Isoflurane: Difference between revisions

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{{drugbox

{{Infobox drug

| verifiedrevid = 418057030

| Verifiedfields = changed

| IUPAC_name = 2-chloro-2-(difluoromethoxy)-1,1,1-trifluoro-ethane OR 1-chloro-2,2,2-trifluoroethyl difluoromethyl ether

| Watchedfields = changed

| verifiedrevid = 443883276

| image = Isoflurane.svg

| width = 150

| alt =

| image2 = Isoflurane-3D-vdW.png

| width2 = 150

| CASNo_Ref = {{cascite|correct|CAS}}

| alt2 =

| caption =

| 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 = <ref name="Drugs.com pregnancy">{{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}}</ref>

| pregnancy_category =

| routes_of_administration = [[Inhalation]]

| class =

| ATCvet =

| ATC_prefix = N01

| ATC_suffix = AB06

| ATC_supplemental =

| legal_AU =

| legal_AU_comment =

| legal_BR = C1

| legal_BR_comment = <ref>{{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}}</ref>

| legal_CA =

| legal_CA_comment =

| legal_DE =

| legal_DE_comment =

| legal_NZ =

| legal_NZ_comment =

| legal_UK = POM

| legal_UK_comment = <ref name="Isoflurane SmPC">{{cite web | title=Isoflurane 100% Inhalation Vapour, Liquid - Summary of Product Characteristics (SmPC) | website=(emc) | date=29 October 2019 | url=https://www.medicines.org.uk/emc/product/9800/smpc | access-date=9 September 2020}}</ref>

| legal_US = Rx-only

| legal_US_comment = <ref name="Forane FDA label">{{cite web | title=Forane- isoflurane inhalant | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3d30eb8d-a62e-475f-926b-78ba63bee9c8 | access-date=11 February 2022}}</ref>

| legal_EU =

| legal_EU_comment =

| legal_UN =

| legal_UN_comment =

| legal_status =

| bioavailability =

| protein_bound =

| metabolism =

| metabolites =

| onset =

| elimination_half-life =

| 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}}

| InChI = 1/C3H2ClF5O/c4-1(3(7,8)9)10-2(5)6/h1-2H

| KEGG = D00545

| InChIKey = PIWKPBJCKXDKJR-UHFFFAOYAP

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEBI = 6015

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 1256

| NIAID_ChemDB =

| PDB_ligand =

| synonyms =

| IUPAC_name = (''RS'')-2-Chloro-2-(difluoromethoxy)-1,1,1-trifluoro-ethane OR (''RS'')-1-chloro-2,2,2-trifluoroethyl difluoromethyl ether

| 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 =

| CAS_number = 26675-46-7

| ~~ATC_prefix~~ = ~~N01~~

| density_notes =

| ~~ATC_suffix~~ = ~~AB06~~

| melting_point =

| ~~ATC_supplemental~~ =

| melting_high =

| ~~ChEBI~~ = ~~6015~~

| melting_notes =

| ~~PubChem~~ = ~~3763~~

| boiling_point =

| boiling_notes =

| DrugBank = APRD00212

| solubility =

| KEGG_Ref = {{keggcite|correct|kegg}}

| ~~KEGG~~ = ~~D00545~~

| sol_units =

| specific_rotation =

| smiles = FC(F)(F)C(Cl)OC(F)F

| C=3 | H=2 | Cl=1 | F=5 | O=1

| molecular_weight = 184.5 g/mol

| bioavailability =

| protein_bound =

| metabolism =

| elimination_half-life =

| pregnancy_category =

| legal_status =

| routes_of_administration =

}}

'''Isoflurane''' (2-chloro-2-(difluoromethoxy)-1,1,1-trifluoro-ethane) is a [[halogenated ether]] used for inhalational [[anesthesia]]. Together with [[enflurane]] and [[halothane]], it replaced the flammable [[Diethyl ether|ethers]] used in the pioneer days of [[surgery]]. Its name comes from being a structural isomer of enflurane, hence they have the same empirical formula. It is a racemic mixture of (R) and (S) optical isomers. Its use in human medicine is now starting to decline, being replaced with [[sevoflurane]], [[desflurane]] and the intravenous anaesthetic [[propofol]]. Isoflurane is still frequently used for [[veterinary anaesthesia]].

