FRCA Notes

Theories of Mechanism of Action of Anaesthetics

  • It is difficult to explain how such a structurally diverse set of molecules all function to achieve similar outcomes
  • Any mechanism to explain the mechanism of action of anaesthetic agents must be able to explain:
    • Loss of conscious awareness
    • Loss of response to noxious stimuli
    • Reversibilty

  • In order to explain these effects, agents must affect the brain and/or spinal cord
  • The thalamus is implicated in the mechanism of action by data from auditory and sensory evoked potentials
  • Secondary sites may also include the limbic system and other cortical areas
  • The Meyer-Overton Hypothesis proposed that the potency of an anaesthetic agent is related to its lipid solubility
    • Potency itself is described by minimum alveolar concentration (MAC)
    • Lipid solubility is described by the oil:gas partition solubility coefficient
  • The hypothesis states that once a certain number of anaesthetic molecules were dissolved in the lipid bilayer of CNS cells, it would disrupt membrane and thus cellular function
Meyer-Overton hypothesis
  • The correlation between lipid solubility and potency suggested a non-specific mechanism of action based on physicochemical properties
  • Problems with the theory include:
    • Ketamine being an extreme outlier
    • R-etomidate has anaesthetic activity though its enantiomer S-etomidate (identical lipid solubility) does not
  • Later interpretation pointed to any highly lipophilic area being a potential site of action (e.g. cell membrane)

MAC

  • The minimum alveolar concentration of an anaesthetic vapour at equilibrium to prevent movement to a standardised surgical stimulus in 50% of un-premedicated patients at sea level (1atm)

  • There are several lipophilic sites in cell membranes that drugs could act on (bilayer, annular lipids around ionic channels)

Critical volume hypothesis

    • Agents penetrate the lipid bilayer and alter the molecular arrangement of phospholipids
    • This expands the membrane and disrupts membrane-spanning ion channels
    • This led to the critical volume hypothesis

    • However a 1°C rise in temperature, which would also increase membrane thickness to a similar extent, should have enhanced anaesthesia - but the reverse occurred

Perturbation theory

  • Further theory suggested agents act at specific lipid sites
    • Annular phospholipids adjacent to ion channels have a different composition
    • Anaesthetic agents disrupted the annular lipids associated with specific ion channels
    • This led to perturbation theory

  • Newer theories are based on protein receptors in the CNS
  • Now seems likely that the correlation between potency and lipid solubility reflects the lipophilic nature of specific, protein-based binding sites

Protein sites of action

  • Potential protein sites of action include:
    • Ligand-gated ion channels
    • Voltage-gated ion channels
    • Two-pore domain K+ channels
    • Intracellular signalling proteins / pre-synaptic exocytosis
  • Ligand-gated protein channels seem particularly sensitive to anaesthetic agents, more so than other proteins
  • Interactions at excitatory (NMDA, neuronal nAChR, 5-HT3) and inhibitory (GABAA, glycine) receptors have been studied
  • All IV and inhaled agents modulate these receptors to varying degrees
Anaesthetic Agent GABAA Glycine NMDA nAChR
Propofol ++++ ++ -
Thiopentone +++++ ++ -
Ketamine -
R-Etomidate +++++
S-Etomidate
Isoflurane ++++ ++++
Nitrous Oxide -
Xenon -
Steroid-based agents ++

GABAA Receptor

  • Pentameric, ligand-gated, ionotropic receptor
  • Anaesthetics increase channel opening time, increasing chloride entry and hyperpolarising
GABA Receptor
  • The stereo-specificity of R-etomidate at the GABAA receptor supports the protein-based action of anaesthetics
  • The S(-) enantiomer has 30x reduced activity at the GABAA receptor and is clinically inactive

  • There are 30 types of GABAA receptor; β2 and β3 subunit variations are more sensitive to etomidate than β1
  • These subtypes are distributed and concentrated in different parts of the CNS

Glycine Receptor

  • Glycine is the major inhibitory neurotransmitter in the brainstem and spinal cord
  • The glycine receptor is a chloride ion channel, similar to the GABAA receptor
  • Volatile agents markedly potentiate the action of glycine
  • Efficacy at glycine receptors correlates more with immobility than hypnosis

NMDA Receptor

  • Is an ionotropic glutamate receptor, along with AMPA and kainite receptors
  • It is ligand-gated but voltage dependent (as extracellular Mg2+ blocks the ion channel)
  • It also has ligand binding sites for glutamate, glycine and an allosteric binding site

  • Binding of an agonist:
    • Opens the ion channel
    • Allows Ca2+ and Na+ entry, and K+ efflux
  • Ca2+ is involved in synaptic plasticity and long-term signal potentiation, associated with learning and memory

  • Ketamine, nitrous oxide and xenon are non-competitive antagonists of the NMDA receptor
  • Other anaesthetic agents (e.g. barbiturates) reduce the effectiveness of glutamate (at lower levels than required for inhibition of the GABAA receptor)

Altered neurotransmitter availability

  • Volatile agents inhibit breakdown of GABA and therefore there is increase activation of GABAA receptor
  • Volatile agents inhibit calcium channels, preventing release of certain neurotransmitters

Multi-site hypothesis

  • Different agents alter higher CNS functions at different concentrations (learning, memory)
  • Certain agents e.g. opioids reduce MAC, but this effect is non-predictable and not additive
  • This implies different sites of action of agents, which may have direct and indirect effects