Effects ofEffects ofAdrenergicAdrenergicDrugs Depend on:Drugs Depend on:1) Expression of the receptor (type and number) in 1) Expression of the receptor (type and number) in a specific tissue/organ (i.e.,a specific tissue/organ (i.e.,brochialbrochialsmooth smooth muscle has muscle has ββ22receptors only)receptors only)2) The affinity of the drug for a2) The affinity of the drug for aspecif adrenergicspecif adrenergicreceptor (i.e., NE=receptor (i.e., NE=α α >>β1β1))3) Indirect or reflex effects (i.e., NE decrease HR)3) Indirect or reflex effects (i.e., NE decrease HR)4) Know: receptor expression and affinity 4) Know: receptor expression and affinity for the drug = predict effect in most cases.for the drug = predict effect in most cases.α1α1RRβ1β1RRβ2β2RRα2α2RRβ2β2RRSynthesisBlockersBlockersAmphetamineCocaineCocaineMetyrosineMetyrosineReserpineReserpineGuanethidineGuanethidineBretyliumBretyliumUptake 1Uptake 2MAOPhenelzinePhenelzineStorageSecretionDA TransportClonidineNE,EpiNEEpiHOHOCOHHCH2NCH3HEpinephrineHOOHHOCHHCNH2DopaCOTyrosineHydrolase(limiting step)HOHOCHHCNH2DopamineHDopamineDecarboxylaseHOHOCOHHCNH2NorepinephrineHDopamineβ-HydroxylasePhenylethanolamineN-methyltransferaseNENE-->>αα1/2>1/2>ββ1> 1> ββ22EpiEpi--> > ββ1/2>1/2>αα1/21/2DADA-->D1/2>>>D1/2>>ββ1>>1>>ααCH(CH3)2Isoproterenolααββββact.act.MAOMAOOHHOHHCNH2TyrosineCOC1236αα&&ββact.act.COMTCOMT54MAOMAO* Substitutions at the * Substitutions at the ααcarbon block MAO and prolong actioncarbon block MAO and prolong action(i.e. Ephedrine and Amphetamine)(i.e. Ephedrine and Amphetamine)* OH* OH--on C3 and C5 increase on C3 and C5 increase ββ2 selectivity 2 selectivity HO-5HO-4HOHHCNH2Norepinephrine126CHO-3Hααββββact.act.* Large alkyl substitutions of the NH* Large alkyl substitutions of the NH22increase increase ββand decrease and decrease ααactivity activity (i.e.(i.e.IsoproterenolIsoproterenol). ). ββ22--specific drugs have large substitutionsspecific drugs have large substitutionsαα&&ββact.act.COMTCOMT* Substitutions of OH* Substitutions of OH--C3 and/or C4 decrease activity, but also C3 and/or C4 decrease activity, but also decreasesdecreasesmetabolizationmetabolizationby COMT increasingby COMT increasingbioavailabilitybioavailability(i.e.(i.e.PhenylephrinePhenylephrine).).* Substitutions at the * Substitutions at the ββcarbcarb. decrease CNS but increase . decrease CNS but increase agonist agonist actionactionEpinephrineDopamineNorepinephrineα1/2Rβ1/2RDARNENE-->>αα1/2>1/2>ββ1> 1> ββ22EpiEpi--> > ββ1/2>1/2>αα1/21/2DADA-->D1/2>>D1/2>ββ1>>1>>ααα1RSmooth muscle contractionSmooth muscle contractionBlood vessels:vasoconst.Iris radial musc:->mydriasisSkin: pilomotor musc.α2RPresynapticPresynapticTerminalsTerminalsdecrease NE releasedecrease NE releasePostsynapticPostsynapticTerminalsTerminalsCNS, multipleCNS, multiplePlatelet aggregationPlatelet aggregationβ1RHEARTHEARTIncrease: contraction, HR, output, conductionβ2RSmoothSmoothmuscmusc. relaxation. relaxationLUNG & UTERUSLUNG & UTERUSβ3RLipolysisLipolysisandandThermogenesisThermogenesisSmoothSmoothmuscmusc.relaxation.relaxationRENAL & RENAL & SPLANCHNICSPLANCHNICβ1RHEARTHEARTIncrease: