Sedative-Hypnotic Agents Flashcards
Sedative
anxiolytic; anti-anxiety
- indicated for patients experiencing symptoms severe enough to produce functional disability
Hypnotic
- promotes sleep
- requires more pronounced CNS depression (reduce excitability of CNS)
Pharmacologic Therapy of GAD
- Shore Term
- – reduce severity and duration of anxiety symptoms
- Long Term
- – remission with minimal or no anxiety symptoms
- – no functional impairment
- – increased quality of life
General Approach to GAD Treatment
- plan depends on (3 factors)
- considerations when initiating drug therapy (3 factors)
- develop patient specific treatment plan; psychotherapy and drug therapy
Plan depends on:
- severity and chronicity of symptoms
- medication history
- comorbid medical and psychiatric conditions
Considerations when initiating drug therapy:
- anticipated adverse effects
- history of prior response in the patient or a family member
- patient preference and compliance
Short-Term Pharmacotherapy for Acute Anxiety States
Benzodiazepines (BZ) - biggest class for ACUTE anxiety treatment - v. good acute, v. bad long term; v. high risk of dependency *** act fast, long duration*** (rapid time to peak blood levels; long half-life)
Alprazolam (Xanax)
BZs
Max time usage for BZ
Max 2-4 weeks (due to risk of physical and mental dependency)
Chlordiazepoxide (Librium)
BZs
Clonazepam (Klonopin)
BZs
Diazepam (Valium)
BZs
Lorazepam (Ativan)
BZs
Oxazepam (Serax)
BZs
Benzodiazepine Mechanism
- BZs bind to GABA receptor in neuronal membranes
- – does NOT bind where GABA binds, binds elsewhere and improves GABA function
- BZs increase the frequency of GABA-gated channel opening events
- – GABA firing = inhibition of CNS
- underlies a “GABAergic” mechanism of action, that results in inhibition at all levels of the neuraxis
BZs Clinical Toxicity/Adverse Effects
- can lead to drowsiness, impaired judgement, and diminished motor skills; intensified by alcohol
- can cause significant dose-related anterograde amnesia, and can impair ability to learn new information
- at high doses, toxicity can present as lethargy, exhaustion, or as gross symptoms of ethanol intoxication
Prolonged use of BZs
- withdrawal symptoms due to abrupt cessation
- can lead to tolerance, psychologic and physiologic dependence
CLASS IV controlled drugs
Withdrawal symptoms:
- increased anxiety
- insomnia
- CNS excitability that may progress to convulsions
BZ OD
- treatment
Flumazenil
- even at very high doses rarely fatal
- with severe toxicity, respiratory depression can be complicated by aspiration of gastric contents
Treatment:
- ensure patient airway, maintenance of plasma volume, renal output, and cardiac function
Flumazenil
- competitive antagonist; binds same site as BZ but does nothing
- approved for use in reversing CNS depressant after BZ overdose
- requires repeated administration
Advantages of BZ
- rapid onset of action
- a relatively high therapeutic index and availability of flumazenil for treatment of overdose
- low risk of drug-drug interactions based on liver enzyme induction
- minimal effects on cardiovascular and autonomic functions
Disadvantages of BZ
- risk of dependence
- depression of CNS functions
- amnesic effects
First-Line Drugs Long-term GAD
Newer Antidepressants
- SSRIs
- SNRIs
Escitalopram
SSRI
Paroxetine (Paxil)
SSRI
Sertraline
SSRI
Duloxetine
SNRI
Venlafaxine XR (Effexor XR)
SNRI
SSRI
Selective Serotonin Reuptake Inhibitors
SNRI
Serotonin-Norepinephrine Reuptake Inhibitors
