Benzodiazepines Flashcards
T/F: Benzodiazepines are positive allosteric modulators
T
How are benzodiazepines different from barbituates and other CNS depressants?
CNS depression produced by benzodiazepines plateaus BEFORE achieving coma or lethal respiratory depression
Which benzodiazepines are short acting (2-5 hours)?
- Triazolam (Halcion)
- Midazolam (Versed)
- Brotizolam (Lenormin)
- Flurazepam (Dalmane)
Which benzodiazepines are intermediate acting (6-24 hours)?
- Alprazolam (Xanax)
- Lorazepam (Ativan)
- Lormetazepam
- Oxazepam (Serax)
- Temazepam (Restoril)
- Chlordiazepoxide (Librium)
- Estazolam (ProSom)
Which benzodiazepines are long-acting (>24 hours)?
- Clobazam (Onfi)
- Clonazepam (Klonopin)
- Chlorazepate (Tranxene)
- Diazepam (Valium)
- Flunitrazepam (Rohypnol)
- Quazepam (Doral)
What is the benzodiazepine target?
GABA(A) receptor
Describe the GABA(A) Receptor
- Macromolecular complex made up 5 subunits forming a Cl- channels
- Alpha, beta, gamma are primary subunits
How is the GABA(A) receptor activated by GABA?
- GABA binds to specific sites between the alpha and beta subunits
- Two molecules of GABA are required to activate the receptor
- Activitating the receptor increases Cl- conductance
- Increasing Cl- conductance increases the threshold to produce an action potential
How are GABA(A) receptors activated by benzodiazepines?
- BZs are positive allosteric modulators that enhance/facilitate GABA binding to the receptor complex. They are NOT receptor agonists
- BZs bind to a site between the alpha and gamma subunits
- BZs shift the GABA dose-response curve to the left
- BZs increase the frequency of channel openings
BZ1
- Responsible for sedation, amnesia, and possibly antiseizure effects
BZ2 and BZ3
Anxiolytic and muscle relaxant properties
What other compounds bind to the GABA(A)-Chloride Channel Complex?
- Allopregnanolone, DHEA
- Flumazenil (Romazicon) - BZ antagonist
- Z-drugs: Zolpidem (Ambien), Zaleplon (Sonata), Eszopiclone (Lunesta) - selective BZ1 receptor agonists
- General anesthetics
- Ethanol
- Barbituates.
Barbiturates (BAR)
- Binds at a different site on the GABA(A) complex to facilitate GABA effect and increase chloride conductance: only alpha and beta subunits are required for action
- Increase duration of each hyperpolarization event
- Shift the GABA dose-response curve to the left and increase its maximum height
- Less potent than BZ
What are the pros of diazepam?
- Rapid onset
- Rapid termination of CNS action due to redistribution to fat
- Completely absorbed PO (94% bioavailability)
What are the cons of diazepam?
Not good to treat seizures b/c less than 30 min duration of action
What are the pros of lorazepam?
- Slower redistribution into fat, therefore longer duration of effect
- Better to treat acute seizures
What are the cons of lorazepam?
- Bioavailability of 90% by PO
- Less lipophilic so slower onset
Clorazepate (Tranxene)
- Prodrug for nordiazepam
- Hydrolyzed in the stomach to desmethyldiazepam
- Used to treat anxiety
- Also used along with other medications to treat seizures
What is the metabolism of BZ?
- Phase 1 N-dealkylation or hydroxylation
- Phase II glucuronidation
What are the drug interactions of benzodiazepines?
- Alcohol
- Opioids
- Insomnia drugs
- Fluoroquinolones
The ‘Z’ Drugs
- NOT benzodiazepines
- To facilitate the onset and maintenance of sleep
- Metabolized differently form benzodiazepines
Zolpidem and Zaleplon
- Selective BZ1 agonists
- Produce sedation, minimal muscle relaxation, antiepileptic, and antianxiety effects
- Indicated for sleep-onset insomnia
Eszopiclone
- Active S(+) isomer of zipiclone
- Classified as a BZ1 agonist
- Used for treatment of insomnia
What is the FDA Boxed Warning of the ‘Z’ drugs?
- Sleepwalking, sleep driving, and enagaging in the other activities while not fully awake
