penyakit jantung katup (kuliah)

8/13/2019 Penyakit Jantung Katup (Kuliah)

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CARDIO VASCULAR SYSTEM

# HEART

# CIRCULATORY SYSTEM

----- PULMONARYSYSTEMIC

# BLOOD VESSELLS

ARTERY

VEIN


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HEART CHAMBERS**RIGHT ATRIAL


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Penyakit Jantung Katup

Disfungsi jantung akibat abnormalitas struktur atauabnormalitas fungsi katup jantung Disfungsi katup jantung dapat menyebabkan pressure

overload akibat keterbatasan pembukaan katup(stenosis gangguan pembukaan) atau volumeoverload akibat penutupan katup yang tidak adekuat(regurgitasi gangguan penutupan)

PJ Katup dapat diklasifikasikan berdasarkan lesipatologis yaitu obstruktif ( stenosis ) atau non-obstruktif ( regurgitasi ) atau berdasarkan patofisiologisebagai pressure overload atau volume overload

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AORTA STENOSIS (AS)

BATASANAS adalah obstruksi pada katup Ao yang menyebabkanaliran darah dari ventrikel kiri ke aorta terganggu.Lokasi obstruksi dapat terjadi di valvular, supravalvularatau subvalvular

PERJALANAN PENYAKITAS berat dapat asimptomatik selama beberapa tahun

walaupun terdapat obstruksi yang berat cenderungbebas dari gejala sampai akhir perjalanan penyakitdengan mortalitas dan morbiditas cukup rendah

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Patofisiologi AS

Obstruksi dari aliran keluar ventrikel kiri akanmeningkatkan tekanan sistolik ventrikel kiri,waktu ejeksi, tekanan diastolik dan

menurunkan tekanan aortik Peningkatan tekanan sistolik ventrikel kiri

bersama dengan beban volume meningkatkan

massa ventrikel kiri, yang dapat menyebabkandisfungsi dan gagal jantung kiri

12-Jan-14 Analisis dan Interprestasi CepatMembaca EKG

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MEMBUAT DIAGNOSIS PENYAKITJANTUNG

I. Anamnesa & Pemeriksaan Fisik * Inspeksi * Palpasi * Perkusi * Auskultasi

II. Foto Thorax ( Chest X-Ray )III.Rekaman EKG

IV. Plan of Dx lain: Laboratorium, Treadmill,Echocardiography, Nuclear Cardiology, Cardiac CTScan, MRI, Catheterisation

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PEMERIKSAAN KLINIK PENYAKITJANTUNG

1. ANAMNESA

2. PEMERIKSAAN FISIK :- Inspeksi- Palpasi

- Perkusi- Auskultasi

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Auscultation

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AREA AUSKULTASI Apeks : Mitral RAI II KI : Pulmonal RAI II KA : Ao RAI IV-V KI : TrikuspidBising Organik : Turbulensi

Bising fungsional : aliran darah melalui katub Normal1. Fase2. Lokasi dan Penjalaran3. Intensitas I VI, IV Thrill +4. Nada : Rendah tinggi5. Lama dan kualitas :

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Crescendo Decrescendo Blowing Rumbling


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Ada 4 area yang harus mendapatperhatian khusus pada auskultasi

RAI II kanan : auskultasi katup Ao RAI II kiri : auskultasi katup Pu RAI IV V kanan : auskultasi katup Tr

Apeks kordis : auskultasi katup Mi

Perubahan posisi tubuh untuk mendengar lebih jelas :

* Terlentang miring ke kiri : katup mitral* Duduk membungkuk ke depan : katup Ao

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Murmurs (Bising)

Grading of Murmurs:Grade 1 - only a staff man can

hearGrade 2 - audible to a residentGrade 3 - audible to a medical

studentGrade 4 - associated with a thrill

or palpable heart sound

Grade 5 - audible with thestethoscope partially off thechest

Grade 6 - audible at the bed-side

Functional Murmur:

short and soft Normal S1 and S2 Normal cardiac

impulse

No evidence forhemodynamicabnormality

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Common Murmurs and Timing

Systolic Murmurs

Aortic stenosis Mitral insufficiency Mitral valve prolapse Tricuspid insufficiencyDiastolic Murmurs

Aortic insufficiency Mitral stenosis

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Aortic Stenosis: Physical Findings

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S1 S2 S1 S2

Mild-Moderate Severe


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A i P l d


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Asia: Prevalence, awareness andtreatment of hypertension

1. Li H, et al. J Hypertens 2010;28:432-8. 2. Sharma AK, et al. Indian Heart J 2006;58:21-7.3. Lee HS, et al. Clin Exp Hypertens 2010;32:166-78. 4. Korean National Health and

Nutrition Examination Survey (KNHANES) 2008 [Korean]. Available at: http 7. Basic HealthResearches, 2008. Indonesian Health Department (c/o Dr Arieska Ann Soenarta).

