神经系统药理2胆碱能神经系统课件

各论3 神经系统药理2 1 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 16 Muscurinicreceptorantagonists McholinoceptorantagonistsAtropine阿托品 Antimuscarinicdrugs NcholinoceptorantagonistsNNcholinoceptorantagonists mecamylamine美加明 GanglionicBlockingdrugs rarelyused NMcholinoceptorantagonists succinylcholine琥珀胆碱 NeuromuscularBlockingdrugs BotulinumToxin肉毒毒素 blocksAChrelease Drugclassificationofcholinergicantagonists MuscarinicAntagonists Antimuscarinicdrugs Tertiaryamines叔胺类 Quaternaryamines季胺类 阿托品 东莨菪碱 异丙托溴铵 噻托溴铵 甲硝阿托品 1 Pharmacologicaleffects Atropine light 调节麻痹 1 Pharmacologicaleffects 2 Antispasmodicactiononsmoothmusclesensitive GI urinarybladder spasmodicstate relativelyinsensitive bileduct urinarytract bronchialtractinsensitive uterus 3 Inhibitionofexocrineglandsecretionsalivary sweatglandstear respiratorytractglandsrelativelyineffective GItract Atropine Pharmacologicaleffects 4 CardiovascularSystem dosedependentLowertherapeuticdoses HR bradycardia Bloodvesselsandbloodpressure noeffectModeratetohightherapeuticdoses highvagaltone HR tachycardia A Vconduction Largerdoses cutaneousvasodilatation 5 CNSstimulationsedation memoryloss psychosis highdose Atropine Lowertherapeuticdoses BlockPre synapticM1receptor AChrelease activatePost synapticM2receptor HR RegulationofK Channels Heartrate Moderatetohightherapeuticdoses BlockPost synapticM2receptor HR 2 Clinicaluses 1 OphthalmologyMeasurementoftherefractiveerrors 验光 childrenAcuteiritisoriridocyclitis mydriatics miotics topreventsynechia adhesion 2 AntispasmodicagentGI biliaryorrenalcolic enuresis 遗尿 3 InhibitingexocrineglandsecretionPreanestheticmedication 4 Bradyarrhythmiasinusornodalbradycardia A Vblock 5 Antidotefororganophosphatepoisoning Atropine 3 Adverseeffects 1 Sideeffectsdrymouth blurredvision sandyeyes 2 toxicityLethaldose 80 130mg adult 10mg child Low xerostomia drymouth anhidrosis dryskin tachycardiadModerate aboveplusmydriasis 扩瞳 cycloplegia 睫状肌麻痹 difficultyonspeaking swallowingcoma 昏迷 i e CNSsymptoms 3 DetoxicationSymptomatictreatment e g diazepam Physostigmine毒扁豆碱orpilocarpine匹鲁卡品 4 Contraindicationsglaucoma prostatauxe 前列腺肥大 fever Atropine ActionsandclinicalusesPeripheraleffectsaresimilartoatropine buthasstrongercentraleffects depression Pre anestheticmedication preventionofmotionsickness Parkinson sdisease Scopolamine 东莨菪碱 Actionsandclinicaluses654 654 2Weakeractionthanatropine lowertoxicity Anisodamine 山莨菪碱 Syntheticorsemi syntheticHomatropine后马托品Tropicamide托吡卡胺Cyclopentolate环喷托酯Eucatropine尤卡托品Lowersideeffectandshorterdurationformydriasis others Syntheticanti spasmagentsIpratropium 异丙托溴胺 asthmaScopolaminemethylbromide 溴甲东莨菪碱 GIHomatropinemethylbromide 溴甲后马托品 GIandcoughMepenzolatebromide 溴化甲哌佐酯 GIPropantheline 普鲁本辛 poorabsorption po andBBBpenetrationantispasmodiceffectsinGI treatmentofpepticulcerdisease others SelectiveM receptorantagonistsPirenzepine哌仑西平 M1andM4Telenzepine替仑西平 moreselectivetoM1ulcerTripitamine M2andM3selectiveDarifenacin达非那新 others Nicotinicreceptorantagonists Actingonsympatheticandparasympatheticganglioniccells reducingbloodpressurebyinhibitingsympatheticganglia havebeenabandonedforclinicaluse duetotheirlackofselectivity Short acting tachyphylaxisUsedfortreatmentofhypertensionTrimethaphan 樟磺咪芬 Mecamylamine 美卡拉明 NNreceptorantagonists GanglionicBlockingdrugs Twoclasses Non depolarizing drugsactascompetitiveantagonistsDepolarizing succinylcholine 琥珀胆碱 司可林 Note