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

List:

· Consciousness

· Lipid hypothesis

· Protein hypothesis

· Other hypotheses

Consciousness:

Definition

· Awareness of one’s physical state, motivational state, 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 interactions causes unconsciousness

Key mediators

· Glutamate

· Noradrenaline

· Acetylcholine

Lipid hypothesis (main discredited theory):

Theory

· Accumulation of volatile agent in CNS bilayer causes distortion of membrane function

o Critical volume hypothesis

o Lateral phase separation hypothesis

Rationale

· Myer-Overton correlation: between anaesthetic potency and solubility in olive oil

Problem

· Imperfect correlation

· Exceptions: existence of inert anaesthetic-like compounds

· Carbon chain length cut-off: molecules beyond a certain length lose anaesthetic effect

· Temperature: minor changes cause membrane distortion comparable to anaesthetics

· 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 anaesthetic potency and solubility in amphipathic substances
(closer correlation than with lipid solubility)

· Correlation between anaesthetic potency and 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

Other hypotheses:

Sleep

· Hypothesis: volatiles agents activate sleep circuitry

· Rationale: EEG signature of volatile agents is similar to slow wave sleep

· Flaw: volatile agents induce unrousable unconsciousness and immobility

Cellular targets

· Hypothesis: volatile agents impair neuronal function specifically

· Rationale: relative preservation of other body functions

· Flaw: proven significant effects on many tissues, e.g. skeletal muscle relaxation

Subcellular targets

· E.g. ↑↓ function of second messengers