Professional Documents
Culture Documents
ANTIHIPERTENSI
Jimmy Posangi
Bagian Farmakologi dan Terapi
FAKULTAS KEDOKTERAN UNIVERSITAS SAM RATULANGI
MANADO 24 Mei 2012
A. Golongan Diuretika
B. Golongan Adrenergik
C. Golongan Vasodilator
Sites of action
Diuretics
MANNITOL
Proximal
Convulated Tubule
65%
FUROSEMIDE
Thick Segment
Ascending
Limb of Henles
Loop
THIAZIDES
Early Distal
Convulated Tubule
10%
20%
Spironolactone,
Triamterene
1%-5%
Late Distal
Convulated
Tubule and
Collecting Duct
(Distal Nephron)
Neurotransmitter
Effectors
cell
Cell Signaling
- Blocker
Noradrenaline
adrenergic
Propranolol
Effectors
cell
- Blocker
Noradrenaline
adrenergic
Prazosin
Effectors
cell
2 - Agonist
Noradrenaline
adrenergic
Clonidine
Effectors
cell
Ganglia Blocker
Acetylcholine
Trimethaphan
cholinergic
adrenergic
Sympathetic
Ganglia
Sympatholitic
Reserpin
Effectors
cell
Acetylcholine
Endothel Cells
Ca 2+ Calmodulin
NO SYNTHASE
Arginine + O2
Citrulline + NO
NO
Fe
Guanylate
Cyclase
GTP
cGMP
Relaxation
Vasodilator
Nitroprusside
Extracellular
NO
Smooth Muscle Cells
Fe
Guanylate
Cyclase
GTP
cGMP
Relaxation
propranolol
Enalkiren
+ Renin
X
Angiotensin I
Captopril
Quinapril, etc
Remikiren
Bradykinine
ACE
Angiotensin II
Peptide inaktif
Angiotensin II Blocker
Angiotensin II
Losartan
Effectors
cell
Endoplasmic reticulum
Voltage-gated
Ca2+ Channel
Ca 2+
Ca 2+
calmodulin
Myosin
light-chain kinase
Phosphorilation
Extra cell
Cytosol
Endoplasmic reticulum
Ca2+
calmodulin
Voltage-gated
Ca2+ Channel
Extra cell
Cytosol
Golongan Obat
Antihipertensi
dan Prototip Obat
Diuretik
TIAZID
Keunggulan
Murah,
tak ada rebound
phenomena
Efek Samping
dan Kerugian
Lain
K+ depletion.
Mg++ dan Ca++
naik .
Glukosa dan
LDL naik.
Perlu replacement
K+.
Golongan Obat
Antihipertensi
dan Prototip Obat
Bloker Beta
PROPANOLOL
Keunggulan
Efek Samping
dan Kerugian
Lain
Efektif, frekuensi
jantung turun.
Menentramkan,
renin turun.
Bronhospasme.
Kongesti nasal.
Kelelahan.
Bradikardi.
Gangguan hantaran
A-V, Raynauds
phenomena.
Impotensi, inhibisi
glukoneogenesis.
rebound +
Golongan Obat
Antihipertensi
dan Prototip Obat
Bloker Alfa
PRAZOSIN
Keunggulan
Efek Samping
dan Kerugian
Lain
Hipotensi
Efek vasodilator ortostatik.
Terpilih bagi
Adanya toleransi
hipertensi + gagal bila pakai lama.
Palpitasi, mulut
jantung kongestif. kering, diare.
Memperbaiki
Kongesti nasal.
rasio HDL/LDL. Disfungsi seksual
Golongan Obat
Antihipertensi
dan Prototip Obat
2-Agonis
KLONIDIN
Keunggulan
Ortostatik efek
kurang.
Baik untuk
hipertensi resisten,
dikombinasi dgn
diuretika dan
dilator
Ada rebound
effect
Sedasi, mulut
kering.
Disfungsi seksual.
Mual, konstipasi.
Golongan Obat
Antihipertensi
dan Prototip Obat
Penghambat
adrenergik
RESERPIN
Keunggulan
Ortostatik kurang.
