ANTIHIPERTENSI

REGULASI TEKANAN DARAH

REFLEKS BARORESEPTOR
Parasimpatis
Denyut
jantung
CO Kontraktilitas
miokard
Isi
sekuncup Volume
Darah
Alir balik Simpatis
vena
TEKANAN Kapasitas
DARAH vena
Tonus arteri
& arteriol
Resistensi
Pmblh darah
Resistensi Elastisitas dinding RAA
Perifer Pembuluh darah
Viskositas
darah
SEKRESI RENIN
KRITERIA HIPERTENSI
ETIOLOGI HIPERTENSI
 90% tidak diketahui penyebabnya →
hipertensi esensial
 10%:
 Penyakit Ginjal
 Tumor Endokrin
 Hipertensi esensial:
- Faktor genetik berperan besar
- Faktor eksternal:
 Stressful Lifestyle
 Intake Sodium ↑
 Obesitas
 Smoking
TERAPI HIPERTENSI
 Tujuan terapi: menurunkan morbiditas &
mortalitas
 Sasaran tekanan darah:
Muda < 140/90
Lansia/80 tahun < 160/90
 Resiko yang diakibatkan hipertensi
 CHF
 Kerusakan Ginjal
 Kerusakan Cerebrovascular
 Penyakit Retina
STRATEGI TERAPI HIPERTENSI
 Non farmakologis & farmakologis
- Hipertensi ringan – modifikasi gaya
hidup, diet rendah garam
- Hipertensi sedang – + 1 jenis obat
antihipertensi
- Hipertensi berat – biasanya +
kombinasi 2/3 obat tergantung kondisi
pasien
 Pendekatan individual
Hipertensi pada pasien sering disertai
adanya penyakit lain, pilih antihipertensi
yang tepat
 Kepatuhan penderita
 Sangat menentukan keberhasilan
 Pengontrolan tensi terus menerus
PRINSIP TERAPI HIPERTENSI
 Nonpharmacological therapy is an
important component of treatment of all
patients with hypertension
 In some stage 1 hypertensives, blood
pressure may be adequately controlled by a
combination of:
 Weight loss (in overweight individuals)
 Restricting sodium intake
 Increasing aerobic exercise
 Moderating consumption of alcohol
TERAPI NONFARMAKOLOGIS
 REDUCTION OF BODY WEIGHT
 SODIUM RESTRICTION
 ALCOHOL RESTRICTION
 PHYSICAL EXERCISE
 RELAXATION AND BIOFEEDBACK THERAPY
 POTASSIUM THERAPY
 TOBACCO, COFFEE, AND OTHER FACTORS
MEKANISME ANTIHIPERTENSI
 Arterial pressure is the product of cardiac output and
peripheral vascular resistance
 Drugs lower blood pressure by actions on peripheral
resistance, cardiac output, or both
 Drugs may reduce the cardiac output by inhibiting
myocardial contractility or by decreasing ventricular
filling pressure
 Reduction in ventricular filling pressure may be
achieved by actions on the venous tone or on blood
volume via renal effects
 Drugs can reduce peripheral resistance by acting on
smooth muscle to cause relaxation of resistance
vessels or by interfering with the activity of systems
that produce constriction of resistance vessels (e.g.,
the sympathetic nervous system)
OBAT ANTI HIPERTENSI
 ANTI HIPERTENSI PILIHAN PERTAMA
1. DIURETIKA
2. BETA BLOKER
3. ACE INHIBITOR
4. Ca ANTAGONIS
5. ALFA BLOKER
 ANTI HIPERTENSI TAMBAHAN
1. ALFA 2 AGONIS
2. PENGHAMBAT ADRENERGIK
3. VASODILATOR
KLASIFIKASI OAH MENURUT
TEMPAT & MEKANISME KERJANYA
A. DIURETIK
1. Thiazid & sejenisnya
2. Diuretik kuat (loop diuretic)
3. Diuretik hemat kalium
B. OBAT SIMPATOLITIK
1. Adrenolitik sentral
2. Penghambat saraf adrenergik
3. Penghambat β adrenergik
4. Penghambat α adrenergik
5. Penghambat mixed (α,β) adrenergik
C. VASODILATOR
1. Arteri
2. Arteri & vena
D. Ca2+ ANTAGONIS
E. ACE INHIBITOR
F. ANTAGONIS RESEPTOR ANGIOTENSIN II
 A. DIURETIK
MEKANISME ANTIHIPERTENSI
• Ekskresi Na, Cl, air → volume plasma
& cairan ekstrasel ↓
• Curah jantung ↓ → normal
• Resistensi perifer ↓ → pemakaian
kronik
A. DIURETIK
1. Tiazid
 Obat tunggal hipertensi ringan-sedang
 Baik digunakan kombinasi dengan OAH
lain
 Efek menurun oleh AINS & gagal ginjal
 Murah, bisa 1x/hari, efek lama
 ES:
 Hipo: kalemia, Mg, Na
 Hiper: kalsemia, urisemia, glikemia, kolesterol
& trigliserida
 Gangguan seksual
 Toksisitas digitalis meningkat
A. DIURETIK
2. Diuretik kuat (furosemid)
 Efektif untuk hipertensi dengan gagal
ginjal & gagal jantung
 ES = tiazid kecuali hiperkalsemia

