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1、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: mecamylaminemecamylam
2、ine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) ) DrugclassificationofcholinergicantagonistsMuscarinicAntago
3、nists(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 paralysisofparalysisofaccommodationaccommodatio
4、nnearsightnearsightspasmofspasmofaccommodationaccommodationfarsightfarsightirisirisAnteriorAnteriorchamberchamberCiliarymuscleCiliarymuscle(contraction)(contraction)zonulezonuleAnteriorAnteriorchamberchamberzonulezonuleCanalofSchlemmCanalofSchlemmposteriorposteriorchamberchamberCiliarymuscleCiliarym
5、uscle(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:relat
6、ivelyinsensitive:bileduct,urinarytract,bileduct,urinarytract,bronchialtractbronchialtract insensitive:insensitive:uterusuterus(3)(3)Inhibitionofexocrineglandsecretion salivary,sweatglandssalivary,sweatglands tear,respiratorytractglandstear,respiratorytractglands relativelyineffective:GItractrelative
7、lyineffective:GItractAtropine1.Pharmacological effects(4)CardiovascularSystem:dosedependent(4)CardiovascularSystem:dosedependent LowerLower therapeutictherapeutic doses:doses: HRHR(bradycardia);(bradycardia); BloodBloodvesselsandbloodpressure:vesselsandbloodpressure: noeffectnoeffect Moderatetohight
8、herapeuticdoses/highvagaltone:Moderatetohightherapeuticdoses/highvagaltone:HRHR(tachycardia);(tachycardia);A-VconductionA-Vconduction Largerdoses:Largerdoses:cutaneousvasodilatationcutaneousvasodilatation(5)CNSstimulation(5)CNSstimulationsedation,memoryloss,psychosis (highdose)(highdose)AtropineLowe
9、rtherapeuticdoses: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
10、 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,biliaryo
11、rrenalcolic,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)Antidotefororga
12、nophosphatepoisoning(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(:xeros
13、tomia(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&
14、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.Symptomatictreatmen
15、t: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;at
16、ropine;butbuthashasstrongerstrongercentralcentraleffectseffects(depression)(depression)Pre-anestheticPre-anesthetic medication,medication, preventionprevention ofofmotionsickness,Parkinsonsdiseasemotionsickness,ParkinsonsdiseaseScopolamine( (东莨菪碱东莨菪碱) )Actions and clinical uses654,654-2654,654-2Weak
17、eractionthanatropine,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 Ipratropi
18、um ( (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
19、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
20、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;reducingbloodpressurebyinhibitingsy
21、mpatheticganglia(havebeeninhibitingsympatheticganglia(havebeenabandonedforclinicaluse,duetotheirlackabandonedforclinicaluse,duetotheirlackofselectivity)ofselectivity)Short-acting;tachyphylaxisShort-acting;tachyphylaxisUsedfortreatmentofhypertensionUsedfortreatmentofhypertension Trimethaphan(Trimetha
22、phan(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 realiz
23、e 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 mus
24、cle 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-theydiffuseawayfromtheneuromuscularjunctionandarehydrolyzedinthep
25、lasmaandliverbypseudocholinesterase(nonspecificcholinesterase,plasmacholinesterase,orbutyrylcholinesterase)andeliminationbykidneyNM receptor antagonists (Neuromuscular Blocking drugs )Succinylcholine琥珀胆碱琥珀胆碱, ScolineSuccinylcholineistheonlydepolarizingagentusedclinically(t1/2=2-4min).Propertiesofact
26、ions: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-bl
27、ockingeffectsattherapeuticdoses thedrugsarehighlypolar,poorbioavailability;i.v.thedrugsarehighlypolar,poorbioavailability;i.v. asquaternarycompounds.donotenterCNSasquaternarycompounds.donotenterCNSacetylcholineacetylcholinesuccinylcholinesuccinylcholineMain pharmacological effectsTransientTransient
