药理学全套课件

药理学总论-绪言PharmacologyAVeryBasicIntroWhatisadrug?anychemicalagentwhich affectsanybiologicalprocess

SourcesofDrugs

AnimalsPlantsMineralsSyntheticMicrobesGeneticengineeringdrugs基因工程药物过程示意图①从细胞中分离出DNA①②③④⑤⑥②限制酶截取DNA片断③分离大肠杆菌中的质粒④DNA重组⑤用重组质粒转化大肠杆菌⑥培养大肠杆菌克隆大量基因AgoalofGenomicsistofindandexpressgenesthatcodeforunknownpeptideswithsignificantbiologicalproperties,likereceptorsorenzymes.InareversePharmacologyapproachthispeptide,e.g.areceptor,isthenusedto"fish"foranaturalligand.Withreceptorandligandinhandthebiologicalroleofthereceptorneedstobedetermined.Finally,screeningforsyntheticligandsaswellasleadoptimizationcanleadtonewdrugcandidates.Incontrast,theclassicalapproachtodrugdiscoverystartswiththeidentificationofaligandthathasbiologicalactivitythatinturnisusedto"fish"forthecorrespondingreceptor.OneexampleforaGenomicsstrategyaimsatidentifyingdrugtargetsbasedonmolecularhomologywithinGene-families.Oneofthemostimportantfamiliesofdrug-targetsforthepharmaceuticalindustryisthefamilyofG-proteincoupledreceptors(GPCRs).Ofthetop200bestsellingprescriptiondrugs,morethan20%interactwithGPCRs,providingworldwidesalesofover$20billion.ThecharacteristicmotifoftheGPCRfamilyisthesevendistincthydrophobicregions,eachof20to30aminoacidsthatformthetransmembranedomainoftheseintegralmembraneproteins.Thiskeyamino-acidsequencemotifcanbefoundwithinalltypesofGPCRsandcanbeusedtoidentifyDNA-sequencesthatcodeforGPCRs.Whatispharmacology?

thestudyofhowdrugs effectbiologicalsystemsWhatisPharmacology?PharmacologyPharmacokineticsPharmacodynamics

WhatthebodydoestodrugWhatthedrugdoestobodyPharmacotherapeuticsPharmacocognosy

ThestudyoftheuseofdrugsIdentifyingcrudematerialsasdrugsToxicologyPharmacokineticsWhatthebodydoestothedrug-Absorption-Distribution-Metabolism(Biotransformation)-Excretion

Half-life(t1/2)-thetimerequiredfortheplasmaconcentrationofadrugtobereducedby50%DRUGCLASSIFICATION

Basedonthechemicalstructure

-Basedonthemaineffect(e.g.analgesics).-Basedonthetherapeuticuse(e.g.antipsychotic安定药).Basedonmechanismofaction(e.g.serotoninagonist).

FromChemisttoFirstInMan…approximately7–10yearsHowaDrugbecomesadrug…H.HaarmannUniversityofMaryland,2002Basic&ClinicalEvaluationofNewDrugsDrugdiscovery&Drugscreening

Chemistry InVitroStudies

Functionincells,tissues,andatreceptors2.Preclinicalsafety&toxicitytesting

InVivo-Animalstudies PharmacologyandBehavioralPharmacology PotencyandEfficacy–ED50 ToleranceandTachyphylaxis(快速耐受)

Toxicity–AcuteandChronic

LD50 Teratogenicity=birthdefects Carcinogenicity=cancerous

3.EvaluationofdruginhumansEvaluatingDrugsinHumansTheFoodandDrugAdministration(FDA)

PhasesofaClinicalTrialsPhaseIPhaseIIPhaseIIIPhaseIV

EvaluatingDrugsinHumansPhaseI–HealthyadultvolunteersEvaluationofsafety,Pharmacokinetics(PK),sideeffects???

