Sedative & Hypnotic Drugs II
Brian J. Piper, Ph.D., M.S.
January 23, 2013
Goals
• Sleep Neurochemistry• Hypnotic Pharmacy– benzodiazepines– “Z” drugs– melatonin agonists
Sleep Across the Lifespan
Roffwarg, Muzio, & Dement (1966). Science, 152(3722), 604-619.
Insomnia Disorder
Epidemiology of Insomnia
Sex: 2 F: 1 M5% of adultsAge: 50% of elderlyOther conditions:
smoking or drinkinganxious or depressedchronic pain
Ohayon (2002) Sleep Medicine Reviews, 67(2), 97-111.
Neurobiology of Sleep
• Hypothalamus– Suprachiasmatic Nucleus (SCN): pacemaker
• Pineal Gland (Melatonin)• Reticular Formation (5-HT, DA, NE, ACh)
Arousal Spectrum
Stahl (2008). Essential Psychopharmacology, p. 817.
Perfect Hypnotic
• On/Off• Non-habit forming
Stahl (2008). Essential Psychopharmacology, p. 840.
Stahl (2008). Essential Psychopharmacology, p. 835.
Stahl (2008). Essential Psychopharmacology, p. 841.
Half-Life ≈ 6 hours
Stahl (2008). Essential Psychopharmacology, p. 841.
FDA Approved For Insomnia (t1/2)Estazolam (17)Flurazepam (70)Quazepam (39)Temazepam (25)Triazolam (2)
Benzodiazepine Dependence
Stahl (2008). Essential Psychopharmacology, p. 841.
“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.
Stahl (2008). Essential Psychopharmacology, p. 838.
Idealized (?)
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.
Modified from Stahl (2008). Essential Psychopharmacology, p. 838.
Melatonin Rhythm
Reiter, R. J. (1995). Experimental Gerontology, 30(3/4), 199-212.
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
SummaryBenzoDiazepam
Z drugZolpidem
Melatonin AgonistRamelteon
MOA GABAA α1,2,3,5 GABAA α1 M1,2
Year Developed
1963 1986 2005
Indication Insomnia (onset & maintenance)
Insomnia (onset) Insomnia (onset)Long-term
Half-Life (hours)
50 3 2
WithdrawalIssues
Yes Yes? No
Stahl (2008). Essential Psychopharmacology, p. 819.
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)