isoflurane
{{short description|General anaesthetic given via inhalation}}
{{cs1 config|name-list-format=vanc|display-authors=6}}
{{Infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 443883276
| image = Isoflurane.svg
| image_class = skin-invert-image
| width = 150
| alt =
| image2 = Isoflurane-3D-vdW.png
| image_class2 = bg-transparent
| width2 = 150
| alt2 =
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| pronounce =
| tradename = Forane, others
| Drugs.com = {{Drugs.com|pro|isoflurane}}
| MedlinePlus =
| licence_CA =
| licence_EU =
| DailyMedID = Isoflurane
| licence_US =
| pregnancy_AU = B3
| pregnancy_AU_comment = {{cite web | title=Isoflurane Use During Pregnancy | website=Drugs.com | date=2 September 2020 | url=https://www.drugs.com/pregnancy/isoflurane.html | access-date=9 September 2020}}
| pregnancy_category =
| routes_of_administration = Inhalation
| class =
| ATCvet=
| ATC_prefix=N01
| ATC_suffix=AB06
| ATC_supplemental={{ATCvet|N01|AB06}}
| legal_AU =
| legal_AU_comment =
| legal_BR = C1
| legal_BR_comment = {{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=2023-03-31 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=2023-08-03 |access-date=2023-08-16 |publisher=Diário Oficial da União |language=pt-BR |publication-date=2023-04-04}}
| legal_CA =
| legal_CA_comment =
| legal_DE =
| legal_DE_comment =
| legal_NZ =
| legal_NZ_comment =
| legal_UK = POM
| legal_US = Rx-only
| legal_EU =
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| legal_UN =
| legal_UN_comment =
| legal_status =
| bioavailability =
| protein_bound =
| metabolism =
| metabolites =
| onset = {{val|1.14|0.35|u=minutes}} to 50% steady-state.{{cite journal | vauthors = Freiermuth D, Mets B, Bolliger D, Reuthebuch O, Doebele T, Scholz M, Gregor M, Haschke M, Seeberger MD, Fassl J | title = Sevoflurane and Isoflurane-Pharmacokinetics, Hemodynamic Stability, and Cardioprotective Effects During Cardiopulmonary Bypass | journal = Journal of Cardiothoracic and Vascular Anesthesia | volume = 30 | issue = 6 | pages = 1494–1501 | date = December 2016 | pmid = 27692704 | doi = 10.1053/j.jvca.2016.07.011 }}
| elimination_half-life=~10 minutes
| duration_of_action =
| excretion =
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 26675-46-7
| CAS_supplemental =
| PubChem = 3763
| IUPHAR_ligand = 2505
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank = DB00753
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 3631
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = CYS9AKD70P
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00545
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 6015
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1256
| NIAID_ChemDB =
| PDB_ligand =
| synonyms =
| IUPAC_name=2-chloro-2-difluoromethoxy-1,1,1-trifluoroethane
| C=3 | H=2 | Cl=1 | F=5 | O=1
| SMILES = FC(F)(F)C(Cl)OC(F)F
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C3H2ClF5O/c4-1(3(7,8)9)10-2(5)6/h1-2H
| StdInChI_comment =
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = PIWKPBJCKXDKJR-UHFFFAOYSA-N
| density = 1.496
| melting_point =
| melting_high =
| melting_notes =
| boiling_point = 48.5
| solubility=13.5 mM (at {{convert|25|C|F}}){{cite journal | vauthors = Seto T, Mashimo T, Yoshiya I, Kanashiro M, Taniguchi Y | title = The solubility of volatile anaesthetics in water at 25.0 degrees C using 19F NMR spectroscopy | journal = Journal of Pharmaceutical and Biomedical Analysis | volume = 10 | issue = 1 | pages = 1–7 | date = January 1992 | pmid = 1391078 | doi = 10.1016/0731-7085(92)80003-6 }}
| sol_units =
| specific_rotation =
}}
Isoflurane, sold under the brand name Forane among others, is a halogenated ether used as a general anesthetic.{{cite book | vauthors = Aglio LS, Lekowski RW, Urman RD |title=Essential Clinical Anesthesia Review: Keywords, Questions and Answers for the Boards |date=2015 |publisher=Cambridge University Press |isbn=9781107681309 |page=115 |url=https://books.google.com/books?id=VJzWBQAAQBAJ&pg=PA115 |language=en|url-status=live |archive-url=https://web.archive.org/web/20161220113456/https://books.google.ca/books?id=VJzWBQAAQBAJ&pg=PA115 |archive-date=2016-12-20}} It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia, due to airway irritation with isoflurane.{{cite book| vauthors = Kliegman R, Stanton B, St Geme J, Schor NF |title=Nelson Textbook of Pediatrics|date=2015|publisher=Elsevier Health Sciences|isbn=9780323263528|page=420|edition=20|url=https://books.google.com/books?id=P9piCAAAQBAJ&pg=PA420|language=en|url-status=live|archive-url=https://web.archive.org/web/20161220113801/https://books.google.ca/books?id=P9piCAAAQBAJ&pg=PA420|archive-date=2016-12-20}} Isoflurane is given via inhalation.
