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RESEARCH OF THE MECHANISM OF GENEKRAL ANESTHESIA-PHARMACOKINETICS OF ANESTHETICS IN THE BRAIN AND ITS RELATION TO ANESTHETIC EFFECT

全麻机制研究——麻醉药脑内药代动力学及其与麻醉效果的关系

基本信息

批准号：
17591648
负责人：
ODA Yutaka
金额：
$ 2.16万
依托单位：
Osaka City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

BACKGROUND : Local anesthetics exert central nervous system (CNS) toxicity by inhibiting intracerebral neuronal activity, while epinephrine augments the CNS toxicity of intravenously administered local anesthetics. Viewed together, increases of extracellular concentrations of local anesthetics in the brain may be directly associated with increased CNS toxicity. The authors examined the hypothesis that epinephrine enhances the CNS toxicity of lidocaine by increasing the extracellular concentration in the brain. METHODS : An awake, spontaneously breathing rat model was used. Twenty male Sprague-Dawley rats received an intravenous infusion of lidocaine (3 mg x kg x min ; group C) or lidocaine with epinephrine (3 mg x kg x min and 2 microg x kg x min, respectively ; group E) for 10 min (n = 10 in each group). Effects of epinephrine on the convulsive dose and concentrations of total (protein-bound and unbound) and unbound lidocaine in plasma were examined. Concentrations of extracellular lidocaine in the cerebral nucleus accumbens were quantitatively determined by a microdialysis method. RESULTS : The convulsive dose of lidocaine was significantly lower in group E than in group C (22.4+/-5.5 vs. 27.9+/-3.1 mg/kg, respectively ; P<0.05). Overall concentrations and area under the plasma concentration-versus-time curve of unbound lidocaine in group E were significantly higher than those in group C. Concentrations of extracellular lidocaine in the nucleus accumbens in group E were comparable to those of unbound fraction in plasma and were also significantly higher than those in group C. CONCLUSIONS : Concomitant administration of epinephrine significantly enhanced the CNS toxicity of intravenously administered lidocaine. Increased extracellular concentration in the brain would be related to this mechanism.

背景技术背景：局麻药通过抑制脑内神经元活动而产生中枢神经系统（CNS）毒性，而肾上腺素则增加静脉给药局麻药的CNS毒性。综合来看，脑中局部麻醉药的细胞外浓度增加可能与CNS毒性增加直接相关。作者检验了肾上腺素通过增加脑细胞外浓度增强利多卡因CNS毒性的假设。方法：采用清醒自主呼吸大鼠模型。20只雄性Sprague-Dawley大鼠接受利多卡因（3 mg x kg x min ; C组）或利多卡因与肾上腺素（分别为3 mg x kg x min和2 μ g x kg x min; E组）静脉输注10 min（每组n = 10）。检查肾上腺素对惊厥剂量和血浆中总（蛋白结合和未结合）和未结合利多卡因浓度的影响。用微透析法定量测定了大脑延髓核细胞外利多卡因的浓度。研究结果：E组的利多卡因惊厥剂量显著低于C组（分别为22.4 ± 5.5和27.9 ± 3.1 mg/kg; P<0.05）。E组游离利多卡因的血药浓度和血药浓度-时间曲线下面积均显著高于C组。E组髓核细胞外利多卡因浓度与血浆游离组分浓度相当，也显著高于C组。结论：肾上腺素的伴随给药显著增强了利多卡因静脉给药的CNS毒性。脑中细胞外浓度的增加与这种机制有关。