Hypnotic Agents Flashcards
Benzodiazepines (2nd generation GABA hypnotics) to know (3)
Flurazepam, temazepam, triazolam
Non-benzodiazepine BZD agonists (3rd generation GABA hypnotics) to know (3)
Eszopiclone, zolpidem, zaleplon
Melatonin receptor agonists
Ramelteon
Orexin receptor antagonists (newest class)
Suvorexant
Ultra-short hypnotics: half-life
2-3 H
Ultra-short hypnotics use
Patients having trouble falling asleep
Advantage of ultra-short hypnotics (half-life 2-3 H)
Little daytime drowsiness
Disadvantages of ultra-short hypnotics (half-life 2-3 H)
Rebound insomnia and REM rebound in early morning, tendency to use higher doses to achieve longer DOA
Short hypnotics half-life
5+ H
Short hypnotics use
Patients wake up in the middle of the night
4 advantages of short hypnotics
- Does not accumulate in the body
- low incidence of residual effects
- not metabolized by CYPs
- tolerance to hypnotic effect is slow
Disadvantage of short hypnotics
Rebound insomnia and REM rebound in early morning
Long hypnotics half-life
24-120 H
Long hypnotics use
Patients wake up early in the morning
3 advantages to long hypnotics
- Maybe more effective on the 2nd night
- rebound insomnia and REM are less intense after DC
- residual daytime anti-anxiety effects may be helpful
2 disadvantages of long hypnotics
- Residual daytime drowsiness (may be severe)
- potential for drug accumulation
Ultra-short acting BZ to know
Triazolam (half-life 1.5-5 H, eliminated in 12-15 H)
1 good and 1 bad about triazolam
- Low incidence of daytime drowsiness;
- rebound insomnia and REM rebound can occur in a single night
**Incidence of anterograde amnesia is higher than with other hypnotics
Triazolam (ultra-short acting BZ)
Short acting BZ to know
Temazepam (half-life 3-18 H)
Why would temazepam be presented for use especially in elderly patients?
Eliminated by conjugation (Phase II processes fairly unaffected by age)
2 good and 1 bad about temazepam
- Little or no tolerance over 2 weeks
- low incidence of daytime drowsiness
- insomnia and REM rebound are possible (short acting BZ)
Long acting BZ to know
Flurazepam (half-life 2.3 H, but active metabolites have 74-90 H half lives)
Residual anti-anxiety effect, maybe more effective on second night
Flurazepam (long acting BZ)
At what rate does tolerance develop to flurazepam?
Slowly (long acting BZ)
Describe the daytime drowsiness AND rebound insomnia/REM likeliness with flurazepam.
Causes daytime drowsiness, but rebound insomnia/REM is unlikely (long-acting BZ)
T/F: Non-benzodiazepine BZD receptor agonists are structurally distinct from BZDs and are allosteric agonists at a distinct region on the GABA-A receptor.
False- allosteric agonists are the BZD receptor on GABA-A
Selectivity of non-BZ BZD receptor agonists
Selective for GABAa receptors containing A1 subunits
What are non-BZ BZD receptor agonists actions limited to?
Hypnotic and amnestic effects (NO anti-anxiety, anti-seizure, muscle relaxation, affect on learning/memory NONE)
What are 3 similarities between zolpidem, eszopiclone, and zaleplon?
Considered ultra-short acting (half-lives 1.5-7 H), schedule IV, do not suppress REM or N3 sleep at therapeutic doses
Has no limitation of how long it can be used
Eszopiclone
How do non-BZ BZD agonists’ ADEs compared to BZDs’?
Similar but frequency and severity may be less (actions limited to hypnotic and amnestic…)
Function: orexin A and orexin B - antagonist?
Hypothalamic neuropeptides that promote wakefulness and regulate the sleep-wake cycle - suvorexant
MOA of suvorexant
Block OX1R and OX2R receptors to prevent binding of orexins A and B
What DOA does suvorexant have?
Short acting (half-life 12 h)
ADE of suvorexant
Similar to other hypnotics, mild cataplexy (leg weakness/paralysis)
Use and schedule of suvorexant
New drug with unclear role in insomnia; CIV
Melatonin is a hormone involved in circadian rhythms and the sleep-awake cycle. How/where does it act?
Stimulates melatonin MT1 and MT2 GPCRs in the suprachiasmatic nucleus of the hypothalamus
MOA= agonist at MT1 receptors
Ramelteon
DOA of ramelteon
Ultra-short acting (half-life 1.5-5 H)
Use and schedule of ramelteon
Improves some sleep parameters but effect size is small, not controlled (melatonin for jet lag?)
ADE of ramelteon
Generally milder than BZDs (somnolence, dizziness)
When to use lower doses: (3)
- Patient is likely to use alcohol
- elderly patients (avoid use if possible)
- patients with hepatic or renal disease
How long should hypnotics be used for?
Used temporarily, avoid successive nightly therapy
When do you taper hypnotics off?
After chronic use (to avoid/deal with withdrawal)
Contraindications for hypnotics (4)
- Sleep apnea (heavy snoring)
- history of alcohol or drug abuse
- pregnancy
- suicidal risk
Non-REM is what % of sleep?
50-60%
How is Non-REM sleep distinguished
increasing arousal threshold and slowing or cortical EEG
REM is what % of sleep?
20-25%
What occurs in REM?
rapid eye movements
dreaming
sleep muscle paralysis
The ascending arousal system is located where?
pons/hypothalamus
What does the ascending arousal system use?
NE, DA, 5-HT, H1, glutamate, Ach
also peptide orexin
Orexin is used for what?
reinforce and maintain wakefulness
sleep-promoting system is located where?
pre optic area/pons/hypothalamus
What does the sleep-promoting system use?
GABA to inhibit arousal system
Hormone involved in circadian rhythms and sleep-awake cycle
melatonin
definition of insomnia
inability to fall asleep
difficulty remaining asleep
waking too early
happens despite adequate opportunity
Short term insomnia
lasts <3 weeks
related to identifiable stressor
Chronic insomnia
occurring >3 times per week, >3 months
specific stressor not identifiable likely
usually requires combo of behavioral therapy and hypnotics
Common causes of insomnia
- increase with age
- poor sleep hygiene
- meds/drugs
- pain and other medical conditions
- psychological stress
Medical conditions that could cause insomnia
sleep apnea
parkinsons
General approach to treating insomnia
- treat underlying disorder
- counsel on sleep hygiene and stimulus control
- behavioral therapy
Types of behavioral therapy for insomnia
relaxation
sleep restriction
cognitive therapy
Rationale for hypnotic therapy
- shorten sleep onset
- prolong duration of sleep
- reduce nocturnal wakefulness
- improve daytime function
Effect of hypnotics on first night
- decrease sleep latency, lengthen duration
- decrease awake time after sleep onset
- decrease N3 and REM time
- increase N2 sleep time
Effect of hypnotics with chronic use
- tolerance to hypnotic effect
- REM returns to previous point
- rebound insomnia upon discontinuation
Side effects common to all hypnotics
- residual daytime sleepiness, drowsiness, dizzy
- cognitive impairment
- sleeping while driving, cooking, sex, phone calls
- suppress respiration that worsen in apnea
- habit forming & rebound
Pregnancy and hypnotics
teratogenicity
neonatal dependency
Alcohol consumption and hypnotics
excessive sedation
respiratory depression
Geriatric patients and hypnotics
decreased renal/hepatic Cl a
increased susceptibility to sedative effects
risk of falls greatly increases
