藥理學教學課件：Chapter 19 Analgesics

1Chapter19Analgesics2paintwocomponentssomaticsensationaffective(emotion)1.ConceptSection132.PaintransmissionpathwayNoxiousstimuliPGsK+、H+BK5-HTPrimaryafferentfibres(C/Aδ)nociceptorSpinalcordLimbicsystemSomato-sensorycortexmoodeffect,theaffectiveaspectofpainthesensoryaspectofpainMedullaMidbrainDorsalhorn4DescendingpaininhibitorypathwaysLocalinhibitoryinterneuroninspinalcordPainAscendingpaintransmissionpathwaysEndogenousopioidpeptides5

MedullaMidbrainCortex

Spinal

cordDorsalhornVentralcaudalthalamusPGsK+、H＋BK5-HTNSAIDsLocalanestheticsOpioidanalgesics，AntidepressantsandGeneralanaestheticsSitesofactionofdifferentdrugs62.Paina.Acutepain(sharppain)：superficialpain,quickresponseofsuddenonset,conductedbyAnervefibersb.Chronicpain(dullpain)：morelingeringandaching,conductedbyCnervefibers7severe,sharppainopioidanalgesics(eg.Morphine)inflammation,elevatedtemperature,chronic-dullpainNSAIDs(eg.Aspirin)smoothmusclecolic(eg.biliaryorrenalcolic)

anginapectorisinducedbycoronaryarteryspasm

trigeminalpain3.Durgtreatmentofpaincholinoceptor-blockingdrugs(eg.Atropine)vasodilatordrugs(eg.Nitroglycerin)

Carbamazepine8AnalgesicsDrugswhichactonCNS,couldrelieveoralleviateseverepainandunhappymoodwithoutaffectingothersenseperception,andconsciousness.1.Concept9FullagonistofopioidreceptorsPartialagonistofopioidreceptorsOtheranalgesics2.Classification10Section2FullagonistofopioidreceptorsHistoryofAnalgesicsIn1803,Serturnerisolatedapureactivealkaline---Morphine.In1962,ChinesepharmacologistsproposedtheanalgesicsiteofopioidsislaminaeIIIofperiventricularandperiaqueductalgraymater.Inearly70’,Opioidreceptorsfoundandsuccessfulclonedin1993In1975,firstendogenousOpioidpeptide(endorphin，內(nèi)啡肽)wasfound.1992~1993197319621975

analgesicsiteislaminaeIIIofperiventricularandperiaqueductalgrayareaputforward“receptors”foropiateanalgesicsinbrainisolatedthefirst“endogenousopioidpeptide”andnamedenkephalin腦啡肽clonedthreeopioidreceptors:μ

κ

δResearchonanalgesicmechanismsSubstancePandendogenous

analgesicsystemSubstancePisaneuropeptide:ashort-chainpolypeptidethatfunctionsasaneurotransmitterandasaneuromodulator.

SubstancePisinvolvedinthetransmissionofpainimpulsesfromperipheralreceptorstothecentralnervoussystem.17enkephalinsPresynapticterminalPostsynapticneuronThecellularmechanismsofanalgesiamorphine18

Presynapticinhibition:activationofopioidreceptorsonpresynapticnerveterminals.Closeavoltage-gatedCa2+channel,decreaseCa2+input,andtherebyreducetransmitterrelease.ThecellularmechanismsofanalgesiaPostsynapticinhibition:activationofpostsynapticopioidreceptors.OpenK+channelsonpostsynapticneurons,increaseK+output,andtherebycausehyperpolarizationandthusinhibitpostsynapticneurons.19SpinalcordDorsalhornenkephalinsCa2+Ca2+谷氨酸神經(jīng)肽PresynapticterminalPostsynapticneuronenkephalins

AMPA受體：α-氨基-3-羥基-5-甲基-4-異惡唑丙酸受體NK1:P物質神經(jīng)激肽121SitesofanalgesiaSupraspinal脊椎areas:thalamus丘腦,periventricular,

periaqueductalgrayareaSpinalcord:substantiagelatinosa脊髓膠狀質22EndogenousopioidpeptidesThreemainfamilies:

