Anxiolytics

Question 1

Main type of anxiety disorder

Answer 1

Generalised anxiety disorder (GAD)

Question 2

Main Therapeutic rationales for anxiety disorders

Answer 2

• CNS is too aroused with continuous activation of adrenergic system
• Therapy find ways to minimise this activation

Question 3

Drugs for anxiety disorders are CNS depressants. A single drug can be anxiolytic, sedative, hypnotic, or anesthesic depending on what factor?

Answer 3

Depends on dose of drug

• Low dose: Anxiolytic + Sedative
• Higher dose: Hypnotic
• Even higher dose: Anesthesia

Question 4

List the Benzodiazepines (BZD) used as:

1. anxiolytics/sedatives
2. Hypnotics
3. Pre-anaesthetics
4. Anti-convulsants (may have anti-convulsant effects)

Answer 4

1. Anxiolytic/sedative: Diazepam, Lorazepam
2. Hypnotics: Diazepam, Triazolam, Temazepam
3. Pre-anaesthetics: Diazepam, Midazolam
4. Anti-convulsant effect: Diazepam

Question 5

List some Non-BZD drugs / drug class also used in anxiety disorders

Answer 5

1. Barbiturates (e.g. phenobarbital)
2. Buspirone
3. Zolpidem
4. Propranolol

Question 6

The most important biological target for anxiolytics

Answer 6

GABA-A receptor

Question 7

Function of GABA

Answer 7

Inhibitory transmitter in brain. It binds to GABA-A receptors to cause chloride ion channels to open, leading to hyperpolarisation of the cell, making cell more difficult to depolarise and become neurally excited

Question 8

Outline the MoA of BZDs

Answer 8

Similar to GABA:

• Binds to GABA-A receptor
• Increases frequency of GABA-induced chloride ion channel opening, hence enhancing entry of chloride ion via chloride ion channel
• Cause greater hyperpolarisation of the cell hence reducing cell neural excitability

Question 9

There are three types of BZDs: Short, Intermediate and Long.

What type is suitable for GAD and why?

Answer 9

Intermediate and long

• Better as GAD may be chronic and long term
• Hence intermediate and long-acting BZDs allow low frequency of dosing, improving patients’ compliance

Question 10

There are three types of BZDs: Short, Intermediate and Long.

What type is suitable for surgical procedures

Answer 10

Short-acting

Question 11

What is the AE of overdose of BZD, and how to treat the overdose?

Answer 11

• Severe respiratory depression, especially if used concurrently with alcohol
• Treat using flumazenil, a BZD antagonist. It binds to GABA-A receptor and facilitate the closure of chloride ion channels to stop chloride ion influx

Question 12

Some side effects of BZDs and their caution

Answer 12

1. Drowsiness
2. Confusion
3. Amnesia
4. Impaired muscle co-ordination (avoid operating heavy machinery)

Question 13

Describe tolerance and dependence of BZDs. Hence what is the precaution when using BZD?

Answer 13

• Dependent on frequency of use
• Dependence can develop (hence abuse potential) and withdrawal effects includes: disturbed sleep, rebound anxiety, tremor, convulsions
• Hence, slowly taper dose and withdraw gradually

Question 14

Outline the MoA of Zolpidem and state its use

Answer 14

• Potentiates GABA-A mediated chloride ion currents. Acts at the same site as BZDs
• Has good hypnotic effect, primarily used to treat insomnia (Insomnia is a common presentation of GAD)
• It is not effective as anxiolytics

Question 15

Outline the MoA of Buspirone. What does it show about the cause of GAD?

Answer 15

• Serotonin 5-HT1A receptor partial agonist, and binds to dopamine receptors
• Shows that anxiety is not only caused by GABA, but other receptors and complex interactions as well

Question 16

How long is the onset of anxiolytic effects for Buspirone?

Answer 16

1-2 weeks

Question 17

Can Buspirone be used for seizure and epilepsey?

Answer 17

No, it lacks anticonvulsant and muscle relaxant properties

Question 18

Outline MoA of Barbiturates

Answer 18

• Potentiates GABA-A mediated chloride currents, but a site distinct from BZDs

Question 19

What was Barbiturates used as? What has replaced it and why has it been replaced?

Answer 19

• Used as sedative-hypnotic
• Replaced by BZDs due to barbiturate’s tendency to develop tolerance and dependence, and also its severe withdrawal symptoms

Question 20

Can flumazenil be used to treat overdose of Barbiturates?

Answer 20

No, Flumazenil displaces BZD from BZD site in GABA-A receptor. However, Barbiturate binds to GABA-A at a different site, which Flumazenil does not bind.

Question 21

What happens when Barbiturates reach high doses in the body?

Answer 21

• Can directly open Cl- channels without binding to GABA-A

- Can block Na+ channels

Question 22

Outline the MoA of Pregabalin and its use

Answer 22

• GABA analogue: Increases synaptic GABA
• Also acts on voltage-gated Ca channels
• Use: GAD, has anticonvulsant effects

Question 23

Possible SE of pregabalin

Answer 23

Emergence of worsening of suicidal thoughts

Question 24

Outline the MoA of Hydroxyzine and its use

Answer 24

• 1st generation antihistamine, also have activities on serotonergic and alpha-adrenergic receptors
• Antagonist of serotonin 5-HT2 receptors hence its anxiolytic effects

Question 25

Advantages of Hydroxyzine

Answer 25

1. Low addictive potential compared to BZDs and barbiturates | 2. Helps to ease itching due to antihistamine activities

Question 26

Outline the MoA of Propranolol and its uses

Answer 26

Beta-adrenergic receptor antagonist - Uses: Performance anxiety, social phobias

Question 27

What is propranolol contraindicated in?

Answer 27

- Asthma | - Heart conditions

Question 28

There are 3 duration classifications of barbiturates. What are they, and what are their uses? Give an example for each

Answer 28

1. Ultrashort acting: As IV, induction of anesthesia E.g. Thiopental 2. Short acting: Used as sedative and hypnotic E.g. Pentobarbital, amobarbital 3. Long acting: Used as anticonvulsant E.g. phenobarbital

Question 29

List other anxiolytics | hint: many are also antidepressants

Answer 29

1. NaSSA: Mirtazapine 2. TCA: Clomipramine 3. SSRI: Fluoxetine, Citalopram, Sertraline, Paroxetine 4. SNRI: Venlafaxine, duloxetine

Question 30

There are some anxiolytics which can act as antidepressants. What does this show about the nature of these 2 conditions?

Answer 30

There might be close association between anxiety and depression. Hence there might be common receptor interactions