Anesthetic action mechanism

It has been generally accepted that anesthetics interact with membrane lipids as a primary step of anesthesia. The detailed mechanism of the anesthetic action is, however, still controversial. This is mainly due to the absence of specific information on delivery sites in membranes. The NMR data for the delivery site of drugs in membranes are of great use. 

Although the contribution is rather small, the partial discharging of the anesthetics in membranes can be important in the mechanism of the anesthetic action. The most plausible mechanism can be summarized as only a small portion of the cationic species are neutralized (deprotonated) at the bilayer surface and the neutral species are deeply penetrated and widely distributed in the hydrophobic bilayer interior, while the cationic species still remain at the hydrophilic bilayer surface where the hydration is significant. 

The local anesthetic actions of cocaine are independent of its well-known actions on monoamines. Rather, the local anesthetic effects occur as a consequence of its interaction with voltage-gated Na-i-channels (Matthews and Collins 1983). Cocaine s cerebral vasoconstrictor effects occur through local anesthetic rather than sympathomimetic mechanisms (Albuquerque and Kurth 1993). 

The wide variation in structure, ranging from complex steroids to the inert monatomic gas xenon, led to several theories of anesthetic action. The mechanism by which inhalation anesthetics manifest their effect is not exactly known. Since they do not belong to one chemical class of compounds, the correlations between structure and activity are also not known. Inhalation anesthetics are nonspecific and therefore there are not specific antagonists. Interaction of inhalation anesthetics with cellular structures can only be described as van der Waals interactions. There are a number of hypotheses that have been advanced to explain the action of inhalation anesthetics however, none of them can adequately describe the entire spectrum of effects caused by inhalation anesthetics. 

A mechanism of local anesthetic action in which they serve as sodium channel blockers has been proposed. According to this mechanism, the molecular targets of local anesthetic action are the voltage-requiring sodium channels, which are present in all the neurons. The process of local anesthesia by respective drugs can be schematically represented in the following manner. 

An analogons mechanism of stretching (changing the fluidity) of the membrane was also suggested as an explanation for the action mechanism of general anesthetics. 

Chlorofluorocarbon (CFC) replacements have recently been used for their lower stability and because they have carbon-hydrogen bonds, which means that their atmospheric lifetime is expected to be much shorter than those of CFCs. The adsorption properties of l,l,2-trichloro-l,2,2-trifluoroethane (CFC 113) and its replacement compounds, l,l-dichloro-2,2,2-trifluoroethane (HCFC123), 1,1-dichloro-l-fluoroethane (HCFC141b), and l,l-dichloro-l,2,2,3,3-pentafluoropropane (HCFC225ca) on four kinds of activated carbons were investigated. The adsorption isotherms of inhalational anesthetics (halothane, chloroform, enflurane, isoflurane, and methoxyflurane) on the activated carbon were measured to evaluate the action mechanism of inhalational anesthesia. The anesthesia of CFC replacements can be estimated by the Freundlich constant N of the adsorption isotherms (Tanada et al., 1997). 

Hemmings HC et al Emerging molecular mechanisms of general anesthetic action. Trends Pharmacol Sci 2005 26 503. [PMID 16126282]... 

FIGURE 13—3. Icon of cocaine. The main mechanism of action is to block reuptake and cause the release of monoamines, principally dopamine (DA), but also norepinephrine (NE) and serotonin (5HT). There is also a local anesthetic action (caine). 

Despite the continuing debate, there is much that is known about anesthetic action. It is clear that local anesthetics significantly change ion currents across neural membranes, that the ion channels through which they pass are composed of protein, and that these proteins are embedded in lipid [53]. However, there is little knowledge of the mechanism by which lipid soluble anesthetics of such widely different structures affect the ion... 

J. L. Coubeils and B. Pullman, "Quantum-Mechanical Study of the Conformational Properties of Drugs with Local Anesthetic Action," Mol. Pharm. 8, 278 (1972). 

Mechanism(s) of action Blocks DA, NE and 5HT Blockade of reuptake of NE and reuptake in CNS local DA, release amines from anesthetic action from mobile pool, weak MAO Na+ channel blockade inhibitors... 

Colloc h, N., Sopkova-de Oliveira Santos, J., et al. (2007). Protein crystallography under xenon and nitrous oxide pressure Comparison with in vivo pharmacology studies and implications for the mechanism of inhaled anesthetic action. Biophysical Journal, 92(1), 217-224. 

Harrison NL, Flood P. Molecular mechanisms of general anesthetic action. Sci Med 1998 (May June) 50 18-27. 

Many herbal remedies that may be antitussive could act indirectly on cough for example, by expectorant, demulcent, bronchodUator, or local anesthetic actions. Ziment (2002) lists 15 such indirect ways in which herbal antitussives may work (see also later) and lists over 120 herbs which are claimed, nearly always with little or no evidence, to act via these indirect mechanisms. With the exception of bronchodilation, there are no effective means of assessing these indirect actions, and the relationship between bronchodilation and cough is little understood. 

Tinker, J.H. Voices from the past—from ice crystals to fruit flies in the quest for a molecular mechanism of anesthetic action. Anesth. Analg. 1993, 77,1-3. 

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