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Which ARB is Suitable For Your Patients?
Tirta Kristina / Scientific Communication / Medical Affairs
Panduan Terapi Hipertensi
ARB’s: Compelling Indications
New studies
CHF
Post-MI
CAD risk
Diabetes mellitus
Renal disease
Recurrent stroke prevention
BB
ACEI
ARB
CCB
AA Diuretic
Mechanism Of Action
AT1R
Inflammation Endhotelial dysfuntion
Sympathetic activation
Cardiac (myocrdial) cells Smooth
muscle
Vascular Edothelium
CNS
Angiotensinogen
Angiotensin I
Angiotensin II
Individual cell growth
Renin
ACE
Adrenal cortex
Kidney
AT2R ARB
Inactive Prorenin
Kidney
Active Prorenin
Prorenin receptor
Fibrosis
Sodium retention
Kidney
Aldosterone
Bradykinin
Inactive fragments
Alternative pathway
(Chymase)
Kaplan’s Clinical Hypertension, 2010
Angiotensin-II Receptor Antagonist
Angiotensin Reseptor
Blocker (ARB) :
• Losartan
• Valsartan
• Irbesartan
• Candesartan
• Telmisartan
Which ARB is Suitable For Your Patients?
Tirta Kristina/ Scientific Communication / Medical Affairs
Pharmacokinetic
4 sites - candesartan 2 sites - losartan
Hydrogen bonds between ligand and receptor are shown as red dotted lines with hydrogen bond lengths. Carbon atoms of the ligands are coloured light
blue and those of the receptors are green
3 sites - valsartan
Bhuiyan et al 2009
Number of AT1-Receptor Binding Sites for Different Angiotensin II Receptor Antagonists
Insurmountable and Surmountable Antagonism: Relation to Duration of Binding
telmisartan olmesartan
candesartan
EXP 3174
valsartan
irbesartan
losartan
0 120 Dissociation t1/2
0
100
Insu
rmo
un
tab
ility
(%
)
80
100 80
60
40
60 40
20
20
Van Liefde et al 2009
EFIKASI PENURUNAN TEKANAN DARAH
Ideal Antihypertensive Agents
Duration of action which is appropriate for
once-daily administration
High trough:peak ratio which is consistent over the
recommended dosage range
Maintenance of control of blood pressure fully and
consistently throughout 24 h
Maintenance of control of blood pressure beyond
24 h despite poor compliance with treatment
No increases in blood pressure variability
Meredith et al, 1995
Range of T/P Ratio
Candesartan 8-16 mg
Losartan 50-100 mg
Irbesartan 150-300 mg
Valsartan 80 mg
Range of trough-to-peak ratio at once daily dosinhg (pacebo adjusted) as measured in various studies (DBP)1
Gordon McInnes. Pocket Reference to Angiotensin II Antagonists. Science Press
Candesartan Cilexetil vs Losartan : Mean Change From Baseline to Week 8 in Systolic ABP
0
-2
-4
-6
-8
-10
-12
-14
-16
-18
12 14 16 18 20 22 24 26 28 30 32 34 36
Hours after dose
Change in SBP (mm Hg)
Lacourcière & Asmar 1999
Losartan 100mg
Candesartan cilexetil 16mg
p=0.004
Maintenance of control of blood pressure fully and consistently throughout 24 h
Maintenance of control of blood pressure beyond 24 h despite poor compliance with
treatment
0 25 50 100 mg Losartan 0 80 160 320 mg Valsartan 0 75 150 300 mg Irbesartan
Reduction in diastolic BP (mmHg)
Elmfeldt et al 2002
Meta-Analysis Based on US New Drug Application Evaluation Reports
Candesartan
0 4 8 16 mg Candesartan
Losartan
Valsartan Irbesartan -6
-4
-2
-0
Clinical and Experimental Hypertension, 2012; 34(2): 86–91
Effect of Switching from Telmisartan, Valsartan, Olmesartan, or Losartan to Candesartan on Morning Hypertension
Hiroshi Hasegawa,1 Hiroyuki Takano,1 Yoshihito Kameda,1 Akihiko Kubota,1 Yoshio Kobayashi,1 Issei Komuro2
1Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chuo-ku, Chiba, Japan, 2Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Method:
Seventy-eight mild to moderate hypertensive patients, who were treated with the
standard doses of ARBs except candesartan (losartan, 50 mg; valsartan, 80 mg;
telmisartan, 40 mg; or olmesartan, 20 mg), were entered into 12-week treatment
period with candesartan 8 mg according to a multicenter, open-label design.
