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)