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1、Chapter 16 Psychotolytics抗精神失常药抗精神失常药Liu YinghuaDepartment of pharmacology PsychotolyticsPsychoses are mental disorders.Schizophrenia antipsychotic drugs (neuroleptics)Mania-antimanic drugsDepression-antidepressive drugsAnxiety-antianxiety drugs (anxiolytics)Antipsychotic Drugs (neuroleptics)Introdu
2、ction of SchizophreniauuChronic, severe mental disease uuType/TypeuuSeveral genes are implicated uu1% of the population, men and women with equal frequencyAntipsychotic Drugs (neuroleptics)Phenothiazines 吩噻嗪类吩噻嗪类Thioxanthenes 硫杂蒽类硫杂蒽类Butyrophenones丁酰苯类丁酰苯类Others黑质黑质纹状体通路（纹状体通路（D1、D2样受体）样受体）：是锥是锥体外系运
3、动功能的高级中枢。体外系运动功能的高级中枢。 DA帕金森病（帕金森综合症）帕金森病（帕金森综合症） DA不自主运动（手足徐动症、舞蹈病）不自主运动（手足徐动症、舞蹈病）中脑边缘系统通路中脑边缘系统通路中脑皮质通路中脑皮质通路结节结节漏斗通路（漏斗通路（ D2样受体）：内分泌调控样受体）：内分泌调控D2D2样受体，样受体，与精神活动、与精神活动、思维、情感反应有关。思维、情感反应有关。 DA DA 精神分裂精神分裂多巴胺能神经通路及主要功能多巴胺能神经通路及主要功能主要功能是主要功能是调节人体的姿调节人体的姿势、肌张力及协调肌肉运势、肌张力及协调肌肉运动，以协助随意运动动，以协助随意运动氯丙嗪氯
4、丙嗪Antipsychotic Drugs (neuroleptics)Pathogenic mechanism: unclear, Dopamine system is too strongMechanism of actions:1. 1.Block dopamine receptor DA1,2,3,4,52. 2.Block serotonin receptor(5-HT)Chlorpromazine 氯丙嗪氯丙嗪Mechanism of action:Block Dopamine receptorBlock receptorBlock M receptorChlorpromazine
5、 氯丙嗪氯丙嗪Pharmacological effects:CNS effect 1.Antipsychotic actions2.Antiemetic effects3.Effects on body temperature regulationEffects on autonomic nervous systemEffects on endocrine systemChlorpromazine 氯丙嗪氯丙嗪1.Antipsychotic actions (neuroleptic action)Mechanism: Block DA, especially D2 in the mesoli
6、mbic system (中脑边缘中脑边缘系统系统)Effects :reduce hallucinations and agitations, easy to sleep, calming, no anesthesia even overdose, invalid for Type schizophrenia.CNS effect Chlorpromazine 氯丙嗪氯丙嗪2.Antiemetic effects (镇吐镇吐)Mechanism: Block D2 dopaminergic receptors of chemoreceptor trigger zone of medulla
7、(延髓催吐化学感受延髓催吐化学感受器器) Effects : efficient to stop vomitting.CNS effect Chlorpromazine 氯丙嗪氯丙嗪3.Effects on body temperature regulationMechanism: inhibit the thermoregulatory centre in hypothalamusEffects : body temperature varies with the environment. Different with Aspirin!Wintermine 冬眠灵冬眠灵冬眠灵冬眠灵CNS e
8、ffect Chlorpromazine 氯丙嗪氯丙嗪 Effects on autonomic nervous systemBlock receptor: decrease BP, Orthostatic (postural) hypotension Block M receptor: xerostomia (dry mouth), constipation, blurred visionClinical applicationsTreatment of Schizophrenia : Prevention vomiting and intractable hiccups 顽固性呃逆Hypo
9、thermic anesthesia and artificial hibernationWintermine 冬眠灵冬眠灵冬眠灵冬眠灵v人工冬眠人工冬眠提高机体对缺氧的耐受力提高机体对缺氧的耐受力减轻机体对伤害性刺激的反减轻机体对伤害性刺激的反应应严重创伤、感染性休克、高热惊厥体温体温基础代谢基础代谢组织耗氧量组织耗氧量人人工工冬冬眠眠冬眠合剂冬眠合剂异丙嗪异丙嗪哌替啶哌替啶氯丙嗪氯丙嗪Adverse effects1.Common adverse reactions: CNS inhibitory symptom, M-R blocking symptom, -R blocking sym
