Principles of general anaesthesia

Question 1

What are the clinically desirable features of general anaesthesia?

Answer 1

All general anaesthetics cause:

• Loss of consciousness (at low concentrations)
• Suppression of reflex responses (at high concentrations)

Other effects:

• Relief of pain (analgesia)
• Muscle relaxation
• Amnesia

Question 2

What are the different types of anaesthetics?

Answer 2

Gaseous/inhalation

• NO
• Diethyl Ether
• Halothane
• Enflurane

Intravenous

• Propofol
• Etomidate

Question 3

Describe the Meyer/Overton theory of GAs

Answer 3

• Anaesthetic potency increases in direct proportion with oil/water partition coefficient. The more lipid soluble the better anaesthetic agents they are - Meyer/Overton correlation

The problem with that theory:

1. At relevant anaesthetic concns, change in bilayer was minute (when tested)
2. How would this change impact membrane proteins?

So this theory fell apart

Question 4

What are the molecular targets for intravenous GAs?

Answer 4

Cause either reduced neuronal excitability or Altered synaptic function. Intravenous agents directly and exclusively target GABA A receptors. They enhance GABA A receptor function = enhance inhibitory effect of GABA.

(E.g Etomidate)

• GABA A receptors (MAIN EFFECT)
  1) Beta3 subunits: Suppression of reflex responses
  2) Alpha5 subunits: Amnesia

Question 5

What are the molecular targets for inhaled GAs?

Answer 5

Cause either reduced neuronal excitability or Altered synaptic function. Inhalation agents have a complete mix of targets compared to intravenous agents.

(E.g Halothane and Eflurane)

• GABA A/Glycine receptors - Glycine receptors, which are homologous to, and often colocalized with, GABAA receptors, are a potential anaesthetic target. Glycine receptors have an inhibitory role, particularly in the lower brainstem and spinal cord, where they might mediate the action of volatile anaesthetics
  1) alpha1: Suppression of reflex responses
• Inhibit neuronal nicotinic ACh receptors - Analgesic effects. Intravenous drugs can act on these targets but only at concentrations above that required for anaesthesia
• TREK (background leak) K+ channels (potentiate these effects) - consciousness

Effects of Nitrous oxide: No effects on GABA
- Blocks NMDA-type glutamate receptors - Assumed to mediate the anaesthetic induced effects on consciousness and mobility. Probably compete with co-agonist glycine

Question 6

Describe the site responsible for the loss of consciousness

Answer 6

Depress excitability of thalamocortical neurons
Suppress reticular activating neurons

RAS - involved in wakefulness. Neurones from the brainstem to the cortex through the thalamus. Very dependent on GABA A (important for suppressing the firing the rate of the relevant neurones). Background leak K+ channels are also vital in terms of mediating consciousness.

Question 7

Describe the site responsible for the suppression of reflex responses

Answer 7

Depression of reflex pathways in the spinal cord = decrease reflex pathways

High density of GABA/Glycine receptors located in the dorsal horn of the spinal cord.

Question 8

Describe the site responsible for amnesia

Answer 8

Decreased synaptic transmission in hippocampus/amgdala. GABA A receptors with the alpha5 subunit heavily involved in this area.

Question 9

Compare inhaled and intravenous GAs

Answer 9

See slide 29. Brain Blood Brain

Low blood:gas partition coefficient and high? Inhale the drug –> enters the lungs. A large proportion of the blood will remain in a gas state and not dissolve into the blood. This means that drugs in the gas from can pass through the BBB easier/faster. Therefore low blood:gas partition coefficient means faster effects. Change in concentration allows quick control of anaesthesia - as soon as you remove it from the lungs it will leave the brain very quickly.

Inhalation anaesthetics

• Rapidly eliminated
• Rapid control of the depth of anaesthesia

Intravenous anaesthetics

• Fast induction
• Less coughing/excitatory phenomena

Question 10

What is the blood:gas partition coefficient?

Answer 10

Describes how the gas will partition itself between the two phases after equilibrium has been reached. Isoflurane for example has a blood/gas partition coefficient of 1.36. Thus if the gas is in equilibrium the concentration in blood will be 1.36 times higher than the concentration in the alveoli. A higher blood gas partition coefficient means a higher uptake of the gas into the blood and therefore a slower induction time. It takes longer until the equilibrium with the brain partial pressure of the gas is reached.

Often causes confusion – A highly soluble agent will dissolve in the blood very effectively. However, this means that the gas component (partial pressure) will be lower and it is this that determines the speed of brain penetration (not the total amount in the blood). Thus a poorly soluble agent will have a very rapid onset of action.

Question 11

Describe the use of anaesthetics in a clinical setting

Answer 11

Loss of consciousness and suppression of reflex responses –> Induction: I.V Propofol. Maintenace by Enflurane (GAS) - better control

Relief of pain (analgesia) - opiods (i.v fentanyl)
Muscle relaxation - neuromuscular blocking drugs (suxamethonium)
Amnesia - benzodiazepines (i.v midazolam)