Sedative - Hypnotic Agents (Pilch) - 10/11/16 Flashcards
Sedative vs. Hypnotic
Sedative (anxiolytic): reduces anxiety and exerts calming effect
Hypnotic: produces drowsiness and encourages the onset and maintenance of a state of sleep
- Require more pronounced CNS depression than sedative effects
- Effects can be achieved with some anxiolytic drugs just be increasing the dose
Benzodiazepines (7)
Most effective and commonly prescribed drugs for rapid relief of acute anxiety symptoms (i.e. panic attacks)
Alprazolam (Xanax)
Chlordiazepoxide (Librium)
Clonazepam (Klonopin)
Clorazepate (Tranxene)
Diazepam (Valium)
Lorazepam (Ativan)
Oxazepam (Serax)
Benzodiazepines: Pharmacokinetics
- Highly lipophilic - can cross BBB with ease (best drug for this) but…
- Cross placental barrier during pregnancy → depression of neonatal vital functions
- BZs also detectable in breast milk → may exert depressant effects in nursing infant
- Clearance reduced in elderly
Benzodiazepines: Pharmacodynamics
GABAA Receptor and its interactions with BZs
- Receptor functions as Cl- ion channel
- Activated by GABA (major inhibitory neurotransmitter in CNS)
- BZs bind to molecular components of GABAA receptor in neuronal membranes in CNS
- GABA-ergic, enhance GABA
- Ultimately, more blockage of transmission –> more sedation
- GABA interacts at 2 sites between alpha and beta subunits, triggering Cl- ion channel opening –> hyperpolarization
- BZs increase frequency of GABA-gated channel opening events
Benzodiazepines: Advantages and Disadvantages
Advantages:
- Rapid onset of action
- Relatively high therapeutic index and availability of flumazenil for treatment of overdose
- Low risk of drug interactions based on liver enzyme induction
- Minimal effects on CV and autonomic functions (doesn’t depress these)
Disadvantages:
- Risk of dependence
- Depression of CNS functions (does affect mentation)
- Amnesic effects (anterograde amnesia)
- Example: if you have anxiety before an exam, this is not good for you
Benzodiazepines: Dosing Considerations
- Get away with the lowest dose you can have for the shortest period of time
- Prescriptions written for short periods (2 to 4 weeks) since addictive
- Since elderly are sensitive to effects of BZs, doses ~1/2 those used in younger adults are safer
- Do not combine with other anti-anxiety agents, antihistamines, anticholingergics, and alcohol
Benzodiazepines: Clinical Toxicology
Direct Toxic Actions
- At anxiolytic doses, BZs → drowsiness, impaired judgment, diminished motor skills
- Anterograde amnesia
- Overdose → common cause of confusional states in elderly
- At high doses → lethargy, state of exhaustion, behavioral disinhibition (like intoxication)
Benzodiazepines: Clinical Toxicology
Tolerance, Psychologic Dependence, and Physiologic Dependence
All result from prolonged use of BZs
- After extended use, abrupt cessation → withdrawal symptoms (rebound anxiety and insomnia)
- BZs with longer half lives → less severe withdrawal signs (eliminated more slowly)
Benzodiazepines: Clinical Toxicology
Overdoses and role of Flumazenil (Romazicon)
- Rarely fatal if discover is made early
- With severe toxicity, respiratory depression can be complicated by aspiration of gastric contents
- Treatment: ensure patent airway and maintenance of plasma volume, renal output, and cardiac function
Flumazenil (Romazicon)
- Synthetic BZ derivative that binds to BZ site on GABAA receptor
- Antagonizes actions of the BZs and newer hypnotics but not barbiturates
- Newer hypnotics:
- Zolpidem
- Zaleplon
- Eszopiclone
- Newer hypnotics:
- Acts rapidly via IV but has short half life (0.7-1.3 hrs)
- Note: Because all BZz have longer duration of action than flumazenil, sedation commonly recurs (repeated administration of antagonist required)
Long-Term Pharmacotherapy
Antidepressants = first-line drugs in chronic management of GAD
SSRIs (4) + SNRIs (2)
Selective Serotonin Reuptake Inhibitors (SSRIs):
- Escitalopram (Lexapro)
- Paroxetine (Paxil)
- Sertraline (Zoloft)
- Fluoxetine (Prozac)
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
- Duloxetine (Cymbalta)
- Venlafaxine (Effexor)
Anti-anxiety response of antidepressants requires 2 to 4 weeks or longer → so not great to treat a panic attack
- SSRIs and SNRIs don’t knock down stress pathways but activate coping pathways
Long-Term Pharmacotherapy
Buspirone (BuSpar)
Description
Mechanism
Toxicology
Description
- Selective anxiolytic effects w/o causing sedative, hypnotic, or euphoric effects → not as depressive as BZs so toxicology profile is good!
- HOWEVER, considered 2nd line agent b/c of inconsistent reports of long-term efficacy and lack of efficacy for other depressive diorders
Mechanism
- Does not interact directly with GABAergic systems
- Acts as partial agonist at brain 5-HT1A receptors (also has affinity for brain dopamine D2 receptors)
- Anxiolytic effects take 2 weeks or longer to become established → not ideal drug for acute anxiety states
Toxicology
- Better toxicological profile than BZs or antidepressants
- Most common adverse reactions typically transient (nausea, abdominal pain, drowsiness, dizziness)
- Drug Interactions:
- Inducers and inhibitors of CYP3A4
- Monoamine oxidase (MAO) inhibitors
- Can result in elevated BP
Hypnotics - drugs used for treatment of insomnia
GABAergic drugs
- Benzodiazepines (5)
- Non-benzodiazepines (3)
Non-GABAergic drugs (2)
GABAergic drugs
- Benzodiazepines
- Triazolam (Halcion)
- Temazepam (Restoril)
- Estazolam (ProSom)
- Flurazepam (Dalmane)
- Quazepam (Doral)
- Non-benzodiazepines
- Zaleplon (Sonata)
- Zolpidem (Ambion)
- Eszopiclone (Lunesta)
Non-GABAergic drugs (2)
- Ramelteon (Rozerem)
- Suvorexant (Belsomra)
Describe the use of benzodiazepines for insomnia.
- Hypnotic doses are higher than those used for anxiolytic applications
- At hypnotic doses, BZs increase total sleep time
- Decrease time to fall asleep and number of awakenings
Describe the use of non-benzodiazepines for insomnia.
Zolpidem (Ambien)
Zaleplon (Sonata)
Eszopiclone (Lunesta)
- Bind to same site on GABAA receptor as BZs and exhibit similar GABAergic effects
- More selective in their binding than BZs (bind only receptor isoforms that contain alpha1 subunit)
- All decrease time to persistent sleep
-
Zolpidem and eszopiclone –> inc. total sleep time
- Zaleplon does not - recover better next day
- Rapid onset of activity, short half lives (1.5-6 hrs)
- Not recommended for long-term use (risk of withdrawal symptoms)
- Unlike certain BZs, all lack anticonvulsant and muscle relaxing activities
Ramelteon (Rozerem)
- Activate two melatonin receptors (MT1 and MT2) in brain
- No GABAergic effects in CNS
- Decreases sleep latency and increases sleep periods, with no rebound insomnia or risk of dependence (i.e., not a controlled substance)
- Effective in treating patients with sleep apnea
