麻醉性镇痛药.ppt

1,Review,Neurolepticdrugs,2,Chapter20,NarcoticAnelgesics,Objectives,Understandthepharmacologicaleffects,mechanismofactions,clinicaluses,aswellasadversedrugreactionsofmorphine.Identifythetherapeuticeffectsandadversedrugreactionsofcodeineandpethidine.,4,Sectionone,Introduction,5,1.2Analgesics,DefinitionDrugsthatselectivelyinhibittheperception(sensation)ofthepainClassification1-Peripheral:-Causal:Atropine,NSAIDs-Non-causal2-Central:-Narcoticanalgesics,Peripheralanalgesics,Causal-TreatthecauseExample:Atropine(antispasmodic)Aspirin,Non-causal-NottreatthecauseExamples:1-Localanaesthetics(forsuperficialtumor)2-Counter-irritant(applypainthatcounteractormasktheoriginalonee.g.acupuncture),Theactionslistedforantagonistsareseenwiththeantagonistalone.Allthecorrelationsinthistablearebasedonstudiesinratsandmice,whichoccasionallyshowspeciesdifferences.,10,SectiontwoMorphine,Naturallyoccurringinthepoppy(16%)-OnlyneedstobeisolatedVerystrongpainrelieverbutalsoveryaddictive(2ndtoHeroin)Usuallyinjectedbutcanbesmoked,sniffedorswallowedCommonlyusedinhospitals,2.1Introduction,12,1)3位-OH的H被-CH3取代，中枢抑制作用。如：可待因（codeine)2)3位和6位-OH的H同时被-COCH3取代，中枢抑制作用。如：海洛因(heroin)3)17位的-CH3被-CH2CH=CH2取代，则变为吗啡受体的部分激动药，如：丙烯吗啡(nalorphine)。若同时将6位的-OH变为=O，则变为吗啡受体的完全拮抗药，如：纳洛酮(naloxone),2.2构效关系,14,15,2.3MechanismsofActionMostneuronsreacttoopioidswithahyperpolarization,reflectinganincreaseinK+conductance.Ca2+influxintonerveterminalsduringexcitationisdecreased,leadingtoadecreasedreleaseoftransmittersanddecreasedsynapticactivity.Dependingonthecellpopulationaffected,thissynapticinhibitiontranslatesintoadepressantorexcitanteffect.,Morphineandopioidsproduceanalgesia,affectmoodandrewardingbehavior,andalterrespiratory,cardiovascular,gastrointestinal,andneuroendocrinefunction.,2.4Pharmacologicaleffectsandmechanisms,17,2.4.1EffectsontheCNS(1)AnalgesiaMechanismsandSitesofOpioid-InducedAnalgesia:Theanalgesiceffectsofopioidsarisefromtheirabilitytodirectlyinhibittheascendingtransmissionofnociceptiveinformationfromthespinalcorddorsalhorn(脊髓背角)andtoactivatepaincontrolcircuitsthatdescendfromthemidbrainviatherostralventromedialmedulla(延脑头端腹内侧区)tothespinalcorddorsalhorn.,18,Characteristics:Asignificantfeatureoftheanalgesiaisthatitoccurswithoutlossofconsciousness.Inadditiontoreliefofdistress,somepatientsexperiencesedation,euphoria,andrewardingproperties.Continuousdullpainisrelievedmoreeffectivelythansharpintermittentpain,butwithsufficientamountsofopioiditispossibletorelieveeventheseverepainassociatedwithrenalorbiliarycolic.,19,(2)Respiration.Theprimarymechanismofrespiratorydepressionbyopioidsinvolvesareductionintheresponsivenessofthebrainstemrespiratorycenterstocarbondioxide.Thesecondmechanismofrespiratorydepressionisviaadirecteffectonthebrainstemrespiratorycenters.,20,(3)Cough.Morphineandrelatedopioidsalsodepressthecoughreflexatleastinpartbyadirecteffectonacoughcenterinthemedulla.