药理学英文版教学课件：Chapter 18 Analgesics

Analgesics

§1Introduction1.Pain:subjectiveexperienceproducedbyexternalstimuli

“Painishighlysubjective（主观的）andthusdifficulttodefine,quantify(量化）andtreat.”PerceptionofpainReactiontopain

Paina.Acutepain(sharppain急性锐痛),superficialpain,quickresponseofsuddenonset,conductedbyAnervefibersb.Chronicpain(dullpain慢性钝痛),morelingeringandaching,conductedbyCnervefibersDrugscanremovepainAnalgesicsAntipyretic&analgesicsAnestheticsAtropineCarbamazepineOthers（angina）Analgesics(p126)

DrugsthatactonCNStorelieveseverepainandfeelingreactionsbypainwithoutaffectingothersenseperception,andconsciousness(1)ClassificationsMorphineandrelatedopioidRagonistspartialopioidRagonistsOtheranalgesics(2)Characteristics

①Potencyanalgesia②Dependencenarcoticanalgesics麻醉药(Anaesthetics)与麻醉药品(Narcotics)addictionanalgesicsopioidanalgesicsOpioidreceptors&endogenousopioidpeptides1964ZuGang,ZhangChang-shao1973SynderproventheexistofopioidR1992identifiedsubtypesofopioidRMu,delta,kappaRsEndogenousanalgesicsystem:EndogenousopioidneuronsopioidpeptidesandopioidreceptorsReceptorStimulationeffects(mu):1,2,PhysicaldependenceEuphoriaAnalgesia(supraspinal)Respiratorydepression(kappa):SedationAnalgesia(spinal)Miosis(delta):1,2analgesia(spinal&supraspinal)releaseofgrowthhormone

(sigma):

opioidreceptorsdistribution

InCNSisnotuniform（不均匀）theyareatareasconcernedwithpainreceptorlocationsbeginningwithhighestconcentrationareas1.cerebralcortex2.amygdala3.septum4.thalamus5.hypothalamus6.midbrain7.spinalcordEndogenousOpioidPeptides(p128)About20opioidpeptideshavebeenidentified.Somedistinctfamiliesofpeptideshavebeenidentified:enkephalins(脑啡肽),

endorphins(内啡肽),

dynorphins(强啡肽),endomorphines(内吗啡肽).

Eachfamilyisderivedfromadistinctprecursorpolypeptide

§2OpioidAlkaloidAnalgesicsPhenanthrenes（菲类）morphine,codeineBenzylisoquimolines（苄基异喹啉类）papaverine

Morphine

(吗啡)

SourceandChemistry

papaversomniferum

（罂粟）

1803separatedfromopium

namedafterdreamGodness

--Morpheus

Opioidreceptoragonists:Structure&Effects氢化菲核海洛因(heroin)—OCOCH3

—OCOCH3DPharmacokineticsAbsorptionreadyfromGItractbutfirstpasseliminationinliver（F=25%）;sc,imabsorbedwell,Distributionnospecialaffinityforbrain,distributedthroughoutofthebody.Metabolismprimarilyinliver,major(60%-70%)conjugatedwithglucuronic(葡萄糖醛酸),M6Gareactivemetabolites,20%freeExcretionMainlybyglomerularfiltration,afewbymilkandbile.t1/22.5-3.5hrs

PharmacologicalActions1.CNS(1)Analgesiaa.Strongerandlonger.MoreeffectiveincontinuousdullpainthansharpintermittentpainOpioidreceptors(O-R)relatedpainatthalamic,laminaeI,II,IIIofspinalcordandperiventricularandperiaqueductalgraymatter(2)Sedation&Euphoria(欣快感)drowiness,cloudingofmentation,impairmentofreasoningability:feelmorecomfortable,senseofwell-beingO-Ratlimbicsystem:orbitalfrontalcortex,partsofhypothalamusandamydala,relatedwithdopaminesystem(3)Respiratorydepression↓RespiratorycenteronthebrainstemresultinCO2retension:rate,volume,tidalexchangeDose-related,mostdeathfrommorphinepoisonduetorespiratoryarrestO-Rinrespiratorycenterofbrainstem(4)Antitussive（镇咳）effectTodepressthecoughreflexoncoughcenterinmedullanucleussolitarius(孤束核)(5)OthereffectsMiosis(pinpointpupils)duetoexcitatoryactiononthenucleusofoculomotornerve(动眼神经)nauseaandvomitingduetostimulatingofCTZ(chemoceptortriggerzone)inhibitthethermoregulationcenter,hypothalamus2.

