藥理學(xué)教學(xué)課件：Chapter 7 Drugs acting on adrenergic receptors

Chapter7DrugsactingonadrenergicreceptorsPeripheralNervousSystem

adrenoceptoragonistsadrenoceptorantagonists

ContentsPart1.Structure-activityrelationshipPart2.Adrreceptoragonist

,receptoragonistAD

receptoragonistNA

receptoragonistISOPPart3.Adrreceptorantagonist

receptorantagonistphentolamine

receptorantagonistpropranolol

Part1.SARandClassificationBasicStructure:

β-Phenylethylamine(β-苯乙胺)Substitution:1,2,3,4,5,6,α,β---H;-NH2βα1.Adrenoceptoragonists(1)Catecholamines(CA,兒茶酚胺)

RapidonsetofactionShortdurationofaction:COMTandMAONotadministeredorallyDonotpenetrateBBB

1.CatecholStructure:

34(2)Non-Catecholamines(remove1or2hydroxy)

LongerdurationofactionAllcanbeadministeredorally

Relatetothereceptorselectivity:Prolongthealkylsubstituent(–CH3totertiarybutyl),↑β-Ractivity,

↓α-Raction;forβ2-Rselectiveagonist.2.Substitutiononthe–HofAmino3.SubstitutiononthealphaandbetaCarbon-Hofalphacarbonreplacedby-CH3,↓oxidationinducedbyMAO→prolongtheaction.

(eg.ephedrine)

-Hofbetacarbonreplacedby–OH,CNSaction↓,PNSaction↑

(1)Catecholamines(兒茶酚胺類)eg:norepinephrine,epinephrine,isoproterenol,dopamine,dobutamineClassificationbasedonstructure(2)Non-Catecholamines(非兒茶酚胺類)

eg:ephedrine,metaraminol,phenylephrine類別drugsRselectivity兒茶酚胺類去甲腎上腺素3-OH,4-OHOHHHα1、α2腎上腺素3-OH,4-OHOHHCH3α、β多巴胺3-OH,4-OHHHHα、β異丙腎上腺素3-OH,4-OHOHHCH(CH3)2β1、β2多巴酚丁胺3-OH,4-OHHHβ1非兒茶酚胺類間羥胺3-OHOHCH3Hα1、α2甲氧明2-OH,5-OCH3OHCH3Hα1去氧腎上腺素3-OHOHHCH3α1麻黃堿

OHCH3CH3α、β沙丁胺醇3-CH2OH,4-OHOHHC(CH3)3β2Structureandreceptorselectivity

α-Rantagonistshasstructuraldiversity;Thestructureofβ-RantagonistsissimilartoISOP.BasicStructure:Arylethanolamine(芳基乙醇胺類)（α,β）

Aryloxypropylalcoholamine(芳氧基丙醇胺類)（β）R1-CH-CH2-N-R2OHH2.AdrenoceptorantagonistsPart2.AdrenergicreceptoragonistsBindtoαorβ-receptor→activate“Adrenomimetics”擬腎上腺素藥“Sympathomimeticamines”擬交感胺藥Classificationbasedonreceptor’sselectivity

,receptoragonistsAD

receptoragonists

1,

2-R

agonists

NA

1-R

agonists

Phenylephrine

2-R

agonist

Oxymetazolinereceptoragonists

1,2-R

agonists

ISOP

1-R

agonistsDobutamine

2-R

agonists

Salbutamol

SynthesisandMetabolismofCASynthesis:nerveterminal;adrenalmedullaMetabolism:uptake1and2Inactivation:MAO,COMTMetabolite:VMA(3-methoxy-4-hydroxy-mandelicacid)AdrenoceptortypesandeffectsMolecularMechanismofReceptorsG-protein-coupledreceptor

cAMPα1

-R

α2

-R

β-R(+)

AC

(-)

AC

GiGqPLC,PLA2,PLD

GscAMP(-)

PKA

(+)

