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1 中枢神经系统药理 Drugs Affecting the Central Nervous System (I) Yun-Bi Lu, PhD 卢韵碧 Dept. of Pharmacology School of Medicine, Zhejiang University

2 1 局麻药 2 镇静催眠药 3 抗癫痫药和抗惊厥药 4 治疗中枢神经系统退行性疾病药 5 抗精神失常药 6 镇痛药 7 解热镇痛抗炎药

3 Classification of CNS drugs Sedative-hypnotics Epilepsy and convulsion Parkinson disease Analgesics Central stimulants Antipsychotic c drugs depression-mania Dementia Neurological euoogca (general and special) Psychological

4 Classification of CNS drugs Sedative-hypnotics e ( 镇静催眠药 ) Antiepileptic drugs and anticonvulsant drugs ( 抗癫痫药和抗惊厥药 ) Anti-Parkinson Drugs ( 抗帕金森病药 ) Analgesics ( 镇痛药 ) Central stimulants ( 中枢兴奋药 ) Antipsychotic drugs ( 抗精神病药 ) Antidepressants, t Drug Treatment t of fm Mania ( 抗抑郁药, 抗躁狂药 ) Anti-Alzheimer Alzheimer Drugs( 治疗阿尔茨海默病药 )

5 兴奋性神经元抑制性神经元 GABA 谷氨酸 Ach NE DA 5-HT

6 略 ACh NE DA 5-HT

7 Local lanesthetics ti ( 局麻药 )

8 Local Anesthetics ( 局麻药,LAs) Definition: drugs that cause loss of sensation without loss of consciousness Reversibly block nerve conduction Act on every type of nerve fiber No structural damage to the nerve cell Also act on cardiac muscle, skeletal muscle and dthe brain

9 1. Structural Classes: Esters ( 酯类 ) and Amides( 酰胺类 ) 酯链酰胺键

10 Structural Classes: Esters ( 酯类 ) and Amides( 酰胺类 ) all are weak bases BH+ B + H+ 芳香族环酯链胺基团可卡因普鲁卡因丁卡因苯佐卡因

11 芳香族环酰胺链胺基团利多卡因甲哌卡因布比卡因布比卡因丙胺卡因

12 2. Pharmacological effects 神经纤维末梢神经节中枢神经节神经系统的突触较为敏感 ; 细的比粗的神经纤维敏感 ; 钝痛比锐痛敏感 ;

13 3. Action mechanism LAs blocks action potential generation by blocking voltage-gated Na + channels. Onset and duration of action The ionized form interacts with the Na + channels to inhibit its function and, thereby, achieve local anesthesia. ph of the tissue pka of the drug lipid solubility

14 Use-dependent Blockade ( 使用依赖性 / 频率依赖性 )

15 局麻药的药理作用特点 Ionic gradient and resting membrane potential are unchanged Decrease the amplitude of the action potential Slow the rate of depolarization Increase the firing threshold Slow impulse conduction Prolong the refractory period

16 4. Modes of Administration Topical local (surface) anesthesia( 表面麻醉 ): for eye, ear, nose, and throat procedures and for cosmetic surgery Infiltration anesthesia ( 浸润麻醉 ): local injection around the region to be operated. Conduction anesthesia ( 传导麻醉 ): local injection around the peripheral nerve trunk Epidural ansthesia ( 硬膜外麻醉 ): local injection into the epidural space Subarachnoid anesthesia ( 蛛网膜下腔麻醉 ): or Spinal anesthesia ( 脊髓麻醉, 腰麻 ): local injection into the cerebrospinal fluid in subarachnoid cavity Regional analgesia ( 区域镇痛 )