27

Country Patients

(n)

Prevalence

(%)

Awareness

(%)

Treated

(%)

Controlled

(%)China 1 13,364 43.8 26.2 22.2 3.9

India 2 4,711 36.0 22.1 36.7 _

Korea 3 (>40 years, rural areas)

6,388 43.8 60.1 91.7 27.2

Korea 4 (30 years)

8,485 24.9 63.5 54.8 38

Malaysia 5 (>18 years)

33,976 32.2 35.8 31.4 26.3

Philippines 6 3,415 21.0 16.0 65.0 20.0

Singapore 7 5,022 41.5 51.8 84.4 27.1Indonesia(>18 years) 8

9,348 31.7 _ _ _


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Data riskesdas 2007 :

1. Satu diantara 3 tiga orang (31,7 %) dewasa di Indonesia menderitaHIPERTENSI

2. 76 % kasus hipertensi belum terdeksi

3 STROKE dan HIPERTENSI adalah penyebab kematian pertama dankedua

4. Indonesia adalah negara ke 4 yang mempunyai penderita DMterbanyak didunia

5. 70 % penderita DM menderita hipertensi

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1/12/2014 29

PATHOPHYSIOLOGY of HTN

C.O X Peripheral Resistance


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WHY HIGH BP ??

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PATHOPHYSIOLOGY of HTN

MECHANISM

Non specific explanation Essensial HTN :Dynamic interaction about :

- genetic factor- environment factor- others

BP formula = C.O X Peripheral Resistance


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CARDIAC OUTPUT = CO= Curah Jantung = pumped blood by heart per minute = HR x SV

BP = HR x SV x Peripheral resistance

HR = frequency per minuteSV = one stroke of the hearts volume

Peripheral Resistance Depend on lumen arteriole diameter

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OTHERS CONTRIBUTING FACTORS FORESSENTIAL HTN

Excess sodium intake Decreased Renal Filtration Increased sympathetic nervous system

activity Increased RAA activity Vascular smooth muscle cell membrane

alteration

Obesity - Hyperinsulinemia Endothelial dysfunction

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PATHOPHYSIOLOGY OF HYPERTENSION

Blood pressure = Cardiac output (CO) x Peripheral resistance (PR)

Hypertension = Increased CO and/or Increased PR

Preload

Fluid volume

Renal sodiumRetention /Decreased Renal

Filtraion

Contractility Fluid volume

Vasoconstriction

Sympathetic

nervoussystem

Renin-Angiotensin-Aldosterone

system

Geneticfactors

Excesssodium

intake (Adapted from Kaplan, 1994)


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RAAS


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Renin-Angiotensin Cascade

Angiotensinogen

Angiotensin I

Angiotensin II

AT 1 AT 2 AT n

Bradykinin

Inactivepeptides

Non-renin(e.g. tPA )

Non-ACE(e.g. chymase ) ACE

Renin

PHYSIOLOGIC EFFECTS OF RAAS AT1 RECEPTOR


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PHYSIOLOGIC EFFECTS OF RAAS: AT1 RECEPTORINHIBITION

37

Degradation

Angiotensinogen

Angiotensin I

Angiotensin II

AT1 Receptor

Renin

ACE

AT2 Receptor

VasoconstrictionReactive oxygen speciesCellular growthApoptosis

Neurohumoral activation

B1 /B 2-Receptor

Bradykinin/Kinins

VasodilationGrowth inhibition

Apoptosis

Nitric Oxide

AT1-Antag


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Recommendations for Multiple-mechanismTherapy: What the Treatment Guidelines Say

12-Jan-14 Analisis dan Interprestasi CepatMembaca EKG 38

JNC VII 1Most patients with hypertension will require two or moreantihypertensive agents to achieve their BP goals

When BP is more than 20 mmHg above systolic goal or 10

mmHg above diastolic goal, consideration should be given toinitiate therapy with 2 drugs, either as separate prescriptions or in fixed-dose combinations

ESH ESC 2To reach target blood pressures, it is likely that a large proportion ofpatients will require therapy with more than one agent

1Chobanian et al. JAMA 2003;289:2560 722ESH ESC Guidelines. J Hypertens 2003;21:1011 53the recommendation


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Single-pills combination therapy

ARB Telmisartan & CCB Amlodipin

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40

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Hypertension management guidelines recommend CCBs and ARBsas preferred combination therapy partners

Diuretics

ACE inhibitors

CCBs

ARBs -blockers

1-blockers

Diuretics

ACE inhibitors

CCBs

ARBs

2007 ESH/ESC Guidelines 1 2009 ESH/ESC Reappraisal 2

The latestThe begining


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Calcium Channel Blockers (CCB)

