Harvard Medical School, Boston, Massachusetts, USA.
Anesthesiology. 2010 Mar;112(3):637-44. doi: 10.1097/ALN.0b013e3181cf40ed.
Etomidate is a sedative hypnotic that is often used in critically ill patients because it provides superior hemodynamic stability. However, it also binds with high affinity to 11beta-hydroxylase, potently suppressing the synthesis of steroids by the adrenal gland that are necessary for survival. The authors report the results of studies to define the pharmacology of (R)-ethyl 1-(1-phenylethyl)-1H-pyrrole-2-carboxylate (carboetomidate), a pyrrole analog of etomidate specifically designed not to bind with high affinity to 11beta-hydroxylase.
The hypnotic potency of carboetomidate was defined in tadpoles and rats using loss of righting reflex assays. Its ability to enhance wild-type alpha1beta2gamma2l and etomidate-insensitive mutant alpha1beta2M286Wgamma2l human gamma-aminobutyric acid type A receptor activities was assessed using electrophysiologic techniques. Its potency for inhibiting in vitro cortisol synthesis was defined using a human adrenocortical cell assay. Its effects on in vivo hemodynamic and adrenocortical function were defined in rats.
Carboetomidate was a potent hypnotic in tadpoles and rats. It increased currents mediated by wild-type but not etomidate-insensitive mutant gamma-aminobutyric acid type A receptors. Carboetomidate was a three orders of magnitude less-potent inhibitor of in vitro cortisol synthesis by adrenocortical cells than was etomidate. In rats, carboetomidate caused minimal hemodynamic changes and did not suppress adrenocortical function at hypnotic doses.
Carboetomidate is an etomidate analog that retains many beneficial properties of etomidate, but it is dramatically less potent as an inhibitor of adrenocortical steroid synthesis. Carboetomidate is a promising new sedative hypnotic for potential use in critically ill patients in whom adrenocortical suppression is undesirable.
依托咪酯是一种镇静催眠药，常用于危重病患者，因其能提供更好的血液动力学稳定性。然而，它也与 11β-羟化酶高亲和力结合，强力抑制肾上腺合成生存所必需的类固醇。作者报告了研究结果，以确定（R）-乙基 1-（1-苯乙基）-1H-吡咯-2-羧酸酯（卡泊依托咪酯）的药理学，这是依托咪酯的吡咯类似物，专门设计为不与 11β-羟化酶高亲和力结合。
使用翻正反射丧失试验，在蝌蚪和大鼠中定义卡泊依托咪酯的催眠效力。使用电生理技术评估其增强野生型α1β2γ2l 和依托咪酯不敏感突变体α1β2M286Wγ2l 人γ-氨基丁酸 A 型受体活性的能力。使用人肾上腺皮质细胞测定法定义其抑制体外皮质醇合成的效力。在大鼠中定义其对体内血液动力学和肾上腺皮质功能的影响。
卡泊依托咪酯在蝌蚪和大鼠中是一种有效的催眠药。它增加了野生型但不增加依托咪酯不敏感突变体γ-氨基丁酸 A 型受体介导的电流。卡泊依托咪酯对体外皮质醇合成的抑制作用比依托咪酯弱三个数量级。在大鼠中，卡泊依托咪酯引起的血液动力学变化最小，在催眠剂量下不抑制肾上腺皮质功能。
卡泊依托咪酯是依托咪酯的类似物，保留了依托咪酯的许多有益特性，但作为肾上腺皮质类固醇合成抑制剂的效力显著降低。卡泊依托咪酯是一种有前途的新型镇静催眠药，可能适用于不希望抑制肾上腺皮质功能的危重病患者。