Enkephalinsmet-enkephalinleu-enkephalin

Endorphins:β-endorphine

Dynorphins強啡肽:

dynorphineA,BEndogenousOpioidPeptidesOpiodsproduceeffectsthatmimictheactionofendogenouspeptideneurotransmitters(1)Endorphins(內(nèi)啡肽類):M-enkephalin(甲硫氨酸腦啡肽),L-enkephalin(亮氨酸腦啡肽),β-endorphin(β-內(nèi)啡肽)(2)Enkephalins(強啡肽類):dynorphineADistributionandfunction

ofopioidreceptors(1)Opioidreceptorsatthalamic,laminaeI,II,III(substantiagalatinosa脊髓膠質區(qū))ofspinalcordandperiventricularandperiaqueductalgraymatter.relatedtotheintergretion,perception,reactionandsensationofpain.(2)Opioidreceptorsatlimbicsystemincludinglocusceruleus（藍斑）,anteriortemporalandorbital（前顳與眶）frontalcortexpartsofhypothalamusandamydala（杏仁）.involvedinemotion,psychitricactivity,mayberelatedtoeuphoria,toleranceanddependence.(3)Opioidreceptoratnucleussolitarius（孤束核）isthelocationofcoughcenter.(4)Opioidreceptoratareapostremaofmedulla

isthechemoceptortriggerzonegoverningnauseaandemesis.TypesofopioidreceptorsThemajoreffectsoftheopioidsaremediatedby4familiesofreceptors,designatedbyμ、κ、σandδ,eachofwhichexhibitsadifferentspecificityforthedrugsitbinds.Fourmajoropioidreceptors:(1)μ(mu)-receptorsTheanalgesicpropertiesoftheopioidsareprimarilymediatedbytheμ-receptor,andforsomemajorunwantedeffects(e.g.respiratorydepression,euphoria,sedationanddependence).Mostoftheanalgesicopioidsareμ-receptoragonist.μ-receptorisdividedinto1and2subtypes,involvinginsupraspinalanalgesia,respiratoryinhibition,euphoria,physicaldependenceandmiosis.(2)δ(delta)-receptorsareprobablymoreimportantintheperipherybutmayalsocontributetoanalgesia.

-receptorisdividedinto1and2subtypes,involvedinspinalanalgesia,respiratorydepression,euphoria,physicaldependence.(3)κ(kappa)-receptorscontributetoanalgesiaatthespinallevelandmayelicitsedation,dysphoria（焦慮）andmiosis.producerelativelyfewunwantedeffectsanddonotcontributetodependence.Someanalgesicsarerelativelyκselectively.(4)σ(sigma)-receptors

arenottrueopioidreceptorsbutarethesiteofactionofcertainpsychotomimeticdrugs,towhichsomeopioidsalsobind.involvinginanalgesia,dysphoria（焦慮）,hallucination,cardiacinhibition,miosis.33Opioidreceptorssupraspinalanalgesia,

sedation,euphoria,respiratorydepression,miosis,

dependencespinalanalgesia,sedationdysphoria,hallucinationspinalanalgesia,

respiratorydepression,sedation,euphoria,dependence

*

:

:

::Subtypesandeffectsofopioidreceptors

：excitation

：inhibitionST

effects

pain

resp

HR-

BP-

pupil

？

Table.functionaleffectsassociatedwiththemaintypesofopioidreceptor

μδκanalgesia

Supraspinal+++--Spinal+++++Peripheral

++-++Respiratorydepression+++++-Pupilconstriction++-+ReducedGImotility+++++euphoria+++--dysphoria--+++sedation++-++Physicaldependence+++-+SignalTransduction

AllopioidreceptorsarecoupledtoinhibitoryG(Gi)proteinsandinhibitadenylylcyclase(AC).TheymayalsobeassociatedwithionchannelstoincreaseK+efflux(hyperpolarization)orreduceCa2+influx,thusimpedingneuronalfiringandtransmitterrelease.37ExtracellularCytoplasmicNH2HOOCOpioid

receptorsGprotein-coupledreceptorsClassifications:

--Opiates:

papaverine罌粟堿,morphine,codeine--Syntheticcompounds--AdditionalanalgesicsAnalgesicsCharacteristics①Potencyanalgesia②Dependence--narcotic(麻醉)analgesics--addictionanalgesics--opioidanalgesics40

