AnalgesicsZhang,Bin1-AnalgesicsZhang,Bin1-paina.Acutepain(sharppain)b.Chronicpain(dullpain)2-paina.Acutepain(sharppain)PaintransmissionpathwayNoxiousstimuliPGsK+、H+BK5-HTPrimaryafferentfibresnociceptorSpinalcordLimbicsystemSomato-sensorycortexmoodeffect,theaffectiveaspectofpainthesensoryaspectofpainDorsalhorn3-PaintransmissionpathwayNoxioseverepainOpioids(eg.Morphine)inflammatorypainNSAIDs(eg.Aspirin)localanaesthesia

smoothmusclecolicanginapectorisinducedbycoronaryarteryspasm

trigeminalpainDrugtreatmentofpaincholinoceptor-blockingdrugsvasodilatordrugs(eg.Nitroglycerin)

CarbamazepineLocalanaesthetics4-severepainOpioids(eg.MorphiCortexSpinalcordDorsalhornPGsK+、H＋BK5-HTNSAIDsOpioidsSitesofactionofdifferentdrugs5-CortexSpinalcordDorsalho

opioidanalgesics

(narcoticanalgesic,addictiveanalgesics)

6-opioidanalgesics

(narcotica

Opium(阿片)

isthedriedexudateobtainedfromunripeseedpodsofthepoppyPapaversomniferum,containingmorphine,codeine,andotheralkaloidsubstances.Opiate

(阿片劑)meansthatasubstanceisextractedfromopiumorissimilarinstructuretonaturalsubstancespresentinopium.Opioid

(阿片樣物質(zhì))isatermthatdesignatessubstancesthatarenotderivedfromopium.Itrefersparticularlytoopioidpeptides,i.e.endogenouscompoundsthatbindtoopioidreceptorsandmimictheeffectofmorphine-likecompounds.Widelyuseterm7-Opium(阿片)isthedriedexudaOpium

TheflowerofpapaverOpium(阿片)8-OpiumTheflowerofpapaveOpiate(阿片劑)MorphineCodeinePapaverine(罌粟堿)

……9-Opiate(阿片劑)Morphine9-structure-activityrelationship海洛因嗎啡納洛酮OH10-structure-activityrelationshiOpioid(阿片樣物質(zhì))Endogenousopioidpeptides:

Enkephalins

Endorphins

Dynorphins

Orphanin11-Opioid(阿片樣物質(zhì))Endogenousopioi1992~197319621975

analgesicsiteislaminaeIIIofperiventricularandperiaqueductalgrayareaputforward“receptors”foropiateanalgesicsinbrainisolatedthefirst“endogenousopioidpeptide”andnamedenkephalinClonedopioidreceptors:μ

κ

δ

Researchhistory12-1992~197319621975analgesicsiExtracellularCytoplasmicNH2HOOCOpioidreceptorsGprotein-coupledreceptors

13-ExtracellularCytoplasmicNH2HOOOpioidreceptorssupraspinalanalgesia,

sedation,euphoria,dependence,respiratorydepression,miosisspinalanalgesia,sedationdysphoria(煩躁不安),hallucinationspinalanalgesia,sedation,euphoria,dependence,

respiratorydepression

:

:

::14-OpioidreceptorssupraspinalanSpinalcordDorsalhornenkephalinsCa2+Ca2+PresynapticterminalPostsynapticneuronenkephalins

Thecellularmechanisms15-SpinalcordDorsalhornenkeenkephalinsPresynapticterminalPostsynapticneuronThecellularmechanismsmorphine16-enkephalinsPresynapticterminMorphine+receptorsOpenK+channelCloseCa2+channel抑制沖動(dòng)傳導(dǎo)Ach,NA,Glu,5-HT,Prelease

presynapticpostsynapticExcitability

Thecellularmechanisms17-Morphine+receptorsOpenK+chThecellularmechanismsPresynapticinhibition:activationofopioidreceptorsonpresynapticnerveterminals.CloseCa2+channel,decreaseCa2+input,andtherebyreducetransmitterrelease(Ach,NA,Glu,5-HT,P).Postsynapticinhibition:activationofpostsynapticopioidreceptors.OpenK+channelsonpostsynapticneurons,increaseK+output,andtherebycausehyperpolarizationandthusreducepostsynapticneuronalexcitability.18-ThecellularmechanismsPresynaDescendingpaininhibitorypathwaysLocalinhibitoryinterneuroninspinalcordPainAscendingpaintransmissionpathwaysEndogenousopioidpeptides19-DescendingpaininhibitorypatPharmacologicalactionsCNSSmoothmuscles3.Cardiovascularsystem20-PharmacologicalactionsCNS21.CNSeffects:principaleffectsAnalgesiaSedation&euphoriaRespiratorydepressionCoughsuppressionOthers:miosis,nausea,hormone

