中枢神经系统药理. Drugs Affecting the Central Nervous System (II)

Transcription

1 中枢神经系统药理 Drugs Affecting the Central Nervous System (II) 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 4. 治疗中枢神经系统退行性疾病药 1) 抗帕金森病药

4 Parkinson s s disease (PD, 帕金森病 ) Rigidity( 肌肉强直 ) Resting Tremor( 静止震颤 ) Bradykinesia ( 运动失调 ) Postural instability ( 姿势步态障碍 ) (propulsion, retropulsion) 帕金森综合征 (Parkinsonism): 相同的主要症状

5 Tremor: one of the common symptoms of PD

6 Normal 尾核 Parkinson disease Dopaminergic neuron degeneration in substantia nigro and striatum 壳核

7 DA 脊髓前角运动神经元起抑制作用, Ach 兴奋

8 黑质 - 纹状体通路 结节 - 漏斗通路 中脑 - 边缘 / 皮层通路 Substantia nigro - striatum dopaminergic pathway is involved in PD pathogenesis

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10 Abnormal balance of DA/ACh neuronal functions in extrapyramidal system of Parkinson disease Dopamine Acetylcholine

11 What is the desired goal of pharmacological therapies for Parkinson s disease? Different approaches include: I. direct activation of post-synaptic receptors II. increases in dopamine synthesis capacity III. inhibition of dopamine metabolism IV. alteration of the interaction/balance with other neurotransmitters V. L-DOPA metabolism inhibitors VI. dopamine releasers Note: All therapies treat the symptoms of the disease; none are neuroprotective and none slow the progression of the disease

12 Abnormal balance of DA/ACh neuronal functions in extrapyramidal system of Parkinson disease Dopamine Levodopa Muscarinic antagonists Acetylcholine

13 Treatment I: Increase dopamine Tyrosine TH DOPA DA receptors Dopamine Decarboxylase Dopamine MAO-B metabolisms DBH Norepinephrine MAO-A metabolisms

14 Drugs for treatment of Parkinson disease and related drugs Levodopa( ( 左旋多巴 ) and related drugs Rationale for L-DOPA Precursor Loading: OH OH L-DOPA decarboxylase OH OH O B 6 OH L-Dopa NH 2 ( 左旋多巴 ) NH 2 Dopamine ( 多巴胺 ) Striatal dopamine levels are low in PD. Dopamine does not pass BBB and, hence, has no therapeutic effect in PD. L-Dopa, an amino acid, the immediate precursor to dopamine, is transported across BBB and is an effective drug for PD.

15 Drugs for treatment of Parkinson disease VitB6 为多巴胺脱羧酶的辅酶 Levodopa 1. ADME Penetrating into the brain, transformed to DA or NE (less( less) Distributed in peripheral tissue (most( most) VitB6 2. Effects and uses Parkinson disease: decreases the rigidity and other symptoms

16 Drugs for treatment of Parkinson disease 3. Adverse effects Early: (1)GI: nausea, vomiting, etc. Levodopa (2)CVS: hypotension, arrhythmia, etc. (3)CNS: emotional depression/ psychosis; abnormal involuntary; hallucinations; etc. Late : (1) fluctuation of response: end of dose/ wearing off periods; on/off periods (sudden loss of symptom control, akinesia 运动不能 ). (2) dyskinesia ( 运动障碍,after, years of chronic L-DOPA, L up to 80%, Involuntary movements: chorea( 舞蹈症 ), ballismus( 投掷症 ), athetosis( 手足徐动症 ), dystonia( 肌张力失常 ), myoclonus( 肌阵挛 ), and tremor

17 L-DOPA peripheral metabolism AADC L- 芳香族氨基酸脱羧酶 carbidopa

18 Carbidopa ( 卡比多巴 ) A peripheral decarboxylase inhibitor reduces peripheral metabolism of L-DOPA, increases L-DOPA bioavailability, can not cross BBB; The combination of L-DOPA & carbidopa, is called Sinemet. (L-DOPA t 1/2 ~ 1.5 h) +carbidopa

