藥理學(xué)總論-緒言PharmacologyAVeryBasicIntroWhatisadrug?anychemicalagentwhich affectsanybiologicalprocess

SourcesofDrugs

AnimalsPlantsMineralsSyntheticMicrobesGeneticengineeringdrugs基因工程藥物過(guò)程示意圖①?gòu)募?xì)胞中分離出DNA①②③④⑤⑥②限制酶截取DNA片斷③分離大腸桿菌中的質(zhì)粒④DNA重組⑤用重組質(zhì)粒轉(zhuǎn)化大腸桿菌⑥培養(yǎng)大腸桿菌克隆大量基因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安定藥).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[弱酸性藥](狗)苯丙胺[弱鹼性藥](人)精神反應(yīng)血漿藥物濃度尿排泄量酸性尿（pH~5）鹼性尿（pH~7）鹼性尿pH7.8-8.0酸性尿pH<7排尿（ml/min）mmol/hmM計(jì)分值尿pH值對(duì)藥物排泄的影響0204060801001200246810血漿阿司匹林濃度(mg/L)時(shí)間（min）口服和靜脈注射阿司匹林659mg後的時(shí)-量曲線時(shí)間CAB血藥濃度MEC三種不同的生物利用度A.吸收速度快、吸收量完全B.吸收速度與A相同，但吸收量?jī)H為A的50%C.吸收量完全，但吸收速度為A的50%血漿地高辛濃度(nmol/L)12345012四種由不同藥廠生產(chǎn)的相同劑量地高辛片劑的生物利用度時(shí)間（h）Eliminationkinetics1.First-ordereliminationkinetics0210123456穩(wěn)態(tài)濃度藥物濃度Css.maxCss.min7多次給藥的時(shí)-量曲線血藥濃度100200300802460002468100200300時(shí)間（半衰期）10020030002460ABC8MTCMEC三種不同給藥方案對(duì)穩(wěn)態(tài)濃度的影響A.縮短給藥時(shí)間B.增加給藥劑量C.負(fù)荷量給藥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蛋白偶聯(lián)CN激動(dòng)藥結(jié)合區(qū)域膜外膜內(nèi)

G-proteincoupledrecptors激動(dòng)藥結(jié)合區(qū)域膜外膜內(nèi)激動(dòng)藥結(jié)合區(qū)域

Ligand-gatedionchannelreceptors激動(dòng)藥結(jié)合區(qū)域膜外膜內(nèi)催化結(jié)構(gòu)區(qū)域Tyrosine-proteinkinasereceptorClassification：1．Anatomy

（1）Autonomicnervoussystem

Sympatheticnerve;parasympatheticnerve

（2）SomaticmotornervoussystemOverviewofneuromuscularjunctionandautonomicganglia

2．Transmittors：（1）Cholinergicnerve

Acetylcholine（2）Noradrenergic

nerve

Noradrenaline（3）Entericnervoussystem，

ENS

細(xì)胞體位於腸壁的壁內(nèi)叢。涉及多神經(jīng)肽和其他遞質(zhì)，如5-羥色胺（5-HT）、一氧化氮（NO）、三磷酸腺苷（ATP）、P物質(zhì)（SP）和神經(jīng)肽（NP）。

小腸神經(jīng)系統(tǒng)（ENS）環(huán)路的高度簡(jiǎn)化圖LM:縱行肌肉層MP:腸肌叢CM:環(huán)行肌肉層SMP:粘膜下叢Transmitterandreceptor：

synapse：junction，運(yùn)動(dòng)終板

突觸前膜;突觸後膜;synapticcleft，15～1000nm

1.Synthesisandstorageoftransmitters

（1）Noradrenaline，NAorNorepinephrin,NENA能N末梢遞質(zhì)合成、貯存、釋放、代謝

A:鈉依賴性載體

B:單胺轉(zhuǎn)運(yùn)載體

P:多肽（2）Acetylcholine，ACh膽鹼能N末梢遞質(zhì)合成、貯存、釋放和代謝

AcCoA:乙醯輔酶AChAc:膽鹼乙醯化酶，

A:鈉依賴性載體

B:乙醯膽鹼載體

P:多肽2．Transductionofnerveimpulseanddisappearoftransmitters（1）Transduction：Ca2+influxExocytosisRelease：QuantalreleaseOthers後膜受體前膜受體（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、腺體興奮瞳孔縮小心血管抑制

