Isoflurane

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Isoflurane
Isoflurane.svg
Isoflurane-3D-vdW.png
Clinical data
Trade names Forane, others
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Routes of
administration 		Inhalation
ATC code
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Legal status
Identifiers
  • (RS)-2-Chloro-2-(difluoromethoxy)-1,1,1-trifluoro-ethane
    OR
    (RS)-1-chloro-2,2,2-trifluoroethyl difluoromethyl ether
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ECHA InfoCard 100.043.528 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C3H2ClF5O
Molar mass 184.49 g·mol−1
3D model (JSmol)
  • FC(F)(F)C(Cl)OC(F)F
  • InChI=1S/C3H2ClF5O/c4-1(3(7,8)9)10-2(5)6/h1-2H Yes check.svgY
  • Key:PIWKPBJCKXDKJR-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Isoflurane, sold under the brand name Forane among others, is a general anesthetic. [4] It can be used to start or maintain anesthesia; however, other medications are often used to start anesthesia, due to airway irritation with isoflurane. [3] [5] Isoflurane is given via inhalation. [4]

Contents

Side effects of isoflurane include a decreased ability to breathe (respiratory depression), low blood pressure, and an irregular heartbeat. [3] Serious side effects can include malignant hyperthermia or high blood potassium. [4] It should not be used in patients with a history of malignant hyperthermia in either themselves or their family members. [3] It is unknown if its use during pregnancy is safe for the fetus, but use during a cesarean section appears to be safe. [3] [4] Isoflurane is a halogenated ether. [6]

Isoflurane was approved for medical use in the United States in 1979. [4] [7] It is on the World Health Organization's List of Essential Medicines. [8] [9]

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, [10] 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. [11] [12] [13]

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. [13]

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. [14] Whether these concerns occur in humans is unclear. [14]

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. [15] This area is important as "some of the commonly used inhaled anesthetics may cause brain damage that accelerates the onset of Alzheimer's disease". [16]

Physical properties

Molecular weight 184.5g/mol [17]
Boiling point (at 1 atm):48.5 °C [17]
Density (at 25 °C):1.496 g/mL [17]
MAC  :1.15 vol %
Vapor pressure:238 mmHg 31.7 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) [17]
Water solubility 13.5 mM(at 25 °C) [18]
Blood:gas partition coefficient:1.4
Oil:gas partition coefficient:98

It is administered as a racemic mixture of (R)- and (S)-optical isomers. [19] Isoflurane has a boiling point of 48.5 - 49 °C (119 - 120 °F). [17] It is non-combustible but can give off irritable and toxic fumes when exposed to flame. [17]

Mechanism of action

Similar to many general anesthetics, the exact mechanism of the action has not been clearly delineated. [20] 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. [21] [22] [23] [24] It potentiates glycine receptor activity, which decreases motor function. [25] It inhibits receptor activity in the NMDA glutamate receptor subtypes. Isoflurane inhibits conduction in activated potassium channels. [26] 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. [27] [28] 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. [29]

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. [30] Its name comes from being a structural isomer of enflurane, hence they have the same empirical formula. [31]

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. [32]

Veterinary use

Isoflurane is frequently used for veterinary anaesthesia. [33] [34]

Related Research Articles

General anaesthetics are often defined as compounds that induce a loss of consciousness in humans or loss of righting reflex in animals. Clinical definitions are also extended to include an induced coma that causes lack of awareness to painful stimuli, sufficient to facilitate surgical applications in clinical and veterinary practice. General anaesthetics do not act as analgesics and should also not be confused with sedatives. General anaesthetics are a structurally diverse group of compounds whose mechanisms encompass multiple biological targets involved in the control of neuronal pathways. The precise workings are the subject of some debate and ongoing research.

<span class="mw-page-title-main">Sodium thiopental</span> Barbiturate general anesthetic

Sodium thiopental, also known as Sodium Pentothal, thiopental, thiopentone, or Trapanal, is a rapid-onset short-acting barbiturate general anesthetic. It is the thiobarbiturate analog of pentobarbital, and an analog of thiobarbital. Sodium thiopental was a core medicine in the World Health Organization's List of Essential Medicines, but was supplanted by propofol. Despite this, thiopental is listed as an acceptable alternative to propofol, depending on local availability and cost of these agents. It was previously the first of three drugs administered during most lethal injections in the United States, but the US manufacturer Hospira stopped manufacturing the drug in 2011 and the European Union banned the export of the drug for this purpose. Although thiopental abuse carries a dependency risk, its recreational use is rare.

