第18章-作用于肾上腺素受体的药物(传出神经药理)

I.classificationbasedontheselectivityforthemainadrenoceptorsubtypes.

α-adrenoceptoragonists

--Noradrenaline（去甲肾上腺素）、Metaraminol（间羟胺）、Phenylephrine（去氧肾上腺素）α,β-adrenoceptoragonists

--Adrenaline（肾上腺素）、Dopamine（多巴胺）、ephedrine（麻黄碱）β-adrenoceptoragonists--Isoprenaline（异丙甲肾上腺素）、Dobutamine（多巴酚丁胺）、Salbutamol（沙丁胺醇）etc.

第一节肾上腺素受体激动药第一页，共36页。1)儿茶酚胺(catecholamines)类肾上腺素、去甲上腺素、多巴胺、异丙肾上腺素；作用强，维持时间短，易被COMT灭活。2)非儿茶酚胺类间羟胺、麻黄碱、甲氧明、苯肾上腺素(新福林）；作用弱，维持时间长（碳原子上的氢被-CH3取代），不易被MAO、COMT灭活。构效关系H第二页，共36页。第三页，共36页。Noradrenaline（去甲肾上腺素）actsmainlyonαreceptors,feweffectsonβ1;shouldbegivenbyiv.

A.Pharmacologicaleffects

1.Bloodvessels

①verystrongbloodvesselsconstrictioneffect

②dilation（扩张）ofcoronarybloodvessels（冠状血管）2.HeartsomeeffectasAdr.--weak,lesslikelytocausetachy-cardia（心动过速）第四页，共36页。3.Bloodpressureincreasesystolic（心脏收缩的）anddiastolic（心脏舒张的）pressure--increasesBPB.Uses①Hypotension（低血压）

②earlyphaseofneurogenicshock（神经源性休克）③uppergastrointestinaltractbleeding（上消化道出血）

C.Sideeffects①anxiety,respiratorydifficulty,forcefulheartbeatandtransientheadache,hypertension（高血压）

②necrosis（坏疽）ofthesiteofintravenousinjection（静脉注射）

③reducedbloodsupplytokidneyandperipheries第五页，共36页。D.contraindicationsandprecautionsHypertension,atherosclerosis（动脉硬化症）,coronaryheartdisease（冠心病）,oliguria（少尿）andanuria（无尿）Metaraminol（间羟胺，又称阿拉明，Aramine）actsonα1receptor;causesNAreleaseactions:increasesBPandcardiacoutput;reflexly（反射性）decreasesheartrateUses:hypotensivestates;attacksofsupraventriculartachycardia（阵发性室上性心动过速）第六页，共36页。Methoxamine（甲氧明）actsonα1receptoractions:inreceasesBP;reflexdecreasesinheartrate;goodforhypotensionwithtachycardia.uses:treathypotensivestates&paroxysmal（发作性的）atria（心房）tachycardia.Phenylephrine（去氧肾上腺素）actsonα1receptoruses:mydriasis（瞳孔散大）forexaminationofretina（视网膜）第七页，共36页。Adrenaline（epinephrine,肾上腺素）actsonα1,α2andβ1,β2receptorsPharmacologicalEffects1.Cardiovascularsystem

a.bloodvessels①skin,mucousmembranes--constriction②smallarteriole（细动脉）--constriction③splanchnic（内脏的）vessels

-renalandmesenteric（肠系膜的）--constriction

-cerebral（脑的）andpulmonary（肺部的）--weak第八页，共36页。④skeletalmuscle(α,β2)lowdoses—dilatationlargerdoses—constrictionlowdosesAdr.activateβ2

largerdosesAdr.activateα⑤coronaryartery（冠状动脉）vessels--dilatation-increasecardiaccontraction-stimulationofβ2-receptor,dilatationofcoronaryartery-increasemyocardial（心肌的）metabolites第九页，共36页。b.Heart(β1)①increasecontractility--正性肌力②increaseheartrate--正性心率③increasestrokevolume（每搏输出量）④increasecardiacoutput⑤increasemyocardium（心肌）oxygenconsumption第十页，共36页。c.Bloodpressure