contraction, HR, output, conductionEffectEffectββ11ReceptorReceptorDrug ConcentrationDrug Concentration100%100%50%50%0%0%100%100%50%50%0%0%αα11ReceptorReceptorEpiEpiNENENENEEpiEpiDADA1001005050β1StartStartStartStartStartStartStartStartStopStopStopStopStopStopStopStopHeart RateHeart Rate1801806060Blood Blood PressurePressure120120SPSPMAPMAPDPDPSPSPMAPMAPDPDPSPSPMAPMAPDPDPMAPMAPSPSPDPDPβ1β1beats/beats/minminmm Hgmm HgPeripheralPeripheralResistanceResistanceα1β2β2D1ReflexReflexBradycBradyc..NE NE (10mg/min)(10mg/min)EPI EPI (10mg/min)(10mg/min)IsoprotIsoprot. . (10mg/min)(10mg/min)Dopamine Dopamine (10mg/min)(10mg/min)α11001005050StartStartStopStopHeart RateHeart Rate1801806060Blood Blood PressurePressure120120SPSPMAPMAPDPDPbeats/beats/minminmm Hgmm HgPeripheralPeripheralResistanceResistanceReflexReflexBradycBradyc..NE NE (10mg/min)(10mg/min)αα1 1 receptors in vascular receptors in vascular smooth muscle= vasoconstrictionsmooth muscle= vasoconstrictionVasomotorCenterCenterNucleusNucleusTractusTractusSolitariusSolitariusInhibitoryInhibitoryNeuronNeuronAutonomicAutonomicGangliaGangliaNENENENEAChAChMotorMotorNucleusNucleusVagusVagusBaroreceptorsBaroreceptors( res( responponse to se to chanchanges ges in MAPin MAPAChAChAChACh↓ ↓ HRHRNENEAChAChNENEExcitatory NeuronExcitatory Neuron1001005050β1StartStartStopStopHeart RateHeart Rate1801806060Blood Blood PressurePressure120120SPSPMAPMAPDPDPbeats/beats/minminmm Hgmm HgPeripheralPeripheralResistanceResistanceβ2EPI EPI (10mg/min)(10mg/min)HRHRCOCOβ2Low DosesLow DosesHigh DosesHigh Dosesα1SA node & Atria:SA node & Atria:Rate Rate ContractilityContractilityAutomaticityAutomaticityVelocVeloc. Conduct.. Conduct.AV node & AV node & Conduction:Conduction:Velocity conduction Velocity conduction Effect. Refract. PeriodEffect. Refract. PeriodVentriculeVentricule::Contractility Work Contractility Work O2 consumption Efficiency O2 consumption Efficiency β2α1α11001005050Heart RateHeart Rate1801806060Blood Blood PressurePressure120120beats/beats/minminmm Hgmm HgPeripheralPeripheralResistanceResistanceβ2β1StartStartStopStopSPSPMAPMAPDPDPβ1β2Isoproterenol Isoproterenol StartStartStopStopSPSPMAPMAPDPDPβ1D1D1Renal/Renal/SplachnicSplachnicDopamineDopamineHRHRHRHRCOCOHigher DosesHigher DosesSkeletalSkeletalmuscmusc..COCOHEART: Most effects are HEART: Most effects are ββ11ElecticalElectical:Increase in Rate,:Increase in Rate,AutomaticityAutomaticity,,VelocVeloc. Conduct..; . Conduct..; Decrease in Effect. Refract. PeriodDecrease in Effect. Refract. PeriodMechanical: Increase contractility, CO, work and O2 consumptionMechanical: Increase contractility, CO, work and O2 consumptionBLOOD VESSELS: Depends on theBLOOD VESSELS: Depends on theagonistagonistand vascular bedand vascular bedSkin/MucousSkin/Mucousmembmembα α −−>>VasoconstVasoconst..SplanchnicSplanchnicα α −−>>VasoconstVasoconst. D1 . D1 −−>>vasodilatvasodilat..SkeletalSkeletalmuscmusc..α α −−>>VasoconstVasoconst. . ββ2 2 −−>>vasodilatvasodilat..VenoseVenoseToneToneα α −−>>VasoconstVasoconst. . ββ2 2 −−>>vasodilatvasodilat..Respiratory Tract: Respiratory Tract: ββ2 in bronchia and 2 in bronchia and αα1 in vessels1 in
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