Chapter 37

1. The mechanisms by which the inhaled general anesthetics work are not fully understood. No single molecular target has been proven to transduce anesthesia.

2. Correlation of the physicochemical character of anesthetics with their potency suggests that target sites are dominantly hydrophobic, with a small degree of polarity and chirality. Internal or interfacial protein cavities best fit this description.

3. Inhaled anesthetic binding site character is not highly specific, predicting more than a few anesthetic binding targets. The interaction at some of these targets may not contribute significantly to anesthetic action but may contribute to side effects.

4. Use of the lipid membrane as a direct target for inhaled anesthetics has been dismissed prematurely. Some components of anesthetic action may occur via this interaction.

5. Many potential protein targets in the synapse have been identified, suggesting that inhaled anesthetic action results from disruption of the specific process of synaptic transmission rather than from a receptor-like interaction with a single molecular target.

6. Anesthetic effects on a process, such as synaptic transmission, may have a different system-level effect depending on placement in the neural circuitry. The circuits that regulate sleep and arousal are well positioned to mediate the hypnotic properties of anesthetics.

General anesthetics were formally introduced into medical practice more than 160 years ago and have been hailed as one of the most significant medical advances of all time. Yet there is still considerable mystery about how the drugs work and how to characterize the state that they produce. This should not be too surprising because a description of the transition from consciousness to unconsciousness necessarily requires an understanding of the former, and the neurobiology of consciousness is still in its infancy. Nevertheless, considerable progress has been made toward the characterization of anesthesia and the potential mechanisms of the drugs that produce it. In this chapter, we summarize the current body of evidence for the mechanism(s) of general anesthesia, with emphasis on the inhaled anesthetics because they are used most commonly. Excellent and comprehensive reviews summarize current knowledge of the molecular, cellular, and in vivo pharmacology,1,2 so we have selected only a few of the putative molecular targets to illustrate the principles and to support the notion that alteration of a neurophysiologic process, rather than the activity of an individual protein, is responsible for the state of general anesthesia.

Mechanistic searches are greatly aided by clear physiologic or behavioral endpoints. Those associated with anesthesia, however, often are ambiguous and arbitrary. Most people associate anesthesia with unconsciousness or "sleep," but the transition to this state often is not apparent to the observer, so the lack of physical movement in response to a noxious stimulus is the most common endpoint associated with the term anesthesia. This is essentially the same endpoint used in Boston more than 160 years ago. But it is immediately apparent that many pathways can lead to such an endpoint, most notably paralysis, which itself is at the end of many pathways. Nevertheless, the ...

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