21-1.CNSeffects:principaleffec(1)Analgesia

insensitive:musclespasmspain,deafferentationpainpartiallysensitive:nervepain,CNScompressioninjury,bonecancersensitive:myocardialinfarction,othertypesofcancersrelieveanxietyanddistress,toleranceofpain1.CNS灼性神經(jīng)痛(causalgia)系指在明確的神經(jīng)損傷后，與損傷神經(jīng)支配范圍相一致的區(qū)域內(nèi)出現(xiàn)的以劇烈灼樣疼痛主要癥狀，表現(xiàn)為痛覺(jué)異常、痛覺(jué)過(guò)敏、交感神經(jīng)機(jī)能障礙、血流障礙、出汗異常、骨、肌肉萎縮，有時(shí)表現(xiàn)出水腫性改變的慢性頑固性疼痛綜合征。22-(1)Analgesia1.CNS灼性神經(jīng)痛(caus(2)Sedationandeuphoria

drowsinessandcloudingofmentation

sleepinducedandarousedeasily

Euphoria

asenseofcontentmentandwell-being

Sedation:themainreasonfordrugabuseSite:limbicsystemandlocusceruleus23-(2)Sedationandeuphoria

respiratoryrate，tidalvolume

themostcommoncauseofdeathfromacutepoisoninginfluencedbystimulusMechanisms:

thesensitivityofrespiratorycentertoincreasedCO2tension

(3)Respiratorydepression24-respiratoryrate，tidalv(4)Cough

suppressionantitussiveeffectbyinhibitingcoughcentercodeine

(5)OtherCNSeffectsMiosis:

pinpointpupilsNauseaandvomiting:

CTZmusculartension:限制

胸廓活動(dòng),影響呼吸Hormone:

↓LH,FSH,

↑prolactin,GH,ADH25-(4)Coughsuppressionantituss2.Smoothmusclesystem

GastrointestinalsystemBiliarytractUrinarysystemgenitalsystem

26-2.Smoothmusclesystem26-(1)Gastrointestinaltract

delayspassage

secretionofdigestiveglandindigestioncentralinhibition

acallofnaturedefecationreflexGITtone

GITmotilityabsorptionofwaterconstipation27-(1)Gastrointestinaltractde

biliarycolic

constrictbiliarysmoothmuscleconstrictOddi'ssphincterpressureinthebiliarytract(2)Biliarytract28-biliarycolicconstrictbilia(3)Urinarytractconstrict

ureteralsmoothmusclebladdersphinctertoneurinaryretention

uterinetone

prolonglabor

(4)Genitaltract29-(3)Urinarytractconstricture

orthostatichypotensionMechanisms:

releaseofhistaminevasomotorcenter3.Cardiovascularsystem(1)peripheralarterialandvenousdilatation(2)intracranialpressuresecondarytorespiratorydepression30-orthostatichypotenClinicalusesAnalgesiaCardiacasthmaAntidiarrheaAntitussiveCombinedanesthesia31-ClinicalusesAnalgesia31-Analgesia

terminalcancermyocardialinfarctionrenalandbiliarycolic(atropine)trauma,burn,operationatregulartimeandquantity32-AnalgesiaatregulartimeandqPulmonaryedemadyspneaAcuteleftventriculardysfunctionshortofbreath(respiratorycenter)

CO2retentionanxietyanddistressAlveolarhypoventilationmorphineReducecardiacpreloadandafterloadReducethesensitivityoftherespiratorycentertoincreasedCO2SedationCardiacasthma

andmorphinetherapy

2.Cardiacasthmaoxygenconsumption

33-Pulmonaryedemadyspne(1)Mechanisms:①

peripheralarterialandvenousdilationpreloadandafterloadpulmonaryedema②

sedation

anxietyanddistress

oxygenconsumption

③

thesensitivityofrespiratorycenterto

CO2

shortnessofbreathCardiacasthma34-(1)Mechanisms:CardiacasthmaOpioidanalgesicdrugsMorphine(嗎啡)Heroin(海洛因，二醋嗎啡)Codeine(可待因)Pethidine(哌替啶)Methadone(美沙酮)Fentanyl(芬太尼)buprenorphine(丁丙諾啡)Tramadol(曲馬多)35-OpioidanalgesicdrugsMorphineMorphine1803Serturnerisolatedapureactivealkalinesubstancefromopium.Heproposedthename“morphine”foritafterMorpheus.36-Morphine1803SerturnerabsorptionexcretiondistributionfreedrugoralFirstpasseliminationsc.im.bloodliverplacentalfetuslittlecrosstheBBB,butenoughforitsfunctionmorphine-6-glucuronidekidney,

breastiv.Bioavailability25-30%metabolism37-absorptionexcretiondistributi美施康定（硫酸嗎啡緩釋片）