BelongtoSkeletalMuscleRelaxants Itisimportanttorealizethatmusclerelaxationdoesnotensureunconsciousness amnesia oranalgesia NMreceptorantagonists NeuromuscularBlockingdrugs 1 Depolarizingneuromuscularblockers Non competitive depolarizingskeletalmusclerelaxants actasacetylcholine ACh receptoragonists导致肌束颤动thedepolarizedmembranesremaindepolarizedandunresponsivetosubsequentimpulses ie theyareinastateofdepolarizingblock notmetabolizedbyAChE使作用延长 过量不能被新斯的明解救theydiffuseawayfromtheneuromuscularjunctionandarehydrolyzedintheplasmaandliverbypseudocholinesterase nonspecificcholinesterase plasmacholinesterase orbutyrylcholinesterase andeliminationbykidney NMreceptorantagonists NeuromuscularBlockingdrugs Succinylcholine琥珀胆碱 Scoline Succinylcholineistheonlydepolarizingagentusedclinically t1 2 2 4min Propertiesofactions initiallytransientfasciculationsanti AChEpotentiatestheireffectstachyphylaxis 快速耐受性 afterrepeatedusesnoganglion blockingeffectsattherapeuticdosesthedrugsarehighlypolar poorbioavailability i v asquaternarycompounds donotenterCNS acetylcholine succinylcholine MainpharmacologicaleffectsTransientexcitation fasciculations肌束震颤 andtheninhibition relaxation RelaxSkeletalMusclesinneck limbs face tongue throat lesseffectiveonbreathmusclesattherapeuticdoses Succinylcholine琥珀胆碱 Scoline ClinicalusesAnadjuvantinanesthesiaoroperationIntubationoftrachea esophagus etc PreventionoftraumaduringelectroshocktherapyContraindicatedinawakepatients shoulduseunderanesthesia Succinylcholine琥珀胆碱 Scoline Adverseeffects 1 Apnea respiratoryparalysis overdoseorhypersensitivepatients neostigminepotentiatesthetoxiceffects 2 Fasciculations肌束震颤muscularpainafteroperation becauseoftransientfasciculations 3 Malignanthyperthermiageneticabnormality Succinylcholine琥珀胆碱 Scoline 4 ElevationofK inplasmacontraindicatedinpatientswithatendencyofhyperkalemia burninjury massivetrauma neurologicaldisorders 5 Cardiovascularresponsevariousarrhythmia 6 Othersriseinintraocularpressure glaucoma histaminerelease Succinylcholine琥珀胆碱 Scoline GeneticVariation EffectsonDurationofActionofSuccinylcholine Thedurationofactionisprolongedbyhighdosesorbyabnormalmetabolism Thelattermayresultfromhypothermia lowpseudocholinesteraselevels orageneticallyaberrantenzyme hypothermiadecreasestherateofhydrolysis Lowpseudocholinesteraselevelsgenerallyproduceonlymodestprolongationofsuccinylcholine sactions 2 20min Onein50patientshasonenormalandoneabnormal atypical pseudocholinesterasegene resultinginaslightlyprolongedblock 20 30min Evenfewer 1in3000 patientshavetwoabnormalgenes homozygousatypical thatproduceanenzymewithlittleornoaffinityforsuccinylcholineandhaveaverylongblockade e g 4 8h followingadministrationofsuccinylcholine ScolineApnea mechanicalventilation DruginteractionsThiopental 硫喷妥 易分解AChEinhibitors AChEinhibitors cyclophosphamide 环磷酰胺 procaine 普鲁卡因 etc Someantibiotics kanamycin 卡那霉素 polymyxins 多粘菌素 etc synergisminneuromuscularblocking Succinylcholine琥珀胆碱 Scoline 2 Nondepolarizingneuromuscularblockers Competitive nondepolarizingskeletalmusclerelaxants Tubocurarine 筒箭毒碱 Reversiblybindtothenicotinicreceptorattheneuromuscularjunction competitiveantagonists note curarerarelyused Effects competitiveblockadeofNMreceptorsPharmacologicaleffects RelaxSkeletalMusclesin眼部肌肉 四肢 颈部 躯干 肋间肌 膈肌 呼吸抑制Uses adjuvanttreatmentofanesthesiaoroperations Tubocurarine 筒箭毒碱 Adverseeffects Respiratoryparalysis canbereversedbyneostigmineEnhancinghistaminerelease BP hypotension