Theflowerofpapaversomniferum41Opium421803Serturnerisolatedapureactivealkalinesubstancefromopium.Heproposedthename“morphine”foritafterMorpheus.Morphine43Structure-activityrelationship海洛因嗎啡納洛酮OH44Pharmacokineticsabsorptionexcretiondistribution

freedrugoralFirstpasseliminationsc.im.bloodliverplacental

fetuslittlecrosstheBBB,butenoughforitsfunctionmetabolismmorphine-6-glucuronidekidney,

breast45PharmacologicalactionsCNSSmoothmuscles3.Cardiovascularsystem4.Others46Pharmacologicalactions1.CNSeffects:principaleffectsanalgesiaeuphoriasedationrespiratorydepression

tolerance47(1)Analgesiapowerfulpain-relievingeffectalltypesofpains:*constant,dull﹥intermittent,sharp(easyaddiction)poorefficiencyonneuropathicpain

withoutaffectingconsciousnessandothersenseperception

duration：4-5h

1.CNS48

(2)Sedationandeuphoria

toleranceofpaindrowsinessandcloudingofmentation

sleepinducedandarousedeasily

*Euphoria

asenseofcontentmentandwell-being

relieveanxietyanddistress

Sedationthemainreasonfordrugabuse49Activatetheopioidreceptoratlimbicsystemandlocusceruleus(藍斑）Mechanisms:50

respiratoryrate，tidalvolume

occursatordinarydoses,

dose-related

themostcommoncauseofdeathfromacutepoisoningMechanisms:thesensitivityofrespiratorycentertoincreasedCO2tensionrespiratorymodulatorycenter(3)Respiratorydepression51PulmonaryedemadyspneaAcuteleftventriculardysfunctionshortofbreath(respiratorycenter)

CO2retentionanxietyanddistressAlveolarhypoventilation

morphineReducecardiacpreloadandafterloadReducethesensitivityoftherespiratorycentertoincreasedCO2SedationCardiacasthma

andmorphinetherapy

53

(4)Coughsuppressionbyinhibitingcoughcenterdirectly

Hasantitussiveeffect54

(5)Miosis:

pinpointpupils

ischaracteristicofacutepoisoningblockedbynaloxoneandatropineNauseaandvomiting:

activatethebrainstemCTZ

55(6)Others

↓releaseofgonadotropin-releasinghormone(GnRH)↓releaseofcorticotropin-releasinghormone(CRF)↓concentrationofluteinizinghormone(LH),folliclestimulatinghormone(FSH)↓adrenocorticotropichormone(ACTH)↑prolactinrelease56Pharmacologicalactions2.SmoothMuscleStimulating

GastrointestinalsystemBiliarytractUrinaryBronchia57(1)Gastrointestinaltract

delayspassage2.Smoothmusclesystem

secretionofdigestiveglandindigestioncentralinhibition

acallofnaturedefecationreflexsphinctertoneGITtone

GITmotilityabsorptionofwaterconstipationClinicaluses?58

biliarycolic

constrictbiliarysmoothmuscleconstrictOddi'ssphincterpressureinthebiliarytract(2)BiliarytractMedicine?59(3)Othersmoothmuscle

①constrict

ureteralsmoothmuscleconstrictbladdersphincterurinaryretention

③antagonize

oxytocin(縮宮素）

uterinetone

prolonglabor

②constrictbronchialsmoothmusclebronchial

asthma

60

orthostatichypotensionMechanisms:

releaseofhistaminevasomotorcenter3.Cardiovascularsystem(1)peripheralarterialandvenousdilatation(2)intracranialpressuresecondarytorespiratorydepression614.Otheractionsinhibitimmunesystem

histaminerelease

bronchospasmflushingarteriolardilatation62ClinicalusesAnalgesia

acute,severepain,particularlyin

terminalcancermyocardialinfarctionrenalandbiliarycolic（atropine)short-termuseonlywhenothersfailed2.*Cardiacasthma

3.Antidiarrhea63PulmonaryedemadyspneaAcuteleftventriculardysfunctionshortofbreath(respiratorycenter)

CO2retentionanxietyanddistressAlveolarhypoventilationmorphineReducecardiacpreloadandafterloadReducethesensitivityoftherespiratorycentertoincreasedCO2SedationCardiacasthma

andmorphinetherapy

64(1)Mechanisms:①

peripheralarterialandvenousdilationpreloadandafterloadpulmonaryedema②

sedation

anxietyanddistress

oxygenconsumption

③

thesensitivityofrespiratorycenterto

CO2

shortnessofbreathCardiacasthma651.Generaladverseeffects1dysphoria5Biliarycolic2Respiratorydepression6Urinaryretention3Nauseaandvomiting7Posturalhypotensionaccentuatedbyhypovolemia4Constipation8IncreasedintracranialpressureAdverseeffects662.AcuteMorphinePoisoning673.Toleranceanddependence(1)Tolerance

agraduallossineffectivenessinCNSwithfrequentlyrepeatedadministration,needlargerdosestoachievethesameclinicaleffect.