PhaseII-PatientsEvaluationofefficacy,safety,PK,andsideeffectsDouble-blindplacebocontrolled

PhaseIII–SpecificpatientsubpopulationsDetermineefficacyforspecificindicationsLargesampleofspecificpatients(1,000)Randomizeddouble-blindplacebocontrolledPhaseIV–PostFDAApprovalDetermineefficacyforspecificindicationDeterminedrugutilizationpatternsandadditionalefficacyMonitorrare,severesideeffects/toxicityTransformationFreeSystemicCirculationBounddrugFreedrugMetabolitesLocusofAction“receptors”BoundFreeTissueReservoirsBoundExceretionAbsorptionAcrossmembraneandlipidAcrossaqueouschannelCarrier-mediatedtransportOutsideInsideMannersofTransportAcrossMembrancePassivetransport

RoutesofDrugAdministrationEnteralwithinorbywayoftheGItractOral(PO),rectal,sublingualParenteralNotwithinthealimentarycanalInhalation,IM,SC,IP,topicalCentralIntothebrainorspinalcordIntrathecalRoutesofDrugAdministrationcommonabbreviations…PO=peros=oralIV=intravenous=intotheveinIM=intramuscular=intothemuscleSC=subcutaneous=betweentheskinandmuscleIP=intraperitoneal=withintheperitonealcavityicv=intracerebroventricular= directlyintotheventricleofthebrain

FactorsAffectingResponsetoDrugsDosageRouteofAdministrationRateofAbsorptionRateofEliminationPhysiochemicalpropertiesofthedrugage,sex,species,metabolism,etc…

清除率(ml/min)5040302010002468020400120153001234567苯巴比妥[弱酸性药](狗)苯丙胺[弱碱性药](人)精神反应血浆药物浓度尿排泄量酸性尿（pH~5）碱性尿（pH~7）碱性尿pH7.8-8.0酸性尿pH<7排尿（ml/min）mmol/hmM计分值尿pH值对药物排泄的影响0204060801001200246810血浆阿司匹林浓度(mg/L)时间（min）口服和静脉注射阿司匹林659mg后的时-量曲线时间CAB血药浓度MEC三种不同的生物利用度A.吸收速度快、吸收量完全B.吸收速度与A相同，但吸收量仅为A的50%C.吸收量完全，但吸收速度为A的50%血浆地高辛浓度(nmol/L)12345012四种由不同药厂生产的相同剂量地高辛片剂的生物利用度时间（h）Eliminationkinetics1.First-ordereliminationkinetics0210123456稳态浓度药物浓度Css.maxCss.min7多次给药的时-量曲线血药浓度100200300802460002468100200300时间（半衰期）10020030002460ABC8MTCMEC三种不同给药方案对稳态浓度的影响A.缩短给药时间B.增加给药剂量C.负荷量给药2.Zero-ordereliminationkineticsPharmacokineticEvaluationofGepironeImmediate-ReleaseCapsulesandGepironeExtended-ReleaseTabletsinHealthyVolunteersJOURNALOFPHARMACEUTICALSCIENCES,

VOL.92,NO.9,SEPTEMBER2003Gepironeisa5-HT1Aagonistforthetreatmentofmajordepression.half-lifeof

3handgoodoralbioavailability,andundergoesextensivefirst-passmetabolismBecauseofitsrapidabsorptionandshorthalf-life,thegepirone-IR(immediate-releaseformulation)mustbeadministeredatleasttwicedaily.Thisregimenresultsinhighpeakconcentrationsandmarkedpeak-to-troughfluctuationsinplasmaconcentrations.

Thesefluctuationsmaycontributetoanincreasedincidenceofadverseevents,suchasnausea,dizziness,headache,andsomnolence,andhavethepotentialtoresultinlowerpatientcomplianceandreducedeffectiveness.extended-releasegepironeformulation(ER)immediate-releaseformulation(IR)Figure1.Meangepironeplasmaconcentrations

followingadministrationofgepirone-IRformulations

(10mgq12h,n=12)orgepirone-ERformulations(ER-1:

20mgq24h,n=12;ER-2:20mgq24h,n=12;ER-3:

25mgq24h,n=12).

Figure2.Mean1-PPplasmaconcentrationsfollowing

administrationofgepirone-IRformulations

(10mgq12h,n=12)orgepirone-ERformulations(ER-

1:20mgq24h,n=12;ER-2:20mgq24h,n=12;ER-3:

25mgq24h,n=12).

