药理学 Chapter 8 抗高血压药物

ⅢCardiovascularpharmacologyReferences1.Pharmocology,4thedition.Lippincott’sillustratedreviews.RichardA.Harvey;PamelaC.Champe.WoltersKluwer/LipincottWilliams＆Wilkins.2.Textbookofpharmocology.周宏灏主编，第2版，科学出版社。3.药理学，第7版，朱依谆、殷明主编，人民卫生出版社。2PharmacologyofcardiovascularsystemAntihypertensivedrugsAntianginaldrugsAntichroniccardiacinsufficiencydrugsAntiarrhythmicdrugsAntiatherosclerosisdrugsCardiovascularsystemiscomprisedofheart,artery,capillaryandvein.

Heartisthedrivingorganforbloodcycle.Arteriestransportbloodfromhearttoeverywhereofbody.

Veinstransportbloodfromeverywhereofbodybacktoheart.Capillariesaretheplaceswhereproductexchangehasbeenperform.3

ANTIHYPERTENSIVEDRUGS

CHAPTER8

Section1Introduction

Hypertension:commonlycardiovasculardiseaseConceptionBP≥18.6/12.6kPa(140/90mmHg)Morbidity:10%~20%5类别

收缩压(mmHg)

舒张压(mmHg)

理想血压正常血压正常高值1级高血压（“轻度”）亚组：临界高血压2级高血压（“中度”）3级高血压（“重度”）单纯收缩期高血压亚组：临界收缩期高血压

<120<130130～139140～159140～149160～179≥180≥140140～149<80<8585～8990～9990～94100～109≥110<90<90

6BloodpressureArterial,capillaryand

venous

pressureDefinition:--Heartconstrictiongeneratesbloodpressure,--thefluidpressurethatbloodexertsagainstvesselwalls.Unit:mmHg,Pa7ArterialpressureHypotension:---Can’tmaintaineffectivebloodcycle,nottosupplyallorganandtissue,especiallyforbrain,affectnormalactions.

8ArterialpressureHypertension:---increasedtheloadofheartandvessel;contractility↑ventricleenlarge,

↓cardiacoutputcycledysfunctionSeverehypertensionbloodvesseloutburstlifedanger9ArterialbloodpressureCardiacoutputPeripheralvascularresistance≈×HeartrateContractilityFillingpressure充盈压ArterialvolumeMajorfactorsinfluencingbloodpressure10Conceptionofbloodpressuresystolicbloodpressure(SBP):thepeakvalueofarterialpressureduringsystoleDecidedfactor:cardiacoutputdiastolicbloodpressure(DBP):thelowestvalueduringdiastoleDecidedfactor:totalperipheralvesselresistance11Pulsepressure(PP):thedifferencebetweenSBPandDBPMeanarterialpressure(MAP):

MAP=1/3PP+DBPBPvarieswiththestrengthoftheheartbeat,

theelasticityofthearterialwalls,thevolumeandviscosityoftheblood,andaperson'shealth,age,andphysicalcondition.concept12Resultingfromincreasedperipheralvascularsmoothmuscletone,whichleadstoincreasedarteriolarresistanceandreducedcapacitanceofthevenoussystem.---isadiseasewhichdefinedasasustainedarterialpressuregreaterthannormal.Hypertension13Complications:CoronarydiseaseCardiacfailureStrokeRenalfailureInducingfactors:Fat,highsalt,alcohol14Complications:CoronarydiseaseCardiacfailureStrokeRenalfailure15Accordingtocause:Primaryhypertension90%Secondaryhypertension10%

TheTypesofHypertension:16Accordingtospeedandstate:AcceleratedHypertension:alsocalledmalignanthypertension,infrequentPostponedHypertension:Subtype:light,moderateandhighdegreeorfirst,second,thirdrankTheTypesofHypertension:17TheTypesofHypertension:Hypertensioncrisis:

---isasevereincreaseinbloodpressureinducedbytransientspasmofallsmallarteries.Extremelyhighbloodpressure-above180/110mmHg-damagesblood.Asaresult,theheartmaynotbeabletomaintainadequatecirculationofblood.18Pathophysiologicalchanges

↑Peripheralvesselresistance,lumenofsmallarterysmaller,↑BP;Relatedto:sympatheticnervoussystemfunctionderangement

