2019B04 Outline the theories, both current and discredited, as to how volatile anaesthetics
cause loss of consciousness.

 

List:

·      Consciousness

·      Lipid hypothesis

·      Protein hypothesis

·      Sleep hypothesis

·      Cellular hypothesis

·      Others

 

Consciousness:

Definition

·  Awareness of one’s physical state, motivations, emotions and thoughts

Mechanism

·  Poorly understood

·  Dependent upon precisely organized interactions between

o Ascending reticular activating system (ARAS) in brainstem

o Thalamus

o Cerebral cortex

·  Disruption of these causes unconsciousness

Mediators

·  Glutamate

·  Noradrenaline

·  Acetylcholine

 

Lipid hypothesis (main discredited theory):

Theory

·  Accumulation of volatile agent in CNS bilayer -> distortion of membrane function

·  Critical volume hypothesis

·  Lateral phase separation hypothesis

Rationale

Myer-Overton correlation: between anaesthetic potency (MAC) and solubility in olive oil

Problem

·  Imperfect correlation

·  Better correlation between potency and solubility in amphipathic substances e.g. octanol

·  Ineffective anaesthetic-like compounds

·  Carbon chain length cut-off: molecules >10 carbons long unlikely to cause hypnosis

·  ↑Temp -> ↑MAC (would expect ↓MAC due to ↑solubility in bilayer)

·  Structural isomeric differences (e.g. isoflurane MAC 1.2%, enflurane MAC 1.7%)

·  Stereoisomeric differences (e.g. R-etomidate 10x more potent than S-etomidate)

 

Protein hypothesis (currently accepted)

Theory

·  Interaction with hydrophobic areas of key membrane proteins including ion channels

Rationale

·  Correlation between potency for GA and potency of inhibition of firefly luciferase, a protein-only structure

Subsequent validation

·  Effect of volatile agents at ion channels

o ↑Activity of GABA, glycine, 2PK, 5-HT

o ↓Activity at nnAChR, NMDA, AMPA

 

Sleep hypothesis:

Theory

·  Volatiles agents activate sleep circuitry

Rationale

·  EEG signature of volatiles agents and propofol is similar to that of slow wave sleep

·  α2 agonists induce a sleep-like state

Flaw

·  Volatile agents cause unrousable unconsciousness, immobility

 

Cellular targets:

Theory

·  Volatile agents impair neuronal function specifically

Rationale

·  Volatile agents cause anaesthesia with relative preservation of other body function

Flaw

·  Proven effects on many tissues

o e.g. inhibit the cardiovascular L-Ca2+ channel

o e.g. skeletal muscle relaxation

 

Other:

·         Subcellular targets (e.g. ↑↓ second messengers)

·         Component theories

·         Pre-programmed response hypothesis

 

 

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