Pharm of Sleep Flashcards
Which drug has SE of anterograde amnesia?
Benzodiazepines (diazepam)
What is phenelzine?
MAO-I
Cholinergic (ACh) pathway of ARAS
pathway from Laterodorsal tegmentum-LDT and Pediculpontine-PPT nuclei facilitates thalamo-cortical transmission
Monoaminergic cell groups of ARAS
activate cerebral cortex to facilitate processing of these thalamic inputs: LC-Locus ceruleus (NE) Raphe (5HT) Tuberomamillary-TMN (His) VTA (DA) plus Basal forebrain-BF (ACh) Lateral hypothalamus-LH (Orexin)
Pedunculopontine tegmental
NT: ACh Awake: active (for REM on/wake on) NREM: off REM: very active Drug actions: muscarinic agonists and ACHE-Is activate REM; antimuscarinic drugs suppress REM sleep
Dorsal Raphe
NT: serotonin
Awake: active
REM: off
Drug actions: Antidepressants (SSRIs/SNRIs/TCADs), increase 5HT/NE in synapse and decrease REM sleep
Locus ceruleus
NT: NE
Awake: active
REM: off
Drug actions: amphetamines/methyphenidate (increase NE release and promote wakefulness)
Ventral Tegmental Area
NT: DA
Awake: active
REM: increased REM–off
Drug actions: amphetamines/methyphenidate (increase DA release and promote wakefulness)
Posterior Hypothalamus
NT: histamine Awake: active NREM: reduced REM: off Drug actions: Antihistamines promote drowsiness and sleep
***anterior hypothalamus
NT: GABA Awake: OFF NREM: active REM: reduced Drug actions: benzodiazepines enhance GABA and promote sleep onset/continuity
Lateral hypothalamus
NT: hyporecretin/orexin Awake: active NREM: off REM: some active? Drug actions: Suvorexant
Basal forebrain
NT: adenosine
Awake: decreased cholinergic arousal centers
Drug actions: adenosine antagonists (caffeine) increase alertness
Categories of sleep
NonREM (70-75%)
REM (25-30%)
occur cyclically over 90 minutes (4-5x/night)
Four stages of NonREM
- Stage 1: Transition phase, EEG like wakefulness.
- Stage 2: Light sleep; short, fragmented thoughts, EEG slower; 50% of total.
- Stage 3 and 4 (delta)= slow wave sleep: EEG very slow, deepest level of sleep (described as “best”); stage where somnambulism and night terrors can occur.
REM sleep
Occurrence of rapid eye movements, decreased muscle tone, increased blood pressure, pulse, and respiration; stage of most recallable dreams.
Effect of sedative hypnotics on sleep
Decrease latency of sleep onset (useful effect to promote onset)
Increase duration of stage 2 sleep (useful effect for maintenance of sleep state)
Decrease of delta sleep (deleterious effect), esp. barbiturates. (Less with flurazepam or zolpidem / zaleplon).
Decrease duration of REM sleep (cause of REM rebound on withdrawal leading to increases in nightmares) (deleterious effect), esp. barbiturates. (Less with flurazepam, temazepam, minimal with zolpidem / zaleplon / eszoplicone).
Use for longer than 1 week generally leads to tolerance, esp. barbiturates. (Less with flurazepam, minimal with zolpidem / zaleplon).
Properties of ideal hypnotic (doesn’t exist)
- agonists at BDZ alpha1 binding site on GABA recep (zolpidem/Zdrugs) are closest to ideal
- should rapidly induce sleep (rate of absorption); maintain sleep but no morning hangover (t1/2); no rebound insomnia if d/c (t1/2); high therapeutic index; should normalize disturbed sleep without disturbing normal sleep
Benzodiazepines and Non-Benzodiazepine Receptor Agonists
- produce sleep by facilitating the action of GABA at the GABA receptor-chloride channel complex (GABA interacts with alpha and beta subunits of heteroligomeric glycoprotein to facilitate Cl entry and hyperpol)
- binding of BDZs or non-BDZs like zolpidem to GAMMA subunit facilitate GABA channel opening but does NOT directly initiate Cl current as does higher levels of barbiturates.
GABA receptors with alpha1 subunits vs alpha2-5
- highly expressed in cortex
- mediate sedative (sleep), amnestic, and anticonvulsant actions of BDZs.
alpha2/5:
-highly expressed in the limbic system / and brain stem and these receptors appear to mediate myorelaxant, motor impairing, anxiolytic, and ethanol-potentiating effects of benzodiazepines
BDZs and sleep stages
sleep latency: decreased stage 1: increased stage 2: increased stage3-4: DECREASED REM (decreased muscle tone, inc HR/BP/RR: DECREASED
Tolerance: if used >1 week
Zdrugs-BDZs
sleep latency decreased stage 1: increased stage 2: increased stage 3-4: REM:
Tolerance: very little
temazepam, flurazepam
BARBs at GABA channel
-prolong channel opening in presence of GABA and at higher doses open channel directly
BDZs bind to ____ on GABA Cl channel
alpha1 and alpha 2-5
-results in BOTH sleep and anxiolysis
-presence of GABA required for BDZ effect
BARBs bind to ___
distinct site on channel
- low dose: similar to BDZs
- higher dose: direct interaction w/ channel–NO GABA required, plus inhibition of excitatory Nts
Ethanol
binds specifically and non-specifically at distinct sites–>similar to BARBs
What are Z drugs
-zolpidem, zaleplon, eszopiclone
-non-BDZs
-bind to alpha 1 subunits
=sleep without anxiolysis (reduced potential for dependence
Pharmacokinetics of BDZs
-Triazolam: Eliminated within 1 dosing cycle (t1/2: 1.5-5 hrs), less daytime sedation (hangover), use cautiously in elderly with dose reduction, rapidly absorbed. Can see REBOUND insomnia next day due to rapid elimination. Rapid oral absorption.
