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GENERAL ARTICLES

Nonimmobilizers and Transitional Compounds May Produce Convulsions by Two Mechanisms

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

*Department of Anesthesia, University of California, San Francisco; Veteran’s Administration Hospital, San Francisco, California; Nuffield Department of Anaesthetics, Oxford, United Kingdom; and §Department of Chemistry, University of Florida, Gainesville, Florida

Address correspondence to Dr. Eger, Department of Anesthesia, S-455, University of California, San Francisco, CA 94143-0464. Address e-mail to edmond-eger{at}quickmail.ucsf.edu

Some inhaled compounds cause convulsions. To better appreciate the physical basis for this property, we correlated the partial pressures that produced convulsions in rats with the lipophilicity (nonpolarity) and hydrophilicity (polarity) of 45 compounds: 3 n-alkanes, 18 n-haloalkanes, 3 halogenated aromatic compounds, 3 cycloalkanes and 3 halocycloalkanes, 13 halogenated ethers, and 2 noble gases (He and Ne). In most cases, convulsions were quantified by averaging the alveolar partial pressures just below the pressures that caused and slightly higher pressures that did cause clonic convulsions (ED₅₀). The ED₅₀ did not correlate with hydrophilicity (the saline/gas partition coefficient), nor was there an obvious correlation with molecular structure. For 80% of compounds (36 of 45), the ED₅₀ correlated closely (r² = 0.99) with lipophilicity (the olive oil/gas partition coefficient). Perhaps because they block the effect of GABA on GABA_A receptors, five compounds were more potent than would be predicted from their lipophilicity. Conversely, four compounds may have been less potent than would be predicted because they (like conventional inhaled anesthetics) enhance the effect of GABA on GABA_A receptors.

Implications: Nonimmobilizers and transitional compounds may produce convulsions by two mechanisms. One correlates with lipophilicity (nonpolarity), and the other correlates with an action on GABA_A receptors.

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