Mechanism of Action of Inhaled Anesthetics
Inhaled anesthetics 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 presynaptic 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 postsynaptic 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 anesthetic potency suggests that inhalation anesthetics have a hydrophobic site of action. Inhalation agents may bind to both membrane lipids and proteins. It is at this time not clear which of the different theories are most likely to be the main mechanism of action of inhalation anesthetics.
The Meyer-Overton theory describes the correlation between lipid solubility of inhaled anesthetics and MAC and suggests that anesthesia occurs when a sufficient number of inhalation anesthetic molecules dissolve in the lipid cell membrane. The Meyer-Overton rule postulates that the number of molecules dissolved in the lipid cell membrane and not the type of inhalation agent causes anesthesia. Combinations of different inhaled anesthetics may have additive effects at the level of the cell membrane.
However, the Meyer-Overton theory does not describe why anesthesia occurs. Mullins expanded the Meyer-Overton rule by adding the so-called Critical Volume Hypothesis. He stated that the absorption of anesthetic 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 anesthesia occurs with significant increase in 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 anesthetics. This theory is supported by the steep dose response curve for inhaled anesthetics. 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 inhalation anesthetics. Volatile agents may activate GABA channels and hyperpolarize cell membranes. In addition, they may inhibit certain calcium channels and therefore prevent release of neurotransmitters and inhibit glutamate channels. Volatile anesthetics share therefore common cellular actions with other sedative, hypnotic or analgesic drugs.
Each of the mentioned theories describes a unitary theory of narcosis. They all concentrate more or less on an unique site of action for inhaled anesthetics. The true mechanism of action of volatile anesthetics may be a combination of two or more such theories described as multisite action hypothesis.