The Meyer-Overton hypothesis

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. 

Potency is described by the minimum alveolar concentration (MAC) of an agent and lipid solubility by the oil gas solubility coefficient. 

The minimum alveolar concentration of an anaesthetic vapour at equilibrium is the concentration required to prevent movement to a standardized surgical stimulus in 50% of unpremedicated subjects studied at sea level 

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 

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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. 

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)... 

In 1933, the Meyer-Overton hypothesis was examined relative to the hypnotic barbiturates by determining the distribution coefficients and other physical properties for a series of such derivatives (see Table 3.2, previous section) [146]. A parallelism between oil solubility and hypnotic... 

According to the Meyer-Overton hypothesis [14,15], the anesthetic potency of anesthetic compounds is proportional to their solubilities in a non-polar phase, similar to the interior of the neuronal membrane. The remarkable aceuracy of this relationship for all elinical and many other anesthetics led to its broader interpretation that anes-theties act inside the neuronal membrane [36]. Then, the Meyer-Overton hypothesis implies that the same concentration is required for all anesthetics to exert anesthetic action, irrespective of their molecular structure. Their action may be either nonspecific or directed at selected membrane receptors. 

C. North andD.S. Cafiso. Contrasting membrane localization and behavior of halogenated cyclobutanes that follow or violate the meyer-overton hypothesis of general anesthetic potency. Biophys. J., 72 (1997) 1754-1761. 

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. 

The second objective is to apply our knowledge of interfacial systems to a concrete problem of considerable medical interest - the determination of a relationship between the interfacial behavior of anesthetics and their anesthetic activity. This represents an alternative view to the century-old Meyer-Overton hypothesis [14,15], which relates anesthetic activity of anesthetics to their solubility in the bulk oily phase. 

The first coherent hypothesis, developed independently by Ernest Overton (1901) and Hans Meyer (1899), had these three principles ... 

As mentioned in Section 2.0, the first coherent hypothesis was developed independently by E. Overton and H. Meyer (Meyer, 1899, Overton, 1901), and stated as three principles ... 

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