17 蛛网膜下腔脊神经阻滞椎旁阻滞硬膜外阻滞骶管阻滞

18 5. Uses of local anesthesia Topical local (surface) anesthesia( 表面麻醉 ): 丁卡因 Infiltration anesthesia ( 浸润麻醉 ): 利多卡因, 普鲁卡因 Conduction anesthesia ( 传导麻醉 ): 利多卡因, 普鲁卡因, 布比卡因 Epidural ansthesia ( 硬膜外麻醉 ): 利多卡因, 布比卡因, 罗哌卡因 Subarachnoid anesthesia ( 蛛网膜下腔麻醉 ): or Spinal anesthesia ( 脊髓麻醉, 腰麻 ): 利多卡因, 普鲁卡因, 丁卡因 Regional analgesia ( 区域镇痛 ): 布比卡因, 罗哌卡因

19 6. Adverse effects 1) CNS Toxicity Correlation between potency and seizure threshold Bupivacaine 2 ug/ml 布比卡因 Lidocaine 利多卡因 10 ug/ml

20 2) Cardiovascular Toxicity Attributable to their direct effect on cardiac muscle Contractility Negative inotropic ( 负性肌力 ) effect that is dose- related and correlates with potency Interference with calcium signaling mechanisms Automaticity Negative chronotropic ( 负性频率 ) effect Rhythmicity y and Conductivity Ventricular arrhythmias 3) Allergic reactions

21 7. Pharmacokinetics Absorption (injected or topical) - affected by vascularity ( 血供 ) - presence of additional vasoconstrictor ( 血管收缩剂 ) - Duration prolonged by vasoconstrictor (epinephrine) - localizes agent to site of action - contraindicated in extremities( 末梢部位 ) - Systemic Toxic Effects: CNS, cardiovascular

22 7. Pharmacokinetics Distribution - LAs bind in the blood to a1-glycoprotein and albumin Alpha phase ( 快速吸收相 ) rapidly redistributed to well-perfused tissues Beta phase ( 再分布相 ) distribution to less perfused or slowly equilibrating tissues Gamma phase ( 消除相 ) clearance representing metabolism and excretion

24 Lidocaine( 利多卡因 ) One of the most widely used local anesthetics Rapid onset, medium duration Also available in ointment( t( 软膏 ), jelly( ( 凝胶 ), and aerosol( 喷雾剂 ) Other uses: anti-arrhythmic

25 局麻药的总结

26 Sedative-Hypnotic e Drugs ( 镇静催眠药 )

27 Sedatives ( 镇静药 ): 能缓和激动, 消除躁动, 恢复安静情绪的药物 -----prescribed to cause sedation (for patients with anxiety) Hypnotics ( 催眠药 ): 能促进和维持近似生理睡眠的药物 -----prescribed to encourage sleep (for patients with insomnia) 中枢抑制药多数随剂量增加而出现镇静催眠等中枢抑制作用, 故合称为镇静催眠药 (sedative-hypnotics)

28 Stage 3 & 4, 统称为慢波睡眠 Molecular Neuropharmacology

29 Sleep histogram shows a normal pattern of sleep in a young adult.

31 Sedative-Hypnotic Drugs Benzodiazepines (BZ / BDZ, 苯二氮艹卓类 ) Barbiturates ( 巴比妥类 ) Others

32 A. Benzodiazepines Diazepam 地西泮地西泮 ( 安定 ) 1. Pharmacological effects and clinical uses (1) Reduction of anxiety at small doses acting on limbic system ( 杏仁核海马的 GABAA 受体 ) (2) Sedative and hypnotic actions( 脑干的 GABAA 受体 ) at relatively larger doses, no anesthetic effect; not remarkably affect on REM used for insomnia ( 失眠 ) and pre-anesthetic medication

33 A. Benzodiazepines (3) Antiepileptic and anticonvulsant effects Convulsion due various causes; status epilepticous p (i.v.) (4) Muscle relaxant effect Relaxing the spasticity of skeletal muscle( 肌肉僵直 ), probably by increasing presynaptic inhibition in the spinal cord. Used for the treatment t t of skeletal l muscle spasms caused by central or peripheral diseases. (5) Others Amnesia ( 短暂性记忆缺失,i.v.) Respiratory and CVS effects

34 2. Mechanisms of actions (1) Sites of action: mainly mainly acts on limbic system and midbrain reticular formation. A schematic drawing showing key components of the ascending reticular activating system (ARAS) 网状结构上行激活系统