<span class="mw-page-title-main">Halothane</span> General anaesthetic

Halothane, sold under the brand name Fluothane among others, is a general anaesthetic. It can be used to induce or maintain anaesthesia. One of its benefits is that it does not increase the production of saliva, which can be particularly useful in those who are difficult to intubate. It is given by inhalation.

<span class="mw-page-title-main">Sevoflurane</span> Inhalational anaesthetic

Sevoflurane, sold under the brand name Sevorane, among others, is a sweet-smelling, nonflammable, highly fluorinated methyl isopropyl ether used as an inhalational anaesthetic for induction and maintenance of general anesthesia. After desflurane, it is the volatile anesthetic with the fastest onset. While its offset may be faster than agents other than desflurane in a few circumstances, its offset is more often similar to that of the much older agent isoflurane. While sevoflurane is only half as soluble as isoflurane in blood, the tissue blood partition coefficients of isoflurane and sevoflurane are quite similar. For example, in the muscle group: isoflurane 2.62 vs. sevoflurane 2.57. In the fat group: isoflurane 52 vs. sevoflurane 50. As a result, the longer the case, the more similar will be the emergence times for sevoflurane and isoflurane.

<span class="mw-page-title-main">Cyclopropane</span> Chemical compound

Cyclopropane is the cycloalkane with the molecular formula (CH2)3, consisting of three methylene groups (CH2) linked to each other to form a ring. The small size of the ring creates substantial ring strain in the structure. Cyclopropane itself is mainly of theoretical interest but many of its derivatives - cyclopropanes - are of commercial or biological significance.

<span class="mw-page-title-main">Propofol</span> Intravenous medication used in anesthesia

Propofol is the active component of an intravenous anesthetic formulation used for induction and maintenance of general anesthesia. It is chemically termed 2,6-diisopropylphenol. The formulation was originally approved under the brand name Diprivan. Numerous generic offerings of this formulation now exist. Intravenous administration is used to induce unconsciousness after which anesthesia may be maintained using a combination of medications. It is manufactured as part of a sterile injectable emulsion formulation using soybean oil and lecithin, giving it a white milky coloration.

<span class="mw-page-title-main">Theories of general anaesthetic action</span> How drugs induce reversible suppression of consciousness

A general anaesthetic is a drug that brings about a reversible loss of consciousness. These drugs are generally administered by an anaesthetist/anesthesiologist to induce or maintain general anaesthesia to facilitate surgery.

<span class="mw-page-title-main">Anesthetic</span> Drug that causes anesthesia

An anesthetic or anaesthetic is a drug used to induce anesthesia ⁠— ⁠in other words, to result in a temporary loss of sensation or awareness. They may be divided into two broad classes: general anesthetics, which result in a reversible loss of consciousness, and local anesthetics, which cause a reversible loss of sensation for a limited region of the body without necessarily affecting consciousness.

<span class="mw-page-title-main">Desflurane</span> Chemical compound

Desflurane (1,2,2,2-tetrafluoroethyl difluoromethyl ether) is a highly fluorinated methyl ethyl ether used for maintenance of general anesthesia. Like halothane, enflurane, and isoflurane, it is a racemic mixture of (R) and (S) optical isomers (enantiomers). Together with sevoflurane, it is gradually replacing isoflurane for human use, except in economically undeveloped areas, where its high cost precludes its use. It has the most rapid onset and offset of the volatile anesthetic drugs used for general anesthesia due to its low solubility in blood.

<span class="mw-page-title-main">Malignant hyperthermia</span> Medical condition

Malignant hyperthermia (MH) is a type of severe reaction that occurs in response to particular medications used during general anesthesia, among those who are susceptible. Symptoms include muscle rigidity, fever, and a fast heart rate. Complications can include muscle breakdown and high blood potassium. Most people who are susceptible to MH are generally unaffected when not exposed to triggering agents.