3. Diuretik hemat kalium (spironolakton)

 Diuretik lemah

 Hiperkalemia

 Efek hipotensi sebanding hidroklortiazid

B. SIMPATOLITIK
1. ADRENOLITIK SENTRAL

 Klonidin
 Resistensi perifer ↓, denyut jantung ↓
→ normal
 Pilihan II, kombinasi diuretika &
vasodilator
 Sediaan parenteral untuk krisis
hipertensi
 ES: sedasi, mulut kering, konstipasi,
retensi cairan, reaksi putus obat
(hentikan bertahap)
ADRENOLITIK SENTRAL

 Metildopa
 Resistensi perifer ↓, denyut jantung ↓ →
normal
 Pilihan I hipertensi pada ibu hamil
 Absorpsi tak lengkap, bioavailabilitas
 25-50%, efek hipotensi maksimal 6-8 jam
setelah dosis oral
 ES: sedasi, hipotensi postural, pusing,
sakit kepala (SSP), fenomena rebound
 Guanefasin & guanebenzen
 Efek & ES mirip klonidin
SIMPATOLITIK
2. PENGHAMBAT SARAF ADRENERGIK
 Prototip: reserpin
 Resistensi perifer ↓, denyut & curah jantung ↓
 Mula kerja lambat, masa kerja panjang
 Hipertensi ringan-sedang, kombinasi tiazid
 Murah 1x sehari (0,25 mg)
 ES: depresi mental, disfungsi seksual, mimpi
buruk, sekresi asam lambung, mual, muntah,
diare, mulut kering, ambang kejang turun,
efek ekstra piramidal, bradikardi
 Obat lain:
- Guanetidin, jarang digunakan karena ES
hipotensi ortostatik & diare
- Guanadrel, mirip guanetidin
SIMPATOLITIK
3. PENGHAMBAT β ADRENERGIK
 Prototip: propranolol
 Denyut jantung menurun, resistensi perifer ↓
 Menghambat pelepasan norepinefrin prasinap
 Menghambat sekresi renin (β1 ginjal)
 Efek sentral, pilihan I hipertensi ringan-sedang
 Efektif untuk usia muda
 Kardioselektif, ISA (+) kurang efektif untuk
MCI
 ES & kontra indikasi: bronkospasme, asma
bronkial, DM, gagal ginjal, penyakit vaskuler
SIMPATOLITIK
4. PENGHAMBAT α ADRENERGIK
 Alfa 1 selektif: prazosin, terazosin, doksazosin,
bunazosin
 Dilatasi arteriol → resistensi perifer ↓ → refleks
takikardi → normal
 Efek baik terhadap lipid darah (LDL & TG ↓, HDL
meningkat)
 Resistensi insulin menurun
 Tak ada interaksi dengan AINS
 Bronkodilatasi, relaksasi prostat, tidak
mengganggu aktivitas fisik
 ES: hipotensi ortostatik, sakit kepala, lelah,
edema, hidung tersumbat, nausea, dll
SIMPATOLITIK
5. KOMBINASI PENGHAMBAT α1, β ADRENERGIK