PKA

EffectsofAdrenoceptorsAdrenaline(epinephrine,AD

)

[Source]

---ADissynthesizedfromtyrosineintheadrenalmedulla.1.α,β-Ragonists[Chemicalproperty]Beunstable:loseefficacyexposedtolight,oxidizedinalkalinesolution;BestableinacidicsolutionAdrenalineDopamineephedrine[Pharmacokinetics]Absorption:i.m.:Rapidonset,shortdurationofaction√i.v.,s.c.,prolongthedurationbyconstrictinglocalvessels×Oraladministrationisineffective,destroybyintestinalenzymes.Elimination:

uptake1,uptake2，Metabolites:VMA(3-甲氧-4-羥扁桃酸)Excretion:Metabolitesareexcretedintheurine.[PharmacologicalActions]Receptorselectivity:Noselectivitytoα,β-receptor

Characteristics:--atlowdoses,βeffects(vasodilation)onthevascularsystempredominate;--athighdoses,αeffects(vasoconstrictor)arestrongest.[PharmacologicalActions]

-typeaction:Vasoconstriction→↑Peripheralresistance→↑BP;Mydriasis(dilatormuscleofpupil↑);BladderSphincter↑β-typeaction:β1:Tachycardia;↑myocardialcontractionβ2:Vasodilation;Bronchodilation;β3:↑lipolysis;↑bloodsugar[PharmacologicalActions](1)Heart:powerfulcardiacstimulantstronglyexcited(+β1-R)

--positiveinotropicaction(strengthenmyocardialcontractility)--positivechronotropicaction(↑HR,↑c(diǎn)onductivity)--↑c(diǎn)ardiacoutputDisadvantages:↑Myocardialmetabolism→↑oxygenconsumptionlargedose→arrhythmiaHalothaneissensitizedarrhythmia.[PharmacologicalActions](2)Vessels:contract(+α-R),dilate(+β2-R)--Constrictsarteriolesintheskin,mucousmembranes,andviscera(α-effects)--Dilatesvesselsgoingtotheskeletalmusclesandcoronaryartery(β2-effects)--Cerebralbloodflow:↑,relatetoBPFeatures:renalbloodflow↓;Coronarybloodflow↑.Note：lowconcentration,+β2-R(3)BP:differentdose,differentBPVerysmalldose:SBP↓,DBP↓;(β2-effects)Therapeuticdose:SBP↑,DBP↓;(α,β2-effects)

moresensitiveto

β2-Ratlowdose→dilationofvesselsofskeletalmuscleLargedose:SBP↑,DBP↑

dominationofα-Reffects[PharmacologicalActions]●turnoverofBPincreaseAD(therapeuticdose)→↑BPα-Rblocker→AD(largedose)

→↓BP

？(4)smoothmuscle:+β2-RBronchialsmoothmusclesrelax→relieveallergic-orhistamine-inducedbronchoconstriction;Constrictionofbronchialsubmucousvessels→permeability↓→relievemucousedema;Smoothmusclesofdigestivetractrelax.

[PharmacologicalActions](5)Metabolism:↑1)Hyperglycemia:--↑glycogenolysisinliver(β2-effects)--↑releaseofglucagon(β2-effects)--↓releaseofinsulin(α2-effects)2)lipolysis:↑FFA(6)CNS--difficulttocrossBBB,noeffectonCNS;--centralexcitation(Largedose)[PharmacologicalActions][ClinicalUses](1)

Cardiacarrest---inducedbyanesthesia,surgeryaccident,drowning,drugtoxication,atrioventricularconductionblock;

Atthesametime,treatwithcardiaccompression,artificialrespiration,improveacidosis

---combinedwithdefibrillatorandlidocaineforcardiacarrestinducedbyelectricshock.

