Isoflurane

Isoflurane

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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 (WHO)
PubChem	CID 3763
DrugBank	APRD00212
Chemical data
Formula	C3H2ClF5O
Molar mass	184.5 g/mol[[]]
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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 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 non-flammable.

A major advantage of isoflurane is that the patent covering its use has expired, therefore it is very economical to use.

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.

Toxicity

Neonates

See also: Anesthetic#Neonatal_safety_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.

Elderly

Concerns exist with regard to long-lasting post-operative cognitive decline in the elderly and its association with anesthesia. 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 post-operative cognitive decline which has been described as a subtle form of dementia. The elderly are the most vulnerable to post-operative cognitive decline. 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. An animal model has shown that anesthesia with isoflurane increases amyloid pathology in mice models of alzheimer's disease and has been shown to induce cognitive decline in mice.

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".

References

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

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External links

• Rx Med

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