To control morning BPs, well-tolerated antihypertensive agents with long durations of action are required.
−10.1 ± 10.5/−4.5 ± 8.4 mmHg −13.1 ± 17.3/−6.2± 11.3 mm Hg
Candesartan treatment significantly reduced the morning
and office BPs compared with other ARBs in Japanese
patients with morning hypertension.
TROPHY TRial Of Preventing HYpertension
TROPHY : Study objectives
TROPHY evaluated 2 years of treatment with candesartan in individuals with
prehypertension*
Primary objective:
• Determine if the incidence of HTN can be reduced for up to 2 years after
discontinuation of active treatment
Secondary objective:
• Evaluate the incidence of HTN during 2 years of treatment with candesartan of
placebo
Average BP 130–139/89 mm Hg; or 139/85–89 mm Hg Julius S et al. N Engl J Med. 2006;354:1685-97.
TROPHY – study design
Two Years Two Years
Qualifying period*
Placebo
Non-pharmacological treatment
Non-pharmacological treatment
Candesartan cilexetil
16 mg daily
n 400
n 400
Placebo
Placebo
*Clinic BP reading of 130-139/ 89 mm Hg
or 139/85-89 mm Hg Julius et al, Hypertension 2006
TROPHY: Reduction in new-onset hypertension
66.3%*
15.6%*
Candesartan vs Placebo Placebo only
*Relative risk reduction †P < 0.001; ‡P = 0.007 Julius S et al. N Engl J Med. 2006;354:1685-97.
†
‡
N = 772
the effect of active treatment on delaying the onset of hypertension can
extend to up to two years after the discontinuation of treatment.
MENCEGAH KERUSAKAN ORGAN TARGET
Scientific Communication / Medical Affairs
OBJECTIVE: The aim of this study was to test the hypothesis that the
angiotensin II type 1 receptor blocker (ARB) candesartan (8 mg OD in the
morning) can reduce the risk of stroke in elderly patients with isolated systolic
hypertension (ISH).
SCOPE
Candesartan mampu menurunkan risiko stroke (fatal dan non fatal) sebesar 42%
J Am Soc Nephrol ●●: –, 2009
Metode:
269 patients who had persistent proteinuria (1 g/d) despite 7 wk of
treatment with the highest approved dosage of candesartan (16 mg/d)
to 16, 64, or 128 mg/d candesartan for 30 wk
Objective:
To evaluated whether supramaximal dosages of candesartan would
reduce proteinuria to a greater extent than the maximum approved
antihypertensive dosage
Penurunan Proteinuria Candesartan (SMART Study)
Ellen Burgess, SMART investigators, et all, J Am Soc Nephrol, 2009, Supramaximal Dose of Candesartan in Proteinuric Renal Disease.
Proteinuria can be reduced by increasing the dosage of candesartan
Method
95 pasien hipertensi-DM tipe II ditreatment selama ≥ 12 bulan dengan
telmisartan 40mg/hari (n=31), candesartan 8mg/hari (n=40) atau losartan
50mg/hari (n=24)
Evaluation
CAVI measurement and changes in blood pressure, blood glucose, HbA1c,
triglyceride, HDL
Relative Effects of Telmisartan, Candesartan and Losartan on Alleviating Arterial Stiffness in Patients
with Hypertension Complicated by Diabetes Mellitus: An Evaluation Using the Cardio Ankle Vascular Index
The Journal of International Medical Research 2008; 36: 1094-1102
Candesartan is a potentially useful therapy against arterial stifness in hypertensive patients with type 2 diabetes mellitus
Comparison of Anti-arteriosclerotic Effects of Candesartan and Valsartan in Type 2 Diabetic Patients with Hypertension —Evaluation by Flow-mediated Dilatation (FMD)
Auteur(s) / Author(s) UEHARA Goro ; MORI Kanako ; SAKAI Takako ; MORITA Yasuko ; TAKEDA Hiroshi ;
Résumé / Abstract Objective To compare the effects of candesartan and valsartan on endothelial function assessed by measurement of flow-mediated vasodilation (FMD) in type 2 diabetes patients with hypertension. Methods Subjects who were receiving treatment with valsartan prior to registration were switched to candesartan 8 mg/day (VC group, n=21) whereas those who were receiving candesartan were switched to valsartan 80 mg/day (CV group, n=19) for an observation period lasting 3 months. Percent FMD, blood pressure, and HbA1c were examined at baseline and 3 months after starting treatment. Results The two groups did not differ in terms of patients' baseline clinical characteristics and laboratory data. At 3 months, there were no significant changes in blood pressure and HbA1c in both groups. In the VC group percent FMD significantly increased at 3 months (from 4.7% to 5.8% ; p<0.001), while in the CV group it significantly decreased (from 4.7% to 4.3% ; p<0.001). Moreover, percent FMD at 3 months in the VC group was significantly higher than that in the CV group (p< 0.05). Conclusions This study indicates that suppression of progression of endothelial dysfunction by
different ARBs is not a class effect ; candesartan is more effective against progression of arterial sclerosis than valsartan.