(4)NauseantandEmeticEffects.Nauseaandvomitingproducedbymorphine-likedrugsaresideeffectscausedbydirectstimulationofthechemoreceptortriggerzoneforemesisintheareapostremaofthemedulla.,21,(5)Miosis.Morphineandmostandagonistscauseconstrictionofthepupilbyanexcitatoryactionontheparasympatheticnerveinnervatingthepupil.Aftertoxicdosesofagonists,themiosisismarked,andpinpointpupilsarepathognomonic.,瞳孔扩大正常瞳孔针尖样瞳孔,22,(6)NeuroendocrineEffects.Morphineactsinthehypothalamustoinhibitthereleaseofgonadotropin-releasinghormone(GnRH)andcorticotropin-releasinghormone(CRH),thusdecreasingcirculatingconcentrationsofluteinizinghormone(LH),follicle-stimulatinghormone(FSH),ACTH,and-endorphin.,23,2.4.2Effectsontheperipheralsmoothmuscle,(1)Stomach.Relativelylowdosesofmorphinedecreasegastricmotility,therebyrolonginggastricemptyingtime.(2)SmallIntestine.Morphinediminishesbiliary,pancreatic,andintestinalsecretionsanddelaysdigestionoffoodinthesmallintestine.Theamplitudeofthenonpropulsivetypeofrhythmic,segmentalcontractionsusuallyisenhanced,butpropulsivecontractionsaredecreasedmarkedly.,24,(3)LargeIntestinePropulsiveperistalticwavesinthecolonarediminishedorabolishedafteradministrationofmorphine.Thetoneoftheanal(肝门）sphincterisaugmentedgreatly,andreflexrelaxationinresponsetorectaldistension（直肠扩张）isreduced.Inattentiontothenormalsensorystimulifordefecation（通便）reflexowingtothecentralactionsofthedrug,contributetomorphine-inducedconstipation.(4)ThesphincterofOddiconstricts,andthepressureinthecommonbileductmayrise.,(5)Ureter（输尿管）andUrinaryBladder.Therapeuticdosesofmorphinemayincreasethetoneandamplitudeofcontractionsoftheureter,althoughtheresponseisvariable.(6)Uterus（子宫）.Iftheuterushasbeenmadehyperactivebyoxytocics（催产素）,morphinetendstorestorethetone,frequency,andamplitudeofcontractionstonormal.(7)Morphinecauseshistaminerelease,whichcancausebronchoconstrictionandvasodilation.,26,2.4.3CardiovascularSystem.Therapeuticdosesofmorphinelikeopioidsdoproduceperipheralvasodilation,reducedperipheralresistance,andaninhibitionofbaroreceptor（压力感受器）reflexes.Therefore,whensupinepatientsassumethehead-upposition,orthostatichypotensionandfaintingmayoccur.Morphineandsomeotheropioidsprovokereleaseofhistamine,whichsometimesplaysalargeroleinthehypotension.opioid-inducedrespiratorydepressionandCO2retentioncanresultincerebralvasodilationandanincreaseincerebrospinal（脑脊髓的）fluidpressure;,27,2.4.4ImmuneSystemTheoveralleffectsofopioidsappeartobeimmunosuppressive,andincreasedsusceptibilitytoinfectionandtumorspreadhavebeenobserved.,28,2.5TherapeuticUses,2.5.1Analgesia.Forthetreatmentofacutepain,trauma,cancer,nonmalignantchronicpain,andpaininchildren.PainofTerminalIllnessandCancerPain.theanalgesia,tranquility,andeveneuphoriaaffordedbytheuseofopioidscanmakethefinaldaysfarlessdistressingforthepatientandfamily.Ingeneral,itisrecommendedthatopioidsalwaysbecombinedwithotheranalgesicagents,suchasNSAIDsoracetaminophen.Inthisway,onecantakeadvantageofadditiveanalgesiceffectsandminimizethedoseofopioidsandthusundesirablesideeffects.,Fig.19-3TheanalgesicregimenrecommendedbyWHOforcancerpain.,2.5.2Dyspnea（呼吸困难）Morphineisusedtoalleviatethedyspneaofacuteleftventricularfailureandpulmonaryedema,andtheresponsetointravenousmorphinemaybedramatic.Itmayinvolveanalterationofthepatientsreactiontoimpairedrespiratoryfunctionandanindirectreductionoftheworkoftheheartowingtoreducedfearandapprehension（忧虑）.However,itismoreprobablethatthemajorbenefitisduetocardiovasculareffects,suchasdecreasedperipheralresistanceandanincreasedcapacityoftheperipheralandsplanchnic（内脏的）vascularcompartments.,2.5.3Cough2.5.4Diarrhea（腹泻）,2.6SideEffects,2.6.1.Morphinehasmanysideeffects.Themostdangerousisrespiratorydepression.-Naloxone2.6.2.Withhigherdosesorinfrailpatients,thepatientbecomesincreasinglysedated,andthepupilsbecomeverysmall.2.6.3.Commonsideeffectsarenauseaandvomitingduetoacentralactionofmorphinestimulatingoneofthecentresinthebrainconcernedwithvomitingcalledthechemotactictriggerzone.,SideEffects,2.6.4.Tolerance.Withrepeatedadministrationofopioids,theirCNSeffectsundergohabituation(adaptation).Inthecourseoftherapy,progressivelylargerdosesarethusneededtoachievethesamedegreeofpainrelief.2.6.5.Othercentralnervoussystemsideeffectsofmorphineisaddiction(dependence).-Methatone(opioidreceptoragonist)-Clonidine(2-Ragonist),SideEffects,2.6.6.Morphinecanalsocausehistaminerelease,whichcausesitchingoftheskinandnoseandamildflushingoftheskin.2.6.7.Morphinealsohasaneffectonthemuscleofthebowelandurinarytract,causingthesphinctertocontractandreducetheperistalsis(thewavelikemovementsofthebowelmusclethatpropelitscontentsforwards).Thisresultsinadelayedemptyingofthestomach,constipation,andmayalsoleadtourinaryretention.,35,2.6.8.Acuteopioidtoxicitymayresultfromclinicaloverdosage,accidentaloverdosageinaddicts,orattemptsatsuicide.Symtoms:ThreeCardinalSymptoms:coma,pinpointpupils,anddepressedrespirationstronglysuggestsopioidpoisoning.Others:bloodpressurewillfallprogressively;hypoxiaissevereandcyanosismaybepresent.urineformationisdepressed.Treatment.Thefirststepistoestablishapatentairwayandventilatethepatient.Theantagonistnaloxone(seebelow)isthetreatmentofchoice.,2.7Kinetics,Morphinecanbegivenorallyorparenterally,aswellasepidurally(硬脑膜外地)orintrathecally(鞘内地)inthespinalcord.Morphineisconjugatedtoglucuronicacidandexcretedrenally.GlucuronidationoftheOHgroupatposition6,unlikethatatposition3,doesnotaffectaffinityforthereceptors.,36,37,Nauseavomitting,Pinpointpupils,Section3,Otheranalgesics,Codeine,Codeineisconsideredaprodrug,sinceitismetabolisedinvivototheprincipalactiveanalgesicagentmorphine.Itis,however,lesspotentthanmorphinesinceonlyabout10%ofthecodeineisconverted.,UsesofCodeine,1.Cough,thoughitsefficacyinlowdoseoverthecounterformulationshasbeendisputed.2.Moderatetoseverepain.Codeineissometimesmarketedincombinationpreparationswithpatacetamol(acetaminophen),withaspirinorwithibuprofen.Thesecombinationsprovidegreaterpainreliefthaneitheragent(drugsynergy).,42,Pethidine(dolantin),Inthetreatmentofmild-t