Direct vasodilators Avoid in patients with CHF Most common side effects

Constipation Peripheral edema Headache


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CCB

Important :Calcium channel blockers are especiallyeffective in isolated systolic hypertension, acommon condition in the elderly that ischaracterized by increased large arterialstiffening manifest as a wide peripheralpulse pressure


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Classification Calcium Antagonists

Generation:First Second Third Latest

NifedipineVerapamilDiltiazem

FelodipineIsradipineNicardipineNimodipineNisoldipineNitrendipine

Amlodipine Lercanidipine(hydrophilic) (lipophilic)

Prototype Tissue selectivity Tissue selectivity Tissue selectivitygradual onset gradual onset

Plasma controlled membrane-controlled

J Clin Basic Cardiol 1999;2:155


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Classes of Calcium Channel Blocker

Examples Nifedipines AmlodipinesLercanidipine

Verapamil Diltiazem

Effect on heartrate

Increase decrease Decrease

Site of action Vasculature Vasculature andheart

Vasculatureand heart

Side effects Headache Ankle swelling(less withlercanidipine)

ConstipationHeart failureHeart block

Heart failureHeart blockconstipation

Dihydropiridines Non - dihydropiridines

Phenylalkylamines Benzothiazepines


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Verapamiland diltiazem

Verapamil anddiltiazem

SELECTIVITY CARDIAC vsVASCULAR

ArteriolesNON-DHPs

Verapamil and diltiazem DHPs to varying extent

(offset by reflexadrenergic activation

Nifedipine and

amlodipine (10 : 1)

Highly selective DHPs

(100 : 1 or more)(felodipine, isradipine,nicardipine,nisoldipine)

DHPsSAnode

AVnode

Contract i l i ty


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First generation: conventionalVerapamil, DiltiazemNifedipine, Felodipine, Isradipine, Nicardepine, Nitrendipine

Evolution of Calcium Antagonist

Second generation: modified release

Verapamil SR, Nifedipine XL/GITS, Felodipine ERDiltizem CD, Isradipine CR

Third generation: intrinsically long-acting

1. Long plasma half-life 2. Long receptor half-lifeAmlodipine Lercanidipine (Zanidip)

Lacidipine

Manidipine

Messerli, AJH 2002; 15:94s-97s


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MECHANISM OF ACTION OF AMLODIPIN

Amlodipine inhibits the transmembrane influx of calciumions into vascular smooth muscle and cardiac muscle Inhibition is selective, with a greater effect on vascular smooth

muscle cells

It binds to both dihydropyridine and non-dihydropyridinebinding sitesAmlodipine is also a peripheral arterial vasodilator

Acts directly on vascular smooth muscle to cause a reduction inperipheral vascular resistance and a reduction in BP

47http://www.pfizer.com/pfizer/download/uspi_norvasc.pdf


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CONCLUSION



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TWYNSTA?

----- L O V E N O XYESSSS !!


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Gress et al .N.Engl.J.Med. 2000;342: 905

6 Year Follow-up of the Atherosclerosis Risk in Communities (ARIC-Study)

0

10

20

30

Incidence of Diabetes(Cases per 1000 Person Years)

No Hypertension(n=8.746)

12,0

All Subjects(n=12.550)

16,6

*RR for Development of Type 2Diabetes in Hypertension: 2.43

Hypertension(n=3.804)

29,1

*


Hypertension:A Significant Risk Factor for Type 2 Diabetes

Rully Roesli , 2008


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Rully Roesli , 2008

DATA WHO



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Type 2 Diabetes Mellitus (T2DM) Is the Tip of theIceberg


0

10

20

30

40

20-44 45-54 55-64 65-74

Impaired glucosetolerance (IGT)

Undiagnosed diabetes

Diagnosed diabetes

(%)

Adapted from: Harris, MI et al. Diabetes Care. 1993;16:642-652.

Age (years)

C i f H i i M b li


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HYPERTENSION IN DIABETICSassociated with

a doubling of the presence of

Diabetic Kidney Disease LVHECG signs of MI

and a prior history

of overt CV events

Kaplan NM. In Ellenberg and Rifkins Diabetes Mellitus:Theory and Practice, 5th ed. 1997.

LVH, left ventricle hypertrophy; ECG,electrocardiogram; MI, myocardialischemia, CV, cardiovascular.

Coexistence of Hypertension in MetabolicSyndrome (Diabetes)


HIGH MORTALITY

The DEADLY CONSPIRATION...


