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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,儿茶酚胺)
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(儿茶酚胺类)eg:norepinephrine,epinephrine,isoproterenol,dopamine,dobutamineClassificationbasedonstructure(2)Non-Catecholamines(非儿茶酚胺类)
eg:ephedrine,metaraminol,phenylephrine类别drugsRselectivity儿茶酚胺类去甲肾上腺素3-OH,4-OHOHHHα1、α2肾上腺素3-OH,4-OHOHHCH3α、β多巴胺3-OH,4-OHHHHα、β异丙肾上腺素3-OH,4-OHOHHCH(CH3)2β1、β2多巴酚丁胺3-OH,4-OHHHβ1非儿茶酚胺类间羟胺3-OHOHCH3Hα1、α2甲氧明2-OH,5-OCH3OHCH3Hα1去氧肾上腺素3-OHOHHCH3α1麻黄碱
OHCH3CH3α、β沙丁胺醇3-CH2OH,4-OHOHHC(CH3)3β2Structureandreceptorselectivity
α-Rantagonistshasstructuraldiversity;Thestructureofβ-RantagonistsissimilartoISOP.BasicStructure:Arylethanolamine(芳基乙醇胺类)(α,β)
Aryloxypropylalcoholamine(芳氧基丙醇胺类)(β)R1-CH-CH2-N-R2OHH2.AdrenoceptorantagonistsPart2.AdrenergicreceptoragonistsBindtoαorβ-receptor→activate“Adrenomimetics”拟肾上腺素药“Sympathomimeticamines”拟交感胺药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-羟扁桃酸)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,↑conductivity)--↑cardiacoutputDisadvantages:↑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(搏动性头痛)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(麻黄碱)[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,脱敏)Ephedrine[ClinicalUses](1)Bronchialasthma(mildcase)chronictreatmentprophylacticallytopreventattacks(2)nasalcongestion(nosedrops)
toconstrictnasalmucosavessels(3)Hypotensivestate(localanesthesia)—↑BP(4)Torelieveskinandmucosasymptom
suchasurticaria(荨麻疹)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-羟扁桃酸)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
(间羟胺,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
(去氧肾上腺素,苯肾上腺素)1)
selectiveα1-Ragonists:2)WeakandlongeractionthanNA3)Renalbloodflow↓,reflexibleHR↓4)UsedforhypotensionstateinducedbyanesthesiaActivateα1-Rinpupildilatormuscle→mydriasis→usedasquick,short-termmydriatic(2)α1-RagonistsOxymetazoline
(羟甲唑啉)1)
Peripheralselectiveα2-Ragonists2)constrictslocalvessels,quickaction3)Usedfornasalcongestionorrhinitis(nosedrop)(3)α2-RagonistsClonidine
(可乐定)Methyldopa(甲基多巴)Centralselectiveα2-Ragonists3.β-RagonistsIsoproterenol(异丙肾上腺素)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-异丙肾上腺素)---β-RantagonismShortactionduration,butlongerthanADorNA[Pharmacokinetics][PharmacologicalActions](1)
Heart:excited(β1-R)weakexcitationonectopicpacemaker→
lessarrhythmia(<AD)
(2)Vessels:dilate(β2-R)
---Dilatesthearterioleofskeletalmuscle---Decreasesperipheralresistance---Dilatesthecoronaryartery[PharmacologicalActions](3)BP:
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