AnalgesicsZhang,BinPaintransmissionpathwayNoxiousstimuliPGsK+、H+BK5-HTPrimaryafferentfibresnociceptorSpinalcordLimbicsystemSomato-sensorycortexmoodeffect,theaffectiveaspectofpainthesensoryaspectofpainDorsalhornseverepainOpioids(eg.Morphine)inflammatorypain

NSAIDs(eg.Aspirin)localanaesthesia

smoothmusclecolicanginapectorisinducedbycoronaryarteryspasm

trigeminalpainDrugtreatmentofpaincholinoceptor-blockingdrugsvasodilatordrugs(eg.Nitroglycerin)

CarbamazepineLocalanaestheticsCortexSpinalcordDorsalhornVentralcaudalthalamusPGsK+、H＋BK5-HTNSAIDsOpioidsSitesofactionofdifferentdrugsNon-opioidformildpainPainpersistingorincreasingWeakOpioidsformoderatepainPainpersistingorincreasingStrongOpioidsforseverepainFreedomfromcancerpainNSAIDse.g.aspirin,acetaminophene.g.codeine，tramadole.g.morphine,fentanyl,methadoneWHOanalgesicladder

Threestepsanalgesiatherapyforcancerpatients

opioidanalgesics

(narcoticanalgesic,addictiveanalgesics)

Opium(阿片)

isthedriedexudateobtainedfromunripeseedpodsofthepoppyPapaver

somniferum,containingmorphine,codeine,andotheralkaloidsubstances.Opiate

(阿片劑)meansthatasubstanceisextractedfromopiumorissimilarinstructuretonaturalsubstancespresentinopium.Opioid

(阿片樣物質(zhì))isatermthatdesignatessubstancesthatarenotderivedfromopium.Itrefersparticularlytoopioidpeptides,i.e.endogenouscompoundsthatbindtoopioidreceptorsandmimictheeffectofmorphine-likecompounds.WidelyusetermOpium

Theflowerofpapaver

TheplantofjoyOpium(阿片)Opiate(阿片劑)MorphineCodeinePapaverine

……Opioid(阿片樣物質(zhì))Endogenousopioidpeptides:

Enkephalins

Endorphins

Dynorphins

Nociceptinandnocistatin

Endomorphin-1/2Others:1992~1993197319621975

analgesicsiteislaminaeIIIofperiventricularandperiaqueductalgrayareaputforward“receptors”foropiateanalgesicsinbrainisolatedthefirst“endogenousopioidpeptide”andnamedenkephalinClonedopioidreceptors:μ

κ

δResearchhistoryExtracellularCytoplasmicNH2HOOCOpioidreceptorsGprotein-coupledreceptors

ThecellularmechanismsPresynapticinhibition:activationofopioidreceptorsonpresynapticnerveterminals.Closeavoltage-gatedCa2+channel,decreaseCa2+input,andtherebyreducetransmitterrelease(Ach,NA,Glu,5-HT,P).Postsynapticinhibition:activationofpostsynapticopioidreceptors.OpenK+channelsonpostsynapticneurons,increaseK+output,andtherebycausehyperpolarizationandthusreducepostsynapticneuronalexcitability.SpinalcordDorsalhornenkephalinsCa2+Ca2+PresynapticterminalPostsynapticneuronenkephalins

enkephalins

PresynapticterminalPostsynapticneuronThecellularmechanismsmorphinePharmacologicalactionsCNSSmoothmuscles3.Cardiovascularsystem4.Others1.CNSeffects:principaleffectsAnalgesiaSedation&euphoriaRespiratorydepressionCoughsuppressionOthers:miosis,nausea,hormone

2.

Smoothmusclesystem

Gastrointestinalsystem

BiliarytractUrinarysystemgenitalsystem

orthostatichypotensionMechanisms:

releaseofhistaminevasomotorcenter3.Cardiovascularsystem(1)peripheralarterialandvenousdilatation(2)intracranialpressuresecondarytorespiratorydepressionClinicalusesAnalgesiaCardiacasthmaAntidiarrheaAntitussiveAnalgesia(severepain)

terminalcancermyocardialinfarctionrenalandbiliarycolic(atropine)trauma,burn,operationatregulartimeandquantityPulmonaryedema

dyspneaAcuteleftventriculardysfunctionshortofbreath(respiratorycenter)

