Neuromuscular blocker-induced asthma during anesthesia

描述(申请人提供)：雷帕库溴铵是一种新的快速起效的非去极化神经肌肉阻滞药，于1999年上市使用。它是专门为在全身麻醉诱导过程中促进气管插管而开发的，但已与危及生命的支气管痉挛有关。至少有五名患者死亡，该药物最近被撤回临床使用。这种呼吸道收缩的机制目前尚不清楚。可能的机制包括组胺释放、胆碱酯酶抑制、M3受体激动剂和M2受体拮抗剂。非常重要的是，我们要了解这种药物引起呼吸道收缩的机制，以防止这种情况在新引入的神经肌肉阻滞剂中再次发生。临床上迫切需要一种安全有效的超短效非去极化神经肌肉阻滞剂，在找到之前，研究将继续进行。我们假设，具有选择性M2拮抗特性的神经肌肉阻滞剂增强了副交感神经释放的乙酰胆碱介导的支气管收缩。在气管插管过程中，副交感神经释放乙酰胆碱，作用于呼吸道平滑肌上的M3 M受体，促进支气管收缩。根据这一建议产生的初步数据强烈表明，雷帕库铵诱导致命性支气管痉挛的机制是通过选择性抑制M2 M受体。我们将使用体内和体外方法来确定神经肌肉阻滞剂诱导的支气管收缩增强的机制。M2和M3受体的神经肌肉亲和力将通过放射性配基结合和功能分析(腺苷环化酶和肌醇磷酸分析)来确定。神经肌肉阻滞剂对乙酰胆碱酯酶活性的影响也将被测量。神经肌肉阻滞剂促进副交感神经释放乙酰胆碱的能力将在器官浴中使用豚鼠气管进行测量。神经肌肉阻滞剂增强迷走神经介导的支气管收缩或通过组胺释放增加呼吸道压力的能力将在体内使用具有良好特征的豚鼠模型进行测量。这一机制需要明确的特征，以便它可以作为临床实践开发的新药物的黄金标准筛选。必须了解神经肌肉阻滞剂可能导致支气管痉挛的机制，以便每年接受全身麻醉的数百万患者不会遭受不必要的危及生命的支气管痉挛。

DESCRIPTION (provided by applicant): Rapacuronium, a new rapidly acting nondepolarizing neuromuscular blocking drug, was released for use in 1999. It was developed specifically to facilitate tracheal intubation during the induction of general anesthesia, but has been associated with life threatening bronchospasm. At least five patients have died and the drug was recently withdrawn from clinical use. The mechanism underlying this airway constriction is not currently known. Possible mechanisms include histamine release, cholinesterase inhibition, M3 muscarinic receptor agonism and M2 muscarinic receptor antagonism. It is extremely important that we understand the mechanism by which this drug induces airway constriction to prevent this from ever occurring again with newly introduced neuromuscular blocking agents. A safe and effective ultra-short acting nondepolarizing neuromuscular blocker is urgently needed for routine clinical use, and until one is found the search will continue. We hypothesize that neuromuscular blocking agents that have selective M2 antagonistic properties potentiate parasympathetic release of acetylcholine mediating bronchoconstriction. During intubation of the trachea, parasympathetic nerves release acetylcholine that act on M3 muscarinic receptors on airway smooth muscle to promote bronchoconstriction. Preliminary data generated from this proposal strongly suggest that the mechanism by which rapacuronium induced fatal bronchospasm is by selective inhibition of M2 muscarinic receptors. We will use in vivo and in vitro approaches to define the mechanism of neuromuscular blocking agent-induced potentiation of bronchoconstriction. Neuromuscular affinities for M2 and M3 muscarinic receptors will be defined by radioligand binding and functional assays (adenylyl cyclase and inositol phosphate assays). Neuromuscular blocking agents effects on acetyl cholinesterase activity will also be measured. The ability of neuromuscular blocking agents to enhance acetylcholine release from parasympathetic nerves will be measured using guinea pig trachea in organ baths. The ability of neuromuscular blocking agents to potentiate vagal nerve mediated bronchoconstriction or to increase airway pressure via histamine release will be measured in vivo using a well-characterized guinea pig model. This mechanism needs to be clearly characterized so that it can serve as a gold standard screen for new agents developed for clinical practice. It is imperative that the mechanism of neuromuscular blocking agents potential to induce bronchospasm be understood so that the millions of patients who undergo general anesthesia on a yearly basis are not subjected to unnecessary life threatening bronchospasm.