PharmacodynamicsWhatthedrugdoestothebody-Drugreceptors-Effectsofdrug-Responsestodrugs-Toxicityandadverseeffectsofdrugs

PharmacodynamicsDoseResponseCurveG蛋白偶联CN激动药结合区域膜外膜内

G-proteincoupledrecptors激动药结合区域膜外膜内激动药结合区域

Ligand-gatedionchannelreceptors激动药结合区域膜外膜内催化结构区域Tyrosine-proteinkinasereceptorClassification：1．Anatomy

（1）Autonomicnervoussystem

Sympatheticnerve;parasympatheticnerve

（2）SomaticmotornervoussystemOverviewofneuromuscularjunctionandautonomicganglia

2．Transmittors：（1）Cholinergicnerve

Acetylcholine（2）Noradrenergic

nerve

Noradrenaline（3）Entericnervoussystem，

ENS

细胞体位于肠壁的壁内丛。涉及多神经肽和其他递质，如5-羟色胺（5-HT）、一氧化氮（NO）、三磷酸腺苷（ATP）、P物质（SP）和神经肽（NP）。

小肠神经系统（ENS）环路的高度简化图LM:纵行肌肉层MP:肠肌丛CM:环行肌肉层SMP:粘膜下丛Transmitterandreceptor：

synapse：junction，运动终板

突触前膜;突触后膜;synapticcleft，15～1000nm

1.Synthesisandstorageoftransmitters

（1）Noradrenaline，NAorNorepinephrin,NENA能N末梢递质合成、贮存、释放、代谢

A:钠依赖性载体

B:单胺转运载体

P:多肽（2）Acetylcholine，ACh胆碱能N末梢递质合成、贮存、释放和代谢

AcCoA:乙酰辅酶AChAc:胆碱乙酰化酶，

A:钠依赖性载体

B:乙酰胆碱载体

P:多肽2．Transductionofnerveimpulseanddisappearoftransmitters（1）Transduction：Ca2+influxExocytosisRelease：QuantalreleaseOthers后膜受体前膜受体（2）DisappearoftransmittersAch:AcetylcholinesteraseAChENA：

uptake1uptake23．Classificationofreceptors

（1）AcetylcholinereceptorsMuscarinereceptor:M1-5Nicotinereceptor:

NMreceptor:nicotinicmuscle

NNreceptor:nicotinicneuron

（2）Adrenoceptorsαreceptor：α1andα2βreceptor：β1、β2andβ35．Biochemicalprocess（1）Ncholinoceptor

Ligandgatedionchannelreceptor，regulateNa+、K+、Ca2+flux.（2）Mcholinoceptor

SuperfamilyofG-protein-coupledreceptors）ActivatePLC(phospholipaseC)InhibitACActivateK+orinhibitCa2+channels（3）Adrenoceptorsα1–RactivatePLC,D,A2α2–RinhibitACβ–RactivateACM-R：平滑肌、腺体兴奋瞳孔缩小心血管抑制

N-R：骨骼肌收缩神经节、肾上腺髓质兴奋

CNS：早期兴奋；晚期抑制Muscarinecholinoceptoragonists

1．胆碱酯类：

Ach,methacholine,carbacholine,bethanechoine

2．天然生物碱类：

pilocarpine,arecoline,muscarineAcetylcholine

极易被体内acetylcholinesterase(AChE）水解，无临床实用价值。内源性神经递质，必须熟悉该递质。ACh不易进入中枢，故尽管中枢神经系统有胆碱受体存在，但外周给药很少产生中枢作用。

Carbacholine

与ACh相似，不易水解，作用时间较长。本品对膀胱和肠道作用明显，故可用于术后腹气胀和尿潴留，仅用于皮下注射，禁用静注给药。该药副作用较多，且阿托品对它的解毒效果差，故目前主要用于局部滴眼治疗青光眼。

Pilocarpine

【Action】1．眼：（1）缩瞳：（2）降低眼内压：（3）调节痉挛：2．腺体

汗腺、唾液腺分泌增加最明显。

人体β1-肾上腺受体

受体-腺苷酸环化酶偶联和受体-磷脂酶偶联示意图

cAMPsignalingintheheart

STindicatessynapticterminal;Nor,norepinephrine;SL,sarcolemma;AC,adenylylcyclase;PKA,proteinkinaseA;andSR,sarcoplasmicreticulum去甲肾上腺素间羟胺去氧肾上腺素甲氧明[体内过程]

[药理作用]

1.心脏：β1

2.血管：α

3.血压：心脏、血管

4.其他

[临床应用]