[ClinicalUses](1)

Cardiacarrest(2)Allergicshock(anaphylacticshock):firstchoice--typeIhypersensitivityreactionsinducedbypenicilin？(3)Bronchialasthma--torelaxbronchialsmoothmuscle--toconstrictmucosavessels→↓exudation--preventreleaseofinflammatorysubstances[ClinicalUses](4)localapplication

↓dosageoflocalanestheticbyvasoconstrictionatinjectionsite↑actionduration

localhemostat:1：1000cottonball(5)angioneuroticedemaandserumdisease[AdverseEffects]1)CNSdisturbances:

anxiety,tension,headache,tremor2)Cerebral

hemorrhage3)Pulsatileheadache(搏動(dòng)性頭痛)4)Arrhythmias2),3),4)---inducedbylargedoseorfastiv.Nitrites,α-Rblockerscanantagonizethem.Correctadministrationmethod:Dilution,thenslowi.v.[Contraindications]HyperthyroidismHypertensionOrganicheartdiseasesASDiabetesUsedonoldpeoplewithcaution

α,β,D-Ragonists

dopamine

(DA)

PrecursorofNA,mainlydistributeinCNS.[Pharmacokinetics]metabolizedbyMAO/COMT;shortt1/2,notacrossBBB(exogenous)---noCNSeffect[Pharmacologicalactions]

activateD,α,β1-R

weakactiononβ2-R[Pharmacologicalactions]

(1)CVS---Vessels:---lowdose,dilate(+D1-R),highdose,contract(α1-R)CVS---Heart:---+β1-R,produceinotropiceffects---largedose,↑HR---lessarrhythmiaCVS---BP:---SBP↑,DBP±→PP↑>25μg/kg·min,SBP↑,DBP↑[PharmacologicalActions]

(2)Kidney:---lowdose,dilaterenalvessels(+D1-R)→↑renalbloodflow,↑glomerulusfiltrationrate

---largedose,+α-R,constrictionofrenalvessels→

↓renalbloodflow---directlyinhibitNa+reabsorptionbykidneytubule→diuresis[ClinicalUses]

(1)Shock

givenbycontinuousinfusion,↑BP,↑perfusiontothekidney,esp.usedforpatientswithlowmyocardialcontractilityandlowurinevolume(2)Acuteheartfailure(AHF)(3)Acuterenalfailure(ARF)

---enhancestheglomerularfiltrationrate---causessodiumdiuresis---combinedwithdiureticsEphedrine(麻黃堿)[Mechanisms](1)directactions:activateα,β-Ronthepostsynapticmembrane(2)indirectactions:

inducethereleaseofNAfrompresynapticmembrane

Ephedrine[Characteristics](1)Stable,√po.(2)Action:weakerandlongerthanAD(3)Centralexcitation:significant(4)Tachyphylaxis(快速耐受性):relatedtoreceptorsaturationandtransmittersexhaustion(desensitization,脫敏)Ephedrine[ClinicalUses](1)Bronchialasthma(mildcase)chronictreatmentprophylacticallytopreventattacks(2)nasalcongestion(nosedrops)

toconstrictnasalmucosavessels(3)Hypotensivestate(localanesthesia)—↑BP(4)Torelieveskinandmucosasymptom

suchasurticaria(蕁麻疹)andangioedema2.α-RagonistsNoradrenaline(Norepinephrine,NA,NE)stronglyactivateα-R,slightlyactivateβ1-R.(1)α1,α2-Ragonists[chemicalproperty]

Beunstable:loseefficacyexposedtolight,oxidizedinalkalinesolution;Bestableinacidicsolution.Noradrenaline[chemicalstructure]Absorption:

×p.o.,vasoconstrictionof

gastricmucosa;destroyinalkalineintestinaljuice；×s.c.andi.m.,severevasoconstrictionwhichresultinlocaltissuenecrosis;×i.v.,rapiduptakebytissue→shortduration√ivgtt.