Isoflurane was approved for medical use in the United States in 1979.{{cite web | title=Forane: FDA-Approved Drugs | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=017624 | access-date=11 February 2022}} It is on the World Health Organization's List of Essential Medicines.{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}
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,{{cite book| vauthors = Niedermeyer E, da Silva FH |title=Electroencephalography: Basic Principles, Clinical Applications, and Related Fields|url=https://books.google.com/books?id=tndqYGPHQdEC&pg=PA1156|year=2005|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-5126-1|page=1156|url-status=live|archive-url=https://web.archive.org/web/20160509001417/https://books.google.com/books?id=tndqYGPHQdEC&pg=PA1156|archive-date=2016-05-09}} its pungency can irritate the respiratory system, negating any possible advantage conferred by its physical properties. Thus, it is mostly used in general anesthesia as a maintenance agent after induction of general anesthesia with an intravenous agent such as thiopentone or propofol.{{cite journal |vauthors=Pauca AL, Dripps RD |title=Clinical experience with isoflurane (Forane): preliminary communication |journal=British Journal of Anaesthesia |volume=45 |issue=7 |pages=697–703 |date=July 1973 |pmid=4730162 |doi=10.1093/bja/45.7.697 |doi-access=free}}{{cite journal |vauthors=Chen Z |title = The effects of isoflurane and propofol on intraoperative neurophysiological monitoring during spinal surgery |journal=Journal of Clinical Monitoring and Computing |volume=18 | issue=4 |pages=303–308 |date=August 2004 |pmid=15779842 |doi=10.1007/s10877-005-5097-5 |s2cid=195331061}}{{cite web |url=https://www.ncbi.nlm.nih.gov/books/NBK532957/ |pmid=30422552 |year=2022 |vauthors = Hawkley TF, Preston M, Maani CV |title=Isoflurane |publisher=StatPearls}}
Mechanism of action
Similar to many general anesthetics, the exact mechanism of the action has not been clearly delineated.{{cite magazine |url=https://www.scientificamerican.com/article/how-does-anesthesia-work/ |title=How does anesthesia work? |date=February 7, 2005 |magazine=Scientific American |url-status=live |archive-url = https://web.archive.org/web/20160529012227/http://www.scientificamerican.com/article/how-does-anesthesia-work/ |archive-date=May 29, 2016 }} 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.{{cite journal |vauthors=Jones MV, Brooks PA, Harrison NL |title=Enhancement of gamma-aminobutyric acid-activated Cl-currents in cultured rat hippocampal neurones by three volatile anaesthetics |journal=The Journal of Physiology |volume=449 |pages=279–293 |date=April 1992 |pmid=1326046 |pmc=1176079 |doi=10.1113/jphysiol.1992.sp019086}}{{cite journal |vauthors=Jenkins A, Franks NP, Lieb WR | title=Effects of temperature and volatile anesthetics on GABA(A) receptors |journal=Anesthesiology |volume=90 |issue=2 |pages=484–491 |date=February 1999 |pmid=9952156 |doi=10.1097/00000542-199902000-00024 |doi-access=free}}{{cite journal |vauthors=Lin LH, Chen LL, Zirrolli JA, Harris RA |title=General anesthetics potentiate gamma-aminobutyric acid actions on gamma-aminobutyric acidA receptors expressed by Xenopus oocytes: lack of involvement of intracellular calcium |journal=The Journal of Pharmacology and Experimental Therapeutics |volume=263 |issue=2 |pages=569–578 | date=November 1992 |pmid=1331405}}{{cite journal |vauthors=Krasowski MD, Harrison NL |title=The actions of ether, alcohol and alkane general anaesthetics on GABAA and glycine receptors and the effects of TM2 and TM3 mutations |journal=British Journal of Pharmacology |volume=129 |issue=4 | pages=731–743 |date=February 2000 |pmid=10683198 |pmc=1571881 |doi=10.1038/sj.bjp.0703087}} It potentiates glycine receptor activity, which decreases motor function.