↑plasmarenin19MechanismforHypertensionNervemechanism:

centralnerveandadrenergicnervehyperfunctionNervemechanism;vesselabnormalregulating;endocrinemechanism;water-electrolyteimbalance,geneticfactor,etc.20EtiopathogenisisNervecenterExcite/inhibit(abnormal)NeurotransmitterreleaseabnormalActiveofADPlasmaCAResistantsmallarterialspasmTotalperipheralvesselresistanceBP21NA:about40％patientswithprimaryhypertension,plasmaNA↑AD：improvetoreleaseNA↑DAand5-HT：abnormalmetabolism，↑

withage↑4.NervepeptideY(NPY)：vesselcontraction5.Vasopressin(加压素):vesselcontractionneurotransmitter22Peripheralautonomyregulatingmechanism—renalwater-sodiumretentionRenin-angiotonin-aldosteronesystem（RAAS）prehypertensinangiotoninⅡ（ATⅡ）↑

BradykininhydrolysisreninangiotoninⅠ（ATⅠ）ACESmallarterycontractionPeripheralresistance↑BPStimulateadrenalcortexAldosteronesecretionWater-sodiumretentionACE:angiotonin-convertingenzyme23sympatheticactivityActivationofβ1-Ronheart

Activationofα

1-RonsmoothmuscleCardiacoutrputPeripheralresistance

Renin

AngiotensinII

Aldosteronesodium,waterretentionbloodvolumeIncreaseinBPResponsemediatedbytherenin-angiotensin-aldosteronesystemReninbloodflowglomerularFiltrationrateResponsemediatedbythesympatheticnervoussystemDecreaseinBPSummary24NOET-ⅠAbnormalfunctionhypertensionAbnormalfunctionofvascularendothelialcell2526non-drugstherapy--controldangerousfactors,suchasfat,hyperlipoprotein,highsalt,smokeandsocietystress--strategies:diet,exercise,controlsmoke,relaxmodeanti-hypertensiondrugstherapy

Therapyofhypertension27Classificationofantihypertensiveagents

Agentsactinginnervecenter:clonidineGanglionicblockingagents:mecamylamineNorepinephrinenerveterminalblocker:reserpineAdrenergic-Rantagonist:prazosin,propranolol28Vasodilators:hydralazineCalciumchannelblockers:nifedipineDiuretics:hydrochlorothiazideRASinhibitors:

ACEI(angiotensinⅠconvertingenzymeinhibitors)

：captopril

AT1receptorantagonist

(angiotensinⅡtypeⅠreceptorantagonist)

Renininhibitors2930MajorclassificationofantihypertensivedrugsDiureticsα-BlockersACEinhibitorsAngiotensinIIantagonistsCalciumantagonistsCentrally-actingdrugsSympatheticagentsReninangiotensinsysteminhibitorsAdrenergicreceptorblockingagentsβ-BlockersDirectvasodilators31

Section2

BasicAntihypertensiveDrugs

32InhibitorsofRAS--TheFirstclass

AngiotensinConvertingEnzymeInhibitors(ACEI)--Captopril(卡托普利)AngiotensinIIReceptorAntagonist

(AT1-ReceptorBlockingAgents)--Losartan(氯沙坦）

33PeripheralresistanceReninAldosterone

sodium,waterretention

DecreaseinBPAngiotensinI

AngiotensinII

AngiotensinogenBradykinininactiveIncreasedprostaglandinsynthesisvasodilationPeripheralresistancevasoconstritionIncreaseinBPACEinhibitorsARBACERAAS

anditsinhibitorsACE

remodelingofheartandvessel

34Captopril

(卡托普利)Enalapril

(依那普利)Lisinopril(赖诺普利)Benazepril

(苯那普利)Cilazapril

(西拉普利)AngiotensinConvertingEnzymeInhibitors(ACEI)35Pharmacologicaleffects1.decreaseBP2.Effectsonhemodynamics:dilatethevessel，decreaseperipheralresistance3.inhibitandreverseremodelingofheartandvessel4.protectvascularendothelialcells5.protectkidney6.antiatherosclerosis(AS):decreaseox-LDL36Themechanismofaction1.InhibitACEincirculationandtissue,dilatethevessel.2.InhibitgenerationofAngIIinlocaltissue,preventremodelingofheartandvessel,decreasealdosterone(ALD)secretion,↓H2OandNa+retention.37Themechanismofaction3.↓degradationofbradykinin↑bradykininlevels↑synthesizeofNOandPGI2dilatethevessel4.↓NArelease,inhibitRASinCNS,↓activityofsympatheticnerve.5.Scavengingfreeradicals