Isoflurane is always administered in conjunction with [[air]] and/or pure [[oxygen]]. Often [[nitrous oxide]] is also used. Although its physical properties imply that anaesthesia can be induced more rapidly than with [[halothane]], its pungency can irritate the respiratory system, negating this theoretical advantage conferred by its physical properties. It is usually used to maintain a state of general anesthesia that has been induced with another drug, such as [[thiopentone]] or [[propofol]]. It vaporizes readily, but is a liquid at room temperature. It is completely nonflammable.

'''Isoflurane''', sold under the brand name '''Forane''' among others, is a [[general anesthetic]].<ref name="Forane FDA label" /> It can be used to start or maintain [[anesthesia]]; however, other medications are often used to start anesthesia, due to airway irritation with isoflurane.<ref name="Isoflurane SmPC" /><ref>{{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}}</ref> Isoflurane is given via [[inhalation]].<ref name="Forane FDA label" />

Side effects of isoflurane include a [[Hypoventilation|decreased ability to breathe]] (respiratory depression), [[low blood pressure]], and an [[irregular heartbeat]].<ref name="Isoflurane SmPC" /> Serious side effects can include [[malignant hyperthermia]] or [[hyperkalemia|high blood potassium]].<ref name="Forane FDA label" /> It should not be used in patients with a history of malignant hyperthermia in either themselves or their family members.<ref name="Isoflurane SmPC" /> It is unknown if its use during [[pregnancy]] is safe for the fetus, but use during a [[cesarean section]] appears to be safe.<ref name="Isoflurane SmPC" /><ref name="Forane FDA label" /> Isoflurane is a [[halogenated ether]].<ref>{{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}}</ref>

Isoflurane was approved for medical use in the United States in 1979.<ref name="Forane FDA label" /><ref>{{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}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{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 }}</ref><ref name="WHO22nd">{{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 }}</ref>

==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]],<ref name="NiedermeyerSilva2005">{{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}}</ref> 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]].<ref>{{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 }}</ref><ref>{{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 }}</ref><ref name = NBK532957>{{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 }}</ref>

==Mechanism of action==

Similar to many general anesthetics, the exact mechanism of the action [[Theories of general anaesthetic action|has not been clearly delineated]].<ref>{{cite magazine | url = http://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 }}</ref> Isoflurane reduces pain sensitivity ([[analgesia]]) and relaxes muscles. Isoflurane likely binds to [[GABA receptor|GABA]], [[Glutamate receptor|glutamate]] and [[Glycine receptor|glycine]] receptors, but has different effects on each receptor. Isoflurane acts as a [[positive allosteric modulator]] of the [[GABAA receptor|GABAA receptor]] in electrophysiology studies of neurons and recombinant receptors.<ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref><ref>{{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 }}</ref> It potentiates glycine receptor activity, which decreases motor function.<ref>{{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 }}</ref> It inhibits receptor activity in the [[NMDA]] glutamate receptor subtypes. Isoflurane inhibits conduction in activated [[potassium channel]]s.<ref>{{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 }}</ref> Isoflurane also affects intracellular molecules. It inhibits [[plasma membrane]] [[calcium ATPase]]s (PMCAs) which affects membrane fluidity by hindering the flow of Ca2+ ([[calcium]] [[ion]]s) out across the membrane, this in turn affects [[neuron]] [[depolarization]].<ref>{{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 }}</ref><ref>{{Cite web |title=Protein kinases A and C phosphorylate...... |url=http://www.diagnosticpathology.eu/content/ejp/ejp_001/ejp-001/001-14.htm |access-date=2022-04-07 |website=www.diagnosticpathology.eu}}</ref> It binds to the D subunit of [[ATP synthase]] and [[NADH dehydrogenase]].

