【Pharmacology】Anxiolytic and hypnotic drugs

Anxiolytic and hypnotic drugs

• Used to treat anxiety and insomnia
• Anxiety: an emotional state characterized by excessive feelings of worry fear and nervousness
• Insomnia: the inability to initiate maintain or achieve restful sleep

Content:

1. Role of GABA in the central nervous system
2. Limbic system
3. Anxiolytic and hypnotic drugs
    a. Benzodiazepines
    b. Barbiturates 
    c. Non-benzodiazepine hypnotics

1. Role of GABA in the central nervous system

Gamma-aminobutyric acid (GABA)

• a major inhibitory neurotransmitter
• when GABA reaches and binds to specific receptor located on a neuron, it reduces the activity level of that neuron and makes it less likely to fire its action potential
• recognized by both ligand-gated and G-protein linked GABA receptors
• ligand-gated GABA receptor (GABA-A): main target of many anxiolytic and hypnotic agents
• GABA-A receptor is made up of five subunit proteins arranged to form a central pore
• 2 alpha, 2 beta, 1 gamma or 1 delta
• alpha-1: sleep
• alpha-2 or alpha-3: anxiety

Activation

When two GABA molecules bind to the GABA-A receptor,

• conformational change is induced
• opening of the central pore
• negatively charged chloride ions to rush into the cell
• increases the negative charge inside the postsynaptic cell 
• more difficult for an excitatory inputs to cause an action potential

2. Limbic system

• GABA-A receptors are present in high concentration in the limbic system 
• amygdala which contains many neurons that use the neurotransmitter GABA
• control feelings of fear and anxiety 
• stress excitatory neurons in the amygdala fire rapidly sending excitatory signals to other areas of the brain, leads to feeling of panic or fear
• the inhibitory interneurons in the amygdala regulate these emotions by releasing GABA and its binding to postsynaptic receptors such as GABA-A inhibits the excitatory signals, thus has a calming tranquilizing effect on our emotions and prevents us from becoming overwhelmed in stressful situations 

3. Anxiolytic and hypnotic drugs

can be divide into 3 groups: benzodiazepines, barbiturates and non-benzodiazepine hypnotics

a. Benzodiazepines

• a benzene ring fused to a diazepine ring
• Binding site: alpha and gamma subunit on the GABA-A receptor
• benzodiazepines do not bind to the GABA recognition site located at the junction of the alpha and beta subunits 👉 they don't induce opening of the channel
• decreased anxiety and greater feeling of calm
• binding of a benzodiazepine to its receptor site
• increases the affinity of GABA for the GABA binding site
• increased frequency of the channel opening 
• increased influx of chloride ions at the postsynaptic cell
• ultimately makes it difficult for any excitatory inputs to cause an action potential
• can also produce mild muscle relaxation 
• their action on GABA receptors in the spinal cord cerebellum and brain stem

Drug:

• Alprazolam 
• Chlordiazepoxide 
• Clonazepam 
• Diazepam 
• Lorazepam
• Temazepam

Side-effects of benzodiazepines

• Drowsiness 
• Dizziness 
• Decreased alertness 
• Decreased concentration
• Impairment of motor coordination
• all due to sedating and muscle relaxing action 

b. Barbiturates 

• Barbiturates bind to GABA-A receptor at the alpha or beta subunit 
• enhance the effect of GABA at the GABA-A receptor
• instead of increasing the ion channel opening frequency, they increase the ion channel opening duration
• (barbiturates hold the ion channel open continuously for long periods)
• can decrease the activity of excitatory neurotransmitters such as acetylcholine and glutamate
• At higher doses, they can also mimic GABA and directly activate GABA receptors, thus leading to profound central nervous system depression
• Hence, its has lower therapeutic index than benzodiazepines

Drug:

• Pentobarbital 
• Phenobarbital 
• Secobarbital

Side effects of barbiturates

• Dizziness 
• Lightheadedness 
• Sedation
• Memory and attention impairments
• coma or death due to respiratory depression
• because of their narrow therapeutic index

c. Non-benzodiazepine hypnotics

• selectively bind to the alpha-1 subunit of the GABA-A receptor thus triggering chloride channel opening with resulting membrane hyperpolarization
• because alpha-1 containing GABA-A receptors are highly expressed in wake promoting regions of the brain 
• results in sleepiness

Drug:

• Zolpidem 
• Zaleplon
• Eszopiclone

Side-effects of non-benzodiazepine hypnotics

• cognitive impairments including memory loss daytime sedation
• impairment of motor function

4. Reference

https://youtu.be/4ZHudeMho8g

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