麻醉性镇痛药专家讲座

ReviewNeurolepticdrugs1麻醉性镇痛药第1页2Chapter20NarcoticAnelgesics麻醉性镇痛药第2页ObjectivesUnderstandthepharmacologicaleffects,mechanismofactions,clinicaluses,aswellasadversedrugreactionsofmorphine.Identifythetherapeuticeffectsandadversedrugreactionsofcodeineandpethidine.

麻醉性镇痛药第3页SectiononeIntroduction4麻醉性镇痛药第4页5麻醉性镇痛药第5页1.2Analgesics

DefinitionDrugsthatselectivelyinhibittheperception(sensation)ofthepainClassification

1-Peripheral:-Causal:

Atropine,

NSAIDs-Non-causal2-Central:-Narcoticanalgesics麻醉性镇痛药第6页Peripheralanalgesics

Causal

-TreatthecauseExample:Atropine(antispasmodic)Aspirin

Non-causal-NottreatthecauseExamples:1-Localanaesthetics(forsuperficialtumor)2-Counter-irritant(applypainthatcounteractormasktheoriginalonee.g.acupuncture)麻醉性镇痛药第7页Narcotics

NSAIDsExamplesMorphineAspirinSiteofactionCortex&thalamusPeripheralAntagonistNaloxoneNoantagonistUsesSever&deeppaine.g.cancer,MI&anginalpainDullpaine.g.headache,toothache&backachePotencyHighLowSideeffectAddictionNoaddiction.↑inbleedingtendency&ulcerMechanismstimulateopiatesreceptors(m,k,d)andreliefthepainInhibitsPGsynthesisbyinhibitionofCOX-2麻醉性镇痛药第8页 Theactionslistedforantagonistsareseenwiththeantagonistalone.Allthecorrelationsinthistablearebasedonstudiesinratsandmice,whichoccasionallyshowspeciesdifferences.麻醉性镇痛药第9页10Sectiontwo

Morphine麻醉性镇痛药第10页Naturallyoccurringinthepoppy(16%)-OnlyneedstobeisolatedVerystrongpainrelieverbutalsoveryaddictive(2ndtoHeroin)Usuallyinjectedbutcanbesmoked,sniffedorswallowedCommonlyusedinhospitals2.1Introduction麻醉性镇痛药第11页121)3位-OHH被-CH3取代，中枢抑制作用↓。如：可待因(codeine)2)3位和6位-OHH同时被-COCH3取代，中枢抑制作用↑。如：海洛因(heroin)3)17位-CH3被-CH2CH=CH2取代，则变为吗啡受体部分激动药，如：丙烯吗啡(nalorphine)。若同时将6位-OH变为=O，则变为吗啡受体完全拮抗药，如：纳洛酮(naloxone)2.2构效关系麻醉性镇痛药第12页麻醉性镇痛药第13页14麻醉性镇痛药第14页152.3MechanismsofActionMostneuronsreacttoopioidswithahyperpolarization,reflectinganincreaseinK+conductance.Ca2+influxintonerveterminalsduringexcitationisdecreased,leadingtoadecreasedreleaseoftransmittersanddecreasedsynapticactivity.Dependingonthecellpopulationaffected,thissynapticinhibitiontranslatesintoadepressantorexcitanteffect.麻醉性镇痛药第15页Morphineandopioidsproduceanalgesia,affectmoodandrewardingbehavior,andalterrespiratory,cardiovascular,gastrointestinal,andneuroendocrinefunction.2.4Pharmacologicaleffectsandmechanisms麻醉性镇痛药第16页172.4.1EffectsontheCNS(1)AnalgesiaMechanismsandSitesofOpioid-InducedAnalgesia: Theanalgesiceffectsofopioidsarisefromtheirabilitytodirectlyinhibittheascendingtransmissionofnociceptiveinformationfromthespinalcorddorsalhorn(脊髓背角)andtoactivatepaincontrolcircuitsthatdescendfromthemidbrainviatherostralventromedialmedulla(延脑头端腹内侧区)tothespinalcorddorsalhorn.麻醉性镇痛药第17页18Characteristics:Asignificantfeatureoftheanalgesiaisthatitoccurswithoutlossofconsciousness.Inadditiontoreliefofdistress,somepatientsexperiencesedation,euphoria,andrewardingproperties.Continuousdullpainisrelievedmoreeffectivelythansharpintermittentpain,butwithsufficientamountsofopioiditispossibletorelieveeventheseverepainassociatedwithrenalorbiliarycolic.麻醉性镇痛药第18页19(2)Respiration.Theprimarymechanismofrespiratorydepressionbyopioidsinvolvesareductionintheresponsivenessofthebrainstemrespiratorycenterstocarbondioxide.Thesecondmechanismofrespiratorydepressionisviaadirecteffectonthebrainstemrespiratorycenters.

