各论各论3：神经系统药理：神经系统药理21、胆碱能神经系统（3）胆碱受体拮抗药2、肾上腺素能神经系统（1）肾上腺素受体激动药2013.10.16Muscurinic receptor antagonistsMcholinoceptorantagonistsAtropineAtropine阿托品阿托品阿托品阿托品(Antimuscarinicdrugs)(Antimuscarinicdrugs)NcholinoceptorantagonistsN NNNcholinoceptorantagonists:cholinoceptorantagonists: mecamylaminemecamylamine美加明美加明美加明美加明( (Ganglionic Blocking drugs, rarely used ) )NNMMcholinoceptorantagonists:cholinoceptorantagonists:succinylcholinesuccinylcholine琥珀胆碱琥珀胆碱琥珀胆碱琥珀胆碱( (Neuromuscular Blocking drugs ) )BotulinumToxin肉毒毒素肉毒毒素( (blocks ACh release) ) DrugclassificationofcholinergicantagonistsMuscarinicAntagonists(Antimuscarinicdrugs)Tertiary amines叔胺类叔胺类Quaternary amines季胺类季胺类阿托品阿托品东莨菪碱东莨菪碱异丙托溴铵异丙托溴铵噻托溴铵噻托溴铵甲硝阿托品甲硝阿托品1.1.Pharmacological effectsPharmacological effectsAtropinelightpilocarpinepilocarpineatropineatropinelenslensmiosismiosis mydriasismydriasis paralysisofparalysisofaccommodationaccommodationnearsightnearsightspasmofspasmofaccommodationaccommodationfarsightfarsightirisirisAnteriorAnteriorchamberchamberCiliarymuscleCiliarymuscle(contraction)(contraction)zonulezonuleAnteriorAnteriorchamberchamberzonulezonuleCanalofSchlemmCanalofSchlemmposteriorposteriorchamberchamberCiliarymuscleCiliarymuscle(relaxation)(relaxation)(1)Eye(1)Eye intraocularpressureintraocularpressure调节麻痹调节麻痹1.Pharmacological effects(2)(2)AntispasmodicactiononsmoothmuscleAntispasmodicactiononsmoothmuscle sensitive:sensitive:GI,urinarybladder(spasmodicstate)GI,urinarybladder(spasmodicstate) relativelyinsensitive:relativelyinsensitive:bileduct,urinarytract,bileduct,urinarytract,bronchialtractbronchialtract insensitive:insensitive:uterusuterus(3)(3)Inhibitionofexocrineglandsecretion salivary,sweatglandssalivary,sweatglands tear,respiratorytractglandstear,respiratorytractglands relativelyineffective:GItractrelativelyineffective:GItractAtropine1.Pharmacological effects(4)CardiovascularSystem:dosedependent(4)CardiovascularSystem:dosedependent LowerLower therapeutictherapeutic doses:doses: HRHR(bradycardia);(bradycardia); BloodBloodvesselsandbloodpressure:vesselsandbloodpressure: noeffectnoeffect Moderatetohightherapeuticdoses/highvagaltone:Moderatetohightherapeuticdoses/highvagaltone:HRHR(tachycardia);(tachycardia);A-VconductionA-Vconduction Largerdoses:Largerdoses:cutaneousvasodilatationcutaneousvasodilatation(5)CNSstimulation(5)CNSstimulationsedation,memoryloss,psychosis (highdose)(highdose)AtropineLowertherapeuticdoses:Lowertherapeuticdoses:Block Pre-synaptic M1 receptor Ach release activate Post-synaptic M2 receptor HR RegulationofK+ChannelsHeart rate ModeratetohighModeratetohightherapeuticdosestherapeuticdoses : :Block Post-synaptic M2 receptor HR 2.Clinical uses(1)Ophthalmology(1)Ophthalmology Measurementoftherefractiveerrors(Measurementoftherefractiveerrors(验光验光验光验光): ):childrenchildren AcuteAcute iritisiritis oror iridocyclitis:iridocyclitis: mydriatics/mioticsmydriatics/miotics （totopreventsynechia/adhesionpreventsynechia/adhesion）(2)Antispasmodicagent(2)Antispasmodicagent GI,biliaryorrenalcolic,enuresis(GI,biliaryorrenalcolic,enuresis(遗尿遗尿遗尿遗尿) )(3)Inhibitingexocrineglandsecretion(3)Inhibitingexocrineglandsecretion PreanestheticmedicationPreanestheticmedication(4)Bradyarrhythmia(4)Bradyarrhythmia sinusornodalbradycardia,A-Vblocksinusornodalbradycardia,A-Vblock(5)Antidotefororganophosphatepoisoning(5)AntidotefororganophosphatepoisoningAtropine3.Adverse effects(1)Sideeffects(1)Sideeffectsdrymouth,blurredvision,“sandyeyes”drymouth,blurredvision,“sandyeyes”(2)toxicity(2)toxicityLethaldose:80130mg(adult),10mg(child)Lethaldose:80130mg(adult),10mg(child) LowLow:xerostomia(:xerostomia(drymouthdrymouth);anhidrosis(d);anhidrosis(dryskinryskin),tachycardiad),tachycardiad