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Hypertension Highlights
http://www.medscape.com/px/viewindex/more?Bucket=columns&SectionId=1603http://www.medscape.com/px/viewindex/more?Bucket=columns&SectionId=1603


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Hypertension Highlights

New US National Hypertension Guidelines --JNC 8 -- To Be Announced? Linda Brookes, MSc Medscape Cardiology. 2008; 2008 MedscapePosted 02/19/2008

12-Jan-14 Analisis dan Interprestasi Cepat

Membaca EKG 60

Insulin Resistance and Angiotensin II
http://www.medscape.com/px/viewindex/more?Bucket=columns&SectionId=1603http://www.medscape.com/px/viewindex/more?Bucket=columns&SectionId=1603


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Insulin Resistance and Angiotensin II


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Insulin Resistance

Hyperinsulinemia

Hypertension

CardiovascularEvents

DM

GlucoseIntolerance

Angiotensin II

Increase in RAS in Blood VesselContractionVSMC Proliferation

Sympathetic Nervous System

Na Retension


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REACHINGGOAL OF TREATMENT

What the guidelines says


Membaca EKG 62

Bl d d i f 2 H d


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Blood pressure reduction of 2 mmHg reducesthe risk of cardiovascular events by 7 10%


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Meta-analysis of 61 prospective,observational studies

1 million adults

12.7 million person-years

Lewington et al. Lancet 2002;360:1903 13

2 mmHgdecrease in

mean SBP 10% reduction inrisk of strokemortality

7% reduction inrisk of ischaemicheart diseasemortality

l f h


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Blood pressure target values for treatment

of hypertension


Membaca EKG 64

Condition TargetSBP and DBP mmHg

Isolated systolic hypertension


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Membaca EKG 65

Hypertension and Antihypertensive


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Hypertension and AntihypertensiveAgents in Diabetic Kidney Disease

ClinicalAssessment

Target BloodPressure

Preferred Agentsfor CKD

Other Agent to Reduce CVDRisk and Reach Target Blood

Pressure

Bloodpressure

> 130/80mmHg

< 130/80 mm Hg B ACE Inhibitoror ARB

A Diuretic preferred, thenbetablocker or calcium-

channel blocker

A

Blood pressure < 130/80 mm Hg ACE inhibitoror ARB

A

Letters in shaded areas denote strength of recommendations

AJKD, Vol 43 No. 5, Suppl 1 (May), 2004, S142

C di H i Ed i P


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Part 2: Recommendations for Hypertension Treatment


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Canadian Hypertension Education Program

2011

Treatment of Hypertension in association with Diabetic


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Membaca EKG 68

Treatment of Hypertension in association with DiabeticNephropathy

THRESHOLD equal or over 130/80 mmHg and TARGET below 130/80 mmHg

If Creatinine over 150 mol/L or creatinine clearance below 30 ml/min ( 0.5 ml/sec), a loop diuretic should be substituted for athiazide diuretic if control of volume is desired

DIABETES withNephropathy

ACE Inhibitoror ARB

IF ACEI and ARB arecontraindicated or nottolerated,SUBSTITUTE Long -acting CCB or Thiazide diuretic

Addition of one or more ofLong-acting CCB or Thiazidediuretic

3 - 4 drugs combination may beneeded

Monitor serum potassium and creatinine carefully in patients with CKD prescribed an ACEI or ARB


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Membaca EKG 69

Treatment of Hypertension in association with DiabetesMellitus: Summary

More than 3 drugs may be needed to reach target values for diabetic patients

If Creatinine over 150 mol/L or creatinine clearance below 30 ml/min ( 0.5 ml/sec), a loop diureticshould be substituted for a thiazide diuretic if control of volume is desired

Threshold equal or over 130/80 mmHg and TARGET below 130/80 mmHg

Diabetes

withNephropathy

> 2-drug combinations

ACE Inhibitoror ARB

withoutNephropathy

1. ACE Inhibitor or ARB

or

2. DHP-CCB orThiazide diuretic

Monitor serum potassium and creatinine carefully in patients with CKD prescribed an ACEI or ARBCombinations of an ACEI with an ARB are specifically not recommended in the absence of proteinuria

A combination of 2 first linedrugs may be considered asinitial therapy if the bloodpressure is >20 mmHg systolicor > 10 mmHg diastolic abovetarget. Combining an ACEi and

a DHP-CCB is recommended.

WHICH IS BETTERARB (SARTAN)OR ACE I?


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WHICH IS BETTERARB (SARTAN)OR ACE-I ?


