12.抗精神病药——山东大学药理学英文课件Antipsychiatric drugs.ppt

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1、 CHAPTER 20 ANTIPSYCHIATRIC DRUGS Psychotic Disorders1.Schizophrenia(thinking disorder)2.Mania(mood disorder)3.Depression(mood disorder)4.Anxiety Antipsychiatric Drugs1.Antipsychotic drugs 2.Antimanic drugs 3.Antidepressive drugs 4.Antianxiety drugs Section 1 Antipsychotic Drugs Schizophrenia Person

2、ality change and behavior disorders with environmentPositive symptoms:thinking disorder,cognition disturbance,hallucination,paranoia,delusion(妄想妄想Negative symptoms:disturbance of feeling,discommunication Natures of Schizophrenian nDopamine theory of schizophrenia pathogenesisn noveractivity of the m

3、eso-limbic dopaminergic neurons Natures of Schizophreniaraphetamineraphetamine：promote DA release and promote DA release and induce Schizophrenia.induce Schizophrenia.decrease synthesis and storage of decrease synthesis and storage of DA can improve the conditionDA can improve the condition DA-R inc

4、rease in DA-R increase in putamenputamen and and nucleus nucleus accumbensaccumbens septisepti Antischizophrenic Agentsn nPhenothiazines吩噻嗪类吩噻嗪类n nThioxanthenes(硫杂蒽类硫杂蒽类n nButyrophenones(丁酰苯类丁酰苯类n nOthers The Main Pathways of DA and Functions in Brain 1.Nigra-striatum 1.Nigra-striatum 黑质黑质黑质黑质-纹状体纹状

5、体纹状体纹状体 DA system DA system From A9 of meso-nigrosubstantia From A9 of meso-nigrosubstantia to caudate nucleus,putamen.to caudate nucleus,putamen.Extrapyramidal function Extrapyramidal function regulation of movement regulation of movement Decrease-PD Decrease-PD Augmentation-Chorea Augmentation-Cho

6、rea 舞蹈症舞蹈症舞蹈症舞蹈症 (irregular,involuntary mucle jerks and impair (irregular,involuntary mucle jerks and impair voluntary activity)voluntary activity)The Main Pathways of DA and Functions in Brain2.Meso-limbic中脑中脑-边缘叶边缘叶DA system the center of emotion and feeling The Main Pathways of DA and Functions i

7、n Brain3.Meso-cortical3.Meso-cortical中脑皮层中脑皮层中脑皮层中脑皮层DA systemDA system Cognition,thinking and consciousness Cognition,thinking and consciousness System 2 and 3 augmentation System 2 and 3 augmentation -schizophrenia -schizophrenia4.Tubero-infundibular(4.Tubero-infundibular(结节结节结节结节-漏斗漏斗漏斗漏斗)DA syst

8、em)DA system Regulate pituitary hormone release Regulate pituitary hormone release The Main Pathways of DA and Functions in Brain5.Area postrema of medulla DAergic system:Central vomitting (chemoreceptor trigger zone,CTZ)The Subtypes of DA Receptorn nIn the early,DA receptors are classified to four

9、subtypes:D1-4n nAccording to protein structure,transmembrane signaling mechanisms,effect properties and sites of receptors,DA receptor classified to D1 and D2 subtypes.The Subtypes of DA Receptorn nD1 is GS coupling receptor，AC，cAMP in brain.n nD2 is Gi coupling receptor，AC，cAMP in brain.The Subtype

10、s of DA Receptorn n分子克隆技术证实脑内存在分子克隆技术证实脑内存在D1，D2，D3，D4，D5亚型受体亚型受体。n nD1-like receptors：D1和和D D5 5的分子同源性的分子同源性超过超过80%80%，与，与G GS S偶联，药理学特性符合偶联，药理学特性符合D1。n nD2-like receptors：D2、D3、D4同源性同源性45%45%，与，与G Gi i偶联，药理学特性符合偶联，药理学特性符合D2。The Subtypes of DA Receptorn nMigro-striatal systemMigro-striatal system：D

11、 D1 1-like receptors-like receptors(D(D1 1,D,D5 5)and Dand D2 2-like receptors(D-like receptors(D2 2、D D3 3、D D4 4).).n nMeso-corticalMeso-cortical and mesolimbic system Dand mesolimbic system D2 2-like receptors(Dlike receptors(D2 2、D D3 3、D D4 4).).n nTubero-infundibular system:Tubero-infundibular

12、 system:D D2 2.Mechanisms of Antipsychotic Drugs1.Block Meso-limbic and Meso-cortical DA receptor2.Block 5-HT receptor Phenothiazines吩噻嗪类吩噻嗪类n nDimethylamine derivativesn n二甲胺类二甲胺类n nPiperazine derivativesn n哌嗪类哌嗪类n nPiperidine derivativesn n哌啶类哌啶类 Chlorpromazine(氯丙嗪氯丙嗪)Wintermine,冬眠灵冬眠灵n nHistoryn

