Specia Sp ial l At Atte tenti tion on to to AC ACE In Inhib - - PowerPoint PPT Presentation

An Anti ti-Hy Hype perte tensi sive ve Tr Treat atment Sp Specia ial l At Atte tenti tion

• n to

to AC ACE In Inhib ibit itor

• r

Quy uy mô mô của vấn đề

Tử vong bệnh tim mạch: > 4 triệu chết ở Châu Âu (2000) Bệnh tim mạch: 43% của tất cả tử vong ở đàn ông và 55% tử vong ở phụ nữ Nguyên nhân chính của nhập viện: 2557/100000 dân (2002)

2010: Tăng huyết áp vẫn là nguyên nhân gây tử vong hàng đầu.

17 triệu cas tử vong mỗi năm; giảm trung bình 5 năm tuổi thọ của bệnh nhân.

Actuality

WHO 2010

50 100 150 200 250 300 350 Established market economies Latin America & the Caribbeans Former socialist economies Middle East crescent China India Other Asia & Islands Sub-saharan Africa Prevalence 2000 Predicted Prevalence 2025 * Estimated number of individuals aged >20 years with BP >140/90 mmHg in 2000 and predicted number of affected individuals in 2025. Kearney PM, et al. Lancet 2005;365:217-23.

Milions

> 500 triệu người bị tăng huyết áp vào năm 2025

Tỉ lệ hi hiện m n mắc tăng huyết á t áp dự báo vào năm 2020

Sử dụng thuốc hạ áp để giảm bệnh tim mạch

Law MR et al, BMJ. 2009; 338: b1665.

Để giảm 10 mm Hg trong HATT hay 5 mm Hg trong HATTr:

Biến cố bệnh mạch vành

• 22 to 25%

Đột quỵ

• 36 to 41%

Current Situation of Blood Pressure Management

7 10 20 30 40 50 60 70 USA awareness England Italy Sweden Canada Germany treatment BP control Spain % of population

< 140/90 mmHg

Wolf-Maier et al 2004

Hypertension Management: Hypertension Awareness, Treatment & Control in Various Countries

a) home BP < 135/85 mmHg clinic BP < 140/90 mmHg b) home BP ≥ 135/85 mmHg clinic BP < 140/90 mmHg c) home BP < 135/85 mmHg clinic BP ≥ 140/90 mmHg d) home BP ≥ 135/85 mmHg clinic BP ≥ 140/90 mmHg e) home BP < 130/80 mmHg clinic BP < 130/80 mmHg f) home BP ≥ 130/80 mmHg clinic BP ≥ 130/80 mmHg

Control Status of BP Levels in Treated Hypertensive Patients

Obata et al. J Hypertens 2005;23:1653-1660. Obata et al. Diabetes Res Clin Pract 2006;73:276-283. modified

Hypertensive patients complicated with diabetes (n=466)

Good controle) 25.1% (n=117) Poor controlf) 74.9% (n=349)

Total hypertensive patients (n=3,400)

Good controla) 19.1% (n=648) Poor controld) 43.4% (n=1,477) Masked hypertensionb) 22.9% (n=777) White coat hypertensionc) 14.7% (n=498)

J-HOME study

Development of Anti-hypertensive Therapies

Direct vasodilators Alpha blockers Others? Aliskiren Peripheral sympatholytics Ganglion blockers Veratrum alkaloids Central alpha2 agonists Non-DHP CCBs Beta blockers Thiazide diuretics DHP CCBs ARBs ACE inhibitors

Effectiveness Tolerability

1940s 1950 1957 1960s 1970s 1980s 1990s 2004+

Origin of RAS Research

Robert Adolf Armand Tigerstedt (ca. 1910) Experiment 1B, 8. November 1896

The Discovery of Renin 1896

• ‘A [rabbit] kidney was pulverized with 21 mL of water. Injection into jugular
• vein. Within 80 seconds, there is a rise in mean arterial pressure from

62–67 mmHg to 100 mmHg, i.e. an increase by ca. 50%.’

