Ad Re Nag On

8/8/2019 Ad Re Nag On

http://slidepdf.com/reader/full/ad-re-nag-on 1/9

Effects of Effects of AdrenergicAdrenergic Drugs Depend on:Drugs Depend on:

1) Expression of the receptor (type and number) in1) Expression of the receptor (type and number) in

a specific tissue/organ (i.e., bronchial smootha specific tissue/organ (i.e., bronchial smooth

muscle hasmuscle has β22 receptors only)receptors only)

2) The affinity of the drug for a2) The affinity of the drug for a specif adrenergicspecif adrenergic

receptor (i.e., NE=receptor (i.e., NE=α >>β11))

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 affinity4) Know: receptor expression and affinity

for the drug = predict effect in most cases.for the drug = predict effect in most cases.

α11R R

β11R R β22R R

α22R R

β22R R Synthesis

BlockersBlockersAmphetamine

CocaineCocaine

MetyrosineMetyrosine

ReserpineReserpine

GuanethidineGuanethidineBretyliumBretylium

Uptake 1

Uptake 2

MAO

ImipramineImipramine

Storage

Secretion

DA Transport

Clonidine

NE,Epi

NE

Epi





Epinephrine DopamineNorepinephrine

α1/2R β1/2R DAR

NENE-->>α1/2>1/2>β1>1> β22

EpiEpi-->> β1/2>1/2>α1/21/2

DADA-->D1/2>>D1/2>β1>>1>>α

α1R Smooth muscle contractionSmooth muscle contraction

Blood vessels:vasoconst.

Iris radial musc:->mydriasis

Skin: pilomotor musc.

α2R

PresynapticPresynaptic TerminalsTerminalsdecrease NE releasedecrease NE release

Postsynaptic TerminalsPostsynaptic Terminals

CNS, multipleCNS, multiple

Platelet aggregationPlatelet aggregation

β1R HEARTHEART

Increase: contraction,

HR, output, conduction

β2R SmoothSmooth muscmusc. relaxation. relaxation

LUNG & UTERUSLUNG & UTERUS

β3R LipolysisLipolysis andand

ThermogenesisThermogenesis

SmoothSmooth

muscmusc.relaxation.relaxation

RENAL &RENAL &

SPLANCHNICSPLANCHNIC

β1R HEARTHEART

Increase: contraction,

HR, output, conduction

100100

5050β1

StartStart StartStart StartStart StartStartStopStop StopStop StopStop StopStop

Heart RateHeart Rate

180180

6060

BloodBloodPressurePressure

120120

SPSP

MAPMAP

DPDP

SPSP

MAPMAP

DPDP

SPSP

MAPMAP

DPDP

MAPMAP

SPSP

DPDP

β1 β1 b e a t s /

b e a t s /

m i n

m i n

m

m H

g

m

m H

g

PeripheralPeripheralResistanceResistance

α1

β2 β2D1

ReflexReflex

BradycBradyc..

NENE(10mg/min)(10mg/min)

EPIEPI(10mg/min)(10mg/min)

IsoprotIsoprot..(10mg/min)(10mg/min)

DopamineDopamine(10mg/min)(10mg/min)



α1

100100

5050

StartStart StopStop


180180

6060


120120

SPSP

MAPMAP

DPDP

b e a t s /

b e a t s /

m i n

m i n

m m H

g

m m H

g


ReflexReflex

BradycBradyc..

NENE(10mg/min)(10mg/min)

α11 receptors in vascularreceptors in vascularsmooth muscle= vasoconstrictionsmooth muscle= vasoconstriction

VasomotorCenterCenter

NucleusNucleus

TractusTractusSolitariusSolitariusInhibitoryInhibitory

NeuronNeuron

AutonomicAutonomicGangliaGanglia

NENE

NENE

AChACh

MotorMotorNucleusNucleusVagusVagus

BaroreceptorsBaroreceptors( res( responponse tose to

chanchangesges in MAPin MAP

AChACh

AChACh↓HR HR NENE

AChACh

NENE

Excitatory NeuronExcitatory Neuron

100100

5050β1

StartStart StopStopHeart RateHeart Rate

180180

6060


120120

SPSP

MAPMAP

DPDP

b e a t s /

b e a t s /

m i n

m i n

m

m H

g

m

m H

g


β2

EPIEPI(10mg/min)(10mg/min)

HR HR

COCO

β2

Low DosesLow Doses

High DosesHigh Doses α1

SA node & Atria:SA node & Atria:RateRate

ContractilityContractility

AutomaticityAutomaticity

VelocVeloc. Conduct.. Conduct.

