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Dr. H.

Wizhar Syamsuri, SpPD


Karawang, 1967 Dokter
FK Univ Udayana, 1992

Pekerjaan
SMF Penyakit Dalam RSUD Gunung Jati Cirebon SMF Penyakit Dalam RS Putra Bahagia Cirebon

SpPD (Internist)
FK Univ Andalas, 2001

Pendidikan Tambahan
Fellowship Hemodialisa (RSCM/FKUI, 2006) Fellowship Endoscopi (RSHS/FK Unpad, 2008)

Riw Pekerjaan
Puskesmas Danau Sembuluh. Kotim. Kalteng RSUD Purwakarta RSUP M Djamil Padang RSUD Pekanbaru Riau Caltex Hospital (Duri.Riau) RSUD Batusangkar

Organisasi :
PAPDI Cabang Cirebon (Sekretaris)

IDI Cabang Cirebon (Bid Org & Kesra) Bulan Sabit Merah Indonesia (BSMI) Kota Cirebon (Ketua) PERNEFRI, PUSKI, InaSH, PEGI (Anggota)

Principles in Management of Hypertension & The Role of Imidapril


Wizhar Syamsuri SMF Penyakit Dalam RSUD Gunung Jati / RS Putra Bahagia

Myths & Misunderstandings


Hypertension is emotional tension No Headache No Hypertension Severity of HT & Grade of HT Hypertension could be cured BP reached normal :
Cured Medicine can be stopped

No symtoms No need more treatment Alternative Medicine (CAM) ?

Prevalence of hypertension : Asia


80 70 60 50 40 30 20 10 0
Men Women Total

Gu DF, et al. Hypertension 2002;40:920-927; Singh RB, et al. J Hum Hypertens 2000;14:749-763; Janus ED. Clin Exp Pharmacol Physiol 1997;24:987-988; National Health Survey 1998, Singapore. Epidemiology and Disease Department, Ministry of Health, Singapore.; Lim TO, et al. Singapore Med J 2004;45:20-27; Tatsanavivat P, et al. Int J Epidemiol 1998;27:405-409; Muhilal H. Asia Pacific J Clin Nutr 1996;5:132-134; Gupta R. J Hum Hypertens 2004;18:73-78; Asai Y, et al. Nippon Koshu Eisei Zasshi 2001;48:827-836 [in Japanese]

Prevalence (%)

Prevalence of Hypertension in Indonesia 2006 Men 28% Women 37%

Prevalence of Hypertension
Hypertension is one of the most frequent clinical discorders.
prevalence of hypertension (%)

70

60
50

SBP > 140 mm Hg DBP > 90 mm Hg


54 44

64

65

40
30

20
10 0
age (yrs) 4 11

21

18-29

30-39

40-49

50-59

60-69

70-79

80+

Franklin, S.S., J Hypertens 1999; 17 (suppl 5): S29-S36

Global Burden of Hypertension : analysis of worldwide data


( Estimated Total Number of Adults with Hypertension )

Measure
Total number worldwide in 2000 Total number in economically developed countries in 2000 Total number in economically developing countries in 2000 Total number worldwide in 2025

N (95% CI)
972 million (957-987) 333 million (329-336) 639 million (625-654) 1056 billion (1.54-1.58)

P.M Kearney et.al Lancet 2005:365; 217-223

Hypertension complication
Eyes retinopathy Brain stroke ( 2,7)
ischaemic heart disease left ventricular hypertrophy heart failure

Target Organ damage!!! Damages depend on:

Heart

How high of the blood


pressures

Kidneys

renal failure

( 2,8)

( 1,5)

How long the


uncontrolled and untreated high blood pressure

Peripheral arterial disease ( 1,8)

Estimated by K/DOKI Guidelines 2002

JNC VII: Classification of Blood Pressure

Blood pressure classification Normal Prehypertension

Systolic BP (mmHg)

Diastolic BP (mmHg)

<120 120-139

or

<80 80-89

or

Stage 1 hypertension
Stage 2 hypertension

140-159
>160

or

90-99
>100

or

The JNC VII. JAMA 2003;289:2560-72

Blood Pressure Measurement


Situation

Tools

Examiner

Patients

Technique for Measuring BP


Take after 5 min. of quiet rest Should NOT smoke or ingest caffeine for 30 min. before taking Initially take in both arms Use appropriate cuff size (too small gives abnormally high BP) Pump to where you lose pulse & then deflate; reinflate to 30mm Hg above previously palpated value Take 2 or more readings (> 2min. apart)

BP Measurement Techniques
Method In-office Brief Description Two readings, 5 minutes apart, sitting in chair. Confirm elevated reading in contralateral arm.