35 2. Mechanisms of actions (2) Interaction with GABA A receptor

36 2. Mechanisms of actions (2) Interaction ti with GABA A receptor Co-agonist

37 A. Benzodiazepines 2. Mechanisms of actions (2) Interaction with GABA A receptor Benzodiazepines bind to specific, high affinity sites on the cell membrane, which are separate from but adjacent to the receptor for -aminobutyric acid (GABA). The binding of benzodiazepines enhances the affinity of GABA receptor for this neurotransmitter, resulting in amore frequent opening of adjacent chloride channels. - coagonist This in turn results in enhanced hyperpolarization( 超极化 )and further inhibition of neuronal firing.

38 Centrally acting muscle relaxant effect: increasing presynaptic inhibition in the spinal cord

39 A. Benzodiazepines 3. Adverse effects (1) Central depression Most common: drowsiness and confusion (potentiated by ethanol or other central depressants). Ataxia ( 共济失调 ); cognitive impairment Antagonized by BZ receptor antagonist flumazenil( ( 氟马西尼 )

40 A. Benzodiazepines 3. Adverse effects (2) Tolerance Dependence Withdrawal syndrome: central excitation

41 A. Benzodiazepines (3) Others local pain, respiratory and CVS reactions (i.v.) teratogenic t effects( ( 致畸效应 ) 药物安全性 (4) Contraindications Myasthenia gravis Infants < 6 months Pregnancy and lactation mothers Elderly, heart/lung/liver/kidney dysfunction

42 A. Benzodiazepines 丁螺环酯阿普唑仑

43 A. Benzodiazepines Other benzodiazepines According to the metabolisms 氯氮艹卓劳拉西泮奥沙西泮三唑仑

44 B. Benzodiazepines Phenobarbital 苯巴比妥

45 1. ADME B. Barbiturates Inducing hepatic enzymes Alkalinization of urine: excretion 硫喷妥钠脂溶性极高, 因而易通过 BBB, 易发生再分布 ; 苯巴比妥脂溶性低, 不易在肝脏代谢 ; 脂溶性高, 血浆蛋白结合率高

46 B. Barbiturates 2. Pharmacological uses effects and clinical (1) Sedative-hypnotic effects 可缩短快动眼睡眠期 (REMS), 反跳明显 ; (2) Pre-anesthetic ti medication (3) Antiepileptic and anticonvulsant effects

47 3. Adverse effects ects B. Barbiturates (1) Central depression: including effect (hangover 宿醉 ) (2) Tolerance and dependence: long uses (3) Acute poisoning i supporting therapies alkalizing urine hemodialysis after long-term

48 C. Others Chloral hydrate 水合氯醛 Sedative-hypnotic effects Anticonvulsant effect: usually used in children Hydroxyzine 羟嗪 ( 安泰乐 ) Meprobamate 甲丙氨酯甲丙氨酯 ( 眠尔通 ) Buspirone 可能与 5-HT 有关丁螺环酮, 抗焦虑, 但无镇静作用, Methaqualone 安眠酮

49 C. Others Antihistamines 抗组胺药 Ethanol 乙醇 Melatonin 褪黑素

50 略 In her circulation system: 8 % chloral hydrate (3% toxic level and 10% lethal level) 4.5 % Nembutal (pentobarbital ) (death level 1.5-4%) In her stomach and duodenum: No drug crystal found! 1962 年 8 月 5 日梦露在洛杉矶布莱登木寓所的卧室内被发现已经去世, 终年 36 岁

51 略

52 Antiepileptic drugs and anticonvulsant drugs 抗癫痫药和抗惊厥药

53 癫痫发作 Epilepsy is not a single entity; it is a family of different recurrent seizure disorders that have in common the sudden, excessive and disorderly discharge of central neurons. This results in abnormal movement or perceptions that are of short duration but that tend to recur.

