This document summarizes the molecular and cellular mechanisms of anesthesia. It discusses that anesthetics act through multiple pathways in the central nervous system and cells. While earlier hypotheses proposed that anesthetics act primarily by disrupting neuronal lipid membranes, more recent evidence suggests that specific protein interactions play a key role. Many anesthetics enhance the effects of the neurotransmitter GABA and inhibit NMDA receptors. Overall, anesthetics seem to exert their effects through direct actions on specific ligand-gated ion channels in the central nervous system.

1. BOOK READING :
MOLECULAR AND CELLULAR
MECHANISMS OF ANESTHESIA
ANESTHESIOLOGY REVIEW 3RD EDITION, CHAPTER 39
中山醫 M5 CLERK 楊 憶

2. INTRODUCTION
¡ A general anesthetic state is obtained with a combination of:
1. Amnesia
2. Analgesia
3. Lack of response to noxious stimuli

3. INTRODUCTION
¡ Potent anesthetic agents include:
1. Small molecules (e.g. nitrous oxide)
2. Alcohols
3. Halogenated ethers
4. Complex compounds (e.g. barbiturates and propofol)
→ The diversity in chemical structure suggests
multiple modes of action

4. INTRODUCTION
¡ Shared characteristics of anesthetics:
1. Hydrophobicity
2. Lack of specific antagonists
¡ Recent findings suggest that most anesthetics have specific
effects on membrane proteins, contributing to their
complex mechanisms of action

5. CENTRAL NERVOUS SYSTEM EFFECTS
¡ Exert inhibitory and excitatory effects on various CNS
structures
¡ Inhibit brain stem reticular formation
→ loss of consciousness

6. CELLULAR EFFECTS
¡ Meyer-Overton rule
1. Direct relationship between lipid solubility and anesthetic
potency

7. CELLULAR EFFECTS
¡ Meyer-Overton rule
2. Hydrophobic anesthetics are concentrated in the lipid
membranes, which contain proteins required for electrical
conduction
3. Potentially change the order and fluidity of the neuronal lipid
bilayer, interact with membrane proteins directly, or alter the
protein-lipid interface

8. CELLULAR EFFECTS
§ Synaptic transmission is sensitive to anesthetics and
may be affected at both presynaptic and postsynaptic sites
§ Axonal conduction is not altered by clinically relevant
concentrations of anesthetics
Presynaptic :
Inhibition of Ca2+ entry in
the axon terminal
→ direct inhibition of
neurotransmitter vesicle
release
Postsynaptic :
Direct effects on the lipid
membrane, lipid-protein
interface, or hydrophobic
pockets within
transmembrane proteins
→ altered protein function

9. CELLULAR EFFECTS
§ Unitary hypothesis
1. Proposes a common mechanism for the action of
all anesthetics
2. Current understanding does not support this hypothesis

10. LIPID-BASED HYPOTHESES
§ Lipid solubility hypothesis
1. Anesthesia is produced when sufficient numbers of molecules
disrupt neuronal lipid membranes
2. * Several findings are inconsistent :
a) Some hydrophobic molecules that are chemically similar to
anesthetics are much less potent than predicted (or even
non-anesthetic)
b) Pressure-reversal effect :Application of increased
pressure to membranes does not alter the lipid solubility of
anesthetic agents (x)
c) Cutoff effect :Additional carbon molecule past 12 or 13 is
associated with loss of anesthetic action

11. LIPID-BASED HYPOTHESES
§ Modifications of the lipid solubility hypothesis
1. Critical volume hypothesis
a) Anesthetics disrupt membrane protein function by
expanding the lipid membrane
b) The membrane expands about 0.4%
→ 1ºc increase in temperature produces similar effects (x)
c) May explain the pressure reversal effect, but fails to
explain the cutoff effect

12. LIPID-BASED HYPOTHESES
3. Lipid fluidity hypothesis
a) Disordering effect on membranes → interfere membrane
protein function (yet to be proven)
b) Anesthetic potency correlates with the disordering
effect on cholesterol membranes
c) The cutoff matches the altered membrane
disordering ability of alcohols
d) Pressure increases reverse the anesthetic-induced
changes in membrane fluidity

13. PROTEIN-BASED HYPOTHESES
§ Recent evidence suggests protein-based effects of
anesthetics :
1. Stereoselective effects for barbiturates, ketamine, and
isoflurane have been shown
(The S isomer is more potent than the R isomer)
2. The steep dose-response curve for volatile anesthetics
suggests receptor occupancy
§ 1 MAC : effective in 50% of subjects
§ 1.3 MAC : effective in 95% of subjects

14. PROTEIN-BASED HYPOTHESES
3. General anesthetic potency correlates well with protein
inhibition
4. The existence of hydrophobic pockets in proteins could
explain the correlation of potency with hydrophobicity
and anesthetic cutoff

15. PROTEIN-BASED HYPOTHESES
§ Studies on ligand- and voltage-gated ion channels show :
1. Selective anesthetic effects
a) Ketamine-induced anesthesia is mediated by antagonism of
NMDA receptors
b) Nitrous oxide also inhibits NMDA receptors
2. Most anesthetics augment GABA activity
3. Anesthetics decrease presynaptic neurotransmitter release
to a small degree (probably by ↓Ca2+entry)
4. Despite the effects on Ca2+, Na+, K+ channels at high
concentrations, voltage-gated channels are largely
insensitive to anesthetics

16. PROTEIN-BASED HYPOTHESES
§ Increasing evidence suggests a more selective mechanism of
action possibly on a more limited number of CNS targets
1. Direct post-synaptic effects on ligand-gated ion
channels are likely the primary effect
2. Further research in this field is required