2009, vol. 37, no9, pp. 757-762 [6 page(s) (article)]
Pemakaian Candesartan
mampu menurunkan
level kolesterol
total dan LDL lebih
superior dibandingkan
dengan ARB lainnya.
Profil Lipid
Hellenic J Cardiol, 2006, Effects of Antihypertensive Treatment with Angiotensin II Receptor Blockers on Lipid Profile
Safety and Tolerability
(Mortality & Morbidity) Scientific Communication / Medical Affairs
CHARM Program: Reduction in mortality and morbidity
CHARM-Overall: Reduction in new-onset diabetes
CHARM is the only study to provide clear evidence of the effects of an ARB in
preventing DM in heart failure patients, most of whom were receiving a diuretic
Treatment with candesartan reduced the incidence of new- onset diabetes in patients with heart failure by 22%
Candesartan aman untuk penderita
ASMA
Bioequivalence Study of Candesartan Cilexetil
(manufactured by PT Dexa Medica)
Quality of Assurance Drug
Mean plasma concentration-time profiles of candesartan in human subjects (n=24) after oral administration of 16 mg candesartan cilexetil tablet
produced by PT Dexa Medica (Test Drug = Candesartan Cilexetil 16 mg) and the Reference (Reference Drug = Blopress® 16 mg)
16 mg Candesartan cilexetil tablets produced by PT Dexa
Medica and the Reference (BLOPRESS 16mg, PT Takeda
Indonesia - Indonesia) are BIOEQUIVALENT
PROFILE PRODUCT
INDIKASI
• HIPERTENSI
• Pengobatan pada pasien dengan gagal jantung dan gangguan fungsi sistolik ventrikel kiri (LVEF < 40%) ketika obat penghambat ACE tidak ditolelir
DOSIS dan CARA PEMBERIAN
• DOSIS PADA HIPERTENSI
– Dosis awal Canderin adalah 4 mg per hari.
– Dosis dinaikkan sesuai dengan respons pengobatan sampai maksimum 16 mg sehari (Efek Maksimal dicapai dalam 4 minggu-6 minggu).
– Pasien dengan gagal ginjal sedang sampai berat, tidak memerlukan penyesuaian dosis, tapi disarankan diberikan dosis awal 2 mg.
– Pasien dengan gangguan hati ringan sampai sedang, direkomendasikan dosis awal 2 mg per hari.
DOSIS dan CARA PEMBERIAN
• DOSIS PADA GAGAL JANTUNG
– Dosis awal 4 mg/hari. Peningkatan dosis sampai 32 mg/hari atau dosis tertinggi yang dpt ditoleransi dalam interval waktu minimal 2 minggu.
– Pasien lanjut usia dan pasien dengan pengurangan volume intravaskular, gangguan ginjal, dan gangguan hati ringan sampai sedang tidak perlu penyesuaian dosis.
• CARA PEMBERIAN
– Sekali sehari sebelum makan atau setelah makan
KONTRAINDIKASI
• Penderita yang sensitif terhadap komponen CANDERIN.
• Wanita hamil dan menyusui
• Kerusakan hati yang berat dan/atau kolestasis
Kesimpulan
Pharmacokinetics Afinitas lebih tinggi, durasi ikatan lebih panjang
Pharmacodinamics Efikasi:
Penurunan tekanan darah lebih baik Efek proteksi terhadap ginjal, otak, jantung Pleiotropic effect: menurunkan kekakuan arteri, memperbaiki profil lipid
Tolerability Aman untuk pasien asma
Quality of Assurance Drug Bioekivalen dengan originator
Cost Lebih cost effective
Tirta Kristina/ Scientific Communication / Medical Affairs
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PRODUK 2013
Akses juga melalui:
http://cme.medicinus.co/
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