ANTAGONIS RECEPTOR
ANGIOTENSIN II,
TEROBOSAN ATAU
MODIFIKASI ?
Dr. Budi Enoch DSPD
Hipertensi normal tinggi
JNC VII,2003 (Joint National Comitte
on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure
WHO-ISH International Society on
Hypertension
Subjek tanpa hipertensi dengan TD 130-
139 sistol atau 85-89 diastole
dikatagorikan TD ‘normal tinggi’
Insiden kumulatif kejadian kardio vaskular
pada subjek tanpa hipertensi
(Framingham Heart Study, 2001)
10
Insidens kumulatif (%)
normal tinggi
8
normal
4
2
optimal
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Pegangan klasifikasi
ESH-ESC Tekanan Darah mHg JNC VII
optimal < 120 / < 80 normal
normal 120-129 / 80-84 Pre-Hp
nl tinggi 130-139 / 85-89 Pre-Hp
Gr 1 (rng) 140-159 / 90-99 Hp st 1
Gr 2 (sdg) 160-179 / 160 / 100 Hp st 2
100-109
Gr 3 (brt) >180/>110
ISH >140 / < 90 ISH
National Health and Nutrition Examination
Survey (NHANES)
Trends in awareness, treatment and control of
high blood pressure in adults aged 18-74*
II III III
(1976-80) (Phase 1 (Phase 2 1999-2000
1988-91) 1991-94)
Awareness 51% 73% 68% 70%
Treatment 31% 55% 54% 59%
Control† 10% 29% 27% 34%
* High blood pressure defined as SBP ≥140
mmHg or
Unpublished data for 1999–2000 compiled by M.
DBP ≥90 mmHg or taking antihypertensive
Wolz, National Heart, Lung and Blood Institute:
medication JNC VI
† SBP <140 mmHg and DBP <90 mmHg
Efek obat-obatan AH terhadap
kejadian kardiovaskuler dilihat dari
hasil gabungan 17 uji klinik acak,
terkontrol dengan plasebo yang
melibatkan 48.000 subjek dengan
basis diuretik atau β blockers
menunjukan prosentasi penurunan
yang sangat bermakna
Penurunan kejadian (%)
60
40
20
Gagal jantung
kongestif
Fatal/non fatal
stroke
LVH
Kematian ec
peny.kardiovask
Kejadian PJK
fatal/non fatal
Comparison of tight BP vs tight glucose
control in UKPDS
Any diabetes- Microvascular Diabetes-related
Stroke related endpoint endpoints deaths
0
-10
Risk reduction (%)
-20
-30
-40
Tight glucose control
-50 Tight BP control
BP, blood pressure; UKPDS, United Kingdom Prospective Diabetes Study UKPDS 38. BMJ 1998;317:703-713;
UKPDS 33. Lancet 1998;352:837-853
Goals of treatment: ESH/ESC 2003
Achieve maximum reduction in total
cardiovascular risk
Treat all reversible risk factors and
associated clinical conditions in addition
to treating raised blood pressure
Target blood pressure <140/90 mmHg
and to lower values, if tolerated
For diabetics, target blood pressure is
<130/80 mmHg
ESH/ESC Guidelines 2003. J Hypertens 2003;21:1011-1053
Goals of treatment: JNC VII
The SBP and DBP targets are
<140/90 mmHg
The primary focus should be on
achieving the SBP goal
In patients with hypertension and
diabetes or renal disease, the BP goal is
<130/80 mmHg
SBP, systolic blood pressure; DBP, diastolic blood pressure;
BP, blood pressure JNC VII. JAMA 2003;289:2560-2572
Goals of treatment: WHO/ISH 2003
Decisions about the management of hypertensive
patients should be based on blood pressure levels
and the presence of other cardiovascular risk
factors, target organ damage and associated
clinical conditions
In hypertensive patients at low to medium risk*,
the SBP goal is <140 mmHg
In hypertensive patients at high risk*, a target of
<130/80 mmHg is appropriate
* Risk of developing a major cardiovascular event (fatal and nonfatal stroke, and
myocardial infarction)
SBP, systolic blood pressure 2003 WHO/ISH statement on hypertension. J Hypertens 2003;21:1983-1992
Hypertension control rates around the
world
<140/90 mmHg (%) <160/95 mmHg (%)
United States 27 Germany 23
France 24 Finland 21
Canada 22 Spain 20
Italy 9 Australia 19
Egypt 8 Scotland 18
England 6 India 9
Korea 5 Zaire 3
China 3
Poland 2
JNC VI. Arch Intern Med 1997;157:2413-2446; Joffres MR, et al. Am J Hypertens 1997;10:1097-1102;
Colhoun HM, et al. J Hypertens 1998;16:747-752; Chamotin B, et al. Am J Hypertens 1998;11:759-762;
Marques-Vidal P, et al. J Hum Hypertens 1997;11:213-220
History of antihypertensive drugs
Effectiveness and general tolerability
1940’s 1950 1957 1960’s 1970’s 1980’s 1990’s 2000
Direct Alpha-
vasodilators blockers
ACE ARB
inhibitors
Peripheral Thiazide s
sympatholytics diuretics
Central 2
Ganglion agonists Calcium
blockers antagonists-
Calcium
Veratrum antagonists- DHPs
alkaloids non-DHPs
Beta-
blockers
DHP, dihydropyridine;
ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker
Factors influencing BP control
Efficacy
+
Adverse effects
+
Convenience
Factors influencing BP control
Efficacy
+
Adverse effects
+
Convenience
Dose-related efficacy and
side-effect profile
Antihypertensive efficacy generally improves with
an increase in dose
Common side effects associated with:
ACE inhibitors – cough
