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镇痛药Analgesics北京协和医学院基础医学院药理学系叶菜英镇痛药AnalgesicsPrimaryeffectonCNS，eliminateoreasepainselectively，tolessenthenervousofpatients，theseagentsrelievepainwithoutproducingalossofconsciousness。Theyareusedprimarilytorelieveacuteandchronicitypainofanyorigin.镇痛药AnalgesicsIthasbeenknowforcenturiesthatextractsoftheopiumpoppycanbeusedtorelievepainandtreatdiarrhea。In1806,MorphinewasfirstisolatedfromthejuiceoftheopiumpoppybyGermanpharmacistFriedrichSertürner；Duringthe1950s,aseriesofmorphine-likepotentanalgesicsweresynthesized,suchaspethidine,methadone,etorphine,fentanyl.镇痛药AnalgesicsPainisacomplexsubjectivesensation，andakindofprotectiveresponsewhenorganismsufferthenociceptivestimulus;Painisalsothebasisforthedoctorsdiagnosingdiseases。Itusuallyaccompanyanxiety,dread,horror,discomfortandsoon,tocausethepatientsdisorder,evenshock。Acutepainthathasbeenmadeadefinitediagnosis,shoulduseanalgesicsimmediately;Butitisinadvisabletousenarcoticanalgesicswhenapainhasn`tbecertified，inordertoavoidmisdiagnosis.阿片类药物OpiumClassification：chemicalconstitutionaffinityandintrinsicactivityAgonists：morphine,Pethidine,adanton……Antagonists：Naloxone,NaltrexonePartialagonist：Pentazocine，NalorphinePhysiologicaldisposition：takeorally,injection→passthroughthebloodbrainbarrier→hepaticmetabolism→renalexcretionHOHOONCH3吗啡morphine阿片(opium)生物碱类(opiatealkaloids)Morphine(1806，10%ofopiumtotalbase）Codeine（1832,methyl-morphine）Heroin（1874,acetomorphine，powerfuladdictivedrugs）PhenanthreneIsoquinolinePapaverine阿片生物碱类镇痛药阿片生物碱类罂粟(poppy）FreshcapsuleofopiumpoppyCutcapsuleshowinglatexexudingfromcut镇痛药阿片生物碱类罂粟(poppy）镇痛药阿片生物碱类含阿片生物碱类植物：罂粟吗啡morphineChemicalconstitutionStructuralfeatures17positionRis－CH3……agonists17positionRis－CH2CH＝CH2……antagonists7positionNCH2CH－……inreversiblecompoundMechanismsandEffects阿片受体opioidreceptorIn1973,threeAmericanlabsdicoveredthereceptoratthesametime.Existoncellmembrane,glycoprotein。HighaffinitySaturabilityStereospecificityDistributionofdefiniteareaSpecificityantagonistsTypesandeffectsμ(mu)δ(delta)κ(kappa)AnalgesiaabovespinalcordlevelspinalcordlevelspinalcordlevelRespiratorydepression＋＋＋＋＋Pupilmyosismyosis－Stomachintestinedecreasedecrease－SMspasm＋＋＋＋－Psychoactivityeuphoria＋＋euphoria＋＋restlessness＋sedative＋＋sedative＋＋sedative＋Physicaldependence＋＋＋＋＋MechanismsandEffectsendopioidpeptideRegulatealgesthesiaEndogenouspaincontrolsystemEffectsonangiocarpyandgastrointestinaltractMechanism：InhibitsensorynerveendingtoreleaseSP，thuspreventingtransmissionofpainimpulsestoCNS.EnkephalinandpainWhenapersonisinjured,painimpulsestravelupthespinalcordtothebrain,whichthenreleasesendorphinsandenkephalins.Enkephalinsblockpainsignalsinthespinalcord,whileendorphinsarethoughttoalleviatepainprincipallyatthebrainstem.MechanismsMorphineItbindstoopioidrecepterswhicharediscretelydistributedinthehumanbrain,exertsitsprincipalpharmacologicaleffectlikeinternalopioidpeptidesCerebralganglion——analgesiaNucleusceruleus——euphoriaLimbicsystem——emotionalreaction、SedationNTS——tussis、stomachintestinePharmacologicaleffectofMorphineCNS：Analgesia、SedationInhibitionofcoughreflexRespiratorydepressionEuphoriaMiosis、NauseaandvomitingPharmacologicaleffectofMorphineGastrointestinalandbiliaryeffectsConstipation(increasedintestinalsmoothmuscletone)IncreasedbiliarysphinctertoneandpressurePharmacologicaleffectofMorphineCardiovasculareffects:PosturalhypotensionandvasodilationDecreasedmyocardialoxygendemandPharmacologicaleffectofMorphineImmunesystemeffects:ImmunesuppressionInhibitproliferationoflymphocytes,reducesecretionofcytokines.InhibittheimmunereactionwhichinducedbyHIVprotein.吗啡morphineClinicalapplicationAnalgesia：acutesharppain,serioustrauma、adustum,myocardialinfarct,terminalcancerCardiacasthmaATAntidiarrhealAombinedanesthesia吗啡morphineUntowardreactionRespiratorydepressionAddictioneuphoria—morphineisahighlyaddictivesubstance,bothpsychologicallyandphysically.withdrawalsyndrome—stimulation、insomnia、lacrimation、perspiration、thrill、vomit、diarrhea、collapse、unconscious。(feelingsof“euphoria”,ambition,nervousness,relaxation,drowsiness,orsleepiness)morphine(吗啡)一词来源于西腊文Morpheus(梦之神)。镇痛药阿片生物碱类吗啡不良反应不良反应反复应用（一般剂量连用1w左右）引起成瘾！镇痛药阿片生物碱类成瘾性镇痛药阿片生物碱类成瘾性戒断综合症状SYMPTOMSOFWITHDRAWAL腹泻出汗抑郁震颤衰弱肌痉挛寒战渴求药物头痛、镇痛药阿片生物碱类鸦片战争镇痛药阿片生物碱类吗啡成瘾机制吗啡成瘾机制Nucleusceruleus:intensiveopioidandNAreceptorsMorphineandendogenousopioidpeptidesinhibitthefiringsofnucleusceruleus，thefiringsofaddictsaredecreasesignificantly.Thefiringsofnucleusceruleusareincreasewhenaddictsstopusingmorphine,naergicneuronsarehyperfunction，withdrawalsymptomappearance.镇痛药人工合成类哌替啶哌替啶pethidine(dolantin,度冷丁）PharmacologicactionApplicationsuccedaneumofmorphineanalgesia、preanestheticmedicationandinducedhibernation、cardiacasthmaItinteractspredominantlywiththeμ-opioidreceptor.CNSeffectsissimilarwithmorphinebutweakerthanmorphine,actiontimeis2~4hlessthanmorphine.Addictionisweakerthanmorphine.度冷丁dolantin（哌替啶pethidine）ArtificialUntowardreactionAddictionRespiratorydepression可待因codeine（3-o-methylderivativeofmorphine）Characteristics：A