28、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;lesseffectiveonbreathmusclesattherapeuticdosesbreath
29、musclesattherapeuticdosesSuccinylcholine琥珀胆碱琥珀胆碱, ScolineClinical uses AnadjuvantinanesthesiaoroperationAnadjuvantinanesthesiaoroperation IntubationofIntubationoftrachea,esophagus,trachea,esophagus,etc.etc. PreventionoftraumaduringelectroshocktherapyPreventionoftraumaduringelectroshocktherapyContrai
30、ndicatedContraindicatedinawakepatients,shoulduseinawakepatients,shoulduseunderanesthesiaunderanesthesiaSuccinylcholine琥珀胆碱琥珀胆碱, ScolineAdverse effects(1)Apnea(respiratoryparalysis)(1)Apnea(respiratoryparalysis)overdoseoroverdoseorhypersensitivepatientshypersensitivepatients; ;neostigminepotentiatest
31、hetoxiceffectsneostigminepotentiatesthetoxiceffects(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)Malignanthyperthermiageneticabnormalitygeneticabnorm
32、alitySuccinylcholine琥珀胆碱琥珀胆碱, Scoline(4)ElevationofK(4)ElevationofK+ +inplasmainplasmacontraindicatedcontraindicatedinpatientswithatendencyinpatientswithatendencyofhyperkalemia(burninjury,massiveofhyperkalemia(burninjury,massivetrauma,neurologicaldisorders)trauma,neurologicaldisorders)(5)Cardiovascu
33、larresponse(5)Cardiovascularresponsevariousarrhythmiavariousarrhythmia(6)Others(6)Othersriseinintraocularpressure(glaucoma);riseinintraocularpressure(glaucoma);histaminereleasehistaminereleaseSuccinylcholine琥珀胆碱琥珀胆碱, ScolineGeneticVariation:EffectsonDurationofActionofSuccinylcholineThedurationofacti
34、onisprolongedbyhighdosesorbyabnormalmetabolism.Thelattermayresultfromhypothermia,lowpseudocholinesteraselevels,orageneticallyaberrantenzyme.(hypothermiadecreasestherateofhydrolysis)Lowpseudocholinesteraselevelsgenerallyproduceonlymodestprolongationofsuccinylcholinesactions(220min).Onein50patientshas
35、onenormalandoneabnormal(atypical)pseudocholinesterasegene,resultinginaslightlyprolongedblock(2030min).Evenfewer(1in3000)patientshavetwoabnormalgenes(homozygousatypical)thatproduceanenzymewithlittleornoaffinityforsuccinylcholineandhaveaverylongblockade(e.g.,48h)followingadministrationofsuccinylcholin
36、e.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(polymyxi
37、ns(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 mus
38、cle relaxants) Tubocurarine (筒箭毒碱筒箭毒碱)ReversiblybindtothenicotinicReversiblybindtothenicotinicreceptorattheneuromuscularreceptorattheneuromuscularjunction(competitiveantagonists)junction(competitiveantagonists)(note: curare rarely used)Effects:Effects:competitiveblockadeofcompetitiveblockadeofN NMMr
39、eceptorsreceptorsPharmacologicaleffects: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
40、:Respiratoryparalysis:canbereversedbyneostigminecanbereversedbyneostigmine Enhancinghistaminerelease:Enhancinghistaminerelease:BPBP ,hypotension,hypotension,bronchoconstriction,salivarysecretionbronchoconstriction,salivarysecretion Blockingganglion:Blockingganglion:BPBP Contraindications:Contraindic
41、ations:myastheniamyastheniagravis,gravis,bronchialbronchialasthma,shock,child(10y)asthma,shock,child(atracuriumrocuronium)BotulinumToxin肉毒毒素肉毒毒素-SkeletalMuscleRelaxants-blocksAChreleasefromcholinergicterminals-selectiveforAChterminals-irreversible;Botoxactsasaproteasethatcleavesspecificproteinsinvol
42、vedinexocytosis.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).ExcessivesweatingCosme
43、ticprocedures( “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)Lacrimalgla
44、ndLacrimalglandStimulates tearsSalivaryglandSalivaryglandCopious, water secretionTracheaandbronchiolesTracheaandbronchiolesConstricts, increase secretionHeartHeartratecontractility GastrointestinalGastrointestinalMuscle motility & tone UretersandbladderUretersandbladderContraction of detrusorRelaxat
