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1、抗精神失常药PHARMACOLOGY OF ANTIPSYCHOTIC DRUGS(NEUROLEPTICS),SOME DEFINITIONS,Neuroleptic:synonym for antipsychotic drug;originally indicated drug w/antipsychotic efficacy but with neurologic(extrapyramidal motor)side effectsTypical neuroleptic:older agents fitting this descriptionAtypical neuroleptic:ne
2、wer agents:antipsychotic efficacy with reduced or no neurologic side effects,NEUROLEPTICS ON THE UUHSC DRUG LIST,TYPICAL NEUROLEPTICS:PHENOTHIAZINES:Chlorpromazine(Thorazine)Thioridazine(Mellaril)Fluphenazine(Prolixin)THIOXANTHENEThiothixene(Navane)OTHERHaloperidol(Haldol),NEUROLEPTICS ON THE UUHSC
3、DRUG LIST(Continued),ATYPICAL NEUROLEPTICS:Risperidone(Risperdal;most frequently prescribed in U.S.)Clozapine(Clozaril)Olanzapine(Zyprexa)Quetiapine(Seroquel),KEY CONCEPTS:,All neuroleptics are equally effective in treating psychoses,including schizophrenia,but differ in their tolerability.All neuro
4、leptics block one or more types of DOPAMINE receptor,but differ in their other neurochemical effects.All neuroleptics show a significant delay before they become effective.All neuroleptics produce significant adverse effects.,GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS,The older,typical neurolep
5、tics are effective antipsychotic agents with neurologic side effects involving the extrapyramidal motor system.Typical neuroleptics block the dopamine-2 receptor.,GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS,Typical neuroleptics do not produce a general depression of the CNS,e.g.respiratory depre
6、ssionAbuse,addiction,physical dependence do not develop to typical neuroleptics.,GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS,Typical neuroleptics are generally more effective against positive(active)symptoms of schizophrenia than the negative(passive)symptoms.,Positive/active symptoms include th
7、ought disturbances,delusions,hallucinationsNegative/passive symptoms include social withdrawal,loss of drive,diminished affect,paucity of speech.impaired personal hygiene,THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS,All appear equally effective;choice usually based on tolerability of side effectsMost
8、 common are haloperidol(Haldol),chlorpromazine(Thorazine)and thioridazine(Mellaril)Latency to beneficial effects;4-6 week delay until full response is common70-80%of patients respond,but 30-40%show only partial response,THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS(Continued),Relapse,recurrence of sym
9、ptoms is common(approx.50%within two years).Noncompliance is common.Adverse effects are common.,ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS,Anticholinergic(antimuscarinic)side effects:Dry mouth,blurred vision,tachycardia,constipation,urinary retention,impotence,ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS,An
10、tiadrenergic(Alpha-1)side effects:Orthostatic hypotension w/reflex tachycardiasedation,ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS,Antihistamine effect:sedation,weight gain,KEY CONCEPT:DOPAMINE-2 RECEPTOR BLOCKADE IN THE BASAL GANGLIA RESULTS IN EXTRAPYRAMIDAL MOTOR SIDE EFFECTS(EPS).,DYSTONIANEUROLEPTI
11、C MALIGNANT SYNDROMEPARKINSONISMTARDIVE DYSKINESIAAKATHISIA,ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS(Continued),Increased prolactin secretion(common with all;from dopamine blockade)Weight gain(common,antihistamine effect?)Photosensitivity(mon w/phenothiazines)Lowered seizure threshold(common with all