Smoothmuscle

StimulatingGI:Constipationa.gastricsecretionandmotilitydecreased,emptyingslowb.smallintestinerestingtoneincrease,propulsivecreepingmovementdimunishedc.largeintestinebowelmovementdelay,waterabsorbedd.CNSeffectBiliarytract:biliarycolicbyOddiconstrictUrinary:Urinationdifficultandurinaryretention.Bronchia:bronchiasthmaUterine:decreasethetention,frequencyandextent

3.CardiovascularsystemDirectvesseldilatationandinducereleasingofhistamineresultinperipheralresistancereduction,BP↓orhypotension.IncreasecerebrospinalfluidpressureduetoCO2retention,cerebrovasodilation,↓Respiration,CO2↑

cerebralvasodilationandincreaseintracranialpressure4.immunesysteminhibitoryeffects:NKcellfunction

Subtypesandeffectsofopioidreceptors

：excitation

：inhibitionsubT

effects

pain

resp

HR-

BP-

pupil

？

TheMechanisms（P物质，SP）theperceptiveafferentnervousterminalreleaseglutamicandsubstancePtoconductthepainfeelingtoCNS.ThereareO-Rdistributedonbothpre-&postsynapticmembranesofperceptiveafferentsynapses.O-RsareGiproteincoupledreceptors.ActivitedO-RsinhibittheAMPcyclase,decrease[cAMP],resultinlessCa++entryintoandmoreK+flowoutoffcells.Lesstransmittersreleasedfromterminal,andpostsynapticmembraneshyperpolarizationleadstoreducedpainconductiontoCNS.ClinicalUses1.AnalgesiaModeratetoseverepain,painofterminalillness,postoperationpain,anginapectoris2.Cardiacasthma(1)Respiratorydepression(2)DilatingtheperipheralvesseltoreducethePre-andpostloadofheart.(3)Sedation3.Constipationeffecttotreatacuteorchronicdiarrhea4.stopcoughing5.pre-anaesthesiausesCase174yrsoldfemalePersistentstuffychestpain2hoursSuddenlyawakefromsleepbystuffychestpain,withfeelingofdyinganddefecation,andsweatprofusely.Noimprovementhappenedafternitroglycerinadministration.EEGshowedcardiacinfarctionchangesTreatment:O2uptake;morphine10mgs.cAdverseReactions1.Sidereactions:respiratorydepression,nausea,vomiting,dizziness,mentalclouding,constipation,biliaryspasm,urinationdifficulty,posturalhypotension2.Tolerance,dependence,addictionandabusedependencepsychicdependence:cravingphysicaldependence:abstinencesyndrome(diarrhea,vomiting,chillsfever,lacrimation,runningnose,tremor,abdominalcrampsandpain)Addiction:psychic&physicaldependence.EuphoriaHarmtosociety:stopuseabstinencesyndromecompulsivedrug-seekingbehavior

Drugabuse:repeateddrugusewithoutmedicalindicationsbutforrecreationalpurposes。3.Acutepoisoning:Respiratoryinhibition,coma,pinepointpupilr,bloodpressureandtemperaturedecrease,deathtreatment:artificialrespiration,O2,O-RantagonistsContraindicationsNewborn,infant,breastingperiod,laboringpain(生产痛),braininjury,bronchialasthma&pulmonaryheartdisease

Codeine(可待因)

Theproperties1.Weakeranalgesia,about1/12ofmorphine,usedinmoderatepain.2.centralantitussives,usedforsuppressingcough.§3syntheticanalgesics

Pethidine(哌替啶)

AlsocalledMeperidine,DOLANTIN(度冷丁)ArtificialsyntheticanalgesicsPharmacologicaleffects1.CNSeffects:Analgesia,sedationandrespiratory,depressionareweakerandshorterthanmorphine.Noantitussive2.Smoothmusclesystem:Weakerthanmorphine,noantidiarrhealeffects,mayinducebiliarycolic,Noantagonisteffectofoxytocin3.CardiovascularsystemsimilartomorphineClinicalUses1.Severepain2.Cardiacasthma3.PremedicationinanesthesiaandartificialhibernationAdverseReactionsThesideeffectsaresimilartomorphineoverdosetoxication:CNSexcitatorysymptoms---tremor,musclespasm,reflexaugumentationorconvulsionSomeOtherNarcoticAnalgesicsMethadone(美沙酮)Pharmacologicalpropertiessimilartomorphine,analgesiaanddurationequaltomorphine,slowtoleranceandaddiction,abstinencelightusedinseverepainandfordetoxificationandformaintenanceofchronicreplacingheroinaddict.Fentanyl（芬太尼）Analgesiaandrespiratoryinhibition100timesthanmorphine,shortduration(1-2hrs),usedforseverepainandcombinedwithanestheticstodecreasethedoseofanesthetics,orcombinedwithdroperidolasneuroleptanalgesiaDihydroetorphine（二氢埃托啡）PotentanalgesicdevelopedbyChinesescientists,10000timesanalgesiaandsevereaddiction.Pentazocine（喷他佐辛）Withmoderateandagonism,weakerantagonism,usedinchronicseverepain,1/3analgesiaofmorphineand½respiratoryinhibitionofmorphine.AlmostnodependenceButorphanol(布托啡诺)Buprenorphine(丁丙诺啡)Nalbuphine(纳布啡)PartialOpioidReceptors

§4OtherAnalgesicsTramadol(曲马朵)Analgesiceffectsthesamedegreeaspentazocine,alsocauseaddictionNon-narcoticAnalgesics

Rotundine(l-tetrahydropalmtine,罗通定)FromtraditionalmedicineCorydalisambi