Membaca EKG 70

Telmisartanbetter

Ramipril

Ramiprilbetter

Telmisartan

0.8 0.9 1.0 1.1 1.2

CompositeEndpoint*

Secondarycomposite: HOPEPrimary endpoint

* ONTARGET primary composite endpoint = CV death + MI + stroke+ hospitalisation for CHF HOPE primary endpoint = CV death + MI + stroke

The ONTARGET Investigators. N Engl J Med 2008;358:1547 1559

p< 0.01 vs.non-inferiority margin (1.13)

ACEof theACE-I

ACEof theARB


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ACEIs in diabetic renal disease ACEIs have proven to be effective in type 1 diabetes and

nondiabetic kidney disease

Micro-HOPE study confirmed that ACEIs reduce the risk of overtproteinuria and CV events in diabetic patients

Before 2001, when DETAIL was designed, ACEIs were consideredfirst line therapy for diabetic patients with nephropathy

Today, ACEI is still the most commonly used antihypertensiveclass used to treat hypertensive diabetics, with usage rangingfrom

49% of patients in Japan 73% of patients in Germany


Membaca EKG 71

Lewis EJ, N Engl J Med 1993;329:1456 1462GISEN group. Lancet 1997;349:1857 1863

Remuzzi et al. Ann.Intern.Med 2002:136:604-615HOPE Study Investigators. Lancet 2000;355:253 259

Vivian et al. Ann Pharmacother 2001;35:452 463Treatment Algorithms: Hypertension 3rd Edition. Datamonitor 2002.

London UK


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ARBs in diabetic renal disease In major clinical trials, ARBs have demonstrated effective

renoprotection in type 2 diabetic nephropathy RENAAL IRMA 2 IDNT

ARBs are a first line therapy for compelling indications inhypertension treatment guidelines

Both ACEIs and ARBS are recommended for diabetichypertension and for the treatment of renal disease in themedical literature and guidelines


Membaca EKG 72

Parving et al. N Engl J Med 2001;345:870 878; Brenner et al. N Engl J Med 2001;345:861 869Lewis et al. N Engl J Med 2001;345:851 860; ESH/ESC Guidelines. J Hypertens 2003;21:1011 1053

JNC 7. JAMA 2003;289:2560 257; Johnson. Intern Med J 2004;34:50 57 American Diabetes Association. Diabetes Care 2004;27(Suppl 1):S65 S67

National Kidney Foundation. Am J Kidney Dis 2002; 39(2 Suppl 1):S1-266

National Kidney Foundation. Am J Kidney Dis 2004; 43(5 Suppl 1):S1 S268


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Stroke

Relative risk

Outcome Relative risk(95% CI)

1.63 ( 0.77 3.44)1.06 ( 0.84 1.33)0.95 ( 0.76 1.17)

1.02 ( 0.87 1.19)

Favours ARB Favours ACEinhibitor

Major CHD

Heart failure

18/1578 11/1574140/2744 132/2733157/4909 166/4909

Trial

161/1578 129/1574 1.24 ( 1.00 1.55)576/2744 533/2733 1.08 ( 0.97 1.20)868/4909 896/4909 0.97 ( 0.89 1.05)

1.06 ( 0.94 1.19)

0.87 ( 0.59 1.28)1.14 ( 0.99 1.31)1.01 ( 0.93 1.11)1.05 ( 0.95 1.15)

46/1578 53/1574 363/2744 318/2733813/4909 801/4909

0.5 1.0 2.0

ELITE II

OPTIMAALVALIANT

Overall

ELITE II

OPTIMAALVALIANTOverall

Overall

ELITE II OPTIMAALVALIANT

ARB ACE inhibitorEvents/n

ARBs vs ACE inhibitors in patients with CHF or MI


Membaca EKG 73Turnbull F. Lancet 2003;362:1527 35.


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Membaca EKG 74

From Medscape Cardiology Angiotensin II Receptor Blockade Expert Column

Angiotensin Receptor Blockers:What Is Their Current Status?Norman K. Hollenberg, MD, PhD

Study Drug Class Clinical Condition Primary Outcome

CONSENSUS I (1987) ACEI CHF Favorable
http://www.medscape.com/cardiologyhttp://www.medscape.com/px/viewindex/more?Bucket=columns&SectionId=1989http://www.medscape.com/px/viewindex/more?Bucket=columns&SectionId=1989http://www.medscape.com/px/viewindex/more?Bucket=columns&SectionId=1989http://www.medscape.com/px/viewindex/more?Bucket=columns&SectionId=1989http://www.medscape.com/px/viewindex/more?Bucket=columns&SectionId=1989http://www.medscape.com/cardiologyhttp://www.medscape.com/cardiologyhttp://www.medscape.com/cardiology


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CONSENSUS I (1987) ACEI CHF Favorable