Temazepam: Intermediate t1/2 (9-13 hrs), slowly absorbed, peak concentration at 2-3 hrs, minimal effect on latency to sleep onset
Flurazepam (Dalmane). Long t1/2 with active metabolite (75-90 hrs), see effect at same dose for 28 consecutive days (i.e., little tolerance). Can accumulate in elderly due to impaired hepatic clearance leading to daytime sedation (“hangover”) / overdosage (t1/2 extended to 120-160 hrs)
Zolpidem and Zaleplon
Z drugs
Zolpidem (Ambien) and Zaleplon (Sonata). Shortest durations of action (6-8 hours) and half-lives of available agents (zolpidem: 2-2.5 hrs; zaleplon: 1 hr). Rapid oral absorption.
Flumazenil
- antagonist that binds to same site as BDZs and Z drugs
- used in treatment of BDZ overdose
- Not effective for BARB or ethanol toxicity
alpha 1
agonist: BDZs, Z drugs
location: cortex
Actions: sleep, anticonvulsant; amnesia, additive CNS depression
alpha2-5
agonist: BDZs
location: limbic system, brain stem
Actions: anxiolytic, myorelaxant; tolerance, dependence, addiction
“Hangover” effect
- decreased attentiveness and impaired cognitive skills
- More likely in drugs with LONGER half lives
[rebound insomnia w/ short t1/2]
Eszopiclone (lunesta)
- Z drug
- Structurally different from zolpidem or zaleplon with longer t1/2 (~6 hrs)
ADRs for BDZs
-daytime sedation and performance impairment
high doses or intermediate-long half lives (flurazepam)
elderly with impaired phase I metabolism (accumulation)
-anterograde amnesia (triazolam>temazepam)
-rebound insomnia (abrupt stop of short half-life agents)
-psychologic and physiologic dependence (sched IV)–increased if high dose, reg usage, prior abuse hx; reduced or avoided with use of lowest effective dose, on intermittent basis, for shortest duration poss.
ADRs (Z drugs)
- safety similar to BDZs
- common SE: drowsy, amnesia, HA, GI complainsts; rarely bizarre behavioral disturbances
- rebound effects or next day psychomotor performance alteration appear minimal w/ zolpidem and zaleplon (increased with eszopiclone–longer t1/2–at higher doses)
tolerance/dependence/withdrawal are possible but less likely than w/ BDZs. But they are Schedule IV
fatal overdoses very rare in Z and BDZs.(unless combo w/ alcohol/CNS depressants)
Z drugs and treatment of insomnia
- first line agents
- alpha 1 subunit
- very little effect on stages III, IV
Zolpidem and insomnia tx
- Effective for reducing sleep latency and nocturnal awakenings with an increase in total sleep time and efficiency
- most widely prescribed hypnotic agent
- minimal impact on sleep stages, little tolerance, less abuse potential compared to BDZs.
-most widely prescribed agent for insomnia (ambien (dec latency), ambien CR –sustained release (dec nocturnal awakenings), intermezzo–low dose sublingual for middle of night awakenings))
Zaleplon and insomnia tx
decreasing time to sleep onset, but not for reducing nighttime awakening (short t1/2) or increasing total sleep time.
Best suited for use as a sleep aid for middle-of-the-night awakenings (rapid onset, short half life, no hangover effect)
Eszopiclone and insomnia tx
- Sleep maintenance
- longest t1/2 of non-BDZs
- safe for long term use with little or no suggestion for development of tolerance, dependence, or abuse
- Sched IV
BDZs and insomnia tx
- declining use due to generally superior pharmacodynamic and safety profile of zolpidem, zaleplon, and eszopiclone
- short term tx of insomnia
- cheaper
Triazolam and insomnia
- BDZ
- rapid oral absorp (quick onset)
- short t1/2 (less daytime sedation, more rebound insomnia)
- caution in elderly
Temazepam and insomnia
- BDZ
- slow absorp (minimal effect on sleep latency)
- intermed t1/2–>less nocturnal awakenings
Flurazepam and insomnia
- BDZ
- longest t1/2–accum in elderly (daytime sedation/overdose possible)
- less tolerance devel than other BDZs
Trazodone
-serotonin receptor agonist and reuptake blocker
-decrease in REM sleep, no change or increase in SWS
ADRs: oversedation, orthostasis (alpha 1 block) priapism (RARE, serious)
-Role: an antidepressant–very sedating and improves sleep continuity
-no concerns with tolerance or dependence
-often used empirically for insomnia, but efficacy in non-depressed pts uncertain
Ramelteon
- agonist at melatonin receptors (MT1–induce sleepiness; MT2–regulate circadian rhythms)
- ADRs:
Diphenhydramine, doxylamine
-antihistamines
-antag at CNS histamine H1 and muscarinic receptors
-ADRs: generally minimal, but antimuscarinic actions can be troublesome
Role: minimally effective, not for use long term
can see tolerance after>10 days use
Consider “off” night after 3 days of use to reduce tolerance
TCADs
- block reuptake of serotonin and/or norepinephrine, probably also a contribution from antagonist action at histamine and muscarinic-cholinergic receptors. [decrease in REM sleep, increased slow wave sleep]
- ADRs: antimuscarinic activity and antiadrenergic activity
Recommendations for treatment of insomnia
- nondrug measures (CBT alone or with drug)
- drug tx (non-BDZs: Z drugs, ramelteon; shorter acting BDZs: temazepam; lowest effective dose)
- address underlying causes
- check that stimulating or sleep interrupting meds not taken hs.
Agents likely to cause anticholinergic SE?
diphenhydramine
doxylamine
