Hypnotic, Sedative and Anxiolytic Drugs-2

Objectives

• Discuss Barbiturates

• Discuss other hypnotic and anxiolytic agents

Mechanism of Action

• Bind to GABAA receptors, enhances GABAergic transmission

• Prolonging the duration of the chloride channel opening

• Blocks excitatory glutamate receptors

Compare and contrast benzos and barbiturates

GABA enhancing action of barbiturate is greater than that of the benzodiazepines

Enhances the efficacy of GABA by increasing the time that the cl- channel stays open

What is the therapeutic action of barbiturates? When would benzos be used?

• Barbiturates have been largely replaced by benzodiazepines in most clinical applications

• Benzodiazepines are safer, cause less tolerance, fewer withdrawal symptoms and induce fewer profound effects on drug metabolizing enzymes

• Used in general anesthesia

• As antiepileptic agents, and for neuroprotection

Adverse effects of barbiturates with other substances

Concomitant administration of barbiturate and other CNS depressants

Administration with ethanol results in CNS depression more severe than that caused by barbiturates alone

Adverse effects of barbiturates

Metabolism of barbiturates

• Barbiturates induce cytochrome P450 (CYP450) microsomal enzymes in the liver

• Chronic barbiturate administration diminishes the action of many drugs that are metabolized by the CYP450 system

What is first line treatment for general anxiety disorder?

Antidepressants

• Efficacy in managing the symptoms of chronic anxiety disorders

• SSRIs and SNRIs, used alone or in combination with low dose of benzodiazepine

Which SSRIs and SNRIs are used for anxiety?

SSRIs: Escitalopram, Citalopram, Fluoxetine, Fluvoxamine, Sertraline

SNRIs: Venlafaxine, Duloxetine

What is the treatment guideline for persistent anxiety?

What are non-benzodiazepine hypnotic agents?

Zolpidem

• What does it act on?

• Describe the onset of action

• Acts on a subset of the benzodiazepine receptor family (GABA)

• Rapid onset of action, effect for approximately 5 hours

What are ADE of zolpidem?

• nightmares

• agitation

• headache

• GI upset

Prolonged use

• little tolerance occurs

• few withdrawal side effect

Zaleplon

• Compare to zolpidem and benzodiazepines

• Who cannot use them?

• Fewer residual effect on psychomotor and cognitive functions compared to zolpidem or benzodiazepines

  • (due to rapid elimination with a half life of approximately 1 hour)

• Not recommended to use during pregnancy and while breast feeding

Eszopiclone

• MOA

• Indication

• ADE

• Bind to GABA receptor

• Used for treating insomnia

• Half life is approximately 7 hours

• Adverse effect

  • Higher dose: cause CNS depression

  • Dose adjustment - concomitant with CNS depressants

• Long-term use of medications in this class is not recommended during pregnancy

Buspirone MOA

• 5HT1A agonist

• Increases serotonin receptor action

• Blocks presynaptic dopamine D2 receptors

• (enhanced dopamine neurotransmission)

Buspirone ADE and Disadvantage

Frequency of adverse effect is low,

Most common adverse effect

• headache, dizziness, nervousness and lightheadedness, and restlessness

Disadvantage: slow onset of action

• (takes days or weeks to produce effect)

Ramelteon

1. MOA

2. Therapeutic Action

3. ADE

1. Selective agonist at the MT1 and MT2

   subtypes of melatonin receptors

2. No evidence of dependence or withdrawal effects

3. ADE: dizziness, fatigue, and somnolence

What drugs are in the Orexin receptor antagonists class?

• Suvorexant (Belsomra)

• Lemborexant (Dayvigo)

• Daridorexant (Quviviq)

Orexin

1. What is it and what is it involved in?

2. What is the MOA?

3. How are they mediated?

1.Orexin (hypocretin) is a neuropeptide

• Regulates arousal, wakefulness and appetite

2.Orexin producing neurons

• Project from the lateral hypothalamus to neurons and brain regions that modulate wakefulness

3.Orexins are mediated via two types of G-Protein coupled receptors (GPCRs), orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R)

• Activated OX2Rs → Depolarize orexin neurons → Increase presynaptic glutamate release (No GABA regulation)

Orexin receptor antagonists MOA

Inhibit OX2Rs → Decrease presynaptic glutamate release

What is the action, advantage and ADE of Orexin receptor antagonists?

1. Action: Inducing sleep by inhibiting the excitatory neurotransmission, mediated through orexin

2. Advantage: target a more localized area of the brain

3. Adverse effects: next day drowsiness, cause dependence

Which drugs in these classes are involved in sleep?

TCAs

• Amitriptyline (Elavil)

• Doxepin (Sinequan)

Atypical Antidepressants

• Trazodone (Desyrel) - very effective in treating sleep disturbance in Alzheimer’s disease

• Mirtazapine (Remeron) - positive impact on insomnia symptoms in people with clinical depression

Antihistamines

• Diphenhydramines (Benadryl)

• Hydroxyzine (vistaril, Atarax)

• Doxylamine (Diclegis)

• To treat mild types of insomnia, over the counter hypnotic agents

Ethanol

1. MOA

2. Action

3. ADE

1. Increases GABA receptor mediated synaptic inhibition AND Inhibits the NMDA glutamate receptor

2. CNS depressant, anxiolytic and sedative effects

3. Liver disease, gastritis, nutritional deficiencies, cardiomyopathy

• Synergize with many other sedative agents and can cause severe CNS depression when used in conjunction with benzodiazepine, antihistamines, and barbiturates

Classification of Anxiolytic Drugs

• Benzodiazepines

• 5-HT1_AReceptor Agonist

• Serotonin Reuptake Inhibitors (SSRIs)

1. Benzodiazepines

   1. Alprazolam

      Chlordiazepoxide

      Diazepam

      Lorazepam

      Oxazepam

      Midazolam

2. 5-HT1_AReceptor Agonist → Buspirone

3. Serotonin Reuptake Inhibitors (SSRIs)

   1. Citalopram

   2. Escitalopram

   3. Fluoxetine

   4. Fluvoxamine

   5. Paroxetine

   6. Sertraline

Drugs to treat Insomnia

1. Benzodiazepines

2. Nonbenzodiazepines

3. Antidepressants

1. Benzodiazepines

   1. Estrazolam

      Flurazepam

      Quazepam

      Temazepam

      Triazolam

2. Nonbenzodiazepines

   1. Zaleplon

   2. Zolpidem

   3. Eszopiclone

   4. Ramelteon

   5. Suvorexant

   6. Lemborexant

   7. Daridorexant

3. Antidepressants

   1. Amitriptyline

   2. Doxepin

   3. Trazodone

   4. Mirtazapine

Which non-benzodiazepin drug is known for its minical muscle relaxant and

A.

B.

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Which non-benzodiazepine drug is often prescribed for

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What is the primary medical application of orexin receptor antagonists?

A.

B.

C.

D.

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