<span class="mw-page-title-main">Nitrous oxide (medication)</span> Gas used as anesthetic and for pain relief

Nitrous oxide is an inhaled gas used as a pain medication and together with other medications for anesthesia. Common uses include during childbirth, following trauma, and as part of end-of-life care. Onset of effect is typically within half a minute, and the effect lasts for about a minute.

<span class="mw-page-title-main">Chloralose</span> Chemical compound

Chloralose is an avicide, and a rodenticide used to kill mice in temperatures below 15 °C. It is also widely used in neuroscience and veterinary medicine as an anesthetic and sedative. Either alone or in combination, such as with urethane, it is used for long-lasting, but light anesthesia.

<span class="mw-page-title-main">Enflurane</span> Chemical compound

Enflurane is a halogenated ether. Developed by Ross Terrell in 1963, it was first used clinically in 1966. It was increasingly used for inhalational anesthesia during the 1970s and 1980s but is no longer in common use.

<span class="mw-page-title-main">Inhalational anesthetic</span> Volatile or gaseous anesthetic compound delivered by inhalation

An inhalational anesthetic is a chemical compound possessing general anesthetic properties that is delivered via inhalation. They are administered through a face mask, laryngeal mask airway or tracheal tube connected to an anesthetic vaporiser and an anesthetic delivery system. Agents of significant contemporary clinical interest include volatile anesthetic agents such as isoflurane, sevoflurane and desflurane, as well as certain anesthetic gases such as nitrous oxide and xenon.

<span class="mw-page-title-main">Halogenated ether</span> Subcategory of ether used in anesthesiology

A halogenated ether is a subcategory of a larger group of chemicals known as ethers. An ether is an organic chemical that contains an ether group—an oxygen atom connected to two (substituted) alkyl groups. A good example of an ether is the solvent diethyl ether.

Minimum alveolar concentration or MAC is the concentration, often expressed as a percentage by volume, of a vapour in the alveoli of the lungs that is needed to prevent movement in 50% of subjects in response to surgical (pain) stimulus. MAC is used to compare the strengths, or potency, of anaesthetic vapours. The concept of MAC was first introduced in 1965.

<span class="mw-page-title-main">Methoxyflurane</span> Chemical compound

Methoxyflurane, sold under the brand name Penthrox among others, is an inhaled medication primarily used to reduce pain following trauma. It may also be used for short episodes of pain as a result of medical procedures. Onset of pain relief is rapid and of a short duration. Use is only recommended with direct medical supervision.

<span class="mw-page-title-main">Flurothyl</span> Chemical compound

Flurothyl (Indoklon) is a volatile liquid drug from the halogenated ether family, related to inhaled anaesthetic agents such as diethyl ether, but having the opposite effects, acting as a stimulant and convulsant. A clear and stable liquid, it has a mild ethereal odor whose vapors are non-flammable. It is excreted from the body by the lungs in an unchanged state.

Emergence delirium is a condition in which emergence from general anesthesia is accompanied by psychomotor agitation. Some see a relation to pavor nocturnus while others see a relation to the excitement stage of anesthesia.

Blood–gas partition coefficient, also known as Ostwald coefficient for blood–gas, is a term used in pharmacology to describe the solubility of inhaled general anesthetics in blood. According to Henry's law, the ratio of the concentration in blood to the concentration in gas that is in contact with that blood, when the partial pressure in both compartments is equal, is nearly constant at sufficiently low concentrations. The partition coefficient is defined as this ratio and, therefore, has no units. The concentration of the anesthetic in blood includes the portion that is undissolved in plasma and the portion that is dissolved. The more soluble the inhaled anesthetic is in blood compared to in air, the more it binds to plasma proteins in the blood and the higher the blood–gas partition coefficient.