19 Levodopa alone Levodopa + Carbidopa

20 一般情况下, 对 L-dopa 制剂的反应可分为 3 个阶段 : 1 良好反应阶段 (2~5 年 ), 为用药的最初阶段, 每 6~8 小时或更长时间服药 1 次, 可使全部症状得到平稳的缓解或改善 2 中间反应阶段 (2~3 年 ), 此阶段中每次服药仅可引起短时间的症状改善, 每个剂量的后期与下一个剂量前, 有 1 个药物无作用期, 称为剂末现象, 此外, 还可出现开关现象和反常性运动不能 ; 这种疗效下降与黑质 DA 能神经元逐渐衰退,DA 合成 贮存进一步下降, 及 DA 受体反应能力降低有关 3 反应衰退阶段, 对 L-dopa 制剂反应明显下降或根本不起反应 ; 运动困难与致残程度更为严重 ; 同时治疗中的一些不良反应更为明显

21 Drugs for treatment of Parkinson disease 1. DA receptor agonists Other drugs 1 st generation agonists: (ergot derivatives 麦角生物碱类 ) bromocriptine* ( 溴隐亭, D 2 agonist) (t 1/2 ~ 12 h) pergolide* ( 培高利特, D 2 /D 3 agonist)(t 1/2 ~ 24 h) 2 nd generation agonists ( 非麦角生物碱类 ): ropinirole (t 1/2 ~ 6 h) ( 罗匹尼罗, D 2 /D 3 agonist) pramipexole (t 1/2 ~ 8-12 h) ( 普拉克索, D 2 agonist) used as monotherapy for mild parkinsonism, or combined with levodopa for advanced disease.

22 the major adverse effects of DA receptor agonists Lower incidence of dyskinesia( 运动障碍 ) and response fluctuation( 症状波动 ) Cause sudden attacks of sleep ( 突然昏睡 ) during ordinary daytime activities Dose-related psychiatric side effects (similar to L-DOPA but may occur more frequently, especially in elderly) Nausea or vomiting (drugs active at chemotrigger zone (CTZ, 化学催吐感受区 ) )

23 罗匹尼罗 普拉克索

24 Drugs for treatment of Parkinson disease 2. MAO-B inhibitors ( Peripheral metabolism of catecholamines (mostly MAO-A) is unaffected.) decreasing DA metabolism in the CNS Selegiline 司来吉兰 Rasagiline 雷沙吉兰 3. COMT inhibitors (decreasing( DA metabolism) itecapone 硝替卡朋 CNS COMT inhibitor: :itecapone entacapone 恩他卡朋 peripheral COMT inhibitor: entacapone

25 L-DOPA peripheral metabolism AADC L- 芳香族氨基酸脱羧酶

26 L-DOPA -/+ COMT Inhibitor: entacapone ( 恩他卡朋 ) Same dose of L-DOPA, iv; plus carbidopa, po L-DOPA Uptake Without With COMT Inhibitor

27 Drugs for treatment of Parkinson disease 4. Amantadine 金刚烷胺 : dopamine releaser Used for mild Parkinson s disease, as an early monotherapy Mechanisms of action may include: release of dopamine, block DA reuptake, actions on glutamate receptors (as an NMDA-receptor antagonist) The dose should be reduced with renal impairment. Potential adverse effects: - CNS reactions (dizziness, anxiety, impaired coordination) - hyperkinesias( 运动亢进 ) - nausea, vomiting - others: convulsion

28 Abnormal balance of DA/ACh neuronal functions in extrapyramidal system of Parkinson disease Dopamine Levodopa Muscarinic antagonists Acetylcholine

29 Drugs for treatment of Parkinson disease Muscarinic antagonists Trihexyphenidyl ( 苯海索 Benzatropine ( 苯扎托品 苯海索,artane, 安坦 苯扎托品 ) 安坦 ) Decreasing CNS cholinergic functions Adjuvant of Parkison disease treatment

