Pharmacology of Insomnia Flashcards Preview

Nervous System: Unit IV > Pharmacology of Insomnia > Flashcards

Flashcards in Pharmacology of Insomnia Deck (28)
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1

Nervous structures/NTs involved in wakefulness

  • Peduncolopontine Tegmental ==> ACh
  • Dorsal Raphe ==> Serotonin (5HT)
  • Ascending Reticular Activating System
    • Locus Ceruleus ==> NE
    • Ventral Tegmental Area ==> DA
    • Posterior hypothalamus ==> Histamine
  • Lateral Hypothalamus ==> hypocretin
  • Basal forebrain ==> Adenosine build-up while awake

2

Nervous structures/NT involved in REM sleep

  • Pedunculpontine Tegmental ==> ACh
  • Anterior Hypothalamus ==> GABA (reduced compared to NREM)
  • Dorsal Raphe ==> Serotonin OFF
  • Lateral Hypothalamus ==> some hypocretin activity possible

3

Drugs actions on NTs involved in sleep/wave

  • Muscarinic agonists and AChEIs activate REM
    • antimuscarinic drugs suppress REM sleep
  • Antidepressants (SSRIs / SNRIs /TCADs) 5HT / NE in the synapse and ¯ REM sleep
  • Amphetamines / methylphenidate 
    • ==> ↑ NE release and promote wakefulness
    • ==> ↑ DA release and promote wakefulness
  • Antihistamines promote drowsiness and sleep
  • Benzodiazepines enhance GABA and promote sleep onset / continuity
  • Adenosine antagonists (caffeine) increase alertness

4

Effects of sedative-hypnotics on sleep

  • positive effects
    • decrease latency of sleep onset
    • increases duration of stage 2 sleep
  • negatibe effects
    • decrease delta sleep (esp. barbiturates)
    • decrease REM sleep (esp. barbiturates)
    • tolerance

5

Benzodiazepines/NBRA/Barbiturates MOA (general)

  • facilitate action of GABA @ GABAA receptor-chloride channel ==> increased inhibition @ CNS
  • increased inhibition ==> promotes sleep

6

NT/drug actions @ GABAA channel

  • consists of combinations of alpha, beta, and gamma subunits
  • GABA incteracts w/alpha or beta ==> open chloride channel
  • GABA channels w/alpha1 subunits:
    • @ cortex
    • mediate sedative/sleep
    • site of action for benzodiazepines and "Z-drugs"
  • GABA channels w/alpha2/alpha5 subunits:
    • @ limbic system/brain stem
    • mediate anxiety
    • site of action for benzodiazepines ONLY

 

7

Benzodiazepines: MOA

  • enhance GABAA channel activity via gamma or alpha1 or alpha2/alpha5 subunit
  • ==> anxiolysis & sleep

8

Z-drugs: MOA

  • enhance GABAA channel activity alpha1 subunit
  • ==> sleep

9

Triazolam: class, pharmK vs. utility

  • Benzodiazepine
  • rapid oral absorption ==>
    • catious use in elderly (reduce dose)
  • short t1/2 = rapid elimination ==>
    • less daytime sedation
    • rebound insomnia

10

Temazepam: class, pharmK

  • Benzodiazepine
  • Intermediate t1/2 and slowly absorbed ==>
    • minimal effect on sleep onset

11

Flurazepam: class, pharmK

  • Benzodiazepine
  • very long t1/2 ==>
    • little tolerance
    • @ elderly/impaired hepatic clearance:
      • daytime sedation
      • overdosage

12

"Z-drugs": class, pharmK

  • Nonbenzodiazepine Benzodiazepine “Receptor” Agonists
  • Zolpidem (Ambien) and Zaleplon (Sonata). 
    • Shortest durations of action (6-8 hours) and half-lives of available agents
    • Rapid oral absorption.
  • Eszopiclone (Lunesta).  Structurally different from zolpidem or zaleplon with longer t1/2 (~ 6 hrs)

13

Side effects of benzodiazepines

  • dose-dependents
  • overdoses rare except in combo w/alcohol or other CNS depressants
  • daytime sedation and performance impairment (esp. w/long or intermediat t1/2)
  • anterograde amnesia
  • rebound insomnia (esp. w/short-int. t1/2)
  • psychologic/physical dependence

14

Tx of benzodiazepine overdose

  • flumazenil (Romazicon) = benzodiazepine receptor antagonist

15

Side effects of Zolpidem

  • drowsiness, amnesia, dizziness, headache and GI complaints.
  • no significat next-day psychomotor performance impairment
  • Rebound effects and w/drawal or tolerance with prolonged use appear minimal

16

Side effects of Zaleplon

  • dizziness, headache, and somnolence
  • no next-day psychomotor impairment or rebound insomnia

17

Side effects of Eszoplicone

  • Similar to zolpidem but longer half-life associated with increased incidence of next day psychomotor impairment with higher doses
  • FDA required lower dose for initiation 

18

"Z-drugs" general role in tx of insomnia

  • first-line agents
  • selective interaction w/alpha1 subunits of GABA receptors
  • little effect on sleep stages III/IV
  • effective and relatively safe
    • low potential for tolerance, dependence, abuse

19

Zolpidem: role in insomnia tx

  • Effective for reducing sleep latency and nocturnal awakenings with an increase in total sleep time and efficiency
  • most widely prescribed

20

Zaleplon: role in insomnia tx

  • sleep aid for falling back to sleep after middle-of-the-night awakenings.
  • Zaleplon can get patient back to sleep (rapid onset), yet be eliminated by morning awakening (short half-life), so no “hangover” effect.

21

Eszopiclone: role in insomnia tx

  • safe for long term use with little or no suggestion for development of tolerance, dependence or abuse

22

Benzodiazepines: role in tx of insomnia (general)

  • previously mainstay of pharmacotherapy for insomnia, now declining in faor of Z-drugs
    • lower safety
    • interupt sleep stages III/IV
  • still suitable for some short-term tx of insomnia

23

Examples of Non-GABA sleep aids

  • Ramelteon
  • Trazodone
  • Diphenhydramine
  • Chloral hydrate

24

Trazodone: MOA, SE

  • MOA: effects on 5HT neurons: inhibition of reuptake + both agonist and antagonist receptor actions
    • antidepressant
    • sedating/increased sleep continuity
  • SE:
    • oversedation/orthostasis
    • NO addiciton/tolerance

25

TCADs: MOA, SE

  • MOA: block serotonin reuptake
    • sedating antidepressant
    • increased sleep continuity
  • SE
    • antimuscarinic activity
    • disturbed cardiac conduction
    • daytime sedation

26

Ramelteon (Rozerem): MOA, SE

  • MOA: agonist @ melatonin receptors
    • decreased sleep latency
  • SE:
    • minor SE/low incidence
    • dizzy, somnolence, fatigue, nausea

27

Antihistamines (Diphenhydramine): MOA, SE

  • MOA: antagonist @ histamine and muscarinic cholinergic receptors
    • ==> sedation
  • SE:
    • minimal
  • NOT recommended as insomnia tx

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