GABA anaesthesia

Question 1

What happens to anaesthetic potency as the number of carbons in alcohol increases?

Answer 1

Increases in potency until about 11 or 12 carbons where the anaesthetic potency starts to dip

Question 2

Which ion(s) do GABAa and glycine receptors conduct?

Answer 2

Chloride ions and when these receptors are activated it causes the influx of chloride that leads to hyperpolarisation

Question 3

Which ion(s) do the excitatory receptors AMPA/kainate, NMDA, a4B2 nicotinic and 5HT3 conduct?

Answer 3

They conduct sodium and potassium ions and in some cases calcium ions

Question 4

In theory, how can general anaesthesia occur using inhibitory and excitatory receptors?

Answer 4

By enhancing the activity of inhibitory receptors or suppressing the excitatory receptors or both

Question 5

What receptor(s) does etomidate have an effect on?

Answer 5

Enhances the inhibitory GABAa receptor and has no effect on any other receptor

Question 6

What receptor(s) does propofol have an effect on?

Answer 6

• Very good at enhancing the GABAa receptor
• Has little effect on the enhancing the glycine receptor
• Reasonable suppression of nicotinic receptor and a small effect on the 5HT3 receptor

Question 7

What receptor(s) does alphaxolone have an effect on?

Answer 7

• Also very good at enhancing GABAa receptor
• Potent inhibition of the nicotinic receptor

Question 8

What receptor(s) does pentobarbitone have an effect on?

Answer 8

Enhances GABAa receptor, inhibits AMPA/kainate, NMDA, nicotinic and 5HT3 receptors

Question 9

Name some examples of drugs that bind to the GABAa receptor

Answer 9

• Benzodiazepines - diazepam, flumenazil
• Barbituates - pentobarbital, hexobarbital
• Steroids - allopregnanolone, alphaxalone
• IV anaesthetics - etomidate, propofol

Question 10

What do positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs) do?

Answer 10

• PAMs enhance function
• NAMs decrease function

Question 11

Where do drugs such as diazepam, flunitrazepam and flumenazil bind to on the GABAa receptor?

Answer 11

They bind at the interface between the alpha and gamma subunit interface

Question 12

GABAa receptors incorporating which subunits are diazepam sensitive?

Answer 12

Gamma 2 and the alpha 1, 2, 3 or 5 subunits

Question 13

GABAa receptors incorporating which subunits are diazepam insensitive?

Answer 13

Gamma 2 and the alpha 4 or alpha 6 subunit

Question 14

What is the difference between alpha receptors 1-3 and alpha receptors 4 and 6 at position 101?

Answer 14

Alpha 1-3 subunits have an H residue at position 101, alpha 4 and 6 subunits have an R residue at this position

Question 15

What are BZDs used to treat?

Answer 15

• Anxiety and insomnia mainly
• They also induce muscle relaxation, control some forms of epileptic seizures and can produce amnesia

Question 16

When bound to the alpha 1 subunit of the GABAa receptor what effect does a BZD have?

Answer 16

Sedative effect

Question 17

When bound to the alpha 2 subunit of the GABAa receptor what effect does a BZD have?

Answer 17

Anxiolytic and analgesic effects

Question 18

When bound to the alpha 5 subunit of the GABAa receptor what effect does a BZD have?

Answer 18

Impaired cognition

Question 19

Describe the heat hyperalgesia test

Answer 19

Paw withdrawal latency upon exposure to a defined radiant heat

Question 20

Describe the mechanical sensitisation test

Answer 20

Paw withdrawal with Von-Frey filaments

Question 21

Describe the cold allodynia test

Answer 21

Time spent lifting, shaking or licking the paw after a drop of acetone on the injured paw

Question 22

The effect of etomidate is dependent on what?

Answer 22

• The beta subunit
• Etomidate works very well on beta 2 and beta 3 receptors but not beta 1 receptors

Question 23

What happens to the tail withdrawal reflex when a wild type mouse is given etomidate?

Answer 23

Etomidate suppresses the tail withdrawal reflex in wild type mice

Question 24

What happens to the tail withdrawal reflex when a Beta 3 knock in mouse is given etomidate?

Answer 24

Etomidate does not suppress the tail withdrawal reflex

Question 25

What is THIP and how does it work in anaesthetics?

Answer 25

• THIP (gaboxadol) is a conformationally restricted analogue of the highly potent GABAa receptor agonist muscimol
• It acts as a low potency agonist of GABAa receptors

Question 26

What kind of sleep does etomidate promote and how does it do this?

Answer 26

Non-REM sleep by enhancing GABA spillover which leads to thalamocortical oscillations in the alpha-beta range

Question 27

Which GABAa receptor subunit is thought to mediate the acute memory impairing effects of etomidate?

Answer 27

• Alpha 5 receptor subunit
• Etomidate, diazepam and isoflurane impair cognitive performance in WT but not in alpha 5 mice

Question 28

What does exposure to a GABAa receptor active general anaesthetic do to memory impairment?

Answer 28

Even brief exposure to a GABAa receptor active general anaesthetic selectively increases cell surface expression of hippocampal alpha 5 GABAa receptors resulting in an increased tonic current and cognitive deficits

Question 29

What is the role of inflammation of IL-1B in memory impairment?

Answer 29

• Inflammation resulting from autoimmune disease, infection, stroke and brain trauma can lead to memory impairment
• Inflammation also contributes to chronic neurodegenerative diseases characterised by memory loss such as AD, PD, MS and AIDS related dementia
• Systemic inflammation increases production of cytokines in the brain, including IL-1B - in patients with sepsis associated encephalopathy increased plasma levels of IL-1B correlated with cognitive deficits