ANESTHETIC POTENCIES OF N-ALKANOLS - RESULTS OF ADDITIVITY AND SOLUBILITY STUDIES SUGGEST A MECHANISM OF ACTION SIMILAR TO THAT FOR CONVENTIONAL INHALED ANESTHETICS

The mechanism by which n-alkanols produce anesthesia and the character istics relevant to those mechanisms (e.g., lipid solubilities versus p otencies) remain unknown. Accordingly, we determined potencies (minimu m alveolar anesthetic concentration [MAC]) and solubilities of normal methanol, ethanol, butanol, hexanol, and octanol. We also determined t he additivity of these alkanols with a conventional anesthetic (desflu rane) and the additivity of methanol with butanol. Finally, we determi ned whether alkanol metabolism influences alkanol potencies. MAC for m ethanol, ethanol, butanol, hexanol, and octanol (0.00200, 0.000989, 0. 000133, 0.0000214, and 0.00000117 atm, respectively) increased with an increasing solubility in olive oil (olive oil/gas partition coefficie nts 48.6, 108, 1,650, 11,600, and 93,500, respectively) and octanol (o ctanol/gas partition coefficients 163, 1,150, 22,900, 135,000, and 4,1 40,000) to give a product of MAC x solubility for olive oil approximat ely 10 times less (values of 0.10-0.25) than that expected from the Me yer-Overton hypothesis (compared with conventional inhaled anesthetics ). There was less deviation for octanol, but the results were more var iable. Inhibition of methanol and butanol metabolism by 4-methylpyrazo le did not alter MAC. Methanol, ethanol, butanol, hexanol, and octanol had approximately additive anesthetic effects with desflurane, with s ome small but statistically significant deviations both above and belo w additivity. In the presence of 0.5 MAC of desflurane, we needed to a dd 0.4-0.6 MAC of each alkanol to inhibit the movement of 50% of the r ats in response to noxious stimulation. Similarly, the effects of meth anol and butanol were additive (with each other). The saline/gas parti tion coefficient for each alkanol was high (3700, 2650, 1400, 900, and 709 for methanol through octanol), which indicates high polarity. We conclude that the potent anesthetic effects of normal alkanols may res ult from an affinity to both polar and nonpolar phases. Our finding of additivity of alkanols with each other is consistent with a common me chanism of action. Similarly, the finding of additivity or slight devi ations from additivity for alkanols with desflurane is consistent with mechanisms of action that have much in common.