AdrenoceptorActivatingDrugs(p58)Case1Female,31yrsGota“cold”yesterdayandself-administerdwithtraditionalChinesemedicine，feelgeneralmalaise,withrash(皮疹)inthefaceandloseconscious10minlater.Returnedtoconsciousonthewaytohospital.PE:pulseandHR102/min,breath20/min,BP78/58mmHg,bodytemp.37.2℃,redrashscatteredonskinoffaceandneck.Diagnosis:anaphylacticshock(過敏性休克)Treatment:adrenalineanddexamethasoneinjectionAdrenomimetic（擬腎上腺素藥）drugsSympathomimetic（擬交感藥）aminesActbyadirectoraindirectmodeReceptoragonistDisplacementofstoredcatecholaminesfromtheadrenergicnerveendingorinhibitionofreuptakeofcatecholaminesalreadyreleased§1structure-activityrelationshipandclassificationCatecholamines(兒茶酚胺,p58)Have–OHon3and4positionsclassification1.-adrenoceptoragonists(NA)2.、-adrenoceptoragonists(Adr)3.-adrenoceptoragonists(Iso)§2

-adrenoceptoragonistsNoradrenaline(NA)ornorepinephrine(NE)(去甲腎上腺素)Metaraminoloraramine(p61)Phenylephrineclonidine

Noradrenaline(NA,p59)Chemistry:stableonlyinacidicsolutionPharmacokinetics:givenbyintravenousinfusion,can’tacrossBBB,shortdurationofaction,metabolizedbyMAOandCOMT,excretionbyurine.PharmacodynamicsActivate-Rstrongly&β1-Rweakly1.Heart:

Weakpositivechronotropiceffect（正性頻率作用）onpacemakeractivity.Butintheintactbody,HR↓Positiveinotropiceffect（正性肌力作用）onintrinsiccontractility2.BloodvesselsStrongactivate

1-Ronthesmoothmusclesofbloodvessels,especiallysplanchnic（內臟的）andskinvesselsPeripheralvascularresistance↑BP↑3.Other

LargedoseincreasebloodglucoseResponsestointravenousinjectionsofdrugsthatcausevasoconstriction(phenylephrine)orvasodilation(histamine)byactingonvascularsmoothmuscle.PhenylephrineHistamineBloodpressuremmHGSympatheticnerveactivity(voltagearbitrary)Vagusnerveactivity(voltagearbitrary)Heartrate(beats/minTime(min)Time(min)ClinicalusesEarlyphaseofshockHypotensioncausedbydrugtoxicationUpperdigestivetractbleedingAdverseeffectsLocaltissuemarkedischemiaandnecrosis,procaineorphentolaminecanbeusedtorelievetheseAcuterenaldysfunctionContraindications(禁忌癥)andprecautionshypertension,Atherosclerosis(動脈粥樣硬化),coronaryheartdisease,Oliguria（少尿）,andanuria（無尿）

Metaraminoloraramine(間羥胺)Chemistry:stable,can’tbedestroyedbyMAO,longdurationofactionThemodeofactionDirectactionIndirectactionProducetachyphylaxis(快速耐受)LesssidereactionthanNABothintravenousinfusionandimUsedtotreathypotensivestates§3,

-adrenoceptoragonistsAdrenalineorepinephrine(腎上腺素)DopamineEphedrine（麻黃素）

Adrenaline(epilephrine)Chemistry:unstable,similartoNAPharmacokinetics:imorsc,metabolizedbyMAOandCOMTinhumanbodyPharmacodynamicsactivateboth

-andβ-receptorsstronglypharmacodynemicsHeart:Markedpositivechronotropiceffect（正性頻率作用）

onbothnormalandabnormalpacemakeractivity;Strongpositiveinotropiceffect（正性肌力作用）

onintrinsiccontractility.Promoteconductionofheart;Cardiacoutput↑;RelaxcoronaryarteriesBloodvessels:Lowdosecanactivateβ2-Ronthesmoothmusclesandcauserelaxation;Largedosecanstrongactivate

1-Ronthesmoothmuscles,peripheralvascularresistance↑Bloodpressure:

Lowdosesystolicpressure↑anddiastolicpressurenormalor↓(heartβ1-Randperipheralβ2-R);Largedosemarkedincreasebloodpressure(peripheral

