4. MOA of General Anaesthetics

selective effects on CNS proteins appear to offer the most complete explanation, much remains unexplained. cause reversible insensibility range from xenon, which is chemically unreactive and whose monoatomic structure could not be simpler, to barbiturates and phenols, whose structures are both more complex and completely dissimilar Unitary Hypothesis acknowledges this but simply asserts that whereas the molecular structures may be very diverse, all general anaesthetic agents must exert their effects via a similar, although as yet a not fully understood, mechanism.

Meyer and Overton (separately) were the first to relate the potency of anaesthetic agents to their lipid solubility. They argued further that the onset of narcosis was evident as soon as the particular substance had attained a certain molar concentration in the lipids of the cell, and that the lipid layers of the cell membrane represented the main site of action. Much early research was based on the hypothesis that disruption of the lipid bilayer affected the function of membrane proteins and mediated an interruption of neuronal traffic. As a unifying theory, however, it was undermined by the observations that temperature rises disrupt lipid membranes without inducing a state of general anaesthesia, and that there are many compounds with high-lipid solubility which exert no anaesthetic effect. Nonetheless, there remains a clear relationship between anaesthetic potency and lipid solubility which any theory of action must accommodate. Clathrate theory + Pressure reversal Dont appear to explain it

Voltage-gated ion channels: general anaesthetic agents appear to exert minimal effect at voltage-gated ion channels. Transmitter-gated ion channels (TGIC): ligand-gated membrane ion channels have been the focus of most recent investigations. They include the gamma-aminobutyric acid (GABAA) receptor, as well as 5-HT3, acetylcholine, glutamate and glycine receptors.

• GABAa • Pore domain K channels • Glycine receptors: • 5-HT3 and neuronal nicotinic acetylcholine receptors

GABAa is the major inhibitory neurotransmitter receptor system (accounting for around 30% of all inhibitory synapses), which makes it a prime candidate for a major site of action of general anaesthetics. volatile and intravenous induction agents, enhance the ability of GABA to open the GABAA receptor ion channel exceptions of xenon and ketamine pentameric arrangement of different subunits around the central ion channel pore. There are 18 subunits (α1–6, β1–3, γ1–3, δ, ε, π, ρ1–3) and a total of around 30 receptor isoforms. Complex research techniques have shown that single amino acid substitutions within the receptor subunit have a marked influence on anaesthetic effect, which confirms the highly specific interaction of drug and receptor

: these channels are found both pre- and postsynaptically throughout the nervous system. They are voltage-independent and appear to become hyperpolarized by some anaesthetic agents, particularly the volatile halogenated hydrocarbons

Glycine receptors: the glycine receptor is the spinal cord and brain stem analogue of the GABAA receptor of the brain. This too contains an integral chloride channel and is affected by general anaesthetic agents

general anaesthesia affects cationic currents through these receptors, but further than this the function of these central receptors is not fully understood.

Glutamate receptors: these consist of the N-methyl-D-aspartate (NMDA) and non- NMDA receptor classes, which comprise the primary excitatory neurotransmitter system in the brain. Inhibition of their function is therefore consistent with a theory of general anaesthesia. Ketamine, xenon and nitrous oxide all inhibit the NMDA receptor

Animal studies substantial increases in neuroapoptosis (programmed cell death) in animals exposed to NMDA-type glutamate receptor antagonists and GABAA agonists, along with evidence of persistent neurocognitive defects - dose-dependent and additive with the use of multiple agents. There are, however, minimal human data. There are a number of retrospective cohort studies in children which have suggested an association between anaesthesia before the age of 4 and developmental or behavioural abnormalities, but overall the findings do not demonstrate a consistent effect, and clearly there are several confounding variables, including the dose and duration and nature of the agent(s) used and in what combination, the nature of the surgical insult and patient co-morbidities. Evidence of acceleration of degeneration in aging but at both extremes of age it might assist the arguments of those who favour regional or neuraxial techniques.

Those who searched originally for a unifying theory of general anaesthetic action could not have envisaged the research techniques that have begun to identify the highly complex structures of CNS receptors. Although many details remain to be elucidated, it now seems clear that the spectrum of altered physiological states characterized by anaesthesia is mediated by highly specific interactions of anaesthetic compounds with receptor proteins.