This PPT is part 2 of 2 lectures given to second year pharmacy students in a pharmacology & toxicology class.

1. Sedative & Hypnotic Drugs II
Brian J. Piper, Ph.D., M.S.
January 23, 2013

2. Goals
• Sleep Neurochemistry
• Hypnotic Pharmacy
– benzodiazepines
– “Z” drugs
– melatonin agonists

3. Sleep Across the Lifespan
Roffwarg, Muzio, & Dement (1966). Science, 152(3722), 604-619.

4. Insomnia Disorder

5. Epidemiology of Insomnia
Sex: 2 F: 1 M
5% of adults
Age: 50% of elderly
Other conditions:
smoking or drinking
anxious or depressed
chronic pain
Ohayon (2002) Sleep Medicine Reviews, 67(2), 97-111.

6. Neurobiology
of Sleep
• Hypothalamus
– Suprachiasmatic Nucleus (SCN): pacemaker
• Pineal Gland (Melatonin)
• Reticular Formation (5-HT, DA, NE, ACh)

7. Arousal Spectrum
Stahl (2008). Essential Psychopharmacology, p. 817.

8. Perfect Hypnotic
• On/Off
• Non-habit forming

9. Stahl (2008). Essential Psychopharmacology, p. 840.

10. Stahl (2008). Essential Psychopharmacology, p. 835.

11. Half-Life ≈ 6 hours
Stahl (2008). Essential Psychopharmacology, p. 841.

12. FDA Approved
For Insomnia (t1/2)
Estazolam (17)
Flurazepam (70)
Quazepam (39)
Temazepam (25)
Triazolam (2)
Stahl (2008). Essential Psychopharmacology, p. 841.

13. Benzodiazepine Dependence
Stahl (2008). Essential Psychopharmacology, p. 841.

14. “Z Drugs”
• Examples: zolpidem, zaleplon
• MOA: α1 GABAA POM
• Indications: insomnia
• Adverse Events
– Allergic reaction
– Automatic behaviors (non-remembered)
Min 1 to 3: http://www.youtube.com/watch?v=FDK1TAkmHjs
Daley et al. (2011). Journal of the American Academy of Psychiatry & the Law, 39, 535-542.

15. Idealized (?)
Stahl (2008). Essential Psychopharmacology, p. 838.

16. Benzo versus “Z drug”
• Insomniacs were randomized to receive 28
days of zolpidem (10 mg/day, N = 79) or
temazepam (20 mg/day, N = 84). Double-blind
• Sleep diaries were completed for 1 week post-
hypnotics
temazepam zolpidem
↓ total sleep time
(40%+)
26% 27%
↑ sleep onset
latency (40%+)
58% 53%
Voshaar et al. (2004). European Neuropsychopharmacology, 14, 301-306.

17. Modified from Stahl (2008). Essential Psychopharmacology, p. 838.

18. Melatonin Rhythm
Reiter, R. J. (1995). Experimental Gerontology, 30(3/4), 199-212.

19. Ramelteon
• MOA: Melatonin (M12) agonist
• Indication: insomnia (sleep onset)
• Half-life: 2 hours
• Adverse effects: limited
• Schedule: not controlled
Bonus (3 min): http://www.youtube.com/watch?v=rIpjfTbCHJ8

20. Summary
Benzo Z drug Melatonin Agonist
Diazepam Zolpidem Ramelteon
MOA GABAA α1,2,3,5 GABAA α1 M1,2
Year 1963 1986 2005
Developed
Indication Insomnia (onset & Insomnia (onset) Insomnia (onset)
maintenance) Long-term
Half-Life 50 3 2
(hours)
Withdrawal Yes Yes? No
Issues

22. Stahl (2008). Essential Psychopharmacology, p. 819.

23. Self-Test #1
• Patient C.D. appears to have over-dosed on
Zolpidem. What agent would be appropriate
in this situation?
– A) zaleplon (Sonata)
– B) flumazenil (Romazicon)
– C) pentobarbital (Nembutal)
– D) ramelteon (Rozerem)
– E) eszopiclone (Lunesta)