General Anaesthesia

Question 1

What is general anaesthesia traits?

Answer 1

Clinically desirable:
 • loss of consciousness (@ low [conc])
 • suppression of reflex responses (@ high [conc])
 • relief of pain (analgesia)
 • muscle relaxation
 • amnesia

LAST 3 are effects generally covered by OTHER/DIFF. DRUGS

Question 2

Molecule targets of GA?

Answer 2

GAs are NOT very structurally similar
• BUT they all have SIMILAR PROPERTIES

GAs are separated into either IV or INHALATIONAL types
• IV - generally contain rings
• Inhalational - generally have halogens

Question 3

What are the 2 school of thoughts about the MoA of GA and which is generally more accepted?

Answer 3

(1) Meyer-Overton Correlation

(2) Molecule targets
• Altered synaptic function
either/and/or
• Reduced neuronal excitability

2ND ONE more accepted!

Question 4

Explain the 1st school of thought regarding MoA of GA - evidence for and against

Answer 4

(1) Meyer-Overton Correlation
• GAs penetrate the LIPID BILAYER & disrupt AP propagation

Evidence FOR:
• anaesthetic potency INCREASES as lipid solubility increases

Evidence AGAINST:
• at relevant [conc]s, changes in the bilayer was minute & NO CHANGES in lipid bilayer proteins was seen (which WOULD be changed if GAs disrupted AP propagation)

Question 5

What makes up the 2nd school of through regarding MoA of GA?

Answer 5

Moleculer targets - so either

• Reduced neuronal excitability
OR
• Altered synaptic function

Question 6

Explain the MoA in terms of ‘Altered synaptic function’?

Answer 6

(i) IV AGENTS

EHANCE the GABAa receptor = enhance GABA transmission (subunits targeted)
• BETA3 = suppression of reflex responses = expressed in SC
• ALPHA5 = amnesia = expressed in hippocampus/amygdala

GABAa receptor also important in causing EUPHORIA
• so when given propofol, will experience euphoria BEFORE being knocked out

(ii) INHALATIONAL AGENTS
(a) Halogen inhalational agents

x Main targets are GABAaR & Glycine R (ENHANCE)
• seem to be more selective for ALPHA1 subunit (so more important in suppressing REFLEX responses)

x Also DECREASE FIRING RATE of neuronal NAChR
• important for amnesia & relief of pain

(b) Nitrous Oxide (non-halogen agents)

x BLOCK NMDA-type glutamate receptors (excitatory synpase)
• compete w. CO-AGONIST GLYCINE

Question 7

Explain the MoA in terms of ‘Reduced neuronal excitability’

Answer 7

(i) INHALATIONAL AGENTS

x ENHANCE background leak of K+channel = TREK
• to cause hyperpolarisation of cells
• important in suppression of reflex responses

Question 8

General difference betwenn IV GAs and inhalational GAs?

Answer 8

IV GAs are MORE SELECTIVE
• mainly affect GABA-A

vs.

Inhalational GAs are more NON-SELECTIVE
• BUT equally as potent (higher dose required)
• not as powerful/selective (hits MORE targets but LESS)

Question 9

Using neuroanatomy, explain how loss of consciousness is brought about by GA

Answer 9

Loss of consciousness:

o Depress thalamocortical neurones
• GAs hyperpolarise thalamocortical neurones by activating TREK channels and/or by potentiating GABA Rs
• result in disconnection of the periphery from the brain

o Influence RAS neurones (reticular activating system)

The GAs will disrupt the communication betw. the RAS, cortex & thalamus

Question 10

Using neuroanatomy, explain how suppression of reflex responses is brought about by GA

Answer 10

Suppression of reflex responses:

o Dorsal horn GABAAR are at a high density:
• depression of reflex pathways in spinal cord
• disconnects brain from periphery

Question 11

Using neuroanatomy, explain how amnesia is brough about by GA

Answer 11

Amnesia:

Via influences on GABAA ALPHA5 subunits:
o Decrease synaptic transmission in the hippocampus and amygdala
 ALPHA5 subunits are at a high conc. here as opposed to the rest of the body.

Question 12

Difference between the way IV agents vs. Inhalational agents are taken in?

Answer 12

IV agents:
o the time the IV agent is active is dependent on the liver metabolism
o the IV agents are injected DIRECTLY into the BLOOD where they pass to the brain

Inhalational agents:
o Inhaled agents pass from the air to the blood and to the brain so have an extra membrane to diffuse through

Question 13

What is the Blood/Gas partition coefficient (BG PC)?

Answer 13

How a gas will partition itself between the 2 phases after an equbilibrium has been reached

Question 14

HIGH vs. LOW BG PC?

Answer 14

Higher BG PC
• SLOWER onset of action
• as a higher uptake of gas into the blood – takes longer for the brain and blood to reach an equilibrium (less in gas phase)

Low BG PC
• FASTER onset of action (drug is more lipophilic and hydrophobic so will not dissolve in blood well)

Question 15

Using the BG PC, which GA is more easy to control?

Answer 15

Inhaled GA

as diffusion occurs very rapidly

Question 16

Which BG PC is preferred?

Answer 16

LOW BG PC

o The effects will come on very fast
o It is very easy to control
o If you remove the anaesthetic from the lungs, then the effects on the brain will go very quickly

Question 17

Inhalation vs. IV anaesthetic comparsion in regards to pharmacokinetics?

Answer 17

Inhalation GA - used for MAINTENANCE
• rapidly ELIMINATED
• rapid control of the depth of anaesthesia

IV GA - used for INDUCTION
• fast INDUCTION
• less coughing/excitatory phenomena

Question 18

Going back to the 5 main effects of GA, in the clinical setting what drugs are used?

Answer 18

Loss of consciousness
• Induction - Propofol

Supression of reflex responses
• Maintenance - Enflurane (inhalational)

Relief of pain
• Opioids (e.g. IV fentanyl)

Muscle relaxation
• NM-blockers (e.g. Suxamethomiun)

Amnesia
• Benzodiazepines (e.g. IV midazolam)

Question 19

Types of GAs?

Answer 19

Inhalational/gaseous
 • Nitrous Oxide
 • Diethyl Ether
 • Halothane
 • Enflurane

IV
• Propofol
• Etomidate