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 characteristics relevant to those mechanisms (e.g., lipid solubilities versus potencies) remain unknown. Accordingly, we determined potencies (minimum alveolar anesthetic concentration [MAC]) and solubilities of normal methanol, ethanol, butanol, hexanol, and octanol. We also determined the additivity of these alkanols with a conventional anesthetic (desflurane) and the additivity of methanol with butanol. Finally, we determined whether alkanol metabolism influences alkanol potencies. MAC for methanol, 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 coefficients 48.6, 108, 1,650, 11,600, and 93,500, respectively) and octanol (octanol/gas partition coefficients 163, 1,150, 22,900, 135,000, and 4,140,000) to give a product of MAC x solubility for olive oil approximately 10 times less (values of 0.10-0.25) than that expected from the Meyer-Overton hypothesis (compared with conventional inhaled anesthetics). There was less deviation for octanol, but the results were more variable. Inhibition of methanol and butanol metabolism by 4-methylpyrazole did not alter MAC. Methanol, ethanol, butanol, hexanol, and octanol had approximately additive anesthetic effects with desflurane, with some small but statistically significant deviations both above and below additivity. In the presence of 0.5 MAC of desflurane, we needed to add 0.4-0.6 MAC of each alkanol to inhibit the movement of 50% of the rats in response to noxious stimulation. Similarly, the effects of methanol and butanol were additive (with each other). The saline/gas partition 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 result from an affinity to both polar and nonpolar phases. Our finding of additivity of alkanols with each other is consistent with a common mechanism of action. Similarly, the finding of additivity or slight deviations from additivity for alkanols with desflurane is consistent with mechanisms of action that have much in common.