[不良反应]肾上腺素多巴胺麻黄碱[体内过程]

[药理作用]

1.心脏：β1

2.血管：α，β2

3.血压：心脏、血管

4.平滑肌：α，β2

5.代谢：α，β

6.CNS：兴奋

[临床应用]

[不良反应][体内过程]

[药理作用]

1.心脏：β1

2.血管：β2

3.血压：心脏、血管

4.平滑肌：β2

5.代谢：β

[临床应用]

[不良反应]异丙肾上腺素多巴酚丁胺沙丁胺醇

儿茶酚胺的代谢

R：硫酸根或葡萄糖醛酸根拟肾上腺素药基本作用的比较抗帕金森病药PARKINSONISM(ParalysisAgitants)Parkinsonismischaracterizedbyacombinationofrigidity,bradykinesia,tremor,andposturalinstabilitythatcanoccurforawidevarietyofreasonsbutisusuallyidiopathic.Thepathophysiologicbasisoftheidiopathicdisordermayrelatetoexposuretosomeunrecognizedneurotoxinortotheoccurrenceofoxidationreactionswiththegenerationoffreeradicals.Studiesintwinssuggestthatgeneticfactorsmayalsobeimportant,especiallywhenthediseaseoccursinpatientsunderage50.Parkinson'sdiseaseisgenerallyprogressive,leadingtoincreasingdisabilityunlesseffectivetreatmentisprovided.Thenormallyhighconcentrationofdopamineinthebasalgangliaofthebrainisreducedinparkinsonism,andpharmacologicattemptstorestoredopaminergicactivitywithlevodopaanddopamineagonistshavebeensuccessfulinalleviatingmanyoftheclinicalfeaturesofthedisorder.Analternativebutcomplementaryapproachhasbeentorestorethenormalbalanceofcholinergicanddopaminergicinfluencesonthebasalgangliawithantimuscarinicdrugs.Thepathophysiologicbasisforthesetherapiesisthatinidiopathicparkinsonism,dopaminergicneuronsinthesubstantianigrathatnormallyinhibittheoutputofγ-aminobutyricacid(GABA)ergiccellsinthecorpusstriatumarelost.Schematicrepresentationofthesequenceofneuronsinvolvedinparkinsonism.

Top:Dopaminergicneurons(color)originatinginthesubstantianigranormallyinhibittheGABAergicoutputfromthestriatum,whereascholinergicneurons(gray)exertanexcitatoryeffect.Middle:Inparkinsonism,thereisaselectivelossofdopaminergicneurons(dashed,color).

Fateoforallyadministeredlevodopaandtheeffectofcarbidopa,estimatedfromanimaldata.

Thewidthofeachpathwayindicatestheabsoluteamountofthedrugpresentateachsite,whilethepercentagesshowndenotetherelativeproportionoftheadministereddose.Thebenefitsofcoadministrationofcarbidopaincludereductionoftheamountoflevodopadivertedtoperipheraltissuesandanincreaseinthefractionofthedosethatreachesthebrain.一、左旋多巴及其增效剂

1.左旋多巴（L-dopa)

药理作用与机制

左旋多巴可使80%PD病人症状明显改善。其中20%的病人可恢复到正常运动状态。起病初期用药疗效更为显著，用药后患者感觉良好，抑制和淡漠症状改善，服药后先改善肌强直和运动迟缓，后改善肌震颤，由于情绪好转，能关心周围环境，思维清晰敏捷，听觉口语学习能力明显改善，生活质量明显提高。特点①奏效慢，用药2~3周后才出现体征的改善，

1~6个月后获得最大疗效。②对轻症及年轻患者疗效好，对重症及年老患者疗效差。机制

L-dopa属DA的前体药，本身无药理活性，脑内转化为DA，补充了纹状体中DA的不足，提高中枢DA神经功能，抑制胆碱能神经功能，产生抗震颤麻痹的作用。

体内过程

口服后主要在小肠经主动转运系统而迅速吸收。进入中枢量不到1%，99%在外周经脱羧换化为DA是引起不良反应的主要原因。因此，提出与外周多巴脱羧酶抑制剂合用达到增效，减少不良反应，还可减少左旋多巴的用量。临床应用

