Sedative & Hypnotic Agents Part I

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This PPT is part 1 of 2 lectures given to second year pharmacy students in a pharmacology & toxicology class.

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  • anesthesia: condition of having sensation taken away.
  • GABAA is a pentemer with each subunit composed of 4 membrane spanning domains.Phenobarbital is currently used for acute seizure management, Amobarbital & butabarbital for insomnia.GAD: Glutamic Acid Decarboxylase; GABA-T: GABA Transaminase; SSA: succinic semialdehydeInteresting history is available here: http://en.wikipedia.org/wiki/Barbiturate
  • Phenobarbital is currently used for acute seizure management, Amobarbital & butabarbital for insomnia.GAD: Glutamic Acid Decarboxylase; GABA-T: GABA Transaminase; SSA: succinic semialdehyde; M1, M2, M3, M4: transmembrane domainsInteresting history is available here: http://en.wikipedia.org/wiki/Barbiturate
  • Norma JeaneMortenson had Nebutal in her system at autopsy.
  • Assisted suicide is explicitly prohibited in 34 states. Lethal injection is allowed in 34 states.The muscle relaxant used is a cousin of curare.
  • The organic chemist Sternbach developed chlordiazepoxide (Librium) in 1958 while working for the Swiss company Hoffman-La Roche.
  • Chloropromazine is a neuroleptic.
  • Pronouncedfloo nee traz a pam.
  • Groups weight was very similar. Half-life is 77% longer in the elderly!
  • 1st dose given at night & second in morning. Behavioral testing completed after 2nd dose.
  • With 1.0 mg CRT was prolonged 2 h after ingestion by 55 ms and 112 ms (median values) in young and elderly groups (doubled). No significant effects were observed with the 0.5 mg dose.
  • Chlordiazepoxide (Librium).
  • (flu may zinul). Risk of seizures, especially with long-term BZD-induced sedation.
  • Similarly, an autoradiography study noted that “ The highest densities of benzodiazepine receptors in human brain were localized in cortical and hippocampal areas, nucleus accumbens, amygdala and mammillary bodies. Intermediate densities were found in the basal ganglia and thalamic and hypothalamic nuclei. [3H]Flunitrazepam binding was low in the brainstem nuclei and very low in white matter.
  • Z drugs = Zolpidem; Zaleplon.
  • Structure of barbituric acid (L) and benzo (R).
  • NY Times: “Valium was the best-selling prescription drug in America”
  • Alprazolam (Xanax).
  • Sedative & Hypnotic Agents Part I

    1. 1. Sedative & Hypnotic Drugs I Brian J. Piper, Ph.D., M.S. January 22, 2013
    2. 2. Goals• Importance• Pharmacodynamics (GABA)• Barbiturates• Benzodiazepines
    3. 3. Structure• intentional overlap• Assessment – 80% drug (PD/PK) – 5% pathophysiology – 5% diagnostic criteria – 10% pioneers
    4. 4. Terminology• sedative: agent that exerts a calming effect, anxiolytic• hypnotic: agent that increases likelihood of sleep onset & maintenance of sleep YES NO
    5. 5. Dose-Response Curve For Sedative- HypnoticsTrevor & Way (2012). Sedative-Hypnotic Drugs. In Katzung’s Basic & Clinical Pharmacology, p. 374.
    6. 6. Barbiturates • Examples: -barbital; phenobarbital, amobartibal, butabarbital • MOA: GABAA, increase duration of Cl- channel openingLoscher & Rogawski (2012). Epilepsia, 53(S8), 12-25.
    7. 7. Barbiturates • Example: phenobarbital • MOA: GABAA, increase duration of Cl- channel opening; AMPA antagonist • Effects: – anticonvulsant – sleep – memory impairment – tolerance/addictionLoscher & Rogawski (2012). Epilepsia, 53(S8), 12-25.
    8. 8. Overdose Potential 1942 - 19701926-1962
    9. 9. Other Uses• Physician Assisted Suicide (WA, OR, MT): – barbiturate + muscle relaxant + potassium chloride• Lethal Injection (34) brown: performs executions blue: does not perform executions green: no one executed 1976 - 2012
    10. 10. Benzodiazepines 1908 - 2005http://www.howjsay.com/index.php?word=chlordiazepoxide&submit=Submit
    11. 11. Benzodiazepine Binding Site on GABAA GABAA = α1 α2 α3 α4 α5 α6 β1 β2 β3 β4 γ1 γ2 γ3 δ ε π ρ Location: Binding α1β2 : GABA α1γ2 : benzodiazepinesTrevor & Way (2012). Sedative-Hypnotic Drugs. In Katzung’s Basic & Clinical Pharmacology, p. 374.
    12. 12. Howland & Mycek (2006). Lippincott’s Illustrated Reviews, p. 107.
    13. 13. Is Flunitrazepam (Rohypnol) special? • In general, the pharmacodynamic differences between benzos are subtle while the pharmacokinetic differences are substantial.http://www.howjsay.com/index.php?word=flunitrazepam
    14. 14. Pharmacokinetic Comparison • Benzos also differ in whether their metabolites are biologically activeHowland & Mycek (2006). Lippincott’s Illustrated Reviews, p. 106.
    15. 15. Age Effects on Benzodiazepine PK• Young (N=10, 23-39 y.o., mean = 28.8) and elderly (N=9, 67-83 y.o., mean = 72.0) received 1 mg loprazolam after an over- night fast• Young t1/2 = 11.2 h Elderly t1/2 = 19.8 hSwift et al. (1985). British Journal of Clinical Pharmacology, 20, 119-128.
    16. 16. Age Effects on Benzodiazepine PD • Young and elderly received 0.5 (left) or 1.0 mg (right) loprazolam (x 2) over 11 hoursSwift et al. (1985). British Journal of Clinical Pharmacology, 20, 119-128.
    17. 17. Age Effects on Benzodiazepine PD • Young and elderly received 0.5 (left) or 1.0 mg (right) loprazolam (x 2) over 11 hoursSwift et al. (1985). British Journal of Clinical Pharmacology, 20, 119-128.
    18. 18. Benzodiazepines & Reproduction• Pregnancy Category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.• Cleft-palate?• Breast-feeding recommended
    19. 19. Flumazenil • History: FDA approval in 1991 • MOA: Benzodiazepine antagonist • Uses: reversal of BZD sedationhttp://www.howjsay.com/index.php?word=flumazenil&submit=Submit
    20. 20. Flumazenil & PET
    21. 21. Benzodiazepine Addiction • gradual recognition • Withdrawal: rebound anxiety & insomniaLader (2011). Addiction, 106, 2086-2109.
    22. 22. Barbiturates Benzodiazepines Most popular era 1950s 1960s - present PAM (low dose only) PAM (all doses) Mechanism of Cl– channel duration Cl– channel frequency Action AMPA/kainate antagonist Monotherapy yes unlikely Overdose Memory yes yes Impairment No!Loscher & Rogawski (2012). Epilepsia, 53(S8), 12-25.
    23. 23. Truth Serum?
    24. 24. Self-Test #1• T or F Benzodiazepines and barbiturates bind to the same site on the GABAA receptor.
    25. 25. Self-Test #2 • T or F Diazepam (valium) was the best selling prescription drug in the U.S. in the 1960s.http://www.nytimes.com/2012/09/30/sunday-review/valium-and-the-new-normal.html?_r=0
    26. 26. Self-Test #3• Which of the following drugs has the highest risk of overdose?• A) Quazepam• B) Chlordiazepoxide• C) Alprazolam• D) Phenobarbital• E) Halazepam

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