ModerateModerate:aboveplusmydriasis(:aboveplusmydriasis(扩瞳扩瞳扩瞳扩瞳) ),cycloplegia(,cycloplegia(睫状肌麻痹睫状肌麻痹睫状肌麻痹睫状肌麻痹););difficultyonspeaking,swallowing&urinating;andhot,red,dryskindifficultyonspeaking,swallowing&urinating;andhot,red,dryskin HighHigh:aboveplusataxia(:aboveplusataxia(共济失调共济失调共济失调共济失调),hallucinations(),hallucinations(幻觉幻觉幻觉幻觉)&delirium()&delirium(谵妄谵妄谵妄谵妄););coma(coma(昏迷昏迷昏迷昏迷)(i.e.CNSsymptoms)(i.e.CNSsymptoms)(3)Detoxication(3)Detoxication Symptomatictreatment:e.g.diazepam.Symptomatictreatment:e.g.diazepam. PhysostigminePhysostigmine毒扁豆碱毒扁豆碱毒扁豆碱毒扁豆碱orpilocarpineorpilocarpine匹鲁卡品匹鲁卡品匹鲁卡品匹鲁卡品(4)Contraindications(4)Contraindications glaucoma,prostatauxe,feverglaucoma,prostatauxe,feverAtropineActions and clinical usesPeripheralPeripheral effectseffects areare similarsimilar toto atropine;atropine;butbuthashasstrongerstrongercentralcentraleffectseffects(depression)(depression)Pre-anestheticPre-anesthetic medication,medication, preventionprevention ofofmotionsickness,Parkinsonsdiseasemotionsickness,ParkinsonsdiseaseScopolamine( (东莨菪碱东莨菪碱) )Actions and clinical uses654,654-2654,654-2Weakeractionthanatropine,lowertoxicityWeakeractionthanatropine,lowertoxicityAnisodamine( (山山山山莨菪碱莨菪碱) )Syntheticorsemi-syntheticHomatropine后马托品后马托品Tropicamide托吡卡胺托吡卡胺Cyclopentolate环喷托酯环喷托酯Eucatropine尤卡托品尤卡托品LowersideeffectandshorterdurationformydriasisothersSyntheticanti-spasmagentsIpratropium Ipratropium ( (异丙托溴胺异丙托溴胺异丙托溴胺异丙托溴胺) ): : asthmaasthmaScopolamine methylbromide Scopolamine methylbromide ( (溴甲东莨菪碱溴甲东莨菪碱溴甲东莨菪碱溴甲东莨菪碱) ): : GIGIHomatropine methylbromide Homatropine methylbromide ( (溴甲后马托品溴甲后马托品溴甲后马托品溴甲后马托品) ): : GI and coughGI and coughMepenzolatebromide(Mepenzolatebromide(溴化甲哌佐酯溴化甲哌佐酯溴化甲哌佐酯溴化甲哌佐酯):GI):GIPropantheline(Propantheline(普鲁本辛普鲁本辛普鲁本辛普鲁本辛) )poorabsorption(po)andBBBpenetrationpoorabsorption(po)andBBBpenetrationantispasmodicantispasmodic effectseffects inin GI,GI, treatmenttreatment ofofpepticulcerdiseasepepticulcerdiseaseothersSelectiveM-receptorantagonistsPirenzepine哌仑西平：哌仑西平：M1andM4Telenzepine替仑西平：替仑西平：moreselectivetoM1 ulcerTripitamine：M2andM3selectiveDarifenacin达非那新达非那新othersNicotinic receptor antagonistsActingonsympatheticandparasympatheticActingonsympatheticandparasympatheticganglioniccells;reducingbloodpressurebyganglioniccells;reducingbloodpressurebyinhibitingsympatheticganglia(havebeeninhibitingsympatheticganglia(havebeenabandonedforclinicaluse,duetotheirlackabandonedforclinicaluse,duetotheirlackofselectivity)ofselectivity)Short-acting;tachyphylaxisShort-acting;tachyphylaxisUsedfortreatmentofhypertensionUsedfortreatmentofhypertension Trimethaphan(Trimethaphan(樟磺咪芬樟磺咪芬樟磺咪芬樟磺咪芬) )Mecamylamine(Mecamylamine(美卡拉明美卡拉明美卡拉明美卡拉明) )NN receptor antagonists(Ganglionic Blocking drugs)Twoclasses:Non-depolarizing: drugs act as competitive antagonistsDepolarizing: succinylcholine (琥珀胆碱琥珀胆碱,司可林司可林) Note: Belong to Skeletal Muscle Relaxants. It is important to realize that muscle relaxation does not ensure unconsciousness, amnesia, or analgesia. NM receptor antagonists (Neuromuscular Blocking drugs )1.1.Depolarizing neuromuscular blockers (Depolarizing neuromuscular blockers (Non-competitive) ) (depolarizing skeletal muscle relaxants) (depolarizing skeletal muscle relaxants)actasacetylcholine(ACh)receptoragonists导致肌束颤动导致肌束颤动thedepolarizedmembranesremaindepolarizedandunresponsivetosubsequentimpulses(ie,theyareinastateofdepolarizingblock).notmetabolizedbyAChE使作用延长，过量不能被新斯的使作用延长，过量不能被新斯的明解救明解救-theydiffuseawayfromtheneuromuscularjunctionandarehydrolyzedintheplasmaandliverbypseudocholinesterase(nonspecificcholinesterase,plasmacholinesterase,orbutyrylcholinesterase)andeliminationbykidneyNM receptor antagonists (Neuromuscular Blocking drugs )Succinylcholine琥珀胆碱琥珀胆碱, ScolineSuccinylcholineistheonlydepolarizingagentusedclinically(t1/2=2-4min).Propertiesofactions:Propertiesofactions: initiallytransientfasciculationsinitiallytransientfasciculations anti-AChEpotentiatestheireffectsanti-AChEpotentiatestheireffects tachyphylaxistachyphylaxis( (快速耐受性快速耐受性快速耐受性快速耐受性) )afterrepeatedusesafterrepeateduses noganglion-blockingeffectsattherapeuticdosesnoganglion-blockingeffectsattherapeuticdoses thedrugsarehighlypolar,poorbioavailability;i.v.thedrugsarehighlypolar,poorbioavailability;i.v. asquaternarycompounds.donotenterCNSasquaternarycompounds.donotenterCNSacetylcholineacetylcholinesuccinylcholinesuccinylcholineMain pharmacological effectsTransientTransient excitationexcitation (fasciculations(fasciculations肌肌肌肌束束束束震震震震颤颤颤颤), ),andthenandtheninhibition(relaxation)inhibition(relaxation)RelaxRelaxSkeletalMusclesSkeletalMusclesinin neck,limbsneck,limbsface,tongue,throat;lesseffectiveonface,tongue,throat;lesseffectiveonbreathmusclesattherapeuticdosesbreathmusclesattherapeuticdosesSuccinylcholine琥珀胆碱琥珀胆碱, ScolineClinical uses AnadjuvantinanesthesiaoroperationAnadjuvantinanesthesiaoroperation IntubationofIntubationoftrachea,esophagus,trachea,esophagus,etc.etc. PreventionoftraumaduringelectroshocktherapyPreventionoftraumaduringelectroshocktherapyContraindicatedContraindicatedinawakepatients,shoulduseinawakepatients,shoulduseunderanesthesiaunderanesthesiaSuccinylcholine琥珀胆碱琥珀胆碱, ScolineAdverse effects(1)Apnea(respiratoryparalysis)(1)Apnea(respiratoryparalysis)overdoseoroverdoseorhypersensitivepatientshypersensitivepatients; ;neostigminepotentiatesthetoxiceffectsneostigminepotentiatesthetoxiceffects(2)Fasciculations(2)Fasciculations肌束震颤肌束震颤肌束震颤肌束震颤muscularpainafteroperationmuscularpainafteroperation(becauseoftransientfasciculations)(becauseoftransientfasciculations)(3)Malignanthyperthermia(3)MalignanthyperthermiageneticabnormalitygeneticabnormalitySuccinylcholine琥珀胆碱琥珀胆碱, Scoline(4)ElevationofK(4)ElevationofK+ +inplasmainplasmacontraindicatedcontraindicatedinpatientswithatendencyinpatientswithatendencyofhyperkalemia(burninjury,massiveofhyperkalemia(burninjury,massivetrauma,neurologicaldisorders)trauma,neurologicaldisorders)(5)Cardiovascularresponse(5)Cardiovascularresponsevariousarrhythmiavariousarrhythmia(6)Others(6)Othersriseinintraocularpressure(glaucoma);riseinintraocularpressure(glaucoma);histaminereleasehistaminereleaseSuccinylcholine琥珀胆碱琥珀胆碱, ScolineGeneticVariation:EffectsonDurationofActionofSuccinylcholineThedurationofactionisprolongedbyhighdosesorbyabnormalmetabolism.Thelattermayresultfromhypothermia,lowpseudocholinesteraselevels,orageneticallyaberrantenzyme.(hypothermiadecreasestherateofhydrolysis)Lowpseudocholinesteraselevelsgenerallyproduceonlymodestprolongationofsuccinylcholinesactions(220min).Onein50patientshasonenormalandoneabnormal(atypical)pseudocholinesterasegene,resultinginaslightlyprolongedblock(2030min).Evenfewer(1in3000)patientshavetwoabnormalgenes(homozygousatypical)thatproduceanenzymewithlittleornoaffinityforsuccinylcholineandhaveaverylongblockade(e.g.,48h)followingadministrationofsuccinylcholine.ScolineApnea：mechanicalventilationDrug interactionsThiopental(硫喷妥硫喷妥)，易分解，易分解AChEinhibitors:AChEinhibitors,cyclophosphamide(AChEinhibitors,cyclophosphamide(环磷酰环磷酰环磷酰环磷酰胺胺胺胺),procaine(),procaine(普鲁卡因普鲁卡因普鲁卡因普鲁卡因),),etcetc. .Someantibiotics:kanamycin(kanamycin(卡卡卡卡那那那那霉霉霉霉素素素素),),polymyxins(polymyxins(多多多多粘粘粘粘菌菌菌菌素素素素),),etc.etc.