30 DRUG THERAPY - Summary Main Line Agents: L-DOPA plus carbidopa (Sinemet ) Dopamine receptor agonists (ropinirole) Lower Efficacy/Second Line or Adjuvant Agents: Anticholinergics Reuptake Inhibitor or releaser (amantadine) COMT Inhibitor (entacapone) MAO B Inhibitors (rasagiline, selegiline)

31 Drug-Induced Parkinsonism Reserpine, which depletes brain catecholamines, induces Parkinson s disease symptoms Antipsychotics (neuroleptics), that block DA receptors, ie, dopamine receptor antagonists. N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) is a by-product of illicit synthesis of isomeperidine (MPPP). MPTP first came to medical attention because it produced symptoms similar to Parkinson s disease.

32 4. 治疗中枢神经系统退行性疾病药 2) 治疗阿尔茨海默病药

33 Pathological characteristics of AD Atrophy of the brain

34 Pathological characteristics of AD Atrophy of the brain

35 Senile plaques Neurofibrillary tangles

36 Pathophysiologic Hypothesis of AD

37 Drugs for treatment of dementia (Alzheimer and related diseases) Anticholinesterase drugs Cholinoceptor agonists NMDA-type glutamate receptor antagonist Neurotrophic factor-like drugs

38 Anticholinesterase drugs Tarcrine 他克林 : Easy to pass BBB; Decrease AChE 70%; activate M and N receptors (especially M receptor); Enhance the release of ACh (throught M receptor). Induce hepatic toxicity. Galantamine 加兰他敏 : similar to tarcrine, except without hepatic toxicity and high specific to neuron AChE. Huperzine 哈伯因 ( 石杉碱甲 ): a high selective AChE inhibitor; improve memory and reorganization. Metrifonate 美曲磷脂 : the first AChE inhibitor; Increase central DA and NE; Decrease the red blood cell AChE 52%.

39 Cholinoceptor agonists Xanomeline 占诺美林 : selective to M1 receptor; high concentration in cortex and striatum; Has GI and CVS side effects. Sabcomedine hydrochloride 沙可美林 : selective to M1 receptor; safe. NMDA receptor antagonist Memantine ( 美金刚 ) : noncompetitive antagonist Neurotrophic factor enhancer AIT 082: increase the release of neurotrophins in injured neurons ALCAR( 盐酸乙酰 L 肉碱 ): protect synapse and increase nurotrophins Propentofylline 丙戊茶碱 : inhibit adrenaline reuptake and camp metabolize; neuroprotective effects;

40 5. 抗精神失常药 Anxiolytics / antianxietics 抗焦虑药 Antipsychotic drugs 抗精神分裂药 Antidepressant and antimanic drugs 抗抑郁药和抗躁狂药

41 Nature of Psychosis ( 精神病 )& Schizophrenia( 精神分裂症 ) The term psychosis denotes a variety of mental disorders: the presence of delusions (false beliefs), various types of hallucinations, usually auditory or visual, but sometimes tactile or olfactory, and grossly disorganized thinking in a clear sensorium. Schizophrenia is a particular kind of psychosis characterized mainly by a clear sensorium but a marked thinking disturbance.

42 Schizophrenia ( 精神分裂症 ) Signs & Symptoms Positive symptoms (I 型 ) Delusions ( 妄想 ) - fixed false belief outside cultural norm (bizarre vs. non bizarre) Hallucinations ( 幻觉 ) - perceptual (hearing), have no outside source Like my voice Not an illusion (a mistaken perception for which there is an actual external stimulus) Disorganization ( 思维紊乱 ) - pattern of speech or behavior, making up words without a meaning (neologisms)

43 Schizophrenia ( 精神分裂症 ) Signs & Symptoms Negative symptoms (II 型 ) Affective flattening Avolition / Amotivation (decreased motivation, 动机缺乏 ) Autistic( 孤独 ) behaviors (social withdrawal ) Anhedonia (inability to experience pleasure ) Ambivalence (coexistence of opposing attitudes or feelings, 矛盾心态 ) Anosognosia ( 疾病感缺失 ) (impaired awareness of illness )