Ambulatory BP monitoring

Self-measurement

Indicated for evaluation of whitecoat HTN. Absence of 1020% BP decrease during sleep may indicate increased CVD risk. Provides information on response to therapy. May help improve adherence to therapy and evaluate white-coat HTN.

Types and Causes of Hypertension


Essential / Primary Hypertension ( 90 %) Secondary Hypertension ( 10 % )
Renal hypertension ( 5 % ) Others :
Coarctation of the aorta Primary aldosteronism Cushings syndrome Phaechromocytoma Oral contraceptive use

Angiotensin II Plays a Central Role in Organ Damage


Atherosclerosis* Vasoconstriction Vascular hypertrophy Endothelial dysfunction Stroke

Hypertension

A II

AT1 receptor

LV hypertrophy Fibrosis Remodeling Apoptosis GFR Proteinuria Aldosterone release Glomerular sclerosis

Heart failure MI

DEATH

Renal failure

*preclinical data LV = left ventricular; MI = myocardial infarction; GFR = glomerular filtration rate

Adapted from Willenheimer R et al Eur Heart J 1999; 20(14): 9971008, Dahlf B J Hum Hypertens 1995; 9(suppl 5): S37S44, Daugherty A et al J Clin Invest 2000; 105(11): 16051612, Fyhrquist F et al J Hum Hypertens 1995; 9(suppl 5): S19S24, Booz GW, Baker KM Heart Fail Rev 1998; 3: 125130, Beers MH, Berkow R, eds. The Merck Manual of Diagnosis and Therapy. 17th ed. Whitehouse Station, NJ: Merck Research Laboratories 1999: 16821704, Anderson S Exp Nephrol 1996; 4(suppl 1): 3440, Fogo AB Am J Kidney Dis 2000; 35(2):179188

Management of Hypertension
The main objective in lowering BP is to reduce the patients absolute risk of premature death and disease, primarily by reducing their risk of cardiovascular diseases.

Ogden LG,et al. Hypertension. 2000

Whats the Importance in Hypertension management:

REACH THE TARGET IMMEDIATELY

12 to 13 mm Hg Drop in Systolic BP Reduces 4-Year Risk of CAD, Stroke, Mortality


CHD
0%

Stroke

CVD mortality

All-cause mortality

Reduction in risk (%)

-10% -13% P=0.005

-20%

-30%

-21% P<0.0001

-25% P<0.001

-40%

-37% P<0.001

Meta-analysis of 10 randomized trials. He and Whelton, J Hypertens, 1999.

In every 23 mmHg reduction in Systolic Blood Pressure, resulting...


0%

Stroke All cardiac Heart end points * Failure

MI

All fatal/ nonfatal cardiovascular end points **

Percent Reduction

-15%

-30%

-26%

-29%

-30%

-31%

-45%

-42%

*Fatal and nonfatal heart failure and nonfatal myocardial infarction and sudden death **Fatal and nonfatal heart failure and nonfatal myocardial infarction, sudden death and stroke

Effect of Long-Term Modest Reductions in CV Risk Factors


45% Reduction in CVD

10% Reduction in BP

10% Reduction in TC

Emberson et al. Eur Heart J. 2004;25:484-491.

BLOOD PRESSURE CONTROL GOAL

Less than 140/90 mm Hg or Less than 130/80 mm Hg (diabetes, chronic kidney disease) or Less than 125/75 mm Hg (protein uria >1g/day)
1999 WHO/ISH Hypertension Guidelines. J Hypertens 1999;17:151-183 ADA Position Statement. Diabetes Care 2002;25:S33-S49

How To Achieve BP Target

Algorithm for Treatment of Hypertension


Lifestyle Modifications Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug Choices

Without Compelling Indications

With Compelling Indications

Stage 1 Hypertension
(SBP 140159 or DBP 9099 mmHg) Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination.

Stage 2 Hypertension
(SBP >160 or DBP >100 mmHg) 2-drug combination for most (usually thiazide-type diuretic and ACEI, or ARB, or BB, or CCB)

Drug(s) for the compelling indications


Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed.

Not at Goal Blood Pressure Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider consultation with hypertension specialist.