54 Local excitatory Abnormal high frequency discharging Abnormal spreading Brain malfunction Accompanied with abnormal EEG (electroencephalograph) 发病率高 ; 突发性, 不可预测 ; 不可根治, 需终身服药

55 Classification of epilepsy

56 International Classification of Epileptic Seizures: Partial Onset Seizures( 局限性发作 ) Simple Partial( 单纯局限性 ) Complex Partial ( 复合性局限性 ) Partial seizures with dyscognitive features Partial Seizures with secondary generalization ( 局限性发作继发全身 - 强直阵挛性发作 ) Partial seizures without dyscognitive features

57 International Classification of Epileptic Seizures: Primary Generalized Seizures 原发性全身性发作 Absence (Petit Mal) ( 失神性发作 / 小发作 ) Myoclonic ( 肌阵挛性发作 ) Generalized Tonic+Clonic ( 全身强直 - 阵挛性发作 )

58 The pathways for seizure propagation in partial seizures and primary generalized seizures

59 Origin of a surface epileptic discharge 强直性发作阵挛性发作表面脑电图发作后抑制细胞外记录细胞内记录 PDS:paroxysmal depolarization shift 阵发性去极化漂移

Seizures are generated by groups of neurons which depolarizing synchronously y Epileptic neurons generate Paroxysmal Depolarizing Shift ( 阵发性去极化飘移, PDS) During a PDS, there is the repetitive

60 Seizures are generated by groups of neurons which depolarizing synchronously y Epileptic neurons generate Paroxysmal Depolarizing Shift ( 阵发性去极化飘移, PDS) During a PDS, there is the repetitive activation of key ion channels. These ion channels These ion channels represent opportunities to prevent or terminate seizures. Surface Spike PDS Sodium Influx Calcium Influx Chloride Influx K efflux

61 Mechanisms of antiepileptic il drugs Electrophysiological Inhibiting excessive discharges ( 抑制过度放电 ) Inhibiting spread of discharges ( 阻止异常放电的扩散 ) Molecular Potentiating GABA neuronal functions Inhibiting excitatory t neuronal functions Modulating Na +, Ca 2+, K +, Cl - channel fuctions

62 兴奋性 Molecular targets for anti-seizure i drugs at the excitatory, glutamatergic synapse.

63 抑制性 Molecular targets for antiseizure drugs at the inhibitory, GABAergic synapse.

64 Imbalance of excitation and inhibitory Na + Ca 2+ NMDA K + Cl - GABA Antiepileptic il drugs Focus formation and epileptic attack Focus shift Spreading Refractory epilepsy

65 A. Antiepileptic drugs Special drugs Phenytoin Sodium 苯妥英钠苯妥英钠, 大仑丁 C6H5 NaO HN N CO C6H5

66 A. Antiepileptic drugs 1. Pharmacological mechanism effects and the (1) Effects Inhibiting spread of abnormal discharges Not on discharge the happening of abnormal

67 苯妥英钠

68 A. Antiepileptic drugs 1. Pharmacological effects and the mechanism (2) Mechanism Blocking Na + channel in inactive state Inhibiting L- and N-type Ca 2+ channel (but not T-type Ca 2+ channel ) Calmodulin kinase activity Neurotransmitter release (NE, 5-HT, DA etc.) Block posttetanic potentiation (PTP) formation

69 A. Antiepileptic drugs 2. Clinical uses (1) Anti-epilepsy Grand mal, status t epilepticus; Partial seizures (simple and complex); Ineffective for petit mal (absence seizures) 失神小发作 (2) Trigeminal ( 三叉神经疼 ) and related neuralgia ( 神经疼 ) (3) Anti-arrhythmia

70 3. ADME A. Antiepileptic drugs Larger doses: non-linear kinetics(> 10 g/ml) Half life = 24 hours Therapeutic range = ug/ml Levels above 20 cause ataxia ( 共济失调 ) and nystagmus( 眼球震颤 ) Hepatic metabolism CYP3A enzyme pathway CYP3A antagonists will raise phenytoin levels Necessary to monitor Necessary to monitor plasma concentrations Initially linear Psuedo first order

