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Anesthesiology:
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Do General Anesthetics Add Up?

Hemmings, Hugh C. Jr M.D., Ph.D.*; Antognini, Joseph F. M.D.†

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ANESTHESIOLOGISTS practice the skilful use of pharmacologic synergism, or supra-additive drug interactions, to enhance desirable anesthetic actions while minimizing agent-specific undesired effects through reduced individual drug doses. Often this art is supported by experimental and clinical evidence (e.g., synergism between midazolam and propofol in hypnosis,1,2 used to advantage in coinduction of anesthesia), but the cellular and molecular mechanisms underlying these important drug interactions are usually poorly understood, if at all. Our incomplete understanding of the molecular mechanisms of the defining drugs of our specialty certainly contributes to this knowledge gap. However, advances in the molecular pharmacology of general anesthetics and drug interactions are facilitating investigations into the mechanisms of anesthetic action. These developments are evident in the complementary reports in this issue of Anesthesiology that compare the interactions of the prototypical intravenous and volatile anesthetics propofol and sevoflurane both at the behavioral level in human volunteers3 and at the level of an anesthetic-sensitive neurotransmitter receptor.4
Current models of general anesthesia suggest that different molecular targets in various regions of the nervous system are involved in the multiple components of anesthetic action and that these targets can vary among specific anesthetics.5,6 Immobilization is a property of anesthetic action that is used as a standard measure of anesthetic potency (as minimum alveolar concentration), whereas lower anesthetic concentrations are required for other anesthetic end points (e.g., amnesia and unconsciousness). Although there is no universal target that explains all of the actions of every general anesthetic, or even of a single anesthetic, neurotransmitter-gated ion channels, particularly certain receptors for γ-aminobutyric acid and glutamate, are modulated by most anesthetics and are probably important molecular targets in vivo.
The studies by Harris et al.3 and Sebel et al.4 represent two extremes of the pharmacologic research spectrum: behavioral responses in vivo and receptor responses in vitro. Although such a comparison is informative (much more than either study alone), much happens between the receptor and the behavioral response, and how anesthetics affect these intermediate processes is poorly understood. So a comparison of the nature of anesthetic interactions on two clinically relevant behavioral end points (loss of consciousness and immobility) thought to involve different sites of action in the central nervous system (forebrain and spinal cord7,8) and on an important molecular target (γ-aminobutyric acid receptor type A [GABAA] receptor) that is positively modulated by both propofol and sevoflurane4 should provide important clues to mechanisms of anesthesia. Such studies are of mechanistic value because an additive drug interaction supports a common mechanism or site of action for each drug, whereas a synergistic interaction suggests separate interacting sites.9 By examining a single point on the predicted lines of additivity for loss of consciousness or immobility (EC50/2 for propofol and sevoflurane), Harris et al. found additivity for both anesthetic end points in vivo. Sebel et al. used response surface modeling (which covers a range of concentrations) of anesthetic enhancement of GABAA receptor affinity for γ-aminobutyric acid to demonstrate an additive interaction in vitro as well.
Numerous examples of synergistic drug interactions exist in anesthesiology, including interactions between two drugs (e.g., propofol and midazolam1,2) or of a single drug delivered to two sites (e.g., spinal and supraspinal morphine10). Such synergistic interactions imply distinct sites of action, such as different anatomical sites, cell populations, or signaling pathways/receptor sites within the same cells. Conversely, additive interactions imply convergent actions on the same protein site, molecular pathway, or cellular site. There is convincing electrophysiologic and genetic evidence that propofol and sevoflurane act on GABAA receptors. Together with the finding that they interact in an additive manner, the indication is that both anesthetics interact at a single site (GABAA receptors) to produce anesthesia. However, a single amino acid substitution in the GABAA receptor β3 subunit second transmembrane domain results in nearly complete resistance to propofol but only modest resistance to volatile anesthetics,11,12 whereas an analogous mutation in the α1 subunit reduces sensitivity to volatile anesthetics without affecting sensitivity to intravenous agents.13 In light of these observations, how could propofol and sevoflurane be acting at the same site, as suggested by their additive effects on immobility and loss of consciousness? The most parsimonious explanation of these findings is that propofol and sevoflurane act at different sites/subunits on GABAA receptors to produce a similar effect on gating. In the case of GABAA receptors in vitro, this seems to involve separate binding sites on the same receptor converging to produce enhanced agonist affinity. However, the in vivo evidence does not allow us to rule out interactions through separate receptors that converge at a common downstream site to yield an additive interaction. Indeed, such a multisite mechanism seems necessary to explain the observation that spinal GABAA receptors are not involved in immobilization by isoflurane.14 Therefore, although synergistic interactions indicate distinct sites of action (and thus are more informative mechanistically), additive interactions do not necessarily indicate an identical site of action, at least at the molecular level.
A simple explanation of the results presented by Harris et al. and Sebel et al. would be that both propofol and sevoflurane produce loss of consciousness and immobility through potentiation of GABAA receptor function. However, 150 yr of investigation have taught us that anesthetic mechanisms are far from simple. Accumulating evidence obtained using a variety of experimental approaches indicates that volatile anesthetics are unlikely to produce immobility solely through potentiation of GABAA receptors.5,6,14 Rather, general anesthetics probably act at multiple sites (anatomical and molecular) to produce the defining anesthetic end points. Therefore, switching from one anesthetic to two does not significantly impact the overall anesthetic effect mediated by the convergent actions of various affected receptors and anatomical sites. Despite the parallel observations of additive interactions between propofol and sevoflurane both in vivo and on a subtype of GABAA receptor in vitro, the reductionist view of a common molecular mechanism does not add up. Nevertheless, the important clinical implication is that propofol and sevoflurane can be combined without concern for overdosing or underdosing as a result of potential synergistic or antagonistic interactions.
Hugh C. Hemmings Jr., M.D., Ph.D., *
Joseph F. Antognini, M.D., †
*Department of Anesthesiology, Weill Medical College of Cornell University, New York, New York. hchemmi@med.cornell.edu. †Department of Anesthesiology and Pain Medicine, University of California, Davis, Davis, California.
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References

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