Isoflurane

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.

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, glutamates 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 channels. 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
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 postoperative 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 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. 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.

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".

Global-warming potential
The twenty-year global-warming potential, GWP(20), for isoflurane is 1401.