Mechanisms of Anesthetic Action

Fig. 9.1
Basic mechanisms of anesthetic action, a working hypothesis
The action of general anesthetics on the brain is responsible for loss of consciousness and
amnesia. More specifically, the inhibition of the reticular activating system (RAS), thalamus, and
cortex leads to the reversible loss of consciousness. The action on the hippocampus, amygdala,
prefrontal cortex, and regions of the sensory and motor cortices is responsible for amnesia.
Analgesia is achieved by blunting nociceptive impulses at the level of the spinal cord.
Minimal alveolar concentration (MAC) represents the end tidal concentration expressed in
standard pressure unit of an inhalational anesthetic necessary to blunt a purposeful movement to
surgical stimulation in 50 % of the subjects (measure of immobility). MAC is used to compare
potency of inhalational anesthetics. When anesthetics are selectively administered to the brain
versus spinal cord versus the whole body in laboratory animals, different MAC values are
elicited. The highest MAC value is obtained when inhalational anesthetics are administered to
the brain only and the lowest when they are administered to the spinal cord in isolation. This
observation has led to the conclusion that the action of inhalational anesthetics on the brain may
sensitize the spinal cord to noxious stimuli and also that there are different molecular targets for
immobility and amnesia.

Molecular Mechanisms of Anesthetic Action

Lipid-Based Theory and Meyer and Overton Correlation

Regarding the molecular mechanism of action of general anesthetics, previous theories purported
a common path of action for all anesthetics due to their diverse chemical structure. Meyer and
Overton independently observed that anesthetic potency is directly proportional with their
solubility in olive oil expressed as olive oil/gas partition coefficient. Based on this observation it
was thought that the anesthetic agents act on a hydrophobic lipid target; the greater the lipid
solubility, the greater the anesthetic potency.
However, one exception to this rule is the “cutoff effect,” which emphasizes that the potency of
an anesthetic from a homologous series increases with the chain length until it reaches a critical
point. Beyond this critical point there is no anesthetic activity. Another exception refers to highly
lipid-soluble molecules which are not anesthetics or produce other physiological effects such as
convulsions (flurothyl, a halogenated ether family drug with opposite effects). Molecules with
low lipid solubility but potent anesthetics (chloral hydrate) and molecules with equal solubility
but unequal anesthetic potency (anesthetic enantiomers) are other exceptions.
Furthermore, experiments with firefly luciferase, a pure soluble protein, showed that anesthetics
could inhibit this enzyme activity at concentrations identical to those required to anesthetize
animals. All the anesthetics tested, including ethers, alkanes, alcohols, and ketones exerted their
action by competitive blockade of a common site, preventing the photon emission secondary to
interaction between the firefly luciferase and its substrate, luciferin.

Protein-Based Theory
Modern theories emphasize the importance of protein structures: neurotransmitters, receptors,
and ion channels as targets for general anesthetics. The most studied receptor is the GABAA
(gamma-aminobutyric acid type A) receptor. It is part of the superfamily of cys-loop ligand-
gated receptors. Together with glycine receptors they have an inhibitory effect (Fig. 9.2). GABA
stimulates GABAA receptors which increases the permeability of chloride channels and causes
hyperpolarization of the cellular membrane. This results in decreased excitability. GABAA
receptors represent a major target for the majority of general anesthetics (halogenated alkanes,
propofol, sodium thiopental, methohexital, etomidate), being responsible for hypnosis and
amnesia. GABA-mediated effects also include unconsciousness, sedation, seizures, apnea,
atonia, myoclonus, and loss of corneal reflex.

Fig. 9.2
Effects of anesthetics on inhibitory receptors and ion channels: currents passed by GABAA
receptors, glycine receptors, and baseline potassium channels are potentiated by anesthetics.
GABAA and glycine receptors allow primarily the influx of chloride ions leading to
hyperpolarization of the cell. Baseline potassium channels also cause hyperpolarization of
neuronal cells by an efflux of potassium ions (K+ = potassium ions, Cl− = chloride ions, GABA = 
gamma-aminobutyric acid)
Glycine receptor stimulation has similar effects as GABAA stimulation, but seems to also result
in immobility (action on spinal cord and brainstem). Nicotinic acetylcholine and serotonin type 3
receptors are also members of the cys-loop ligand-gated receptor family, but with excitatory
effects. Nicotinic acetylcholine receptors (neuronal and muscular) are involved in memory,
autonomic function, and muscle relaxation through high permeability for monovalent cations and
calcium with the resulting release of neurotransmitters. Serotonin type 3 receptors have been
implicated in arousal and possible emesis through enhancing the excitability by inhibiting the
resting potassium leak currents.
Glutamate receptors facilitate fast excitatory neurotransmission (Fig. 9.3). NMDA (N-methyl-d-
aspartate) receptors and AMPA (alpha amino 3 hydroxy 5 methyl 4 isoxazolepropionic acid)
receptors are the most relevant members of this class. NMDA receptors function in perception,
learning and memory, and nociception by increasing conductance for calcium and magnesium.
NMDA antagonists, such as ketamine, N2O (nitrous oxide), and xenon, produce analgesia,
dissociative state, hallucinations, lacrimation, salivation, papillary dilatation, bronchodilation,
tachycardia, and nystagmus. The AMPA receptors are associated with perception and memory
and cause increased conductance of calcium and magnesium ions.