(synergisminneuromuscularblocking)(synergisminneuromuscularblocking)Succinylcholine琥珀胆碱琥珀胆碱, Scoline2. Nondepolarizing Nondepolarizing neuromuscular neuromuscular blockers blockers ( (Competitive )(nondepolarizing skeletal muscle relaxants)(nondepolarizing skeletal muscle relaxants) Tubocurarine (筒箭毒碱筒箭毒碱)ReversiblybindtothenicotinicReversiblybindtothenicotinicreceptorattheneuromuscularreceptorattheneuromuscularjunction(competitiveantagonists)junction(competitiveantagonists)(note: curare rarely used)Effects:Effects:competitiveblockadeofcompetitiveblockadeofN NMMreceptorsreceptorsPharmacologicaleffects:Pharmacologicaleffects: RelaxRelaxSkeletalMusclesSkeletalMusclesinin 眼部肌肉，四肢、颈部、躯干、肋间肌、膈肌呼吸抑制Uses:Uses: adjuvanttreatmentofanesthesiaoroperationsadjuvanttreatmentofanesthesiaoroperationsTubocurarine (筒箭毒碱筒箭毒碱)Adverseeffects:Adverseeffects: Respiratoryparalysis:Respiratoryparalysis:canbereversedbyneostigminecanbereversedbyneostigmine Enhancinghistaminerelease:Enhancinghistaminerelease:BPBP ,hypotension,hypotension,bronchoconstriction,salivarysecretionbronchoconstriction,salivarysecretion Blockingganglion:Blockingganglion:BPBP Contraindications:Contraindications:myastheniamyastheniagravis,gravis,bronchialbronchialasthma,shock,child(10y)asthma,shock,child(atracuriumrocuronium)BotulinumToxin肉毒毒素肉毒毒素-SkeletalMuscleRelaxants-blocksAChreleasefromcholinergicterminals-selectiveforAChterminals-irreversible;Botoxactsasaproteasethatcleavesspecificproteinsinvolvedinexocytosis.resultsinflaccidparalysis（松弛性麻痹）inmuscles;(canalsobeusedforexcessivesweating,tension/migraine)Acts by cleaving SNARE proteins inhibits ACh releaseStrabismus(lack of parallelism of eyes，斜视斜视), blepharospasm (eyelid spasm), dystonia (abnormal tonicity，肌张力障碍肌张力障碍).ExcessivesweatingCosmeticprocedures( “frown lines” or “crows feet”)Note:effectscanlastfor3-6months.LA TimesBotulinumToxinApplicationsAdrenergic PharmacologyParasympatheticNSParasympatheticNSEYEEYEContraction of iris sphincter muscle(pupil dilates)Contraction of ciliary muscle(lens accommodates for near vision)LacrimalglandLacrimalglandStimulates tearsSalivaryglandSalivaryglandCopious, water secretionTracheaandbronchiolesTracheaandbronchiolesConstricts, increase secretionHeartHeartratecontractility GastrointestinalGastrointestinalMuscle motility & tone UretersandbladderUretersandbladderContraction of detrusorRelaxation of trigone &sphincter Genitalia-maleGenitalia-maleStimulates erectionSympatheticNSSympatheticNSEYEEYEcontraction of iris radial muscle (pupil dilates)contraction of ciliary muscle(lens accommodates for near vision)SalivaryglandSalivaryglandcopious, water secretionTracheaandbronchiolesTracheaandbronchiolesdilatesHeartHeartratecontractility BloodvesselsBloodvesselsdilatation (Skeletal muscle) constriction (skin,mucus, membranes & splanchin area) GastrointestinalGastrointestinalmuscle motility & tone contraction of sphinctersUretersandbladderUretersandbladderrelaxes detrusorcontraction of trigone &sphincterGenitalia-femaleGenitalia-femaleRelaxation of uterusNoradrenergicNerve:Synthesis,storageandreleaseofNETyrosine tyrosine hydroxylase (TH)L-DOPA DOPA decarboxylasedopamine (DA) dopamine beta-hydroxylase (DBH) norepinephrine (NE) UptakeUptakeneurotransmittertransportersneurotransmittertransporters uptake1:neuronaluptakeuptake1:neuronaluptake uptake2:non-neuronaluptakeuptake2:non-neuronaluptake EnzymaticdegradationEnzymaticdegradation monoamineoxidase(MAO)monoamineoxidase(MAO) catechol-O-methyltransfereasecatechol-O-methyltransferease(COMT)(COMT)Regulation of NE Synthesis and TurnoverTyrosinehydroxylase(TH)activityisratelimitingTHactivityinhibitedbyNEproductTHactivitymodulatedbypresynapticautoreceptors-alpha2receptorscanreduceNErelease-beta2receptorscanincreaseNEreleasePresynapticheteroreceptorscanmodulateNErelease-AChcanreduceNEreleaseTHactivityincreasesordecreasestomaintainsteady-statelevelsofnorepinephrine.Theaboveprocessescontributetoregulationofsteady-stateNElevels(rateofsynthesis=rateofoutput)Catecholamine Biosynthetic PathwayNorepinephrineandEpinephrineSynthesisintheAdrenalMedulla- NE is stored in vesicles- DBH