Tigerstedt R, Bergman PG. 1898

114 Years of RAAS Research

1898 Tigerstedt R. Finding of renin 1954 Simpson & Tait: Struct. Ident. of aldosterone 1955 Skeggs: Isol. of horse AngⅡ 1956 Sequencing 1960 Kagawa, Develop. of spirolactone 1966 Arakawa: Isol.& synth. of human Ang Ⅰ 1969 Haber: RIA for PRA 1970 Bumpus: Peptide ARB: Goodfriend: finding of AngⅡ-R 1975 Misono&Inagami: Isol. of mouse renin 1977 Ondetti: ACE inhibitor captopril 1982 Furukawa: Non-peptide ARB 1983 Imai: Cloning of human renin 1984 Kageyama: human Aogen 1990 Urata: Isol. of human heart chymase 1991 Cloning 1991 Hubert: Cloning of human ACE Sasaki/Murphy: Cloning of mouse AT1R Timmermans: Develop. of losartan (AIIA, ARB) 1993 Kanbayashi/Mukoyama: Cloning of rat AT2R 2003 Wood: Develop. of aliskiren (non-peptide renin inhibitor)

114 Years of RAAS Research

1898 Tigerstedt R. Finding of renin 1954 Simpson & Tait: Struct. Ident. of aldosterone 1955 Skeggs: Isol. of horse AngⅡ 1956 Sequencing 1960 Kagawa, Develop. of spirolactone 1966 Arakawa: Isol.& synth. of human Ang Ⅰ 1969 Haber: RIA for PRA 1970 Bumpus: Peptide ARB: Goodfriend: finding of AngⅡ-R 1975 Misono&Inagami: Isol. of mouse renin 1977 Ondetti: ACE inhibitor captopril 1982 Furukawa: Non-peptide ARB 1983 Imai: Cloning of human renin 1984 Kageyama: human Aogen 1990 Urata: Isol. of human heart chymase 1991 Cloning 1991 Hubert: Cloning of human ACE Sasaki/Murphy: Cloning of mouse AT1R Timmermans: Develop. of losartan (AIIA, ARB) 1993 Kanbayashi/Mukoyama: Cloning of rat AT2R 2003 Wood: Develop. of aliskiren (non-peptide renin inhibitor)

Angiotensin II

Direct and indirect effects in organ damage

Angiotensin II AT1 receptor

Death

 Glomerular filtration rate Proteinuria Glomerulosclerosis  Aldosterone release Renal failure Left ventricular hypertrophy Fibrosis Remodelling Apoptosis Heart failure/ myocardial infarction Vasoconstriction Vascular hypertrophy Endothelial dysfunction Atherosclerosis Stroke Hypertension New-onset diabetes

The proven benefits of ACE inhibitors across the cardiovascular continuum

Risk Factors Diabetes Hypertensio n

Atherosclerosis and LVH

Myocardial Infarction Remodelling Ventricular Dilatation Chronic Heart Failure End-Stage Heart Disease and Death Death

CONSENSUS

SOLVD SAVE ,AIRE TRACE,SMILE ISIS 4 GISSI 3 HOPE CAPP EUROPA

ASCOT HOPE EUROPA ADVANCE GISSI-3 ISIS-4 AIRE SAVE TRACE CONSENSUS I SOLVD CONSENSUS II QUIET PEACE Before AMI After AMI AMI

Primary prevention Secondary prevention Treatment after MI

ACE inhibitor trials

• Provides highly selective blockade of Ang II

directly at AT1 receptor

ARB : SELECTIVE

ANGIOTENSIN II

AT1 AT2

• Proliferation
• Vasoconstriction
• Increase sympathetic tone
• Anti proliferation
• Vasodilation
• Coronary flow

Deleterious Effect Beneficial Effect

ARBs selective block at AT1 receptor

Risk Factors Diabetes Hypertension Hyperlipidemia Smoking

Atherosclerosis and LVH Ventricular Dilatation Chronic Heart Failure End-Stage Heart Disease

Myocardial Infarction

Remodelling

Death

LIFE SCOPE VALUE ONTARGET

OPTIMAAL VALIANT

Emerging benefits of the ARBs across the cardiovascular continuum

ELITE 2 Val-HeFT CHARM NAVIGATO RSMOOTH

Comparision of Antiypertensive Effects

Kind of drugs

Diuretic Beta-blocker (including Alpha/Beta-blocker) Alpha-blocker Calcium antagonist ACE inhibitor ARB