Characteristic:

ordinarytherapeuticdoses2-3wlargedosesatshortintervalsreadily

developnottomiosis,constipation68

physicaldependence：

withdrawalsyndromepsychologicaldenpendence:euphoriapromotecompulsiveuseandcraving(2)Dependence69戒斷綜合癥狀

SYMPTOMSOFWITHDRAWAL腹瀉出汗抑郁震顫衰弱肌痙攣寒戰(zhàn)渴求藥物頭痛、嗎啡與藍斑核μ受體結合后，NA能神經(jīng)元受抑制71

rhinorrhealacrimation

chills

gooseflesh(piloerection)yawningsweatingmuscularachesvomitingdiarrhea

anxiety

hostilityhyperventilation

Withdrawal

syndromeofOpioid72Contraindications

reasonsthatresultinpainarenotclear

obstetriclabor,breastingperiod

corpulmonale,bronchialasthma

headinjuries

seriouslyimpairedhepaticorrenalfunction

newborninfant,infant

biliaryandrenalcolic73Codeine(methyl－morphine)Characteristics:1.hasahigher

oralefficacy

2.weakeranalgesia,about1/10－1/12，antitussive：1/43.usedinmoderatepain4.mailyuseasantitussive,severe

drycough.

74Pethidine(dolantin,meperidin)

analgesia:weaker(1/7-1/10)andshorter(2-4h)sedation,euphoria,respiratorydepression:equal

noantitussiveactionMetabolismsnormeperidine

muscle

tremors,witches,convulsion2.Pharmacologicalproperties(1)CNS75(3)Cardiovascularsystem

similartomorphine(2)Smoothmuscle

lessconstipationandurinaryretention

donotprolonglabor

mayinducebiliarycolic

largedosesthecontractionofbronchialsmoothmuscle763.Clinicaluses(1)Analgesiaobstetriclabor

but

shouldnotbeusedin2-4hbeforelabor

donotlongtimeuseinchronicpain.

(2)Cardiacasthma(3)Premedicationinanesthesia

sedative,anxiolytic,andanalgesia77

(4)Artificialhibernation

pethidinechlorpromazinepromethazinelyticcocktailⅠ4.AdverseeffectsCNSexcitatorysymptoms

muscletremors,twitches,convulsion

shouldbecombinedwithanticonvulsive

drugswhentreatoverdosepoisoning(2)somesymptomslikeatropine78IncreasedCNSdepression,particularlyrespiratorydepressionOpioidanalgesics

MAOIsTricyclicantidepressantschlorpromazinepromethazineSedative-hypnoticsAbsolutecontraindicationtopethidine,relativecontraindicationtootheropioidanalgesics,becauseofhighincidenceofhyperpyreticcomaDrug–Druginteractions79Methadone美沙酮Characteristics:

1.analgesia:equaltomorphine2.givereliableeffectsorally,longerdurationofaction3.toleranceandphysicaldependencemoreslowly4.withdrawalsignsattenuatedbutprotracted5.detoxificationofthemorphineandheroindependentaddict80Fentanyl

Characteristics:

1.moreanalgesicpotentcythanmorphine:100times2.hasarapidonsetandshortdurationofaction

3.highlipid-soluble,transdermaladministration4.+droperidol(氟哌利多）

neuroleptanalgesia(神經(jīng)阻滯鎮(zhèn)痛術）

orusuallycombinedwithanaesthetics5.highdosecausetruncalrigidity81ShortactingfentanylsufentanilalfentanilAgonistsmixedAgonists/AntagonistsAntagonists

WEAK:codeinepentazocineSTRONG:methadonemorphine

pethidine

buprenorphinenalbuphinelongactingnaltrexonenaloxoneClassificationofopioidanalgesics82

Section3Partialagonistsofopioidreceptor

83Pentazocine噴他佐辛Characteristic:

κ,σagonist,μweakantagonist

1.CNSanalgesia:1/3respiratorydepression:1/2*psychomimeticaction(60-90mg)