CO2retentionanxietyanddistressAlveolarhypoventilationmorphineReducecardiacpreloadandafterloadReducethesensitivityoftherespiratorycentertoincreasedCO2SedationCardiacasthma

andmorphinetherapy

2.CardiacasthmaOpioidanalgesicdrugsMorphine(嗎啡)Codeine(可待因)Pethidine(哌替啶)Methadone(美沙酮)Fentanyl(芬太尼)Tramadol(曲馬多)absorptionexcretiondistributionfreedrugoralFirstpasseliminationsc.im.bloodliverplacentalfetuslittlecrosstheBBB,butenoughforitsfunctionmetabolismmorphine-6-glucuronidekidney,

breastiv.activeBioavailability25-30%Morphine美施康定（硫酸嗎啡控釋片）

1.強效，作用持續(xù)12hr。主要用于晚期癌癥患者第三階梯止痛。

2.抑制呼吸，可引起惡心、嘔吐、便秘及排尿困難，長期應(yīng)用可產(chǎn)生耐受性、身體依賴性和成癮性。Codeine1.hasahigher

oral

efficacy,demethylationtomorphine2.lowerefficacythanmorphine3.mainlyuseasantitussive,severe

drycough.

聯(lián)邦止咳露：麻黃堿+可待因+氯苯那敏+氯化銨注意事項抑制支氣管腺體分泌，使痰液粘稠難以咳出，不宜用于痰多粘稠者。連續(xù)應(yīng)用不宜

2周，因久用可成癮。7歲兒童禁用。Pethidine(dolantin)SyntheticsubstanceWeakerpotencythanMorphine,noantitussiveactionMoresedative,morerapidonsetandshorterduration(2-4h)thanmorphineMetabolite:normeperidine

convulsion

LyticcocktailMethadone

1.syntheticcompound,oralbioavailabilityis80%2.milderphysicalabstinencesyndrome3.routinelyusedindetoxificationofthemorphineandheroinaddictsFentanyl1.moreanalgesicpotentcythanmorphine:100times2.

rapidonsetandshortdurationofaction3.

fentanyl,alfentanil,remifentanil:adjunctivedrugforgeneralanaesthesia

4.breakthroughcancerpain:癌癥患者的突發(fā)性疼痛，突然出現(xiàn)，不能被患者的常規(guī)疼痛治療方案緩解。口腔經(jīng)粘膜芬太尼拘櫞酸鹽

(OralTransmucosal

FentanylCitrate,OTFC)FentanyllollipopACTIQ

芬太尼口腔粘膜貼片

(Fentanylsublingualtablets)ABSTRAL

適應(yīng)證：年齡18歲以上，已連續(xù)24小時使用阿片類藥，對高劑量阿片類藥物耐受者。TramadolAtypicalopioidWeakμ

activation,alsointeractswithmonoaminergicsystemsAlternativetotraditionalopioidanalgesics(improvedsideeffectprofile)1.Tolerance2.Dependence

physicaldependence：withdrawalsyndrome

psychologicaldenpendence:

compulsivedrug-seekingbehaviorWhenareusedforthereliefofpain,toleranceanddependencearenotsignificantandprevalentproblemAdverseeffects3.Generaladverseeffects1Constipation5Respiratorydepression2Biliarycolic6Posturalhypotension3Nauseaandvomiting7Increasedintracranialpressure4Urinaryretention8Dysphoria4.AcuteMorphinePoisoningNaloxone1.competitivefullantagonistforopioidR(μ)2.Uses:opioidoverdose3.shortt1/2(1h),repeatedinjectionsContraindications

obstetriclabor,breastingperiod

obstructiveairwaydisease,bronchialasthma

headinjuriesseriouslyimpairedhepaticorrenalfunctionModeofadministrationofopioidsOraladministrationSublingualadministrationRectaladministrationIntravenousadministrationIntramuscularadministrationIntrathecalandepiduraladministrationTransdermalpatchadministrationPatientControlledAnalgesia

(病人自控鎮(zhèn)痛，PCA)Non-opioidanalgesicsIntroduction

Non-steroidalanti-inflammatorydrugs(NSAIDs)Antipyretic-analgesicandanti-inflammatorydrugsAspirin-likedrugs

共同作用機制:

Inhibitionofcyclo-oxygenaseenzymes(COX),andresultinginhibitionofthesynthesisofprostaglandins(PGs)花生四烯酸的代謝途徑及主要代謝產(chǎn)物的生物活性保護胃粘膜比較COX-1&COX-2生物學(xué)作用

COX-1COX-2類型結(jié)構(gòu)型(血管，腎臟，胃)誘導(dǎo)型作用保護胃粘膜調(diào)節(jié)血小板聚集發(fā)熱、疼痛、致炎調(diào)節(jié)外周血管阻力調(diào)節(jié)腎血流量作用類型生理性作用病理性作用NSAIDs