12、)Leucopenia,agranulocytosis(rare;w/phenothiazines)Retinal pigmentopathy(rare;w/phenothiazines),ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS(Continued),Chlorpromazine and thioridazine produce marked autonomic side effects and sedation;EPS tend to be weak(thioridazine)or moderate(chlorpromazine).Haloperido
13、l,thiothixene and fluphenazine produce weak autonomic and sedative effects,but EPS are marked.,MECHANISMS OF ACTION OF TYPICAL NEUROLEPTICS,DOPAMINE-2 receptor blockade in meso-limbic and meso-cortical systems for antipsychotic effect.DOPAMINE-2 receptor blockade in basal ganglia(nigro-striatal syst
14、em)for EPSDOPAMINE-2 receptor supersensitivity in nigrostriatal system for tardive dyskinesia,LONG TERM EFFECTS OF D2 RECEPTOR BLOCKADE:,Dopamine neurons reduce activity.Postsynaptic D-2 receptor numbers increase(compensatory response).When D2 blockade is reduced,DA neurons resume firing and stimula
15、te increased#of receptors hyper-dopamine state tardive dyskinesia,MANAGEMENT OF EPS,Dystonia and parkinsonism:anticholinergic antiparkinson drugsNeuroleptic malignant syndrome:muscle relaxants,DA agonists,supportiveAkathisia:benzodiazepines,propranololTardive dyskinesia:increase neuroleptic dose;swi
16、tch to clozapine,ADDITIONAL CLINICAL USES OF TYPICAL NEUROLEPTICS,Adjunctive in Rx of acute manic episodeTourettes syndrome(esp.Haldol)Rx of drug-induced psychosesPhenothiazines are effective anti-emetics,Esp.prochlorperazine(Compazine)Also,anti-migraine effect,GENERAL CHARACTERISTICS OF ATYPICAL NE
17、UROLEPTICS,Effective antipsychotic agents with greatly reduced or absent EPS,esp.reduced Parkinsonism and tardive dyskinesiaAll atypical neuroleptics block dopamine and serotonin receptors;other neurochemical effects differAre effective against positive and negative symptoms of schizophrenia;and in
18、patients refractory to typical neuroleptics,PHARMACOLOGY OF CLOZAPINE(CLOZARIL),FDA-approved for patients not responding to other agents or with severe tardive dyskinesiaEffective against negative symptomsAlso effective in bipolar disorderLittle or no parkinsonism,tardive dyskinesia,PRL elevation,ne
19、uro-malignant syndrome;some akathisia,Blockade of alpha-1 adrenergic receptorsBlockade of muscarinic cholinergic receptorsBlockade of histamine-1 receptors,PHARMACOLOGY OF CLOZAPINE(Continued),Other adverse effects;Weight gainIncreased salivationIncreased risk of seizuresRisk of agranulocytosis requ
20、ires continual monitoring,PHARMACOLOGY OF OLANZAPINE(ZYPREXA),Olanzapine is clozapine without the agranulocytosis.Same therapeutic effectivenessSame side effect profile,PHARMACOLOGY OF QUETIAPINE(SEROQUEL),Quetiapine is olanzapine without the anticholinergic effects.Same therapeutic effectivenessSam
21、e side effect profile,Highly effective against positive and negative symptomsAdverse effects:EPS incidence is dose-relatedAlpha-1 receptor blockadeLittle or no anticholinergic or antihistamine effectsWeight gain,PRL elevation,HYPOTHESIZED MECHANISMS OF ACTION OF ATYPICAL NEUROLEPTICS,Combination of
22、Dopamine-4 and Serotonin-2 receptor blockade in cortical and limbic areas for the“pines”Combination of Dopamine-2 and Serotonin-2 receptor blockade(esp.risperidone),General Therapeutic Principles for Use of Neuroleptics in Schizophrenia(NIH Consensus Statement,1999),Use atypical for:1st acute episod
23、e w/+or+/-symptoms Switch to atypical if:Breakthrough after Rx w/typicalUse typical(depot prep)when:Patient is noncompliant,General Therapeutic Principles for Use of Neuroleptics in Schizophrenia,If response is inadequate to:Typical;switch to AtypicalAtypical;raise dose or switch to another AtypicalTypical and Atypical;switch to Clozaril For maintenance,lifetime Rx is required.,