CCBs – ankle oedema, flushing
Beta-blockers – tiredness, impotence
ARBs have demonstrated placebo-like tolerability
even at higher doses
ACE, angiotensin-converting enzyme;
CCB, calcium-channel blocker; ARB, angiotensin II
receptor blocker
ACE inh pada hipertensi
Menurunkan morbiditas dan mortalitas
akibat gagal jantung dan stroke
Tetapi insiden gagal jantung tetap
meningkat setiap tahun, terutama pada
kelompok orang tua
Penyebab : - kelompok usia tua
- remodelling otot jantung
Remodelling :
HIPERTENSI
Hipertrofi ventrikel kiri
Dilatasi
Fibrosis
Perubahan jaringan matrik
KEMAMPUAN KONTRAKSI
Main classes of antihypertensive drugs
Diuretics
Inhibit the reabsorption of salts and water from kidney
tubules into the bloodstream
Calcium-channel antagonists
Inhibit influx of calcium into cardiac and smooth
muscle
Beta-blockers
Inhibit stimulation of beta-adrenergic receptors
Angiotensin-converting enzyme (ACE)
inhibitors
Inhibit formation of angiotensin II
Angiotensin II receptor blockers (ARBs)
Inhibit binding of angiotensin II to type 1 angiotensin
II receptors
Penelitian ACE inhibitor
Mengendalikan hipertensi
Mortalitas GJ akibat HP
Mortalitas GJ akibat PJK
Terutama pada disfungsi sistolik
ventrikel kiri dimana ejection
fraction < 40%
Effek samping ACEInh
Angioneurotik edema
Batuk
First dose hypotension
Effek samping ACE-Inh
Angioneurotik edema
Batuk
First dose hypotension
AIIRA
Angiotensin II Receptor
Antagonists
Khasiat setara dengan ACEI pada HP/GJ
Losartan obat pertama
olmesartan generasi lanjutan
Meskipun penelitian klinis pemakaian
AIIRA berskala besar untuk GJ belum
ada, namun penelitian klinis sementara
ini yang sudah dipublikasikan
menunjukan hasil yang lebih baik
dibanding ACEI
Renin-angiotensin-aldosterone system
Angiotensinogen
(-)
Renin
Angiotensin I Bradykinin
Angiotensin-
converting
enzyme
Angiotensin II Inactive kinins
BP AT1 AT2
• Vasoconstriction • Vasodilation
• Aldosterone secretion • Inhibition of cell growth
• Catecholamine release • Cell differentiation
• Proliferation • Injury response
• Hypertrophy • Apoptosis
Ellis ML, et al. Pharmacotherapy 1996;16:849-860;
BP, blood pressure Carey RM, et al. Hypertension 2000;35:155-163
Inhibition of the RAAS by ACE inhibitors
ACE
Angiotensinogen
(-) inhibitor
Renin
Angiotensin I Bradykinin
Non- Angiotensin-
Non-
renin converting
ACE enzyme
Angiotensin II Inactive kinins
BP AT1 AT2
• Vasoconstriction • Vasodilation
• Aldosterone secretion • Inhibition of cell growth
• Catecholamine release • Cell differentiation
• Proliferation • Injury response
• Hypertrophy • Apoptosis
RAAS, renin-angiotensin-aldosterone system; Ellis ML, et al. Pharmacotherapy 1996;16:849-860;
ACE, angiotensin-converting enzyme; BP, blood pressure Carey RM, et al. Hypertension 2000;35:155-163
Inhibition of the RAAS by ARBs
Angiotensinogen
Renin
Angiotensin I Bradykinin
Angiotensin-
converting
enzyme
Angiotensin II Inactive kinins
ARB
BP AT1 AT2
Ellis ML et al. Pharmacotherapy 1996;16:849-860;
RAAS, renin-angiotensin-aldosterone system; Carey RM et al. Hypertension 2000;35:155-163;
ARB, angiotensin II receptor blocker; BP, blood pressure Mizuno M et al. Eur J Pharmacol 1995;285:181-188
Potential advantages of
Angiotensin II Receptor Antagonists
Complete and sustained blockade of the RAAS,
independent of the pathway of angiotensin II production
Placebo-level tolerability
no accumulation of bradykinin
compared with ACE inhibitors, virtually no cough
Stimulation of AT2 receptor may be associated with
clinical benefits and anti-proliferative activity
Future guidelines are likely to emphasize lower BP goals
and well-tolerated agents to help meet those goals
Ellis ML, et al. Pharmacotherapy 1996;16:849-860;
RAAS, renin-angiotensin-aldosterone system; ACE, Pylypchuk GB. Ann Pharmacother 1998;32:1060-1066;
angiontesin-converting enzyme; BP, blood pressure Carey RM, et al. Hypertension 2000;35:155-163
losartan, valsartan, ibesartan
Oparil S, et al. J Clin Hypertens 2001;3:283-291
After 8 weeks of treatment, olmesartan
20 mg/d was significantly more
effective for reducing BP than losartan,
valsartan and irbesartan at maintenance
doses
2 weeks after the initiation of treatment,
olmesartan was associated with
significantly greater reductions in DBP
and SBP than the 3 comparator drugs
BP, blood pressure; DBP, diastolic blood pressure; Oparil S, et al. J Clin Hypertens 2001;3:283-291
SBP, systolic blood pressure
contraindications
Hypersensitivity to the active ingredient
or any of the other excipients of
Olmetec® tablets
Pregnancy
Lactation
Biliary obstruction
Source: Product Information, BPOM Approval 18 July 2005
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