1.帕金森病治疗广泛用于各种类型PD病人，运动障碍症状不明显者一般不用。对抗精神病药物所致锥体外系症状无效。病人长期用药效果有较大个体差异。服药6年后，约半数病人失效。

2．肝昏迷辅助治疗肝昏迷病人，由于肝功能障碍，血中苯乙胺、酪胺升高，在神经细胞内经β-羟化酶作用生成苯乙醇胺和章胺（伪递质）妨碍正常神经功能。用左旋多巴后，转化为NA恢复正常神经功能，病人逐渐转为清醒。鱼不良反应

大多是由于左旋多巴在体内生成DA所致。1．胃肠道反应厌食、恶心、呕吐、腹部不适。是由于DA兴奋延脑催吐化学感受区所致。继续治疗，由于产生耐受性，胃肠道反应可减轻。2．心血管反应部分病人出现体位性低血压反应，表现头晕，偶见晕厥。少数病人心律失常(DA兴奋心脏β1受体)。3．不自主异常运动如咬牙、吐舌、点头、做怪相及舞蹈样动作，发生率约40~80%，多在长期用药后出现，主要是由于DA补充过度，须减量。少数病人长期用药后，可出现“开关现象”，表现为突然多动不安(开)，转为全身产生强直不动(关)，二者交替出现，机制尚无完满解释。4．精神障碍与DA过度兴奋中脑一边缘系统DA受体有关。2.外周多巴脱羧酶抑制剂卡比多巴（Carbidopa）、苄丝肼（benserazide）外周多巴脱羧酶抑制剂，不易通过血脑屏障。单独应用对PD无治疗作用，主要与左旋多巴按一定比例制成复方左旋多巴制剂供临床应用，可增加血和脑内L-dopa达3~4倍。信尼麦（sinemet,心宁美） 左旋多巴:卡比多巴=10:1（100mg:10mg）复方苄丝肼（美多巴，Madopar） 左旋多巴:苄丝肼=4∶1（100mg∶25mg）联合用药主要优点

1、提高左旋多巴疗效（增效）

2、减少外周副作用（减毒）

3、减少左旋多巴用量（70~80%）3.COMT抑制剂

L-dopa代谢有两条途径：

L-dopaDA3-OMD（3-O-甲基多巴）而3-OMD又可与L-dopa竞争转运载体而影响L-dopa的吸收和进入脑组织（生物利用度降低）-co2COMT

硝替卡朋（nitecapone）托卡朋（tocapone）安托卡朋（entocapone）可增加纹状体中L-dopa和DA。当与卡比多巴合用时，只抑制外周COMT，增加L-dopa生物利用度，而不影响脑内COMT（不易通过血脑屏障）。抗老年性痴呆药

DownsizedTarget

AtinyproteincalledADDLcouldbethekeytoAlzheimer's

ScientificAmerican2004ScientistshavelongsuspectedthattheproteinclumpsandtanglesidentifiedbyAloisAlzheimerin1907somehowcausethediseasethatbearshisname,probablybykillingneurons.Nowsomeresearchersareblamingamuchsmallerformofprotein,onethatapparentlyproducesmemorydeficitsmerelybybindingtoneuronsanddisruptingtheirabilitytotransmitsignals.Thesearchhasbegunforanantibodythatwoulddestroythesetinyproteins--orADDLs--therebypreventingtheonsetofAlzheimer'sdiseaseandpossiblyevenreversingtheearlysymptoms.