Lifestyle Modification
Modification Approximate SBP reduction (range)

Weight reduction
Adopt DASH eating Dietary sodium Physical activity

520 mmHg/10 kg weight loss


814 mmHg 28 mmHg 49 mmHg

Moderation of alcohol consumption

24 mmHg

Classification and Management of BP for adults


BP classification Normal SBP* mmHg <120 DBP* mmHg and <80 Lifestyle modification Encourage Yes No antihypertensive drug indicated. Thiazide-type diuretics for most. May consider ACEI, ARB, BB, CCB, or combination. Two-drug combination for most (usually thiazide-type diuretic and ACEI or ARB or BB or CCB). Drug(s) for compelling indications. Drug(s) for the compelling indications. Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB) as needed. Initial drug therapy Without compelling indication With compelling indications

Prehypertension 120139 or 8089

Stage 1 Hypertension

140159 or 9099

Yes

Stage 2 Hypertension

>160

or >100

Yes

*Treatment determined by highest BP category. Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension. Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg.

Diabetes? Chronic kidney disease? Stroke? High coronary disease risk? Heart failure? Post myocardial infarction?
NO Treatment in the absence of specific indication YES

Individualized treatment
(compelling indication)

INDICATIONS FOR INDIVIDUAL DRUG CLASSES


Compelling indications Heart failure Post-MI High coronary disease risk Diabetes Chronic kidney disease Stroke prevention Diuretic -blocker ACE inhibitor ARB CCB

The JNC VII Report. JAMA 2003;289:2560-2572

Majority of Hypertensive Patients Need Multiple Medications for Effective Management


More Than 1 Agent Is Usually Required to Get to BP Goal IDNT (135/85 mm Hg) UKPDS 83 (< 85 mm Hgdiastolic) ABCD (<75 mm Hgdiastolic) MDRD (<92 mm Hgmean arterial pressure) HOT (<80 mm Hgdiastolic) ALLHAT (<140/90 mm Hg)

3.80 2.70 2.75 3.70 3.25 2.00 0 1 2 3 Number of Agents 4

Multiple medications can increase the complexity of treatment


Bakris et al. Am J Kidney Dis. 2000;36:646-661; Brenner et al. N Engl J Med. 2001;345: 861-869; Lewis et al. N Engl J Med. 2001;345:851-860; Cushman et al. J Clin Hypertens. 2002;4:393-404.

European Society Of Hypertension 2003 Beta blocker

Diuretic

AT1 receptor blocker

Alpha blocker
Possible combination of different classes of anti hypertension drugs

CCB
Most rational combination

ACE inhibitor
Journal Of Hypertension 2003

Proven beneficial in trials

Key Messages JNC-VII


For persons over age 50, SBP is a more important than DBP as CVD risk factor. Starting at 115/75 mmHg, CVD risk doubles with each increment of 20/10 mmHg throughout the BP range. Most patients will require two or more antihypertensive drugs to achieve goal BP. If BP is >20/10 mmHg above goal, initiate therapy with two agents, one usually should be a thiazide-type diuretic. The most effective therapy prescribed by the careful clinician will control HTN only if patients are motivated.
JAMA, 21 May 2003

LONG-ACTING BLOOD PRESSURE CONTROL


IN THE WORDS OF JNC VI :
THE OPTIMAL FORMULATION SHOULD PROVIDE 24-H EFFICACY WITH A ONCE-DALY DOSE, WITH AT LEAST 50% OF THE PEAK EFFECT REMAINING AT THE END OF THE 24-H

LONGACTING FORMULATIONS THAT PROVIDE 24-H EFFICACY ARE PREFERRED OVER SHORT-ACTING AGENTS FOR MANY REASONS :
1. ADHERENCE IS BETTER WITH ONCE-DAILY DOSING 2. FOR SOME AGENTS, FEWER TABLETS INCUR LOWER COST 3. CONTROL OF HYPERTENSION IS PERSISTENT AND SMOOTH RATHER THAN INTERMITTENT 4. PROTECTION IS PROVIDED AGAINTS WHATEVER RISK FOR SUDDEN DEATH, HEART ATTACK, AND STROKE THAT IS DUE TO TE ABRUPT INCREASE OF BP AFTER ARISING FROM OVERNIGHT SLEEP

ACEI MECHANISM OF ACTION


VASOCONSTRICTION ALDOSTERONE VASOPRESSIN SYMPATHETIC
Angiotensinogen
RENIN

VASODILATATION PROSTAGLANDINS Kininogen Kallikrein


tPA

Angiotensin I

BRADYKININ
Kininase II
Inactive Fragments

A.C.E. ANGIOTENSIN II

Inhibitor

Organ Protective Effects of ACE Inhibitor


ACE inhibitor

Heart
Inhibition of hypercardia Inhibition of fetus type gene expression Inhibition of TGF- b1 expression Decrease of collagen Inhibition of fibrosis

