isoflurane

Isoflurane
Systematic (IUPAC) name
2-chloro-2-(difluoromethoxy)-1,1,1-trifluoro-ethane
OR
1-chloro-2,2,2-trifluoroethyl difluoromethyl ether
Identifiers
CAS number 26675-46-7
ATC code N01AB06
PubChem CID 3763
DrugBank APRD00212
ChemSpider 3631
UNII CYS9AKD70P
KEGG D00545
ChEMBL CHEMBL1256
Chemical data
Formula C3H2ClF5O 
Mol. mass 184.5 g/mol
SMILES eMolecules & PubChem
Therapeutic considerations
Pregnancy cat. ?
Legal status ?
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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 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.

Anesthesia gases used globally contribute the equivalent of one million cars to global warming.[1] Isoflurane is a greenhouse gas, with a global warming potential of 1401. One tonne of sevoflurane emitted is equivalent to 1401 tonnes of carbon dioxide in the atmosphere. Taking into account the different amounts typically used in 1 hour of anesthesia (1 minimal alveolar concentration-hour), isoflurane causes 2.2 times the global warming of sevoflurane, but is much less damaging than desflurane, which causes 26.8 times the damage.[2]

Contents

Physical properties

Molecular weight 184.5g/mol
Boiling point (at 1 atm): 48.5 °C
Density (at 25 °C): 1.496 g/mL
MAC : 1.15 vol %
Vapor pressure: 238 mmHg 31.7 kPa (at 20°C)
295 mmHg 39.3 kPa (at 25°C)
367 mmHg 48.9 kPa (at 30°C)
450 mmHg 60.0 kPa (at 35°C)
Water Solubility Insoluble
Blood:Gas Partition coefficient: 1.4
Oil:Gas Partition coefficient: 98

Mechanism of action

Isoflurane reduces pain sensitivity (analgesia) and relaxes muscles. The mechanism by which general anesthetics produce the anesthetic state is not clearly understood, but likely involves interactions with multiple receptor sites to interfere with synaptic transmission. Isoflurane binds to GABA receptors, glutamate receptors and glycine receptors, and also inhibits conduction in activated potassium channels. Glycine inhibition helps to inhibit motor function, while bonding to glutamate receptors mimics the effects of NMDA. It activates calcium ATPase through an increase in membrane fluidity, and binds to the D subunit of ATP synthase and NADH dehydrogenase. In addition, a number of general anesthetics attenuate gap junction communication, which could contribute to anesthetic action.

Neonates

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.[3]

Elderly

Concerns exist with regard to long-lasting postoperative cognitive decline in the elderly and its association with anesthesia.[4] 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.[5] 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.[6]

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".[7]

References

  1. ↑ Sulbaek Andersen MP, Sander SP, Nielsen OJ, Wagner DS, Sanford Jr TJ, Wallington TJ (July 2010). . British Journal of Anaesthesia 105 (6): 760-766. http://bja.oxfordjournals.org/content/105/6/760.abstract. 
  2. ↑ Ryan SM, Nielsen CJ (July 2010). . Anesthesia and Analgesia 111 (1): 92-98. http://www.anesthesia-analgesia.org/content/111/1/92.long. 
  3. ↑ Mellon, RD.; Simone, AF.; Rappaport, BA. (Mar 2007). . Anesth Analg 104 (3): 509–20. . . http://www.anesthesia-analgesia.org/cgi/content/full/104/3/509. 
  4. ↑ M. C. Lewis, I. Nevoa, M. A. Paniaguaa, A. Ben-Aric, E. Prettoa, S. Eisdorfera, E. Davidsona, I. Matotc, C. Eisdorfer (2007). . Medical Hypotheses 68 (3): 484–492. . . 
  5. ↑ Z. Xie, Y. Dong, U. Maeda, R. D. Moir, W. Xia, D. J. Culley, G. Crosby, R. E. Tanzi (2007). . Journal of Neuroscience 27 (6): 1247–1254. . . 
  6. ↑ S. L. Bianchi, T. Tran, C. Liu, S. Lin, Y. Li, J. M. Keller, R. G. Eckenhoff, M. F. Eckenhoff (2007). . Neurobiology of Aging 28 (in press): in press. . . 
  7. ↑ Kuehn, BM. (Apr 2007). . JAMA 297 (16): 1760. . . 
  1. Bigger sized anesthetics may be better Scientific American Mind 7th April 2007
  2. Anesthetics and Alzheimer disease proved JAMA April 23rd 2007
  3. 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).
  4. 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)
  5. 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
  6. Pravat K. Mandal*, Daniela Schifilliti, Federica Mafrica, and Vincenzo Fodale "Inhaled Anesthetics and Cognitive Performance" Drugs of Today, (45: 47-54, 2009).
  7. 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)
  8. 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
  9. 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)
  10. 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