不良反應(yīng)解熱、鎮(zhèn)痛、抗炎【COXisoforms:】

COX-1COX-2productionConstitutiveInduciblefunctionsPhysiological：GIprotectionRegulationofplateletaggregationRegulationofkidneybloodflowRegulationofperipheralvascularresistance

Pathological：

InflammationPainFeverNSAIDseffectsSideeffectsTherapeuticeffects【ThreemajoractionsofNSAIDs】

AntipyreticeffectAnalgesiceffect

Anti-inflammatoryeffect

heatproductionheatdissipationpathogenandtoxinsneutrophilsendogenouspyrogens(ILs,TNF)setpointbodytemperaturecox

NSAIDsPGE2

(hypothalamus)AntipyreticeffectCharacteristics

①

Central

②“Elevated”temperature—reduced“Normal”temperature—noinfluenceClinicalapplications

symptomatictreatmentPaintransmissionpathwayNoxiousstimuliPGsK+、H+BK5-HTnociceptorSpinalcordLimbicsystemSomato-sensorycortexDorsalhornNSAIDsAnalgesiceffectCharacteristics①Peripheral(probablyalsoinhibitpainstimuliatasubcorticalsite)②mildtomoderatepain③NoaddictionorrespiratoryinhibitionClinicalapplications

①havegoodeffectsonchronicdullpain—headache,toothache,neuralgia,musclepain,arthralgia,dysmenorrhea

②arenotveryeffectivefortraumaticpain,severevisceralpain—myocardialinfarctionorrenalorbiliarycolic

Threestepsanalgesiatherapyforcancerpatients

Drug

location

mechanism

characteristics

representative

Analgesics

NSAIDs

CNSperiphery(+)opiumreceptor(-)PGsynthesismorphineaspirinpowerfuldullandsharppaininflammatorypaincauseeuphoriaandaddictionrespiratoryinhibitionmoderate

chronicdullpaincancerpainnotaddictive

no

respiratoryinhibition比較NSAIDs和嗎啡的鎮(zhèn)痛作用Mechanismofinflammation:

phospholipidsinjuryfactorPLA2

neutrophilic

arachidonicacidgranulocyte

cytokinesinduceCOX-2

(ILs,TNF)

PGs

inflammation(redness,swelling,heatandpain)Anti-inflammatoryeffect:AccordingtoselectivityforCOX:

①Non-selectiveCOXinhibitors ②SelectiveCOX-2inhibitorsAccordingtochemicalstructures:

【NSAIDsclassifications】化學(xué)分類非選擇性COX抑制藥選擇性COX-2抑制藥水楊酸類阿司匹林苯胺類對乙酰氨基酚吲哚類吲哚美辛依托度酸芳基丙酸類布洛芬芳基乙酸類雙氯芬酸烯醇酸類吡羅昔康美洛昔康吡唑酮類保泰松烷酮類奈丁美酮二芳基吡唑類塞來昔布二芳基呋喃酮類羅非昔布磺酰苯胺類尼美舒利

(1)Antipyretic-analgesiceffect(2)Anti-inflammatoryandantirheumaticeffects(3)Plateleteffect

Aspirin(Acetylsalicylicacid)

PGI2TXA2

Plateleteffect:

thrombosisinhibitionAATXA2PGI2

(-)plateletaggregationvasculardilation(+)platelet

aggregationvascularconstriction血小板血管內(nèi)皮

AATXA2PGI2

(-)plateletaggregationvasculardilation(+)platelet

aggregationvascularconstriction血小板血管內(nèi)皮

Aspirin小劑量thrombosisinhibition:AATXA2PGI2

(-)plateletaggregationvasculardilation(+)platelet

aggregationvascularconstriction血小板血管內(nèi)皮

Aspirin大劑量

AspirinirreversiblyacetylatesandblocksplateletCOX1→TXA2biosynthesis(-)→plateletaggregation(-)→thrombosis(-).TXA2↓LowdosethrombosisisinhibitedPGI2notaffected

TXA2↓HighdoseunbeneficialforthrombosisinhibitionPGI2↓Clinicaluses:

①lowdose(40~100mg)isrecommended

②preventthrombosis:

cardiacorbrainischemicdiseasesangioplasty(血管成形術(shù))coronaryarterybypassgrafting

③Pregnancy-inducedhypertensionsyndrome(PIH)【Adverseeffects】GastrointestinalsideeffectsDisturbanceofbloodcoagulationSalicylismreactionHypersensitivityreactionsReye’ssyndromeNephrotoxicity

SalicylismreactionLargedosage(>5g/d)headache,vertigo,nausea,vomiting,tinnitus,decreasedvisionandhearing；hyperpnea,acid-basedisturbance,insanity.Therapy:①aspirinmus