bronchoconstriction salivarysecretionBlockingganglion BP Contraindications myastheniagravis bronchialasthma shock child 10y DruginteractionsSimilartotheseofscoline Tubocurarine 筒箭毒碱 Benzylisoquinolines 苄基异喹啉类 Atracurium 阿曲库铵 Doxacurium 多库氯铵 Mivacurium 咪库铵 AmmoniosteroidsPancuronium 潘库铵 Vecuronium 维库铵 Pipecuronium 派库铵 Rocuronium 罗库铵 Othernondepolarizingneuromuscularblockers Itisimportanttorealizethatneuromuscularjunctionblockingagentsproduceparalysis notanesthesia Inotherwords musclerelaxationdoesnotensureunconsciousness amnesia oranalgesia note currentlyusedNMJblockersdifferintimeofonsetandclinicalduration pancuronium atracurium rocuronium BotulinumToxin肉毒毒素 SkeletalMuscleRelaxantsblocksAChreleasefromcholinergicterminalsselectiveforAChterminals irreversible Botoxactsasaproteasethatcleavesspecificproteinsinvolvedinexocytosis resultsinflaccidparalysis 松弛性麻痹 inmuscles canalsobeusedforexcessivesweating tension migraine ActsbycleavingSNAREproteins inhibitsAChrelease Strabismus lackofparallelismofeyes 斜视 blepharospasm eyelidspasm dystonia abnormaltonicity 肌张力障碍 Excessivesweating Cosmeticprocedures frownlines or crow sfeet Note effectscanlastfor 3 6months LATimes BotulinumToxinApplications AdrenergicPharmacology ParasympatheticNSEYEContractionofirissphinctermuscle pupildilates Contractionofciliarymuscle lensaccommodatesfornearvision LacrimalglandStimulatestearsSalivaryglandCopious watersecretionTracheaandbronchiolesConstricts increasesecretionHeartrate contractility GastrointestinalMusclemotility tone UretersandbladderContractionofdetrusorRelaxationoftrigone sphincterGenitalia maleStimulateserection SympatheticNSEYEcontractionofirisradialmuscle pupildilates contractionofciliarymuscle lensaccommodatesfornearvision Salivaryglandcopious watersecretionTracheaandbronchiolesdilatesHeartrate contractility Bloodvesselsdilatation Skeletalmuscle constriction skin mucus membranes splanchinarea Gastrointestinalmusclemotility tone contractionofsphinctersUretersandbladderrelaxesdetrusorcontractionoftrigone sphincterGenitalia femaleRelaxationofuterus NoradrenergicNerve Synthesis storageandreleaseofNE Uptakeneurotransmittertransportersuptake1 neuronaluptakeuptake2 non neuronaluptakeEnzymaticdegradationmonoamineoxidase MAO catechol O methyltransferease COMT RegulationofNESynthesisandTurnover Tyrosinehydroxylase TH activityisratelimitingTHactivityinhibitedbyNEproductTHactivitymodulatedbypresynapticautoreceptors alpha2receptorscanreduceNErelease beta2receptorscanincreaseNEreleasePresynapticheteroreceptorscanmodulateNErelease AChcanreduceNEreleaseTHactivityincreasesordecreasestomaintainsteady statelevelsofnorepinephrine Theaboveprocessescontributetoregulationofsteady stateNElevels rateofsynthesis rateofoutput CatecholamineBiosyntheticPathway NorepinephrineandEpinephrineSynthesisintheAdrenalMedulla NEisstoredinvesiclesDBHislocatedinvesiclesPNMT苯乙胺N甲基转移酶islocatedinthecytosol EPIisstoredinvesicles EPI 80 andNE 20 releasedintoblood Thesehormonesbindadrenergicreceptorsontargetcells inducingthesameeffectsasdirectsympatheticnervousstimulation Chromaffincell肾上腺嗜铬细胞 EPIdisposition metabolismbyCOMT 儿茶酚 O 甲基转移酶 MAO sulfation uptakeintoNEterminals NEMetabolism takesplacewithinthesamecellswheretheaminesaresynthesized andinliverExtraneuronalO methylationofnorepinephrineandepinephrinetometanephrines 尿甲氧基肾上腺素 representminorpathwaysofmetabolism MHPG wasusedasanindexofCNSNEturnoverbutgeneratedmostlyfromperiphery VMA