Post on 03-Nov-2014
description
Sedative & Hypnotic Drugs I
Brian J. Piper, Ph.D., M.S.
January 22, 2013
Goals
• Importance• Pharmacodynamics (GABA)• Barbiturates• Benzodiazepines
Structure• intentional overlap• Assessment– 80% drug (PD/PK)– 5% pathophysiology– 5% diagnostic criteria– 10% pioneers
Terminology• sedative: agent that exerts a calming effect,
anxiolytic• hypnotic: agent that increases likelihood of
sleep onset & maintenance of sleep
NO YES
Dose-Response Curve For Sedative-Hypnotics
Trevor & Way (2012). Sedative-Hypnotic Drugs. In Katzung’s Basic & Clinical Pharmacology, p. 374.
Barbiturates• Examples: -barbital; phenobarbital,
amobartibal, butabarbital• MOA: GABAA, increase duration of Cl- channel
opening
Loscher & Rogawski (2012). Epilepsia, 53(S8), 12-25.
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.
Overdose Potential
1926-1962
1942 - 1970
Other Uses
• Physician Assisted Suicide (WA, OR, MT): – barbiturate + muscle relaxant + potassium chloride
• Lethal Injection (34)
brown: performs executionsblue: does not perform executionsgreen: no one executed 1976 - 2012
Benzodiazepines
1908 - 2005
http://www.howjsay.com/index.php?word=chlordiazepoxide&submit=Submit
Benzodiazepine Binding Site on GABAA
Location: Bindingα1β2 : GABAα1γ2 : benzodiazepines
Trevor & Way (2012). Sedative-Hypnotic Drugs. In Katzung’s Basic & Clinical Pharmacology, p. 374.
GABAA =α1 α2 α3 α4 α5 α6β1 β2 β3 β4γ1 γ2 γ3δεπρ
Howland & Mycek (2006). Lippincott’s Illustrated Reviews, p. 107.
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
Pharmacokinetic Comparison
• Benzos also differ in whether their metabolites are biologically active
Howland & Mycek (2006). Lippincott’s Illustrated Reviews, p. 106.
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.
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.
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.
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
Flumazenil• History: FDA approval in 1991• MOA: Benzodiazepine antagonist• Uses: reversal of BZD sedation
http://www.howjsay.com/index.php?word=flumazenil&submit=Submit
Flumazenil & PET
Benzodiazepine Addiction• gradual recognition• Withdrawal: rebound anxiety & insomnia
Lader (2011). Addiction, 106, 2086-2109.
Barbiturates Benzodiazepines
Most popular era 1950s 1960s - present
Mechanism of Action
PAM (low dose only)Cl– channel durationAMPA/kainate antagonist
PAM (all doses)Cl– channel frequency
Monotherapy Overdose
yes unlikely
Memory Impairment
yes yes
Loscher & Rogawski (2012). Epilepsia, 53(S8), 12-25.No!
Truth Serum?
Self-Test #1
• T or F Benzodiazepines and barbiturates bind to the same site on the GABAA receptor.
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
Self-Test #3
• Which of the following drugs has the highest risk of overdose?
• A) Quazepam• B) Chlordiazepoxide• C) Alprazolam• D) Phenobarbital• E) Halazepam