AV node &AV node &Conduction:Conduction:Velocity conductionVelocity conduction

Effect. Refract. PeriodEffect. Refract. Period

VentriculeVentricule::Contractility Work Contractility Work

O2 consumption EfficiencyO2 consumption Efficiency

β2

α1α1



100100

5050


180180

6060


120120

b e a t s /

b e a t s /

m i n

m i n

m m H

g

m m H

g

PeripheralPeripheralResistanceResistanceβ2

β1

StartStart StopStop

SPSP

MAPMAP

DPDP

β1

β2

IsoproterenolIsoproterenolStartStart StopStop

SPSP

MAPMAP

DPDP

β1

D1D1Renal/Renal/

SplachnicSplachnic

DopamineDopamine

HR HR HR HR

COCOHigher DosesHigher Doses

SkeletalSkeletal muscmusc..

COCO

HEART: Most effects areHEART: Most effects are β11

ElecticalElectical:Increase in Rate,:Increase in Rate, AutomaticityAutomaticity,, VelocVeloc. Conduct..;. Conduct..;

Decrease in Effect. Refract. PeriodDecrease in Effect. Refract. Period

Mechanical: Increase contractility, CO, work and O2 consumptionMechanical: Increase contractility, CO, work and O2 consumption

BLOOD VESSELS: Depends on the agonist and vascular bedBLOOD VESSELS: Depends on the agonist and vascular bed

Skin/MucousSkin/Mucous membmemb α −> VasoconstVasoconst..

SplanchnicSplanchnic α −> VasoconstVasoconst. D1. D1 −> vasodilatvasodilat..

SkeletalSkeletal muscmusc.. α −> VasoconstVasoconst.. β22 −> vasodilatvasodilat..

VenoseVenose ToneTone α −> VasoconstVasoconst.. β22 −> vasodilatvasodilat..

Respiratory Tract:Respiratory Tract: β2 in bronchia and2 in bronchia and α1 in vessels1 in vessels

Bronchial SmoothBronchial Smooth muscmusc.. β22 −> dilationdilation

VesselsVessels α −> VasoconstVasoconst..



EYE:EYE:

RadialRadial pupillarypupillary dilatordilator α −> contractioncontraction

IntraocularIntraocular PressurePressure α −> decreasesdecreases β −> increasesincreases

GASTROINTESTINAL:GASTROINTESTINAL:

Smooth muscleSmooth muscle α andand β −> relaxationrelaxation

GENITOURINARY:GENITOURINARY:

UterusUterus β22 −> relaxationrelaxationBladder base, urethral sphincter,Bladder base, urethral sphincter,

prostateprostate α −> contraction (urine continence)contraction (urine continence)DuctusDuctus deferens, seminaldeferens, seminal vesves.,.,

prostateprostate α −> contraction (ejaculation)contraction (ejaculation)

METABOLIC:METABOLIC:Fat cellsFat cells β33 −> increasesincreases lipolysislipolysisLiverLiver β −> glycogenolysisglycogenolysis

CellsCells β22 −> increases K uptakeincreases K uptakeInsulin/Insulin/ReninRenin//GlucagonGlucagonsecretionsecretion β22 −> increaseincrease α22 −> decreasedecrease

Mechanism of ActionMechanism of Action

1) Directly Acting1) Directly Acting SympathomimeticsSympathomimetics

Their effects are not abolished by chronicTheir effects are not abolished by chronic denervationdenervation

of postof post--ganglionicganglionic neurons,neurons, reserpinereserpine or cocaineor cocaine

2) Indirectly Acting2) Indirectly Acting SympathomimeticsSympathomimetics

Their effect is abolished byTheir effect is abolished by reserpinereserpine,, denervationdenervation of of

postpost--ganglionicganglionic neurons, and cocaineneurons, and cocaine

3) Mixed action3) Mixed action

Some effectsSome effects arepresentarepresent afterafter reserpinereserpine or cocaine.or cocaine.



HO

CH

OH

CH2 NCH3

H

PhenylephrinePhenylephrine ((NeosynephrineNeosynephrine))(αα1 only, direct acting)1 only, direct acting)

H3CO

CH

OH

CH NH2

CH3H3CO

MethoxamineMethoxamine(αα1 only, direct acting)1 only, direct acting)

HO

CH

OH

CH NH2

CH3

HO

α--MethylnorepinephrineMethylnorepinephrine

(αα1>>1>>β1, long1, long--acting)acting)

Systemic VasoconstrictorsSystemic Vasoconstrictors((hypotensionhypotension))

Ophtalmic MydriaticsOphtalmic MydriaticsNasal DecongestantsNasal DecongestantsAppetite SuppressantAppetite Suppressant

HO

HO

CH

OH

CH2 NH2

For ComparisonFor ComparisonNorepinephrineNorepinephrine

(αα1>1>β1)1)

MetaraminolMetaraminol(αα1>>1>>β1, direct and indirect acting1, direct and indirect acting

longlong--action)action)