44 Antipsychotic drugs The dopamine hypothesis of schizophrenia The serotonin hypothesis of schizophrenia The glutamate hypothesis of schizophrenia

45 Antipsychotic drugs Classified according to chemical structures 1. Phenothiazines( ( 吩噻嗪类 ) Chlorpromazine 氯丙嗪 perphenazine 奋乃静 ; fluphenazine trifluoperazine 三氟拉嗪 ;thioridazine; 2. Thioxanthenes ( 硫杂蒽类 ) Chlorprothixene 氯普噻吨 ( 泰尔登 ) 3. Butyrophenones( ( 丁酰苯类 ) Haloperidol 氟哌啶醇 Droperidol 氟哌利多 ( 氟哌啶 ) 氟奋乃静 硫利达嗪 Typical Typical antipsychotic drugs are dopamine D 2 receptor antagonists

46 Others Penfluridol 五氟利多 Longer duration of action, taking once weekly Sulpride 舒必利 selectively acts on mesolimbic D 2 receptors few extrapyramidal reactions Clozapine 氯氮平 Blocking D 4 and 5-HT 5 receptors Risperidone 利培酮 Blocking D 2 and 5-HT5 2 receptors Atypical Actions of some secondary generation drugs

47 Antipsychotic drugs High potency Low potency 普马嗪 氟哌利多 三氟哌啶醇 苯哌利多 螺环哌啶酮

48 Antipsychotic drugs Phenothiazines( ( 吩噻嗪类 ) Chlorpromazine 氯丙嗪 (7) S (10) N (CH2)3 (2) Cl N(CH3)2

49 Antipsychotic drugs Phenothiazines( ( 吩噻嗪类 ) Chlorpromazine 氯丙嗪

50 1. Pharmacological effects Antipsychotic drugs (1)Central effects: Blocking central D 2 dopamine receptors a) Antipsychotic effects (neuroleptic( effects) for treatment of schizophrenia controlling excitation and then hallucinations (weeks to months) b) Antiemetic effects( 镇吐作用 ) inhibiting chemoreceptor trigger zone (CTZ) dopaminergic function c) Poikilothermic effects ( 体温调节作用 ) hypothermic anesthesia artificial hibernation ( 人工冬眠 ) d) Extrapyramidal effects( 锥体外系反应 ) primary adverse effects e) Potentiating the effects of central depressants sedative-hypnotics, analgesics, general anesthetics, ethanol

51 Antipsychotic drugs (2) Autonomic nervous system effects a) Hypotensive effects receptor blockade, postural hypotension b) Anticholinergic effects dry mouth, constipation, blurred vision, urinary retention, etc. (3) Endocrine effects prolactin ACTH, growth hormone

52 2. Clinical uses Antipsychotic drugs (1) Treatment of schizophrenia (2) Treatments of emesis and hiccough used for emesis ( 止吐 ) and hiccough( ( 呃逆 ) but ineffective on motion sickness (3) Hypothermic anesthesia (combined( with lowering room temperature) and artificial hibernation (combined( with Pethidine 哌替啶 and promethazine 异丙嗪 )

53 Antipsychotic drugs 3. Adverse effects (1) Side effects Central depression Peripheral effects: postural hypotension, dry mouth, and other effects resulting from muscarinic and receptor blockade

54 Antipsychotic drugs (2) Extrapyramidal effects Due to DA receptor block: a) Parkinsonism b) Akathisia ( 静坐不能 ) c) Acute dystonia ( 急性肌张力障碍 急性肌张力障碍 ) attenuated by central muscarinic antagonists Due to supersensitive to DA: Tardive dyskinesia ( 迟发性运动障碍 )

55 Antipsychotic drugs (3) Other central reactions neuroleptic maglinant syndrome ( 神经阻滞药恶 性综合征 ) psychotic reactions ( 药源性精神异常 ) epilepsy and convulsion: lowering seizure threshold (4) Allergic and hemological reactions skin reactions, leukopenia, obstructive jaundice, liver damage

