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GENERAL ARTICLES

Polyhalogenated Methyl Ethyl Ethers: Solubilities and Anesthetic Properties

Donald D. Koblin, PhD, MD^*, Michael J. Laster, DVM, Pompiliu Ionescu, MD, Diane Gong, BS, Edmond I Eger, II, MD, Michael J. Halsey, D Phil, and Tomas Hudlicky, PhD^§

Departments of Anesthesia, *Veteran's Administration Hospital, San Francisco, California, and University of California, San Francisco, California; Nuffield Department of Anaesthetics, Oxford, England; and §Department of Chemistry, University of Florida, Gainesville, Florida

Address correspondence to Edmond I Eger II, MD, Department of Anesthesia, University of California, San Francisco, CA 94143-0464.

The several potent inhaled anesthetics released for clinical use in the past four decades have been halogenated ethers, and, with one exception, methyl ethyl ethers. In the present report, we detail some structural and physical properties associated with anesthetic potency in 27 polyhalogenated methyl ethyl ethers. We obtained new data for 22 compounds. We used response/nonresponse of rats to electrical stimulation of the tail as the anesthetic end point (i.e., we measured the minimum alveolar anesthetic concentration [MAC]). For compounds that did not produce anesthesia when given alone (they only produced excitation/convulsions), we studied MAC by additivity studies with desflurane. We obtained MAC values for 20 of 22 of the studied ethers, which gave products of MAC x oil/gas partition coefficient ranging from 1.27 to 18.8 atm, compared with a product of 1.82 ± 0.56 atm for conventional inhaled anesthetics. Despite solubilities in olive oil and application of partial pressures predicted by the Meyer-Overton hypothesis to provide anesthesia, 2 of 22 ethers (CCIF₂OCCIFCF₃ and CCIF₂OCF₂CClF₂) had no anesthetic (immobilizing) effect when given alone, did not decrease the anesthetic requirement for desflurane, and had excitatory properties when administered alone. As with other inhaled anesthetics, anesthetic potency seemed to correlate with both polar and nonpolar properties. These ethers, representing structural analogs of currently used clinical volatile anesthetics, may be useful in identifying and understanding the mechanisms by which inhaled anesthetics act.

Implications: The several potent, inhaled, polyhalogenated methyl ethyl ether anesthetics released for clinical use in the past four decades seem to have specific useful characteristics that set them apart from other methyl ethyl ethers. Properties of this class of compounds have implications for the future development of anesthetics and the mechanisms by which they act.

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