MECHANISM OF ANESTHETIC ACTION
Among the earliest proposals to explain the mechanism of action of anesthetics is the concept that they interact physically rather than chemically with lipophilic mem-brane components to cause neuronal failure. However, this concept proposes that all anesthetics interact in a common way (the unitary theory of anesthesia), and it is being challenged by more recent work demonstrating that specific anesthetics exhibit selective and distinct in-teractions with neuronal processes and that those inter-actions are not easily explained by a common physical association with membrane components. Proposals for the production of anesthesia are described next.
The idea that a physical interaction is important stems from experimental observations made in the late nine-teenth and early twentieth centuries, when it was recog-nized that noble gases such as xenon, which do not chemically interact with tissues, produce unconsciousness. Also, anesthesia produced at ambient atmospheric pres-sure can be attenuated by physically raising the pressure to 100 atm, a phenomenon known as pressure reversal. Finally, a clear correlation exists between anesthetic po-tency and the physical parameter lipid solubility, suggest-ing that anesthesia may be produced when anesthetics physically dissolve into the cell membrane’s lipid bio-phase (Meyer Overton rule). Such a correlation is shown in Fig. 25.6, where anesthetic potency is expressed as MAC and lipid solubility is estimated as the oil–gas partition.
Membrane conformational changes are observed on exposure to anesthetics, further supporting the impor-tance of physical interactions that lead to perturbation of membrane macromolecules. For example, exposure of membranes to clinically relevant concentrations of anes-thetics causes membranes to expand beyond a critical volume (critical volume hypothesis) associated with nor-mal cellular function. Additionally, membrane structure becomes disorganized, so that the insertion of anesthetic molecules into the lipid membrane causes an increase in the mobility of the fatty acid chains in the phospholipid bilayer (membrane fluidization theory) or prevent the interconversion of membrane lipids from a gel to a liq-uid form, a process that is assumed necessary for normal neuronal function (lateral phase separation hypothesis).
While current observations do not rule out that anes-thetics may require a hydrophobic environment near the site of their action, they do suggest that various agents may also have distinct interactions with tissues. For example, enantiomers of newer agents have selec- tive and unique actions, even though they have identical physical properties; for example, stereoisomers of isoflurane are differentially potent but have identical oil–gas partition coefficients.
Contemporary research has shown that at clinically relevant concentrations, various anesthetics interact specifically with different components of the GABAA-receptor–chloride ionophore and enhance chloride con-ductance, some directly and others by enhancing the ac-tion of GABA. Inhalational agents directly activate the chloride channel as well as facilitate the action of GABA, while barbiturates, propofol, benzodiazepines, and etomidate primarily enhance the action of GABA by interacting with specific receptor sites (Fig. 25.7). Also, anesthetics enhance other processes known to inhibit neuronal function, such as the glycine recep-tor–gated chloride channel. A smaller number of anes-thetics, including ketamine, N2O, and xenon, produce neuronal inhibition by antagonizing excitatory neu-ronal transmission mediated via the N-methyl-D-aspar-tic acid (NMDA) receptor. In addition, some inhala-tional drugs activate K+ channels and so contribute to hyperpolarization and reduced neuronal excitability; they also inhibit the function of the protein complex in-volved in neurotransmitter release.
Clearly much must be explained of the complex changes in the CNS that eventually produce uncon-sciousness. Although physical interactions of anesthet-ics with hydrophobic membrane components may lead to conformational changes that alter neuronal function, specific interactions at critical receptors and ion chan-nels are also likely to contribute to anesthesia. Thus, structurally and pharmacologically diverse anesthetic drugs produce unconsciousness through qualitatively different mechanisms and through actions occurring at anatomically distinct sites in the nervous system.