Votey S R, Bosse G M, Bayer M J, Hoffman J R
UCLA School of Medicine.
Ann Emerg Med. 1991 Feb;20(2):181-8. doi: 10.1016/s0196-0644(05)81219-3.
Flumazenil is a recently discovered pharmacologic antagonist of the CNS effects of benzodiazepines. It acts by binding CNS benzodiazepine receptors and competitively blocking benzodiazepine activation of inhibitory GABAergic synapses. Animal studies and some human studies appear to demonstrate that flumazenil has weak intrinsic agonist activity; on the other hand, studies are inconclusive in demonstrating any inverse agonist effects of this agent. Evidence available suggests that flumazenil is well tolerated in human beings over a broad range of doses when given either orally or parenterally and does not produce serious adverse effects. In the setting of isolated benzodiazepine overdose, flumazenil is capable of completely reversing coma within one to two minutes, with this effect lasting between one and five hours. Repeat doses can be given safely to reverse recurrent effects of longer-acting benzodiazepines. Flumazenil is undergoing further evaluation by the Food and Drug Administration; should this drug receive approval, it is likely to be used in emergency departments as well as in a variety of other clinical settings. First, it could be used to effect rapid reversal of benzodiazepine-induced sedation that has been administered to facilitate medical, orthopedic, and surgical procedures, particularly in the event of inadvertent respiratory depression. Second, flumazenil might have a therapeutic role in the management of patients who have taken benzodiazepine overdoses. Although most of these patients can be managed successfully with supportive therapy alone, it is possible that the use of flumazenil may obviate the need for intubation and respiratory support in such patients and eliminate the possible adverse effects of even short-term endotracheal intubation. Finally, flumazenil could have both diagnostic and therapeutic value in patients with acute alterations of mental status of unknown etiology, particularly when possible drug overdose is a consideration. Because flumazenil appears to be specific in its antagonism of benzodiazepine-induced respiratory and CNS depression, it could be used empirically to confirm or exclude a role of benzodiazepines in the generation of mental status changes in the setting of overdose or coma of unknown origin. This in turn might obviate the need for further expensive (eg, computed tomography) and sometimes invasive (eg, lumbar puncture) diagnostic modalities. This might be particularly useful because there is nothing about benzodiazepine-induced coma that clearly distinguishes it from other causes of coma; thus, there are no signs or symptoms that may reasonably allow benzodiazepine overdose to be confirmed or eliminated on clinical grounds. Further studies will continue to define the ultimate use of this new agent.
氟马西尼是最近发现的一种苯二氮䓬类药物中枢神经系统作用的药理学拮抗剂。它通过与中枢神经系统苯二氮䓬受体结合，竞争性阻断苯二氮䓬对抑制性γ-氨基丁酸能突触的激活。动物研究和一些人体研究似乎表明氟马西尼具有微弱的内在激动剂活性；另一方面，关于该药物是否具有反向激动剂作用的研究尚无定论。现有证据表明，氟马西尼口服或胃肠外给药时，在很宽的剂量范围内人体耐受性良好，不会产生严重不良反应。在单纯苯二氮䓬类药物过量的情况下，氟马西尼能够在1至2分钟内完全逆转昏迷，这种作用持续1至5小时。可以安全地重复给药以逆转长效苯二氮䓬类药物的反复作用。美国食品药品监督管理局正在对氟马西尼进行进一步评估；如果该药物获得批准，很可能会在急诊科以及其他各种临床环境中使用。首先，它可用于快速逆转用于辅助医疗、骨科和外科手术而给予的苯二氮䓬类药物引起的镇静作用，特别是在发生意外呼吸抑制的情况下。其次，氟马西尼在治疗服用苯二氮䓬类药物过量的患者中可能具有治疗作用。虽然这些患者中的大多数仅通过支持性治疗就能成功处理，但使用氟马西尼有可能避免此类患者进行插管和呼吸支持的需要，并消除即使短期气管插管可能产生的不良反应。最后，氟马西尼在病因不明的急性精神状态改变患者中可能具有诊断和治疗价值，特别是在考虑可能存在药物过量的情况下。由于氟马西尼似乎特异性地拮抗苯二氮䓬类药物引起的呼吸和中枢神经系统抑制，它可凭经验用于确认或排除苯二氮䓬类药物在不明原因的过量或昏迷导致的精神状态改变中所起的作用。这反过来可能避免进一步进行昂贵的（如计算机断层扫描）和有时具有侵入性的（如腰椎穿刺）诊断方法。这可能特别有用，因为苯二氮䓬类药物引起的昏迷与其他昏迷原因没有明显区别；因此，没有任何体征或症状可以合理地凭临床依据确认或排除苯二氮䓬类药物过量。进一步的研究将继续确定这种新药的最终用途。
