Olkkola K T, Ahonen J
Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University Hospital, PO Box 52, kiinamyllynkatu 4-8, FI-20521, Turku, Finland.
Handb Exp Pharmacol. 2008(182):335-60. doi: 10.1007/978-3-540-74806-9_16.
The actions of benzodiazepines are due to the potentiation of the neural inhibition that is mediated by gamma-aminobutyric acid (GABA). Practically all effects of the benzodiazepines result from their actions on the ionotropic GABA(A) receptors in the central nervous system. Benzodiazepines do not activate GABA(A) receptors directly but they require GABA. The main effects of benzodiazepines are sedation, hypnosis, decreased anxiety, anterograde amnesia, centrally mediated muscle relaxation and anti-convulsant activity. In addition to their action on the central nervous system, benzodiazepines have a dose-dependent ventilatory depressant effect and they also cause a modest reduction in arterial blood pressure and an increase in heart rate as a result of a decrease of systemic vascular resistance. The four benzodiazepines, widely used in clinical anaesthesia, are the agonists midazolam, diazepam and lorazepam and the antagonist flumazenil. Midazolam, diazepam and flumazenil are metabolized by cytochrome P450 (CYP) enzymes and by glucuronide conjugation whereas lorazepam directly undergoes glucuronide conjugation. CYP3A4 is important in the biotransformation of both midazolam and diazepam. CYP2C19 is important in the biotransformation of diazepam. Liver and renal dysfunction have only a minor effect on the pharmacokinetics of lorazepam but they slow down the elimination of the other benzodiazepines used in clinical anaesthesia. The duration of action of all benzodiazepines is strongly dependent on the duration of their administration. Based on clinical studies and computer simulations, midazolam has the shortest recovery profile followed by lorazepam and diazepam. Being metabolized by CYP enzymes, midazolam and diazepam have many clinically significant interactions with inhibitors and inducers of CYP3A4 and 2C19. In addition to pharmacokinetic interactions, benzodiazepines have synergistic interactions with other hypnotics and opioids. Midazolam, diazepam and lorazepam are widely used for sedation and to some extent also for induction and maintenance of anaesthesia. Flumazenil is very useful in reversing benzodiazepine-induced sedation as well as to diagnose or treat benzodiazepine overdose.
苯二氮䓬类药物的作用是通过增强由γ-氨基丁酸（GABA）介导的神经抑制作用来实现的。实际上，苯二氮䓬类药物的所有效应都源于它们对中枢神经系统中离子型GABA(A)受体的作用。苯二氮䓬类药物不会直接激活GABA(A)受体，而是需要GABA的存在。苯二氮䓬类药物的主要作用包括镇静、催眠、减轻焦虑、顺行性遗忘、中枢介导的肌肉松弛以及抗惊厥活性。除了对中枢神经系统的作用外，苯二氮䓬类药物还具有剂量依赖性的通气抑制作用，并且由于全身血管阻力降低，它们还会导致动脉血压适度下降和心率增加。在临床麻醉中广泛使用的四种苯二氮䓬类药物分别是激动剂咪达唑仑、地西泮和劳拉西泮以及拮抗剂氟马西尼。咪达唑仑、地西泮和氟马西尼通过细胞色素P450（CYP）酶和葡萄糖醛酸结合进行代谢，而劳拉西泮则直接进行葡萄糖醛酸结合。CYP3A4在咪达唑仑和地西泮的生物转化中起重要作用。CYP2C19在地西泮的生物转化中起重要作用。肝肾功能不全对劳拉西泮的药代动力学影响较小，但会减慢临床麻醉中使用的其他苯二氮䓬类药物的消除速度。所有苯二氮䓬类药物的作用持续时间在很大程度上取决于给药时间的长短。根据临床研究和计算机模拟，咪达唑仑的恢复情况最快，其次是劳拉西泮和地西泮。由于咪达唑仑和地西泮通过CYP酶代谢，它们与CYP3A4和2C19的抑制剂和诱导剂存在许多具有临床意义的相互作用。除了药代动力学相互作用外，苯二氮䓬类药物还与其他催眠药和阿片类药物存在协同相互作用。咪达唑仑、地西泮和劳拉西泮广泛用于镇静，在一定程度上也用于麻醉诱导和维持。氟马西尼在逆转苯二氮䓬类药物引起的镇静以及诊断或治疗苯二氮䓬类药物过量方面非常有用。