13、nOriginally developed as an antihypertensive agent.n nIn 1952 chlorpromazine was used to treat schizophrenia in France Chlorpromazine(氯丙嗪)Wintermine,冬眠灵1.Blocks D2 receptor in the mesolimbic and Meso-cortical 2.Block-R3.Block M-R Pharmacological Actions1.1.E Eff ffets on CNSets on CNS (1)(1)Behavior

14、al and psychological effects Behavioral and psychological effects(2)(2)a.a.for animals:for animals:docidocilele and friendl and friendly.y.(3)(3)b.for normal person:sedation,b.for normal person:sedation,induce induce(4)(4)to sleep.to sleep.Pharmacological Actions c.for schizophrenia patients:c.for s

15、chizophrenia patients:Antipsychotic effect(neuroleptic effect):Antipsychotic effect(neuroleptic effect):6 wks-6 ms to Emax.6 wks-6 ms to Emax.Mechanism:Mechanism:Block D2 receptor in the mesolimbic Block D2 receptor in the mesolimbic and meso-cortical pathways of brain.and meso-cortical pathways of

16、brain.Chlorpromazine(2)Antiemetic action(2)Antiemetic actionBlocks D2 receptor of CTZ on area Blocks D2 receptor of CTZ on area postrema of medulla(IV ventricule)postrema of medulla(IV ventricule)Large doses inhibit the vomiting Large doses inhibit the vomiting center directly.center directly.Chlorp

17、romazine(3)On temperature regulation(3)On temperature regulation inhibit inhibit temperature-regulating center in temperature-regulating center in hypothalamus to poikilothermiahypothalamus to poikilothermia a.The temperature changed dependent a.The temperature changed dependent with environment tem

18、perature.with environment temperature.cold environmentcold environment,T (hypothermia),T (hypothermia)hot hot environment,environment,T (hyperthermia)T (hyperthermia)Chlorpromazine(4)Potentiate the effects of CNS depressants sedation and synergism with other CNS depressants(analgesics,sedative-hypno

19、tics,anesthetics)Chlorpromazine(5)On extrapyramidal systemBlock DA receptors on Nigra-striatal DA system Pharmacological Actions2.Autonomic nervous system(1)Block-R result in orthostatic hypotension.(2)Block M-R induce atropine-like effects.Pharmacological Actions3.Endocrine system3.Endocrine system

20、 Tuberoinfundibular DA pathway blockade.Tuberoinfundibular DA pathway blockade.a.prolactin release-inhibiting factor.a.prolactin release-inhibiting factor.b.b.corticotropin and growth hormone.corticotropin and growth hormone.Pharmacological Actions3.Endocrine system3.Endocrine systemc.c.luteinizing

21、hormone-releasing factor.luteinizing hormone-releasing factor.d.follicl-stimulating hormone-releasing factord.follicl-stimulating hormone-releasing factor Pharmacokinetics1.Absorption slow and unpredictable after oral administration2.Distribution PPBR 90%3.lipid solubility plays a major role Clinica

22、l Uses1.Schizophrenia1.Schizophrenia mania,paraniod states,schizophrenia mania,paraniod states,schizophrenia and psychoses with chronic and psychoses with chronic alcoholism.alcoholism.2.Vomiting and intractable hiccups2.Vomiting and intractable hiccups3.Artificial hibernation3.Artificial hibernatio

23、n LyticcocktailLyticcocktail (chlorchlorpromazine pluspromazine plus doldolantinantin plus plus promethazine)promethazine)Adverse Reactions1.Common adverse reactions Excessive sedation M block effects Adverse Reactions2.Extrapyramidal reactions2.Extrapyramidal reactions (1)Parkinsons syndrome (1)Par

24、kinsons syndrome (2)Akathisia (2)Akathisia (3)Acute dystonia (3)Acute dystonia facial grimacing and torticollisfacial grimacing and torticollis block DA receptors block DA receptors in in the nigrothe nigrostriatumstriatum artanartane e Adverse Reactions(4)Tardive dyskinesia sucking and macking of t

25、he lips and other involuntary facial movements.3.Psychotic Disorders Adverse Reactions4.Convulsion and epilepsy5.Allergic reactions6.Cardiovascular and Endocrine system7.Acute intoxation Contraindictions1.Epilepsy and Convulsion2.Glaucoma 3.Cyclomastopathy and breast carcinoma4.Coronary heart diseas

26、e吩噻嗪类抗精神病作用比较吩噻嗪类抗精神病作用比较吩噻嗪类抗精神病作用比较吩噻嗪类抗精神病作用比较药物药物药物药物 抗精神病抗精神病抗精神病抗精神病 副作用副作用副作用副作用 剂量剂量剂量剂量mg/d)mg/d)mg/d)mg/d)镇静镇静镇静镇静 锥体外作用锥体外作用锥体外作用锥体外作用 降压作用降压作用降压作用降压作用 氯丙嗪氯丙嗪氯丙嗪氯丙嗪 300-800 +(iv)300-800 +(iv)300-800 +(iv)300-800 +(iv)+(po)+(po)+(po)+(po)氟奋乃静氟奋乃静氟奋乃静氟奋乃静 1-20 +1-20 +1-20 +1-20 +三氟拉嗪三氟拉嗪三氟拉