is located in vesicles - PNMT苯乙胺N甲基转移酶 is located in the cytosol . - EPI is stored in vesicles- EPI (80%) and NE (20%) released into blood- These hormones bind adrenergic receptors on target cells, inducing the same effects as direct sympathetic nervous stimulation.Chromaffin cell肾上腺嗜铬细胞NEPNMTNEEPIEPIEPIdisposition:metabolism by COMT（儿茶酚-O-甲基转移酶）, MAO, sulfation, uptake into NE terminalsNE Metabolism-takesplacewithinthesamecellswheretheaminesaresynthesized,andinliver-ExtraneuronalO-methylationofnorepinephrineandepinephrinetometanephrines(尿甲氧基肾上腺素尿甲氧基肾上腺素)representminorpathwaysofmetabolism.MHPG:was used as an index of CNS NE turnoverbut generated mostly from peripheryVMA:sometimes used as an index of NE turnoverSulfateconjugates also prevalentAdrenergic Receptors/Adrenoceptors 1 2 1G-Protein Coupled ReceptorsNorepinephrine (NE) releasesignaltransductionresponsereceptorbinding(reversible)receptoractivation(23)low affinity for binding NE 1AdrenergicReceptors:GproteintermedGqphospholipaseCactivation,IP3mechanism:mobilizesandincreasesintracellularfreecalciumeffects:primarilysmoothmusclecontraction 2AdrenergicReceptors:InhibitionofadenylylcyclasethroughGiproteinsmechanism:decreasesintracellularcAMPlevelseffects:decreasedproteinphosphorylation,decreasedcellularfunction AdrenergicReceptors:ActivationofadenylylcyclasethroughGsproteinsmechanism:increasesintracellularcAMPlevelseffects:phosphorylationofintracellularproteinssmoothmusclerelaxation,cardiacmusclecontractionAdrenergicReceptorSubtypes & G-ProteinCoupledMechanismsAdrenergicReceptor(adrenoreceptors)ThesearereceptorsactivatedbyNE,EPI,ordrugswithsimilaractions3fatcells(notNE)Drug actions and classification1.1. Mechanisms of drug actions Mechanisms of drug actions1.1Directactionsonthereceptors1.1Directactionsonthereceptors AgonistsAgonists AntagonistsAntagonists1.2Indirectactions1.2Indirectactionsvia via affectingtransmittersaffectingtransmitters SynthesisSynthesis(L-dopa)(L-dopa) TransportandstorageTransportandstorage(imipramine,reserpine)(imipramine,reserpine) ReleaseRelease( (ephedrine,amphetamine)ephedrine,amphetamine) InactivationInactivation(MAOI)(MAOI)1.3Mimeticsandantagonists1.3Mimeticsandantagonists(1)Mimetics(1)Mimetics direct-acting:direct-acting:receptoragonistsreceptoragonists indirect-acting:indirect-acting:increasingamountsand/oreffectsoftransmittersincreasingamountsand/oreffectsoftransmitters(2)Antagonists(2)Antagonists direct-acting:direct-acting:receptorantagonistsreceptorantagonists indirect-acting:indirect-acting:decreasingamountsand/oreffectsoftransmittersdecreasingamountsand/oreffectsoftransmittersNon-catecholamineNon-catecholamine Indirect-actingbyIndirect-actingbycausingthereleaseofcausingthereleaseofstoredcatecholamine.storedcatecholamine. NotinactivatedbyNotinactivatedbyCOMT;somearepoorCOMT;somearepoorsubstrateforMAOsubstrateforMAO(orallyactive,a(orallyactive,aprolongeddurationofprolongeddurationofaction)action) GreateraccesstotheGreateraccesstotheCNSCNSCatecholamineCatecholamine HighpotencyinHighpotencyinactivatingactivating oror receptorsreceptors RapidinactivationbyRapidinactivationbyCOMTandbyMAOCOMTandbyMAO PoorpenetrationintothePoorpenetrationintotheCNSCNSSympathomimeticaminesSympathomimeticaminesStructure-activityrelationshipofStructure-activityrelationshipofcatecholaminesandrelatedcompoundscatecholaminesandrelatedcompounds -receptoractivity麻黄碱苯乙胺Bioavailability of oral admin.Duration.CNS distributionBlock MAO uptake-1For activation of receptorAdrenoceptors Direct mode Direct mode e.g.Norepinephrinee.g.Norepinephrineepinephrineepinephrineisoproterenolisoproterenol Indirect modeIndirect mode Mixed modeMixed mode e.g.ephedrinee.g.ephedrineThemodeofactionThemodeofactionofsympathomimeticdrugsofsympathomimeticdrugs