①Cardiacoutput—SP(systolicbloodpressure)②peripheralvascularresistance—DP(diastolicbloodpressure)③meanarterialbloodpressure--berelatedwithdosesmalldose-SP-DP(relaxvesselsinskeletalmuscle—β2)-BPmaybedecreasedorremainunchangedlargerdose-SP-DP-BP（双相反应）

④pretreatment（预处理）withαblocker--reverseoftheAdr.effect→decreaseBP第十一页，共36页。2.Smoothmuscle

①relaxationofbronchialsmoothmuscle(β2)②mydriasis(α)3.metaboliceffects

①bloodsugar(α,β2)②freefattyacid(β1,β3)③oxygenconsumption④renin(β1)第十二页，共36页。B.ClinicalUses

1.Cardiacarrest（心脏骤停）--drowning,intoxicationofCNSinhibitors,acuteinfectiousdisease,etc.--intraventricular（心室内的）injection

（过敏性疾病）--anaphylacticshock--TypeIallergicreactions

第十三页，共36页。3.Bronchialasthma（支气管哮喘）--relaxationmuscle--inhibitionthesecretionofhistamineandleukotaxine（白细胞诱素）4.Localapplication

--usewithlocalanesthetics--epistaxis（鼻衄）--gingival（齿龈的）bleeding第十四页，共36页。C.SideEffects

cardiovascularandCNS-restlessness（烦躁）,anxiety,insomnia（失眠）,headache-elevationofBP,thedangerofcerebralhemorrhage（出血）,arrhythmia（心律不齐）,etc.D.Contraindicationhypertension,sclerosis（硬化）ofcerebralartery,ischemic（局部缺血的）heartdisease,CHF(congestiveheartfailure)第十五页，共36页。Dopamine（多巴胺）precursor（前体）ofNAandAdr,actsonDA,β1,β2,α1receptors,metabolizedbyCOMTandMAO,t1/2=1~2min,noeffectonCNS--notpenetrateBBB.A.PharmecologicalEffects

(dosedependent)a.lowdose(1)increasecardiaccontractility--β1+NArelease(2)increasesystolicbloodpressure(3)diastolicpressurenochangeordecrease(4)increaseinglomerularfiltration（肾小球滤过）rate,renalbloodflowandNa+excretion(DA)第十六页，共36页。b.largedoseactsonα1–vasoconstriction--decreasesrenalbloodflow.B.Uses

(1)sometypesofshock--cardiogenic（心源性的）andseptic（脓毒性的）shock--hemorrhagicshockespeciallywithcardiacdysfunction,oliguria（少尿）oranuria（无尿）(2)acuterenalinsufficiency--withdiuretics（利尿剂）C.SideEffects

(1)tachycardia,arrhythmia,headacheandhypertension–infused（滴注）veryfast(2)actsonα1receptor:inreceasesBP;reflexdecreasesinheartrate;goodforhypotensionwithtachycardia第十七页，共36页。Ephedrine（麻黄碱）αandβagonist;enhancesthereleaseofNA–indirectsympathomimetic（拟交感神经的）A.Pharmacologicaleffect①similartoadrenaline②actiondurationlonger③lowerpotency④bronchialmusclerelaxationlessprominentbutmoresustainedB.Uses①preventhypotension②asthma③nasal（鼻的）decongestant（消除充血药）第十八页，共36页。C.Sideeffectstachyphylaxis（快速耐受性）,hypertension,anxiety,insomnia,etc.Isoprenaline（异丙肾上腺素）syntheticderivative（衍生物）ofnoradrenalineA.Pharmacologicaleffects

Cardiovascularsystem①β1,β2receptorsagonist②intravenous--lowerperipheralvascularresistance③increaseheartrate,increasecontractility→increasecardiacoutput第十九页，共36页。④cardiaceffectsmayleadtopalpitations（心悸）,sinus（窦性）tachycardiaandmoreseriousarrhyth-mias2.Bronchialsmoothmuscle①relaxationofbronchialmuscle(β2)②inhibitreleaseofhistamineandothermediatorsofinflammation--strongerthanAdr.3.Metabolismincreaseoxygenconsumption,fattyacid,bloodsugar.第二十页，共36页。B.Uses1.asthma(treatacuteasthma)2.cardiacarrest3.shock---nowseldomusedC.Sideeffects①palpitation,tachycardia,headacheandflushedskinarecommon.②cardiacischemia（局部缺血）andarrhythmiasmayoccur.D.ContraindicationCoronaryheartdisease,myocarditis（心肌炎）,hyperthyroidism（甲状腺功能亢进）第二十一页，共36页。讨论：比较几种拟交感胺类药的作用，分析其作用机制。第二十二页，共36页。I.classificationα-AdrenoceptorBlockingDrugs