Murah.
Efek hanya berobah
sedikit walau pasien
tak patuh.
Masa kerja panjang.
Rebound effect
relatif tak ada.
Efek samping
depresi.
Dapat terjadi ulkus
peptikum.
Kongesti nasal.
Disfungsi seksual.
Dampak EkstraPiramidal.
Ginekomasti.
Golongan Obat
Antihipertensi
dan Prototip Obat
Vasodilator
arteriole
HIDRALAZIN
Keunggulan
Sakit kepala.
Dipakai pada krisis
Tahikardi.
hipertensi dan
GIT intolerance.
Eklamsi
Golongan Obat
Antihipertensi
dan Prototip Obat
Ca-channel
blocker
NIFEDIPIN
Keunggulan
Fungsi seksual
relatif normal.
Baik pakai pada
usia lanjut.
Boleh dipakai pada
Emergency.
Sakit kepala.
Edema, konstipasi.
Palpitasi dan
Bradikardi.
Golongan Obat
Antihipertensi dan
Prototip Obat
ACE-inhibitor
KAPTOPRIL
Keunggulan
Efektif bagi
hipertensi berat.
Fungsi seks relatif
normal.
Dapat dipakai pada
gangguan ginjal.
Dosis/cara
0,5-10
gr/kgbb/
mnt i.v
drips
Mula
Kerja
Lama
Kerja
Keterangan
Beri bersama
Blocker
bila
ao.disekans
15-30
1-5
mg/mnt-300 menit
mg i.v drips
4-12 jam
Bahaya pada
penyakit
koroner
1-5 mg/mnt
i.v
10 menit
1-3
menit
Dosis/cara
Mula
Kerja
Lama
Kerja
Keterangan
Esmolol
Blocker
Labetalol
&
blockers
20-300
mg/10 mnt
parenteral
Bahaya pada
asma & CHF
Hidralazin
Vasodilator
5-20 mg
i.v/i.m
10-30
menit
2-6 jam
Bahaya pada
p. Koroner
15
menit
6 jam
Baik +
diuretik
Enalaprilat
1,25 mg/6
ACE inhibitor jam i.m
Dosis/cara
Mula
Kerja
Lama
Kerja
Keterangan
10-80 mg
i.v/i.m
15
menit
4 jam
Hipokalemi
10 mg
ulangi tiap
30 mnt/oral
15
menit
2-6 jam
Awas angina
0,2 mg lalu -1
+ 0,1-0,8
jam
Simpatolitik mg/jam/oral
6-8 jam
Awas rebound
Kaptopril
4-6 jam
Hipotensi
berlebihan
Diuretik
Nifedipin
Ca-blocker
Klonidin
ACE inhibitor
6,25-25 mg
oral
15-30
menit
Strategi Pengobatan
Hipertensi The stepped care
Stepped care
Kaku
Individualized approach
(mempertimbangkan)
Umur
Ras
Penyakit penyerta
Gaya hidup
Status sosial-ekonomi
Kesimpulan
- Mengurangi mortalitas dan morbiditas
- Aksi farmakologi: volume, arus, dinding
- Penggunaan seyogianya:
rasional
efektif
aman
ekonomis
TERIMA KASIH
Pressure
Lowering Effect
of ARBs:
Are They All the
Same?
