Ans- A Meyer-Overton rule Ref- Inhaled anaesthetic agents act in different ways at the level of the central nervous system. They may disrupt normal synaptic transmission by interfering with the release of neurotransmitters from pre-synaptic nerve terminal (enhance or depress excitatory or inhibitory transmission), by altering the re-uptake of neurotransmitters, by changing the binding of neurotransmitters to the post-synaptic receptor sites or by influencing the ionic conductance change that follows activation of the post-synaptic receptor by neurotransmitters. Both pre- and post-synaptic effects have been found. Direct interaction with the neuronal plasma membrane is very likely, but indirect action via production of a second messenger also remains possible. The high correlation between lipid solubility and anaesthetic potency suggests that inhalational anaesthetic agents have a hydrophobic site of action. Inhalational agents may bind to both membrane lipids and proteins. It is not clear which of the different theories are most likely to be the main mechanism of action of inhalational anaesthetic agents. The Meyer-Overton theory describes the correlation between lipid solubility of inhaled anaesthetics and MAC and suggests that anaesthesia occurs when a sufficient number of inhalational anaesthetic molecules dissolve in the lipid cell membrane. The Meyer-Overton theory postulates that it is the number of molecules dissolved in the lipid cell membrane, and not the type of inhalational agent, that causes anaesthesia. Combinations of different inhaled anesthetics may have additive effects at the level of the cell membrane. Exceptions to the Meyer-Overton rule Enflurane and isoflurane are structural isomers and have similar oil:gas partition coefficients. However, the MAC for isoflurane is only approximately 70% of that for enflurane; thus, it would appear that there are other factors which influence potency. These include: Convulsant properties Complete halogenation, or complete end-methyl halogenation of alkanes and ethers results in decreased anaesthetic potency and the appearance of convulsant activity. Specific receptors For a given MAC reduction, plasma levels of morphine, alfentanyl, sufentanyl and fentanyl vary around 5000 fold. Levels of these four agents in brain lipid vary 10 fold; thus, studies of the reduction in MAC by opioids suggests two sites of action: the opioid receptor and some hydrophobic site. D-medetomidine This alpha-2-agonist results in a marked reduction in MAC, whereas its optical isomer, with identical lipid solubility, has no effect. Hydrophilic site of action L. Pauling & S. Miller (1961) independently proposed that anaesthesia may result from the formation of clatharates of water in membranes. In this model, anaesthetic molecules act as seeds for crystals of water, which subsequently alter membrane ion transport. This is less likely than the unitary theory, as there is a poor correlation between the ability of agents to form clatharates and their anaesthetic potency. Traube (1904) and Clements & Wilson (1962) proposed that potency correlated with a reduction in surface tension. However, these latter physical properties are closely related to those properties which determine hydrophobicity. Hence, the Meyer-Overton theory does not describe why anaesthesia occurs. Mullins expanded the Meyer-Overton rule by adding the 'Critical Volume Hypothesis'. He stated that the absorption of anaesthetic molecules could expand the volume of a hydrophobic region within the cell membrane and subsequently distort channels necessary for sodium ion flux and the development of action potentials necessary for synaptic transmission. The fact that anaesthesia occurs with a significant increase in the volume of hydrophobic solvents and is reversible by compressing the volume of the expanded hydrophobic region of the cell membrane supports Mullins' 'Critical Volume Hypothesis'. The protein receptor hypothesis postulates that protein receptors in the central nervous system are responsible for the mechanism of action of inhaled anaesthetics. This theory is supported by the steep dose-response curve for inhaled anaesthetics. However, it remains unclear if inhaled agents disrupt ion flow through membrane channels by an indirect action on the lipid membrane, via a second messenger or by direct and specific binding to channel proteins. Another theory describes the activation of gamma-aminobutyric acid (GABA) receptors by the inhalational anaesthetics. Volatile agents may activate GABA channels and hyperpolarise cell membranes. In addition, they may inhibit certain calcium channels and therefore prevent the release of neurotransmitters and inhibit glutamate channels. Volatile anaesthetics therefore may share common cellular actions with other sedative, hypnotic and analgesic drugs.