Principles of general anaesthesia

Question 1

What is clinially desirable in general anaesthaesia

Answer 1

Loss of consciousness

Suppression of reflex responses

Relief of pain (analgesia)

Muscle relaxation

Amnesia

Question 2

What do general anaesthetics all possess and at which concentration

Answer 2

Loss of consciousness at low concn

Suppression of reflex responses at high concn

The other clinically desirable things, some GAs do, some don’t

Question 3

T/F GAs all have similar structures. If not, how are GAs classified?

Answer 3

F

Classified by inhalational vs iv

Question 4

Name some gasous/inhalation GAs

Answer 4

Nitrous Oxide

Diethyl Ether

Halothane

Enflurane

Question 5

Name some intravenous GAs

Answer 5

Propofol

Etomidate

Question 6

Why was it hard to establish PD of GAs

Answer 6

Because they all have such different structures

Question 7

What is the meyer overton correlation

Why was it rejected as MAO for GAs

Answer 7

Anaesthetic potency increases
in direct proportion with oil/water
partition coefficient

Disruption of lipid bilayer was thought to cause GA effect

i.e. more lipid soluble, more powerful

PROBLEMS:
1. At relevant anaesthetic concns,
change in bilayer was minute

2. So must involve proteins- but ow would this change impact
   membrane proteins?

Question 8

Outline the possible actual MOA of GAs

Answer 8

Either;

Reduced neuronal excitability or

Altered synaptic function

Question 9

What do IV GA agents target

Answer 9

GABA- A

Promotes hyperpolarisation and enhances inhibitory effect

5 subunit molecle

Question 10

Structure of GABA-A receptor and how this affects action of GA

Answer 10

5 subunits

If there are lots of b3 i.e. in the brainstem and the spinal cord, this GABA receptor probably responsible for suppression of reflexes

The proteins with lots of a5 e..g hippocampus- responsible for amnesia

Question 11

How might Halothane and Enflurane have their effects (they are inhalational)

Answer 11

1. Still act on GABA/glycine (which are often co-expressed and usually do the same thing) but 50% less selective than IV

May target GABA-A which have a1 subunit (this is important in suppression of reflex response)

2. Neuronal nAChR antagonism (only contributes to analgesic, NOT the hypnotic effects)
3. TREK (contributes to the lack of conscioussness, these could be involved in normal sleep/wake cycle)

TREK= bakground leak K+ channels

i.e. this is the component involving altered NEURONAL EXCITABILITY as opposed to altered synaptic function

Question 12

How does NO have GA

Answer 12

No effect on GABA

1. Blocks NMDA-type glutamate receptors
   Probably compete with co-agonist glycine (note that glycine is usually inhibitory but in some areas of brain they do promote the excitatory effect of glutatmate at NMDA)

Assumed to mediate the anaesthetic induced effects on consciousness and mobility

2. Also blocks the nAChR (not just at the nAChR in the brain, like it was for isoflurane, but also in muscle, so it is a NM blocker too)

Question 13

How do some inhlaaltional GAs affect nAChR

Answer 13

They can reduce the activation of nAChR

Question 14

What can the inhalatinal GAs do for TREK channels

Answer 14

TREK (background leak) K+ channels

These are involved in transition for sleep to conscioussness

GAs can POTENTIATE the effect of TREK channels

Question 15

T/F the Inhalational and IV GAs have similar selectivity

Completely separately, what is the effect of glycine

Answer 15

F…..

the inhalational ones act on many more receptors with less selectivity. This might be responsile for the greater number of clinical effects

The IV ones are speciifc to GABA-A and glycine

Glycine is inhibitor !

Question 16

What is conscioussness usually dependent on

Answer 16

reticular activating system (RAS) emanates from the brainstem and projects upward to the cerebral cortex via the thalamus.

Acetylcholine is released from cholinergic nerve terminals projecting from RAS to the thalamus and cortex. High ACh–> higher conscioussness (i.e. wakefullness)

Question 17

Which structures are affected by GAs to induce LOC

Answer 17

1. Influences retiuclar activating neurons
2. Depresses excitability of thalamocortical neuorns

(remember RAS involved brainstem to thamaus= RA neurons, and then from the thalamus to the cortex= thalamocortical neurons)

Question 18

How does GA affect thalamocortical neurons

Answer 18

Anaesthetics can directly hyperpolarize thalamocortical neurons by activating TREK channels and/or by potentiating GABAAreceptors - information transfer through the thalamus is disrupted.

Although the thalamus might control the state of consciousness, processing in the cortex is responsible for the detailed content of consciousness, and during anaesthetic-induced LOC the cortex is profoundly deactivated.

Question 19

T/f GAs, such as NO/propofol, only causes consciousness loss

Answer 19

F they are also causing euphoria too. This is because GABA-A receptors are also involved in euphoia

Question 20

How can you account for GAs causing suppression of reflex responses

Answer 20

Depression of reflex pathways
in the spinal cord

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

High concentration of b3

Question 21

How can you account for GAs causing amnesia

Answer 21

Reduced synaptic transmission in hippocampus/amygdala

GABA-A receptor

Question 22

Why is memory sensitive to GA

Answer 22

Because amnesia occurs at concentrations well below those that cause sedation and analgesia.

Proportion of GABA-A receptors that have a5 is low, but they are distributed at extrasynapse of the hippocampus in relatively high ratio.

Question 23

What is important with regard to gas getting into the blood from the lungs

What is the effect of the blood gas partition coefficient on speed of induction

Answer 23

If there is low blood:gas partition coefficient:

• large proportion dissolves POORLY into the blood (large proportion remains as a gas)
• in the brain, any gas dissolved in the blood will find it harder to get into the brain. If it’s in gas form in the blood, it gets into the brain quicker

LOW blood gas –> MORE going into the brain

High blood gas –> more gas dissolves ino the blood and much less in gas form in the blood, then there is slower transfer of anaesthetic agent into the brain, so the speed of anaesthesia induction reduces. And more difficult to control

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.

Question 24

Advantages of low blood: gas partition

Answer 24

I.E., not much dissolved in the blood, most staying as gas in the blood

1. Gain access to brain more readily
2. Better control because, when you want the patient to come around, you just remove gas from the airway, and then the gas will diffuse from the blood into the lungs, and be removed from the circulation rapidly due to concentratin gradients. Cannot happen if the blood is dissolved

Question 25

Inhalation anaesthetics advantages

Answer 25

• Rapidly eliminated

- Rapid control of depth of amnesia

Question 26

IV anaesthetics advantages

Answer 26

• Fast inductions

- Less coughing/excitatory phenomena (i.e they can have seizures on the table)

Question 27

What is usually given in an operation for GA

Answer 27

induction with: propofol (any IV)

Maintenance with enflurane (any inhalational, so then you can directly control the amount of drug)

Question 28

What else would be given to allow: relief of pain

Answer 28

Opioid (e.g. i.v. fentanyl)

Question 29

What drug might be given for muscle relaxation

Answer 29

Neuromuscular blocking drugs (e.g. suxamethonium)

Question 30

What drug might be given for amnesia

Answer 30

Benzodiazepines (e.g. i.v. midazolam)

Question 31

What is the solubulity of GA drugs

Answer 31

They sit in your adipose tissue for a long time

So you can get drowsy again

Question 32

Why can inhalatinal anaesthetics lead to cough

Answer 32

Airway irritation can lead to the cough reflex being initiated

Question 33

T/F low solubility inhalational GAs will induce anaesthesia more quikcly

Answer 33

T 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.