sometimesusedasanindexofNEturnover Sulfateconjugatesalsoprevalent AdrenergicReceptors Adrenoceptors 1 2 1 G ProteinCoupledReceptors Norepinephrine NE release signaltransduction response receptorbinding reversible receptoractivation 2 3 lowaffinityforbindingNE a1AdrenergicReceptors GproteintermedGqphospholipaseCactivation IP3 mechanism mobilizesandincreasesintracellularfreecalcium effects primarilysmoothmusclecontraction 2AdrenergicReceptors InhibitionofadenylylcyclasethroughGiproteins mechanism decreasesintracellularcAMPlevelseffects decreasedproteinphosphorylation decreasedcellularfunctionbAdrenergicReceptors ActivationofadenylylcyclasethroughGsproteins mechanism increasesintracellularcAMPlevelseffects phosphorylationofintracellularproteins smoothmusclerelaxation cardiacmusclecontraction AdrenergicReceptorSubtypes G ProteinCoupledMechanisms AdrenergicReceptor adrenoreceptors ThesearereceptorsactivatedbyNE EPI ordrugswithsimilaractions b3fatcells notNE Drugactionsandclassification 1 Mechanismsofdrugactions1 1DirectactionsonthereceptorsAgonistsAntagonists1 2IndirectactionsviaaffectingtransmittersSynthesis L dopa Transportandstorage imipramine reserpine Release ephedrine amphetamine Inactivation MAOI 1 3Mimeticsandantagonists 1 Mimeticsdirect acting receptoragonistsindirect acting increasingamountsand oreffectsoftransmitters 2 Antagonistsdirect acting receptorantagonistsindirect acting decreasingamountsand oreffectsoftransmitters Non catecholamineIndirect actingbycausingthereleaseofstoredcatecholamine NotinactivatedbyCOMT somearepoorsubstrateforMAO orallyactive aprolongeddurationofaction GreateraccesstotheCNS CatecholamineHighpotencyinactivatingaorbreceptorsRapidinactivationbyCOMTandbyMAOPoorpenetrationintotheCNS Sympathomimeticamines 儿茶酚胺 苯乙胺 Structure activityrelationshipofcatecholaminesandrelatedcompounds b receptoractivity 麻黄碱 苯乙胺 Bioavailabilityoforaladmin Duration CNSdistribution BlockMAO uptake 1 Foractivationofreceptor Adrenoceptors Directmodee g NorepinephrineepinephrineisoproterenolIndirectmodeMixedmodee g ephedrine Themodeofactionofsympathomimeticdrugs Enhancesreleaseofstoredcatecholaminese g amphetamineInhibitionofreuptakeofreleasedcatecholaminese g cocaineInhibitionofMAOe g pargyline 拟交感药 Adrenoceptoragonists receptoragonistsepinephrine adrenaline dopamine ephedrine 2 receptoragonists 1 2receptoragonists norepinephrine 1receptoragonists phenylephrine 2receptoragonists clonidine 3 receptoragonists 1 2receptoragonists isoproterenol 1receptoragonists dobutamine 2receptoragonists salbutenol Drugactionsandclassification Pharmacologicaleffects 1 2 1 2receptoragonists 1 Cardiaceffects 1 contractility positiveinotropic HR positivechronotropic cardiacoutput oxygenconsumption inducingarrhythmia 2 Vasculareffects 1 vasoconstriction skin mucous viscera especiallyatlargerdoses 2 vasodilatationofskeletalmusclesandcoronaryvessels Epinephrine Adrenaline 肾上腺素 DIRECT Concentration dependentresponseinvascularsmoothmuscletoepinephrine PredominantEffectslow EPI 2 high EPI 2 Epinephrinereversal adrenalinereversal 3 BloodpressureSystolicBP DiastolicBP slight 4 Respiratory 2 dilatationofbronchialsmoothmuscles Bronchodilatation 1 reducingcongestionandedemaofbronchialmucosa 5 Metaboliceffectsbloodglucose hyperglycemia freefattyacids lipolysis Epinephrine Adrenaline Effectsofcatecholamines therapeuticdoses PredominantEffects NE 1effectsEPI 1 2thenathigherconcentrations effectspredominateISO 