Long-Term Treatment GAD Second Line
- TCA
- Anxiolytic
- Anticonvulsant
TCA
Tricyclic Antidepressant
Mechanism of Action for Antidepressants for Anxiety
not GABA
- block manifestations of anxiety by increasing amount of serotonin available to interact with postsynaptic 5-HT(1A) receptors Calming-sedative effect
- downregulates 5-HT(2) receptors which cause anxiety
Response time for antidepressants
2-4 weeks+
Buspirone
- Anxiolytic (anxiety only; doesn’t help with depression)
- second-line treatment GAD
- does NOT interact with GABAergic systems
- takes 2+ weeks to take effect * NOT good for acute anxiety treatment*
Pregabalin
- Anticonvulsant
- second-line treatment GAD
- increases GABA synthesis and release
- DOES NOT BIND TO GABA RECEPTORS
- produces effects similar to BZs and anti-depressants
- controlled substance; dependence risk (V) (less than BZs)
- is GABAergic
Imipramine
- TCA
- second line treatment GAD
- acts like SNRI
- higher toxicity and adverse effect rates than newer antidepressants
Imipramine Side-effects
- antihistamine (sedation/somnolence)
- anticholinergic (dry mouth; constipation; burred/double vision/ tachycardia)
- antiadrenergic (orthostatic hypotension/BP dips)
- risk of serious toxicity (including seizures, rapid heart rate, and cardiac arrest) with high doses
Hypnotics
- drugs used for treatment of insomnia
- SHORT t1/2: want to be able to get up in the morning
GABAergic Hypnotics
- Benzodiazepines (higher doses than used for anxiety)
- Non-Benzodiazepines hypnotics (also bind to GABA receptors)
Triazolam (Halcion)
BZ Hypnotic
Temazepam (Restoril)
BZ Hypnotic
Estazolam (ProSom)
BZ Hypnotic
Flurazepam (Dalmane)
BZ Hypnotic
Quazepam (Doral)
BZ Hypnotic
Zaleplon
Non-BZ Hypnotic
- help fall asleep DOESNT help KEEP asleep
Zolpidem (Ambion)
Non-BZ Hypnotic
- helps fall asleep & stay asleep
Eszopiclone
Non-BZ Hypnotic
- helps fall asleep & stay asleep
Newer Non-GABAergic Hypnotics
- Melatonin (MT) Receptor Agonists
- Orexin (OX) Receptor Antagonist
Ramelteon
Melatonin (MT) Receptor Antagonist
Tasimelteon
Melatonin (MT) Receptor Antagonist
Suvorexant (Belsomra)
Orexin (OX) Receptor Antagonist
Goals of Treatment for Hypnotics
- correct underlying sleep complaint
- consolidate sleep (fall asleep and stay asleep)
- improve daytime functioning (can wake up and function)
- avoid adverse effects from drug therapies
** Drug therapy should be used in the LOWEST possible dose for the SHORTEST possible period of time **
BZ as Hypnotic Agents
- decreases number of awakenings
- higher dose than used for GAD
- after prolonged use, can result in withdrawal and increased insomnia
Non-BZ Hypnotics
- bind to same site on GAGA receptor as BZs; exhibit similar effects
- all decrease time to persistent sleep
- rapid onset of activity, short half lives, few amnesic effects
- schedule IV controlled substance: SHORT TERM USE ONLY
All Non-BZ Hypnotics Increase Total Sleep Time EXCEPT
Zaleplon
- helps fall asleep, does not help stay asleep
MT Receptor Agonists
- Ramelteon & Tasimelteon
- act as agonists at MT1 and MT2 receptors
- NO GABAergic effects in the CNS
- no risk of dependency
- promote sleep
Tasimelteon is uniquely approved for:
non-24 hour sleep-wake disorder
Orein (OX) Receptor Antagonist
- BLOCKER of WAKE receptor
- acts as antagonist at OX1 and OX2 receptors in the brain, with non GABAergic CNS effects
- BLOCKS WAKEFULNESS
- schedule IV controlled substance
- “sleep-driving” behavior and amnesic effects
