4. MOA of General Anaesthetics

Question 1

Theories about Mechanisms Underlying General Anaesthesia

Answer 1

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.

Question 2

Meyer–Overton hypothesis:

Answer 2

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

Question 3

How do they work so

Answer 3

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.

Question 4

Channels implicated

Answer 4

1. GABAa
2. Pore domain K channels
3. Glycine receptors:
4. 5-HT3 and neuronal nicotinic acetylcholine receptors

Question 5

GABAa

Answer 5

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

Question 6

Two-pore domain K+ channels

Answer 6

: 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

Question 7

Glycine receptors:

Answer 7

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

Question 8

5-HT3 and neuronal nicotinic acetylcholine receptors

Answer 8

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

Question 9

Glutamate receptors:

Answer 9

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

Question 10

Neurotoxicity:

Answer 10

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.

Question 11

Conclusion

Answer 11

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.