pharm of sleep Flashcards
- Review the pharmacodynamics of benzodiazepine and nonbenzodiazepine receptor agonist interaction with the GABA-chloride channel complex presented in anti-anxiety drug lecture.
(BDZs): (bind to a site on the α subunit of the GABA-A receptor in the presence of GABA, Nonbenzodiazepine receptor agonists (NBRAs): Relatively selective interaction with BZ1 (α1, cortex) receptors.
- Relate the pharmacokinetic profile of benzodiazepines and nonbenzodiazepine receptor agonists (NBRAs) to their clinical utility in the treatment of insomnia
Benzodiazepines are effective in the treatment of insomnia by reducing sleep latency and increasing total sleep time. They increase stage 2 sleep (good) while decreasing REM, stage 3 and stage 4 sleep (not so good). These actions vary depending on the individual benzodiazepine. • Traizolam: o Short half-life and rapid oral absorption means appropriate for treating prolonged sleep latency rebound insomnia next day due to rapid elimination • Temazepam: o Slow absorption means minimal effect on latency to sleep onset o Intermediate half-life, so less nocturnal awakenings • Flurazepam: o Longest half-life means that it can accumulate, especially in the elderly or with impaired hepatic function o Result is likely daytime sedation and overdose risk Nonbenzodiazepine receptor agonists (NBRAs): • Zolpidem (Ambien): o Shortest half-life = shortest duration of action (still 6-8 hours) with rapid oral absorption o Effective for decreasing sleep latency and decreasing nocturnal awakenings • Increase in total sleep time and efficiency • Most frequently prescribed hypnotic agent • Zaleplon: o Duration of action and half-life similar to Zolpidem. Also has rapid oral absorption o Effective for decreased time to sleep onset o NOT good for decreasing nighttime awakenings or increasing total sleep time o Best suited for use as a sleep aid for middle-of-the-night awakenings • Eszopiclone: o Structurally different from Zolpidem and Zaleplon o Longer duration and half-life: increases daytime sedation
- Relate the effects of benzodiazepines and nonbenzodiazepine receptor agonists on sleep stages to their clinical utility in the treatment of insomnia.
Stage__BDZs__“Z” drugs-BDZs*
Sleep latency ↓ ↓
Duration ↑ ↑
1: transition phase, wake-like EEG
2: light sleep, EEG slower, ~ 50% of total ↑ ↑
3-4: deep sleep, EEG very slow, ↓ =
SWS is described as “best”,
night terrors - somnambulism
REM: ↓ muscle tone, ↑ HR-BP-RR, ↓ =
stage of most recallable dreams [also EtOH-BARBS]
Tolerance If used > 1 week very little
- Compare the side effect profiles of the three broad categories of drugs for insomnia (BDZs, NBRAs, and non-GABA drugs) as they relate to limitations on the clinical utility of each.
Benzodiazapines
Daytime sedation and performance impairment
Anterograde amnesia
Rebound insomnia with abrupt discontinuation
Psychologic and physiologic dependence – controlled substances C-IV
Non-benzodiazapine Receptor Agonists
drowsiness, amnesia, headache, GI
Tolerance-dependence-withdrawal are possible but less likely than with BDZs
non-GABA Drugs
Ramelteon
Dizziness, somnolence, fatigue, nausea
Trazodone
Oversedation, orthostasis (α-1 block), priapism (rare but serious)
Diphenhydramine - Doxylamine
Minimal side effects, BUT antimuscarinic actions are troublesome in the elderly
TCAD
Antimuscarinic activity and antiadrenergic activity (especially in the elderly) and cardiac conduction disturbances (problematic in OD situations). Daytime sedation can be a problem.
Zolpidem,
1
Benzodiazepines adverse drug reactions
Daytime sedation and performance impairment
High doses or intermediate-long half-lives (flurazepam)
Elderly with impaired Phase I metabolism à accumulation
Anterograde amnesia – triazolam > temazepam
Rebound insomnia – abrupt stop of short half-life agents
Psychologic and physiologic dependence – schedule IV
Increased if: high dose, regular usage, prior abuse history
Reduced or avoided with use of lowest effective dose - on intermittent basis - for shortest duration possible
Non-GABA Actions- Ramelteon - Melatonin Trazodone Diphenhydramine Chloral hydrate
1
Administration of which of the following drugs is most likely to produce memory disturbances such as anterograde amnesia? Diazepam Escitalopram Amitriptyline Methylphenidate Phenelzine
Diazepam
Zolpidem (Ambien) and Zaleplon (Sonata)
Z drugs
- Rapid oral absorption
- Shortest durations of action (6-8 hours) and half-lives of available agents (zolpidem: 2-2.5 hrs - zaleplon: 1 hr)
- Zolpidem eliminated more slowly in females - dose recommendation halved to prevent daytime hangover
Eszoplicone (lunesta)
Z drug,
•Structurally different from zolpidem or zaleplon with longer t1/2 (~ 6 hrs)
Triazolam (Halcion)
BDZ Rapid oral absorption
- Short t1/2: 1.5-5 hrs - eliminated in 1 dosing cycle
- Less daytime sedation (hangover)
- Rebound insomnia next day due to rapid elimination
Temazepam (Restoril)
BDZ
- Slow absorption - minimal effect on sleep latency
- Intermediate t1/2 (9-13 hrs)
Flurazepam (Dalmane)
BDZ
- Long t1/2 + active metabolite (75-90 hrs) - low tolerance
- Can accumulate in elderly - impaired hepatic clearance à daytime sedation (“hangover”) / overdosage
Z drug adverse drug reactions
- Safety similar to benzodiazepines
- Common side effects: drowsiness, amnesia, headache, GI complaints – rarely bizarre behavioral disturbances
- Rebound effects or next-day psychomotor performance alteration appear minimal with zolpidem and zaleplon
Increased with eszopiclone (longer t1/2) at higher doses
•Tolerance-dependence-withdrawal are possible but less likely than with BDZs - BUT they are Schedule IV
Trazadone
Serotonin receptor antagonist and reuptake blocker
Decrease in REM sleep – no change or increase in SWS
ADRs: Oversedation, orthostasis (α-1 block), priapism (rare but serious)
Role: An antidepressant – very sedating and improves sleep continuity
No concerns with tolerance or dependence if abuse concerns with patient
Often used empirically for insomnia, but efficacy in non-depressed patients uncertain