10、ptom2.Parkinsonism, akathisia（静坐不能）（静坐不能）, and acute dystonia（肌张力障碍）（肌张力障碍）3.Psychosis4.Convulsion and epilepsy5.Allergy6.CVD and Endocrine abnormalities7.Acute poisoningChlorpromazine 氯丙嗪氯丙嗪PharmacokineticsA: intramuscular injectionD: all over the body, the concentration in brain is 10 times of the
11、 bloodM: P450With large individual differenceChlorpromazine 氯丙嗪氯丙嗪Drug interaction: avoid to be used with sedative drugs.Contraindication: Convulsion and epilepsyChlorpromazine 氯丙嗪氯丙嗪Other Phenothiazines u mild effects chlopromazine, the aged， obvious delusion 妄想妄想u severe extra-pyramid reactionHalo
12、peridol 氟哌啶醇氟哌啶醇Perphenazine 奋乃静奋乃静u Antagonist D2 receptoruuBlockers of 5-HT and DA (S2/D4)uuGold standard of atypical antipsychotic druguuMild extra-pyramid reaction, but agranulocytosis（粒细胞缺乏症）（粒细胞缺乏症）, seizures, weight gain and diabetesuuOnly for treatment-resistant patientsClozapine 氯氮平氯氮平奥氮平奥氮
13、平 olazapineBlockers of 5-HT2 R, Blockers of D1, D2, M, H1, 1 RAntiaxiety, antipsychotics/Type 2ADR: Increase of body weight, postural hypotension Antimanic Drugs Lithium Carbonate 碳酸锂碳酸锂uuMechanism of Drug: unclear, maybe due to inhibiting the release of NA and DA, and promote their uptake.uuSignifi
14、cant effect for mania(躁狂躁狂), also for manic-depressive psychosisLithium Carbonate 碳酸锂碳酸锂Pharmacokinetics: A: oral.E: kidney. Na+ -competitive reabsorptionLow therapeutic index: optimal, 0.8-1.5mM; max, 2mM; severe adverse reactions, even death.Antidepressant Drugs Antidepressant Drugs神经递质神经递质NEDA5-H
15、TReuptakeImipramine 丙米嗪丙米嗪 Pharmacological effects:uCNS: anti-depression and make spirited, 2-3week. Block the uptake of NA and 5-HTuANS: blurred vision, dry mouth, constipation. Block M-RuCVS: Hypotension, Arrhythmia. Block -RImipramine 丙米嗪丙米嗪 TherapeuticalTherapeutical use: Depression, enuresis( u
16、se: Depression, enuresis(遗尿遗尿遗尿遗尿), ), anxiety and phobia(anxiety and phobia(恐惧症恐惧症恐惧症恐惧症) )Adverse effects: M-R blocking symptom and Adverse effects: M-R blocking symptom and -R -R blocking symptom.blocking symptom.Contraindications: Contraindications: Benign prostatic hypertrophyBenign prostatic h
17、ypertrophy（良性前列腺肥大）（良性前列腺肥大）（良性前列腺肥大）（良性前列腺肥大） and glaucoma and glaucoma （青光眼）（青光眼）（青光眼）（青光眼） SSRIsSelective serotonin-reuptake inhibitorsFluoxetine 氟西汀氟西汀 (百忧解百忧解)pThe second generation of anti-depressantpNo effects on other receptorpLess side effects要要 求求【掌握掌握】氯丙嗪的药理作用、氯丙嗪的药理作用、临床应用和不良反应。临床应用和不良反应。【熟悉熟悉】多巴胺受体的分型，多巴胺受体的分型，DA通路。抗精神失常药的分类。通路。抗精神失常药的分类。碳酸锂的临床应用及不良反应。碳酸锂的临床应用及不良反应。