1.強(qiáng)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(zhǎng)期應(yīng)用可產(chǎn)生耐受性、身體依賴性和成癮性。38-美施康定（硫酸嗎啡緩釋片）38-Heroin(diamorphine)Semisyntheticsubstance,prodrugofmorphineMorelipidsolublethanmorphineMorerapidonset德國(guó)拜爾公司heroin在德文中意為英雄萬(wàn)能藥藥品轉(zhuǎn)變?yōu)槎酒钒追?9-Heroin(diamorphine)SemisyntheCodeinehigher

oral

efficacy2.lowerefficacythanmorphine3.useasantitussive,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(xiàng)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。40-Codeinehigheroralefficacy注意Pethidine(dolantin)WeakerpotencythanMorphine,noantitussiveactionMorerapidonsetandshorterduration(2-4h)thanmorphineMetabolite:normeperidine

convulsion

Lyticcocktail41-Pethidine(dolantin)WeakerpotMethadone

1.syntheticcompound,equalanalgesiatomorphine2.milderabstinencesyndrome3.routinelyusedindetoxification

ofmorphineaddicts42-Methadone1.syntheticcompoFentanyl1.moreanalgesicpotentcythanmorphine:2.

rapidonsetandshortdurationofaction3.

fentanyl,alfentanil,remifentanil:adjunctivedrugforgeneralanaesthesia

4.Fentanyl+

Droperidol(氟哌利多):

neuroleptanalgesia(神經(jīng)阻滯鎮(zhèn)痛術(shù))Usedforminorsurgery5.breakthroughcancerpain:43-Fentanyl1.moreanalgesicpot口腔經(jīng)粘膜芬太尼拘櫞酸鹽

(OralTransmucosalFentanylCitrate,OTFC)FentanyllollipopACTIQ

芬太尼口腔粘膜貼片

(Fentanylsublingualtablets)ABSTRAL

芬太尼透皮貼劑

(Fentanyltransdermalsystem)多瑞吉

highlipid-soluble44-口腔經(jīng)粘膜芬太尼拘櫞酸鹽

(OralTransmucosaPentazocineκ,

agonist,μpartialagonist

increasebloodpressureandcausetachycardia(

NA)weakactiononμ:

littleaddictiveliabilityprecipitatewithdrawalsyndromeofmorphineabuser列入非麻醉藥品。但久用仍會(huì)成癮！analgesiaandrespiratorydepression:weaker45-Pentazocineκ,agonist,μpaTramadolAtypicalopioid:weakμ

activation,alsointeractswithmonoaminergicsystems(inhibitNAand5-HTreuptake)Alternativetotraditionalopioidanalgesics2008年1月1日國(guó)家將曲馬多列為精神藥品進(jìn)行管理46-TramadolAtypicalopioid:weak延胡索乙素和羅通定羅通定為左旋體的延胡索乙素，是有效部分。鎮(zhèn)靜安定鎮(zhèn)痛和中樞性肌肉松弛作用解熱鎮(zhèn)痛抗炎藥＜鎮(zhèn)痛作用＜哌替啶，鎮(zhèn)痛作用與阿片受體及前列腺素均無(wú)關(guān)無(wú)明顯成癮性口服后10-30min起效，維持2-5h，對(duì)慢性持續(xù)性鈍痛效果好不影響產(chǎn)程47-延胡索乙素和羅通定羅通定為左旋體的延胡索乙素，是有效部分。41.ToleranceAdverseeffects

largedosesatshortintervalsreadilycrosstolerancefullagonist:moreobvious48-1.ToleranceAdverseeffects48-2.Dependence

physicaldependence：withdrawalsyndrome

psychologicaldenpendence:

compulsivedrug-seekingbehaviorAdverseeffects49-2.Dependencephysicaldepend身體依賴性精神依賴性渴求戒斷綜合征強(qiáng)迫性用藥依賴性藥物濫用50-身體依賴性精神依賴性渴求戒斷綜合征強(qiáng)迫性藥物濫用（drugabuse）:非醫(yī)療目的反復(fù)使用具有依賴性潛能的精神活性物質(zhì)。體驗(yàn)該物質(zhì)產(chǎn)生的特殊精神效應(yīng)。

藥物誤用(drugmisuse)：用藥適應(yīng)證選擇不當(dāng)/用量過(guò)大、療程過(guò)長(zhǎng)等錯(cuò)誤用藥行為。51-藥物濫用（drugabuse）:非醫(yī)療目的反復(fù)使用具有依

rhinorrheaLacrimation

chills

gooseflesh(piloerection)yawningsweatingmuscularachevomitingdiarrhea

anxiety

hostilityhyperventilation

Withdrawal

syndromeofOpioid52-rhinorrheaLacrimation3.Generaladverseeffects1Constipation5Respiratorydepression2Biliarycolic6Posturalhypotension3Nauseaandvomiting7Increasedintracranialpressure4Urinaryretention8Dysphoria53-3.Generaladverseeffects1

Clinicaloverdose

Accidentalpoisoninginaddicts

30mg

–toxicthreshold120mg–lethalthresholdPinpointpupilsDeeprespiratorydepressionComaTreatments:

EstablishpatentairwayAdequateventilation

Naloxone

iv.Thetriad：4.AcuteMorphinePoisoning54-ClinicaloverdoseTreatments:TNaloxone1.competitivefullantagonistforopioidR(μ)2.opioidoverdose:reversescomaandrespiratorydepression3.differentialdiagnosisinmorphineabuser:precipitateswithdrawalsymptom4.shortt1/