General anaesthesia with isoflurane reduces plasma [[Endocannabinoid system|endocannabinoid]] [[Anandamide|AEA]] concentrations, and this could be a consequence of [[Stress management|stress reduction]] after [[Unconsciousness|loss of consciousness]].<ref>{{cite journal | vauthors = Weis F, Beiras-Fernandez A, Hauer D, Hornuss C, Sodian R, Kreth S, Briegel J, Schelling G | display-authors = 6 | 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 }}</ref>

==Adverse effects==

Isoflurane can cause a sudden decrease in blood pressure due to dose-dependent peripheral vasodilation. This may be specially marked in hypovolemic patients.<ref name = NBK532957/>

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]].<ref name=Mel2007>{{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 }}</ref> Whether these concerns occur in humans is unclear.<ref name=Mel2007/>

===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.<ref name="Mandal-2009">{{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 }}</ref> This area is important as "some of the commonly used inhaled anesthetics may cause brain damage that accelerates the onset of Alzheimer's disease".<ref name="Kuehn-2007">{{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 }}</ref>

==Physical properties==

{|

|[[Molecular weight]] ||align=right| 184.5g/mol<ref name=":0">{{Cite web | work = PubChem | publisher = U.S. National Library of Medicine |title=Isoflurane |url=https://pubchem.ncbi.nlm.nih.gov/compound/3763 |access-date=2022-04-07 |language=en}}</ref>||

|[[Molecular weight]] ||align=right| 184.5g/mol ||

|-

|[[Boiling point]] (at 1 [[atmosphere (unit)|atm]]): ||align=right| 48.5 °C ||

|[[Boiling point]] (at 1 [[atmosphere (unit)|atm]]): ||align=right| 48.5 °C<ref name=":0" />||

|

|-

|[[Density]] (at 25 °C): ||align=right| 1.496 g/mL ||

|[[Density]] (at 25 °C): ||align=right| 1.496 g/mL<ref name=":0" />||

|-

|[[Minimum alveolar concentration|MAC]] : ||align=right| 1.15 vol %||

|-

|[[Vapor pressure]]: ||align=right| 238 [[torr|mmHg]] ||align=right| 31.7 [[pascal (unit)|kPa]] || (at 20°C)

|[[Vapor pressure]]: ||align=right| 238 [[torr|mmHg]] ||align=right| 31.7 [[pascal (unit)|kPa]] || (at 20 °C)

|-

| ||align=right|295 mmHg ||align=right| 39.3 kPa || (at 25°C)

| ||align=right|295 mmHg ||align=right| 39.3 kPa || (at 25 °C)

|-

| ||align=right|367 mmHg ||align=right| 48.9 kPa || (at 30°C)

| ||align=right|367 mmHg ||align=right| 48.9 kPa || (at 30 °C)

|-

| ||align=right|450 mmHg ||align=right| 60.0 kPa || (at 35°C)

| ||align=right|450 mmHg ||align=right| 60.0 kPa || (at 35 °C)<ref name=":0" />

|-

| Water [[solubility]] ||align=right| 13.5 mM || (at 25 °C)<ref>{{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 }}</ref>

|Water [[Solubility]] ||align=right|Insoluble

|-

|Blood:~~Gas~~ ~~Partition~~ coefficient: ||align=right|1.4

|[[blood/gas partition coefficient|Blood:gas partition coefficient]]: ||align=right|1.4

|-

|Oil:~~Gas~~ ~~Partition~~ coefficient: ||align=right|98

| Oil:gas partition coefficient: ||align=right|98

|}

It is administered as a [[racemic mixture]] of (''R'')- and (''S'')-optical isomers.<ref>{{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 }}</ref> Isoflurane has a boiling point of 48.5 - 49 °C (119 - 120 °F).<ref name=":0" /> It is non-[[Combustibility and flammability|combustible]] but can give off irritable and [[Toxicity|toxic]] fumes when exposed to flame.<ref name=":0" />