Elimination:uptake1,uptake2，Metabolites:VMA(3-甲氧-4-羥扁桃酸)Excretion:kidney[Pharmacokinetics][PharmacologicalActions]Receptorselectivity:Noselectivityto

1,

2receptor(+);weakactionto

1;

noactionto

2receptor

-typeaction:Vasoconstriction→↑Peripheralresistance→↑BP;Mydriasis(dilatormuscleofpupil↑);BladderSphincter↑[PharmacologicalActions]1）Vessels:contract(+α-R)vasoconstriction,smallveinandsmallartery

---coronaryvesselsdilate

(relateto↑adenosine),CBF↑

2）Heart:excited(+β1-R),<AD---invivo→inducesreflexbradycardiaThisisduetotheincreasedBPthatinducesareflexriseinvagalactivitybystimulatingbaroreceptor.

---atlargedose,inducearrhythmia(<AD)[Pharmacologicalactions]

3）BP:↑atsmalldose,SBP↑,DBP↑,PP↑atlargedose:SBP↑,DBP↑,PP↓→PR↑perfusionbloodflow↓

4）Others:bloodsugar↑(atlargedose)×CNS[ClinicalUses]1）Shock:↑vascularresistance,↑BP;Largedose→severeconstriction→aggravateshockonlyusedonearlystageofneurogenicshock.Note:renalvesselsconstriction→renalfailure→keepurinevolumeto25ml/hduringusage.

(Dopamineisbetter,whichdoesnotreducebloodflowtothekidney)

2）Upperdigestivetracthemorrhage

suchasgulletveinbreakage,gastrorrhagia[AdverseReactions]1)localischemiaandnecrosis√hotcompress;α-Rblockers;changeinjectionsite2)acuterenalfailurelargedose,longtime→severeconstrictionofrenalvessels→renalinjury(urinevolume>25ml/h)3)drugwithdrawal→BP(vasodilationrapidly)4)Arrhythmiaatlargedose

[Contraindications]Hypertension;AS;Heartdisease;anuriapatientsmetaraminol

(間羥胺，aramine)Mechanisms:↑BP

1)directactionstoadrenoceptor(α1,α2);2)indirectaction:↑NAreleasefromnerveterminalCharacteristics:

1)

weakerandlongeractionthanNA2)lessadversereactions:renalfailure,arrhythmias3)stable,im.4)tachyphylaxis(快速耐受性)Uses:substituteforNAintreatmentofshockPhenylephrine

(去氧腎上腺素，苯腎上腺素)1)

selectiveα1-Ragonists:2)WeakandlongeractionthanNA3)Renalbloodflow↓,reflexibleHR↓4)UsedforhypotensionstateinducedbyanesthesiaActivateα1-Rinpupildilatormuscle→mydriasis→usedasquick,short-termmydriatic(2)α1-RagonistsOxymetazoline

(羥甲唑啉)1)

Peripheralselectiveα2-Ragonists2)constrictslocalvessels,quickaction3)Usedfornasalcongestionorrhinitis(nosedrop)(3)α2-RagonistsClonidine

(可樂定)Methyldopa（甲基多巴）Centralselectiveα2-Ragonists3.β-RagonistsIsoproterenol(異丙腎上腺素)Noeffectsonα-R.(1)β1,β2-Ragonists

Absorption:

×p.o.,loseefficacybybindingtosulfateinintestinalmucosa；

rapiduptakebytissue→shortduration√i.v.,i.m.,inhalation,sublingualad..

Elimination:byMAO,COMT，Metabolites:3-methoxyl-ISOP(3-甲氧-異丙腎上腺素)---β-RantagonismShortactionduration,butlongerthanADorNA[Pharmacokinetics][PharmacologicalActions](1)

Heart:excited(β1-R)weakexcitationonectopicpacemaker→

lessarrhythmia(<AD)

(2)Vessels:dilate(β2-R)

---Dilatesthearterioleofskeletalmuscle---Decreasesperipheralresistance---Dilatesthecoronaryartery[PharmacologicalActions](3)BP: