新型降壓藥物課件

新型降壓藥物

內(nèi)容

RAS抑制劑直接腎素抑制劑（DRI）

血管肽酶抑制劑

雙受體阻滯劑高血壓疫苗內(nèi)皮素受體拮抗劑CCB-Cilnidipine新型-受體阻制劑-Nebivolol

RASRAS在控制血壓中起了重要作用調(diào)節(jié)血容量調(diào)節(jié)外周血管阻力調(diào)節(jié)CV功能RAS在下列情況下被激活血容量減少血壓下降交感活性

DRIs(directrenininhibitor)研發(fā)背景

腎素在RAS激活點離解血管緊張素原、

Ang1、AngII、激活A(yù)T1R、BP

DRIs為理想RS抑制劑DRIs直接抑制腎素的作用,

抵銷由ACEIsorARBs

引起PRA

減弱

由ACEIsorARBs引起抑制AT1R

而喪失反饋機制、導(dǎo)致PRA腎素產(chǎn)生由RAS反饋環(huán)所控制

FeedbackLoopAT1ReceptorReninAngIAngiotensinogenAngIIBiologicaleffectsACENonACEpathwaysAdaptedfrom:Müller&Luft.2006DRIsactatthepointofactivationofRASandneutralizeinPRAinducedbyACEIsandARBs

FeedbackLoopAT1ReceptorReninAngIAngiotensinogenAngIIDirectrenininhibitorBiologicaleffectsACENonACEpathwaysPRAARBsACEIsAdaptedfrom:Müller&Luft.2006已研發(fā)與合成的DRIs包括

enalkiren,zankiren與remikiren上述DRIs由于以下原因未用于臨床:生物利用度低療效低半衰期短費效比差Stanton.2003

DRIs

研發(fā)的挑戰(zhàn)Rasilez?

（阿利吉侖）生物有效性高

生物有效性為2.6%

其它DRI<1%,限制它們在臨床上的應(yīng)用

2.6%足以產(chǎn)生持續(xù)效應(yīng)

Novartis,dataonfile2001(StudyPK01)現(xiàn)有RAS抑制劑

會升高

PRA

FeedbackLoopAT1ReceptorReninAngIAngiotensinogenAngIIBiologicaleffectsACENonACEpathwaysARBsACEIsPRAAdaptedfrom:Müller&Luft.2006ARB作用機制

JCardiovascPharmacol,Vol.39.No4.2002AGI↑AGII↑Ang-(1-7)↑無活性片段ACEAT1AT2Ang（1-7）受體B2受體緩激肽↑激肽原激肽釋放酶NEP旁路()()ARB非旁路

ACEIs、ARBs與

DRIs對RAS

要素的影響

↓↑↓↓↑↑↑↑ARB↑↑↓↑ACEIPRAReninAngIIAngIDRI↑

=increase ↓

=decreasePRAprovidesanindicationoftheactivityofRS

Nussbergeretal.2002;Azizietal.2006

Vaidyanathanetal.2006a;Vaidyanathanetal.2006b

Rasilez?

藥代動力學(xué)

T1/240hrs一天一次tmax1–3hourspostdose5–7天血漿濃度達穩(wěn)態(tài)狀態(tài)

特殊人群Novartis,dataonfile(Summaryofclinicalpharmacologyandstudies2209,2210);Vaidyanathanetal.2006在肝腎功能損害或糖尿病病人不必調(diào)節(jié)劑量

Rasilez?臨床前研究為第一個有效的口服DRI臨床前研究表明Rasilez?

有很好的降壓作用高血壓動物模型研究表明Rasilez?可減少蛋白尿、預(yù)防LVH證明有心臟與腎臟保護作用Rasilez?

與ACEIs比較有劑量依賴降低PRA作用

1000.1101TreatmentDay8PRA(ng/mL/h)0Time(hours)Rasilez?40mgRasilez?80mgRasilez?160mg24810264Rasilez?640mgEnalapril20mgPlaceboNussbergeretal.2002Rasilez?

可降低AngI與AngII、ACEI僅降低AngII

15040mg80mg160mg640mgEnalapril

20mgPlaceboRasilez?0AngIIlevel(%ofbaseline)Time(hours)2410050081240AngIlevel(%ofbaseline)Time(hours)2480001501501005008124

Treatmentday8Nussbergeretal.2002Rasilez?降低醛固酮排出

Urinaryaldexcretion(μg/24h)2104680PlaceboRasilez?

