ANTIHIPERTENSI

Dr. M. Yulis Hamidy, M.Kes., M.Pd.Ked

REGULASI TEKANAN DARAH

REFLEKS BARORESEPTOR Denyut jantung Parasimpatis

CO

Kontraktilitas miokard Volume Darah Kapasitas vena

Isi sekuncup Alir balik vena Tonus arteri & arteriol

Simpatis

TEKANAN DARAH Resistensi Pmblh darah Viskositas darah

Resistensi Perifer

Elastisitas dinding Pembuluh darah SEKRESI RENIN

RAA

KRITERIA HIPERTENSI

ETIOLOGI HIPERTENSI

90% tidak diketahui penyebabnya hipertensi esensial 10%:

Hipertensi esensial: - Faktor genetik berperan besar - Faktor eksternal:

Penyakit Ginjal Tumor Endokrin

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. 2. 3. 4. 5.

DIURETIKA BETA BLOKER ACE INHIBITOR Ca ANTAGONIS ALFA BLOKER ALFA 2 AGONIS PENGHAMBAT ADRENERGIK VASODILATOR

ANTI HIPERTENSI TAMBAHAN

1. 2. 3.

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 adrenergik 4. Penghambat adrenergik 5. Penghambat mixed (,) 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:

Gangguan seksual Toksisitas digitalis meningkat

Hipo: kalemia, Mg, Na Hiper: kalsemia, urisemia, glikemia, kolesterol & trigliserida

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 Efek & ES mirip klonidin

Guanefasin & guanebenzen

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 ADRENERGIK

Prototip: propranolol Denyut jantung menurun, resistensi perifer Menghambat pelepasan norepinefrin prasinap Menghambat sekresi renin (1 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 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 1, ADRENERGIK

Obat: labetalol, carvedilol Labetalol: resistensi vaskuler tekanan arteri , CO tetap, IV untuk hipertensi emergensi Carvedilol
ratio

1- 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 Permeabilitas K+ meningkat hiperpolarisasi Poten untuk hipertensi refrakter

Minoksidil

C. VASODILATOR
o

Diazoksid
o

o o o

Aktivasi kanal K+ (ATP) hiperpolarisasi dilatasi arteriol denyut jantung Efektif: hipertensi ensepalopati, hipertensi berat, pre eklamsia (IV) T 20-60 jam, efek hipotensi 4-20 jam Ekskresi: ginjal (1/3), hati (2/3) ES: retensi cairan & hiperglikemia, hipotensi, takikardi, iskemia, mual, muntah, relaksasi uterus

C. VASODILATOR
o

Natrium nitroprusid
o

o o

NO mengaktifkan guanilat siklase otot polos pembuluh darah dilatasi arteriol & venule Pilihan untuk krisis hipertensi, lebih poten dari diazoksid, hidralazin & minoksidil Infus IV , kerja maksimal 1-2 menit, cepat hilang, dosis rata-rata 3 g/kg/menit ES: hipotensi, mual, muntah, muscle twitching 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 T 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%, T 2,2 jam, ekskresi melalui urin 40% b. Enalapril Enalaprilat (aktif) Bioavailabilitas 40%, tidak dipengaruhi oleh makanan T 11 jam, ekskresi melalui urin c. Lisinopril Bioavailabilitas 30-50%, tidak dipengaruhi oleh makanan Tidak terikat protein plasma, T 12 jam, ekskresi melalui urin

MEKANISME KERJA ACE INHIBITOR & ANTAGONIS RESEPTOR

Angiotensinogen Renin Kalikrein Kininogen

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, postmyocardial 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.