Anxiolytics

Question 1

What system in the brain when dysfunctional can give rise to anxiety?

Answer 1

Limbic system

Question 2

Describe the pathophysiology of anxiety

Answer 2

Limbic dysfunction → Reduce 5-HT (serotonin) release → Reduce binding of 5-HT to post synaptic neuron and reduce GABA release → less GABA binds to GABA-A receptors → reduced opening of Cl- channels → depolarisation → increase action potential → sympathetic nervous system activation

Question 3

How does GABA reduce neuronal excitability?

Answer 3

GABA is an inhibitory transmitter in the brain and acts on GABA-A receptors Cl- channels

ABA binds to the receptor on an inactive Cl- channel -> opening of Cl- ion channel and influx of Cl- ions -> hyperpolarisation of cells -> decrease active potentials

Question 4

What are anxiolytics/sedative-hypnotics?

Answer 4

Sedative-hypnotics are a class of drugs that depress CNS function, inducing sedation, sleep, and unconsciousness with increasing dose

Question 5

What are the 2 main groups of sedative-hypnotics, anxiolytics

Answer 5

1. Benzodiazepines
2. Barbituates

Question 6

What does anxiolytics target?

Answer 6

GABA-A receptors

Question 7

What is the difference between benzodiazepines and barbiturates?

Answer 7

Benzodiazepines: Potentiate GABA actions by increasing the frequency of GABA-induced channel opening

Barbiturates: Increase the duration of GABA-induced channel opening

Question 8

Which subunits of GABA-A receptors does benzodiazepines bind to

Answer 8

Binds onto GABA-A receptor ɑ and γ subunits

Question 9

Mechanism of benzodiazepines

Answer 9

Positive Allosteric Modulator of GABA-A receptor (NOT AGONIST!)

↑ GABA action → ↑ opening frequency of chloride channels → hyperpolarization of the postsynaptic neuronal membrane → ↓ neuronal excitability

Question 10

What are some examples of typical benzodiazepines?

Answer 10

(onset of action/ half life)

Short-acting:
1. Midazolam (0.5-1.5/3)
2. Triazolam (2/2.3)

Intermediate acting:
1. Lorazepam (2/12)
2. Clonezepam (0.33-0.66/30)

Long acting:
1. Diazepam (0.5/43)
2. FLurazepam (0.5-1/74)

Question 11

What are short acting benzodiazepines (midazolam) indicated for?

Answer 11

pre-anaesthesia, allows for fast sedation and fast waking up

Question 12

What are long acting benzodiazepines (diazepam) indicated for?

Answer 12

more chronic conditions like
1. alcohol withdrawal syndrome
2. refractory seizures

Question 13

What can be used to treat status epilepticus (emergency condition)?

Answer 13

Diazepam (due to short onset of action 0.5hrs)

Question 14

Alcohol withdrawal syndrome prescribe what?

Answer 14

Lorazepam, Oxazepam, and Temazepam are preferred for individuals who drink a LOT (have alcoholic liver disease), because hepatic dysfunction does not have a strong effect on their metabolism. All benzodiazepines are metabolized by the liver, but these three undergo biotransformation through glucuronidation, not CYP450 activation, and are less affected by liver disease.

Question 15

What are some common side effects of benzodiazepines?

Answer 15

1. Overdose / toxicity (severe respiratory depression, especially w alcohol)
2. Drowsiness, confusion, amnesia
3. Impaired muscle coordination
4. Tolerance and dependance (Gradual withdrawal necessary)

Question 16

Treatment of acute overdose/toxicity of benzodiazepines

Answer 16

Flumazenil, a benzodiazepine antagonist
(However not effective for treatment of barbiturates overdose)

Question 17

Mechanism of Zolpidem

Answer 17

• Also potentiates GABAA mediated Cl- currents at the same site as benzodiazepines.
• Has good hypnotic effect: primarily used to treat insomnia
• ONLY TARGETS INSOMNIA NO ANXIOLYTIC EFFECT (EXAM HINT!)

Question 18

Mechanism of Buspirone

Answer 18

• A serotonin 5-HT1A receptor partial agonist. Also binds dopamine receptors.
• Indicated for GAD but anxiolytic effects takes 1-2 weeks
• Lacks anticonvulsant and muscle relaxant properties

Question 19

Which subunit of GABA-A receptors does barbiturates bind to?

Answer 19

β subunit

Question 20

Why is barbiturates no longer actively used?

Answer 20

1. Dose-dependant depression of CNS (worse than benzodiazepines)
2. High tendency of tolerance development
3. Severe withdrawal symptoms

Question 21

Examples of barbiturates

Answer 21

Ultra short acting (20mins)
Induction of anaesthesia: Thiopental

Short acting (3-8hrs)
Sedative & hypnotic: pentobarbital, amobarbital

Long acting (1-2 days)
Anticonvulsant: Phenobarbital

Question 22

What is the mechanism of pregabalin?

Answer 22

• GABA analogue, increases synaptic GABA  GABA receptor mediated Cl- currents resulting in hyperpolarization.
• Also acts on voltage-gated Ca2+ channels.
• Used to treat GAD, also has anticonvulsant effects
• Associated with emergence of suicidal thoughts

Question 23

What is the mechanism of Hydroxyzine?

Answer 23

• A first generation antihistamine with activities on serotonergic and α-adrenergic receptors.
• Anxiolytic effects attributed to antagonism of serotonin 5-HT2 receptors.
• Has low addictive potential compared to BZDs and barbiturates.
• Because of antihistamine activities, also helps with itching.

Question 24

What is the mechanism of propranolol?

Answer 24

• A beta-adrenergic receptor antagonist.
• Used for treating performance anxiety and social phobias
• Reduces physical symptoms associated with adrenergic activation
• Contraindicated in patients with asthma and heart conditions.