Anesthetic potencies of n-alkanols: Results of additivity and solubility studies suggest a mechanism of action similar to that for conventional inhaled anesthetics
Anesthetic potencies of n-alkanols: Results of additivity and solubility studies suggest a mechanism of action similar to that for conventional inhaled anesthetics
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DOI：
10.1097/00000539-199705000-00017
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发表时间：
1997-05-01
影响因子：
5.7
通讯作者：
Eger, EI
中科院分区：
文献类型：
--
作者：
Fang, Z;Ionescu, P;Eger, EI
正烷醇产生麻醉的机制以及与这些机制相关的特征（例如，脂溶性与效价）仍然未知。因此，我们测定了正常甲醇、乙醇、丁醇、己醇和辛醇的效价（最低肺泡麻醉浓度[MAC]）和溶解度。我们还测定了这些烷醇与常规麻醉剂（地氟醚）的可加性以及甲醇与丁醇的可加性。最后，我们确定了烷醇代谢是否会影响烷醇效价。甲醇、乙醇、丁醇、己醇和辛醇（分别为0.00200、0.000989、0.000133、0.0000214和0.00000117 atm）的MAC随着在橄榄油（橄榄油/气体分配系数分别为48.6、108、1,650、11,600和93,500）和辛醇(辛醇/气体分配系数分别为163、1,150、22,900、135,000、与传统吸入麻醉剂相比，橄榄油的MAC x溶解度比Meyer-Overton假说的预期值低约10倍（值0.10-0.25）。辛醇的偏差较小，但结果变化较大。4-甲基吡唑对甲醇和丁醇代谢的抑制作用没有改变MAC。甲醇、乙醇、丁醇、己醇和辛醇与地氟醚近似具有加性麻醉作用，在加性上和加性下都有一些很小但有统计学意义的偏差。在地氟醚浓度为0.5 MAC的情况下，我们需要添加0.4-0.6 MAC的每种醇来抑制50%的大鼠对有害刺激的反应。同样，甲醇和丁醇的作用是相互添加的。每种醇的盐气分配系数都很高（甲醇-辛醇的盐气分配系数分别为3700、2650、1400、900和709），表明极性较高。我们得出结论，正常烷醇的强麻醉作用可能是由于对极性相和非极性相的亲和力。我们发现烷醇之间的可加性与一个共同的作用机制是一致的。类似地，烷醇与地氟醚的可加性或与可加性的轻微偏差的发现与有许多共同之处的作用机制是一致的。
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.