ThediscoveryofADDLsexplainsglaringanomaliesintheconventionalthinkingaboutAlzheimer's,whichholdsthatfragmentsofamyloidprecursorprotein,producedbynormalneurons,aggregateintosticky,insolubleplaquesthatdamageneurons.Theproblemwiththistheoryisthatvirtuallyeveryolderpersoncarriessomeamyloidplaque,butonlyafewdevelopAlzheimer's.Conversely,thosewithAlzheimer'softenhaverelativelyfewplaques.Anotherproposedculpritisthepresenceoftanglesoftauprotein,whichforminsideneuronsandcoincidewiththecollapseofmicrotubulesthatsupportthecellbodyandtransportnutrients.Thetautanglescorrelatemuchbetterwiththediseasebuttendtoappearlater,suggestingthattheyareaconsequence,notacause.In1994CalebE.Finch,aneurogerontologistattheUniversityofSouthernCalifornia,attemptedtocreateamyloidplaquebymixingasolutionofamyloidprecursorproteinfragmentswithclusterin,asubstanceproducedathigherlevelsinthebrainsofpeoplewithAlzheimer's.Theclusterindidnottriggertheformationofamyloidplaques,buttheresultingsolutionprofoundlydisruptedtheabilityoftheneuronstotransmitsignals.FinchreportedthisfindingtoGrantA.KrafftandWilliamL.Klein,twocolleaguesatNorthwesternUniversity,whosetouttodiscoverwhatwasinthesolution.Usinganatomic-forcemicroscope,theyobtainedextraordinarypicturesofglobulesnoonehadeverseen."Theylookedlikelittlemarbles,"Krafftrecalls."Itturnedouttheseglobulescontainedonlyafewoftheamyloidpeptidebuildingblocks,whereasthelongfibrilscontainedthousands,ifnotmillions,ofthesesubunits."ThethreescientistsdecidedtocallthesubstanceADDL,whichstandsforamyloidbeta-deriveddiffusibleligand.(Themoleculeisderivedfromamyloidprecursorprotein;itdiffusesthroughoutthebraininsteadofaggregatingintofixedplaques;asaligand,itattachestoreceptorsonneurons.)

KleindevelopedanantibodythatrevealedhowADDLsattachtodendritesinthehippocampus,therebydisruptingsignalsneededtoproduceshort-termmemories.AndlastsummerKlein,Krafft,FinchandtheircolleaguesfoundhugequantitiesofADDLsinpostmortembrainsfrompeoplewithAlzheimer's,whereasbrainsfromnormalpatientswerevirtuallyfreeofADDLs.Whatismore,theydiscoveredthatneuronsofmicefunctionednormallyoncetheADDLswereremoved.

TheobvioussolutiontotreatAlzheimer'sdisease,inKrafft'sopinion,istoremovetheADDLsorpreventthemfromforming.Attemptstoeradicateamyloidplaquesaremisguided,hebelieves,andanyattempttointerveneafterneuronshavestartedtodiecomestoolatetodomuchgood."It'sprettycleartomethatwe'rewastingabout90percentoftheAlzheimer'sresearchbudgetonthingsthatareworthless,"hesays.SOMEDEFINITIONSNeuroleptic:synonymforantipsychoticdrug;originallyindicateddrugw/antipsychoticefficacybutwithneurologic(extrapyramidalmotor)sideeffectsTypicalneuroleptic:olderagentsfittingthisdescriptionAtypicalneuroleptic:neweragents:antipsychoticefficacywithreducedornoneurologicsideeffectsNEUROLEPTICSONTHEUUHSCDRUGLISTTYPICALNEUROLEPTICS:PHENOTHIAZINES:Chlorpromazine(Thorazine®)Thioridazine(Mellaril®)Fluphenazine(Prolixin®)THIOXANTHENEThiothixene(Navane®)OTHERHaloperidol(Haldol®)NEUROLEPTICSONTHEUUHSCDRUGLIST(Continued)ATYPICALNEUROLEPTICS:Risperidone(Risperdal®;mostfrequentlyprescribedinU.S.)Clozapine(Clozaril®)Olanzapine(Zyprexa®)Quetiapine(Seroquel®)KEYCONCEPTS:

Allneurolepticsareequallyeffectiveintreatingpsychoses,includingschizophrenia,butdifferintheirtolerability.AllneurolepticsblockoneormoretypesofDOPAMINEreceptor,butdifferintheirotherneurochemicaleffects.Allneurolepticsshowasignificantdelaybeforetheybecomeeffective.Allneurolepticsproducesignificantadverseeffects.

