoflurane and propofol on intraoperative neurophysiological monitoring during spinal surgery". Journal of Clinical Monitoring and Computing. 18 (4): 303–308. doi:10.1007/s10877-005-5097-5. ISSN 1573-2614. PMID 15779842. S2CID 195331061.
  12. Mellon RD, Simone AF, Rappaport BA (March 2007). "Use of anesthetic agents in neonates and young children". Anesthesia and Analgesia. 104 (3): 509–20. doi:10.1213/01.ane.0000255729.96438.b0. PMID 17312200. S2CID 43818997. Archived from the original on 2009-03-09.
  13. Kuehn BM (April 2007). "Anesthesia-Alzheimer disease link probed". JAMA. 297 (16): 1760. doi:10.1001/jama.297.16.1760. PMID 17456811.
  14. PubChem. "Isoflurane". pubchem.ncbi.nlm.nih.gov. Retrieved 2022-04-07.
  15. Seto T, Mashimo T, Yoshiya I, Kanashiro M, Taniguchi Y (January 1992). "The solubility of volatile anaesthetics in water at 25.0 degrees C using 19F NMR spectroscopy". Journal of Pharmaceutical and Biomedical Analysis. 10 (1): 1–7. doi:10.1016/0731-7085(92)80003-6. PMID 1391078.
  16. "Isoflurane - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2022-04-07.
  17. Bu, Weiming; Pereira, Luis M.; Eckenhoff, Roderic G.; Yuki, Koichi (2014-05-06). "Stereoselectivity of Isoflurane in Adhesion Molecule Leukocyte Function-Associated Antigen-1". PLOS ONE. 9 (5): e96649. Bibcode:2014PLoSO...996649B. doi:10.1371/journal.pone.0096649. ISSN 1932-6203. PMC 4011845. PMID 24801074.
  18. "How does anesthesia work?". Scientific American. February 7, 2005. Archived from the original on May 29, 2016.
  19. Jones MV, Brooks PA, Harrison NL (April 1992). "Enhancement of gamma-aminobutyric acid-activated Cl- currents in cultured rat hippocampal neurones by three volatile anaesthetics". The Journal of Physiology. 449: 279–93. doi:10.1113/jphysiol.1992.sp019086. PMC 1176079. PMID 1326046.
  20. Jenkins A, Franks NP, Lieb WR (February 1999). "Effects of temperature and volatile anesthetics on GABA(A) receptors". Anesthesiology. 90 (2): 484–91. doi:10.1097/00000542-199902000-00024. PMID 9952156.
  21. Lin LH, Chen LL, Zirrolli JA, Harris RA (November 1992). "General anesthetics potentiate gamma-aminobutyric acid actions on gamma-aminobutyric acidA receptors expressed by Xenopus oocytes: lack of involvement of intracellular calcium". The Journal of Pharmacology and Experimental Therapeutics. 263 (2): 569–78. PMID 1331405.
  22. Krasowski MD, Harrison NL (February 2000). "The actions of ether, alcohol and alkane general anaesthetics on GABAA and glycine receptors and the effects of TM2 and TM3 mutations". British Journal of Pharmacology. 129 (4): 731–43. doi:10.1038/sj.bjp.0703087. PMC 1571881. PMID 10683198.
  23. Grasshoff C, Antkowiak B (November 2006). "Effects of isoflurane and enflurane on GABAA and glycine receptors contribute equally to depressant actions on spinal ventral horn neurones in rats" (PDF). British Journal of Anaesthesia. 97 (5): 687–94. doi:10.1093/bja/ael239. PMID 16973644. S2CID 14269792. Archived from the original (PDF) on 2017-09-10.
  24. Buljubasic N, Rusch NJ, Marijic J, Kampine JP, Bosnjak ZJ (June 1992). "Effects of halothane and isoflurane on calcium and potassium channel currents in canine coronary arterial cells". Anesthesiology. 76 (6): 990–8. doi:10.1097/00000542-199206000-00020. PMID 1318010.
  25. Franks, J. J.; Horn, J. L.; Janicki, P. K.; Singh, G. (January 1995). "Halothane, isoflurane, xenon, and nitrous oxide inhibit calcium ATPase pump activity in rat brain synaptic plasma membranes". Anesthesiology. 82 (1): 108–117. doi:10.1097/00000542-199501000-00015. ISSN 0003-3022. PMID 7832292. S2CID 26993898.
  26. "Protein kinases A and C phosphorylate..." www.diagnosticpathology.eu. Retrieved 2022-04-07.
  27. Weis F, Beiras-Fernandez A, Hauer D, Hornuss C, Sodian R, Kreth S, et al. (August 2010). "Effect of anaesthesia and cardiopulmonary bypass on blood endocannabinoid concentrations during cardiac surgery". British Journal of Anaesthesia. 105 (2): 139–44. doi:10.1093/bja/aeq117. PMID 20525978.
  28. Terrell, Ross C.; Warner, David S. (2008-03-01). "The Invention and Development of Enflurane, Isoflurane, Sevoflurane, and Desflurane". Anesthesiology. 108 (3): 531–533. doi:10.1097/ALN.0b013e31816499cc. ISSN 0003-3022. PMID 18292690.
  29. CALVEY, T. N. (August 1995). "Isomerism and anaesthetic drugs". Acta Anaesthesiologica Scandinavica. 39: 83–90. doi:10.1111/j.1399-6576.1995.tb04316.x. ISSN 0001-5172. PMID 8533553. S2CID 24183480.
  30. Martin K. Vollmer; Tae Siek Rhee; Matt Rigby; Doris Hofstetter; Matthias Hill; Fabian Schoenenberger; Stefan Reimann (2015). "Modern inhalation anesthetics: Potent greenhouse gases in the global atmosphere". Geophysical Research Letters. 42 (5): 1606–1611. Bibcode:2015GeoRL..42.1606V. doi:10.1002/2014GL062785.
  31. Ludders, J W (1992-03-01). "Advantages and guidelines for using isoflurane". The Veterinary Clinics of North America Small Animal Practice. 22 (2): 328–331. doi:10.1016/s0195-5616(92)50626-x. ISSN 1878-1306. PMID 1585568.
  32. "Veterinary Anesthesia - an overview | ScienceDirect Topics". www.sciencedirect.com. Retrieved 2022-04-07.
  33. "Isoflurane-Vet 100% w/w Inhalation vapour, liquid". www.noahcompendium.co.uk. Retrieved 2022-04-07.
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