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.
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
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
Hinweis der Redaktion
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”