72 A. Antiepileptic drugs 4. Adverse effects (1) Local reactions GI reactions; gingival hyperplasia ( 齿龈增生 ) (2) CNS reactions Particularly in the cerebellum and vestibular systems: nystagmus ( 眼球震颤 ), ataxia ( 共济失调 ), etc. Behavioral changes: confusion, hallucination, coma (3) Hemological reactions Megaloblastic anemia ( 巨幼红细胞性贫血,affect the metabolism of folic acid, 以甲酰四氢叶酸防治 )

73 A. Antiepileptic drugs (4) Allergic reactions Skin reactions; blood cell abnormality (including thrombocytopenia, agranulocytosis 粒细胞缺乏 ); hepatic toxicity; ect. (5) Skeletal l reactions Osteomalacia ( 骨质疏松 ) by increase vitamin D metabolism and calcium absorption (inducer) (6) Others Birth defects, hirsutism( 多毛症 ), etc

74 A. Antiepileptic drugs 5. Drug interactions( 蛋白结合代谢 ) (1) Increases plasma concentrations of drugs by displacement of plasma protein binding (salicylates) (2) Drug metabolizing enzyme inhibitor decrease the metabolism of phenytoin (isoniazid 异烟肼, chloramphenicol 氯霉素 ) (3) Drug metabolizing enzyme inducer increase the metabolism of phenytoin (phenobarbital, carbamazepine) (4) Phenytoin enhances the metabolism of corticosteroids and vitamin D

A. Antiepileptic drugs Carbamazepine 卡马西平 Blocks Na + and Ca 2+ channels Enhance GABA Effective against psychomotor seizures, and grand mal Effective for mania, depression, and neuralgia( 神经痛 ) Like

75 A. Antiepileptic drugs Carbamazepine 卡马西平 Blocks Na + and Ca 2+ channels Enhance GABA Effective against psychomotor seizures, and grand mal Effective for mania, depression, and neuralgia( 神经痛 ) Like phenytoin, metabolized by CYP3A pathway (an inducer) Need titration up! Safety and Toxicity N CONH2 Dose dependence-double vision, ataxia rash 5-10% rare marrow suppression rare hepatitis frequent hyponatremia/water intoxication (Dose dependence) fetal malformations( 致畸 )

76 A. Antiepileptic drugs Phenobarbital 苯巴比妥可提高病灶周围组织的兴奋阈值 Sedative and hypnotic effect Inhibiting both formation and spread of discharges. Postsynaptic Cl - influx Presynaptic Ca 2+ influx neurotransmitter release (NE, ACh, Glu, etc.) Effective for grand mal( 大发作 ), status epilepticus, partial simple seizures.

77 A. Antiepileptic drugs Drugs acting at the chloride channel Benzodiazepines 苯二氮卓类 Binds to specific receptors Phenobarbital 苯巴比妥 Binds to barbiturate bit t specific receptor 丙戊酸钠 Valproate 丙戊酸钠 Decreases GABA degradation in presynaptic terminal

78 A. Antiepileptic drugs Ethosuximide 乙琥胺 Block T-type Ca 2+ channel Block Na + -K + -ATPase Inhibit cerebral metabolism and GABA transaminase Effective for petit mal ( 小发作 ) Combined with phenobarbital 副作用较少

79 A. Antiepileptic drugs Valproate sodium 丙戊酸钠 Broad spectrum Inhibiting spread of discharges but not formation Increases GABA levels via GABA transaminase, GABA transporter, Glutamate decarboxylase Inhibit Na + and L-type Ca 2+ Enhance K +? GI side effects Tremor Hepatitis Pancreatitis Serious neural tube and cardiac defects in fetus in 1%

80 A. Antiepileptic drugs Other antiepileptic drugs Primidone 扑米酮 :analogues of phenobarbital, used for phenobarbital- and phenytoin- ineffective patients Mephenytoin 美芬妥英, Ethotoin 乙苯妥英 analogues of phenytoin 乙苯妥英 : Diazepam 地西泮 : status epilepticus p (i.v. i.v.) ) Nitrozepam 硝西泮, Clonazepam 氯硝西泮 :petit mal Lamotrigine 拉莫三嗪