• No. of study

6 16+4 5 11 11 5

• Ave. Rate of Efficacy

68.7 % (64.4-73.1) 64.7 % (56.4-76.0) 63.7 % (52.7-76.5) 83.0 % (76.8-90.0) 73.4 % (65.0-80.8) 78.9 % (69.7-84.7)

Efficacy rates mainly on essential hypertension from insertions of respective drugs excluding slow release formulas

European Heart Journal 2012

Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis

• f randomized clinical trials of

renin–angiotensin–aldosterone system inhibitors involving 158 998 patients

Background and aim

• Background and Aim

－Renin–angiotensin–aldosterone system (RAAS) inhibitors are well established for the reduction in cardiovascular morbidity, but their impact on all-cause mortality in hypertensive patients is uncertain. －Objective of this study was to analyze the effects

• f RAAS inhibitors as a class of drugs, as well

as of angiotensin-converting enzyme (ACE) inhibitors and AT1 receptor blockers (ARBs) separately, on all-cause mortality.

Laura C. van Vark et al.:European Heart Journal 2012

Method

Randomized controlled trials, published between 1st January, 2000 1st March, 2011, are included in meta-analysis (n=20).

Laura C. van Vark et al.:European Heart Journal 2012

All-cause mortality and Cardiovascular mortality

In all 20 trials grouped together, all-cause mortality was reduced significantly by 5% by the treatment with an RAAS inhibition. In addition, the cardiovascular mortality was significantly reduced by 7%.

Laura C. van Vark et al.:European Heart Journal 2012

Angiotensin-converting enzyme inhibitors vs. AT1 receptor blockers

The all-cause mortality reduction in the overall group of RAAS inhibitors in the previous slide was completely driven by the beneficial effect of the ACE inhibitors.

Laura C. van Vark et al.:European Heart Journal 2012

ACEI ARB

Major Large Scale Clinical Trials using ACE Inhibitors

Lewis AIPRI REIN AASK BENEDICT

CONSENSUS II

ISIS 4 GISSI 3 SAVE AIRE TRACE SMILE OPTIMAAL CONSENSUS V-HeFT II SOLVD ELITE II (ARB) ALLHAT ANBP 2 (D) ABCD FACET UKPDS CAPPP (B&D) STOP2 HT TOMHS

Renal disorder Cardiac Infarction Cardiac failure Hypertension

HOPE EUROPA PEACE

Cardiovascul ar disease

Significant and won Equivalent

• ns. Against placebo

RENAAL IDNT１＆２ IRMA MA2 ORIENT(plac) Nav avigat ator(plac ac) OPTIMA MAAL * VALIANT T * JIKEIKYOTO HEART STUDY ELITEⅡ * Val-HeFT * * CHARM ( M (plac) iPR PRESE SERVE(plac ac ) LIFE(βB) SCOPE（plac) VALUE(CCB CB） ONTARGET* TRANSC SCEND(plac ac) ACTIVE I (plac) PRoFESS(plac) VART(CCB CB)

DM & C CKD MI & A AP HF HF HT HT

*, v vs.

• s. AC

ACE inhibitor

• r

Significant win Equivalent

• ns. against placebo

Major Large Scale Clinical Trials using Angiotensin Receptor Blocker

Blood Pressure Lowering Treatment Trialists’ Collaboration

Second cycle of overview analyses

Institute for International Health

Comparative effects of ACE inhibitors and ARBs

Blood Pressure Lowering Treatment Trialists Collaboration(BPLTTC)

Meta-regressions Trials including randomisation to an ACE inhibitor arm or an ARB arm

0.6 0.8 1 1.2 1.4

• 9%

+8% Coronary Disease

(CHD Death, MI)

STROKE

(Fatal, Nonfatal)

Heart Failure

(Fatal, Hospitalized)

+2%

• 1%
• 5%
• 17%

P=0.001 P=NS P=NS

Beyond Blood Pressure Lowering Effects Negate Blood Pressure Lowering Effects

ACEIs ARBs

BPLTTC J Hypertens 2007, 25:951-958

* *

* significant

ACEIs significantly reduced the risk of coronary heart disease

BPLTTC

BPLTTC CONTRIBUTING TRIALS

Beyond Blood Pressure Lowering Effects of ACEIs and ARBs on Primary Outcomes

Ngoài những tác dụng đã biết,

thuốc ƯCMC còn có cơ chế tác động có lợi nào nữa trong các bệnh ĐMV ?