HO

CH

OH

CH NH2

CH3

α11--SelectiveSelective

TetrahydrozolineTetrahydrozoline

(Visine;(Visine;α1 only)1 only)

C

NH CH2

CH2N

α22--SelectiveSelective

Cl

CH2 C NH

OGuanfacineGuanfacine

(αα2 in CNS, decreases BP)2 in CNS, decreases BP)

Cl

C

NH

NH2

Cl

CH N NH C

NH

NH2

Cl GuanabenzGuanabenz

(αα2 in CNS, decreases BP)2 in CNS, decreases BP)

Cl

NH N

ClN

H

N

ClonidineClonidine ((CatapresCatapres))(αα2 agonist,2 agonist, α1 antagonist).1 antagonist).

AntihypertensiveAntihypertensive..PosturalPostural hypotensionhypotension

ActivatesActivates α2 in CNS2 in CNS-->decreases:>decreases:NE release, BP & HR. Sedation andNE release, BP & HR. Sedation and

sexual dysfunction.sexual dysfunction.

HO

CH2 CH NH2

CH3

HO

α--MethylDOPAMethylDOPA

AntihypertensiveAntihypertensive, CNS act. It is, CNS act. It is

metabolized tometabolized to α--methylNEmethylNE andand

displaces NE from storage.displaces NE from storage.

ActivatesActivates presynappresynap.. α22

COOH



CH3

CH

OH

CH2 NCH3

H

EphedrineEphedrine (β>αβ>α))

Crosses BBBCrosses BBB-->CNS stimulant>CNS stimulantBroncodilatorBroncodilator

α && β SelectivitySelectivityHO

CH

OH

CH2 NCH3

H

For Comparison:For Comparison:EpinephrineEpinephrine

(β>αβ>α))

HO

NH2

CH3

CH2 CH2

AmphetamineAmphetamine

CH3

CH2 CH2 NH2

HydroxyamphetamineHydroxyamphetamine

HO

Potency: l > Potency: l >periphery,periphery, d >d >CNSCNS

Increase SP & DP, reflex decrease HR,Increase SP & DP, reflex decrease HR, arrithmiasarrithmias

ReleasesReleases biogenicbiogenic amines from storage sites.amines from storage sites.

AnoreticAnoretic-->used in obesity. Attention deficit>used in obesity. Attention deficit

hyperactivity disorder.hyperactivity disorder.

Toxicity: restlessness, hyperactive reflexes,Toxicity: restlessness, hyperactive reflexes,

insomnia, convulsions and coma.insomnia, convulsions and coma.

Treatment: NaTreatment: Na--NitoprusideNitopruside oror α--blockerblocker--

phentolaminephentolamine ((hyperthypert.) sedation, urine acidification,.) sedation, urine acidification,

β--SelectiveSelectiveHO

CH

OH

CH2 NCH3

H

EpinephrineEpinephrine(β>αβ>α))

Used in anaphylactic shock, cardiac arrestUsed in anaphylactic shock, cardiac arrest

HO

HO

CH

OH

CH2 NCH(CH3)2

H

IsoproterenolIsoproterenol

(ββ only)only)

Used inUsed in bradycardiabradycardia or heart shock or heart shock

HO

HO

CH2 CH2 NHCH H2C

DobutamineDobutamine (ββ only)only)

((--) isomer) isomer α1 agonist, (+)1 agonist, (+) α 1 antagonist1 antagonist

β--receptor agonist: (+)>>(receptor agonist: (+)>>(--))

InotropicInotropic>>>>chronotropicchronotropic, TPR unchanged, TPR unchanged

Indications: Cardiac Heart Failure, MI.Indications: Cardiac Heart Failure, MI.

HOCH3

H2C OH



β22--SelectiveSelectiveHO

CH

OH

CH2 N

CH(CH3)2

H

MetaproterenolMetaproterenol ((AlupentAlupent))

(β2>>ββ2>>β1)1)

HO

HO

CH CH NH CH2

RitodrineRitodrine (β2>>ββ2>>β1)1)

HO H2C OH

CH3

HO

CH

OH

CH2 NCH(CH3)3

H

HOTerbutalineTerbutaline ((BrethineBrethine))

(β2>>ββ2>>β1)1)

BroncodilatorsBroncodilatorsUterine relaxantUterine relaxantNo COMTNo COMT substsubst..

HO

CH

OH

CH2 N

CH(CH3)2

H

AlbuterolAlbuterol ((VentolinVentolin))

(β2>>ββ2>>β1)1)

CH2-HO

HO

CH

OH

CH2 NCH(CH3)2

H

IsoproterenolIsoproterenol

(β1+2β1+2 only)only)

HO

use to compareuse to compare

Documents

Ad Re Nag On