Blood Vessel
Bradykinin increase NO increase Protection of endothelial function Vascular dilation Inhibition of smooth muscle proliferation
Inhibition of arteriosclerosis

Kidney
Decrease of interior pressure of glomeruli NO increase Preservation of size barrier and charge barrier of glomerular basal lamina Inhibition of mesangial proliferation
Anti-proteinuria

Inhibition of remodeling

Improvement of cardiac function Revised from Mebio Vol.17, No.11

Improvement of blood flow

Prevention of glomerulosclerosis

RENIN-ANGIOTENSIN CASCADE
ANGIOTENSINOGEN RENIN ANGIOTENSIN I ACE ANGIOTENSIN II

ACE Inhibitors

A2RBs
AT 1 Receptor AT 2 Receptor

Sympathetic Angiotensin Interactions Long-Term Disadvantage


LVH, vasc. hypertrophy Trophic effects Enhanced coagulation Thrombosis

Endothelial dysfunction

High blood pressure

Sympathetic tone
Angiotensin II

Weight increase

Tachycardia arrhythmia Sudden death


Julius S. 2000

Insulin resistance Abnormal lipids Atherosclerosis

Classification of ACE Inhibitors


Noda K, sasaguri M et al, 1993 ; linz W, Scholkens BA, 1992

A - type ACE inhibitors


preferentially inhibit Ang I conversion useful for pts who can not tolerate coughing imidapril

B - type ACE inhibitors


preferentially inhibit bradykinin breakdown useful for pts who are likely to benefit from bradykinin ramipril

C - type ACE inhibitors


combined or immediate type captopril & enalapril, other most currently available ACE inhibitors
Sasaguri M, Ideishi M, Kinoshita A, Arakawa K, Hypertens Res, 17;4, 1994

PHARMACOKINETIC CHARACTERISTICS OF ACE-INHIBITORS


CAPTO Pro-Drug Absorption w/ Meals T (hours) Tissue Affinity Dosage T/P Ration Elimination No 35% 2 + 2-3 X 25% Renal LISINO No 0 13 ++ 1X 48% Renal PERIN DO Yes 35% 3-5 +++ 1X 70% Renal IMIDA Yes 0 8 +++ 1X 78-84% 40% Renal RAMI Yes 0 9-18 ++++ 1X 56% Renal QUINA Yes 30% 3 ++++ 1X 27% Renal BENA ZE Yes Slightl y 10 ++ 1X 40% Renal

IMIDAPRIL HCl as ACE-I improved fibrinolytic function and ventricular function in acute MI

Oshima et al., American Heart Journal Vol. 134 No. 5, 1997

Venticular Dysfunction was Improved by Early IMIDAPRIL HCl Therapy

Mizuno et al., Journal of Cardiac Failure Vol. 3 No. 4, 1997

High-Versus Low-Dose ACE Inhibition in Chronic Heart Failure a Double-Blind, PlaceboControlled Study of Imidapril. Dirk J van Veldhuisen et al. J am Coll Cardial 1998;32:1811-1818 - High dose ACE inhibition ( with imidapril ) is superior to low dose

Change in Exercise Duration after 12 weeks treatment with IMIDAPRIL 60 50 Exercise duration (soc) 40 30 20 10 0
p < 0.05 Vs placebo, p < 0.05 Vs Imidapril 2,5 mg

Change in Physical Working Capacity (PWC) after 12 weeks treatment with IMIDAPRIL 10
*

p < 0.05 Vs placebo

Physical Working Capacity (Watt)

*
0 -5

-10
Placebo Imidapril Imidapril Imidapril 2,5 mg 5 mg 10 mg Placebo Imidapril Imidapril Imidapril 2,5 mg 5 mg 10 mg

Veldhuisen, D J, et al. J Am Coll Cardiol 1999;32:1811-1818

Dosage of ACE inhibitors in Patients with Impaired Renal Function

If creatinine clearance is 50 ml/min (normal = about 100 ml/min)


ACEIs excreted through kidneys 1 50/100 = 0.5 ACEIs excreted both through kidneys and biliary tract (1:1) 0.5 0.5 50/100 = 0.75

1. 2. 3. 4.

Start ACEIs at a half of the usual dosage Determine serum creatinine and potassium levels within 2-4 wk Continue ACEIs if the serum creatinine level is slightly increase Stop ACEIs if the serum creatinine level is more than 1.5 times of the basal level.

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