References

  1. ↑ "Isoflurane Use During Pregnancy". Drugs.com. 2 September 2020. Retrieved 9 September 2020.
  2. ↑ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  3. 1 2 3 4 5 "Isoflurane 100% Inhalation Vapour, Liquid - Summary of Product Characteristics (SmPC)". (emc). 29 October 2019. Retrieved 9 September 2020.
  4. 1 2 3 4 5 6 "Forane- isoflurane inhalant". DailyMed. Retrieved 11 February 2022.
  5. ↑ Kliegman R, Stanton B, St Geme J, Schor NF (2015). Nelson Textbook of Pediatrics (20 ed.). Elsevier Health Sciences. p. 420. ISBN   9780323263528. Archived from the original on 2016-12-20.
  6. ↑ 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.
  7. ↑ "Forane: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 11 February 2022.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ Pauca AL, Dripps RD (July 1973). "Clinical experience with isoflurane (Forane): preliminary communication". British Journal of Anaesthesia. 45 (7): 697–703. doi: 10.1093/bja/45.7.697 . PMID   4730162.
  12. ↑ Chen Z (August 2004). "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. PMID   15779842. S2CID   195331061.
  13. 1 2 Hawkley TF, Preston M, Maani CV (2022). "Isoflurane". StatPearls. PMID   30422552.
  14. 1 2 Mellon RD, Simone AF, Rappaport BA (March 2007). "Use of anesthetic agents in neonates and young children". Anesthesia and Analgesia. 104 (3): 509–520. doi: 10.1213/01.ane.0000255729.96438.b0 . PMID   17312200. S2CID   43818997. Archived from the original on 2009-03-09.
  15. ↑ Mandal, et al. (April 2009). "Isoflurane and desflurane at clinically relevant concentrations induce amyloid b-peptide oligomerization: An NMR study". Biochemical and Biophysical Research Communications. 379 (3): 716–720. doi:10.1016/j.bbrc.2008.12.092. PMID   19116131.
  16. ↑ Kuehn BM (April 2007). "Anesthesia-Alzheimer disease link probed". JAMA. 297 (16): 1760. doi:10.1001/jama.297.16.1760. PMID   17456811.
  17. 1 2 3 4 5 6 "Isoflurane". PubChem. U.S. National Library of Medicine. Retrieved 2022-04-07.
  18. ↑ 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.
  19. ↑ Bu W, Pereira LM, Eckenhoff RG, Yuki K (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 . PMC   4011845 . PMID   24801074.
  20. ↑ "How does anesthesia work?". Scientific American . February 7, 2005. Archived from the original on May 29, 2016.
  21. ↑ 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: 279–293. doi:10.1113/jphysiol.1992.sp019086. PMC   1176079 . PMID   1326046.
  22. ↑ Jenkins A, Franks NP, Lieb WR (February 1999). "Effects of temperature and volatile anesthetics on GABA(A) receptors". Anesthesiology. 90 (2): 484–491. doi:10.1097/00000542-199902000-00024. PMID   9952156.
  23. ↑ 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): 569–578. PMID   1331405.
  24. ↑ 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): 731–743. doi:10.1038/sj.bjp.0703087. PMC   1571881 . PMID   10683198.
  25. ↑ 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): 687–694. doi: 10.1093/bja/ael239 . PMID   16973644. S2CID   14269792. Archived from the original (PDF) on 2017-09-10.
  26. ↑ 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): 990–998. doi: 10.1097/00000542-199206000-00020 . PMID   1318010.
  27. ↑ Franks JJ, Horn JL, Janicki PK, 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 . PMID   7832292. S2CID   26993898.
  28. ↑ "Protein kinases A and C phosphorylate..." www.diagnosticpathology.eu. Retrieved 2022-04-07.
  29. ↑ 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): 139–144. doi: 10.1093/bja/aeq117 . PMID   20525978.
  30. ↑ Terrell RC (March 2008). "The invention and development of enflurane, isoflurane, sevoflurane, and desflurane". Anesthesiology. 108 (3): 531–533. doi: 10.1097/ALN.0b013e31816499cc . PMID   18292690.
  31. ↑ Calvey TN (August 1995). "Isomerism and anaesthetic drugs". Acta Anaesthesiologica Scandinavica. Supplementum. 106: 83–90. doi:10.1111/j.1399-6576.1995.tb04316.x. PMID   8533553. S2CID   24183480.
  32. ↑ Vollmer MK, Rhee TS, Rigby M, Hofstetter D, Hill M, Schoenenberger F, Reimann S (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 .
  33. ↑ Ludders JW (March 1992). "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 . PMID   1585568.
  34. ↑ "Isoflurane-Vet 100% w/w Inhalation vapour, liquid". www.noahcompendium.co.uk. Retrieved 2022-04-07.
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