38Effectsofangiotensinconvertingenzyme(ACE)inhibitors39ThemeritsofACEI1.Havenotachycardia2.Havenoelectrolytedisturbanceandlipidmetabolismdisturbance3.InhibitproliferationandhypertrophyofVSMCandmyocardialcells4.Improvelifequality,↓mortality40Clinicaluse1.Alltypesofhypertension

--especiallyforhypertensionwithhighornormalrenin

--bestforhypertensionwithdiabetes,CHF,AMI2.congestiveheartfailure(CHF)

Adversereactionshypotension(2%),cough(5-20%),acuterenalfailure,angioedema,hyperkalemia,hypoglycemia,influenceondevelopmentoffetus.41AngiotensinIIReceptorAntagonist

(AT1-ReceptorBlockingAgents)Losartan(氯沙坦）

Valsartan（缬沙坦）

Irbesartan（伊白沙坦）42ArrestAngIIcombinewithAT1-R1.TheeffectblockingAngⅡismoreselectivethanACEI2.Noeffectiveonbradykininmetabolism

ClinicalUseandEvaluation1.TheactionsissimilartoACEI2.Dosenotcausecoughandangioedema.PharmacologicalActions43Renininhibitors

enalkiren（依那克林)remikiren(雷米克林)

Inhibitreninactivity，↓synthesizeofAngⅡ

种属特异性高，动物模型难得。依那克林属肽类，生物利用度低。44PeripheralresistanceReninAldosterone

sodium,waterretention

DecreaseinBPAngiotensinI

AngiotensinII

AngiotensinogenBradykinininactiveIncreasedprostaglandinsynthesisvasodilationPeripheralresistancevasoconstritionIncreaseinBPACEinhibitorsARBACERAAS

anditsinhibitorsACE

remodelingofheartandvessel

4546

CalciumChannelBlockers

Nifedipine

(硝苯地平）

Amlodipine（氨氯地平）

Verapamil

（维拉帕米）

Diltiazem

（地尔硫卓）Thesecondclass47Pharmacologicaleffects1.Effectonsmoothmuscle:dilationsensitivityinsmallarterygreaterthansmallvein2.Effectonheart:

Heartrateandcontractilitydecrease,blockCa2+channelinsinusnodeandatrioventricularnode3.Protectiveeffectsoftissuedamageinducedbyischemiaandhypoxia4.other:

inhibitplateletaggregation48Mechanismofantihypertension

BlockingLtypesCa2+channel→↓Ca2+inflow→VSMdilation→BP↓VSM:VascularSmoothMuscle49CharacteristicsofeverydrugNifedipineDilatesmallA.,↓peripheralR.↓BPWeakentheBPpromotionofNA,AngIIIncreaseconformabilityoflargevessels50Nifedipine

Advantages1.Actionofdilatingvesselisstrongerthanothercalciumantagonist;2.Don’tdecreasebloodflowofmajororgan;3.Preventorreverseventricularandvesselhypertrophy;4.Anti-atherosclerosisaction;515.Inherentdiuresis,don’tinducewater-sodiumretention;6.Don’tinducelipidmetabolismdisturbanceandchangeofglucosetolerance;7.Treatmentofalltypeshypertension;8.Lowcost,notolerance,longtimeuse.Nifedipine

Advantages52firstpasseffecthighReflexincreaseinsympatheticactivity:

tachycardia,↑Cardiacoutput,↑reninactivityDisadvantageNifedipine53Amlodipine（氨氯地平）1.Takeeffectslowly(1～2w),long–acting(t1/2,50h),reduceBPactionissteadilyandcontinuously.2.Donoteffectonheartobviously3.Canreversemyocardialhypertrophy54Nimodipine（尼莫地平）Acrossthebloodbrainbarrier,goodeffectoncerebralbloodvessels

Verapamil

（维拉帕米）Goodeffectonheart

Diltiazem

（地尔硫卓）Goodeffectonheart55Diuretics---↓sodiumandbodyfluidretention↓bloodvolume↓BP

widespreaduse:commonly,usesingleorcombinationAdvantageforcombination:Raisingcurativeeffect,relievewater-sodiumretentionofotherdrugsThethirdclass56

Characteristics:

Mildness,Lasting,Notolerance.↓morbidityandmortalityofhypertensioncomplications.Hydrochlorothiazide

(氢氯噻嗪)57ThemechanismofBPreduction

1.Early:↑Na+andH2Oexcretion,↓extracellularvolumeandbloodvolume,↓cardiacoutput2.Long:↓Na+invesselwall,↓Na+-Ca2+exchange,↓intracellularCa2+,peripheralresistance↓3.↓sensitivityofVSMtovasoconstrictors(NA)anddilateVSMdirectly4.generatePGs,BK---dilatevessel58

