Anesthetics, membrane interactions

Non-polm- and weakly polarizable molecules would be expected to interact mainly with the hydrophobic parts of the membrane lipids or proteins. Non-polar or weakly polar but highly polarizable anesthetics could interact with both hydrophobic and ionic or polar sites. 

Local anesthetics interact with peripheral nerve cell membranes and exert a pharmacological effect [34]. Potential oscillation was measured in the presence of 20 mM hydrochlorides of procaine, lidocaine, tetracaine, and dibucaine (structures shown in Fig. 16) [19]. Amplitude and the oscillatory and induction periods changed, the extent depending on the... 

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. 

Shimooka, T., Shibata, A. and Terada, H. (1992). The local anesthetic tetracaine destabilizes membrane structure by interaction with polar headgroups of phospholipids, Biochim. Biophys. Acta, 1104, 261-268. 

The mechanism of action of inhalational anesthetics is unknown. The diversity of chemical structures (inert gas xenon hydrocarbons halogenated hydrocarbons) possessing anesthetic activity appears to rule out involvement of specific receptors. According to one hypothesis, uptake into the hydrophobic interior of the plasmalemma of neurons results in inhibition of electrical excitability and impulse propagation in the brain. This concept would explain the correlation between anesthetic potency and lipophilicity of anesthetic drugs (A). However, an interaction with lipophilic domains of membrane proteins is also conceivable. Anesthetic potency can be expressed in terms of the minimal alveolar concentration (MAC) at which 50% of patients remain immobile following a defined painful stimulus (skin incision). Whereas the poorly lipophilic N2O must be inhaled in high concentrations (>70% of inspired air has to be replaced), much smaller concentrations (<5%) are required in the case of the more lipophilic halothane. 

Ion channel hypothesis Anesthetics block ion channels by interacting with cellular membranes and reducing the flow of Na+ ions and increasing the flow of K+ ions into the cell, which leads to the development of anesthesia. 

It is interesting that a nnmber of antihistamine, anticholinergic, and adrenergenic drngs having analogous chemical structures, also exhibit local anesthetic properties. It is possible that by interacting with internal axoplasmic membranes, they rednce the ion flow in particnlar, the flow of sodinm ions inside nerve cells. 

The inhalation anesthetics belong to diverse chemical classes. There main indication is the maintenance of anesthesia after intravenous induction. There are no suggestions that they interact with pharmacologically-defined receptors like some of the injectable anesthetics do and they have no specific site of action. Apparently they cause physical changes in cells such as changes in cell membrane fluidity. 

Among the earliest proposals to explain the mechanism of action of anesthetics is the concept that they interact physically rather than chemically with lipophilic membrane 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 interactions with neuronal processes and that those interactions are not easily explained by a common physical association with membrane components. Proposals for the production of anesthesia are described next. 

Membrane conformational changes are observed on exposure to anesthetics, further supporting the importance of physical interactions that lead to perturbation of membrane macromolecules. For example, exposure of membranes to clinically relevant concentrations of anesthetics causes membranes to expand beyond a critical volume (critical volume hypothesis) associated with normal 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 liquid form, a process that is assumed necessary for normal neuronal function (lateral phase separation hypothesis). 

No difference has been observed in the interactions of the two enantiomers of isoflurane with hpid bilayers. But the (5)-enantiomer of isoflurane is two times more active than the (7 )-enantiomer toward a calcium channel receptor, that is sensitive to volatile anesthetic agents, while nodifference in activity has been observed toward an anesthetic nonsensitive receptor. The (5)-enantiomer of isoflurane is also more active than the (R)-enantiomer toward acetylcholine nicotinic receptor and GABA receptor. These data strongly suggest that fluoroethers interact not only with cerebral membranous lipids but also with receptor proteins. 

Both the inhaled and the intravenous anesthetics can depress spontaneous and evoked activity of neurons in many regions of the brain. Older concepts of the mechanism of anesthesia evoked nonspecific interactions of these agents with the lipid matrix of the nerve membrane (the so-called Meyer-Overton principle)—interactions that were thought to lead to secondary changes in ion flux. More recently, evidence has accumulated suggesting that the modification of ion currents by anesthetics results from more direct interactions with specific nerve membrane components. The ionic mechanisms involved for different anesthetics may vary, but at clinically relevant concentrations they appear to involve interactions with members of the ligand-gated ion channel family. 

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