==Mechanism of action==

Similar to many general anesthetics, how isoflurane works remains incompletely understood. Isoflurane reduces pain sensitivity ([[analgesia]]) and relaxes muscles. Isoflurane binds to [[GABA]], [[glutamate]]s and [[glycine]] receptors, but has different effects on each receptor. It inhibits glycine receptor activity, which decreases motor function. It increases receptor activity in the [[NMDA]] glutamate receptor subtype. Isoflurane inhibits conduction in activated [[potassium channel]]s. Isoflurane also affects intracellular molecules. It activates [[calcium ATPase]] by increasing membrane fluidity. It binds to the D subunit of [[ATP synthase]] and [[NADH dehydrogenase]].

==~~Toxicity~~==

==History==

Together with [[enflurane]] and [[halothane]], Isoflurane began to replace the flammable [[Diethyl ether|ethers]] used in the pioneer days of [[surgery]]; this shift began in the 1940s to the 1950s.<ref>{{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 }}</ref> Its name comes from being a [[structural isomer]] of enflurane, hence they have the same [[empirical formula]].<ref>{{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 }}</ref>

===Neurotoxicity concerns in neonates and infants===

{{See also|Anesthetic#Neonatal and infant neurotoxicity concerns}}

Concerns have been raised as to the safety of certain general anesthetics, in particular [[ketamine]] and isoflurane in [[neonates]] and young children due to significant [[neurodegeneration]]. The risk of neurodegeneration is increased in combination of these agents with nitrous oxide and benzodiazepines such as [[midazolam]]. This has led to the FDA and other bodies to take steps to investigate these concerns.<ref>{{Cite journal | last1 = Mellon | first1 = RD. | last2 = Simone | first2 = AF. | last3 = Rappaport | first3 = BA. | title = Use of anesthetic agents in neonates and young children. | url = http://www.anesthesia-analgesia.org/cgi/content/full/104/3/509 | journal = Anesth Analg | volume = 104 | issue = 3 | pages = 509–20 | month = Mar | year = 2007 | doi = 10.1213/01.ane.0000255729.96438.b0 | pmid = 17312200 }}</ref>

==~~=Elderly=~~==

==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.<ref>{{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 }}</ref>

Concerns exist with regard to long-lasting [[post-operative cognitive decline|postoperative cognitive decline]] in the elderly and its association with anesthesia.<ref>{{cite journal

| title=Uncomplicated general anesthesia in the elderly results in cognitive decline: Does cognitive decline predict morbidity and mortality?

| author= M. C. Lewis, I. Nevoa, M. A. Paniaguaa, A. Ben-Aric, E. Prettoa, S. Eisdorfera, E. Davidsona, I. Matotc, C. Eisdorfer

| journal=Medical Hypotheses

| volume=68

| issue=3

| pages=484–492

| year=2007

| doi= 10.1016/j.mehy.2006.08.030

| pmid=17141964

}}</ref> Exposure of cultured human cells to isoflurane has been reported to induce [[apoptosis]] and accumulation and aggregation of [[amyloid beta]] protein, and is proposed to be the cause of postoperative cognitive decline (PCD) which has been described as a subtle form of dementia. The elderly are the most vulnerable to PCD. The study, however, was based on ''[[in vitro]]'' research; further ''[[in vivo]]'' research is needed to determine the relevance of these findings in clinical practice and to improve the safety of anesthesia.<ref>{{cite journal

| title=The Inhalation Anesthetic Isoflurane Induces a Vicious Cycle of Apoptosis and Amyloid β-Protein Accumulation

| author= Z. Xie, Y. Dong, U. Maeda, R. D. Moir, W. Xia, D. J. Culley, G. Crosby, R. E. Tanzi