ThemechanismforreductionofBPThiazidediureticssodium,waterretentionbloodvolume

CardiacoutputPeripheralresistanceDecreaseinBPNa+invesselwallNa+-Ca2+exchangeCa2+insmoothmusclecellinitialLong-term3-4wBK,PGsLong-term59ClinicalUses(1)Low-doseofthiazidediuretictherapyissafeandeffectiveforhypertension.Thiazidediureticsareappropriateformostpatientswithmildhypertension,particularlyelderlypatients.60(2)Thiazidesareusefulincombinationtherapywithotherantihypertensivedrugsincludingβ-blockersandACEinhibitors.Treatmentformoderateandseverehypertension611.Electrolytedisturbance:

hypokalemia,hypomagnesemia

hyperglycemia2.Metabolism

disturbance:ThiazidediureticscanincreaseTC,TG,LDLlevelandreninactivity;impairglucosetolerance.Adverseeffects62

↑renalbloodflow,↑Na+andH2Oexcretion.

Onlybeusedinhypertensiveemergenciesorhypertensioncombinedwithrenalfunctionfailure.Furosemide(呋塞米)63SympatheticnerveinhibitorsThefourthclass1.Centrallyactingadrenergicdrugs

:Clonidine2.Ganglionicblockingagents:mecamylamine3.Adrenergicneuronblockingagents:ReserpineGuanethidine641.Centrallyactingadrenergicdrugs

α2-Rimidazoline-R(brainstem)–咪唑啉受体

adrenergicnerveimpulsefromcentrum↓vesseldilatation，BP↓

++Clonidine,-methydopa65Clonidine-α2-RagonistPharmacologicalaction1.Antihypertensiveeffect(ivororal)2.Sedativeeffect3.Inhibitgastrointestinalsecretionandenterocinesia(browelcreeping

motion)66PharmacokineticsOral,rapidlyabsorption,2~4hatpeakconcentration;EasytotransportthroughBBB;Liver,partlymetabolismKidney,partlyexcretionClonidine67Themechanismofaction1.Exciteα2-Rofpostsynapticmembraneinmedullaoblongataneuronwhichisrepressiveneuron

↓sympatheticactivityBP↓2.ExciteI1imidazoline-Rofrostralventrolateralmedulla(RVLM，延髓腹外侧嘴部),↓sympatheticactivity，BP↓3.Exciteα2-Rofperipheralsympatheticpresynapticmembrane,

decreasethereleaseofNAClonidine68ClinicalUse

Moderatehypertension1.Drymouth,sedation,headache,sexualdysfunction,constipation.2.Withdrawalreaction:tachycardia,sweating,acuterisinginBP.3.Water-sodiumretentionAdverseEffects69--SpecificallyactonN1-R,blocktheionchanneloftheautonomicganglia--NoselectivitytowardthesympatheticorparasympatheticgangliaMecamylamine(美加明)Trimethaphan(咪噻吩)---short-acting---usedforhypertensioncrisis2.Ganglionicblockingagents703.Adrenergicneuronblockingagentssympatheticnerveendingsuppressant

--decreaseBPbyexhaustingNA,interferingwiththereleaseorstoreofNA.

Reserpine(利舍平,利血平)

Guanethidine(胍乙啶)

71Reserpine（利舍平）Pharmacologicalaction:slowly,mild,longduration;Heartratedecrease--overcomebyatropineandhavenoeffectsonthedecreaseofBPSedation,stabilization

similarwithChlorpromazine.72Mechanisms

RelatedtotheexhaustofNAinvesiclesofcentralandperipheraladrenergicnerveending.Inhibittheuptakeofaminetransmitter---combinedwithaminepumpinvesiclemembraneandmetabolizedbyMAOlater.DyssynthesisofNA

InhibittheintakeofDA,thesynthesisofNAdecrease,BP↓.

MAO:monoamineoxidase73moderatehypertension,beunitedwithdiuretics.