 Obat: labetalol, carvedilol

 Labetalol: ↓ resistensi vaskuler →
tekanan arteri ↓, CO tetap, IV
untuk hipertensi emergensi
 Carvedilol
 ratio α1-β adrenergik reseptor
antagonis = 1:10
 indikasi: hipertensi esensial & disfungsi
sistolik
C. VASODILATOR
 Hidralazin
 Dilatasi arteriol > Vena
 Kombinasi dengan diuretika & beta bloker
 ES: retensi Na & air, takikardi, sindroma lupus,
neuropati perifer, diskrasia darah, hepatotoksik
 Kontra indikasi: aneurisma aorta dissecting
 Minoksidil
 Permeabilitas K+ meningkat → hiperpolarisasi
 Poten untuk hipertensi refrakter
C. VASODILATOR
o Diazoksid
o Aktivasi kanal K+ (ATP) → hiperpolarisasi →
dilatasi arteriol → denyut jantung ↑
o Efektif: hipertensi ensepalopati, hipertensi
berat, pre eklamsia (IV)
o T½ 20-60 jam, efek hipotensi 4-20 jam
o Ekskresi: ginjal (1/3), hati (2/3)
o ES: retensi cairan & hiperglikemia, hipotensi,
takikardi, iskemia, mual, muntah, relaksasi
uterus
C. VASODILATOR
o Natrium nitroprusid
o NO mengaktifkan guanilat siklase otot polos
pembuluh darah → dilatasi arteriol & venule
o Pilihan untuk krisis hipertensi, lebih poten dari
diazoksid, hidralazin & minoksidil
o Infus IV , kerja maksimal 1-2 menit, cepat
hilang, dosis rata-rata 3 µg/kg/menit
o ES: hipotensi, mual, muntah, muscle twitching
o Efek toksik akibat konversi menjadi sianida &
tiosianat, diperburuk oleh hipoksemia arteri
pada penderita PPOK, hipertensi rebound
D. Ca2+ ANTAGONIS
I. Verapamil, Diltiazem, Nifedipin
II. Nikardipin, Isradipin, Felodipin, Amlodipin
 Golongan DHP (N, NK, I, F, A): vaskuloselektif,
resistensi perifer ↓, efek jantung (-), aman
dikombinasikan dengan beta bloker
 Bioavailabilitas oral rendah
 Metabolisme lintas pertama amlodipin tinggi
 Kadar puncak cepat dicapai → iskemik
miokardium
 Absorbsi amlodipin lambat, TD turun perlahan
 T½ pendek kecuali amlodipin 24 jam
 I & A tidak meningkatkan digoksin
 Metabolisme di hati, ekskresi di ginjal
 ES: hipotensi, edema perifer, bradiaritmia,
gangguan konduksi, konstipasi, penghentian
mendadak → infark miokard
E. ACE INHIBITOR
 Resistensi perifer ↓, tanpa refleks takikardi
 Efektif untuk hipertensi ringan-berat, hipertensi
mendesak
 Kombinasi diuretika (sinergis)
 Menurunkan resistensi insulin
 Efek hipotensi dilawan oleh AINS
 ES: batuk kering, rash, gangguan pengecapan,
hipotensi, edema angioneurotik, hiperkalemia,
GGA
 Kontra indikasi kehamilan trimester 2-3 (GGA,
fetus mati)
 Obat: Captopril, Enalapril, Lisinopril
E. ACE INHIBITOR
FARMAKOKINETIK
a. Captopril
 Bioavailabilitas 60-65%, diturunkan oleh
makanan → berikan 1 jam ac
 Ikatan protein plasma 30%, T½ 2,2 jam,
ekskresi melalui urin 40%
b. Enalapril → Enalaprilat (aktif)
 Bioavailabilitas 40%, tidak dipengaruhi oleh
makanan
 T½ 11 jam, ekskresi melalui urin
c. Lisinopril
 Bioavailabilitas 30-50%, tidak dipengaruhi oleh
makanan
 Tidak terikat protein plasma, T½ 12 jam,
ekskresi melalui urin
 MEKANISME KERJA ACE INHIBITOR
& ANTAGONIS RESEPTOR
Angiotensinogen Kininogen