N-R：骨骼肌收縮神經(jīng)節(jié)、腎上腺髓質(zhì)興奮

CNS：早期興奮；晚期抑制Muscarinecholinoceptoragonists

1．膽鹼酯類(lèi)：

Ach,methacholine,carbacholine,bethanechoine

2．天然生物鹼類(lèi)：

pilocarpine,arecoline,muscarineAcetylcholine

極易被體內(nèi)acetylcholinesterase(AChE）水解，無(wú)臨床實(shí)用價(jià)值。內(nèi)源性神經(jīng)遞質(zhì)，必須熟悉該遞質(zhì)。ACh不易進(jìn)入中樞，故儘管中樞神經(jīng)系統(tǒng)有膽鹼受體存在，但外周給藥很少產(chǎn)生中樞作用。

Carbacholine

與ACh相似，不易水解，作用時(shí)間較長(zhǎng)。本品對(duì)膀胱和腸道作用明顯，故可用於術(shù)後腹氣脹和尿?yàn)z留，僅用於皮下注射，禁用靜注給藥。該藥副作用較多，且阿托品對(duì)它的解毒效果差，故目前主要用於局部滴眼治療青光眼。

Pilocarpine

【Action】1．眼：（1）縮瞳：（2）降低眼內(nèi)壓：（3）調(diào)節(jié)痙攣：2．腺體

汗腺、唾液腺分泌增加最明顯。

人體β1-腎上腺受體

受體-腺苷酸環(huán)化酶偶聯(lián)和受體-磷脂酶偶聯(lián)示意圖

cAMPsignalingintheheart

STindicatessynapticterminal;Nor,norepinephrine;SL,sarcolemma;AC,adenylylcyclase;PKA,proteinkinaseA;andSR,sarcoplasmicreticulum去甲腎上腺素間羥胺去氧腎上腺素甲氧明[體內(nèi)過(guò)程]

[藥理作用]

1.心臟：β1

2.血管：α

3.血壓：心臟、血管

4.其他

[臨床應(yīng)用]

[不良反應(yīng)]腎上腺素多巴胺麻黃堿[體內(nèi)過(guò)程]

[藥理作用]

1.心臟：β1

2.血管：α，β2

3.血壓：心臟、血管

4.平滑?。害?，β2

5.代謝：α，β

6.CNS：興奮

[臨床應(yīng)用]

[不良反應(yīng)][體內(nèi)過(guò)程]

[藥理作用]

1.心臟：β1

2.血管：β2

3.血壓：心臟、血管

4.平滑肌：β2

5.代謝：β

[臨床應(yīng)用]

[不良反應(yīng)]異丙腎上腺素多巴酚丁胺沙丁胺醇

兒茶酚胺的代謝

R：硫酸根或葡萄糖醛酸根擬腎上腺素藥基本作用的比較抗帕金森病藥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、左旋多巴及其增效劑

1.左旋多巴（L-dopa)

藥理作用與機(jī)制

左旋多巴可使80%PD病人癥狀明顯改善。其中20%的病人可恢復(fù)到正常運(yùn)動(dòng)狀態(tài)。起病初期用藥療效更為顯著，用藥後患者感覺(jué)良好，抑制和淡漠癥狀改善，服藥後先改善肌強(qiáng)直和運(yùn)動(dòng)遲緩，後改善肌震顫，由於情緒好轉(zhuǎn)，能關(guān)心周?chē)h(huán)境，思維清晰敏捷，聽(tīng)覺(jué)口語(yǔ)學(xué)習(xí)能力明顯改善，生活品質(zhì)明顯提高。特點(diǎn)①奏效慢，用藥2~3周後才出現(xiàn)體征的改善，

1~6個(gè)月後獲得最大療效。②對(duì)輕癥及年輕患者療效好，對(duì)重癥及年老患者療效差。機(jī)制

L-dopa屬DA的前體藥，本身無(wú)藥理活性，腦內(nèi)轉(zhuǎn)化為DA，補(bǔ)充了紋狀體中DA的不足，提高中樞DA神經(jīng)功能，抑制膽鹼能神經(jīng)功能，產(chǎn)生抗震顫麻痹的作用。

