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