麻醉性镇痛药

ReviewNeurolepticdrugs1第1页2Chapter20NarcoticAnelgesics第2页ObjectivesUnderstandthepharmacologicaleffects,mechanismofactions,clinicaluses,aswellasadversedrugreactionsofmorphine.Identifythetherapeuticeffectsandadversedrugreactionsofcodeineandpethidine.

第3页SectiononeIntroduction4第4页5第5页1.2Analgesics

DefinitionDrugsthatselectivelyinhibittheperception(sensation)ofthepainClassification

1-Peripheral:-Causal:

Atropine,

NSAIDs-Non-causal2-Central:-Narcoticanalgesics第6页Peripheralanalgesics

Causal

-TreatthecauseExample:Atropine(antispasmodic)Aspirin

Non-causal-NottreatthecauseExamples:1-Localanaesthetics(forsuperficialtumor)2-Counter-irritant(applypainthatcounteractormasktheoriginalonee.g.acupuncture)第7页Narcotics

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

Morphine第10页Naturallyoccurringinthepoppy(16%)-OnlyneedstobeisolatedVerystrongpainrelieverbutalsoveryaddictive(2ndtoHeroin)Usuallyinjectedbutcanbesmoked,sniffedorswallowedCommonlyusedinhospitals2.1Introduction第11页121)3位-OH旳H被-CH3取代，中枢克制作用↓。如：可待因（codeine)2)3位和6位-OH旳H同步被-COCH3取代，中枢克制作用↑。如：海洛因(heroin)3)17位旳-CH3被-CH2CH=CH2取代，则变为吗啡受体旳部分激动药，如：丙烯吗啡(nalorphine)。若同步将6位旳-OH变为=O，则变为吗啡受体旳完全拮抗药，如：纳洛酮

(naloxone)2.2构效关系第12页第13页14第14页152.3MechanismsofActionMostneuronsreacttoopioidswithahyperpolarization,reflectinganincreaseinK+conductance.Ca2+influxintonerveterminalsduringexcitationisdecreased,leadingtoadecreasedreleaseoftransmittersanddecreasedsynapticactivity.Dependingonthecellpopulationaffected,thissynapticinhibitiontranslatesintoadepressantorexcitanteffect.第15页Morphineandopioidsproduceanalgesia,affectmoodandrewardingbehavior,andalterrespiratory,cardiovascular,gastrointestinal,andneuroendocrinefunction.2.4Pharmacologicaleffectsandmechanisms第16页172.4.1EffectsontheCNS(1)AnalgesiaMechanismsandSitesofOpioid-InducedAnalgesia: Theanalgesiceffectsofopioidsarisefromtheirabilitytodirectlyinhibittheascendingtransmissionofnociceptiveinformationfromthespinalcorddorsalhorn(脊髓背角)andtoactivatepaincontrolcircuitsthatdescendfromthemidbrainviatherostralventromedialmedulla(延脑头端腹内侧区)tothespinalcorddorsalhorn.第17页18Characteristics:Asignificantfeatureoftheanalgesiaisthatitoccurswithoutlossofconsciousness.Inadditiontoreliefofdistress,somepatientsexperiencesedation,euphoria,andrewardingproperties.Continuousdullpainisrelievedmoreeffectivelythansharpintermittentpain,butwithsufficientamountsofopioiditispossibletorelieveeventheseverepainassociatedwithrenalorbiliarycolic.第18页19(2)Respiration.Theprimarymechanismofrespiratorydepressionbyopioidsinvolvesareductionintheresponsivenessofthebrainstemrespiratorycenterstocarbondioxide.Thesecondmechanismofrespiratorydepressionisviaadirecteffectonthebrainstemrespiratorycenters.

第19页20(3)Cough.Morphineandrelatedopioidsalsodepressthecoughreflexatleastinpartbyadirecteffectonacoughcenterinthemedulla.(4)NauseantandEmeticEffects.Nauseaandvomitingproduced

bymorphine-likedrugsaresideeffectscausedbydirectstimulationofthechemoreceptortriggerzoneforemesisintheareapostremaofthemedulla.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第21页22(6)NeuroendocrineEffects.Morphineactsinthehypothalamustoinhibitthereleaseofgonadotropin-releasinghormone(GnRH)andcorticotropin-releasinghormone(CRH),thusdecreasingcirculatingconcentrationsofluteinizinghormone(LH),follicle-stimulatinghormone(FSH),ACTH,andβ-endorphin.第22页232.4.2Effectsontheperipheralsmoothmuscle(1)

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

第23页24(3)LargeIntestinePropulsiveperistalticwaves

inthe

colonarediminishedorabolishedafteradministrationofmorphine.Thetoneoftheanal(肝门）sphincterisaugmentedgreatly,andreflexrelaxationinresponsetorectaldistension（直肠扩张）isreduced.