麻醉性镇痛药第19页20(3)Cough.Morphineandrelatedopioidsalsodepressthecoughreflexatleastinpartbyadirecteffectonacoughcenterinthemedulla.(4)NauseantandEmeticEffects.Nauseaandvomitingproduced

bymorphine-likedrugsaresideeffectscausedbydirectstimulationofthechemoreceptortriggerzoneforemesisintheareapostremaofthemedulla.麻醉性镇痛药第20页21(5)Miosis.Morphineandmostμandκ

agonistscauseconstriction

ofthepupilbyanexcitatoryactionontheparasympatheticnerveinnervatingthepupil.Aftertoxicdosesofμagonists,themiosisismarked,andpinpointpupilsarepathognomonic.瞳孔扩大正常瞳孔针尖样瞳孔麻醉性镇痛药第21页22(6)NeuroendocrineEffects.Morphineactsinthehypothalamustoinhibitthereleaseofgonadotropin-releasinghormone(GnRH)andcorticotropin-releasinghormone(CRH),thusdecreasingcirculatingconcentrationsofluteinizinghormone(LH),follicle-stimulatinghormone(FSH),ACTH,andβ-endorphin.麻醉性镇痛药第22页232.4.2Effectsontheperipheralsmoothmuscle(1)

Stomach.Relativelylowdosesofmorphinedecreasegastricmotility,therebyrolonginggastricemptyingtime.(2)SmallIntestine.Morphinediminishesbiliary,pancreatic,andintestinalsecretionsanddelaysdigestionoffoodinthesmallintestine.Theamplitudeofthenonpropulsivetypeofrhythmic,segmentalcontractionsusuallyisenhanced,butpropulsivecontractionsaredecreasedmarkedly.

麻醉性镇痛药第23页24(3)LargeIntestinePropulsiveperistalticwavesinthecolonarediminishedorabolishedafteradministrationofmorphine.Thetoneoftheanal(肝门)sphincterisaugmentedgreatly,andreflexrelaxationinresponsetorectaldistension（直肠扩张)isreduced.Inattentiontothenormalsensorystimulifordefecation（通便)reflexowingtothecentralactionsofthedrug,contributetomorphine-inducedconstipation.(4)ThesphincterofOddiconstricts,andthepressureinthecommonbileductmayrise.麻醉性镇痛药第24页(5)Ureter（输尿管)andUrinaryBladder.Therapeuticdosesofmorphinemayincreasethetoneandamplitudeofcontractionsoftheureter,althoughtheresponseisvariable.(6)Uterus（子宫).Iftheuterushasbeenmadehyperactivebyoxytocics（催产素),morphinetendstorestorethetone,frequency,andamplitudeofcontractionstonormal.(7)Morphinecauseshistaminerelease,whichcancausebronchoconstrictionandvasodilation.麻醉性镇痛药第25页262.4.3CardiovascularSystem.Therapeuticdosesofmorphinelikeopioidsdoproduceperipheralvasodilation,reducedperipheralresistance,andaninhibitionofbaroreceptor（压力感受器)reflexes.Therefore,whensupinepatientsassumethehead-upposition,orthostatichypotensionandfaintingmayoccur.Morphineandsomeotheropioidsprovokereleaseofhistamine,whichsometimesplaysalargeroleinthehypotension.opioid-inducedrespiratorydepressionandCO2retentioncanresultincerebralvasodilationandanincreaseincerebrospinal（脑脊髓)fluidpressure;麻醉性镇痛药第26页272.4.4ImmuneSystemTheoveralleffectsofopioidsappeartobeimmunosuppressive,andincreasedsusceptibilitytoinfectionandtumorspreadhavebeenobserved.麻醉性镇痛药第27页2.5TherapeuticUses2.5.1Analgesia.