GENERALCHARACTERISTICSOFTYPICALNEUROLEPTICSTheolder,typicalneurolepticsareeffectiveantipsychoticagentswithneurologicsideeffectsinvolvingtheextrapyramidalmotorsystem.Typicalneurolepticsblockthedopamine-2receptor.GENERALCHARACTERISTICSOFTYPICALNEUROLEPTICSTypicalneurolepticsdonotproduceageneraldepressionoftheCNS,e.g.respiratorydepressionAbuse,addiction,physicaldependencedonotdeveloptotypicalneuroleptics.GENERALCHARACTERISTICSOFTYPICALNEUROLEPTICSTypicalneurolepticsaregenerallymoreeffectiveagainstpositive(active)symptomsofschizophreniathanthenegative(passive)symptoms.Positive/activesymptomsincludethoughtdisturbances,delusions,hallucinationsNegative/passivesymptomsincludesocialwithdrawal,lossofdrive,diminishedaffect,paucityofspeech.impairedpersonalhygieneTHERAPEUTICEFFECTSOFTYPICALNEUROLEPTICSAllappearequallyeffective;choiceusuallybasedontolerabilityofsideeffectsMostcommonarehaloperidol(Haldol®),chlorpromazine(Thorazine®)andthioridazine(Mellaril®)Latencytobeneficialeffects;4-6weekdelayuntilfullresponseiscommon70-80%ofpatientsrespond,but30-40%showonlypartialresponse

THERAPEUTICEFFECTSOFTYPICALNEUROLEPTICS(Continued)Relapse,recurrenceofsymptomsiscommon(approx.50%withintwoyears).Noncomplianceiscommon.Adverseeffectsarecommon.

ADVERSEEFFECTSOFTYPICALNEUROLEPTICSAnticholinergic(antimuscarinic)sideeffects:Drymouth,blurredvision,tachycardia,constipation,urinaryretention,impotenceADVERSEEFFECTSOFTYPICALNEUROLEPTICSAntiadrenergic(Alpha-1)sideeffects:Orthostatichypotensionw/reflextachycardiasedationADVERSEEFFECTSOFTYPICALNEUROLEPTICSAntihistamineeffect:sedation,weightgainKEYCONCEPT:DOPAMINE-2

RECEPTORBLOCKADEINTHEBASALGANGLIARESULTSINEXTRAPYRAMIDALMOTORSIDEEFFECTS(EPS).DYSTONIANEUROLEPTICMALIGNANTSYNDROMEPARKINSONISMTARDIVEDYSKINESIAAKATHISIAADVERSEEFFECTSOFTYPICALNEUROLEPTICS(Continued)Increasedprolactinsecretion(commonwithall;fromdopamineblockade)Weightgain(common,antihistamineeffect?)Photosensitivity(v.commonw/phenothiazines)Loweredseizurethreshold(commonwithall)Leucopenia,agranulocytosis(rare;w/phenothiazines)Retinalpigmentopathy(rare;w/phenothiazines)ADVERSEEFFECTSOFTYPICALNEUROLEPTICS(Continued)Chlorpromazineandthioridazineproducemarkedautonomicsideeffectsandsedation;EPStendtobeweak(thioridazine)ormoderate(chlorpromazine).Haloperidol,thiothixeneandfluphenazineproduceweakautonomicandsedativeeffects,butEPSaremarked.MECHANISMSOFACTION

OFTYPICALNEUROLEPTICSDOPAMINE-2receptorblockadeinmeso-limbicandmeso-corticalsystemsforantipsychoticeffect.DOPAMINE-2receptorblockadeinbasalganglia(nigro-striatalsystem)forEPSDOPAMINE-2receptorsupersensitivityinnigrostriatalsystemfortardivedyskinesiaLONGTERMEFFECTSOFD2RECEPTORBLOCKADE:Dopamineneuronsreduceactivity.PostsynapticD-2receptornumbersincrease(compensatoryresponse).WhenD2blockadeisreduced,DAneuronsresumefiringandstimulateincreased#ofreceptors>>hyper-dopaminestate>>tardivedyskinesiaMANAGEMENTOFEPSDystoniaandparkinsonism:anticholinergicantiparkinsondrugsNeurolepticmalignantsyndrome:musclerelaxants,DAagonists,supportiveAkathisia:benzodiazepines,propranololTardivedyskinesia:increaseneurolepticdose;switchtoclozapineADDITIONALCLINICALUSESOFTYPICALNEUROLEPTICSAdjunctiveinRxofacutemanicepisodeTourette’ssyndrome(esp.Haldol®)Rxofdrug-inducedpsychosesPhenothiazinesareeffectiveanti-emetics,Esp.prochlorperazine(Compazine®)Also,anti-migraineeffectGENERALCHARACTERISTICSOFATYPICALNEUROLEPTICSEffectiveantipsychoticagentswithgreatlyreducedorabsentEPS,esp.reducedParkinsonismandtardivedyskinesiaAllatypicalneurolepticsblockdopamineandserotoninreceptors;otherneurochemicaleffectsdifferAreeffectiveagainstpositiveandnegativesymptomsofschizophrenia;andinpatientsrefractorytotypicalneurolepticsPHARMACOLOGYOF

