Anesthesia - Modern View of Mechanisms (Lecture 9A)

Question 1

Thompson and Wafford critiques of traditional anesthetic mechanism theory

Answer 1

Critiques of traditional theory - lipid

Some compounds that destabilize the membrane are not anesthetics

Anesthetics exist as enantiomers with the same coefficient but different effects

Question 2

Thompson and Wafford current anesthetic mechanism theory

Answer 2

Current thinking - protein theory

Anesthetics interact with specific proteins - especially NT receptors
- The enantiomer effects on proteins match their anesthetic effects
- Non anesthetic drugs that disrupt the membrane don’t act on proteins

Question 3

Hypnotic general anesthetics probable receptors

Answer 3

• Can enhance inhibition or block excitation to have a net inhibitory effect
• Enhancing inhibition: GABA-A, glycine, K+ channels
• Blocking excitation: nicotinic cholinergic
• The list would be different today to include arousal systems → 5HTergic, NEergic, histaminergic, orexin, DAergic

Question 4

Hypnotic inhalational (volatile) anesthetics probable receptors

Answer 4

GABA-A (major player)
- Volatile anesthetics and ethanol potentiate GABA-A activity
- S-isoflurane is stronger than R-isoflurane clinically and in potentiating GABA system

Glycine
- Volatile anesthetics and ethanol potentiate glycine receptor activity
- Glycine doesn’t have a big effect in the forebrain, acts on spinal cord and medulla with GABA → may be contributory

K+ channels
- Some activated by halothane, isoflurane, chloroform and ether → may be contributory

Question 5

IV anesthetics probable receptors

Answer 5

GABA-A (major player)
- IV anesthetics potentiate GABA-A activity
- At low concentrations: help GABA open the channel
- At high concentrations: open it themselves

Glycine
- Only propofol interacts with glycine receptors and the other ones don’t seem to

Question 6

Dissociative anesthetics probable receptors (both gaseous and IV)

Answer 6

NDMA
- Ketamine (IV) inhibits NMDA receptors
- Nitrous oxide and xenon (gaseous) inhibit NMDA receptors

Nicotinic cholinergic
- Ketamine may inhibit these → nicotine is a stimulant so inhibiting the activity of the receptor is helpful

Question 7

What molecular effect do all hypnotic anesthetics and alcohol have?

Answer 7

all hypnotic anesthetics and alcohol enhance GABA-A activity

Question 8

What molecular effect do all dissociative anesthetics and alcohol have?

Answer 8

All dissociative anesthetics inhibit NMDA receptors

Question 9

Current theory of hypnotic IV

Answer 9

Hypnotic IV - ex. Propofol
- Potentiate GABA-A receptor activity → acts as GABA-A receptor positive allosteric modulator

Question 10

Current theory of hypnotic gasses

Answer 10

Hypnotic gaseous - ex. Sevoflurane
- Positive allosteric modulator of GABA-A receptor

Question 11

Current theory of dissociative anesthetics

Answer 11

Dissociative - ex. Ketamine
- Antagonism of NMDA receptor

Question 12

Current theory - molecular mechanisms

Answer 12

Parietal cortex - highest order association cortex → probably where put together picture of world, get split brain if you split the connection between them → seat of consciousness is probably here

Hypnotic anesthesia schema: acting via sleep system
- 5 arousal systems keeping cortex awake
- Major system: cholinergic muscarinic (if you turn this system off it results in dementia like symptoms and delirium)
- Minor systems: DA, 5HT, orexin/hypocretin, histamine
- GABA-A (gabaergic neurons) is the major sleep system that turns them all off
- If general anesthetics enhance GABA they should turn off arousal systems and put someone to sleep → hypnotic drugs