Budi Yuli Setianto, MD, FIHA, FINASIM
Department of Cardiology and Vascular Medicine Faculty of Medicine Gadjah
Mada University Sardjito Hospital, Yogyakarta
Hypertension
More Than Just High BP
A complex syndrome in which neurohumoral and
metabolic abnormalities influence development
and progression of vascular disease and clinical
events
A complex inherited syndrome of cardiovascular risk
factors
Hypertension Syndrome
Obesity
Decreased
Arterial
Compliance
Endothelial
Dysfunction
High
HighBlood
BloodPressure
PressureisisaaLate
Late
Manifestation
of
the
Hypertension
Manifestation
of
the
Hypertension
Hypertension
Syndrome
Syndrome
Abnormal Lipid
Metabolism
Accelerated
Atherogenesis
Abnormal
Glucose
Metabolism
Neurohormonal
Dysfunction
LV Hypertrophy
Renal-Function
Neutel JM et all, Am J Hypertens, 1999; 12:215-223
and Dysfunction
Changes
Neutel JM et all, Am J Hypertens, 1999; 12:215-223
Abnormal
Blood-Clotting
Insulin
Mechanism
Metabolism
Changes
Study
Multiple
Cardiovascular
Cardiovascular
GLUCOSE TOXICITY
-cell
-cell
dysfunction
dysfunction
Insulin signalling
signalling
Insulin
defect
defect
Loss of
of early
early phase
phase
Loss
insulin release
release
insulin
Insulin resistance
resistance
Insulin
Postprandial
Postprandial
glucose spikes
spikes
glucose
Increased basal
basal
Increased
glucose levels
levels
glucose
Hyperglycaemia
Hyperglycaemia
Adapted from Lebovitz, Ward and Yki-Jrvinen
1 Lebovitz HE. Diab Rev 1999; 7: 139-153. 2 Ward W, et al. Diab Care 1984; 7: 491-502. 3 Yki-Jarvinen H. Endocrine Revs 1992; 13: 415-431.
Antihypertensive Agent
Blood pressure
lowering effect
ACEIs
ALL inhibit the renin-angiotensin
system
+
ALL
bradykinin
ARBs
ALL inhibit the
renin-angiotensin
system
+
Some PPAR
(Telmisartan)
Angiotensin II Formation
Angiotensinogen
Renin
Angiotensin I
ACE
CAGE
Cathepsin G
Chymase
t-PA
Cathepsin G
Tonin
Angiotensin II
Angiotensin II Receptors
Dzau VJ et al. J Hypertens. 1993;11(suppl):S13-S18.
Angiotensin
II
ARBs
Expressed
Expressed only
only after
after injury
injury
Constantly
Constantly expressed
expressed
AT11 receptor
Non-Hemodynamic
Non-Hemodynamic
Stress
Stress oxidative
oxidative //
inflammation
inflammation
TGF
TGF -- &
& ECM
ECM
PAI
PAI 11
Aldosterone
Aldosterone
Symphatic
Symphatic Activity
Activity
Hemodynamic
Hemodynamic
Vasocontriction
Vasocontriction
RBF
RBF
P
P gc
gc
AT22 receptor
Vasodilatation
Vasodilatation
Natriuresis
Natriuresis
Growth
Growth Inhibition
Inhibition
Wiecek
Wiecek A
A et
et al.
al. NDT
NDT 2003;18(suppl
2003;18(suppl 5):v16-v20
5):v16-v20
Chemical structures of the most widely used angiotensin receptor blockers (ARBs), illustrating the
unique nature of telmisartan. The circle encloses the biphenyl tetrazole moiety that is common to
losartan and its related ARBs.
