Pharmacology of Insomnia

Question 1

Nervous structures/NTs involved in wakefulness

Answer 1

• 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

Question 2

Nervous structures/NT involved in REM sleep

Answer 2

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

Question 3

Drugs actions on NTs involved in sleep/wave

Answer 3

• _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

Question 4

Effects of sedative-hypnotics on sleep

Answer 4

• 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

Question 5

Benzodiazepines/NBRA/Barbiturates MOA (general)

Answer 5

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

Question 6

NT/drug actions @ GABA_A channel

Answer 6

• 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

Question 7

Benzodiazepines: MOA

Answer 7

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

Question 8

Z-drugs: MOA

Answer 8

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

Question 9

Triazolam: class, pharmK vs. utility

Answer 9

• Benzodiazepine
• rapid oral absorption ==>
  
  • catious use in elderly (reduce dose)
• short t_1/2 = rapid elimination ==>
  
  • less daytime sedation
  • rebound insomnia

Question 10

Temazepam: class, pharmK

Answer 10

• Benzodiazepine
• Intermediate t_1/2 and slowly absorbed ==>
  
  • minimal effect on sleep onset

Question 11

Flurazepam: class, pharmK

Answer 11

• Benzodiazepine
• very long t_1/2 ==>
  
  • little tolerance
  • @ elderly/impaired hepatic clearance:
    
    • daytime sedation
    • overdosage

Question 12

“Z-drugs”: class, pharmK

Answer 12

• 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)

Question 13

Side effects of benzodiazepines

Answer 13

• dose-dependents
• overdoses rare except in combo w/alcohol or other CNS depressants
• daytime sedation and performance impairment (esp. w/long or intermediat t_1/2)
• anterograde amnesia
• rebound insomnia (esp. w/short-int. t_1/2)
• psychologic/physical dependence

Question 14

Tx of benzodiazepine overdose

Answer 14

• flumazenil (Romazicon) = benzodiazepine receptor antagonist

Question 15

Side effects of Zolpidem

Answer 15

• 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

Question 16

Side effects of Zaleplon

Answer 16

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

Question 17

Side effects of Eszoplicone

Answer 17

• 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

Question 18

“Z-drugs” general role in tx of insomnia

Answer 18

• 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

Question 19

Zolpidem: role in insomnia tx

Answer 19

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

Question 20

Zaleplon: role in insomnia tx

Answer 20

• 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.

Question 21

Eszopiclone: role in insomnia tx

Answer 21

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

Question 22

Benzodiazepines: role in tx of insomnia (general)

Answer 22

• 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

Question 23

Examples of Non-GABA sleep aids

Answer 23

• Ramelteon
• Trazodone
• Diphenhydramine
• Chloral hydrate

Question 24

Trazodone: MOA, SE

Answer 24

• 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

Question 25

TCADs: MOA, SE

Answer 25

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

Question 26

Ramelteon (Rozerem): MOA, SE

Answer 26

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

Question 27

Antihistamines (Diphenhydramine): MOA, SE

Answer 27

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