Information de reference pour ce titreAccession Number: | 00000539-200808000-00025.
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Author: | Shafer, Steven L. MD *+++; Hendrickx, Jan F. A. MD, PhD +[P]; Flood, Pamela MD *; Sonner, James MD [S]; Eger, Edmond I II MD [S]
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Institution: | From the *Department of Anesthesiology, Columbia University, New York, New York; +Department of Anesthesia, Stanford University, Stanford, California; ++Departments of Biopharmaceutical Sciences and [S]Anesthesia and Perioperative Care, University of California at San Francisco, San Francisco, California; and [P]Department of Anesthesiology and Critical Care Medicine, OLV Hospital, Aalst, Belgium.
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Title: | |
Source: | Anesthesia & Analgesia. 107(2):507-524, August 2008.
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Abstract: | 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, kd. 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.
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.
(C) 2008 International Anesthesia Research Society
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References: | 1. Cullen SC, Eger EI II, Cullen BF, Gregory P. Observations on the anesthetic effect of the combination of xenon and halothane. Anesthesiology 1969;31:305-9
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Language: | English.
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Document Type: | Anesthetic Pharmacology: Research Report.
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Journal Subset: | Nursing. Clinical Medicine.
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ISSN: | 0003-2999
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NLM Journal Code: | 4r8, 1310650
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DOI Number: | https://dx.doi.org/10.1213/ane.0...- ouverture dans une nouvelle fenêtre
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