CLOZAPINE(CLOZARIL®)

FDA-approvedforpatientsnotrespondingtootheragentsorwithseveretardivedyskinesiaEffectiveagainstnegativesymptomsAlsoeffectiveinbipolardisorderLittleornoparkinsonism,tardivedyskinesia,PRLelevation,neuro-malignantsyndrome;someakathisiaBlockadeofalpha-1adrenergicreceptorsBlockadeofmuscariniccholinergicreceptorsBlockadeofhistamine-1receptorsPHARMACOLOGYOFCLOZAPINE(Continued)Otheradverseeffects;WeightgainIncreasedsalivationIncreasedriskofseizuresRiskofagranulocytosisrequirescontinualmonitoringPHARMACOLOGYOFOLANZAPINE(ZYPREXA®)Olanzapineisclozapinewithouttheagranulocytosis.SametherapeuticeffectivenessSamesideeffectprofilePHARMACOLOGYOFQUETIAPINE(SEROQUEL®)Quetiapineisolanzapinewithouttheanticholinergiceffects.SametherapeuticeffectivenessSamesideeffectprofileHighlyeffectiveagainstpositiveandnegativesymptomsAdverseeffects:EPSincidenceisdose-relatedAlpha-1receptorblockadeLittleornoanticholinergicorantihistamineeffectsWeightgain,PRLelevationHYPOTHESIZEDMECHANISMSOFACTIONOFATYPICALNEUROLEPTICSCombinationofDopamine-4andSerotonin-2receptorblockadeincorticalandlimbicareasforthe“pines”CombinationofDopamine-2andSerotonin-2receptorblockade(esp.risperidone)GeneralTherapeuticPrinciplesforUseofNeurolepticsinSchizophrenia

(NIHConsensusStatement,1999)Useatypicalfor:1stacuteepisodew/+or+/-symptomsSwitchtoatypicalif:BreakthroughafterRxw/typicalUsetypical(depotprep)when:PatientisnoncompliantPainTreatmentAnalgesicsAntipyretic-analgesicandanti-inflammatorydrugs*Anunpleasantexperienceassociated

withactualorpotential

tissuedamage.PainPainPhysiologyIonFluxes(H+/K+)NeurochemistryTissueInjuryMastCellSensitizedNociceptorAspartate,Neurotensin,Glutamate,SubstancePTobrainHistamineBradykininLeukotrienesDorsalhornProstaglandinsPainTransmissionPain

perceptionSpinal

cordEnkephalininter-

neuronNociceptorDescending

pathwayAscending

pathwayDescendingPainControlPathwaysDescendingimpulseEnkephalinOpioidreceptorOpportunitiesforPainTreatmentAtthereceptorAlongthenerveAtreceptorsinspinalcolumnandbrainAcutevschronicNociceptivevsNeuropathicPainAcutevs.ChronicPainCfibers:dull,aching,burningpainDorsalrootganglionTobrainA-deltafibers:sharp,shootingpainAscendingpainpathwayTissueinjurySpinal

cordNociceptivePainAscendingpainpathwayNerveinjurySpinal

cordNeuropathicPainPrinciplesofPainManagement

Goldstandard:patientdeterminesseverityTradition:painhasbeenundertreatedPreventionorearlytreatmentbestPainkillsPainisrealBalancepainreliefwithsideeffectsofdrugsAntipyretic-analgesicandAnti-inflammatoryDrugsNon-steroidalanti-inflammatorydrugs,NSAIDs.Aspirin-likedrugs.MechanismofNSAIDsArachidonicacid,AAProstaglandin,PGLeukotrienes,LTsPGE2PGF2

PGI2TXA2PLA2phospholipidCOXNSAIDsSalicylatesAspirinandNSAIDsAnti-inflammatoryInhibitscyclooxygenasepathwayforbreakdownofarachidonicacidtoprostaglandinsandthromboxaneIbuprofen,Naprosyn&naproxenCOX-2inhibitorsAcetaminop