SedativeHypnotic Drugs Zhang Bin Institute of Pharmacology School

Sedative-Hypnotic Drugs Zhang Bin Institute of Pharmacology School of Medicine Shandong University 1

Insomnia 指尽管有充分的睡眠条件和环境却存在对睡眠时间和质 量不满足，并影响到白天社会功能的一种主观体验。 Symptoms of insomnia： 1. have trouble falling asleep 2. have trouble staying asleep 3. early morning waking 4. daytime drowsiness (嗜睡), fatigue or difficulty concentrating 2

Potential complications of insomnia World Sleep Day 3

Causes of insomnia 1. Psychological problems: anxiety 2. Medical problems 3. Medication anxiety: the most common cause 4

Sedative-hypnotic drugs Definition CNS depression (dose-dependent) Its major therapeutic use is to cause Ø sedation (with concomitant relief of anxiety) — small dose Ø encourage sleep — large dose 5

Classifications § Benzodiazepines (BZ，苯二氮卓类): § Barbiturates (巴比妥类) § Others some are popular 6

Characteristics 1. Graded dose-dependent depression of CNS function Dose-response curves for two hypothetical sedative-hypnotics Drug A: barbiturates Drug B: benzodiazepines and certain newer hypnotics 7

Ratio of lethal dose to effective dose for phenobarbital and diazepam 8

*2. Different influences on sleep phases 3. Tolerance 4. Dependence Physiological dependence withdrawal symptoms Psychological dependence 9

Phases of sleep 1. NREMS (non rapid eye movement sleep, 非快动眼睡眠) SWS ( slow wave sleep，慢波睡眠) Stages 1 - 4 (入睡期、浅睡期、中度睡眠期、深度睡眠期) Characterists: Ø Play roles in eliminating the fatigue and promote growth Ø night-waking（夜惊）, sleep-walking（梦游, somnambulism） occur in stage 3 and 4 Ø shorten stage 3 and 4 will clean up night-waking and sleep-walking. 10

Phases of sleep 2. REMS ( rapid eye movement sleep, 快动眼睡眠） FWS ( fast wave sleep，快波睡眠 ) Characterists: Ø Play roles in brain and intellectual development. Ø Rapid eye movement, dream, muscle relaxation, fast breathing et al. Ø Long-term shorten will induce “rebound （反跳）” （反跳） after withdrawal, significantly increase the frequency and duration of REMS, cause dreaminess, nightmare, aggravate anxiety and insomnia, finally lead to dependence. 11

Phases of sleep Sleep latency 80 -120 min 20 -30 min NREM REM NREM 4 -5 cycles of alternating REMS and NREMS 8 h 2 h 25% 5% 4 h � 2 h 50% 10% 12

Section 1 Benzodiazepines (BZ，苯二氮卓类) 14

Classifications Drugs Long-acting T 1/2 (h) 24~72 h Diazepam (地西泮，安定） Flurazepam (氟西泮，氟安定） Chlordiazepoxide (氯氮卓，利眠宁) Intermediate-acting 10 -20 h Alprazolam (阿普��，佳�定 ) Estazolam (艾司��，舒�安定 ) Clonazepam (�硝西泮 ) Short-acting 3 -8 h Oxazepam (奥沙西泮，去甲羟安定，舒宁) Triazolam (三唑仑，海乐神) 15

Diazepam (地西泮，安定） 【Pharmacological actions and clinical uses】 1. Antianxiety Ø at the lowest effective doses Ø relieve the anxiety state induced by various causes Uses: For anxiety 16

2. Sedation and Hypnosis Ø decrease sleep-induction time Ø decrease the number of awakenings Ø increase the duration of sleep prolong stage Ⅱ of NREMS shorten stage Ⅲ，Ⅳ of NREMS (reduce night-waking and sleep-walking， deep sleep) * seldom effect on REMS (little rebound) 17

Uses: Premedication (术前给药）: an adjunct in anesthesia For insomnia (not for depression) 18

3. Anticonvulsant and antiepileptic effects Uses: For convulsion and epilepsy Ø convulsions due to various causes: tetanus (破伤风) eclampsia (子痫) febrile convulsion (高热惊厥) drug toxic convulsion (药物中毒性惊厥） Ø status epilepticus (癫痫持续状态): Diazepam（iv. ）is first choice 19

4. Central muscle relaxation Uses: For skeletal muscle spasms Spasticity from degenerative disorders, such as multiple sclerosis and cerebral palsy Spasticity from cerebral vascular accident and spinal cord injury Spasticity from anxiety Skeletal muscle spasms caused by local disease such as lumbar muscle strain(腰肌劳损) 20

5. Amnesia (遗忘): anterograde amnesia Uses: Endoscopy (内窥镜检查) Electric defibrillation(电除颤) 6. Effects on respiration and cardiovascular function Ø Respiratory depression Ø Cardiovascular depression larger dose→side effect 21

【 Mechanisms of action 】 Sites of action: Mainly acts on limbic system（边缘系统） and brainstem reticular formation（网状结构） 22

【 Mechanism of action 】 GABAA 受体 GABA Barbiturates BZs + + - Cl- 23

【 Mechanism of action 】 24

【 Mechanism of action 】 25

Receptor binding GABA(no and. GABA benzodiazepine Benz empty Receptor binding agonists) GABAodiaz epine Benzodia zepine receptor Cl. Cl Cl - - Cl. Cl- - Cl Cl Cl- Cl GABA receptor Empty receptor is inactive, and the Binding of GABA coupled chloride causes the chloride Entry of Cl- hyperpolarizes cell making ionchannelistoclosed. open it more difficult to depolarize and therefore reduces neural excitability. Binding of GABA is enhanced by benzodiazepine, resulting in a greater 26 entry of chloride ion.