Enhances release of stored Enhances release of stored catecholaminescatecholamines e.g.amphetaminee.g.amphetamine Inhibition of reuptake of Inhibition of reuptake of released catecholaminesreleased catecholamines e.g.cocainee.g.cocaine Inhibition of MAOInhibition of MAOe.g.pargylinee.g.pargyline拟交感药Adrenoceptoragonists(1) , , receptoragonistsreceptoragonists epinephrine(adrenaline)epinephrine(adrenaline)，dopamine,dopamine,ephedrineephedrine(2)(2) receptoragonistsreceptoragonists 1 1 22receptoragonists:receptoragonists: norepinephrinenorepinephrine 11receptoragonists:receptoragonists:phenylephrinephenylephrine 22receptoragonists:receptoragonists:clonidineclonidine(3)(3) receptoragonistsreceptoragonists： 1 1 22receptoragonists:receptoragonists: isoproterenolisoproterenol 11receptoragonists:receptoragonists: dobutaminedobutamine 22receptoragonists:receptoragonists: salbutenolsalbutenolDrug actions and classificationPharmacological effects 1, 2, 1, 2receptoragonists(1)Cardiaceffects(1)Cardiaceffects 1 1: :contractilitycontractility (positiveinotropic),(positiveinotropic),HRHR (positivechronotropic),(positivechronotropic),cardiacoutputcardiacoutput , ,oxygenconsumptionoxygenconsumption , ,inducingarrhythmiainducingarrhythmia(2)Vasculareffects(2)Vasculareffects 1 1：vasoconstriction(skin,mucous,viscera),vasoconstriction(skin,mucous,viscera),especiallyatlargerdosesespeciallyatlargerdoses 2 2：vasodilatationofskeletalmusclesvasodilatationofskeletalmusclesandcoronaryvesselsandcoronaryvesselsEpinephrine, Adrenaline (肾上腺素肾上腺素):DIRECTConcentration-dependentresponseinvascularsmoothmuscletoepinephrinePredominant Effectslow EPI 2 high EPI 2 Epinephrine reversal（adrenaline reversal） BP antagonistepinephrineepinephrine(3)BloodpressureSystolicBPSystolicBP ,DiastolicBP,DiastolicBP(slight) (4)Respiratory 2 2：dilatationofbronchialsmoothmusclesdilatationofbronchialsmoothmuscles(Bronchodilatation) 1 1：reducingcongestionandedemaofreducingcongestionandedemaofbronchialmucosabronchialmucosa(5)Metaboliceffectsbloodglucosebloodglucose (hyperglycemia)(hyperglycemia); ;freefattyacidsfreefattyacids (lipolysis)(lipolysis)Epinephrine, AdrenalineEffectsofcatecholaminesEffectsofcatecholamines（therapeuticdosestherapeuticdoses）PredominantEffects:PredominantEffects:NE:NE: & & 1 1 effectseffectsEPI:EPI: 1 1, , 2 2 thenathigherconcentrationsthenathigherconcentrations effectspredominateeffectspredominateISO:ISO: 1 1andand 2 2Clinical usesSystematic uses:Systematic uses:Cardiac arrestCardiac arrestAnaphylactic shockAnaphylactic shock（过敏性休克）（过敏性休克）（过敏性休克）（过敏性休克）Acute bronchial asthmaAcute bronchial asthmaTopical uses:Topical uses:Adjuvant of Adjuvant of local anesthesialocal anesthesiaBleedingBleedingEpinephrine, AdrenalineAdverse effects(1)Cardiacarrhythmias(2)Hemorrhage(cerebralorsubarachnoid)(cerebralorsubarachnoid) : :reason:amarkedelevationofBPreason:amarkedelevationofBP(3)Centralexcitation：anxiety,headache.anxiety,headache.(4)Contraindications:heartdiseases,heartdiseases,hypertension,coronaryarterialdisease,hypertension,coronaryarterialdisease,arteriosclerosis,hyperthyroidismarteriosclerosis,hyperthyroidismEpinephrine, Adrenaline(1)Cardiaceffects(1)Cardiaceffects： 1receptor1receptor,weak,weak(2)Vasculareffects(2)Vasculareffects：DAreceptorDAreceptor：vasodilatationofrenalvasodilatationofrenalandmesentericarteries,bloodflowandmesentericarteries,bloodflow (smalldoses);(smalldoses); 1receptor1receptor：vasoconstrictionofvasoconstrictionofskin,mesentericvessels(largerdoses)skin,mesentericvessels(largerdoses)(3)Renaleffects(3)Renaleffects：renalvasodilatation;renalvasodilatation;natriureticeffectsnatriureticeffectsDopamine (多巴胺多巴胺): DIRECTPharmacological effects : Pharmacological effects : , , receptor,dreceptor,dopaminergicreceptoropaminergicreceptoragonistsagonistsClinical uses (1)Shockcardiacandsepticshockcardiacandsepticshock(2)AcuterenalfailurecombinedwithfurosemidecombinedwithfurosemideAdverse effects short-livedshort-lived tachycardia,arrhythmia,reductioninurinetachycardia,arrhythmia,reductioninurineflow(renalvasoconstriction)flow(renalvasoconstriction)Dopamine PromotingPromotingreleasereleaseofofNE,NE,weakweakagonistagonisteffectseffects onon 1 1、 2 2、 1 1、 2 2receptorsreceptorsProperties：chemicallystable,orallyeffectivechemicallystable,orallyeffective； lesspotentbutlongeractionduration;lesspotentbutlongeractionduration;centralcentral stimulating:stimulating:alertnessalertness , ,fatiguefatigue , ,preventssleeppreventssleep(adverseeffects)(adverseeffects)Tachyphylaxis(Tachyphylaxis(快速耐受快速耐受快速耐受快速耐受). ).Ephedrine ( (麻黄碱麻黄碱):): MIXEDMIXED EpinephrineEpinephrineEphedrineEphedrineClinical uses (1)Preventionofhypotension:(1)Preventionofhypotension:anestheticsanesthetics(2)Nasaldecongestion:(2)Nasaldecongestion:nasaldropnasaldrop(3)Bronchialasthma:(3)Bronchialasthma:mild,chroniccasesmild,chroniccases(4)Relievingallergicdisorders:(4)Relievingallergicdisorders:urticaria(urticaria(风疹风疹风疹风疹),),angioneuroticedemaangioneuroticedemaEphedrine Norepinephrine, Noradrenaline(去甲肾上腺素去甲肾上腺素去甲肾上腺素去甲肾上腺素): DIRECTDIRECT Pharmacological effect 1, 2receptoragonists(1)Vasculareffects： 1 1：vasoconstriction(skin,renal,brain,vasoconstriction(skin,renal,brain,hepatic,mesenteric,hepatic,mesenteric,etcetc.),bloodflow.),bloodflow 2 2：inhibitingNEreleaseinhibitingNEreleaseActionsofnorepinephrineonpost-synaptic( 1)andpre-synaptic( 2 )receptors(2)Bloodpressure：SystolicBP ,DiastolicBP (especiallyatlargerdoses)(3)Cardiaceffects：Weakdirectstimulation( 1);inhibitionviareflex(in vivo)Netresult:littlecardiacstimulatesCoronaryarterydilationNorepinephrine, Noradrenaline EffectsofcatecholaminesEffectsofcatecholamines（therapeuticdosestherapeuticdoses）PredominantEffects:PredominantEffects:NE:NE: & & 1 1 effectseffectsEPI:EPI: 1 1, , 2 2 thenathigherconcentrationsthenathigherconcentrations effectspredominateeffectspredominateISO:ISO: 1 1andand 2 2Clinical uses ( (limitedlimitedtherapeuticvalue)therapeuticvalue)(1)Shock(1)Shockusedused inin earlyearly phasephase ofof somesome typestypes ofof shock:shock:smalldosesandshorterdurationsmalldosesandshorterduration ( (dopaminedopamine isisbetter;better;replacedreplacedbybyMetaraminolMetaraminol间间间间羟胺羟胺羟胺羟胺) )(2)Hypotensionduetodrugpoisoning(2)Hypotensionduetodrugpoisoningespeciallyforespeciallyforchlorpromazinechlorpromazine( (氯丙嗪氯丙嗪氯丙嗪氯丙嗪) )(3)Hemorrhageinupperalimentarytract(3)HemorrhageinupperalimentarytractorallygivenafterdilutionorallygivenafterdilutionNorepinephrine, Noradrenaline Adverse effects(1)Ischemiaandnecrosisatthesiteof(1)Ischemiaandnecrosisatthesiteofiviv administrationadministrationrelievedbyfiltratingthearearelievedbyfiltratingtheareawithwithphentolaminephentolamine( ( receptorantagonist)receptorantagonist)(2)(2) AcuteAcute renalrenal failurefailureavoidingavoiding largerlarger dosesdosesandandlongerlongerduration;duration;monitoringmonitoringurinaryurinaryvolumevolume(3)Contraindication(3)Contraindicationhypertension,hypertension,arteriosclerosis,heartdiseases,severearteriosclerosis,heartdiseases,severeurinaryvolumeurinaryvolume ,microcirculationdisorders,microcirculationdisordersNorepinephrine, Noradrenaline ActingonActingon receptorsdreceptorsdirectlyirectly,promoting,promotingNEreleaseindirectlyNEreleaseindirectly；WeakereffectsandlongerdurationthanNE,WeakereffectsandlongerdurationthanNE,Weakeffectsonrenalvessels;Weakeffectsonrenalvessels;Usedinearlyphaseofshock,hypotensionUsedinearlyphaseofshock,hypotension