《药理学》英文课件 Opioid Analgesics and Antagonists

OpioidAnalgesicsandAntagonistspainItwouldbeagreatthingtounderstandpaininallitsmeanings

19’scenturyPeterMereLathamanEnglishphysicianandeducator

(1789-1875)OpiumOpiumisobtainedfromtheopiumpoppybyscrapingtheunripeseedcapsuleOVERVIEWOpioidsarenaturalorsyntheticcompoundsthatproducemorphine-likeeffects.Thetermopiatesisreservedfordrugs,suchasmorphineandcodeine,obtainedfromthejuiceoftheopiumpoppy.Thebriefintroductionofopium

andmorphineSource:Opiumisobtainedfromtheopiumpoppy4000BC18031)FriedrichSertÜrner(1783-1841)successfullyisolatedthemorphinecrystals

2)Thestructurewasfirstproposedin1925bySirRobertRobinson3)ThefirstreportedchemicalsynthesisofmorphinewasmadebyMarshallGatesandwasdescribedintheJournaloftheAmericanChemicalSociety(20February1952).

structureGod’sownmedicine

SirWilliamOslarcalledmorphine(1849-1919)ChairofClinicalMedicineattheUniversityofPennsylvania

OPIOIDRECEPTORSThemajoreffectsoftheopioidsaremediatedby4familiesofreceptors,μ,

,

and

,eachofwhichexhibitsadifferentspecificityforthedrug(s)itbindsTheanalgesicpropertiesoftheopioidsareprimarilymediatedbytheμreceptorsAllopioidreceptorsarecoupledtoinhibitoryGproteins,andinhibitadenylyl

cyclase.TheymayalsobeassociatedwithionchannelstoincreaseK+efflux(hyperpolarization)orreduceCa2+influx,thusimpedingneuronalfiringandtransmitterrelease.DistributionofreceptorsBrainstem:Medialthalamus:Spinalcord:Hypothalamus:Limbicsystem:Periphery:Immunecells:MorphineMechanismofaction:Opioidscausehyperpolarizationofnervecells,inhibitionofnervefiring,andpresynapticinhibitionoftransmitterrelease.ActionsAnalgesia:Morphinecausesanalgesia(reliefofpainwithoutthelossofconsciousness).Opioidsrelievepainbothbyraisingthepainthresholdatthespinalcordlevel,andmoreimportantly,byalteringthebrain'sperceptionofpain.ActionsEuphoria:Morphineproducesapowerfulsenseofcontentmentandwell-being.actionsRespiration:Morphinecausesrespiratorydepressionbyreductionofthesensitivityofrespiratorycenterneuronstocarbondioxide.Depressionofcoughreflex:Morphineandcodeinehaveanti-tussiveproperties.ActionsMiosis:Emesis:Gastrointestinaltract:Morphinerelievesdiarrheaanddysentery.Cardiovascular:atlargedoses,whenhypotensionandbradycardiamayoccur.BecauseofrespiratorydepressionandcarbondioxideretentionactionsHistaminerelease:Morphinereleaseshistaminefrommastcells,causingurticaria,sweating,andvasodilation.Hormonalactions:Morphineinhibitsreleaseofgonadotropin-releasinghormoneandcorticotropin-releasinghormoneanddecreasestheconcentrationofluteinizinghormone,follicle-stimulatinghormone,adrenocorticotropichormone.TherapeuticusesAnalgesia:

Opioidsinducesleep,andinclinicalsituationswhenpainispresentandsleepisnecessary.TreatmentofdiarrheaReliefofcough:Pharmacokineticsa.Administration:Absorptionofmorphinefromthegastrointestinaltractisslow,andthedrugisusuallynotgivenorally.Codeine,bycontrast,iswellabsorbedwhengivenbymouth.Intramuscular,subcutaneous,orintra-venousinjectionsproducethemostreliableresponses.DistributionMorphinerapidlyentersallbodytissues,includingthefetusesofpregnantwomen,andshouldnotbeusedforanalgesiaduringlabor.Onlyasmallpercentageofmorphinecrossestheblood-brainbarrier,Thiscontrastswiththemorefat-solubleopioids,suchasfentanylandheroin,whichreadilypenetrateintothebrainandrapidlyproduceanintense"rush"ofeuphoria.FateMorphineismetabolizedinthelivertoglucuronides.Morphine-6-glucuronideisaverypotentanalgesic,whereastheconjugateatthe3-positionisinactive.Theconjugatesareexcretedprimarilyintheurine,withsmallquantitiesappearinginthebile.AdverseeffectsSevererespiratorydepressionoccurs.Othereffectsincludevomiting,dysphoria,andallergy-enhancedhypotensiveeffectsTheelevationofintracranialpressure,particularlyinheadinjury.Morphineenhancescerebralandspinalischemia.ToleranceandphysicaldependenceRepeateduseproducestolerancetotherespiratorydepressant,analgesic,euphoric,andsedativeeffectsofmorphine.Physicalandpsychologicdependencereadilyoccurwithmorphineandwithsomeoftheotheragoniststobedescribed.Withdrawalproducesaseriesofautonomic,motorandpsychologicalresponsesthatincapacitatetheindividualandcausesserious,almostunbearablesymptoms.Meperidine

(Pethidine)Meperidineisasyntheticopioidwithastructureunrelatedtomorphine.Itisusedforacutepain.MechanismofactionMeperidinebindstoopioidreceptors,par-ticularly

receptors.Actions:Meperidinecausesadepressionofrespirationsimilartothatofmorphine,butthereisnosignificantcardiovascularactionwhenthedrugisgivenorally.Onintravenous(IV)administration,meperidineproducesadecreaseinperipheralresistanceandanincreaseinperipheralbloodflow,andmaycauseanincreaseincardiacrate.TherapeuticusesMeperidineprovidesanalgesiaforanytypeofseverepain.Unlikemorphine,meperidineisnotclinicallyusefulinthetreatmentofdiarrheaorcough.Meperidineproduceslessofanincreaseinurinaryretentionthandoesmorphine.Pharmacokineticsmeperidineiswellabsorbedfromthegastrointestinaltractandisusefulwhenanorally-administered,potentanalgesicisneeded.However,meperidineismostoftenadministeredintramuscularly.Thedrughasadurationofactionof2to4hours.AdverseeffectsLargedosesofmeperidinecausetremors,muscletwitches,andrarely,convulsions.Thedrugdiffersfromopioidsinthatinlargedosesitdilatesthepupilandcauseshyperactivereflexes.Severehypotensioncanoccurwhenthedrugisadministeredpostoperatively.Administrationtopatientstakingmonoamineoxidaseinhibitorscanprovokeseverereactionssuchasconvulsionsandhyperthermia.Meperidinecansubstituteformorphineorheroininusebyaddicts.methadoneMethadoneisasynthetic,orallyeffectiveopioidthatisapproximatelyequalinpotencytomorphine,butinduceslesseuphoriaandhasalongerdurationofaction.MechanismofactionMethadonehasitsgreatestactiononμreceptors.ActionsTheanalgesicactivityofmethadoneisequivalenttothatofmorphine.Methadoneexhibitsstronganalgesicactionwhenadministeredorally.Themioticandrespiratorydepressantactionsofmethadonehaveaveragehalf-livesof24hours.Likemorphine,methadoneincreasesbiliarypressure,andisalsoconstipating.TherapeuticusesMethadoneisusedinthecontrolledwithdrawalofaddictsfromheroinandmorphine.Methadonecausesamilderwithdrawalsyndrome,whichalsodevelopsmoreslowlythanthatseenduringwithdrawalfrommorphine.PharmacokineticsReadilyabsorbe