1-Randβ1-Rofjuxtaglomerularcells,excretionofrenin)a

2ARs

ARsStimulateRelaxationStimulateContractionAtlow[Epi],the

2ARwillbeoccupiedbecausethesereceptorshaveahigheraffinityforE.（E,epinephrine）aEEEEERelaxationAthigh[Epi],the

1ARwouldalsobeoccupied.Becausetherearemore

1ARs,thepredom-instanteffectatthehigh[Epi]isVSMcontraction.EEEEERelaxationContractionEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEEESmoothmuscles:

BronchialSMrelaxation,β2-R(+),strongly;Gastrointestinaltracttone↓,β1-R(+)Metabolism:

Lipolysis（脂解）↑,β3-R(+);Glycogenolysis（糖原分解）inliver↑,

-&β2-R(+),bloodsugar↑markedly;↓plasmaK+whenstressorexercise,β2-R(+)ClinicalusesCardiacarrest(心臟驟停)：administration？Anaphylacticshock（過敏性休克）:scorimBronchialasthma:scorimLocalapplication:localanaesthesia(1∶250000)；stopbleedingAdverseeffectsB.Pmarkedelevation,cerebralhemorrhageorpulmonaryedemaSevereangina（心絞痛）ormyocardialinfarctionSinustachycardiaorseriousventriculararrhythmiasContraindicationsHypertension,sclerosisofcerebralartery,ischemicheartdisease,congestiveheartfailure,hyperthyroidismDopaminePharmacokineticsDopamineistheprecursor（前體）ofNAandAdr.intravenousinfusion,destroyedbyMAO&COMTrapidly,t1/2=1-2min.can’tacrossBBB,PharmacodynamicsLowconcentrationactivatesDA1-Rinrenal（腎的）,coronaryarteryandmesentery（腸系膜）vascularbeds,leadstovasodilationLargedoseactivateβ1-Rand

-Rleadingtovasoconstriction,includingrenalbloodvessels，BP↑,ItalsocausesthereleaseofNAfromnerveendings.Infusionoflowdoseofdopaminecausesanincreaseinglomerulusfiltrationrate,renalbloodflowandNa+excretion

Dose Receptor

2-5μg/kg/min DA1

,

5-10μg/kg/min

DA1,

>10μg/kg/min DA1,

b

ClinicalusesTreatmentofvariousshockAcuterenaldysfunctionandheartfailure,combinationofdopamineanddiuretics,AdverseeffectsIfinfusedveryfast,itmayinduceTachycardia（心動過速）,arrhythmia,headacheandhypertension.Ephedrine(麻黃堿)Stablechemistryproperty,haseffectafteroraladministrationPharmacodynemicsactivateboth

andβreceptorDirectactionIndirectaction:enhancesthereleaseofNAfromadrenergicnerveendingsSympathomimeticactionlessthanadr.Butlongerdurationthanthatofadr.MarkedlyexcitementeffectsofCNS,becauseitcancrossBBBProducetachyphylaxis(快速耐受性)rapidlyClinicalusesBronchialasthma,lightsymptomsNasaldecongestant（鼻塞）;Preventhypotensioninducedbyepidermalanesthesiaorsubarachnoidanesthesia;RelievesymptomsofallergicreactionontheskinandmucousmembraneAdverseeffectsAnxiety,insomnia,tachyphylaxis;ContraindicationsHypertension,atherosclerosis,hyperthyroidism,coronaryheartdisease.§4-adrenoceptoragonists-adrenoceptoragonistsIsoprenaline,dobutamine1-selectiveagonists2-selectiveagonistsIsoprenaline(異丙腎上腺素)Chemistry:synthesisproductPharmacokinetics:administrationbyinhalationasaerosolorsublingual,absorbedfast,mostaredestroyedbyCOMT,fewbyMAO,durationlongerthanadr.PharmacodynamicsExtremelypotentnonselectiveβ-Ragonist,havinglittleeffecton-R.HeartPositivechronotropicandinotropicaction,promoteconduction,cardiacoutput↑↑,consumeoxygen↑,BloodvesselsapotentvasodilatorBloodpressureAfallindiastolicandmeanarterialpressure,andalesserdecreaseoraslightincreaseinsystolicpressure.thebloodflowofcoronaryarteryincreaseSmoothmusclesBronchialSMdilate,longtimeadministrationcausetoleranceofbody,↑oxygenconsume,metabolism↑,difficulttocrossBBB,(+)CNSweak.ClinicalusesBronchialasthma:controlacuteattack,sublingualorinhalatio