Sedative Hypnotics

1. What is the MOA of Anxiety (3)

2. What are the effects of Sedative Hypnotics (3)

Anxiety MOA:

• Overactivity of circuits mediated by NE 

• Functional deficiency of GABA and serotonin mediated systems.

• Alterations in autonomic functions 

  • (tachycardia, sweating, increased blood pressure)

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Sedative Hypnotics Effects:

• Sedation:

  • Decreased anxiety

  • Decreased motor/mental activity

• Hypnosis:

  • Drowsiness & Increased tendency to sleep.

Differentiate between GABAA and GABAB receptors:

• Mediate…

• Fx? (2)

GABAA receptors:

• Mediate fast inhibitory synaptic transmissions

• Fx: 

  • Regulate neuronal excitability

  • Responsible for rapid mood changes 

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GABAB receptors:

• Mediate slow inhibitory potentials

• Fx:

  • Memory and mood (depression)

  • Pain response

Describe the Therapeutic Approach for Anxiety:

• Drug Classes

• First line?

Therapeutic Approach for Anxiety:

Drug Classes: 

• Antidepressants:

  • (SSRIs)

  • (SNRI’s)

  • (TCAs)

  • (MAOIs)

• Benzodiazepines

• Buspirone

• B- Blockers

• Cognitive-behavioral therapy

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First line:

• Antidepressants 

  • broad-spectrum efficacy

  • Venlafaxine, Paroxetine, Escitalopram

• Full therapeutic response may take 10-12 weeks

What are the Pros/Cons of SSRIS on Anxiety

1. List the names of the SNRIS

2. Side effects of SSRI/SNRI (10)

   • What side effects are associated w/ specific SNRIs

3. Drug Course?

SNRIs

• Venlafaxine (ER) (Effexor)

• Duloxetine (Cymbalta)

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Side Effects of SSRI/SNRI

• sexual disturbance

• sleep disturbance

• Sedation

• Jitteriness

• GI distress

• headaches

• Weight gain

• discontinuation-related effects 

• Increased BP at higher doses (VLFX)

• Urinary retention and liver effects (DLX)

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Drug Course:

• Start low to minimize exacerbation of anxiety

  • Consider Adjuncts:

    • BZD, ß-blocker, anticonvulsant

Describe Benzodiazepines

• List the members

• Timing?

  • Short acting

  • Int. Acting

  • Long Acting

• Effects (5)

  • MEMTIP:

• AE (3)

• Caution

• PK

Benzodiazepines

Members:

• Alprazolam (Xanax) *

• Chlordiazepoxide (Librium)

• Clonazepam (Klonopin) *

• Clorazepate (Tranxene)

• Diazepam (Valium) *

• Flurazepam (Dalmane)

• Lorazepam (Ativan) *

• Oxazepam (Serax) *

• Triazolam (Halcion)

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Timing:

• Short-acting (3-8hrs)

  • Triazolam, Oxazepam

• Intermediate-acting (10-20 hrs)

  • Alprazolam, Lorazepam

• Long-acting (1-3 days)

  • Diazepam, Flurazepam, Chlordiazepoxide, Clorazepate

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Effects: MEMTIP: RAAMs

• Reduce anxiety & aggression

• Anticonvulsant 

• Alcohol detox

• Muscle relaxant

• Sedative and hypnotic actions.

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AE:

• CNS depression

  • Lightheadedness, 

  • drowsiness, 

  • difficulty concentrating

  • Incoordination,

• Anterograde amnesia

• Respiratory depression

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Caution:

• Pregnancy:

  • Birth Defects if used in 1st trimester

  • Neonatal CNS depression and withdrawal if near term

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PK:

• Highly lipophilic

  • rapidly absorbed orally 

  • distributed well.

• Extensive metabolism by CYP 3A4 & CYP2C19

  • Clorazepate decarboxylated in gastric juice -> desmethyldiazepam

1. What are the Potential benefits of using benzodiazepines: (6)

2. What are the Potential Drawbacks Of Benzodiazepines (5)

Potential benefits of using benzodiazepines:

• Effective

• Rapid onset

• Well Tolerated

• Rapid dose adjustment feasible

• Can be used PRN for situational

• Reduces antidepressant-induced activation

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Potential Drawbacks Of Benzodiazepines

• Sedation, cognitive, and psychomotor impairment

• Interaction with alcohol

• Dependence/Abuse

• Discontinuation-related difficulties

• Not effective for comorbid depression

1. Which Benzo do we give for insomnia?

2. Which Benzo do we give for elderly? Why?

3. Which Benzo for Acute Relief/Panic Symptoms

Triazolam:

• rapid onset to facilitate sleep (h.s), 

  • sustained action,

  •  no residual action.

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Oxazepam/Lorazepam:

• Indicated for Elderly Pts

  • Not likely to accumulate with repeated dosing

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For Acute Relief/Panic Symptoms:

• Alprazolam:

• Clonazepam:

What are the uses of Flumazenil (Romazicon)

Flumazenil (Romazicon)

Uses:

• Reverses Benzo’s sedative effects

  • competitive antagonist of receptor

• Benzo Overdose

Describe Benzos:

• Pt Advising

• How to discontinue?

Pt Advising:

• Warn PT to not:

  • Increase Dose

  • Stop abruptly

  • COMBINE w/ Alcohol or other CNS Depressants -> Resp. Depression, Coma, Death

    • antipsychotic agents, TCA’s, opioids

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How to Discontinue:

• Gradually tapering dose over several weeks or months

• Can switch from longer -> shorter acting agent

• Monitor pts for ~ 3 weeks after treatment is discontinued

1. List the things that can inhibit CYP3A4 (7)

2. Effects on Benzo?

Inhibition of CYP3A4

• Erythromycin, 

• clarithromycin, 

• ritonavir, 

• itraconozole,

• ketoconazole, 

• nefadozone 

• grapefruit juice

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Effect on Benzo:

• metabolism and possibility of potential drug interactions

What are the potential benefits of Combining Antidepressants With Benzodiazepines (2) (3)

Combining Antidepressants With Benzodiazepines Potential Benefits

• Rapid anxiolysis

  • during antidepressant lag

  • During antidepressant initiation

  • Residual Anxiety w/ Antidepressant treatment 

• Better prevention + Tx of depression compared to BZD monotherapy

Describe Buspirone

• Usage (2)

• MOA

• Benefits (3)

• AE

• Meta

Buspirone

• Usage:

  • Anxiolytic 

    • Slow onset

  • SAFE IN pregnancy & lactation

• MOA:

  • Partial agonist 5-HT 1A receptors

• Benefits:

  • NO sedation

  • No abuse 

  • NO CNS Depressants intensification 

• AE:

  • Minor psychomotor impairment

• Metabolism:

  • CYP3A4

    • Rifampin decreases plasma levels

    • Erythromycin, ketoconazole increases plasma levels.

Describe Benzodiazepine Receptor Agonists

• Drugs

• Benefits (3;3)

• Usage

Benzodiazepine Receptor Agonists

• Drugs:

  • Zolpidem (Ambien)

  • Zaleplon (Sonata)

• Benefits:

  • Fast Onset

  • Short Duration (4-6 hrs)

  • NO

    • anxiolytic, muscle relaxant or anticonvulsant

• Usage:

  • short-term treatment of insomnia