Metaraminol间羟胺间羟胺Inducesreflexbradycardia,usedinhypotension,Inducesreflexbradycardia,usedinhypotension,paroxysmalsupraventriculartachycardiaparoxysmalsupraventriculartachycardia；ActivateActivate receptoratnormaldosereceptoratnormaldoseBlockBlock receptorathighdosereceptorathighdosePhenylephrine:Phenylephrine: Mydriasis,pupillarydilatorMydriasis,pupillarydilatormuscles,noorlesseffectonintraocularmuscles,noorlesseffectonintraocularpressure,short-acting(forseveralhours);pressure,short-acting(forseveralhours);可作为快速扩瞳药可作为快速扩瞳药可作为快速扩瞳药可作为快速扩瞳药 Methoxamine甲氧明甲氧明甲氧明甲氧明: DIRECTINDIRECTDIRECTINDIRECT Phenylephrine苯苯苯苯肾上腺素肾上腺素肾上腺素肾上腺素: DIRECTINDIRECTDIRECTINDIRECT 1receptoragonistsClonidine: DIRECTUses:antihypertensivedrug;canbeadministeredastransdermalpatch(permitscontinuousadministration)Mechanismofaction:2-adrenergicpartialagonist;actionspredominantlyinCNSlowersbloodpressurebyinhibitingsympatheticvasomotortoneAdverseeffects:(ivadministrationmayresultintransientincreaseinbloodpressure(activationofpost-synapticreceptors);drymouth,sedation 2receptoragonists(1)Cardiaceffects(1)Cardiaceffects( ( 1 1receptor)receptor) (2)(2) VascularVascular effectseffects andand bloodbloodpressurepressure 22receptor:receptor: dilatationdilatationofofskeletalskeletalmusclesandcoronaryvesselsmusclesandcoronaryvessels； SPSP ， DPDP oror ， pulsepulsepressurepressure (3)Bronchodilatation(3)Bronchodilatation( ( 22receptor)receptor)(4)Metabolism(4)MetabolismPromotingeffectsasepinephrinePromotingeffectsasepinephrineIsoproterenol, Isoprenaline异丙肾上腺素异丙肾上腺素:DIRECTDIRECTPharmacological effects : Pharmacological effects : 1 1, 2 2receptoragonistsreceptoragonistsEffectsofcatecholaminesEffectsofcatecholamines（therapeuticdosestherapeuticdoses）PredominantEffects:PredominantEffects:NE:NE: & & 1 1 effectseffectsEPI:EPI: 1 1, , 2 2 thenathigherconcentrationsthenathigherconcentrations effectspredominateeffectspredominateISO:ISO: 1 1andand 2 2Clinical uses(1)Cardiacarrest/A-Vblock:(1)Cardiacarrest/A-Vblock:inemergenciesinemergencies(2)Shock(2)Shock/ /BronchialBronchialasthma:asthma:replacedreplacedbybyotherothersympathomimeticssympathomimeticsAdverse effects(1)Heartstimulation,arrhythmia(1)Heartstimulation,arrhythmia(2)Contraindications:(2)Contraindications:coronaryheartcoronaryheartdisease,myocarditis,hyperthyroidismdisease,myocarditis,hyperthyroidismIsoproterenol, Isoprenaline 1receptoragonistsHeartfailure(aftercardiacsurgeryor(aftercardiacsurgeryorcongestiveHForacutemyocardialinfarction;congestiveHForacutemyocardialinfarction;short-termtreatment)short-termtreatment)CardiacstimulationDobutamine (多巴酚丁胺多巴酚丁胺): DIRECTDIRECT 2 2receptoragonistsreceptoragonistsTerbutaline:博利康尼，博利康尼，DIRECTUses: BronchialBronchialasthmaasthma Dilationofbronchialsmoothmuscle; 2 1agonist(partiallyselective):preferentialactivationofpulmonary 2receptorsbyinhalation.PrematureLaborPrematureLabor(combinewithritodrine，羟苄羟麻黄碱羟苄羟麻黄碱 ).Adverseeffects: headache,cardiacstimulationandskeletalmusclefinetremor( 2receptorsonpresynapticmotorterminals;theiractivationenhancesAChrelease). 2receptoragonistsTerbutaline (特布他林特布他林): DIRECTUses：BronchialBronchialasthmaasthma dilationofbronchialsmoothmuscle; 2 1agonist(partiallyselective):preferentialactivationofpulmonary 2receptorsbyinhalation.Use:PrematureLabor(withritodrine).Adverseeffects: headache,cardiacstimulationandskeletalmusclefinetremor( 2receptorsonpresynapticmotorterminals;theiractivationenhancesAChrelease).TerbutalineTerbutaline: :博利康尼博利康尼博利康尼博利康尼间羟异丁肾上腺素Metaproterenol间羟异丙肾上腺 Albuterol舒喘灵，沙丁胺醇Isoetharine，N-异丙基乙基降肾上腺素异丙基乙基降肾上腺素Pirbuterol，吡舒喘宁吡丁醇，吡舒喘宁吡丁醇Bitolterol，叔丁肾上腺素双甲苯酸酯，叔丁肾上腺素双甲苯酸酯Fenoterol，培罗坦克，培罗坦克Salmeterol，沙美特罗，沙美特罗Ritodrine，羟苄麻黄碱，羟苄麻黄碱Procaterol，异丙喹喘宁，异丙喹喘宁 2receptoragonistsDrug actions and classificationSeeyounextClass!