81 A. Antiepileptic drugs Other antiepileptic drugs Oxarbazepine( 奥卡西平 ): weaker ( 奥卡西平 ):similar as carbamazepine but Antiepilepsirine( ( 抗痫灵 ): broad spectrum, esp. grand mal Lamotrigine 拉莫三嗪 : 拉莫三嗪 : Na + channel antagonist. Effective against both partial and generalized epilepsy Flunarizine i 氟桂利嗪 spectrum 氟桂利嗪 : Inhibit L- and T-type Ca 2+ channel. broad Topiramate 托吡酯 : Blocks AMPA+kainate receptors Also blocks Na + and Ca 2+ channels

82 卡马西平拉莫三嗪苯妥英钠丙戊酸钠

83 丙戊酸钠二甲双酮乙琥胺

84 丙戊酸钠苯二氮卓类巴比妥类

85 A. Antiepileptic drugs Common toxicity of antiepileptic drugs: CNS reactions Hemological reactions Hepatic toxicity Teratogenicity( ( 致畸 )

86 Teratogenicity it All AED's cause fetal malformations in at least 6% of infants. Highest risk with phenytoin, valproate, phenobarbital, and carbamazepine (Class D drugs) Folate supplementation prevents neural tube defects.

87 A. Antiepileptic drugs Principals of antiepileptic drug uses 1. Choice of drugs (1) Grand mal / Partial: Phenytoin, Carbamazepine, Phenobarbital Primidone, Valproate sodium (2) Petit mal: Ethosuximide Clonazepam, Valproate sodium (3) Psychomotor:Carbamazepine, Phenytoin (4) Status t epilepticus:diazepan Phenytoin (i.v.), Phenobrbital (i.m.) Diazepan (i.v.)

88 A. Antiepileptic drugs 2. Dosage: small larger doses; dose individualization; plasma necessary concentration 3. Usage: drug combination monitoring if 4. Withdrawal:gradually and slowly

89 B. Anticonvulsant drugs Magnesium Sulfate 硫酸镁 1. Effects:central depression; vasodilatation, BP ; relaxing skeletal muscles 2. Uses:convulsion;hypertension crisis 3. Adverse effects: depression of respiratory and vasomotor centers, antagonized by calcium preparations (i.v.)

90 B. Anticonvulsant drugs Other anticovulsant drugs Sedative-hypnotic drugs

91 略抗癫痫药的辅助药物 Increased expression of ABC transport in epilepsy Transporters

92 略抗癫痫药敏感大鼠抗癫痫药耐药大鼠 Control 耐药癫痫大鼠耐药癫痫大鼠 P-gp 表达增加

93 略 P-gp 基因敲除及其抑制剂增加脑内抗癫痫药浓度 P-gp 抑制剂增强抗癫痫药 Oxarbazepine(OXC, OXC, 奥卡西平 ) 作用及延长癫痫病人入院间隔时间

94 略 Contribution of CYPs to drug metabolism

95 略 CYP Enzymes 底物抑制剂诱导剂 (from Guengerich 2003)

96 略 AEDs and Hepatic CYP450 Interactions Induction increase in amount of enzyme protein, resulting in an increase in the rate of metabolism of the affected drug Inhibition competition at the enzyme site that results in a decrease in metabolism of the affected drug Valproic acid CYP2C inhibitor (inhibits phenobarbital, phenytoin metabolism) Phenytoin CYP inducer (3A4 and 2C); metabolized by 2C9 Carbamazepine CYP inducer (CYP inducer (3A4 and 2C); metabolized by 3A4... induces its own metabolism Phenobarbital CYP inducer (3A4 and 2C)

97 ? 1 药物分类 2 药理作用作用机制临床应用作用机制不良反应 3 特殊的药代动力学

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幻灯片1 Drugs Affecting the Central Nervous System 中枢神经系统药理卢韵碧 yunbi@zju.edu.cn 浙江大学医学院药理学系 Neurons and glia in the CNS The Synapse SNAREs GPCR NT (ligand)-gated Ion Channel NEUROTRANSMISSION in the CNS The basic