Anxiolytics Flashcards
What system in the brain when dysfunctional can give rise to anxiety?
Limbic system
Describe the pathophysiology of anxiety
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
How does GABA reduce neuronal excitability?
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
What are anxiolytics/sedative-hypnotics?
Sedative-hypnotics are a class of drugs that depress CNS function, inducing sedation, sleep, and unconsciousness with increasing dose
What are the 2 main groups of sedative-hypnotics, anxiolytics
- Benzodiazepines
- Barbituates
What does anxiolytics target?
GABA-A receptors
What is the difference between benzodiazepines and barbiturates?
Benzodiazepines: Potentiate GABA actions by increasing the frequency of GABA-induced channel opening
Barbiturates: Increase the duration of GABA-induced channel opening
Which subunits of GABA-A receptors does benzodiazepines bind to
Binds onto GABA-A receptor ɑ and γ subunits
Mechanism of benzodiazepines
Positive Allosteric Modulator of GABA-A receptor (NOT AGONIST!)
↑ GABA action → ↑ opening frequency of chloride channels → hyperpolarization of the postsynaptic neuronal membrane → ↓ neuronal excitability
What are some examples of typical benzodiazepines?
(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)
What are short acting benzodiazepines (midazolam) indicated for?
pre-anaesthesia, allows for fast sedation and fast waking up
What are long acting benzodiazepines (diazepam) indicated for?
more chronic conditions like
1. alcohol withdrawal syndrome
2. refractory seizures
What can be used to treat status epilepticus (emergency condition)?
Diazepam (due to short onset of action 0.5hrs)
Alcohol withdrawal syndrome prescribe what?
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.
What are some common side effects of benzodiazepines?
- Overdose / toxicity (severe respiratory depression, especially w alcohol)
- Drowsiness, confusion, amnesia
- Impaired muscle coordination
- Tolerance and dependance (Gradual withdrawal necessary)
Treatment of acute overdose/toxicity of benzodiazepines
Flumazenil, a benzodiazepine antagonist
(However not effective for treatment of barbiturates overdose)
Mechanism of Zolpidem
- 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!)
Mechanism of Buspirone
- 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
Which subunit of GABA-A receptors does barbiturates bind to?
β subunit
Why is barbiturates no longer actively used?
- Dose-dependant depression of CNS (worse than benzodiazepines)
- High tendency of tolerance development
- Severe withdrawal symptoms
Examples of barbiturates
Ultra short acting (20mins)
Induction of anaesthesia: Thiopental
Short acting (3-8hrs)
Sedative & hypnotic: pentobarbital, amobarbital
Long acting (1-2 days)
Anticonvulsant: Phenobarbital
What is the mechanism of pregabalin?
- 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
What is the mechanism of Hydroxyzine?
- 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.
What is the mechanism of propranolol?
- 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.
