Harvard Medical School, Boston, Massachusetts, USA.
Anesthesiology. 2011 Mar;114(3):695-707. doi: 10.1097/ALN.0b013e3181ff72b5.
This review focuses on the unique clinical and molecular pharmacologic features of etomidate. Among general anesthesia induction drugs, etomidate is the only imidazole, and it has the most favorable therapeutic index for single-bolus administration. It also produces a unique toxicity among anesthetic drugs: inhibition of adrenal steroid synthesis that far outlasts its hypnotic action and that may reduce survival of critically ill patients. The major molecular targets mediating anesthetic effects of etomidate in the central nervous system are specific γ-aminobutyric acid type A receptor subtypes. Amino acids forming etomidate binding sites have been identified in transmembrane domains of these proteins. Etomidate binding site structure models for the main enzyme mediating etomidate adrenotoxicity have also been developed. Based on this deepening understanding of molecular targets and actions, new etomidate derivatives are being investigated as potentially improved sedative-hypnotics or for use as highly selective inhibitors of adrenal steroid synthesis.
这篇综述重点介绍了依托咪酯的独特临床和分子药理学特征。在全身麻醉诱导药物中，依托咪酯是唯一的咪唑类药物，其单次给药的治疗指数最佳。它还在麻醉药物中产生了一种独特的毒性：对肾上腺皮质类固醇合成的抑制作用远远超过其催眠作用，这可能会降低危重病患者的生存率。介导依托咪酯在中枢神经系统中麻醉作用的主要分子靶标是特定的γ-氨基丁酸 A 型受体亚型。在这些蛋白质的跨膜结构域中已经确定了形成依托咪酯结合位点的氨基酸。还开发了介导依托咪酯肾上腺毒性的主要酶的依托咪酯结合位点结构模型。基于对分子靶标和作用的深入了解，正在研究新的依托咪酯衍生物，以期作为潜在的改良镇静催眠药，或作为肾上腺皮质类固醇合成的高选择性抑制剂。