Tác động lên quá trình ly giải Fibrin

Tác động AII và Bradykinin lên ly giải fibrin

32

EC VSMC

KININOGEN

BRADYKININ

ANGIOTENSINOGEN ANG I ANG II ANG IV PAI-1 t-PA

ACE

Brown et al. Heart Failure Reviews 1999

33

ACE inhibitor and PAI-1

Vaughan DE ; 18th World Congress of the International Union of Angiology, Tokyo, Japan

AngiotensinⅠ

AT1-receptor

（Angiotensin type I receptor)

Various organ damage AngiotensinⅡ

Angiotensinogen

Inactive peptide

Kininogen Bradykinin

ACE

×:ACE-I

Angiotensin IV receptor

PAI-1

Ang IV

PAI-1

Ang IV

tPA

tPA

34

ARB and PAI-1

Angiotensin I

AT1-receptor

（Angiotensin type I receptor)

Various organ damage Angiotensin II

Angiotensinogen

×：ARB

×

Inactive placebo

Kininogen Bradykinin

tPA

ACE

Angiotensin IV receptor

PAI-1

Ang IV

PAI-1

Ang IV

Vaughan DE ; 18th World Congress of the International Union of Angiology, Tokyo, Japan

FISIC-II study Background and aim

• FISIC-II Study

－Fibrinolysis and Insulin Sensitivity in Imidapril and

Candesartan in essential hypertension patients with metabolic syndrome

• Background

－While fibrinolysis and insulin sensitivity were evaluated in FISIC study, relation between PAI-1 and Ang II was not

• evaluated. Therefore, it was observed in FISIC-II
• Aim

－To assess the role of Ang II in plasma PAI-1 changes induced by the ACE-I imidapril and the ARB candesartan

Study Design

IMIDAPRIL 10 mg (n=45) CANDESARTAN 16 mg (n=45)

wash-out

• 2 0 2 4 8 12 16 WEEK

(n= 42) (n= 42)

BP BP BP BP BP BP PAI-1 PAI-1 PAI-1 PAI-1 PAI-1 PAI-1 Ag II Ag II Ag II Ag II Ag II Ag II TITRATION TITRATION

Change in Plasma PAI-1 Level

• 15
• 10
• 5

5 10

Delta PAI-1 (ng/ml)

Imidapril Candesartan

Week 2 Week 4 Week 8 Week 12 Week 16

* * ** * ** ** ° * + * +

* p< 0.05; ** p< 0.01 vs baseline ° p< 0.05; + p< 0.01 vs imidapril Fogari et al., Hypertension Research 34, 1321-6, 2011

**

Change in Plasma Ang II Level

• 25
• 15
• 5

5 15 25 35

Delta Ag II (pg/ml)

Imidapril Candesartan

Week 2 Week 4 Week 8 Week 12 Week 16

* * * * * * ** + ** + * °

• p< 0.05; ** p< 0.01 vs baseline
• ; ° p< 0.05; + p< 0.01 vs imidapril

Fogari et al., Hypertension Research 34, 1321-6, 2011

Relationships between Plasma PAI-1 and Ang II changes in Imidapril group

• 40
• 30
• 20
• 10

Delta

PAI-1 (ng/ml) Ag II (pg/ml)

Week 2 Week 4 Week 8 Week 12 Week 16 r=0.48 p<0.01 Ag II PAI-1 Ag II Ag II PAI-1 PAI-1 r=0.64 p<0.001 r=0.61 p<0.001

* ** * ** ** * * * * *

* p< 0.05; ** p< 0.01 vs baseline Fogari et al., Hypertension Research 34, 1321-6, 2011