| journal=Journal of Neuroscience

| volume=27

| issue=6

| pages=1247–1254

| year=2007

| doi= 10.1523/JNEUROSCI.5320-06.2007

| pmid=17287498

}}</ref> An animal model has shown anesthesia with isoflurane increases amyloid pathology in mice models of Alzheimer's disease, and has been shown to induce cognitive decline in mice.<ref>{{cite journal

| title=Brain and behavior changes in 12-month-old Tg2576 and nontransgenic mice exposed to anesthetics

| author= S. L. Bianchi, T. Tran, C. Liu, S. Lin, Y. Li, J. M. Keller, R. G. Eckenhoff, M. F. Eckenhoff

| journal=Neurobiology of Aging

| volume=28

| issue=in press

| pages=in press

| year=2007

| doi= 10.1016/j.neurobiolaging.2007.02.009

| pmid=17346857

}}</ref>

Biophysical studies using state-of-the-art NMR spectroscopy has provided molecular details 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".<ref name="Kuehn-2007">{{Cite journal | last1 = Kuehn | first1 = BM. | title = Anesthesia-Alzheimer disease link probed. | journal = JAMA | volume = 297 | issue = 16 | pages = 1760 | month = Apr | year = 2007 | doi = 10.1001/jama.297.16.1760 | pmid = 17456811 }}</ref>

== Veterinary use ==

==References==

Isoflurane is frequently used for [[veterinary anaesthesia]].<ref>{{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 }}</ref><ref>{{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}}</ref>

== References ==

#Bigger sized anesthetics may be better Scientific American Mind 7 April 2007

# Anesthetics and Alzheimer disease proved JAMA April 23, 2007

# Pravat K. Mandal*, J. W. Pettegrew,” Abeta Peptide interactions with Isoflurane, Propofol, Thiopental and combined Thiopental with Halothane: A NMR Study” Biochemica Biophysica Acta, Biomembrane, (1778: 2633-2639 , 2008).

# Pravat K. Mandal*, J. W. Pettegrew,” Clinically relevant concentration determination of inhaled anesthetics (halothane, soflurane, sevoflurane and desflurane) by 19F NMR” Cell Biochemistry and Biophysics, (52:31-35, 2008)

# Pravat K. Mandal* and Vincenzo Fodale :" Smaller molecular-sized anaesthetics oligomerize Abeta peptide simulating Alzheimer’s disease: a relevant issue" European Journal of Anesthesiology, Vol 26(10) Page 805-806 , 2009 - Editorial

# Pravat K. Mandal*, Daniela Schifilliti, Federica Mafrica, and Vincenzo Fodale "Inhaled Anesthetics and Cognitive Performance" Drugs of Today, (45: 47-54, 2009).

# Pravat K Mandal*, Vincenzo Fodale "Isoflurane and desflurane at clinically relevant concentrations induce amyloid beta-peptide oligomerization: An NMR study" Biochemical and Biophysical Research Communications. (379: 716-720, 2009)

# Pravat K Mandal*, Virgil Simplaceanu and Vincenzo Fodale : "Intravenous Anesthetic Diazepam does not induce Amyloid beta-peptide Oligomerization but Diazepam Co-administered with Halothane Oligomerizes Amyloid Beta-peptide: An NMR study" Journal of Alzheimer Disease April, 2010

# V. Fodale, L.B. Santamaria, D. Schifilliti and P. K. Mandal : "Anaesthetics and post-operative cognitive dysfunction: a pathological mechanism mimicking Alzheimer’s Disease" Anesthesia Journal (Vol 65(4) page 388-395, April 2010)

#Juan Perucho1, Isabel Rubio2, Maria J. Casarejos1, Ana Gomez1, Jose A. Rodriguez-Navarro1, Rosa M. Solano1, Justo Garcia De Yébenes2, Maria A. Mena1 Anesthesia with Isoflurane Increases Amyloid Pathology in Mice Models of Alzheimer'S Disease, Journal of Alzheimer Disease, March 2010

==External links==

== External links ==

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/isoflurane | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Isoflurane }}

*[http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20(General%20Monographs-%20F)/FORANE.html Rx Med]

* {{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

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