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Neuro 4 > Pharm of Sleep > Flashcards

Pharm of Sleep Flashcards

1
Q

Which drug has SE of anterograde amnesia?

A

Benzodiazepines (diazepam)

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2
Q

What is phenelzine?

A

MAO-I

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3
Q

Cholinergic (ACh) pathway of ARAS

A

pathway from Laterodorsal tegmentum-LDT and Pediculpontine-PPT nuclei facilitates thalamo-cortical transmission

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4
Q

Monoaminergic cell groups of ARAS

A 
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)
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5
Q

Pedunculopontine tegmental

A 
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
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6
Q

Dorsal Raphe

A

NT: serotonin
Awake: active
REM: off
Drug actions: Antidepressants (SSRIs/SNRIs/TCADs), increase 5HT/NE in synapse and decrease REM sleep

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7
Q

Locus ceruleus

A

NT: NE
Awake: active
REM: off
Drug actions: amphetamines/methyphenidate (increase NE release and promote wakefulness)

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8
Q

Ventral Tegmental Area

A

NT: DA
Awake: active
REM: increased REM–off
Drug actions: amphetamines/methyphenidate (increase DA release and promote wakefulness)

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9
Q

Posterior Hypothalamus

A 
NT: histamine
Awake: active
NREM: reduced
REM: off
Drug actions: Antihistamines promote drowsiness and sleep
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10
Q

***anterior hypothalamus

A 
NT: GABA
Awake: OFF
NREM: active
REM: reduced
Drug actions: benzodiazepines enhance GABA and promote sleep onset/continuity
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11
Q

Lateral hypothalamus

A 
NT: hyporecretin/orexin
Awake: active
NREM: off
REM: some active?
Drug actions: Suvorexant
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12
Q

Basal forebrain

A

NT: adenosine
Awake: decreased cholinergic arousal centers
Drug actions: adenosine antagonists (caffeine) increase alertness

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13
Q

Categories of sleep

A

NonREM (70-75%)
REM (25-30%)
occur cyclically over 90 minutes (4-5x/night)

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14
Q

Four stages of NonREM

A
  • 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.
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15
Q

REM sleep

A

Occurrence of rapid eye movements, decreased muscle tone, increased blood pressure, pulse, and respiration; stage of most recallable dreams.

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16
Q

Effect of sedative hypnotics on sleep

A

 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).

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17
Q

Properties of ideal hypnotic (doesn’t exist)

A
  • 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
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18
Q

Benzodiazepines and Non-Benzodiazepine Receptor Agonists

A
  • 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.
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19
Q

GABA receptors with alpha1 subunits vs alpha2-5

A
  • 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

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20
Q

BDZs and sleep stages

A 
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

21
Q

Zdrugs-BDZs

A 
sleep latency decreased
stage 1: increased
stage 2: increased
stage 3-4: 
REM:

Tolerance: very little

temazepam, flurazepam

22
Q

BARBs at GABA channel

A

-prolong channel opening in presence of GABA and at higher doses open channel directly

23
Q

BDZs bind to ____ on GABA Cl channel

A

alpha1 and alpha 2-5
-results in BOTH sleep and anxiolysis

-presence of GABA required for BDZ effect

24
Q

BARBs bind to ___

A

distinct site on channel

  • low dose: similar to BDZs
  • higher dose: direct interaction w/ channel–NO GABA required, plus inhibition of excitatory Nts
25
Q

Ethanol

A

binds specifically and non-specifically at distinct sites–>similar to BARBs

26
Q

What are Z drugs

A

-zolpidem, zaleplon, eszopiclone
-non-BDZs
-bind to alpha 1 subunits
=sleep without anxiolysis (reduced potential for dependence

27
Q

Pharmacokinetics of BDZs

A

-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)

28
Q

Zolpidem and Zaleplon

A

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.

29
Q

Flumazenil

A
  • antagonist that binds to same site as BDZs and Z drugs
  • used in treatment of BDZ overdose
  • Not effective for BARB or ethanol toxicity
30
Q

alpha 1

A

agonist: BDZs, Z drugs
location: cortex
Actions: sleep, anticonvulsant; amnesia, additive CNS depression

31
Q

alpha2-5

A

agonist: BDZs
location: limbic system, brain stem
Actions: anxiolytic, myorelaxant; tolerance, dependence, addiction

32
Q

“Hangover” effect

A
  • decreased attentiveness and impaired cognitive skills
  • More likely in drugs with LONGER half lives

[rebound insomnia w/ short t1/2]

33
Q

Eszopiclone (lunesta)

A
  • Z drug

- Structurally different from zolpidem or zaleplon with longer t1/2 (~6 hrs)

34
Q

ADRs for BDZs

A

-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.

35
Q

ADRs (Z drugs)

A
  • 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)

36
Q

Z drugs and treatment of insomnia

A
  • first line agents
  • alpha 1 subunit
  • very little effect on stages III, IV
37
Q

Zolpidem and insomnia tx

A
  • 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))

38
Q

Zaleplon and insomnia tx

A

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)

39
Q

Eszopiclone and insomnia tx

A
  • 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
40
Q

BDZs and insomnia tx

A
  • declining use due to generally superior pharmacodynamic and safety profile of zolpidem, zaleplon, and eszopiclone
  • short term tx of insomnia
  • cheaper
41
Q

Triazolam and insomnia

A
  • BDZ
  • rapid oral absorp (quick onset)
  • short t1/2 (less daytime sedation, more rebound insomnia)
  • caution in elderly
42
Q

Temazepam and insomnia

A
  • BDZ
  • slow absorp (minimal effect on sleep latency)
  • intermed t1/2–>less nocturnal awakenings
43
Q

Flurazepam and insomnia

A
  • BDZ
  • longest t1/2–accum in elderly (daytime sedation/overdose possible)
  • less tolerance devel than other BDZs
44
Q

Trazodone

A

-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

45
Q

Ramelteon

A
  • agonist at melatonin receptors (MT1–induce sleepiness; MT2–regulate circadian rhythms)
  • ADRs:
46
Q

Diphenhydramine, doxylamine

A

-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

47
Q

TCADs

A
  • 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
48
Q

Recommendations for treatment of insomnia

A
  • 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.
49
Q

Agents likely to cause anticholinergic SE?

A

diphenhydramine

doxylamine

Neuro 4 (23 decks)

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