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

1. Sedative & Hypnotic Drugs I
Brian J. Piper, Ph.D., M.S.
January 22, 2013

2. Goals
• Importance
• Pharmacodynamics (GABA)
• Barbiturates
• Benzodiazepines

3. Structure
• intentional overlap
• Assessment
– 80% drug (PD/PK)
– 5% pathophysiology
– 5% diagnostic criteria
– 10% pioneers

4. Terminology
• sedative: agent that exerts a calming effect,
anxiolytic
• hypnotic: agent that increases likelihood of
sleep onset & maintenance of sleep
YES
NO

5. Dose-Response Curve For Sedative-
Hypnotics
Trevor & Way (2012). Sedative-Hypnotic Drugs. In Katzung’s Basic & Clinical Pharmacology, p. 374.

6. Barbiturates
• Examples: -barbital;
phenobarbital, amobartibal, butabarbital
• MOA: GABAA, increase duration of Cl- channel
opening
Loscher & Rogawski (2012). Epilepsia, 53(S8), 12-25.

7. Barbiturates
• Example: phenobarbital
• MOA: GABAA, increase duration of Cl- channel
opening; AMPA antagonist
• Effects:
– anticonvulsant
– sleep
– memory impairment
– tolerance/addiction
Loscher & Rogawski (2012). Epilepsia, 53(S8), 12-25.

8. Overdose Potential
1942 - 1970
1926-1962

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. Benzodiazepines
1908 - 2005
http://www.howjsay.com/index.php?word=chlordiazepoxide&submit=Submit

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 : benzodiazepines
Trevor & Way (2012). Sedative-Hypnotic Drugs. In Katzung’s Basic & Clinical Pharmacology, p. 374.

12. Howland & Mycek (2006). Lippincott’s Illustrated Reviews, p. 107.

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. Pharmacokinetic Comparison
• Benzos also differ in whether their
metabolites are biologically active
Howland & Mycek (2006). Lippincott’s Illustrated Reviews, p. 106.

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 h
Swift et al. (1985). British Journal of Clinical Pharmacology, 20, 119-128.

16. Age Effects on Benzodiazepine PD
• Young and elderly received 0.5 (left) or 1.0 mg
(right) loprazolam (x 2) over 11 hours
Swift et al. (1985). British Journal of Clinical Pharmacology, 20, 119-128.

17. Age Effects on Benzodiazepine PD
• Young and elderly received 0.5 (left) or 1.0 mg (right) loprazolam (x 2) over
11 hours
Swift et al. (1985). British Journal of Clinical Pharmacology, 20, 119-128.

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. Flumazenil
• History: FDA approval in 1991
• MOA: Benzodiazepine antagonist
• Uses: reversal of BZD sedation
http://www.howjsay.com/index.php?word=flumazenil&submit=Submit

20. Flumazenil & PET

21. Benzodiazepine Addiction
• gradual recognition
• Withdrawal: rebound anxiety & insomnia
Lader (2011). Addiction, 106, 2086-2109.

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. Truth Serum?

24. Self-Test #1
• T or F Benzodiazepines and barbiturates
bind to the same site on the GABAA
receptor.

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. Self-Test #3
• Which of the following drugs has the highest
risk of overdose?
• A) Quazepam
• B) Chlordiazepoxide
• C) Alprazolam
• D) Phenobarbital
• E) Halazepam