Remembering the Classics-Reviewing Fundamentals: The Origin of the Inhalation Anesthetic Species
Alan Jay Schwartz, MD, MSEd
Original Article
Roy RC. Agents That Came in From the Cold: Enflurane, Isoflurane, Desflurane, and Sevoflurane. Anesth Analg. 2025 Jan 1;140(1):205-209. doi: 10.1213/ANE.0000000000007017. Epub 2024 Dec 16. PMID: 39316549.
Of what current day value would an article about the chemistry of inhaled anesthetic agents be to clinical anesthesiologists? An answer to this question is provided in a recently penned Open Mind essay in Anesthesia & Analgesia.1 This article by Raymond Roy explains the link between refrigerants and inhalation anesthetic agents. The article delves into the chemistry of these compounds, a topic that may be arduous for clinicians to grasp. Roy’s narrative, however, has great value as it sparks a stroll down memory lane enlightening readers about the origin of modern-day inhalation agents. Digesting Roy’s text immediately reminded me that when I arrived on the scene as a new anesthesiology resident in 1973, I entered an ongoing transition phase of modern-day inhalation anesthetics. My introduction to inhalation anesthesia provided two choices.
One choice was to administer Diethyl ether or cyclopropane. These explosive agents were waning mainstays of clinical inhalation anesthesia practice. When I performed open drop ether, I realized what an ineffective anesthetic it could be when administered to a robust young patient. Cyclopropane, while often nicknamed the “champagne of bottled gas”, was so arrhythmogenic that I unintentionally learned the full spectrum of dysrhythmias when I chose to administer it. Though ether and cyclopropane produced the anesthetic state, their potential negative effects and explosivity propelled the hunt for safer agents.
The other choice was Halothane.
“Modern anesthetic agents emerged as derivatives of carbonfluorine refrigerants (halothane) or from the industrial application of the Swarts fluorination reaction first applied in the refrigeration industry.”1
While Halothane was the go-to inhalation agent it too was not clinically ideal. It was a myocardial depressant and was associated with high acuity complications, Halothane hepatitis and malignant hyperthermia (MH).
Other inhalation compounds were investigated and expanded our armamentarium of safer alternatives including Enflurane, Isoflurane, Desflurane and Sevoflurane provided. Roy’s Open Mind article highlights the fact that modification of the elements of halogenated hydrocarbon compounds alters their characteristics as refrigerants and anesthetics. Modification of the chemical structure of halogenated hydrocarbons has resulted in inhalation agents that approach the desired traits of the ideal anesthetic.
“The ideal inhaled anesthetic agent has ample potency and a low solubility in blood and tissues (rapid recovery from anesthesia), resists physical and metabolic degradation, and protects and does not injure vital tissues. It also does not cause seizures, respiratory irritation, or circulatory stimulation or deplete the ozone layer. It has a low acquisition cost…Halothane is too soluble and poses a risk of severe hepatotoxicity. Desflurane, isoflurane, and sevoflurane are preferred because they have an adequate potency, appropriate solubility, and minimal to no risk for hepatotoxicity.”2
I encourage our readers to read Roy’s article as a way to delve into the basic chemistry traits of inhalation anesthetic agents that we take for granted. The halogenated hydrocarbon inhaled anesthetic agents, as we would say 50 years ago, are really cool!
References
1. Roy RC. Agents That Came in From the Cold: Enflurane, Isoflurane, Desflurane, and Sevoflurane. Anesthesia and analgesia 2025;140(1):205-209. (In eng). DOI: 10.1213/ane.0000000000007017.
2. Eger EI, 2nd. Characteristics of anesthetic agents used for induction and maintenance of general anesthesia. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists 2004;61 Suppl 4:S3-10. (In eng). DOI: 10.1093/ajhp/61.suppl_4.S3.