1. Sedatives And Anxiolytic Drugs 镇静和 抗焦虑药 Anxiety (Edvard Munch, 1894) The Scream (Edvard Munch, 1893)

2. 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

3. Clinical Disorders  Panic 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

4. 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-HT 1A partial agonist (buspirone 丁螺环酮 ) ** The most commonly used anxiolytics

5. Benzodiazapine Structures

6. Barbiturates.

7. Benzodiazepine Mechanism of Action GABA A receptor composition varies in different regions BNZs bind to receptors with alpha & gamma subunits. BNZ binding “enhances” the effect of GABA on the Cl - current BNZs - increase the frequency of Cl- channel openings in presence of GABA BNZs exert no effect in the absence of GABA

8. 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 GABA A R isoforms) BNZs - high doses commonly produce anterograde 顺 行的, 前进的 amnesia 遗忘. Retrograde amnesia ( 逆行性遗忘 )

9. Barbiturates Benzodiazepines GABA Multiple mechanisms Bind to GABA A receptors at different site Don’t compete for BNZ binding & are not blocked by flumazenil Increase the duration of Cl - channel openings

10. Barbiturate 1.Increase GABA effect (increased duration of openings) 2.Directly activate GABA A channels at high concentrations 3.Block effects of glutamate NT* 4.Block Na channels * Glutamate is an excitatory NT

11. CNS Effects Increasing dose Coma 昏迷 Barbiturates Medullary 延髓 depression Benzodiazepines Anesthesia 麻醉 Hypnosis 催眠 Sedation, disinhibition, anxiolysis 抗焦虑 Possible selective anticonvulsant & muscle- relaxing activity Dose Response Relationships

12. Buspirone (BuSpar ®) 丁螺环酮 Anxiolytic but not sedating 5-HT 1A 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

13. Zolpidem (Ambien ®) & Zaleplon (Sonata ®) Benzodiazepine “like” drugs –Bind to a subset of GABA A 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

14. Chloral hydrate An older sedative-hypnotic Institutional 惯例的, 公共团体的, use (cheap) Converted to trichlorothanol Slow clearance

15. 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

16. 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)

17. 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)

18. Clinical Uses Alcohol Withdrawal 戒酒 –Benzodiazepines are useful because: Exhibit cross tolerance w/ alcohol Have anticonvulsant effects Little respiratory depression

19. 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.

20. Enzyme Induction Barbiturates (cyt P450) Toxicity Cognitive impairment, daytime sedation Elderly require lower doses Anterograde amnesia Additive CNS depression Respiratory & CV depression