體內(nèi)過(guò)程

口服後主要在小腸經(jīng)主動(dòng)轉(zhuǎn)運(yùn)系統(tǒng)而迅速吸收。進(jìn)入中樞量不到1%，99%在外周經(jīng)脫羧換化為DA是引起不良反應(yīng)的主要原因。因此，提出與外周多巴脫羧酶抑制劑合用達(dá)到增效，減少不良反應(yīng)，還可減少左旋多巴的用量。臨床應(yīng)用

1.帕金森病治療廣泛用於各種類(lèi)型PD病人，運(yùn)動(dòng)障礙癥狀不明顯者一般不用。對(duì)抗精神病藥物所致錐體外系癥狀無(wú)效。病人長(zhǎng)期用藥效果有較大個(gè)體差異。服藥6年後，約半數(shù)病人失效。

2．肝昏迷輔助治療肝昏迷病人，由於肝功能障礙，血中苯乙胺、酪胺升高，在神經(jīng)細(xì)胞內(nèi)經(jīng)β-羥化酶作用生成苯乙醇胺和章胺（偽遞質(zhì)）妨礙正常神經(jīng)功能。用左旋多巴後，轉(zhuǎn)化為NA恢復(fù)正常神經(jīng)功能，病人逐漸轉(zhuǎn)為清醒。魚(yú)不良反應(yīng)

大多是由於左旋多巴在體內(nèi)生成DA所致。1．胃腸道反應(yīng)厭食、噁心、嘔吐、腹部不適。是由於DA興奮延腦催吐化學(xué)感受區(qū)所致。繼續(xù)治療，由於產(chǎn)生耐受性，胃腸道反應(yīng)可減輕。2．心血管反應(yīng)部分病人出現(xiàn)體位性低血壓反應(yīng)，表現(xiàn)頭暈，偶見(jiàn)暈厥。少數(shù)病人心律失常(DA興奮心臟β1受體)。3．不自主異常運(yùn)動(dòng)如咬牙、吐舌、點(diǎn)頭、做怪相及舞蹈樣動(dòng)作，發(fā)生率約40~80%，多在長(zhǎng)期用藥後出現(xiàn)，主要是由於DA補(bǔ)充過(guò)度，須減量。少數(shù)病人長(zhǎng)期用藥後，可出現(xiàn)“開(kāi)關(guān)現(xiàn)象”，表現(xiàn)為突然多動(dòng)不安(開(kāi))，轉(zhuǎn)為全身產(chǎn)生強(qiáng)直不動(dòng)(關(guān))，二者交替出現(xiàn)，機(jī)制尚無(wú)完滿解釋。4．精神障礙與DA過(guò)度興奮中腦一邊緣系統(tǒng)DA受體有關(guān)。2.外周多巴脫羧酶抑制劑卡比多巴（Carbidopa）、芐絲肼（benserazide）外周多巴脫羧酶抑制劑，不易通過(guò)血腦屏障。單獨(dú)應(yīng)用對(duì)PD無(wú)治療作用，主要與左旋多巴按一定比例製成複方左旋多巴製劑供臨床應(yīng)用，可增加血和腦內(nèi)L-dopa達(dá)3~4倍。信尼麥（sinemet,心寧美） 左旋多巴:卡比多巴=10:1（100mg:10mg）複方芐絲肼（美多巴，Madopar） 左旋多巴:芐絲肼=4∶1（100mg∶25mg）聯(lián)合用藥主要優(yōu)點(diǎn)

1、提高左旋多巴療效（增效）

2、減少外周副作用（減毒）

3、減少左旋多巴用量（70~80%）3.COMT抑制劑

L-dopa代謝有兩條途徑：

L-dopaDA3-OMD（3-O-甲基多巴）而3-OMD又可與L-dopa競(jìng)爭(zhēng)轉(zhuǎn)運(yùn)載體而影響L-dopa的吸收和進(jìn)入腦組織（生物利用度降低）-co2COMT

硝替卡朋（nitecapone）托卡朋（tocapone）安托卡朋（entocapone）可增加紋狀體中L-dopa和DA。當(dāng)與卡比多巴合用時(shí)，只抑制外周COMT，增加L-dopa生物利用度，而不影響腦內(nèi)COMT（不易通過(guò)血腦屏障）?？估夏晷园V呆藥

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