CONSENSUS II (1992) ACEI Post-MI Neutral

SOLVD I (1991) ACEI Ventricular dysfunction Favorable

SOLVD II (1992) ACEI Post-MI Favorable

SAVE (1992) ACEI Post-MI Favorable

AIRE (1993) ACEI Post-MI Favorable

TRACE (1995) ACEI Post-MI Favorable

ATLAS (1999) ACEI CHF Favorable

ELITE (1997) ARB CHF Favorable

ELITE II (2000) ARB CHF Neutral vs ACEI

HOPE (2000) ACEI High-risk profile Favorable

PROGRESS (2001) ARB Stroke Favorable

IDNT (2001) ARB ESRD Favorable

IRMA 2 (2001) ARB ESRD Favorable

RENAAL (2001) ARB DM, microalbuminuria, HF Favorable

Val-HeFT (2001) ARB CHF Favorable

ALLHAT (2002) ACEI High-risk profile Neutral

LIFE (2002) ARB Hypertension Favorable

OPTIMAAL (2002) ARB High-risk profile --

EUROPA (2003) ACEI Chronic stable CAD Favorable

ANBP2 (2003) ARB Elderly FavorableVALIANT (2003) ARB High-risk profile Neutral vs ACEI

ONTARGET (2003) ARB High-risk profile --

CHARM (2003) ARB CHF Favorable

VALUE (2004) ARB Hypertension Neutral

BENEDICT (2004) ACEI DM, microalbuminuria Favorable

DETAIL (2004) ARB DM, microalbuminuria Neutral vs ACEI

PEACE (2004) ACEI Post-MI Neutral

Medscape Cardiology. 2005;9(2) 2005 Medscape12-Jan-14 Analisis dan Interprestasi Cepat

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Outcome trials

completing the picture


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Antihypertensive therapy:


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yp pyunanswered questions

What effects do the newer drug classes (ACE inhibitors, ARBs, CCBs)have on major CV events?

Do these newer classes produce greater reductionsin CHD?

Does more intensive BP-lowering produce greater benefits?

Are there special benefits associated with inhibitionof the RAAS?


Membaca EKG 77

No single study is likely to answerall these questions


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Are the metabolic effects of all ARBs the same ?

Quest ion :

Answer :

No Some ARBs may have special metabolic benefitsthat go beyond angiotensin receptor blockade


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valsartan losartan candesartan telmisartanirbesartanolmesartan


Membaca EKG 80


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Volum e of Dis t r ibu t ion o f Differen t A RBs


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50100

150

200

250

300

350

400

Telmisartan

L i t e r s

(Index o f the Ab i l i ty o f a Drug to En te r Tis sues Throug hou t the Body )

450

500

Valsartan Olmesartan Losartan LosartanMetabolite

Candesartan Irbesartan

Telmisartan unique structure

1. Highly lipophilic molecule

2. Longest half life of all ARBs

- Good 24 hour control of BP

3. Very high tissue penetrating ability

- ability to access PPAR inside cells

4. Ability to interact more effectively

with PPAR than other ARBs


Membaca EKG 82

A bil i ty of Different A RBs To A ct ivate PPA R


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Candesartan

10

20

30

Eprosartan Valsartan LosartanMetabolite

Irbesartan Telmisartan

Foldactivation

Olmesartan

10 micromolar

Benson SC et al. Hyper tens ion 2004; 43:993-100212-Jan-14 Analisis dan Interprestasi Cepat

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Comparative pharmacokinetics of ARBs

Telmisartan Losartan IrbesartanCandesartan

Cilexetil Valsartan

Active metabolite No EXP3174 No Candesartan No

Oralbioavailability

40 60% ~30% 60 80% 15% 25%

Volume ofdistribution

500L 12L 15 93L 10L 17L

Terminal half-life

~24 hours 6 9 hours 11 15 hours 5 9 hours 6 9 hours

Hepatic:renalelimination

98:2no CYP450

65:35CYP450

80:20CYP450

60:40CYP450

69:31no CYP450

Protein binding >99.5% 99.8% 90 92% >99% 94 97%


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Unique properties of telmisartanbeyond RAAS inhibition


Membaca EKG 86


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Table 2. Antidiabetic mechanisms of ACE inhibitors andparticular ARBs that may go beyond their effects on therenin-angiotensin system

ACE inhibitors may enhance glucose metabolism by :Activating bradykinin / nitric oxide pathways

Particular ARBs (e.g. telmisartan) may improve glucoseand lipid metabolism by :

Activating PPAR

ACE, angiotensin-converting enzyme; ARBs, angiotensin receptorblockers; PPAR , peroxisome proliferator activated receptor gamma

Journal of Hypertension 2004, 22:2253-226112-Jan-14

Analisis dan Interprestasi CepatMembaca EKG 87

Table 3 Potential anti-atherosclerotic


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Table 3. Potential anti atheroscleroticmechanisms of PPAR activators

Increase insulin sensitivityDecrease fatty acid and triglyceride levelsIncrease reverse cholesterol transport and HDL levelsIncrease buoyancy of LDL particles