{{cite journal |vauthors=Grasshoff C, Antkowiak B |title=Effects of isoflurane and enflurane on GABAA and glycine receptors contribute equally to depressant actions on spinal ventral horn neurones in rats |journal=British Journal of Anaesthesia |volume=97 |issue=5 |pages=687–694 |date=November 2006 |pmid=16973644 |doi=10.1093/bja/ael239 |s2cid=14269792 |doi-access=free}} It inhibits receptor activity in the NMDA glutamate receptor subtypes. Isoflurane inhibits conduction in activated potassium channels.{{cite journal | vauthors = Buljubasic N, Rusch NJ, Marijic J, Kampine JP, Bosnjak ZJ |title= Effects of halothane and isoflurane on calcium and potassium channel currents in canine coronary arterial cells |journal=Anesthesiology |volume=76 |issue=6 |pages=990–998 |date=June 1992 |pmid=1318010 |doi=10.1097/00000542-199206000-00020 |doi-access=free}} Isoflurane also affects intracellular molecules. It inhibits plasma membrane calcium ATPases (PMCAs) which affects membrane fluidity by hindering the flow of {{chem2|Ca(2+)}} (calcium ions) out across the membrane, this in turn affects neuron depolarization.{{cite journal |vauthors = Franks JJ, Horn JL, Janicki PK, Singh G |title=Halothane, isoflurane, xenon, and nitrous oxide inhibit calcium ATPase pump activity in rat brain synaptic plasma membranes |journal=Anesthesiology |volume=82 |issue=1 |pages=108–117 |date=January 1995 |pmid=7832292 |doi=10.1097/00000542-199501000-00015 |s2cid=26993898 |doi-access=free}} 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.{{cite journal |vauthors=Weis F, Beiras-Fernandez A, Hauer D, Hornuss C, Sodian R, Kreth S, Briegel J, Schelling G |title=Effect of anaesthesia and cardiopulmonary bypass on blood endocannabinoid concentrations during cardiac surgery |journal=British Journal of Anaesthesia |volume=105 |issue=2 |pages=139–144 |date=August 2010 |pmid=20525978 |doi=10.1093/bja/aeq117 |doi-access=free}}
Adverse effects
Side effects of isoflurane include a decreased ability to breathe (respiratory depression), low blood pressure, and an irregular heartbeat. Isoflurane can cause a sudden decrease in blood pressure due to dose-dependent peripheral vasodilation. This may be specially marked in hypovolemic patients.
Serious side effects can include malignant hyperthermia or high blood potassium. It should not be used in patients with a history of malignant hyperthermia in either themselves or their family members.
It is unknown if its use during pregnancy is safe for the fetus, but use during a cesarean section appears to be safe.
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.{{cite journal | vauthors = Mellon RD, Simone AF, Rappaport BA | title = Use of anesthetic agents in neonates and young children | journal = Anesthesia and Analgesia | volume = 104 | issue = 3 | pages = 509–520 | date = March 2007 | pmid = 17312200 | doi = 10.1213/01.ane.0000255729.96438.b0 | url = http://www.anesthesia-analgesia.org/cgi/content/full/104/3/509 | url-status = live | s2cid = 43818997 | archive-url = https://web.archive.org/web/20090309165832/http://www.anesthesia-analgesia.org/cgi/content/full/104/3/509 | archive-date = 2009-03-09 | doi-access = free }} Whether these concerns occur in humans is unclear.
