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Thursday, March 31, 2011
How do anesthetics work?
Each one of us comes to work and uses one or more drugs whose mechanism of action we have yet to completely understand. I remember learning how the volatile anesthetics worked in medical school; unfortunately, it turns out that my “knowledge” was incorrect. Propofol was introduced during my residency and its mechanism of action is simple: It binds to GABA receptors, thus activating inhibitory neurons. Exactly how that produced anesthesia was never clarified. An article in the April issue of Anesthesiology by UnCheol Lee et al. finally begins to explain what, exactly, propofol does to the brain.

Lee takes a novel approach to understanding propofol’s mechanism of action: He and his colleagues anesthetized 20 healthy male subjects with a single dose of propofol. They did this while continuously recording a 21-channel electroencephalogram (EEG). They then did a sophisticated analysis on the signals that they recorded, and it is this analysis that sets their study apart from others. Instead of simply looking at frequency, amplitude, and phase, they treated the brain as a series of networks that exchange information. Much like the “hub and spoke” system of modern airline transportation, the brain has specific areas that receive information, process it, and then send it on to other areas. Lee looked for these networks in the parietal and frontal regions of the brain and then examined propofol-induced changes in their communication, correlating these changes with the expected concentration of propofol in the brain.

The study found that propofol affects both the structure of the brain’s networks and the communication between them. Interestingly, propofol seemed to change the network topology of each subject’s brain in the same way, but the strength of the connections between networks fell into two distinct groups. In one group, the strength of the connections between networks increased just before the subjects returned to consciousness; in the other, connection strength gradually returned to baseline. Lee also discovered that a significant amount of processing seemed to occur in the parietal lobe and suggests that the parietal lobe may play a significant role in the propofol’s mechanism of action. This is important because nearly all of the so-called “depth of consciousness” monitors on the market monitor electrical activity in the frontal lobe.

So, how do anesthetics work? In a recent review article in the New England Journal of Medicine and also in an interview in the New York Times, Emery Neal Brown, M.D., a professor of anesthesiology at Harvard Medical School, explains his thoughts on what anesthetics do to our brains. His work with functional MRI also suggests that anesthetic agents alter the ways in which the brain transmits information. With the advent of sophisticated EEG monitoring, computational modeling, and functional MRI, we may be getting closer to an answer. Lee correctly called his work a “hypothesis-generating” study. By asking one question, he opened the door to a series of new ones. In the meantime, we may now be closer to fully understanding propofol’s mechanism of action.

Reference
1. Brown EN, Lydic R, Schiff ND: General anesthesia, sleep, and coma. N Engl J Med 2010; 363: 2638-50

Your comments are welcome.

Posted by Keith J Ruskin, M.D.
Keith J Ruskin, MD
About the Author

J. Lance Lichtor, M.D
J. Lance Lichtor, M.D. is a professor of anesthesiology and pediatrics at The University of Massachusetts Medical School. He is the web editor and an associate editor for Anesthesiology.

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