Decrease inflammantionDecrease oxidative stressDecrease blood pressureDecrease vascular smooth muscle cell proliferation andmigration

PPAR , peroxisome proliferator activated receptor gamma; HDL, high-densitylipoprotein cholesterol; LDL, low-density lipoprotein cholesterol

Journal of Hypertension 2004, 22:2253-226112-Jan-14


Telmisartan


89/113

Insulin

resistanceHypertension

Cell

inflammation

Cell

proliferation

Oxidative

stressDyslipidemia

Telmisartan

PPAR pathways An gio tens in pa thways

Atherosclerosis

Activates Blocks

Journal of Hypertension 2004, 22:2253-22

Potential influence of telmisartan on

pathways that are likely primarily tomediate the anti-atheroscleroticeffects of peroxisome proliferatoractivated receptor gamma (PPAR )activation and angiotensin II receptorblockade


Membaca EKG 89

Dual ARB / PPAR Ligand


90/113


NF-B CRP

TNF- IL-6 PAI-1 VCAM Fibrinogen NO

Dyslipidemia

Adiponectin Insulinemia Insulin sensitivity Leptin ACC2 Weight gain

AT1-R Blockade

AT2-R Activation

Blood pressure

Tissue fibrosis Tissue inflammation Cell proliferation Oxidative stress Endothelial dysfunction SNS activity

Atherosclerosis Atherogenesis

Steatohepatitis Cardiac function Cardiomyopathy

Neuroregulation

Glomerulosclerosis

Islet function

PPARModulation

Ang - II

12-Jan-14

Two Classes of PPAR Activators


91/113

AdipocyteHypertrophy

Non-SelectivePPAR Activators

Rosiglitazone,Pioglitazone

SelectivePPAR Modulators

Telmisartan,nTZDpa

Yes No

Fluid retention Yes No

Weight gain Yes No

Improve glucose &lipid metabolism Yes Yes


Membaca EKG 91


92/113

ARBs induce PPAR- activity


93/113

Schupp M, et al. Circulation 2004;109:2054 7.

EC 50 Telmisartan 5.02 mmol/LEC 50 Pioglitazone 0.2 mmol/L

EC 50 Irbesartan 26.97 mmol/L

EC 50 Losartan >50 mmol/L


Membaca EKG 93

PPAR- target gene regulation

600

500

400

300

200

100

0

a P 2 - m

R N A e x p r e s s

i o n

10 0.1 100 0.1 1000.1 1000.1 100

PioglitazoneEprosartanLosartanIrbesartanTelmisartan

0,1 1 10 1000

5

10

15

20

25 PioglitazoneTelmisartanIrbesartanLosartan

PPAR- binding domain activation

B i n d i n g

Effects on Adiponectin and hs-CRP Levels of Replacing Valsartan orCandesartan by Telmisartan


94/113

Adiponectin hs-CRP

0

1

2

3

4

5

67

8

9

10mg/dl )

TelmisartanCandesartan/Valsartan

**

0

0.05

0.1

0.15

0.2

TelmisartanCandesartan/Valsartan

mg/dl )*

y


Membaca EKG 94

P


95/113

0

20

40

60

80

100

120

140

Telmisartan Eprosartan Placebo

Before treatment

After treatment

T r i g l y c e r i

d e s

( m g

( d L )

p


96/113

Valsartan 80mg/day, n=11

Candesartan 8mg/day, n=7

All patients

Telmisartan 40mg/day

12 weeksFasting insulinFasting glucoseHbA 1cTotal cholesterolHDL cholesterolAdiponectin

CRP

HDL, high-density lipoprotein; CRP, C-reactive protein.

Miura Y, et al. Diabetes Care 2005;28:757 8.

Fasting insulin levelp


97/113


98/113

Cardio/cerebrovascular

death

End-stageheart disease/

brain damage anddementia

End-stagerenal disease

Endothelialdysfunction

Micro-albuminuria

Congestiveheart failure/

secondary stroke

NephroticProteinuria

Macro-proteinuria

MI and stroke

Atherosclerosis

Ventricular dilation/cognitive dysfunction

Remodelling

Risk factors,e.g. hypertension,diabetes, obesity

Telmisartan: from to


Membaca EKG 98

The progr mme


99/113

The programme


Membaca EKG 99

Early morning BP surgeTelmisartan vs ramipril

Elderly/systolic hypertensionTelmisartan+HCTZ vs

Amlodipine+HCTZ

Diabetic obeseTelmisartan + HCTZ vs

valsartan + HCTZ

Early morning BP surge

Telmisartan+HCTZ vsLosartan+HCTZ

Diabetic nephropathy Telmisartan vs valsartan

Diabetic nephropathy Telmisartan vs losartan

Diabetic nephropathy

Telmisartan vs placebo

Renal endothelial dysfunctionTelmisartan vs ramipril

Diabetic nephropathy Telmisartan vs enalapril

Programme of Research tO show Telmisartan End-organ proteCTION


100/113

COMBINATION OF

ARB and/or ACE-I and CCBA FIRST LINE TREATMENT

ARB & CCB ??


