Download Barbiturates

Sedatives And Anxiolytic Drugs
镇静和抗焦虑药
The Scream
(Edvard Munch, 1893)
Anxiety
(Edvard Munch, 1894)
Anxiety
•
•
•
•
•
•
•
•
feeling of helplessness
difficulty in concentrating
irritability易怒& insomnia失眠[
GI disturbances
muscle tension
excessive perspiration大汗
palpitations心悸
dry mouth
dread恐怖
Clinical Disorders
disorder 急性焦虑症
 Obsessive-compulsive disorder 强迫性(精神)
障碍
 Social phobia 社会恐怖
 Social anxiety disorder 社交焦虑障碍
 Generalized anxiety disorder 一般焦虑症
 Specific phobias 特异(单－)恐怖
 Panic
Drug Choices
Older:
• Barbiturates (drugs ending in “barbital”)
• Alcohols / Choral Hydrate
Newer:
• Benzodiazepines (drugs ending in “lam” or
“pam” such as Diazepam)**
• Benzodiazepine “Like” (zolpidem & zaleplon)
• 5-HT1A partial agonist (buspirone丁螺环酮)
**
The most commonly used anxiolytics
Benzodiazapine Structures
Barbiturates.
Benzodiazepine Mechanism of Action
• GABAA receptor composition varies in different
regions
• BNZs bind to receptors with alpha & gamma subunits.
• BNZ binding “enhances” the effect of GABA on the Clcurrent
•BNZs
increase
the
frequency
channel openings in presence of GABA
• BNZs exert no effect in the absence of GABA
of
Cl-
Benzodiazepine Mechanism of Action
•The effects & binding of BNZ was blocked by
flumazenil氟马西尼(BNZ antagonist)
• Not all BNZs are identical (may be due to differences
in effects on different GABAA R isoforms)
• BNZs - high doses commonly produce anterograde顺
行的,前进的amnesia遗忘.
•Retrograde amnesia (逆行性遗忘)
Barbiturates
Multiple mechanisms
Bind to GABAA receptors at different site
• Don’t compete for BNZ binding & are not
blocked by flumazenil
• Increase the duration of Cl- channel openings
GABA
Barbiturates
Benzodiazepines
Barbiturate
1. Increase GABA effect (increased duration
of openings)
2. Directly activate GABAA channels at high
concentrations
3. Block effects of glutamate NT*
4. Block Na channels
* Glutamate is an excitatory NT
Dose Response Relationships
Coma昏迷
Barbiturates
Medullary 延髓 depression
CNS Effects
Benzodiazepines
Anesthesia麻醉
Hypnosis 催眠
Sedation, disinhibition,
anxiolysis抗焦虑
Increasing dose
Possible selective
anticonvulsant & musclerelaxing activity
Buspirone (BuSpar ®)丁螺环酮
•
•
•
•
•
Anxiolytic but not sedating
5-HT1A partial agonist
No drug dependence
Slow onset of action (week or more)
Indication:
- chronic anxiety disorders (generalized
anxiety disorder)
- anxiety disorders in patients with history of
drug dependence or abuse
Zolpidem (Ambien ®) & Zaleplon (Sonata ®)
• Benzodiazepine “like” drugs
– Bind to a subset of GABAA receptors w/ 1
subunits
– Effects are blocked by flumazenil (BNZ antagonist)
• Produce pure sedation (without anxiolytic,
anticonvulsant or muscle relaxing effects)
• Minimal effect on REM sleep
• Indications:
– Insomnia
• Advantages: less daytime impairment vs. BNZs
Chloral hydrate
•
•
•
•
An older sedative-hypnotic
Institutional惯例的,公共团体的,use (cheap)
Converted to trichlorothanol
Slow clearance
Pharmacodynamic Effects
BNZs & Barbiturates:
• Medullary Depression
- A cause for respiratory arrest
•
Tolerance & Dependence
- Physiological tolerance
- Physiological dependence (w/ withdrawal)
- Withdrawal: anxiety, tremors, seizures
- Cross tolerance
- Buspirone - no dependence
- Zolpidem & zaleplon - very low dependence liability
Clinical Uses
Anxiety Disorders
– Alprazolam & Clonazepam - esp. useful in panic
& phobic disorders (greater efficacy)
– Buspirone - chronic forms of anxiety
• Little sedative effect, slow onset
• No drug dependence (Rx. Pts w/ history of
drug abuse)
Clinical Uses
Insomnia
– BNZs (estazolam,flurazepam, trizolam)
• Day time sedation side effect
• REM sleep reduced; rebound
– Zolpidem & Zaleplon
• Less daytime sedation*
• No effect on REM sleep
– Other Drugs:
• Antihistamines (Excedrin PM ®)
* w/o anxiolytic, anticonvulsant, muscle relaxant side effects)
Clinical Uses
Alcohol Withdrawal戒酒
– Benzodiazepines are useful because:
• Exhibit cross tolerance w/ alcohol
• Have anticonvulsant effects
• Little respiratory depression
BNZ Metabolism
•
Chemical structures of barbiturates and other sedative-hypnotics.
• hepatic metabolism, active metabolites
• elimination half life  duration of action
• most have half lives >10 hrs.
Enzyme Induction
• Barbiturates (cyt P450)
Toxicity
• Cognitive impairment, daytime sedation
• Elderly require lower doses
• Anterograde amnesia
• Additive CNS depression
•Respiratory & CV
depression