Soukup Ondrej, Winder Michael, Killi Uday Kumar, Wsol Vladimir, Jun Daniel, Kuca Kamil, Tobin Gunnar
Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic.
Institute of Neuroscience and Physiology, Department of Pharmacology, the Sahlgrenska Academy at the University of Gothenburg, Sweden.
Curr Neuropharmacol. 2017;15(4):637-653. doi: 10.2174/1570159X14666160607212615.
Pharmaceuticals with targets in the cholinergic transmission have been used for decades and are still fundamental treatments in many diseases and conditions today. Both the transmission and the effects of the somatomotoric and the parasympathetic nervous systems may be targeted by such treatments. Irrespective of the knowledge that the effects of neuronal signalling in the nervous systems may include a number of different receptor subtypes of both the nicotinic and the muscarinic receptors, this complexity is generally overlooked when assessing the mechanisms of action of pharmaceuticals.
We have search of bibliographic databases for peer-reviewed research literature focused on the cholinergic system. Also, we have taken advantage of our expertise in this field to deduce the conclusions of this study.
Presently, the life cycle of acetylcholine, muscarinic receptors and their effects are reviewed in the major organ systems of the body. Neuronal and non-neuronal sources of acetylcholine are elucidated. Examples of pharmaceuticals, in particular cholinesterase inhibitors, affecting these systems are discussed. The review focuses on salivary glands, the respiratory tract and the lower urinary tract, since the complexity of the interplay of different muscarinic receptor subtypes is of significance for physiological, pharmacological and toxicological effects in these organs.
Most pharmaceuticals targeting muscarinic receptors are employed at such large doses that no selectivity can be expected. However, some differences in the adverse effect profile of muscarinic antagonists may still be explained by the variation of expression of muscarinic receptor subtypes in different organs. However, a complex pattern of interactions between muscarinic receptor subtypes occurs and needs to be considered when searching for selective pharmaceuticals. In the development of new entities for the treatment of for instance pesticide intoxication, the muscarinic receptor selectivity needs to be considered. Reactivators generally have a muscarinic M2 receptor acting profile. Such a blockade may engrave the situation since it may enlarge the effect of the muscarinic M3 receptor effect. This may explain why respiratory arrest is the major cause for deaths by esterase blocking.
作用于胆碱能传递靶点的药物已使用数十年，至今仍是许多疾病和病症的基础治疗药物。此类治疗可针对躯体运动和副交感神经系统的传递及效应。尽管已知神经系统中神经元信号传导的效应可能涉及烟碱样受体和毒蕈碱样受体的多种不同受体亚型，但在评估药物作用机制时，这种复杂性通常被忽视。
我们检索了文献数据库，以查找专注于胆碱能系统的同行评审研究文献。此外，我们利用了我们在该领域的专业知识来推导本研究的结论。
目前，对乙酰胆碱、毒蕈碱样受体及其效应在人体主要器官系统中的生命周期进行了综述。阐明了乙酰胆碱的神经元和非神经元来源。讨论了影响这些系统的药物实例，特别是胆碱酯酶抑制剂。该综述重点关注唾液腺、呼吸道和下尿路，因为不同毒蕈碱样受体亚型相互作用的复杂性对这些器官的生理、药理和毒理效应具有重要意义。
大多数作用于毒蕈碱样受体的药物使用剂量很大，因此无法预期其选择性。然而，毒蕈碱拮抗剂不良反应谱的一些差异仍可能由不同器官中毒蕈碱样受体亚型表达的变化来解释。然而，毒蕈碱样受体亚型之间存在复杂的相互作用模式，在寻找选择性药物时需要考虑。在开发用于治疗例如农药中毒的新药物时，需要考虑毒蕈碱样受体的选择性。复活剂通常具有作用于毒蕈碱M2受体的特性。这种阻断可能会加剧病情，因为它可能会扩大毒蕈碱M3受体效应的影响。这可能解释了为什么呼吸骤停是酯酶阻断导致死亡的主要原因。
