General anasethesia

Question 1

What happens under the influence of general anaesthesia?

Answer 1

1. Loss of consciousness – all the general anaesthetic agents can do this at low concentration
2. Suppression of reflex responses – all the general anaesthetic agents can do this at high concentration
3. Relief of pain (analgesia)
4. Muscle relaxation
5. Amnesia

Question 2

What are the types of general anaesthesia?

Answer 2

• Gaseous (inhalational) anaesthetics

- Intravenous anaesthetics

Question 3

What is the Meyer/Overton correlation?

Answer 3

• This theory was believed for a long time: anaesthetic potency increases in direct proportion with oil/water partition coefficient
• Anaesthetic potency is directly correlated with lipid solubility
• The main explanation was that these drugs disturbed the lipid bilayer, but there were two main problems with that explanation:
  
  • At therapeutic doses, changes to the lipid bilayer were minute
  • How would the change in the membrane impact on membrane proteins anyway?

A rise in temperature seemed to have the same effect on the membrane as the general anaesthetic so this was a poor explanation. The real mechanism of action is either:

   - Reduced neuronal excitability
   - Altered synaptic function

Question 4

Intravenous general anaesthetic agents - what do they act on and what do they do?

Answer 4

• Intravenous GA agents alter synaptic function, primarily through GABA-A receptors – potention
• The IV GAs are slightly more selective: they target the GABA-A receptor
• GABA-A receptor is made up of 5 subunits – subunit composition is different in different brain regions
• GABA-A is also an important receptor in causing euphoria
• So when given propofol, you will experience euphoria before you are knocked out
• GABA-A is a type 1 ionotropic receptor so it is comprised of 5 subunits
• IV agents seem to target specific subunits in the GABA-A receptor:
  Beta-3 = suppression of reflex responses (important at the synaptic level)
  Alpha-5 = amnesia (extra-synaptic)

Question 5

What does suppression of the beta 3 and alpha 5 subunit of GABA-A lead to?

Answer 5

Beta-3 = suppression of reflex responses (important at the synaptic level)

Alpha-5 = amnesia (extra-synaptic)

Question 6

Inhaled general anaesthetics - what do they act on?

Answer 6

• Inhalational GA agents alter synaptic function
• They have an affect on GABA, but this is probably 50% less powerful (other targets are involved):
  GABA-A Receptors
  Glycine Receptors
• They are far less selective for GABA-A than the IV agents
• They seem to be more selective for alpha-1 containing GABA
• This is important in suppression of reflex responses

(Glycine is also an inhibitory neurotransmitter)

Question 7

What do the halogenated GA act on?

Answer 7

GABA

Question 8

Nitrous oxide - how does it work?

Answer 8

• Blocks the NMDA-type glutamate receptors to induce its anaesthetic effect
• Nitrous oxide is less GABA specific and more glutamate specific
• It competes at the binding site for glycine on the glutamate receptor
• Glycine is an important COAGONIST of NMDA receptors
• It allows the full receptor response to be transduced
• Interfering with glycine will interfere with NMDA

Question 9

What is the importance of the neuronal nicotinic acetylcholine receptors?

Answer 9

• These seem to be important for the analgesic effects
• They don’t really influence the loss of consciousness or hypnotic effects
• Increasing the concentration of the inhalational agent leads to a reduction in nerve conduction
• This is via an effect on nicotinic acetylcholine receptors – Inhibition
• The agent enters the brain, binds to and blocks the ACh receptor -> analgesia
• Cholinergic neurones do seem important to switch off to achieve general anaesthesia
• But at the moment we can’t find an effect of nicotinic acetylcholine receptors in terms of loss of consciousness and suppression of reflexes
• Nicotinic acetylcholine receptors are important for:
  amnesia and relief of pain