AdversereactionSymptoms:

--duetoprominentparasympatheticnervousfunctionCNS

sedation,lethargy昏睡,depressivedisorderClinicaluse74Guanethidine(胍乙啶)Pharmacologicalaction:--potentandlongactionDilateA.andV.,Reducerenalandcerebralbloodflow---sodiumandwaterretention.75MechanismsInhibitthereleaseoftransmitter--enrichinpresynapticmembrane,hasmembrane-stabilizingaction,NAreleaseInhibittheuptakeoftransmitter

--inhibitaminepump,uptake,resultintransmitterexhausted.Note:transientBP↑,GuanethidinewereintakeinvesicleandreplaceNA.ClinicaluseSeverehypertensionwhenotherdrugshavenoeffects.76α1-adrenoreceptorantagonistPharmacologicalaction:Blockingα1-RselectivelyDilateAandVvesselBP↓Noblockingon

2-R(presynapticmembrane)AdrenergicAntagonistPrazosin,Terazosin(特拉唑嗪)77Actionofantihypertensionaction:moderate-potentdilatesmallA.andV.，peripheralresistance↓BP↓nochangeofcardiacoutputor↑

78DonotreducetherenalbloodandrenalglobulefiltrationDonotincreasereninactivityDonotreflexincreaseinheartrate↓TG,TC,LDL-c,↑HDL-c

Merit

2-R79ClinicalUses

Alltypesmoderatehypertension,--especiallywithkidneydysfunction--beunitedwithβ-Rantagonistanddiuretics.

Chronicheartfailure

AdverseReactions1.Firstdosephenomenon:

overcome:½dose,beforesleeping2.Retentionofsaltandfluid80

Propranolol

Metoprolol

Atenolol

β-adrenergicantagonist

81TheMechanismofAction(1)Blockingβ1–Rofheart

,↓cardiacoutput,↓peripheralresistance(2)Blockingβ1–Rofjuxtaglomerularcell

inkidney,inhibitreninrelease,↓RASactivity.angiotoninII↓,Aldosterone↓8283(3)Blockingperipheralsympatheticpresynapticβ2-R,↓NArelease.(4)Blockingβ-RofCNS,inhibitvasomotorcenter,↓peripheralsympatheticactivity.(5)IncreasesynthesisofPGI2.84β-Rblockersblockadeofβ1-Ronheart

CardiacoutputPeripheralresistanceReninAngiotoninII

Aldosteronesodium,waterretentionbloodvolume

DecreaseinBPblockadeofβ-RinperipheralandcentralnervoussystemInhibitNAreleaseandvasomotorcenterThemechanismofantihypertensiveactionblockadeofβ2-R85ClinicalUsesandEvaluationAlltypesofhypertension,especiallyinhighreninactivity,highcardiacoutput.Hypertensionaccompaniedwithangina,previousmyocardialischemic(MI)orarrhythmia.

unitedwithvasodilatoranddiuretics86ApplicationAttention1.Smalldosebeginning2.Combinewithdiuretics.3.Notbediscontinuedabruptly

ContraindicationSeriousAVconductionblock,bradycardia,bronchialasthma.87AdversereactionsCommon:CNSsideeffects,fatigue,lethargy,insomniaandhallucinations;Alterationsinlipidpattern:lipidmetabolism,↑TG↓HDL;Drugwithdrawal:reboundhypertension,upregulationof-R88α,β-RAntagonist

Labetalol

Carvedilol

(卡维地洛）

Blockingβ1=β2>α1

Blockingα1andβ-R,↓BP

LighteffectonHRandcardiacoutput

actionintensity<Propranolol,prazosinUsedforalltypeshypertension89Vasodilators--

1.directvasodilators

2.potassiumchannelopeners3.otherhypotensors:

ketanserin(酮舍林,酮色林)Thefifthclass901.Vasodilators

Hydralazine(肼屈嗪)Mainlydilatesmallarterial---becauseofCa2+decrease.↑sympatheticreflexes,↑reninactivity,caninduceangina.Usedinmoderatehypertension9192SodiumNitroprusside(硝普钠)

ReleaseNOdilationofA.andV.BP↓Theefficacyisquickly(iv1~2min),actionlastingtimeisshort(3min).Usedinhypertensioncrisis,serious

heartfailure.Contraindication:liverandrenalfunctionfailure93Minoxidil(米诺地尔),Diazoxide(二氮嗪)

Themechanismofaction:↑KATP→↑K+efflux→cellmembranehyperpolarization---↓Ca2+influx→arterydilation→BP↓

ClinicalUsesSerioushypertension(hypertensioncrisisandhypertensiveencephalopathy)2.Potassiumchannelopeners943.otherhypotensors:

ketanserin(酮舍林,酮色林)Dilatevesselby--selectivelyblocking5-HT2Areceptor,--blockingα1andH1receptor--alsoinhibitvasoconstrictionofCAandAn