1、抗精神失常药抗精神失常药PHARMACOLOGY OF ANTIPSYCHOTIC DRUGS (NEUROLEPTICS)SOME DEFINITIONSnNeuroleptic: synonym for antipsychotic drug; originally indicated drug w/antipsychotic efficacy but with neurologic (extrapyramidal motor) side effectsnTypical neuroleptic: older agents fitting this descriptionnAtypical n
2、euroleptic: newer agents: antipsychotic efficacy with reduced or no neurologic side effectsNEUROLEPTICS ON THE UUHSC DRUG LISTnTYPICAL NEUROLEPTICS:nPHENOTHIAZINES:nChlorpromazine (Thorazine )nThioridazine (Mellaril )nFluphenazine (Prolixin )nTHIOXANTHENEnThiothixene (Navane )nOTHERnHaloperidol (Hal
3、dol )NEUROLEPTICS ON THE UUHSC DRUG LIST (Continued)nATYPICAL NEUROLEPTICS:nRisperidone (Risperdal ; most frequently prescribed in U.S.)nClozapine (Clozaril )nOlanzapine (Zyprexa )nQuetiapine (Seroquel ) KEY CONCEPTS: nAll neuroleptics are equally effective in treating psychoses, including schizophr
4、enia, but differ in their tolerability.nAll neuroleptics block one or more types of DOPAMINE receptor, but differ in their other neurochemical effects. nAll neuroleptics show a significant delay before they become effective. nAll neuroleptics produce significant adverse effects. GENERAL CHARACTERIST
5、ICS OF TYPICAL NEUROLEPTICSnThe older, typical neuroleptics are effective antipsychotic agents with neurologic side effects involving the extrapyramidal motor system. nTypical neuroleptics block the dopamine-2 receptor. GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICSnTypical neuroleptics do not prod
6、uce a general depression of the CNS, e.g. respiratory depressionnAbuse, addiction, physical dependence do not develop to typical neuroleptics.GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICSnTypical neuroleptics are generally more effective against positive (active) symptoms of schizophrenia than the
7、 negative (passive) symptoms.nPositive/active symptoms include thought disturbances, delusions, hallucinationsnNegative/passive symptoms include social withdrawal, loss of drive, diminished affect, paucity of speech. impaired personal hygieneTHERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICSnAll appear equ
8、ally effective; choice usually based on tolerability of side effectsnMost common are haloperidol (Haldol ), chlorpromazine (Thorazine ) and thioridazine (Mellaril )nLatency to beneficial effects; 4-6 week delay until full response is commonn70-80% of patients respond, but 30-40% show only partial re
9、sponse THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS (Continued)nRelapse, recurrence of symptoms is common ( approx. 50% within two years). nNoncompliance is common. nAdverse effects are common. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICSnAnticholinergic (antimuscarinic) side effects:nDry mouth, blurred v
10、ision, tachycardia, constipation, urinary retention, impotenceADVERSE EFFECTS OF TYPICAL NEUROLEPTICSnAntiadrenergic (Alpha-1) side effects:nOrthostatic hypotension w/ reflex tachycardiansedationADVERSE EFFECTS OF TYPICAL NEUROLEPTICSnAntihistamine effect: sedation, weight gainKEY CONCEPT: DOPAMINE-
11、2 RECEPTOR BLOCKADE IN THE BASAL GANGLIA RESULTS IN EXTRAPYRAMIDAL MOTOR SIDE EFFECTS (EPS).nDYSTONIAnNEUROLEPTIC MALIGNANT SYNDROMEnPARKINSONISMnTARDIVE DYSKINESIAnAKATHISIAADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued)nIncreased prolactin secretion (common with all; from dopamine blockade)nWe
12、ight gain (common, antihistamine effect?)nPhotosensitivity (v. common w/ phenothiazines)nLowered seizure threshold (common with all)nLeucopenia , agranulocytosis (rare; w/ phenothiazines)nRetinal pigmentopathy (rare; w/ phenothiazines)ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued)nChlorpromazin
13、e and thioridazine produce marked autonomic side effects and sedation; EPS tend to be weak (thioridazine) or moderate (chlorpromazine).nHaloperidol, thiothixene and fluphenazine produce weak autonomic and sedative effects, but EPS are marked. MECHANISMS OF ACTION OF TYPICAL NEUROLEPTICSnDOPAMINE-2 r
14、eceptor blockade in meso-limbic and meso-cortical systems for antipsychotic effect.nDOPAMINE-2 receptor blockade in basal ganglia (nigro-striatal system) for EPSnDOPAMINE-2 receptor supersensitivity in nigrostriatal system for tardive dyskinesiaLONG TERM EFFECTS OF D2 RECEPTOR BLOCKADE:nDopamine neu
15、rons reduce activity.nPostsynaptic D-2 receptor numbers increase (compensatory response).nWhen D2 blockade is reduced, DA neurons resume firing and stimulate increased # of receptors hyper-dopamine state tardive dyskinesia MANAGEMENT OF EPSnDystonia and parkinsonism: anticholinergic antiparkinson dr
16、ugsnNeuroleptic malignant syndrome: muscle relaxants, DA agonists, supportivenAkathisia: benzodiazepines, propranololnTardive dyskinesia: increase neuroleptic dose; switch to clozapineADDITIONAL CLINICAL USES OF TYPICAL NEUROLEPTICSnAdjunctive in Rx of acute manic episodenTourettes syndrome (esp. Ha
17、ldol )nRx of drug-induced psychosesnPhenothiazines are effective anti-emetics,nEsp. prochlorperazine (Compazine )nAlso, anti-migraine effectGENERAL CHARACTERISTICS OF ATYPICAL NEUROLEPTICSnEffective antipsychotic agents with greatly reduced or absent EPS, esp. reduced Parkinsonism and tardive dyskin
18、esianAll atypical neuroleptics block dopamine and serotonin receptors; other neurochemical effects differnAre effective against positive and negative symptoms of schizophrenia; and in patients refractory to typical neurolepticsPHARMACOLOGY OF CLOZAPINE (CLOZARIL ) nFDA-approved for patients not resp
19、onding to other agents or with severe tardive dyskinesianEffective against negative symptomsnAlso effective in bipolar disordernLittle or no parkinsonism, tardive dyskinesia, PRL elevation, neuro-malignant syndrome; some akathisianBlockade of alpha-1 adrenergic receptorsnBlockade of muscarinic choli
20、nergic receptorsnBlockade of histamine-1 receptorsPHARMACOLOGY OF CLOZAPINE (Continued )nOther adverse effects;nWeight gainnIncreased salivationnIncreased risk of seizuresnRisk of agranulocytosis requires continual monitoringPHARMACOLOGY OF OLANZAPINE (ZYPREXA )nOlanzapine is clozapine without the a
21、granulocytosis. nSame therapeutic effectivenessnSame side effect profilePHARMACOLOGY OF QUETIAPINE (SEROQUEL )nQuetiapine is olanzapine without the anticholinergic effects.nSame therapeutic effectivenessnSame side effect profilenHighly effective against positive and negative symptomsnAdverse effects
22、:nEPS incidence is dose-relatednAlpha-1 receptor blockadenLittle or no anticholinergic or antihistamine effectsnWeight gain, PRL elevationHYPOTHESIZED MECHANISMS OF ACTION OF ATYPICAL NEUROLEPTICSnCombination of Dopamine-4 and Serotonin-2 receptor blockade in cortical and limbic areas for the “pines
23、”nCombination of Dopamine-2 and Serotonin-2 receptor blockade (esp. risperidone)General Therapeutic Principles for Use of Neuroleptics in Schizophrenia(NIH Consensus Statement, 1999)nUse atypical for: n1st acute episode w/ + or +/- symptoms nSwitch to atypical if:nBreakthrough after Rx w/ typicalnUs
24、e typical (depot prep) when:nPatient is noncompliantGeneral Therapeutic Principles for Use of Neuroleptics in SchizophrenianIf response is inadequate to:nTypical; switch to AtypicalnAtypical; raise dose or switch to another AtypicalnTypical and Atypical; switch to Clozaril nFor maintenance, lifetime Rx is required.