Relationships between Plasma PAI-1 and Ang II changes in Candesartan group

• 10

10 20 30 40

Delta

PAI-1 (ng/ml) Ag II (pg/ml)

Week 2 Week 4 Week 8 Week 12 Week 16 r= 0.09 ns PAI-1 PAI-1 PAI-1 Ag II Ag II Ag II r= 0.27 p< 0.05 r= 0.37 p< 0.005

• p< 0.05; ** p< 0.01 vs baseline
• ; ° p< 0.05; + p< 0.01 vs imidapril

* ° * + * + * * ° ** + ** +

Fogari et al., Hypertension Research 34, 1321-6, 2011

HOÄI CHÖÙNG THIEÁU MAÙU CUÏC

BOÄ CÔ TIM MÔÙI: CÔ TIM THÍCH NGHI TRÖÔÙC

• PRECONDITIONING

CAÙC HOÄI CHÖÙNG THIEÁU MAÙU CUÏC BOÄ CÔ TIM MÔÙI: CÔ TIM THÍCH NGHI TRÖÔÙC

Thích nghi tröôùc: Töø thöïc nghieäm ñeán aùp duïng treân BN

Repeat ischemia (prolonged) REPERFUSION PROTECTION

REPEAT ISCHEMIA

Opie (1998)

Smaller than expected infract ? Smaller than expected infract REPEAT ISCHEMIA AMI

THROMBOLYSIS EXPERIMENTAL PRECONDITIONING

Rezkalla SH (2004). Nat Clin Pract Cardiovasc Med 1: 96 doi:10.1038/ncpcardio0047

Kinins

ACE

Degradation ACE Inhibitor

B2

Icatibant IP3

↑ Ca++

PLA2

PGI2

L-arginine

NO ↑cAMP

AC GC

↑cGMP

Relaxation Anti-ischemic Anti-proliferative Anti-atherosclerotic

+ Smooth muscle cell Endothelial cell

ACE Inhibitor AII Receptor Blocker Blocks formation

• f AII incompletely Blocks Kininase II

↑ Kinins ↓ AII effects

& aldosterone PROTECTION Blocks AT-1R AT-2R Free More complete Inhibition

• f AII effects

Preserve Anti- proliferative effect

Adenosine

Bradykinin

Opioids

protect the heart

Contribute equally to PC

PKC

Acetylcholine

Activates PKC and is a useful tool for studying pathways even though there is no mechanism for its release in ischemic preconditioning

Tissue ACE Activity Inhibition

Inhibitory Effects on Tissue ACE Activity

Masami Kubo. et al., Jpn J Pharmacol 1991; 57:517

5 15

(nmol/min/mg protein)

distilled water (10ml/kg/day)

Imidapril

(1mg/kg/day)

Enalapril

(5mg/kg/day)

Captopril

(5mg/kg/day)

n=7～8 mean±SE

* p＜0.05 (vs distilled water)

*

ACE activity in the thoracic aorta 10

ACE activity in the thoracic aorta was measured 24 hours after the last administration of drugs following 10 weeks admiration.

Phân bố của men chuyển:

Hệ Renin-Angiotensin (III)

• mod. from Dzau V, Arch Intern Med 153 (1993)

R A S

Tuần hoàn (huyết tương) Tại chỗ (mô) 10 %

90 %

Tác động cấp và ngắn hạn

Tim mạch/ Nội môi thận

Tác động dài hạn

“Cơ quan thích nghi“ tại chỗ

hoạt hóa thận độc lập

Metalloproteinases và xơ vữa ĐM

Yếu tố hoạt hóa phân tử:

Mảng xơ vữa

Endothelial cells Smooth muscle cells Macrophages Foam-cells T-lymphocytes Yếu tố Paracrine/autocrine IL-1, IL-6 TNF- PDGF FGF etc. Tính không ổn định của MXV Cellular Secretion

• accord. to Libby P, Circulation 91 (1995) & Zhu et al., J Cardiovasc Pharmacol 36 (2000)

Ang II +

"Men chuyển-mảng xơ" và xơ vữa động mạch

Vai trò chính trong con đường XVĐM:

