Meyer-Overton

General anesthetics are usually small solutes with relatively simple molecular structure. As overviewed before, Meyer and Overton have proposed that the potency of general anesthetics correlates with their solubility in organic solvents (the Meyer-Overton theory) almost a century ago. On the other hand, local anesthetics widely used are positively charged amphiphiles in solution and reversibly block the nerve conduction. We expect that the partition of both general and local anesthetics into lipid bilayer membranes plays a key role in controlling the anesthetic potency. Bilayer interfaces are crucial for the delivery of the anesthetics. 

Pohorille, A. Wilson, M.A. New, M.H. Chipot, C., Concentrations of anesthetics across the water-membrane interface the Meyer-Overton hypothesis revisited, Toxicology Lett. 1998,100, 421 130. 

It thus follows that the membrane concentration of typical P-gp substrates for halfmaximum activation of P-gp falls in the range of 1 to 10 mmole drug per mole lipid. This is a much narrower concentration range than that required for the same substances in the aqueous phase 10 8 to 10 3 M. A similar phenomenon has been observed in anesthesia. The membrane concentration of anesthetics required for anesthesia has been found to be 33 mM, independent of the anesthetic applied (Meyer-Overton rule). 

Meyer-Overton hypothesis, 17 376-377 Meyer-Schuster rearrangement,... 

The Meyer-Overton hypothesis is the theory of anaesthetic action which proposes that the potency of an anaesthetic agent is related to its lipid solubility. 

The Meyer-Overton hypothesis proposed that once a sufficient number of anaesthetic molecules were dissolved in the lipid membranes of cells within the central nervous system, anaesthesia would result by a mechanism of membrane disruption. While an interesting observation, there are several exceptions to the rule that make it insufficient to account fully for the mechanism of anaesthesia. 

Meyer-Overton graph of potency versus lipid solubility... 

E) Enantiomers of inhalational agents provide support for the Meyer Overton rule. 

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. 

BORONCOMPOUNDS - BORON OXIDES, BORIC ACID AND BORATES] (Vol 4) Meyer-Overton hypothesis... 

The first chemical clue relating the structure of anesthetics to their potency was discovered in 1899 by a pharmacologist, Hans Horst Meyer, and an anesthetist, Charles Ernst Overton. Working independently, Meyer and Overton noted a strong correlation between the polarity of a compound and its potency as an anesthetic. They expressed polarity as the oil/gas partition coefficient, while anesthetic potency was expressed as the partial pressure in atmospheres. Figure 11.10 is a Meyer-Overton correlation for 18 anesthetics used on mice. Note that olive oil is used, and it has become the most commonly used reference solvent. 

The slope of the regression line implies that the MAC (minimal alveolar concentration effective in 50 percent of animals) is inversely proportional to partition coefficient or potency is directly proportional to partition coefficient. The Meyer-Overton correlation suggests that the site at which anesthetics bind is primarily a hydrophobic environment. Although a wide variety of compounds lie on the Meyer-Overton correlation line, there are many compounds that do not. This suggests that the chemical properties of the anesthetic site differ from those of olive oil. 

Figure 11.10 Meyer-Overton correlation for volatile general anesthetics in mice. The slope of the regression line is -1.02 and the correlation coefficient, r2 = 0.997. CTF, carbon tetrafluoride NIT, nitrogen ARG, argon PFE, perfluoroethane SHF, sulfur hexafluoride KRY, krypton N02, nitrous oxide ETH, ethylene XEN, xenon DDM, dichlorodifluoromethane CYC, cyclopropane FLU, fluroxene DEE, diethylether ENF, enflurane ISO, isoflurane HAL, halothane CHL, chloroform MOF, methoxyflurane.

General anesthetics are soluble in lipids. Only a few are soluble in water. Furthermore, there is a well known correlation between anesthetic potency and lipid solubility. It is the Meyer-Overton rule that has been known for 80 years to researchers in anesthesia.. This relationship was thoroughly studied and reexamined in recent years (See ). In its most modem form the lipid solubility or oil/water partition coefTicient is plotted against the so-called righting reflex taken for a measure of anesthetic potency. It is log 1/p where p is the effective anesthetic pressure in atmospheres required to suppress the righting reflex of mice in half of the experimental animals On this relationship arc based the unitary hypothesis and the hydrophobic site theory which state that all general anesthetics act by the same mechanism at the same molecular or sub-cellular sites of the membrane and that the sites are hydrophobic. 

Bovill J G 2000 Mechanisms of anaesthesia time to say farewell to the Meyer-Overton rule. Current Opinion in Anaesthesiology 13 433-436 Carter A J 1999 Dwale an anaesthetic from old England. British Medical Journal 319 1623-1626 (use of medicinal herbs to render a patient unconscious for surgery, before modem general anaesthesia)... 

Ostwald solubility coefficient. The graph shows that an anaesthetic gas with a high oil solubility is effective at a low alveolar concentration and has a high potency. This relationship is the basis of the Meyer-Overton hypothesis of anaesthesia. 

The correlation between anaesthetic potency and lipid solubility shown in Fig. 2.10 is valid for most inhaled anaesthetics and the product MAC X oil/gas partition coefficient (which should of course be a constant) varies by only a factor of 2 or 3 for potencies ranging over 100 000-fold. This constancy implies that inhaled anaesthetics act in the same manner at a specific hydrophobic site (the so-called unitary theory of anaesthesia). This has been challenged by more recent work that has identified compounds, including alkanes and poly-halogenated and perfluorinated compounds, which do not obey the Meyer- Overton hypothesis. It has been suggested that a contributory cause of deviation from this hypothesis may be the choice of lipid to represent the anaesthetic site of action of these compounds, implying that there may be multiple sites of action for inhaled anaesthetics. 

J. Liu, M. J. Laster, S. Taheri, E. 1. et al. Effect of n-alkane kinetics in rats on potency estimations and the Meyer-Overton hypothesis. Anesth. Analg., 79, 1049-55 (1994)... 

The quantitative property-activity models, commonly referred to as those marking the beginning of systematic QSAR/QSPR studies [Richet, 1893], have come out from the search for relationships between the potency of local anesthetics and the oil/water partition coefficient [Meyer, 1899], between narcosis and chain length [Overton, 1901, 1991], and between narcosis and surface tension [Traube, 1904]. In particular, the concepts developed by Meyer and Overton are often referred to as the Meyer-Overton theory of narcotic action [Meyer, 1899 Overton, 1901]. 

The search for physical chemical correlates of drug action began as early as 1899 with the Meyer-Overton theory which stated that the potency of an anesthetic was directly proportional to its oil. water partition coefficient. The more lipid soluble the compound was, the more readily it was thought to penetrate the central nervous system. 

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