Shafer Steven L, Hendrickx Jan F A, Flood Pamela, Sonner James, Eger Edmond I
Department of Anesthesiology, Columbia University Medical Center, 622 W. 168th St, PH 5-505, New York, NY 10032-3725, USA.
Anesth Analg. 2008 Aug;107(2):507-24. doi: 10.1213/ane.0b013e31817b7140.
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?
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.
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 on different receptors.
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.
吸入麻醉药被认为作用于多个受体，每个位点的作用适度累加，从而产生对有害刺激的无反应状态。最近的实验结果证实了先前的发现，即吸入麻醉药的相互作用具有相加性。协同作用按定义意味着多个作用位点。在本文中，我们探讨相反的问题：相加性是否意味着单一作用位点？
运用质量作用定律探讨一种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，研究通过将抑制剂排列成串联电路以及将增强剂排列成并联电路，药物的效价和浓度与反应关系的陡峭程度是如何被放大的。接着探讨将抑制剂和增强剂电路组装成信号处理单元，以研究信号处理单元对相加性相互作用的限制。最后，探讨协同作用、相加性和受体占有率分数之间的关系，以了解相加性所施加的限制。
竞争单一受体且对受体有相似影响的药物，其作用必定是相加的。在串联电路中结合抑制剂或在并联电路中结合增强剂的受体，会增加药物的表观效价以及浓度与反应关系的陡峭程度。当抑制剂和增强剂电路组装成信号处理单元时，相互作用可能是相加的或协同的。主要决定因素是与感兴趣的效应相关的药物浓度和与50%受体占有率（kd）相关的浓度之间的关系。由极低浓度介导的效应更可能是相加的。同样，如果麻醉药效应在受体占有率达到或超过50%的浓度下发生，作用于不同位点的吸入麻醉药不太可能表现出相加性相互作用。然而，如果麻醉药效应在极低的受体占有率水平下发生，那么即使是作用于不同受体的麻醉药也预期会有相加性。
只有当引起感兴趣的药物效应的浓度远低于与50%受体占有率相关的浓度时，作用于不同受体的药物之间才可能具有相加性。