56 Antipsychotic drugs (5) CVS reactions arrhythmia hypotension: treated by receptor agonists sudden death (elderly with CVS diseases) (6) Endocrine reactions hyperplasia of mammary glands ( 乳腺增生 ), galactorrhea ( 溢乳 ), amenorrhea ( 闭经 ), child growth retard( 生长抑制 )

57 Antipsychotic drugs (6) Acute intoxication severe CNS depression, coma, severe hypotension (7) Contraindications epilepsy coma elderly with CVS disorders severe hepatic and renal dysfunction

58 Antipsychotic drugs Other phenothiazines perphenazine fluphenazine trifluoperazine thioridazine 奋乃静 氟奋乃静 三氟拉嗪 硫利达嗪 more potent therapeutic effects and extrapyramidal effects

59 Antipsychotic drugs Thioxanthenes ( 硫杂蒽类 ) Chlorprothixene 氯普噻吨 ( 泰尔登 ) Used for the patients with symptoms of depression and anxiety

60 Antipsychotic drugs Butyrophenones( ( 丁酰苯类 ) Haloperidol 氟哌啶醇 Droperidol 氟哌利多 ( 氟哌啶 ) Combined with fentanyl 安定 [ 镇痛 ] 麻醉术 ) fentanyl: neuroleptanalgesia( ( 神经

61 Others Antipsychotic drugs Penfluridol 五氟利多 Longer duration of action, taking once weekly Sulpride 舒必利 selectively acts on mesolimbic D 2 receptors few extrapyramidal reactions Clozapine 氯氮平 Blocking D 4 and 5-HT 5 receptors Risperidone 利培酮 Blocking D 2 and 5-HT5 2 receptors

62 Antimanic Drugs Lithium carbonate Carbamazepine Chlorpromazine Other related antiepileptic and antipsychotic drugs

63 Antimanic Drugs Lithium carbonate 碳酸锂 1. Pharmacological effects and clinical uses Mood-stabilizing agent( ( 情绪稳定药 ) (1) Inhibiting NE and DA release (2) Interfering phosphatidylinositol (PI) metabolism (3) Substitute for sodium in generating action potentials and in Na + -K + exchange across the membrane.

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65 Antimanic Drugs 2. Adverse effects Related to the serum concentration of Li mmol/l: therapeutic level mmol/l: GI reactions > 2.0 mmol/l: CNS toxicity Monitoring serum concentration of Li + if possible

66 Antimanic Drugs (1) Side effects Nausea, vomiting, abdominal pain, diarrhea, sedation, finger tremor, polyuria, etc. (2) Acute intoxication Mental confusion, coma, hyperreflexia( 反射亢进 ), gross tremor, dysarthria( 构音困难 ), seizures, etc. (3) Others Benign thyroid enlargement, renal damage

67 Antidepressant Drugs

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69 Monoamine hypothesis of Depression ( 单胺假说 ) 5-HT genetic basis of depression & mania NE depression NE mania Modulation of monoamines in the synaptic space and/or the related post-synaptic synaptic receptors is of therapeutic importance

70 Long-term adaptations to antidepressant treatment

71 Model of the neurotrophic hypothesis of antidepressant treatments and stress-related related disorders

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73 Classes of Antidepressants Tricyclic Antidepressants (TCAs) Monoamine Oxidase Inhibitors (MAOIs) Norepinephrine Reuptake Inhibitors (NARIs) Selective Serotonin Reuptake Inhibitors (SSRIs) Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs) Noradrenergic and specific serotonergic antidepressants (NaSSAs)

74 Antidepressant Drugs Tricyclic Antidepressants (TCAs) Imipramine 丙米嗪 ( 米帕明 ) Tricyclic structure N CH2CH2CH2N CH3 CH3

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76 Imipramine 丙米嗪 1. Pharmacological effects 丙米嗪 ( 米帕明 ) (1) Central effects Inhibiting reuptake of monoamine transmitters Improving patient s s mood after 2 weeks Sedative effects in normal subjects (anti- histaminergic or -adrenergic blocking properties) (2) Autonomic effects Muscarinic blocking effects (3) Cardiovascular effects Hypotension, tachycardia, arrhythmia