Renin Kalikrein

sintesis
Prostaglandin ↑
Angiotensin I Bradikinin
1 Converting enzyme (kininase II)
Angiotensin II Inaktif
2
Vasokonstriksi Sekresi aldosteron
Vasodilator
Resistensi vascular Retensi air &
Perifer ↑ natrium ↑ Resistensi vaskuler
perifer menurun
Tekanan darah ↑
Tekanan darah ↓
1. Titik tangkap ACE inhibitor, 2. Titik tangkap antagonis reseptor
F. ANTAGONIS RESEPTOR
ARB (Angiotensin Reseptor Blocker)
Irbesartan (Avapro)R, Losartan (Cozar)R,
Valsartan (Diovan)R
o Mekanisme kerja: memblok pada tempat
pengikatan angiotensin II (reseptor AT
yang ada di pembuluh darah dan
jaringan)
o Efektifitas ~ ACE inhibitor
o Efek samping sedikit karena metabolisme
bradikinin dan prostaglandin tidak
terpengaruhi
SELECTION OF ANTIHYPERTENSIVE
DRUGS IN INDIVIDUAL PATIENTS
 Recent guidelines recommend diuretics as preferred initial
therapy for most patients with uncomplicated stage 1
hypertension who are unresponsive to nonpharmacological
measures.
 Patients are also commonly treated with other drugs:
receptor antagonists, ACE inhibitors/AT1-receptor
antagonists, and Ca2+ channel blockers.
 Patients with uncomplicated stage 2 hypertension will
likely require the early introduction of a diuretic and
another drug from a different class.
 Subsequently, doses can be titrated upward and additional
drugs added in order to achieve goal blood pressures
(blood pressure <140/90 mm Hg in uncomplicated
patients).
 Some of these patients may require four different drugs to
reach their goal.
SELECTION OF ANTIHYPERTENSIVE
DRUGS IN INDIVIDUAL PATIENTS

 A most important and high-risk group of patients

with hypertension are those with compelling
indications for specific drugs on account of other
underlying serious cardiovascular disease (heart
failure, post–myocardial infarction, or with high risk
for coronary artery disease), chronic kidney disease,
or diabetes (Chobanian et al., 2003).
 A hypertensive patient with congestive heart failure
ideally should be treated with a diuretic, receptor
antagonist, ACE inhibitor/AT1 receptor antagonist,
and spironolactone because of the benefit of these
drugs in congestive heart failure, even in the
absence of hypertension.
SELECTION OF ANTIHYPERTENSIVE
DRUGS IN INDIVIDUAL PATIENTS

 ACE inhibitors/AT1 receptor antagonists should be

first-line drugs in the treatment of diabetics with
hypertension in view of their well-established
benefits in diabetic nephropathy.
 A hypertensive patient with symptomatic benign
prostatic hyperplasia might benefit from having an 1
receptor antagonist as part of his therapeutic
program, since 1 antagonists are efficacious in both
diseases.
 A patient with recurrent migraine attacks might
particularly benefit from use of a receptor antagonist
since a number of drugs in this class are efficacious
in preventing migraine attacks.
SELECTION OF ANTIHYPERTENSIVE
DRUGS IN INDIVIDUAL PATIENTS

 Patients with isolated systolic

hypertension (systolic blood
pressure >160 mm Hg and diastolic
blood pressure <90 mm Hg) benefit
particularly from diuretics and also
from Ca2+ channel blockers.
SELECTION OF ANTIHYPERTENSIVE
DRUGS IN INDIVIDUAL PATIENTS

 These considerations have been addressed with

regard to patients with hypertension that need
treatment to reduce long-term risk, not patients in
immediately life-threatening settings due to
hypertension.
 Rapid reduction in blood pressure has considerable
risks for the patients; if blood pressure is decreased
too quickly or extensively, cerebral blood flow may
diminish due to adaptations in the cerebral
circulation that protect the brain from the sequelae
of very high blood pressures.