45、ion of trigone &sphincter Genitalia-maleGenitalia-maleStimulates erectionSympatheticNSSympatheticNSEYEEYEcontraction of iris radial muscle (pupil dilates)contraction of ciliary muscle(lens accommodates for near vision)SalivaryglandSalivaryglandcopious, water secretionTracheaandbronchiolesTracheaandb
46、ronchiolesdilatesHeartHeartratecontractility BloodvesselsBloodvesselsdilatation (Skeletal muscle) constriction (skin,mucus, membranes & splanchin area) GastrointestinalGastrointestinalmuscle motility & tone contraction of sphinctersUretersandbladderUretersandbladderrelaxes detrusorcontraction of tri
47、gone &sphincterGenitalia-femaleGenitalia-femaleRelaxation of uterusNoradrenergicNerve:Synthesis,storageandreleaseofNETyrosine tyrosine hydroxylase (TH)L-DOPA DOPA decarboxylasedopamine (DA) dopamine beta-hydroxylase (DBH) norepinephrine (NE) UptakeUptakeneurotransmittertransportersneurotransmittertr
48、ansporters 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 Turnov
49、erTyrosinehydroxylase(TH)activityisratelimitingTHactivityinhibitedbyNEproductTHactivitymodulatedbypresynapticautoreceptors-alpha2receptorscanreduceNErelease-beta2receptorscanincreaseNEreleasePresynapticheteroreceptorscanmodulateNErelease-AChcanreduceNEreleaseTHactivityincreasesordecreasestomaintains
50、teady-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
51、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
52、, 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
53、 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 1Adr
54、energicReceptors:GproteintermedGqphospholipaseCactivation,IP3mechanism:mobilizesandincreasesintracellularfreecalciumeffects:primarilysmoothmusclecontraction 2AdrenergicReceptors:InhibitionofadenylylcyclasethroughGiproteinsmechanism:decreasesintracellularcAMPlevelseffects:decreasedproteinphosphorylat
55、ion,decreasedcellularfunction AdrenergicReceptors:ActivationofadenylylcyclasethroughGsproteinsmechanism:increasesintracellularcAMPlevelseffects:phosphorylationofintracellularproteinssmoothmusclerelaxation,cardiacmusclecontractionAdrenergicReceptorSubtypes & G-ProteinCoupledMechanismsAdrenergicRecept
56、or(adrenoreceptors)ThesearereceptorsactivatedbyNE,EPI,ordrugswithsimilaractions3fatcells(notNE)Drug actions and classification1.1. Mechanisms of drug actions Mechanisms of drug actions1.1Directactionsonthereceptors1.1Directactionsonthereceptors AgonistsAgonists AntagonistsAntagonists1.2Indirectactio
57、ns1.2Indirectactionsvia via affectingtransmittersaffectingtransmitters SynthesisSynthesis(L-dopa)(L-dopa) TransportandstorageTransportandstorage(imipramine,reserpine)(imipramine,reserpine) ReleaseRelease( (ephedrine,amphetamine)ephedrine,amphetamine) InactivationInactivation(MAOI)(MAOI)1.3Mimeticsan
58、dantagonists1.3Mimeticsandantagonists(1)Mimetics(1)Mimetics direct-acting:direct-acting:receptoragonistsreceptoragonists indirect-acting:indirect-acting:increasingamountsand/oreffectsoftransmittersincreasingamountsand/oreffectsoftransmitters(2)Antagonists(2)Antagonists direct-acting:direct-acting:re
59、ceptorantagonistsreceptorantagonists indirect-acting:indirect-acting:decreasingamountsand/oreffectsoftransmittersdecreasingamountsand/oreffectsoftransmittersNon-catecholamineNon-catecholamine Indirect-actingbyIndirect-actingbycausingthereleaseofcausingthereleaseofstoredcatecholamine.storedcatecholam
60、ine. NotinactivatedbyNotinactivatedbyCOMT;somearepoorCOMT;somearepoorsubstrateforMAOsubstrateforMAO(orallyactive,a(orallyactive,aprolongeddurationofprolongeddurationofaction)action) GreateraccesstotheGreateraccesstotheCNSCNSCatecholamineCatecholamine HighpotencyinHighpotencyinactivatingactivating or
61、or receptorsreceptors RapidinactivationbyRapidinactivationbyCOMTandbyMAOCOMTandbyMAO PoorpenetrationintothePoorpenetrationintotheCNSCNSSympathomimeticaminesSympathomimeticaminesStructure-activityrelationshipofStructure-activityrelationshipofcatecholaminesandrelatedcompoundscatecholaminesandrelatedco
62、mpounds -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
63、 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