Forthetreatmentofacutepain,trauma,cancer,nonmalignantchronicpain,andpaininchildren.PainofTerminalIllnessandCancerPain.theanalgesia,tranquility,andeveneuphoriaaffordedbytheuseofopioidscanmakethefinaldaysfarlessdistressingforthepatientandfamily.Ingeneral,itisrecommendedthatopioidsalwaysbecombinedwithotheranalgesicagents,suchasNSAIDsoracetaminophen.Inthisway,onecantakeadvantageofadditiveanalgesiceffectsandminimizethedoseofopioidsandthusundesirablesideeffects.28麻醉性镇痛药第28页Fig.19-3TheanalgesicregimenrecommendedbyWHOforcancerpain.麻醉性镇痛药第29页2.5.2Dyspnea（呼吸困难)Morphineisusedtoalleviatethedyspneaofacuteleftventricularfailureandpulmonaryedema,andtheresponsetointravenousmorphinemaybedramatic.Itmayinvolveanalterationofthepatient’sreactiontoimpairedrespiratoryfunctionandanindirectreductionoftheworkoftheheartowingtoreducedfearandapprehension（忧虑).However,itismoreprobablethatthemajorbenefitisduetocardiovasculareffects,suchasdecreasedperipheralresistanceandanincreasedcapacityoftheperipheralandsplanchnic（内脏)vascularcompartments.麻醉性镇痛药第30页2.5.3Cough2.5.4Diarrhea（腹泻)麻醉性镇痛药第31页2.6SideEffects2.6.1.Morphinehasmanysideeffects.Themostdangerousisrespiratorydepression.------Naloxone2.6.2.Withhigherdosesorinfrailpatients,thepatientbecomesincreasinglysedated,andthepupilsbecomeverysmall.2.6.3.Commonsideeffectsarenauseaandvomitingduetoacentralactionofmorphinestimulatingoneofthecentresinthebrainconcernedwithvomitingcalledthechemotactictriggerzone.麻醉性镇痛药第32页SideEffects2.6.4.Tolerance.Withrepeatedadministrationof

opioids,theirCNSeffectsundergohabituation(adaptation).Inthecourseoftherapy,progressivelylargerdosesarethusneededtoachievethesamedegreeofpainrelief.2.6.5.Othercentralnervoussystemsideeffectsofmorphineisaddiction(dependence). ---Methatone(opioidreceptoragonist) ---Clonidine(

2-Ragonist)

麻醉性镇痛药第33页SideEffects2.6.6.Morphinecanalsocausehistaminerelease,whichcausesitchingoftheskinandnoseandamildflushingoftheskin.2.6.7.

Morphinealsohasaneffectonthemuscleofthebowelandurinarytract,causingthesphinctertocontractandreducetheperistalsis(thewavelikemovementsofthebowelmusclethatpropelitscontentsforwards).Thisresultsinadelayedemptyingofthestomach,constipation,andmayalsoleadtourinaryretention.麻醉性镇痛药第34页352.6.8.Acuteopioidtoxicitymayresultfromclinicaloverdosage,accidentaloverdosageinaddicts,orattemptsatsuicide.Symtoms:

ThreeCardinalSymptoms:coma,pinpointpupils,anddepressedrespirationstronglysuggestsopioidpoisoning.Others:bloodpressurewillfallprogressively;hypoxiaissevereandcyanosismaybepresent.urineformationisdepressed.Treatment.

Thefirststepistoestablishapatentairway

andventilatethepatient.Theantagonistnaloxone(seebelow)isthetreatmentofchoice.麻醉性镇痛药第35页2.7KineticsMorphinecanbegivenorallyorparenterally,aswellasepidurally(硬脑膜外地)orintrathecally(鞘内地)inthespinalcord.Morphineisconjugatedtoglucuronicacidandexcretedrenally.GlucuronidationoftheOHgroupatposition6,unlikethatatposition3,doesnotaffectaffinityforthereceptors.36麻醉性镇痛药第36页37NauseavomittingPinpointpupils麻醉性镇痛药第37页Section3Otheranalgesics麻醉性镇痛药第38页Codeine麻醉性镇痛药第39页Codeineisconsideredaprodrug,sinceitismetabolisedinvivototheprincipalactiveanalgesicagentmorphine.Itis,however,lesspotentthanmorphinesinceonlyabout10%ofthecodeineisconverted.麻醉性镇痛药第40页UsesofCodeine1.Cough,thoughitsefficacyinlowdoseoverthecounterformulationshasbeendisputed.2.Moderatetoseverepain.Codeineissometimesmarketedincombinationpreparationswithpatacetamol(acetaminophen),withaspirinorwithibuprofen.Thesecombinationsprovidegreaterpainreliefthaneitheragent(drugsynergy).麻醉性镇痛药第41页42

Pethidine(dolantin)

Inthetreatmentofmild-to-moderatepain.Pethidinecanbeusedtotreatlaborpainandmaycauselessneonatalrespiratorydepression.麻醉性镇痛药第42页43Commonsideeffectsofpethidineincludenausea,vomiting,dizziness,drymouth,sedation,andheadache.

Respiratorydepressionappearstobelessthanwithequianalgesicdosesofmorphine,andthedegreeofconstipationislessthanthatseenafterequivalentdosesofcodeine.麻醉性镇痛药第43页MethadoneComparedtomoststronganalgesicsitisweaker.Hasbeensynthesizedtonothaveeuphoricpropertiesandmildwithdrawaleffectsbutisstilladdictive.Usedasananalgesicbutmostcommonlytohelpinthewithdrawal