Inattentiontothenormalsensorystimulifordefecation（通便）reflexowingtothecentralactionsofthedrug,contributetomorphine-inducedconstipation.(4)

ThesphincterofOddiconstricts,andthepressureinthecommonbileductmayrise.第24页(5)Ureter（输尿管）andUrinaryBladder.Therapeuticdoses

ofmorphinemayincreasethetoneandamplitudeofcontractionsoftheureter,althoughtheresponseisvariable.(6)Uterus（子宫）.Iftheuterushasbeenmadehyperactivebyoxytocics（催产素）,

morphinetendstorestorethetone,frequency,andamplitudeofcontractionstonormal.(7)Morphinecauseshistaminerelease,whichcancausebronchoconstrictionandvasodilation.第25页262.4.3CardiovascularSystem.Therapeutic

dosesofmorphinelikeopioidsdoproduceperipheralvasodilation,reducedperipheralresistance,andaninhibitionofbaroreceptor（压力感受器）reflexes.Therefore,whensupinepatientsassumethehead-upposition,orthostatichypotensionandfaintingmayoccur.Morphineandsomeotheropioidsprovokereleaseofhistamine,whichsometimesplaysalargeroleinthehypotension.opioid-inducedrespiratorydepressionandCO2retentioncanresultincerebralvasodilationandanincreaseincerebrospinal（脑脊髓旳）fluidpressure;第26页272.4.4ImmuneSystemTheoveralleffectsofopioidsappeartobeimmunosuppressive,andincreasedsusceptibilitytoinfectionandtumorspreadhavebeenobserved.第27页2.5TherapeuticUses2.5.1Analgesia.

Forthetreatmentofacutepain,trauma,cancer,nonmalignantchronicpain,andpaininchildren.PainofTerminalIllnessandCancerPain.theanalgesia,tranquility,andeveneuphoriaaffordedbytheuseofopioidscanmakethefinaldaysfarlessdistressingforthepatientandfamily.Ingeneral,itisrecommendedthatopioidsalwaysbecombinedwithotheranalgesicagents,suchasNSAIDsoracetaminophen.Inthisway,onecantakeadvantageofadditiveanalgesiceffectsandminimizethedoseofopioidsandthusundesirablesideeffects.28第28页Fig.19-3TheanalgesicregimenrecommendedbyWHOforcancerpain.第29页2.5.2Dyspnea（呼吸困难）

Morphineisusedtoalleviatethedyspneaofacuteleftventricularfailureandpulmonaryedema,andtheresponsetointravenousmorphinemaybedramatic.Itmayinvolveanalterationofthepatient’sreactiontoimpairedrespiratoryfunction

andanindirectreductionoftheworkoftheheartowingtoreducedfearandapprehension（忧虑）.However,itismoreprobablethatthemajorbenefitisduetocardiovasculareffects,suchasdecreasedperipheralresistanceandanincreasedcapacityoftheperipheralandsplanchnic（内脏旳）vascularcompartments.第30页2.5.3Cough2.5.4Diarrhea（腹泻）第31页2.6SideEffects2.6.1.Morphinehasmanysideeffects.Themostdangerousisrespiratorydepression.------Naloxone2.6.2.Withhigherdosesorinfrailpatients,thepatientbecomesincreasinglysedated,andthepupilsbecomeverysmall.2.6.3.Commonsideeffectsarenauseaandvomitingduetoacentralactionofmorphinestimulatingoneofthecentresinthebrainconcernedwithvomitingcalledthechemotactictriggerzone.第32页SideEffects2.6.4.Tolerance.Withrepeatedadministrationof

opioids,theirCNSeffectsundergohabituation(adaptation).Inthecourseoftherapy,progressivelylargerdosesarethusneededtoachievethesamedegreeofpainrelief.2.6.5.Othercentralnervoussystemsideeffectsofmorphineisaddiction(dependence). ---Methatone(opioidreceptoragonist) ---Clonidine(2-Ragonist)

第33页SideEffects2.6.6.Morphinecanalsocausehistaminerelease,whichcausesitchingoftheskinandnoseandamildflushingoftheskin.2.6.7.

Morphinealsohasaneffectonthemuscleofthebowelandurinarytract,causingthesphinctertocontractandreducetheperistalsis(thewavelikemovementsofthebowelmusclethatpropelitscontentsforwards).Thisresultsinadelayedemptyingofthestomach,constipation,andmayalsoleadtourinaryretention.第34页352.6.8.Acuteopioidtoxicitymayresultfromclinicaloverdosage,accidentaloverdosageinaddicts,orattemptsatsuicide.Symtoms:

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

Thefirststepistoestablishapatentairway

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

Pethidine(dolantin)

Inthetreatmentofmild-to-moderatepain.Pethidinecanbeusedtotreatlaborpainandmaycauselessneonatalrespiratorydepression.第42页43Commonsideeffectsofpethidineincludenausea,vomiting,dizziness,drymouth,sedation,andheadache.

Respiratorydepressionappearstobelessthanwithequianalgesicdosesofmorphine,andthedegreeofconstipationislessthanthatseenafterequivalentdosesofcodeine.第43页MethadoneComparedtomoststronganalgesicsitisweaker.Hasbeensynthesizedtonothaveeuphoricpropertiesandmildwithdrawaleffectsbutisstilladdictive.Usedasananalgesicbutmostcommonlytohelpinthewithdrawal