64、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 22receptor
65、agonists:receptoragonists: norepinephrinenorepinephrine 11receptoragonists:receptoragonists:phenylephrinephenylephrine 22receptoragonists:receptoragonists:clonidineclonidine(3)(3) receptoragonistsreceptoragonists： 1 1 22receptoragonists:receptoragonists: isoproterenolisoproterenol 11receptoragonists
66、:receptoragonists: dobutaminedobutamine 22receptoragonists:receptoragonists: salbutenolsalbutenolDrug actions and classificationPharmacological effects 1, 2, 1, 2receptoragonists(1)Cardiaceffects(1)Cardiaceffects 1 1: :contractilitycontractility (positiveinotropic),(positiveinotropic),HRHR (positive
67、chronotropic),(positivechronotropic),cardiacoutputcardiacoutput , ,oxygenconsumptionoxygenconsumption , ,inducingarrhythmiainducingarrhythmia(2)Vasculareffects(2)Vasculareffects 1 1：vasoconstriction(skin,mucous,viscera),vasoconstriction(skin,mucous,viscera),especiallyatlargerdosesespeciallyatlargerd
68、oses 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 a
69、ntagonistepinephrineepinephrine(3)BloodpressureSystolicBPSystolicBP ,DiastolicBP,DiastolicBP(slight) (4)Respiratory 2 2：dilatationofbronchialsmoothmusclesdilatationofbronchialsmoothmuscles(Bronchodilatation) 1 1：reducingcongestionandedemaofreducingcongestionandedemaofbronchialmucosabronchialmucosa(5
70、)Metaboliceffectsbloodglucosebloodglucose (hyperglycemia)(hyperglycemia); ;freefattyacidsfreefattyacids (lipolysis)(lipolysis)Epinephrine, AdrenalineEffectsofcatecholaminesEffectsofcatecholamines（therapeuticdosestherapeuticdoses）PredominantEffects:PredominantEffects:NE:NE: & & 1 1 effectseffectsEPI:
71、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 bronchia
72、l asthmaTopical uses:Topical uses:Adjuvant of Adjuvant of local anesthesialocal anesthesiaBleedingBleedingEpinephrine, AdrenalineAdverse effects(1)Cardiacarrhythmias(2)Hemorrhage(cerebralorsubarachnoid)(cerebralorsubarachnoid) : :reason:amarkedelevationofBPreason:amarkedelevationofBP(3)Centralexcita
73、tion：anxiety,headache.anxiety,headache.(4)Contraindications:heartdiseases,heartdiseases,hypertension,coronaryarterialdisease,hypertension,coronaryarterialdisease,arteriosclerosis,hyperthyroidismarteriosclerosis,hyperthyroidismEpinephrine, Adrenaline(1)Cardiaceffects(1)Cardiaceffects： 1receptor1recep
74、tor,weak,weak(2)Vasculareffects(2)Vasculareffects：DAreceptorDAreceptor：vasodilatationofrenalvasodilatationofrenalandmesentericarteries,bloodflowandmesentericarteries,bloodflow (smalldoses);(smalldoses); 1receptor1receptor：vasoconstrictionofvasoconstrictionofskin,mesentericvessels(largerdoses)skin,me
75、sentericvessels(largerdoses)(3)Renaleffects(3)Renaleffects：renalvasodilatation;renalvasodilatation;natriureticeffectsnatriureticeffectsDopamine (多巴胺多巴胺): DIRECTPharmacological effects : Pharmacological effects : , , receptor,dreceptor,dopaminergicreceptoropaminergicreceptoragonistsagonistsClinical u
76、ses (1)Shockcardiacandsepticshockcardiacandsepticshock(2)AcuterenalfailurecombinedwithfurosemidecombinedwithfurosemideAdverse effects short-livedshort-lived tachycardia,arrhythmia,reductioninurinetachycardia,arrhythmia,reductioninurineflow(renalvasoconstriction)flow(renalvasoconstriction)Dopamine Pr
77、omotingPromotingreleasereleaseofofNE,NE,weakweakagonistagonisteffectseffects onon 1 1、 2 2、 1 1、 2 2receptorsreceptorsProperties：chemicallystable,orallyeffectivechemicallystable,orallyeffective； lesspotentbutlongeractionduration;lesspotentbutlongeractionduration;centralcentral stimulating:stimulatin
78、g: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:anesthet
79、icsanesthetics(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,
80、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：inhibitingNEreleaseinhibitingNErelease