77 Imipramine 丙米嗪 2. Clinical uses (1) Depression Endogenous, melancholic, etc. (2) Enuresis ( 遗尿 ) 丙米嗪 ( 米帕明 ) (3) Anxiety ( 焦虑 ) and panic disorder ( 惊恐症 )

78 3. Adverse effects (1) Antimuscarinic effects dry mouth, constipation( 便秘 ), intraocular pressure increase, blurred vision, urinary retention, etc. Contraindicated in prostatauxe and glaucoma (2) CNS reactions Confusion or delirium( 谵妄 ), depression-mania (bipolar patients) (3) CVS reactions Imipramine 丙米嗪 丙米嗪 ( 米帕明 ) Postural hypotension, sinus tachycardia, potential of arrhythmia

79 4. Drug interactions (1) Plasma protein binding displacement by phenytoin, aspirin, scopolamine( 东莨菪碱 ), phenothiazines ( 吩噻嗪类 ), etc. (2) MAO inhibitors Imipramine 丙米嗪 丙米嗪 ( 米帕明 ) potentiating the effects of TCA, contraindicated for combination with MAOIs (3) Potentiating the effects of CNS depressant drugs

80 双向增强 TCA 对生物胺的作用 调节 NE 合成的药物无法进入细胞 Interaction of TCA with other types of drugs

81 临床应用 副作用 阿米替林 氯丙咪嗪 多塞平 丙咪嗪

82 Antidepressant Drugs NE reuptake inhibitors (NRIs) Selective norepinephrine reuptake inhibits rapid actions weaker sedative, anticholinergic and hypotensive effects desipramine ( 地昔帕明 ) maprotiline ( 马普替林 ) nortriptyline ( 去甲替林 ) protriptylin ( 普罗替林 ) amoxapine ( 阿莫沙平 )

83 Antidepressant Drugs Selective 5-HT 5 reuptake inhibitors Selective serotonin reuptake inhibits (SSRIs( SSRIs) weaker sedative effects with anti-anxiety anxiety effects fluoxetine ( 氟西汀, 百忧解百 ):: 抑郁症 神经性贪食症 paroxetine ( 帕罗西汀 ) sertraline ( 舍曲林 )

84 Antidepressant Drugs 5-HT/NE reuptake inhibitors Mixed serotonin/norepinephrine norepinephrine reuptake inhibits (SNRIs) rapid action less affinity with receptors higher safety venlafaxine ( 文拉法辛 ) milnacipram ( 米那普仑 ) lofepramine ( 洛夫帕明 )

85 Antidepressant Drugs Noradrenergic and specific serotonergic antidepressant (NaSSA) mirtezapine blocking presynaptic (auto- or hetero-) 2 norepinephrine and serotonin (5-HT) pre-synaptic axons - increasing NE and 5-HT 5 release; mirtezapine ( 米氮平 米氮平 ) receptor on both stimulating postsynaptic 1 receptors on serotonergic cell bodies - increasing the firing rate of serotonergic neurons potently blocking postsynaptic 5-HT5 2A, 5-HT5 2C and 5-HT5 3 receptors attenuating 5-HT5 2C -mediated anxiety The net outcome of these effects is: increased noradrenergic activity increased serotonergic activity,, esp. 5-HT5 1A receptors HT 1A

86 Antidepressant Drugs Monoamine oxidase inhibitors (MAOIs) Selective for central MAO-B, less selective for enteric MAO-A; A; Used in treatments of depression (non-sensitive to TCAs) ) and Parkinson disease phenelzine ( 苯乙肼 selegiline ( 司来吉兰 苯乙肼 ): non-selective 司来吉兰 ): also used in Parkinson disease

87 Anxiolytic drugs 1. Benzodiazepines see details in S 2. Buspirone( ( 丁螺环酮 ) see details in Sedative-Hypnotic Drugs 5-HT 1A receptor selective partial agonist, lowering 5-HT release Fewer sedative, hypnotic, memory-deficient effects No cross tolerance to benzodiazepines, and less potential of dependence

88 Thanks