Membaca EKG 100

Recommendations for Multiple-mechanism


101/113

Therapy: What the Treatment Guidelines Say


Membaca EKG 101

JNC VII 1Most patients with hypertension will require two or moreantihypertensive agents to achieve their BP goals

When BP is more than 20 mmHg above systolic goal or

10 mmHg above diastolic goal, consideration should begiven to initiate therapy with 2 drugs, either as separate prescriptionsor in fixed- dose combinations

ESH ESC 2To reach target blood pressures, it is likely that a large proportion of

patients will require therapy with more than one agent

1Chobanian et al. JAMA 2003;289:2560 722ESH ESC Guidelines. J Hypertens 2003;21:1011 53the recommendation

Hypertension management guidelines recommend CCBs and


102/113

10212-Jan-14


yp g gARBs as preferred combination therapy partners

Diuretics

ACE inhibitors

CCBs

ARBs -blockers

1-blockers

Diuretics

ACE inhibitors

CCBs

ARBs

2007 ESH/ESC Guidelines 1 2009 ESH/ESC Reappraisal 2

The latestThe begining

Practical Guideline for Hypertension Management


103/113

FIXED COMBINATION FREE COMBINATION

12-Jan-14

Analisis dan Interprestasi Cepat

Membaca EKG 103

In Asian Popolation (cough with ACE-I = 30 )

ARB ACE-I

CCBdiuretics


104/113


105/113

Renal Hyperfiltration Induced by Amlodipine is reduced byT l i


106/113

Telmisartan

12-Jan- 14 Analisis dan Interprestasi Cepat

Membaca EKG106

DecreasedGlomerular pressureand filtration

Amlodipine + TelmisartanL type Cachannels

IncreasedGlomerular pressureand filtration

Amlodipine

L type Cachannels

Peti-Peterdi ; Abstract ESC 2010 (submitted).

WHY AMLODIPINE ?
http://wwwdcm4ipool.eu.boehringer.com/iidea:/Archive/P10-10533?DMW_FORMAT=PDFhttp://wwwdcm4ipool.eu.boehringer.com/iidea:/Archive/P10-10533?DMW_FORMAT=PDFhttp://wwwdcm4ipool.eu.boehringer.com/iidea:/Archive/P10-10533?DMW_FORMAT=PDFhttp://wwwdcm4ipool.eu.boehringer.com/iidea:/Archive/P10-10533?DMW_FORMAT=PDFhttp://wwwdcm4ipool.eu.boehringer.com/iidea:/Archive/P10-10533?DMW_FORMAT=PDF


107/113


Membaca EKG107

A l di i Th l h lf lif i l


108/113


Membaca EKG108

Amlodipine The longest half-life in class

57

912

1416

19

> 30

0

5

10

15

20

25

30

35

Based on available online product information.

P l a s m a e

l i m

i n a

t i o n

h a

l f - l

i f e

( h )

Lercani-dipine

Nife-dipine

Nimo-dipine

Nisol-dipine

Nicar-dipine

Felo-dipine

Laci-dipine

Amlo-dipine

Changes in Visceral Fat


109/113

50

100

150

200

250

300

V F A c m

2

Telmisartan

BeforeTreatment

After6 months

P< .01

(Shimabukuro et al, Japanese Circulation Society, 2006)

Amlodipine

BeforeTreatment

50

100

150

200

250

300

V F A c m

2

After6 months

P< .05


Membaca EKG109


110/113

Benefits of single-pills

combination therapyRationale for fixed-dose combinations (FDCs):

efficacy; tolerability; compliance and persistence

Beneficial impact of FDCs on compliance andpersistence, and costs


Membaca EKG110

CONCLUSION


111/113


Membaca EKG111

There isNO such a BEST drug

While thereare GOOD DOCTOR s

who knowwhich drug isBEST for their P TIENTS


112/113

atur NuhunMatur Sushme

SALAM TWYNSTA12-Jan-14 Analisis dan Interprestasi Cepat

Membaca EKG112

ESH ESC RECOMMENDATIONS FOR COMBINING BP-LOWERINDRUGS AND AVAILABILITY AS FIXED DOSE COMBINATIONS


113/113

DRUGS AND AVAILABILITY AS FIXED-DOSE COMBINATIONS

Diuretics

Angiotensinreceptor blockers(ARBs)

Calcium channelblockers (CCBs)

Angiotensin-converting enzyme (ACE) inhibitors

b-blockers

-blockers

?

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