81、Actionsofnorepinephrineonpost-synaptic( 1)andpre-synaptic( 2 )receptors(2)Bloodpressure：SystolicBP ,DiastolicBP (especiallyatlargerdoses)(3)Cardiaceffects：Weakdirectstimulation( 1);inhibitionviareflex(in vivo)Netresult:littlecardiacstimulatesCoronaryarterydilationNorepinephrine, Noradrenaline Effect
82、sofcatecholaminesEffectsofcatecholamines（therapeuticdosestherapeuticdoses）PredominantEffects:PredominantEffects:NE:NE: & & 1 1 effectseffectsEPI:EPI: 1 1, , 2 2 thenathigherconcentrationsthenathigherconcentrations effectspredominateeffectspredominateISO:ISO: 1 1andand 2 2Clinical uses ( (limitedlimi
83、tedtherapeuticvalue)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)Hypotensiondue
84、todrugpoisoning(2)Hypotensionduetodrugpoisoningespeciallyforespeciallyforchlorpromazinechlorpromazine( (氯丙嗪氯丙嗪氯丙嗪氯丙嗪) )(3)Hemorrhageinupperalimentarytract(3)HemorrhageinupperalimentarytractorallygivenafterdilutionorallygivenafterdilutionNorepinephrine, Noradrenaline Adverse effects(1)Ischemiaandnecr
85、osisatthesiteof(1)Ischemiaandnecrosisatthesiteofiviv administrationadministrationrelievedbyfiltratingthearearelievedbyfiltratingtheareawithwithphentolaminephentolamine( ( receptorantagonist)receptorantagonist)(2)(2) AcuteAcute renalrenal failurefailureavoidingavoiding largerlarger dosesdosesandandlo
86、ngerlongerduration;duration;monitoringmonitoringurinaryurinaryvolumevolume(3)Contraindication(3)Contraindicationhypertension,hypertension,arteriosclerosis,heartdiseases,severearteriosclerosis,heartdiseases,severeurinaryvolumeurinaryvolume ,microcirculationdisorders,microcirculationdisordersNorepinep
87、hrine, Noradrenaline ActingonActingon receptorsdreceptorsdirectlyirectly,promoting,promotingNEreleaseindirectlyNEreleaseindirectly；WeakereffectsandlongerdurationthanNE,WeakereffectsandlongerdurationthanNE,Weakeffectsonrenalvessels;Weakeffectsonrenalvessels;Usedinearlyphaseofshock,hypotensionUsedinea
88、rlyphaseofshock,hypotension Metaraminol间羟胺间羟胺Inducesreflexbradycardia,usedinhypotension,Inducesreflexbradycardia,usedinhypotension,paroxysmalsupraventriculartachycardiaparoxysmalsupraventriculartachycardia；ActivateActivate receptoratnormaldosereceptoratnormaldoseBlockBlock receptorathighdosereceptor
89、athighdosePhenylephrine: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: DIR
90、ECTINDIRECTDIRECTINDIRECT 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;actionspredominantlyinCNSlowersbloodp
91、ressurebyinhibitingsympatheticvasomotortoneAdverseeffects:(ivadministrationmayresultintransientincreaseinbloodpressure(activationofpost-synapticreceptors);drymouth,sedation 2receptoragonists(1)Cardiaceffects(1)Cardiaceffects( ( 1 1receptor)receptor) (2)(2) VascularVascular effectseffects andand bloo
92、dbloodpressurepressure 22receptor:receptor: dilatationdilatationofofskeletalskeletalmusclesandcoronaryvesselsmusclesandcoronaryvessels； SPSP ， DPDP oror ， pulsepulsepressurepressure (3)Bronchodilatation(3)Bronchodilatation( ( 22receptor)receptor)(4)Metabolism(4)MetabolismPromotingeffectsasepinephrin
93、ePromotingeffectsasepinephrineIsoproterenol, 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: &
94、 & 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:replac
95、edreplacedbybyotherothersympathomimeticssympathomimeticsAdverse effects(1)Heartstimulation,arrhythmia(1)Heartstimulation,arrhythmia(2)Contraindications:(2)Contraindications:coronaryheartcoronaryheartdisease,myocarditis,hyperthyroidismdisease,myocarditis,hyperthyroidismIsoproterenol, Isoprenaline 1re
96、ceptoragonistsHeartfailure(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
97、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,cardiacstimulationandskeletalmusclefinetrem
98、or( 2receptorsonpresynapticmotorterminals;theiractivationenhancesAChrelease). 2receptoragonistsTerbutaline (特布他林特布他林): DIRECTUses：BronchialBronchialasthmaasthma dilationofbronchialsmoothmuscle; 2 1agonist(partiallyselective):preferentialactivationofpulmonary 2receptorsbyinhalation.Use:PrematureLabor
99、(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!