ARBs Comparison of
pharmacological properties
Olmesartan
Losartan
Candesartan
Irbesartan
Telmisartan
Eprosartan
Valsartan
Yes
Yes
Yes
No
No
No
No
Noncompetitive
Competitive
(active
metabolite
is noncompetitive
Noncompetitive
Noncompetitive
Noncompetitive
Competitive
Noncompetitive
AT1:AT2
affinity
12,500
1,000
>10,000
8,500
>3,000
1,000
20,000
t1/2 (hours)
10-15
6-9
11-15
24
5-9
1-2
3-4
3-4
1.5-2
0.5-1
1-2
2-4
Vd (L)
16-29
34
0.1 L/kg
53-93
500
~13
~23
Bioavailability (%)
25.6
~33
14
60-80
50
13
23
Prodrug
Receptor
antagonism
Tmax (hours)
56
Losartan
Candesarta
Irbesartan
Telmisartan
Eprosartan
Valsartan
Faecal
elimination
(%)
50-65
60
67
80
98
90
83
Urinary
elimination
(%)
35-50
35
33
20
<1
13
CYP450
metabolism
No
Yes
CYP 3A4
No
Yes
CYP 2C9
No
No
No
Drug
interactions
No
Rifampin,
fluconazo
le
No
No
Digoxin
No
No
Effect of
food
( AUC%)
None
10
None
None
6-20
25
40-50
Dosing
frequency
od
od/bid
od/bid
od
od
od/bid
od
57
Peroxisome Proliferator-Activated
Receptors (PPARs)
Members of nuclear receptor superfamily
Transcription factors that regulate gene expression in
response to certain endogenous and exogenous ligands
Acts as a central transcriptional mediators in the regulation
of several important metabolic processes that influence :
adipogenesis, insulin sensitivity, glucose homeostasis,
lipid metabolism, vascular endothelial function,
inflammation, atherosclerosis progression, and
ultimately cardio-reno-vascular risk
Liver
Kidney
Heart
GITs
Skeletal muscle
Fat tissue
Retina
Peroxisome proliferation
Lipid Oxidation
Gluconeogenesis
PPAR
All tissue
except smooth muscle
Fat Differentiation
PPAR
Fat tissue
Skeletal muscle
Liver
Heart
Kidney
Endothel
VSMC
Glucose uptake
Gluconeogenesis
Glycogenesis & Glycolysis
Fatty acids uptake
Lipogenesis
Fat Differentiation
L
L
RA
PPAR
RXR
Target Genes
FA binding protein
FA transport protein
Acyl CoA oxidase
PAI-1; VCAM; IL-6
Target gene
transcription
DNA
Response element
Target gene
Regulation of
Target
Gene Transcription
RA
PPAR
RXR
Response element
DNA response
element receptor
Glucose Transporters
TNF -
Target gene
transcription
Benificial effect on
Hyperglycemia
Hyperinsulinemia
Dyslipidemia
Inflammation
Endothelial Dysfunction
Target gene
DNA
PPAR
Modulation
NF-B
TNF-
PAI-1
Fibrinogen
CRP
IL-6
VCAM
NO
Dyslipidemia
Adiponectin
Insulinemia
Insulin sensitivity
Leptin
ACC2
Weight gain
Blood pressure
Tissue fibrosis
Tissue inflammation
Cell proliferation
Oxidative stress
Endothelial dysfunction
SNS activity
Steatohepatitis
Cardiac function
Cardiomyopathy
Atherosclerosis
Atherogenesis
AT1-R Blockade
AT2-R Activation
Ang - II
Glomerulosclerosis
Neuroregulation
Islet function
30
20
10
Valsartan
Losartan
Irbesartan
Metabolite
Telmisartan
10 micromolar
Benson SC et al. Hypertension 2004;43:993-1002
Plasma half-life of
ARBs
FPG
FPI
HOMA-IR
HbA1c
0
-5
-10
P < 0.05
P < 0.05
P < 0.06
-15
-20
Losartan
-25
Telmisartan
-30
P < 0.05
P-values indicate telmisartan-losartan comparison
4
2
0
-2
-4
-6
-8
Losartan
Insulin
HOMA Index
Insulin Resistance
Losartan
Losartan
Telmisartan
p<0.06
Telmisartan
Telmisartan
p<0.05
p<0.05
(G. Rosano et al., VII Forum on the Renin-Angiotensin System, 2004)
SCOPE (candesartan)
PROFESS (telmisartan)
TRANSCEND (telmisartan)
44% diuretics
26% B-Blocker
88% CCB
1st Generation
ARBs
AT1 Receptor
Blockade
2nd Generation
ARB
Telmisartan
~ Metabosartan
3rd Generation
ARBs
More than AT1
Blockade
Stage of
development
Additional action
beyond AT1
blockade
Preclinical
Preclinical
Phase III
Preclinical
Natriuretic peptides
Phase II /III
Natriuretic peptides
Phase IIb
Preclinical
Preclinical
3-[(nitrooxy)methyl]
benzoate ester of losartan
SUMMARY
1) The risk for developing type 2 diabetes is doubled in patients with
hypertension and is increased 5 9 fold by the metabolic syndrome
2) Telmisartan is a dual ARB / selective PPAR modulator is a
3) Telmisartan