--NonselectiveαReceptorBlocker—Phentolamine（酚妥拉明）etc.--α1-Rblocker—Prazosin（哌唑嗪）--α2-Rblocker—Yohimbine（育亨宾）β-ReceptorBlockingDrugs--Nonselectiveβ-Rblocker–propranolol（普萘洛尔）--Selectiveβ-Rblocker–atenolol（阿替洛尔）αandβ-ReceptorBlockingDrugs--labetalol（拉贝洛尔）

第二节肾上腺素受体阻断药第二十三页，共36页。Phentolamine（酚妥拉明）A.Pharmacologicaleffects

1.Reducesperipheralresistance--blockα1

2.Cardiacstimulation

--reflexeffect--blockspresynaptic（突触前的）α2→

enhancedNArelease

3.Inhibits5-HT1,H2agonist1.Peripheralvasculardiseases2.Excesslocalvasoconstrictor3.Shockα-ReceptorBlockingDrugs第二十四页，共36页。（心肌的）infarction（梗死形成）andstubborn（顽固的）congestiveheartfailure5.Pheochromocytoma（嗜铬细胞瘤）Tolazoline（妥拉唑啉）

1.Effectssimilartophentolaminebutlesspotent.（拟胆碱样作用）effectandhistaminelikeeffectsarestronger.A.Sideeffects

posturalhypotension（体位性低血压）,tachycardia(reflex),arrhythmiaandangina（绞痛）第二十五页，共36页。1.Peripheralvasospastic（血管痉挛的）disease（溢出）ofiv.NAPhenoxybenzamine（酚苄明，又名苯苄胺dibenzyline）1.Bindstoαreceptorsproducingirreversible（不可逆的）blockade(14-48h).2.Inhibitsreuptake（再摄取）ofNA3.BlocksH1and5-HTreceptors.第二十六页，共36页。A.Pharmacologicalactions（对抗）αreceptor2.Blocksvasoconstrictionbutlittlefallinbloodpressure3.Cardiacoutputincreased--reflexeffect--blockadeofpresynapticα21.Peripheralvasculardiseases（嗜铬细胞瘤）第二十七页，共36页。C.Sideeffects1.Nasalstuffiness（鼻塞）（疲乏）,sedation（嗜睡）,nausea（恶心）4.PosturalhypotensionPrazosin（哌唑嗪）1.Highlyselectiveforα1,lowaffinityforα2

2.Relaxationofbotharterialandvenoussmoothmuscle--fallinbloodpressure第二十八页，共36页。3.Decreasespreloadandafterloadofheart4.EffectiveinthemanagementofhypertensionYohimbine（育亨宾）--usedasatoolinlab.第二十九页，共36页。β-ReceptorBlockingDrugs第三十页，共36页。A.PharmacologicalEffects1.β-blockingeffectsa.Heart(1)Decreasesheartrate,cardiaccontractility,andcardiacoutput(2)Decreasesmyocardialoxygenconsumptionb.BloodvesselandBP--decreasesbloodpressureinhypertensionpatients(1)heartβ1-Rblockade(2)smoothmuscleofbloodvesselsβ2-Rblockade(3)inhibitsrenin（肾素）-angiotensin（血管紧张素）system(RAS)第三十一页，共36页。c.RespiratorytractIncreasesairwayresistance-β2-Rblockade--patientswithasthmad.MetaboliceffectsInhibitslipolysis（脂解）andglycogenolysis（肝糖原分解）e.OthereffectsBlockspresynapticβ2-R--decreasesNAsecretion2.Intrinsicsympathomimeticactivity(ISA)partialagonisticaction--Pindolol（吲哚洛尔）第三十二页，共36页。3.Membranestabilizingaction①Localanaestheticeffect--decreasesmembraneionchannelpermeability(Na+channels)②Needshighconcentrations--50-10