Additivity versus synergy: A theoretical analysis of implications for anesthetic mechanisms
Additivity versus synergy: A theoretical analysis of implications for anesthetic mechanisms
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DOI：
10.1213/ane.0b013e31817b7140
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发表时间：
2008-08-01
影响因子：
5.7
通讯作者：
Eger, Edmond I., II
中科院分区：
文献类型：
--
作者：
Shafer, Steven L.;Hendrickx, Jan F. A.;Eger, Edmond I., II
背景：吸入麻醉剂被假定作用于多个受体，每个部位的适度作用加起来对有害刺激产生不动。最近的实验结果证实了先前的发现，吸入麻醉剂相互作用。根据定义，协同作用意味着多个作用点。在这篇文章中，我们探讨了相反的观点：可加性是否意味着一个单一的行动点？方法：利用质量作用定律探讨了一种配体与两种配体在受体上竞争同一结合位点的相互作用。然后构建电路来研究药物的效力和浓度与反应关系的陡峭程度如何通过将抑制因子排列成串行电路而将增强因子排列成并行电路来放大。然后探讨了信号处理单元中抑制电路和增强电路的组合，以研究信号处理单元对加性相互作用的约束。最后，探讨了协同性、可加性和分数受体占用之间的关系，以了解可加性所施加的约束。结果：竞争单一受体并对受体产生类似影响的药物，其作用必须是加性的。在串联回路中结合抑制因子的受体，或在平行回路中结合增强因子的受体，增加了药物的表观效力和浓度与反应关系的陡度。当抑制电路和增强电路组合成信号处理单元时，相互作用可以是相加的或协同的。主要决定因素是与兴趣效应相关的药物浓度与50%受体占用率相关的浓度k(d)之间的关系。极低浓度介导的效应更可能是加性的。同样，如果麻醉药物的作用浓度达到或高于受体占用率的50%，则作用于不同部位的吸入麻醉剂不太可能表现出加性相互作用。然而，如果麻醉药物效应发生在非常低的受体占用水平，那么即使在不同受体作用的麻醉剂之间也可能存在加和性。结论：作用于不同受体的药物之间的加和性只有在引起感兴趣的药物效应的浓度远低于50%受体占用的浓度时才有可能。
BACKGROUND: Inhaled anesthetics have been postulated to act at multiple receptors, with modest action at each site summing to produce immobility to noxious stimulation. Recent experimental results affirm prior findings that inhaled anesthetics interact additively. Synergy implies multiple sites of action by definition. In this essay, we explore the converse: does additivity imply a single site of action?METHODS: The interaction of one versus two ligands competing for the same binding site at a receptor was explored using the law of mass action. Circuits were then constructed to investigate how the potency of drugs and the steepness of the concentration versus response relationship is amplified by the arrangement of suppressors into serial circuits, and enhancers into parallel circuits. Assemblies of Suppressor and enhancer circuits into signal processing units were then explored to investigate the constraints signal processing units impose on additive interactions. Lastly, the relationship between synergy, additivity, and fractional receptor occupancy was explored to understand the constraints imposed by additivity.RESULTS: Drugs that compete for a single receptor, and that similarly affect the receptor, must be additive in their effects. Receptors that bind suppressors in serial circuits, or enhancers in parallel circuits, increase the apparent potency of the drugs and the steepness of the concentration versus response relationship. When assemblies of suppressor and enhancer circuits are arranged into signal processing units, the interactions may be additive or synergistic. The primary determinant is the relationship between the concentration of drug associated with the effect of interest and the concentration associated with 50% receptor occupancy, k(d). Effects mediated by very low concentrations are more likely to be additive. Similarly, inhaled anesthetics that act at separate sites are unlikely to exhibit additive interactions if anesthetic drug effect occurs at concentrations at or above 50% receptor occupancy. However, if anesthetic drug effect occurs at very low levels of receptor occupancy, then additivity is expected even among anesthetics acting oil different receptors.CONCLUSIONS: Additivity among drugs acting on different receptors is only likely if the concentrations responsible for the drug effect of interest are well below the concentration associated with 50% receptor occupancy.