2019B Question 04

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

Examiner Report

70.3 % of candidates achieved a pass in this question.

The domains that were assessed in this question were - an appreciation of the uncertainty in the theories, evidence related to discarded theories, evidence related to modern theories and of anatomical targets in the CNS leading to loss of consciousness. Other relevant detail also received credit.

Common problems were: not addressing important parts of the question in sufficient detail, drawing graphs inaccurately (such as not having correctly labeled axes), and irrelevant descriptions of the pharmacology and mode of action of a wide range of non-inhalational agents. Inhalational anaesthetics include gaseous as well as volatile agents. Description of wash-in and wash-out was not relevant.

Some candidates’ handwriting was a problem.

A good reference on this topic is chapter 25 in Miller’s Anaesthesia.

Model Answer


  • Consciousness
  • Lipid hypothesis
  • Protein hypothesis
  • Sleep hypothesis
  • Cellular hypothesis
  • Others


Factor Details
Definition - Awareness of one’s physical state, motivations, emotions and thoughts

- Poorly understood

- Dependent upon precisely organized interactions between

 - Ascending reticular activating system (ARAS) in brainstem

 - Thalamus

 - Cerebral cortex

- Disruption of these causes unconsciousness


- Glutamate

- Noradrenaline

- Acetylcholine

Lipid Hypothesis

Main discredited theory

Element Details

- Accumulation of volatile agent in CNS bilayer → Distortion of membrane function

- Critical volume hypothesis

- Lateral phase separation hypothesis


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


- 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

Element Details
Theory - Interaction with hydrophobic areas of key membrane proteins including ion channels

- 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

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

 - ↓ Activity at nnAChR, NMDA, AMPA

Sleep Hypothesis

Element Details
Theory - Volatiles agents activate sleep circuitry

- 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

Element Details
Theory - Volatile agents impair neuronal function specifically
Rationale - Volatile agents cause anaesthesia with relative preservation of other body function

- Proven effects on many tissues

 - e.g. Inhibit the cardiovascular L-Ca2+ channel

 - e.g. Skeletal muscle relaxation

Other Theories

  • Subcellular targets (e.g. ↑ ↓ second messengers)
  • Component theories
  • Pre-programmed response hypothesis

Last updated 2021-08-23

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