40mgRasilez?

80mgRasilez?

160mgRasilez?

640mgEnalapril

20mg***Pretreatment(Day-1)Day8Nussbergeretal.2002*p<0.05vspretreatment(Day-1)

n=18Rasilez?

抵銷

ARB引起PRA升高n=12mildlysodium-depletednormotensivesubjects08426PRA(ng/mL/h)0Time(hours)48242641218Rasilez?300mgPlaceboRasilez?

150mg+valsartan80mgValsartan160mg301Azizietal.2004Rasilez?抵銷

ARB引起AngI與AngII升高01608040120PlasmaAngI

(pg/mL)0Time(hours)482461280PlasmaAngII

(pg/mL)604020004824612Rasilez?

300mgPlaceboRasilez?150mg

+valsartan80mgValsartan160mgTime(hours)n=12mildlysodium-depletednormotensivesubjectsAzizietal.2004Rasilez?

降壓療效與

irbesartan相同

0?15?5?20?10n=133n=129n=130n=127n=130******p=0.005p=0.01Placebo

150300

600150*p<0.02vsplacebo;**p<0.005;***p<0.001vsplacebo

n=133n=129n=130n=127n=130************Rasilez?

(mg)DBPSBPIrbesartan

(mg)Rasilez?

(mg)Irbesartan

(mg)Placebo150300600150***ChangefrombaselineinmeansiBP(mmHg)?6.3?9.3?11.8?11.5?5.3?11.4?15.8?15.7?12.5?8.9Gradmanetal.2005(Study2201)Rasilez?toACEIs,CCBsordiuretics合用會明顯加強降壓療效，抵消上述藥物所致PRAVillamiletal.2006(Study2204)Rasilez?

明顯降低清晨高血壓

MeanambulatorySBP(mmHg)Clockhour240246810121416182022Week0Week8155120135115130125145150140Novartis,dataonfile2005(Study2308)Rasilez?

停藥后

PRA緩慢上升400?20?80?100?60?4020ChangefrombaselineinPRA

(%)Week1008Placebo(n=66)Rasilez?150mg(n=66)Rasilez?300mg(n=66)Rasilez?600mg(n=66)Double-blindtreatmentTreatment-free

withdrawalDataonfileNovartis2005;Herronetal.2006(Study2308)Rasilez?與利

尿劑聯(lián)合應(yīng)用抵銷利

尿劑引起PRA升高

?60?40?204080Rasilez?HCTZ75Combination40424242404336423640391503007515030030075150751506.2512.5256.2512.5256.2512.52512.525Rasilez?(mg)HCTZ(mg)?80n=changefrombaselineinPRA(%)20600454538411?54?65?5844572?55?51?49?64?50?46?49?62Calhounetal.2006;Novartis,dataonfile2005(Study2204)

Rasilez?與

CCB

聯(lián)用降低PRA

?7458ChangeinPRAfrombaseline(%)?100806040200?20?40?60?80n=55n=48Rasilez?/amlodipine

150/5mgAmlodipine

10mgNovartis,dataonfile2005(Study2305)

Rasilez?與

ACEI

聯(lián)用降低PRA

?8080604020?20?40?60120100?68111ChangeinPRAfrombaseline(%)n=79Rasilez?n=74n=75RamiprilRasilez?/ramipril?440Kiloetal.2006(Study2307)Rasilez?與ramipril聯(lián)用比單劑增加降壓療效

Change

from

baselineinmeansittingBP(mmHg)

Rasilez?/

ramipril

combinationRamipril

monoRasilez?mono?18?60?14DBPSBP?8?10?12?16Rasilez?/

ramipril

combinationRamipril

monoRasilez?

mono

*p<0.05forsuperiorityvsramiprilmonotherapy;?p<0.05forsuperiorityvsRasilez?monotherapy;?p<0.05fornon-inferiorityforRasilez?monotherapyvsramiprilmonotherapy?20*n=274n=279n=275n=274n=279n=275?12.8?10.7?11.3?16.6?12.0?14.7*??*?Uresinetal.2006(Study2307)Rasilez?is不良反應(yīng)