1and 2 Clinicaluses Systematicuses CardiacarrestAnaphylacticshock 过敏性休克 Acutebronchialasthma Topicaluses AdjuvantoflocalanesthesiaBleeding Epinephrine Adrenaline Adverseeffects 1 Cardiacarrhythmias 2 Hemorrhage cerebralorsubarachnoid reason amarkedelevationofBP 3 Centralexcitation anxiety headache 4 Contraindications heartdiseases hypertension coronaryarterialdisease arteriosclerosis hyperthyroidism Epinephrine Adrenaline 1 Cardiaceffects 1receptor weak 2 Vasculareffects DAreceptor vasodilatationofrenalandmesentericarteries bloodflow smalldoses 1receptor vasoconstrictionofskin mesentericvessels largerdoses 3 Renaleffects renalvasodilatation natriureticeffects Dopamine 多巴胺 DIRECTPharmacologicaleffects receptor dopaminergicreceptoragonists Clinicaluses 1 Shockcardiacandsepticshock 2 AcuterenalfailurecombinedwithfurosemideAdverseeffects short livedtachycardia arrhythmia reductioninurineflow renalvasoconstriction Dopamine PromotingreleaseofNE weakagonisteffectson 1 2 1 2receptorsProperties chemicallystable orallyeffective lesspotentbutlongeractionduration centralstimulating alertness fatigue preventssleep adverseeffects Tachyphylaxis 快速耐受 Ephedrine 麻黄碱 MIXED Epinephrine Ephedrine Clinicaluses 1 Preventionofhypotension anesthetics 2 Nasaldecongestion nasaldrop 3 Bronchialasthma mild chroniccases 4 Relievingallergicdisorders urticaria 风疹 angioneuroticedema Ephedrine Norepinephrine Noradrenaline 去甲肾上腺素 DIRECT Pharmacologicaleffect 1 2receptoragonists 1 Vasculareffects 1 vasoconstriction skin renal brain hepatic mesenteric etc bloodflow 2 inhibitingNErelease Actionsofnorepinephrineonpost synaptic 1 andpre synaptic 2 receptors 2 Bloodpressure SystolicBP DiastolicBP especiallyatlargerdoses 3 Cardiaceffects Weakdirectstimulation 1 inhibitionviareflex invivo Netresult littlecardiacstimulatesCoronaryarterydilation Norepinephrine Noradrenaline Effectsofcatecholamines therapeuticdoses PredominantEffects NE 1effectsEPI 1 2thenathigherconcentrations effectspredominateISO 1and 2 Clinicaluses limitedtherapeuticvalue 1 Shockusedinearlyphaseofsometypesofshock smalldosesandshorterduration dopamineisbetter replacedbyMetaraminol间羟胺 2 Hypotensionduetodrugpoisoningespeciallyforchlorpromazine 氯丙嗪 3 Hemorrhageinupperalimentarytractorallygivenafterdilution Norepinephrine Noradrenaline Adverseeffects 1 Ischemiaandnecrosisatthesiteofivadministrationrelievedbyfiltratingtheareawithphentolamine receptorantagonist 2 Acuterenalfailureavoidinglargerdosesandlongerduration monitoringurinaryvolume 3 Contraindicationhypertension arteriosclerosis heartdiseases severeurinaryvolume microcirculationdisorders Norepinephrine Noradrenaline Actingon receptorsdirectly promotingNEreleaseindirectly WeakereffectsandlongerdurationthanNE Weakeffectsonrenalvessels Usedinearlyphaseofshock hypotension Metaraminol间羟胺 Inducesreflexbradycardia usedinhypotension paroxysmalsupraventriculartachycardia Activate receptoratnormaldoseBlock receptorathighdosePhenylephrine Mydriasis pupillarydilatormuscles noorlesseffectonintraocularpressure short acting forseveralhours 可作为快速扩瞳药 Methoxamine甲氧明 DIRECT INDIRECTPhenylephrine苯肾上腺素 DIRECT INDIRECT 1receptoragonists Clonidine DIRECTUses antihypertensivedrug canbeadministeredastransdermalpatch permitscontinuousadministration Mechanismofaction 2 adrenergicpartialagonist actionspredominantlyinCNSlowersbloodpressurebyinhibitingsympatheticvasomotortoneAdverseeffects ivadministrationmayresultint