Endothelial dysfunction

Huyết khối

Viêm Co mạch

Tổn thương mạch máu Tái cấu trúc

Vỡ MXV MC-MXV

Yếu tố trung gian tại chỗ VCAM ICAM Cytokines Endothelin PAI-1 Yếu tố tăng trưởng Thủy phân Ang II Bradykinin NO

Biến chứng lâm sàng

Ang II

• adapt. from Pepine C, Can J Cardiol 14; suppl D (1998)

Ức chế xơ vữa của “mảng xơ – men chuyển“ hoạt động bằng ức chế men chuyển (I)

Cơ chế chống xơ vữa của UCMC:

Suy chưc năng nội mạc

Huyết khối Viêm

Tổn thương mạch máu Tái cấu trúc

Vỡ mảng xơ

Mảng xơ - MC Yếu tố trung gian tại chỗ

VCAM ICAM Cytokines Endothelin PAI-1 Yếu tố tăng trưởng Proteolysis Ang II Bradykinin NO

• accord. to Pepine C, Can J Cardiol 14; suppl D (1998)

Ang II

UCMC

Cải thiện

Giảm biến chứng lâm sàng

Co mạch

Điều trị thông thường

(bao gồm ASA, Statins)

Mảng xơ giảm hoạt Mảng xơ hoạt hóa Hoạt động MC tại mảng xơ

Hiệu quả chống xơ vữa của ƯCMC trên hệ mạch

Cách “giảm hoạt mảng xơ“:

Hoạt động MC tại mảng xơ Điều trị thông thường + ƯCMC Hoạt động MC tại mảng xơ

THUỐC ƯCMC CÓ THỂ TÁC ĐỘNG TÍCH CỰC VÀO NHIỀU VỊ TRÍ KHÁC NHAU CỦA VÒNG XOẮN BỆNH LÝ TIM MẠCH BÊ̤NH ĐMV THIẾU MÂU CƠ TIM

NMCT

RỐI LOẠN NHỊP R/L CHỨC NĂNG CƠ TIM

SUY TIM

YẾU TỐ NGUY CƠ (THA, RL LIPID, ĐTĐ...

VƯ̄A XƠ ĐM DÁY THẤT TRÂI TÂI CẤU TRÚC GIĀN THẤT TRÂI

ACEI

CCB

ARB/ ACE I Diuretic

beta-B

Left ventricular hypertrophy   Cardiac failure    *1 Prevention of atrial fibrillation  Tachycardia  *2  Angina pectoris   *3 Post-myocardial infarction   Proteinuria  Chronic renal failure   *4 Cerebrovascular disorder    Diabetes/MetS＊5  Aged hypertension  *6  

Encouraged Indications of Major Hypotensive Drugs

Treatment with hypotensive drug

Development of Pneumonia in Patients with History of Stroke and Its Estimated Mechanism

Vital Statistics of 2002 & 2004, the Ministry of Health, Welfare and Labor (2002)

Trends of Annual Mortality by Causes

50 100 150 200 1950 1960 1960 1970 1980 1990 1999

Heart Diseases Cerebrovascular Diseases Subarachnoidal Bleeding Cerebral Bleeding Cerebral infarction

245.3 126.4 104.7

2002 (year)

Pneumonia

Pneumonia in Elderly Increasing!

75.2

Malignant Neoplasm

Mortality (per 10,0000)

• T. Nakagawa et al: Arch Intern Med 157: 321, 1997

With cerebral infarction No cerebral infarction

25 50 (%)

＊＊＊：p＜0.001 （vs no cerebral infarction） † ＊ ＊ ＊

Relationship between Cerebral Infarction and Pneumonia Incidence

• ca. 3-fold

Incidence of Pneumonia

Pathogenesis of Pneumonia caused by subclinical aspiration

Substance P

lung stomach Cerebrovascular Disorder/Basal ganglia

1 4 Symptomless dysphagia

Prevention of pneumonia

3

Dopamine (nigrostriatum)

2

Swallowing reflex Cough reflex

Substance P

Mechanism from Subclinical Aspiration to Pneumonia

Subclinical aspiration develops when a small amount of sputum, including bacteria, enters the trachea while patients do not notice it, such as while sleeping. Sputum and bacteria gradually enter the lung through the trachea. When sputum reaches the lung, inflammation occurs gradually. In general, subclinical aspiration is thought to start to develop at the lower lung (inferior lobe). If inflammation is not detected, it may spread throughout the lung.

