Meyer-Overton theory

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. 

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. 

There have been many attempts to produce a unified theory detailing the mechanism of action of inhalation anaesthetics but no single theory has been accepted. Early theories on the mechanism of action of inhalation anaesthetics can by summarised by means of the Meyer-Overton theory, which indicated that the potency of anaesthetic action was related to the lipophilicity of an anaesthetic compound. The Meyer-Overton theory suggested that lipids within the brain could be dissolved by anaesthetic agents, thereby interfering with brain cell activity, leading to anaesthesia. 

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. 

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 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. 

General anaesthetics have been in use for more than a centuiy, but unfortunately so far no exact mechanism of action has been put forward. Of coiuse, a few theories, namely lipid, physical, biochemical, miscellaneous, Meyer-Overton, minimum alveolar concentration (MAC), stereochemical effects and ion-channel and protein receptor theories have been advocated from time to time in support of the mode of action of the general anaesthetics. These will be discussed briefly in this context. 

Professor Meyer was born at Dorpat, Estonia, on September 29, 1883, the elder son of Hans Horst Meyer—who held the chair of experimental pharmacology at the University of Vienna and formulated the modern theory of narcosis known as the Overton-Meyer theory. Two years later, his father became professor at Marburg/Lahn, and it was in this city that Kurt H. Meyer had his early education. The scholarly atmosphere in which he matured, where chemistry and medicine were always very much in the foreground, was to influence him throughout his lifetime. From his father, he inherited his desire for scientific study and research, and from his mother, his taste for the fine arts. His younger brother became a famous heart-surgeon. 

The coefficient of partition of organic substances between water and lipins (these are fat-like constituents of the cell wall) is of great importance in biological processes (H. H. Meyer and Overton s theory of narcosis). 

It was at the turn of the twentieth century that the importance of lipid solubility in drug action was also independently described by Meyer and Overton (the significance of the oil/water partition coefficient was discussed in Chapter 2). The importance of lipid solubility in drug action subsequently became manifested in the lipoid theory of cellular depression. In essence, this theory correlated a pharmacological effect (e.g., CNS depression) with a physical property (i.e., lipid solubility) rather than a structure-activity relationship. In the process, the theory was attempting to explain the diverse chemical structures that exist within the hypnotic and general anesthetic classes of drugs (see Chapter 11). Today, we realize the limitations of the lipoid theory and appreciate that the distinction between physical and chemical factors is illusory, since chemical structure is a determinant of physical properties. 

Meyer and Overton further expanded their theory and suggested that the correlation may be established and observed between lipid solubility and the central nervous system (CNS) depressant aetivity profde. The CNS-depressant activity is foimd to be directly proportional to the partition coefficient of the drug substance . 

Attention was first drawn to the overriding importance of a physical property when, at the turn of the present century, Ernest Overton and Hans Meyer independently put forward a Lipoid Theory of Cellular Depression (Meyer, 1899 Overton, 1901). This stated that chemically inert substances, of widely different molecular structures, exert depressant properties on those cells (particularly those of the central nervous system) that are rich in lipids and that the higher the partition coefficient (between any lipid solvent and water) the greater the depressant action. This statement requires only insertion of the words, up to the point where hydrophilic properties are almost extinguished after partition coefficient to outline the present day viewpoint. Overton and... 

The manner of action of narcotics has been discussed extensively, and some of these discussions are relevant to permeability. The adsorption theory of Traube (86) has not proved to be successful in many cases. It seems questionable for ethylene, for reasons just discussed, and probably for the action of ethylene on permeability. The lipoid theory" of narcotics has been advanced by Overton (69) and Meyer (52), and seems stronger. It depends on the correlation between narcotic effect and the distribution coefficients between lipides and water. Those narcotics with higher solubilities in lipides have been widely found to have higher narcotic effects. 

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