Enflurane: Biological Mechanisms, Surgical Applications and Side Effects

February 5, 2020

Enflurane is an inhaled drug used for general anesthesia.1 It is a clear, colorless, stable liquid often sold under the name Ethrane.1 It is similar in structure and mechanism to halothane, desflurane, sevoflurane and isoflurane.2 Enflurane became available for use in 1972, but in recent years it has been replaced by more modern anesthetic agents.2 Enflurane must be administered in a controlled environment by a licensed anesthesiologist or certified registered nurse anesthetist (CRNA), and it is typically given in concentrations between 1.5 and four percent with oxygen or nitrous oxide.2,3 Though enflurane is not as commonly used as it once was, anesthesia providers should be familiar with its biological mechanisms, surgical applications and side effects.

Enflurane is a nonflammable fluorinated ethyl methyl ether with a scientific name of 2-chloro-1-(difluoromethoxy)-1,1,2-trifluoroethane.3 It is metabolized in the liver by CYP2E1 via oxidative dehalogenation, which creates reactive intermediates that bind to proteins.3 In humans, enflurane is metabolized between two and four percent.3 Because it is metabolized in the body, it can cause minor, transient liver damage that results in elevated hepatic enzyme levels and antibody production.2 Additionally, the inorganic fluoride produced by enflurane metabolism is linked to increased seizure activity.4 As with other inhalational anesthetics, the mechanism of action of enflurane remains unclear.5 However, it likely acts on neuronal membranes to disrupt transmission, probably via an action at the lipid matrix of the membrane.5 Enflurane may also enhance the activity of gamma-aminobutyric acid (GABA), an inhibitor neurotransmitter, and reduce activity of glutamate, which is an excitatory neurotransmitter.5 Overall, its actions contribute to nervous system inhibition that is essential to anesthesia.

Clinicians can use enflurane during surgery to maintain anesthesia after induction with other agents.2 Enflurane is generally used to maintain anesthesia, rather than induce it, due to its slow onset of action.2 Though its onset and elimination times are shorter than those of halothane, enflurane has a longer induction and emergence timeline than isoflurane.6 Like other inhaled anesthetics, enflurane enhances the action of neuromuscular blocking agents, reduces arterial blood pressure, increases intracranial pressure and causes cerebrovascular vasodilation.6 Deeper enflurane concentrations lead to hypotension, which can be managed by lightening the level of anesthesia.7 It also produces a generalized, reversible depression of the central nervous system, which allows for loss of consciousness in general anesthesia.6 In low concentrations, enflurane provides analgesia for vaginal delivery.7 Enflurane is similar to other inhaled anesthetics in its ability to maintain general anesthesia and provide pain control.

Enflurane differs substantially from other halogenated ethers in its side effects, which are partly responsible for its lack of modern-day use. For one, high concentrations of enflurane are associated with seizure-like EEG activity3 and muscle contractions.6 Though seizure activities have been reported in use of halothane, isoflurane and sevoflurane, enflurane is more well-known for its proconvulsant effects.6 Also, enflurane’s biotransformation leads to byproducts such as inorganic fluoride and trifluoroacetyl chloride, which causes immune system-mediated hepatitis.6 Other inhaled anesthetics, such as desflurane, are more resistant to biodegradation and thus have fewer effects on the liver.6 Enflurane is also associated with malignant hyperthermia, a risk that is shared by all inhalational anesthetics.8 Other side effects of enflurane include hypotension, respiratory depression, arrhythmia, shivering, nausea, vomiting and elevated white blood count.9 Overall, the clinical and side effects of enflurane are similar to other inhalational general anesthetics, with added risk of seizures and liver damage.

Enflurane has been widely used to maintain general anesthesia, but in recent years has been replaced by anesthetics with faster onsets, quicker recoveries and fewer side effects. Enflurane has an inhibitory effect on the central nervous system and leads to reduced arterial blood pressure. However, enflurane can also cause seizure-like muscle contractions and brain activity, as well as liver damage from its metabolites. Its side effects include nausea, vomiting, shivering, arrhythmia and more, which are common across the inhaled anesthetics. Enflurane is not preferred for induction of anesthesia given its slow onset of action, and it may be less popular in general due to its proconvulsant effects.

1.         RxList. Drug Description. Ethrane 2020; https://www.rxlist.com/ethrane-drug.htm#description.

2.         Enflurane. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases; January 1, 2018.

3.         Enflurane. ScienceDirect: Neuroscience 2020; https://www.sciencedirect.com/topics/neuroscience/enflurane.

4.         Hoggard A, Shienbaum R, Mokhtar M, Singh P. Gaseous Anesthetics. StatPearls. Web: StatPearls Publishing LLC; June 24, 2019.

5.         Enflurane. PubChem Database. Web: National Center for Biotechnology Information; 2020.

6.         Enflurane. ScienceDirect: Pharmacology, Toxicology and Pharmaceutical Science 2020; https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/enflurane.

7.         RxList. Indications. Ethrane 2020; https://www.rxlist.com/ethrane-drug.htm#indications.

8.         Caropreso PR, Gittleman MA, Reilly DJ, Patterson LT. Malignant Hyperthermia Associated With Enflurane Anesthesia. Archives of Surgery. 1975;110(12):1491–1493.

9.         RxList. Side Effects & Drug Interactions. Ethrane 2020; https://www.rxlist.com/ethrane-drug.htm#side_effects.