Relationship between symptomless dysphagia and substance P

• T. Arai et al. Lancet 1998; 352: 115

Hypertensive patients with no dysphagia (n=10) : Group B Healthy controls (n=7) Group C

80 60 40 20 （pg/mL）

23.3 76.5 72.7

Serum substance P concentration

Hypertensive patients with history of stroke and symptomless dysphagia (n=16) : Group A

ACE Inhibitors Promote Cough / Deglutition Reflexes and Correct Aspiration

Geriatric Medicine 2000; 39: 231

Angiotensin I

X: Action Points of ACE Inhibitors

Bradykinin

× ×

Substance P Inactive Peptides Renin-Angiotensin System Angiotensin II Kallikrein-Kinin System

ACE

Promotion of Cough / Deglutition Reflexes Improving Subclinical Aspiration

Pneumonia Prevention

Tanatril Administration Normalizes Serum Substance P

• T. Arai et al：Lancet 352：115，1998

（pg/mL）

80 60 40 20

Healthy Adults (n = 7) Hypertensives with Subclinical Aspiration (n = 16) Hypertensives without Subclinical Aspiration (n = 10) P Before Tanatril After Tanatril

Change of Serum Substance P Concentrations by Presence or Absence of Subclinical Aspiration

[Subject] 16 hypertensive patients with a history of cerebral infarction and complicated with subclinical aspiration [Dosing] Tanatril 5 – 10mg, once daily, 12 weeks

72.7 76.5 76.7

79.8 23.3

Serum Substance P Concentration

Beneficial effect of TANATRIL

• n the prevention of pneumonia

Improvement of aspiration pneumonia by TANATRIL

Int J Mol Med 5 : 609 (2000)

before

2 weeks after treatment

Methods : Imidapril (5mg/kg) was administered for 12 weeks. 1ml of Technetium Tin Colloid was administered during sleep via a nasal catheter placed in the mouth. At 9:00 the next day, Technetium Tin Colloid was checked by imaging. Subjects ：77-year-old female with cerebral infarction

6 weeks after treatment 12 weeks after treatment

Composite photos of RI photo and radiograph 99mTC 99mTC 99mTC

Prevention of onset of pneumonia

3 6 9 12 12 15 15 18 18 21 21 24 24 27 27 30 30 36 36 33 33

Control (14/160)： 8.8％

Tanatril

（12/430）：2. 2.8％ Diuretic (29/351)：8.3 .3％ CCB (36/409)：8.8 .8％

8.8％ 2.8％

１／３

ACE-I diuretic Control CCB

T Arai , K Sekizawa, H Matsuoka et al. Neurology 2005

1.00- 0.98- 0.96- 0.94- 0.92- 0.90- 0-

Time (mont nths hs)

Elderly hypertensive patients with a history of stroke Subjects：

Cumulative number of patients without pneumonia

Reason Why ACE Inhibitors should be Re-evaluated

• 2. Cl

Clear r eff ffic icacy wit ith lo long g te term rm use se

• 3. Recom
• mme

mended in in a s seri ries s of

• f gu

guid ideli lines

• 4. Su

Superi rior

• r in

in cos

• st

t eff ffic icie iency

• 5. ARB doe
• es

s not

• t su

supers rsede ACE CE i inhib ibit itor

• rs

1.

• 1. Reduces

s mo mort rtali lity ty ra rate te and a a vari riety ty of

• f

card rdio iovasc scula lar r dis isease ses

High risk hypertensives, particularly with coronary artery disease Combine with diuretics Use high doses of a high performance ACE inhibitor

How can we use ACE inhibitors?

• ARBs are not equal to ACEIs without cough.
• ACEI should be re-evaluated due to recent

reports, such as BPLTTC, BMJ and other articles.

• Not all ACEIs are the same, and high-

performance ACEIs like imidapril should be chosen for patient benefit.

• Imidapril is a high-performance ACEI with best

tolerability and preventing pneumonia.

Conclusion