The Development of Research on the Application and Pharmacology of Remifentanil<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />

徐志鹏^＊ 综述    岳云^※ 审校

^＊首都医科大学研究生, 北京 100054

^※首都医科大学附属北京朝阳医院麻醉科，北京 100020

Zhi-peng Xu^＊ Yun Yue^※

^＊Capital University of Medical Sciences，Beijing，100054

^※Department of Anesthesiology，Beijing Chaoyang Hospital，Affiliate of Capital University of Medical Science，Beijing，100020

ABSTRACT

Remifentanil is a new opioid. It is widely used abroad and its domestic product has been administered clinically. Remifentanil which has unique pharmacological character is almost an ideal opioid for continuous infusion. It affects on central nervous system, respiratory system and cardiovascular system function. This article reviewed the development of research about the application and pharmacology of remifentanil.

Key words: Remifentanil; Pharmacology; EEG

Corresponding author: Zhipeng Xu; E-mail: xuzhipeng1977@hotmail.com

雷米芬太尼(remifentanil)是一种新型的芬太尼衍生物,具有理想的阿片类μ受体激动剂特性和独特的药理学特点,比较接近理想的阿片类镇痛药。

一、雷米芬太尼的理化性质<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" />

雷米芬太尼是一种哌啶衍生物，其化学名称为4-(甲氧羰基)-4-[(1-氧丙基)苯胺基]-1-哌啶丙酸甲酯(3-{-4methoxycarbonyl -4-[(L-oxopropyl)-phenylamino]-L-piperidine} propanoic acid methylester)，分子量为413，水溶液pKa7.07，药用其盐酸盐。雷米芬太尼是冻干粉制剂，使用时可以用乳酸林格氏液或生理盐水等稀释后静脉输注。冻干粉剂溶后只能保存24 h，呈高度脂溶性, 在pH7.4时其辛醇/水分配系数为17.9。由于雷米芬太尼制剂含有载体甘氨酸，是一种抑制性神经递质,所以不能用于椎管内^[1]。

二、雷米芬太尼的药代动力学

雷米芬太尼与其它哌啶衍生物的化学结构非常相似,但它在哌啶环上连接一个酯的结构,使它的药代动力学过程不同于其它阿片类药,它主要经血液和组织中的非特异性酯酶丙醇酸甲酯水解代谢^[2], 而血浆胆碱酯酶(假性胆碱酯酶) 受到抑制或功能不良时,它的分解并不受到影响。一般认为雷米芬太尼的代谢符合三室模型^[1,3-5]，t1/2α(0.5～1.5)min，t1/2β(8～20)min,t1/2γ(0.7～1.2)h, Vdss(0.3～0.4)L*kg^-1,Vdc(0.06～0.08)L*kg^-1, C1(40～60)ml*min^-1*kg^-1,血浆蛋白结合率70%～90%,t1/2keo为1.0～1.5min,负荷量后的药效峰值时间1.5min。

其时-量相关半衰期(context sensitive half time,t1/2CS )是相当恒定的,并且时间极短,不论输注时间多长,均为3～5min^[6]。药物连续输注后, 输注时程和累积剂量影响药物在体内的消失时间,在停止连续输注药物后,血药浓度降低50%所需的时间称之为时-量相关半衰期,在临床上具有重要意义。Dershwitz等^[7]实测了雷米芬太尼在输注3h后的血浆t1/2CS为3.2min±0.9min,阿芬太尼为47.3min±12min。药效消失(pharmacodynamic off set)时间分别为5.4min±1.8min和54.0min±48min。雷米芬太尼在滴注3h后,呼吸恢复短于15min。终止输注5min,需纳络酮对抗者为17%。

雷米芬太尼主要由非特异性酯酶水解为羧酸代谢产物雷米芬太尼酸(GI90291),它对μ受体。δ受体和κ受体均有很弱的亲和力,但其药效仅仅为雷米芬太尼的1/300～1/4600,80%以上由肾脏排泄^[1], 但在肾衰病人其t1/2β则明显延长,在体内积聚达一定程度即能发挥阿片类的床效应^[8]。另一代谢产物为GI94219,仅占很小部分。

雷米芬太尼的清除不依赖于肝、肾功能。肝脏疾病和肝血流变化、肾功能不全等不影响雷米芬太尼的药代动力学。一般来说, 雷米芬太尼用于肝、肾功能不全病人是安全的,但是肝功能不全病人对雷米芬太尼引起的呼吸抑制作用更为敏感,小剂量即可使分钟通气量降低50%以上,而对肾功能不全患者呼吸抑制与正常人无差异^[9,10]。静脉注射雷米芬太尼后,可迅速经循环到达脑,血-脑平衡时间短,在肺不发生首过效应^[11]。以上特性说明雷米芬太尼适合长时间持续输注。

雷米芬太尼的药代动力学特点在2～12岁儿童与成人相同。在老年人中,此药的起效较缓,对药物较敏感(老年人对所有的μ受体激动剂都敏感),老年人的分布容积较小,清除较慢,随年龄增加,雷米芬太尼用药剂量要减少,对年龄超过65岁的患者,剂量应减半,并注意个体差异^[12]。

雷米芬太尼容易通过胎盘, 但对早产儿和新生儿均无严重影响,脐带静脉∶孕母动脉内药物比率为0.88±0.78。在胎儿体内快速代谢,脐带动脉∶静脉中的雷米芬太尼浓度比率为0.29±0.07。在静注雷米芬太尼0.1μg*kg^-1*min^-1和硬膜外用芬太尼100μg对比研究中显示对新生儿Apgar评分没有明显差异,表明其不引起胎儿呼吸抑制和镇静作用^[4]。对产妇来说,静注雷米芬太尼0.1μg*kg^-1*min^-1可以达到良好的镇静效果。

在肥胖病人中,雷米芬太尼的中央清除率和稳态分布容积都明显减少,提示雷米芬太尼用药应根据标准体重。

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