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[每周一问]NO.19-Alpha 2 Adrenoceptor Agonists
1.  What are the sedative effects of alpha 2 agonists?
2.  Can the central sedation lead to respiratory depression?
1.  α-2受体激动剂的镇静效果机理是什么？
2.  α-2受体激动剂的中枢镇静能导致呼吸抑制吗？

参考答案
1.α-2受体激动剂的镇静效果机理是什么？
位于第四脑室尾部的蓝斑核调节睡眠与觉醒。α-2受体受到兴奋后出现镇静和睡眠，而该过程可以被α-1受体的兴奋所对抗[1]。这种α-2受体的镇静作用受G-蛋白介导[2]，并包括钾通道的超极化，并可能包含钙通道的超极化[3]。
在蓝斑核上的这种效应部分解释了α-2受体激动剂时麻醉药物的使用减少。Bhana等[4]，在其关于右旋美托咪啶（一种强效的α-2受体激动剂，其与α-2受体结合力的强度为可乐定的８倍）的三期临床试验中使用0.2-0.7µg/kg/h发现，该剂量的右旋美托咪啶具有显著的临床镇静作用并明显减少术后、机械通气、ICU患者中镇痛剂的使用。同时观察到，辅助通气停止后无临床显著的呼吸抑制出现。作者结论认为，右旋美托咪啶对于术后机械通气患者可产生迅速而稳定的镇静作用，而维持病人在较高程度的常规稳定和减少焦虑状态。最常见的副作用为低血压、心动过缓和恶心。
2. α-2受体激动剂的中枢镇静能导致呼吸抑制吗？
虽然在对成人的临床研究剂量下没有显著的呼吸抑制发生[4]，但是这可能是使用的剂量相对较小而已。Hedrick等[5]在动物模型中发现，在使用可乐定时可以出现dysrhythmic呼吸的偶发事件，此时肌电图（EMG）监测显示吸气和呼气肌活动出现衰减或变化。
此外，Bissonnette[6]建议认为，胎儿和新生儿出现急性缺氧时的呼吸反应可被蓝斑核内的作用于α-2受体的儿茶酚胺所减弱。通过总结这种永久性和可逆性损伤，Fos蛋白活性、双重标记免疫组化研究，其结论认为，蓝斑核的活性更可能促进胎儿和新生儿出现缺氧导致的呼吸暂停事件的发生。

What are the sedative effects of alpha 2 agonists?
The locus ceruleus, found the the caudal portion of the fourth ventricle, regulates sleep and arousal. Stimulation of the alpha 2 adrenoceptors found in the locus causes sedation and sleep, a process antagonized by alpha 1 adrenoceptor stimulation (1). This alpha 2 sedative effect is mediated by G proteins (2) and consists of hyperpolarization of potassium channels and possibly calcium channels (3).
These effects on the locus ceruleus partially accounts for the anesthetic-sparing effect noted with alpha-2 agonists. Bhana et al. (4), in their review of phase III clinical trials with dexmedetomidine (a potent alpha 2 agonist with 8 times higher affinity for the alpha 2 adrenoceptor than clonidine) 0.2 to 0.7 µg/kg/h, noted clinically effective sedation and significantly reduced analgesic requirements for postsurgical, ventilated, intensive care unit patients. Of note, no clinically apparent respiratory depression occurred after cessation of assisted ventilation. The authors concluded that dexmedetomidine produced rapid and stable sedation in postsurgical ventilated patients while maintaining a high degree of patient rousability and anxiety reduction. The most frequently observed adverse events were hypotension, bradycardia, and nausea.
Can the central sedation lead to respiratory depression?
Although no clinically apparent respiratory depression has occurred in the doses studied in adult clinical populations (4), this may be a reflection of the relatively small doses utilized. In animal models, Hedrick et al. (5) noted that dysrhythmic breathing episodes could be induced by clonidine, with electromyographic (EMG) measurements demonstrating attenuated or altered inspiratory and expiratory muscle activity.
In addition, Bissonnette suggested that respiratory responses to acute hypoxia in the fetus and newborn may be impaired by catecholamines acting at alpha 2 adrenoreceptors within the locus ceruleus. By reviewing the work done with permanent and reversible lesions, Fos protein activation, and double-labeling immunohistochemical studies, the author concluded that activity at the locus ceruleus most likely contributes to hypoxia-induced apneic episodes in the fetus and newborn.
References:
1.  DeBels D, Coriat P. Alpha 2 adrenoceptor agonists: An increasing role in modern anesthesia. Problems in Anesthesia 2000;12:65-72.
2.  Vulliemoz Y, Whittington RA, Virag L. The nitric oxide-cGMP system of the locus coeruleus and the hypnotic action of alpha-2 adrenergic agonists. Brain Res 1999;849(1-2):169-74.
3.  Horvath G, Szikszay M, Benedek G. Calcium channels are involved in the hypnotic-anesthetic action of dexmedetomidine in rats. Anesth Analg 1992;74:884-8.
4.  Bhana N, Goa KL, McClellan KJ. Dexmedetomidine. Drugs 2000;59(2):263-8; discussion 269-70.
5.  Hedrick MS, Dwinell MR, Janssen PL et al. Differential respiratory muscle recruitment induced by clonidine in awake goats. J Appl Physiol 1998;84(4):1198-207.
6.  Bissonnette JM. Mechanisms regulating hypoxic respiratory depression during fetal and postnatal life. Am J Physiol Regul Integr Comp Physiol 2000;278:R1391-R1400.
Site Editor: Stephen B. Corn, M.D. and B. Scott Segal, M.D.
Department of Anesthesia, Harvard Medical School
Founders and Editors-in-Chief: Stephen B. Corn, M.D. and B. Scott Segal, M.D.
Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Medical School