與irbesartan相似Patientswithadverseevents(%)Placebo

n=131Rasilez?Irbesartan150mgn=134150mg

n=127300mg

n=130600mg

n=130AnyAE32.126.836.233.136.6DiscontinuationsduetoAE2.33.93.12.32.2SeriousAE1.50.00.00.01.5MostfrequentAEs(≥2%inanygroup)Headache5.32.46.24.63.0Diarrhoea1.51.60.86.91.5Dizziness3.81.63.12.33.7Fatigue3.10.83.81.51.5Backpain0.01.62.31.54.5Gradmanetal.2005;Novartis,dataonfile2003(Study2201)

Rasilez?系列靶器官保護研究

AVOID– AliskirenintheeValuationofprOteinuriaIntype2

DiabetesALOFT

– ALiskiren

ObservationofheartFailureTreatmentALLAY– ALiskiren

LeftventricularAssessmentofhypertrophY

ALiskiren

Leftventricular

OF

AssessmentofhypertrophYALLAYAliskiren左室肥厚的評估ALiskiren

LeftventricularAssessment

ofhypertrophY(ALLAY)

首個DRI逆轉(zhuǎn)LVH對照研究研究人群：伴LVH的超重高血壓患者多中心、前瞻性、隨機雙盲、陽性對照試驗8個國家77個臨床中心觀察36周SolomonS,AppelbaumE,ManningWJ,etal.LateBreakerpresentationatACC2008.

阿利吉侖對LVH的影響滴定期維持期34周阿利吉侖150mg氯沙坦50mg阿利吉侖/氯沙坦聯(lián)合150/50mg阿利吉侖300mg氯沙坦100mg阿利吉侖/氯沙坦聯(lián)合300/100mg篩選&洗脫期

2或12周隨機化

*靶血壓

<

140/90

mmHg(糖尿病患者<

130/80

mmHg)+*必要時增加利尿劑，CCB，受體阻滯劑和/或血管擴張劑。無ACEI/ARB預(yù)治療

12周ACEI/ARB預(yù)治療

12周2周基線時MRI最后隨診時MRISolomonS,AppelbaumE,ManningWJ,etal.LateBreakerpresentationatACC2008.

460例BMI>25kg/m2，并且具有LVH證據(jù)的高血壓患者，隨機分為3組:研究方法

治療36周后，平均坐位血壓變化情況收縮壓和舒張壓(mmHg)8082848688135140145150基線124812202836隨訪時間（周）收縮壓舒張壓腎素抑制劑組145/90138/86=–6.5/–3.8mmHgARB組145/88140/85=–5.5/–3.7mmHg聯(lián)合治療組144/89138/84=–6.6/–4.6mmHgSolomonS,AppelbaumE,ManningWJ,etal.LateBreakerpresentationatACC2008.左室重量指數(shù)變化(g/m2)-4.9±1(-5.4%)-4.8±1(-4.7%)-5.8±0.9(-6.4%)-7-6-5-4-3-2-10聯(lián)合治療組腎素抑制劑組ARB與基線時相比P均<0.0001(非劣性)P<0.0001(優(yōu)越性)P=0.52n=132n=123n=136SolomonS,AppelbaumE,ManningWJ,etal.LateBreakerpresentationatACC2008.

治療36周時，LVMI變化情況

<–16–16to–5.7–5.7to+4.7>+4.7–10–9–8–7–6–5–4–3–2–10與基線時相比左室重量指數(shù)變化(g/m2)與基線時相比，SBP變化四分位數(shù)(mmHg)P<0.001

SBP幅度與LVH逆轉(zhuǎn)程度顯著相關(guān)

SolomonS,AppelbaumE,ManningWJ,etal.LateBreakerpresentationatACC2008.ALLAY研究結(jié)論這項替代終點研究表明：在降低伴LVH的超重高血壓者LVMI，DRI或DRI聯(lián)合ARB并不比ARB單藥更有效對于伴LVH的高血壓者，DRI可作為選擇的一種替代ARB藥物有效降壓可能是逆轉(zhuǎn)左室肥厚主要決定因素SolomonS,AppelbaumE,ManningWJ,etal.LateBreakerpresentationatACC2008.CMT.2008.4