Anxiolytics and Hypnotics

Question 1

What is the difference between anxiolytics and hypnotics?

Answer 1

Anxiolytics are used to treat anxiety

Hypnotics treat insomnia - anxiety can cause insomnia

Question 2

Describe the GABAa receptor

Answer 2

• Ligand gated ion channel that allows Chloride ions through when open
• causes hyperpolarisation as it brings in negative charge
• Has a pentameric structure
• 6 alpha subtypes, 3 beta, three gamma
• most common configuration is 2 alpha, 2 beta and a gamma
• Found postsynaptically
• Has multiple binding sites - GABA binds at the alpha and beta interfaces, BZDs bind to alpha/gamma interface

Question 3

How is GABA taken back up?

Answer 3

GABA activity terminated by GABA reuptake transporter (GAT)

Question 4

What does allosteric mean?

Answer 4

• When something binds to a site that is distinct to the agonist binding site

Question 5

What are NAMs and PAMs?

Answer 5

Positive Allosteric Modulators either increase binding (making it easier to open) or enhance the functional response (e.g. allowing more Cl- in)

Negative Allosteric Modulators do the opposite

Question 6

Give examples of PAMs

Answer 6

Barbiturates
BZDS
Z-drugs

Question 7

What are barbiturates?

Answer 7

• PAMs
• bind to increase the time the channel is open - enhance functional response
• at high concentrations they are direct agonists of the GABAa receptor

Question 8

What are Barbiturates still used for?

Answer 8

Still used in epilepsy, GA, euthanasia and capital punishment

Question 9

Why have barbiturates been widely replaced by BZDs?

Answer 9

largely replaced by BZDs as they are cleaner, lower risk of OD and have an antidote

Question 10

How do BZDs work?

Answer 10

• PAMs - increase binding by stabilising the GABA binding site into a configuration where it is more exposed, increasing GABA’s affinity
• Binds to the alpha/gamma interface

Question 11

Why don’t BZDs bind to all GABA receptors?

Answer 11

• Only binds to a1,2,3,5 as they have a Histidine residue, whereas a4 and 6 have Arginine.

Question 12

What is the antidote for BZD overdose?

Answer 12

Flumenazil - acompetetive antagonist at the BZD binding site

- Should only be a last resort as it has very bad withdrawal symptoms

Question 13

Why are BZDs the most commonly used anxiolytic/hypnotic?

Answer 13

• They decrease anxiety AND have a sedative effect

* They give a reduction in muscle tone and an anticonvulsant effect (reduction in epilepsy)

Question 14

Why are short acting BZDs better for use as hypnotics?

Answer 14

• They are preferred because their sedative effects will have worn off by the day time

Question 15

Give 3 examples of BZDs

Answer 15

Midazolam (short) - premedication/induction
Temazepam (medium) - hypnotic
Diazepam (long) - anxiolytic and used to treat alcohol withdrawal

Question 16

What are Z-drugs?

Answer 16

• Act at the BZD site on the GABA receptor - also stabilise the binding site to increase the affinity
• Structurally different to BZDs
• Hypnotics - NO ANXIOLYTIC EFFECTS

Question 17

Why does going cold turkey from BZDs after tolerance cause seizures?

Answer 17

• When on the drug, GABA receptors will be getting much more stimulation than normal, hyperpolarising the membrane and reducing the amount of firing
• After a while, the synapse will insert more Glutamate receptors to deal with the increased stimulation / lack of firing
• When you come off of the drug, the GABA receptors wont be stimulated much, however, there will still be more Glutamate receptors
• less inhibition for the increased stimulation –> lots of AP firing
• Symptoms get worse than before

Question 18

Why would you take BZDs for alcohol tolerance?

Answer 18

• A healthy person has a balance of excitation and inhibition
• Alcohol increases inhibition as it increases GABA’s effects
• When you become tolerant to alcohol, the body upregulates the glutamate receptor to cause more excitation
• If you completely remove alcohol, then you get way more stimulation than inhibition –> seizures
• Therefore you can take BZDs to give some GABA stimulation to provide more inhibition

Question 19

Summary of BZDs

Answer 19

INCREASE INHIBITION TO DECREASE EXCITATION

Question 20

Where does Serotonin act?

Answer 20

• Acts on 5-HT metabotropic receptors
• there are 7 families of these
• Serotonin is metabolised in synapses by Monoamine oxidase (MAO) and recaptured by selective reuptake transporters (SERT)

Question 21

What is the mechanism of 5-HT1A agonists?

Answer 21

• 5-HT1A receptors are found presynaptically
• They are auto-inhibitory receptors - once the neuron releases serotonin, it shuts it off so more cannot be released
• they are found in areas that deal with mood, sensation, cognition and memory processing - work to decrease their innervation

Question 22

Give an example of a 5-HT1A agonist

Answer 22

Buspirone

• used for GAD
• long-term disorder so wouldn’t use BZDs
• Low risk of tolerance and withdrawal symptoms

Question 23

Summary of 5-HT1A agonists

Answer 23

DECREASE THE SEROTONERGIC DRIVE

Question 24

Different types of adrenoceptors

Answer 24

a1 = Gq –> PLC
a2 = Gi –> inhibits AC
B1 + 2 –> Gs –> activates AC

Question 25

How is the NA removed from the synapse?

Answer 25

Metabolised by monoamine oxidase (MAO)

Recaptured by a selective NA active transporter (NERT)

Question 26

Give an example of a beta adrenoceptor agonist

Answer 26

Propanolol

Question 27

How do beta blockers help with anxiety?

Answer 27

They combat the peripheral symptoms of anxiety

• reduce blood pressure by reducing renin release by juxtoglomerular cells (b1 and b2)
• reduce HR by reducing contraction and conduction (b1)

Question 28

B-blocker summary

Answer 28

DECREASE PERIPHERAL MANIFESTATIONS OF ANXIETY

Question 29

How are anti-histamines hypnotics?

Answer 29

• histamine causes arousal in the brain
• drowsy AHs are lipophilic so can cross the BBB and reduce the arousal
• ANTIHISTAMINES ANTAGONISE CNS H-RECEPTORS RESPONSIBLE FOR WAKEFULNESS