【 Mechanism of action 】 Increase the efficiency of GABAergic synaptic inhibition 1. Bind with BZ site on the GABAA receptor 2. Enhance the affinity of GABAA receptor for GABA ， promote GABA binding to GABAA receptor. 3. Increase the frequency of Cl- channel opening 4. Enhance hyperpolarization and further inhibit neural excitability 5. not substitute for GABA, but appear to enhance GABA’s effects 27

Biotransformation of benzodiazepines 氯氮卓 地西泮 普拉西泮 阿普唑仑 三唑仑 奥沙西泮 氟西泮 劳拉西泮 Boldface: drugs available for clinical use * : active metabolite 28

【 Adverse Reactions 】 1. CNS depression Ø Hangover (宿醉）： residual effect, most common drowsiness（嗜睡）, exhaustion（乏力）, dizziness（头晕）, memory decay（记忆力下降） Ø Diminished motor skills, impaired judgment, ataxia → impact on driving ability Ø iv. too quick →inhibit respiratory and cadiovascular fuction 29

【 Adverse reactions 】 2. Tolerance and dependence (addiction) Tolerance 1 -2 w Dependence Physiological dependence withdrawal symptoms Psychological dependence 30

3. toxic reaction and detoxifcation § Washing stomach § Symptomatic treatment § Benzodiazepine specific antagonist Flumazenil (氟马西尼，安易醒）: diagnosis and treatment short t 1/2, repeated administration induce epilepsy BZs GABA Flumazenil 31

Advantages of BZs 1. higher therapeutic index, great margin of safety, no anesthesia and coma in large dose 2. little influences on REMS, little rebound , less dependence and withdrawal syndrome 3. shorten stage Ⅲ，Ⅳ of NREMS，reduce nightwaking and sleep-walking 4. little effects on hepatic microsomal drugmetabolizing enzymes（肝药酶） 5. Less general adverse reactions 32

Section 2 Barbiturates 33

Classifications Long-acting: phenobarbital (苯巴比妥, luminal, 鲁米那) Intermediate-acting: pentobarbital (戊巴比妥) Short-acting: secobarbital (司可巴比妥) Ultra-short-acting: thiopental sodium (硫喷妥钠) 34

【Pharmacological actions and clinical uses dose-dependent effects 1. Sedation and hypnosis （not for routinely use ） shorten REMS→ “rebound” Ø Easy to produce tolerance and dependence Ø Hepatic enzyme inducer (肝药酶诱导剂） Ø more adverse reactions , severe intoxication 35

【Pharmacological actions and clinical uses 2. Anticonvulsant and antiepileptic effects Phenobarbital（苯巴比妥）： generalized tonic-clonic seizure (大发作) 3. Anesthesia 4. Enhance the effects of other CNS depressants Adverse reaction: respiration center paralysis 36

【Mechanisms】 Ø GABA mimetic (high dose activate GABA - R) Ø Extend opening time of Cl- channel Ø inhibit excitatory neurotransmitter 37

Detoxifcation（中毒解救） Alkalization of the urine （碱化尿液） often aids in the elimination of phenobarbital —iv. Na. HCO 3 38

Section 3 Other sedative-hypnotics 39

Other sedative-hypnotics Older sedative-hypnotics Chloral hydrate (水合氯醛) Meprobamate (甲丙氨酯，眠尔通) Newer drugs for anxiety and sleep disorders Buspirone (丁螺环酮) Zolpidem (唑吡坦 , 思诺思) Zopiclone (佐匹克隆) Zaleplone (扎来普隆) Melatonin (褪黑素) Ramelteon（雷美尔通） 40

Chloral hydrate（水合氯醛） 1. Hypnosis : onset rapidly (15 min), no effect on REM, no hangover, used for obstinate insomnia (顽固性失眠) 2. Anticonvulsant effects: febrile convulsion in children, etc. 3. gastic mucosal irritation: not used for gastritis and ulcer patients oral: dilute (10%), rectal administration 4. toxicity on heart, liver, kidney 5. Tolerance and dependence 6. Low therapeutic index 41

Zolpidem (唑吡坦, 思诺思Stilnox, 舒睡晨爽) 非苯二氮卓类GABAA-R agonist 1. only has sedative-hypnotic effects 2. almost does not change the normal sleep phase 3. little residual effects, tolerance and dependence 4. detoxification: flumazenil 42

Buspirone（丁螺环酮） 1. Used for anxiety 2. a partial agonist of 5 -HT 1 A-R in brain, inhibit the release of 5 -HT, have no effect on GABAA-R 3. no sedative-hypnotic effects 4. no tolerance and dependence 44

Melatonin（褪黑素, MT, 美乐通宁） Mechanism: activate MT-R on suprachiasmatic nucleus(视 交叉上核), enhance the function of GABA Clinical uses：sleep- wake rhythm disorders used for adults and the elderly can not be used by teenagers 45

Ramelteon (雷美尔通, 拉米替隆) 1. selective agonist at the MT 1 and MT 2 subtypes of melatonin receptors 2. mainly decrease sleep latency 3. no dependence or withdrawal effects, long-term use 4. can not be used by teenagers 46

The basic principles of drug therapy for insomnia 1. begin at the lowest effective doses 2. best used intermittently（2 - 4 times/week） 3. short-term use（less than 2 - 4 weeks） 4. gradual discontinuation 47

“Ideal” hypnotics 1. induce sleep rapidly 2. does not affect normal sleep phases 3. there is no residual effects the next day 4. long-term use does not cause drug dependence 5. no interaction with alcohol and other drugs 卓别林 （1889. 4. 16 -1977. 12. 25） 48

Thank you! 49