Sedative & Hypnotic Drugs Part II

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

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  • Other factors: marital status (higher for divorced) and lower income have been less consistently observed.
  • The term "reticulum" means "netlike structure," which is what the reticular formation resembles at first glance. RF includes raphe and locus coeruleus and projects to thalamus.
  • Half-life< 3 hours is too short.
  • A half-life of 15-30 hours is too long (e.g. estazolam or ProSom).
  • Half-lifes includes half-life of major metabolites and are from Katzung.
  • Do a search for benzodiazepine addiction in youtube for videos of people ranting about their benzo experience.
  • Complex automatic behaviors occur in 1-5% of patients.
  • Rebound insomnia (compared to placebo baseline) does not differ between these agents. Interestingly, this study was funded by the manufacturer of zolpidem (Sanofi-Synthelab).
  • Adverse reactions from PDR.net include dizziness, somnolence, fatigue, nausea, and exacerbated insomnia.
  • Excessive stimulants (amphetamine) can go beyond arousal and result in hallucinations.
  • Sedative & Hypnotic Drugs Part II

    1. 1. Sedative & Hypnotic Drugs II Brian J. Piper, Ph.D., M.S. January 23, 2013
    2. 2. Goals• Sleep Neurochemistry• Hypnotic Pharmacy – benzodiazepines – “Z” drugs – melatonin agonists
    3. 3. Sleep Across the LifespanRoffwarg, Muzio, & Dement (1966). Science, 152(3722), 604-619.
    4. 4. Insomnia Disorder
    5. 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 painOhayon (2002) Sleep Medicine Reviews, 67(2), 97-111.
    6. 6. Neurobiology of Sleep• Hypothalamus – Suprachiasmatic Nucleus (SCN): pacemaker• Pineal Gland (Melatonin)• Reticular Formation (5-HT, DA, NE, ACh)
    7. 7. Arousal SpectrumStahl (2008). Essential Psychopharmacology, p. 817.
    8. 8. Perfect Hypnotic• On/Off• Non-habit forming
    9. 9. Stahl (2008). Essential Psychopharmacology, p. 840.
    10. 10. Stahl (2008). Essential Psychopharmacology, p. 835.
    11. 11. Half-Life ≈ 6 hoursStahl (2008). Essential Psychopharmacology, p. 841.
    12. 12. FDA Approved For Insomnia (t1/2) Estazolam (17) Flurazepam (70) Quazepam (39) Temazepam (25) Triazolam (2)Stahl (2008). Essential Psychopharmacology, p. 841.
    13. 13. Benzodiazepine DependenceStahl (2008). Essential Psychopharmacology, p. 841.
    14. 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=FDK1TAkmHjsDaley et al. (2011). Journal of the American Academy of Psychiatry & the Law, 39, 535-542.
    15. 15. Idealized (?)Stahl (2008). Essential Psychopharmacology, p. 838.
    16. 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. 17. Modified from Stahl (2008). Essential Psychopharmacology, p. 838.
    18. 18. Melatonin RhythmReiter, R. J. (1995). Experimental Gerontology, 30(3/4), 199-212.
    19. 19. Ramelteon • MOA: Melatonin (M12) agonist • Indication: insomnia (sleep onset) • Half-life: 2 hours • Adverse effects: limited • Schedule: not controlledBonus (3 min): http://www.youtube.com/watch?v=rIpjfTbCHJ8
    20. 20. Summary Benzo Z drug Melatonin Agonist Diazepam Zolpidem RamelteonMOA GABAA α1,2,3,5 GABAA α1 M1,2Year 1963 1986 2005DevelopedIndication Insomnia (onset & Insomnia (onset) Insomnia (onset) maintenance) Long-termHalf-Life 50 3 2(hours)Withdrawal Yes Yes? NoIssues
    21. 21. Stahl (2008). Essential Psychopharmacology, p. 819.
    22. 22. 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)

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