27、嗪三氟拉嗪 6-20 +6-20 +6-20 +6-20 +奋乃静奋乃静奋乃静奋乃静 8-32 8-32 8-32 8-32 +硫利达嗪硫利达嗪硫利达嗪硫利达嗪200-600 +200-600 +200-600 +200-600 +Thioxanthenes(硫杂蒽类硫杂蒽类)Chloprothixene (氯普噻吨氯普噻吨，tardan,泰尔登泰尔登)1.Stronger sedative action.2.Weak anti-depressant effect.Butyrophenones(丁酰苯类丁酰苯类)Haloperidol(氟哌啶醇氟哌啶醇)1.More effects in an

28、tipsychotic,to treat the schizophrenia and the mania.2.The extrapyramidal reaction is very severe.3.Strong antiemetic activity.Other Antipsychotic Drugs Clozapine(氯氮平氯氮平)n nIt is an atypical antipsychotic agent.1.Low affinity for D2,high affinity for D4 and 5-HT2A.2.More effective for positive and n

29、egative symptoms of schizophrenia Clozapine3.Onset rapidly:a week4.Lacking in extrapyramidal adverse effects5.Major adverse effect is agranulocytosis(粒细胞缺乏粒细胞缺乏 Sulpiride1.Stronger antipsychotic and antiemetic activity.2.Having antidepressant efficacy.3.The extrapyramidal reaction is slight.Risperid

30、one利培酮利培酮1.Effective against negative as well as positive symptoms2.Improve the cognition disturbance 3.Few adverse reactions New Theory of Psychosis D1 function,D2 function New drugs(by Jin Guo-zhang)l-stepholidine (l-SPD,左旋千金藤啶碱左旋千金藤啶碱 Stimuli D1,block D2 Section 2 Antimanic Drugsn nManic-depressi

31、ve disorder(bipolar affective),emotional disordersn nBiochemical bases:amine theory Mania 5-HT NE Depression 5-HT NE Lithium carbonate(碳酸锂碳酸锂)“Mood-stabilizing agent1.Effects on neurotransmitters and their release.NE and DA release from synapse in the brain,those reuptake.Lithium carbonate(碳酸锂碳酸锂)2.

32、Effects on second messengers that 2.Effects on second messengers that mediate transmitter action mediate transmitter action a.inhibits the transformation of inositol a.inhibits the transformation of inositol monophosphate(IP)to PIPmonophosphate(IP)to PIP2 2,leads to a,leads to a reduction of PIPredu

33、ction of PIP2 2,then IP,then IP3 3 and DAG and DAG decrease.decrease.b.inhibits ACb.inhibits AC Lithium Carbonaten nClinical Uses 1.mania 2.manic-depressive psychosis Lithium Carbonaten nAdverse reactions Lithium toxicity due to overdose:nausea,vomit,abdominal pain,profuse diarrhea,and ataxia more s

34、evere:mental confussion,hyper-reflexia,tremor,convulsion Lithium Carbonaten nIntoxication can be usually be reversed Intoxication can be usually be reversed by osmotic diuresis or in more cases by by osmotic diuresis or in more cases by dislysis.dislysis.n nUse Nacl by intravenous to treatUse Nacl b

35、y intravenous to treatn nSerum concentration is carefully Serum concentration is carefully maintainted between 0.8 and 1.5mmol/L.maintainted between 0.8 and 1.5mmol/L.Section 3 Antidepressant Agents1.Tricyclic agentsNon-selective monoamine reuptake inhibitorsImipramine(丙米嗪丙米嗪,米帕明米帕明)Doxepin(多塞平多塞平)A

36、ntidepressant Agents2.Norepinepherine reuptake inhibitorsDesipramine(地昔帕明地昔帕明)3.5 HT reuptake inhibitorsFluoxetine(氟西汀氟西汀)4.Others Imipramine(丙米嗪丙米嗪,米帕明米帕明)n nPharmacological effects and mechanismPharmacological effects and mechanism 1.CNS effects 1.CNS effects Elevating the mood that is depressed.E

37、levating the mood that is depressed.It blocks the reuptake of NE or 5-HT.It blocks the reuptake of NE or 5-HT.onset is slow and requires 23w.The onset is slow and requires 23w.The latency period can be as long as 4w.latency period can be as long as 4w.Imipramine2.Autonomic nervous system2.Autonomic

38、nervous system Anticholinergic activity Anticholinergic activity3.Cardiovascular system3.Cardiovascular system Tachycardia,arrhythmias,Tachycardia,arrhythmias,orthostatic hypotension orthostatic hypotension quinidine-like action quinidine-like action ImipramineClinical UsesDepressionEnuresis遗尿遗尿Anxiety and phobia恐怖症恐怖症Adverse reactions1.Atropine-like action2.Cardiovascular reactionNew developed antidepressantsn nMaprotiline(马普替林马普替林)n nA“tetracyclic drug;reduce reuptake of NA New developed antidepressantsn nFluoxetine(氟西汀氟西汀)n nSelectively inhibits reuptake of 5-HTn nLess adverse reactions