Isoflurane

Isoflurane (sold as Forane, among other names) is a halogenated ether used for general anesthesia. It can initiate or sustain anesthesia, though other drugs are typically preferred for induction because isoflurane irritates the airways. It is administered by inhalation.

Approved for medical use in the United States in 1979, it appears on the World Health Organization’s List of Essential Medicines.

**Medical uses** Isoflurane is used to induce and maintain general anesthesia, always given with air or pure oxygen, and often with nitrous oxide. While its physical properties allow faster induction than halothane, its pungency irritates the respiratory system, canceling that advantage. Consequently, it is mainly used to maintain anesthesia after induction with an intravenous agent like thiopentone or propofol.

**Mechanism of action** As with many general anesthetics, its exact mechanism is not fully understood. Isoflurane reduces pain sensitivity (analgesia) and relaxes muscles. It likely binds to GABA, glutamate, and glycine receptors, with different effects on each. It acts as a positive allosteric modulator of the GABAA receptor, potentiates glycine receptor activity (decreasing motor function), and inhibits NMDA glutamate receptor subtypes. It also blocks conduction in activated potassium channels and affects intracellular molecules, including inhibiting plasma membrane calcium ATPases (PMCAs), which disrupts calcium flow and neuron depolarization. It binds to the D subunit of ATP synthase and NADH dehydrogenase. General anesthesia with isoflurane lowers plasma endocannabinoid AEA concentrations, possibly due to stress reduction after loss of consciousness.

**Adverse effects** Side effects include respiratory depression, low blood pressure, and irregular heartbeat. It can cause a sudden drop in blood pressure from dose-dependent peripheral vasodilation, especially in hypovolemic patients. Serious side effects include malignant hyperthermia and high blood potassium. It should not be used in patients with a personal or family history of malignant hyperthermia. Its safety during pregnancy is unknown, though use during cesarean section appears safe. Animal studies have raised concerns about neurodegeneration in young children when isoflurane is combined with nitrous oxide and benzodiazepines like midazolam; whether this occurs in humans is unclear.

**Elderly** NMR spectroscopy studies show that inhaled anesthetics like isoflurane interact with three amino acid residues (G29, A30, I31) of amyloid beta peptide, inducing aggregation. This is relevant because some commonly used inhaled anesthetics may cause brain damage that accelerates the onset of Alzheimer’s disease.

**Anesthetic physical properties** Isoflurane has a minimum alveolar concentration (MAC) of 1.15 vol%, a blood/gas partition coefficient of 1.4, and an oil/gas partition coefficient of 98. Its vapor pressure at 20 °C (68 °F) is 31.7 kPa (238 mmHg). It is administered as a racemic mixture of (R)- and (S)-optical isomers. It is non-combustible but can release irritable and toxic fumes when exposed to flame.

**History** Along with enflurane and halothane, isoflurane began replacing the flammable ethers used in early surgery, a shift that started in the 1940s to 1950s. Its name comes from being a structural isomer of enflurane, meaning they share the same empirical formula.

**Environment** Isoflurane’s average atmospheric lifetime is 3.2 years, its global warming potential is 510 times that of carbon dioxide, and yearly emissions as of 2015 were 880 tons.

**Veterinary use** Isoflurane is used to induce and maintain general anesthesia in horses, dogs, and koalas. It is also commonly used in laboratory settings for anesthesia in mice and rats.