=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.{{cite journal | vauthors = Mandal et al | title = Isoflurane and desflurane at clinically relevant concentrations induce amyloid b-peptide oligomerization: An NMR study | journal = Biochemical and Biophysical Research Communications| volume = 379 | pages = 716–720 | date = April 2009 | issue = 3 | doi = 10.1016/j.bbrc.2008.12.092 | pmid = 19116131 }} This area is important as "some of the commonly used inhaled anesthetics may cause brain damage that accelerates the onset of Alzheimer's disease".{{cite journal | vauthors = Kuehn BM | title = Anesthesia-Alzheimer disease link probed | journal = JAMA | volume = 297 | issue = 16 | pages = 1760 | date = April 2007 | pmid = 17456811 | doi = 10.1001/jama.297.16.1760 }}
Anesthetic Physical properties
Isoflurane has a Minimum alveolar concentration (MAC) of 1.15 vol %. The blood/gas partition coefficient is 1.4, and the oil/gas partition coefficient is 98.{{citation needed|date=June 2025}} Its vapor pressure at {{convert|20|C|F}} is {{convert|31.7|kPa|mmHg}}.
It is administered as a racemic mixture of (R)- and (S)-optical isomers.{{cite journal | vauthors = Bu W, Pereira LM, Eckenhoff RG, Yuki K | title = Stereoselectivity of isoflurane in adhesion molecule leukocyte function-associated antigen-1 | journal = PLOS ONE | volume = 9 | issue = 5 | pages = e96649 | date = 2014-05-06 | pmid = 24801074 | pmc = 4011845 | doi = 10.1371/journal.pone.0096649 | doi-access = free | bibcode = 2014PLoSO...996649B }} It is non-combustible but can give off irritable and toxic fumes when exposed to flame.
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.{{cite journal | vauthors = Terrell RC | title = The invention and development of enflurane, isoflurane, sevoflurane, and desflurane | journal = Anesthesiology | volume = 108 | issue = 3 | pages = 531–533 | date = March 2008 | pmid = 18292690 | doi = 10.1097/ALN.0b013e31816499cc | doi-access = free }} Its name comes from being a structural isomer of enflurane, hence they have the same empirical formula.{{cite journal | vauthors = Calvey TN | title = Isomerism and anaesthetic drugs | journal = Acta Anaesthesiologica Scandinavica. Supplementum | volume = 106 | pages = 83–90 | date = August 1995 | pmid = 8533553 | doi = 10.1111/j.1399-6576.1995.tb04316.x | s2cid = 24183480 }}
Environment
The average lifetime of isoflurane in the atmosphere is 3.2 years, its global warming potential is 510 (times greater than carbon dioxide) and yearly emissions as of 2015 were 880 tons.{{cite journal| vauthors = Vollmer MK, Rhee TS, Rigby M, Hofstetter D, Hill M, Schoenenberger F, Reimann S | year = 2015| title = Modern inhalation anesthetics: Potent greenhouse gases in the global atmosphere| journal = Geophysical Research Letters| volume = 42| issue = 5| pages = 1606–1611| doi = 10.1002/2014GL062785|bibcode=2015GeoRL..42.1606V |url=https://www.dora.lib4ri.ch/empa/islandora/object/empa%3A6687 |doi-access=free }}{{update inline|reason=Need a current number.|date=June 2025}}
Veterinary use
Isoflurane is frequently used for veterinary anaesthesia.{{cite journal | vauthors = Ludders JW | title = Advantages and guidelines for using isoflurane | journal = The Veterinary Clinics of North America. Small Animal Practice | volume = 22 | issue = 2 | pages = 328–331 | date = March 1992 | pmid = 1585568 | doi = 10.1016/s0195-5616(92)50626-x | doi-access = free }}{{Cite web |title=Isoflurane-Vet 100% w/w Inhalation vapour, liquid |url=https://www.noahcompendium.co.uk/ |access-date=2022-04-07 |website=www.noahcompendium.co.uk |language=en}}
References
{{Reflist}}
External links
- {{US patent|3535388}} - 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether
- {{US patent|3535425}} - 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether as an anesthetic agent
{{General anesthetics}}
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