OBAT ANTIHIPERTENSI

dr. M. Fadhol Romdhoni, M.Si

Tensimu berapa ?

130

Banyakan aku
donk, 200
Sites of action of the
major classes of
antihypertensive drugs
 Penggolongan antiHT
berdasarkan tempat kerjanya
Sistem Saraf Simpatis di :

Sentral (CNS) : clonidin, methyldopa

Ganglion : heksamethonium, trimethapan

Ujung saraf : reserpin, guanethidin

Reseptor adrenergik : Prazosin(1 blocker), Propanolol

( blocker), atenolol (1 blocker)

Ginjal : Diuretik

Otot polos vaskuler : CCB, Vasodilator

RAAS : ACE inhibitor, ARB, Direct Renin Inhibitor

 DIURETIK
Mekanisme kerja Ada 3 kelas diuretik utk HT

Thiazide
Hidrochlorothiazide (HCT),
Chlorothalidone
Loop diuretics
Furosemide, Torsemide,
Bumetanide
Diuretik Hemat K+
Amiloride, Triamterene,
Spironolacton
Diuretik
 DIURETIK
Mekanisme kerja : ES :
- ekskresi Na & H2O - dizziness,
Efek pd CVS : - electrolit imbalance
- akut : COP - hypokalemia,
- kronik : TPR ,COP N
- hyperlipidemia,
KI :
- hyperglycemi(Thiazid)
hypersensitivity,
compromised kidney - gout
function, Tx cardiac glycosides
(K+ effects),
hypovolemia,hyponatremia
Sympatholitics Agents
 Blok Adrenergik di CNS
(CNS agents)
Site of action : CNS medullary ,
cardiovasc centers ES : dry mouth, sedasi,
impotence
Mekanisme kerja :
KI : mental depression
- agonis R/ -2 di CNS : NOT 1st line drug,
Clonidine, Guanabenz, Prolong used retensi Na
Guanfacine & air sering digunakan
bersama diuretic
Aktivasi R/-2 di medulla
stop mendadak
NE release dr SSP rebound SymNS TD
peripheral sympathetic Methlydopa : DOC in
activity vasc tone pregnancy
vasodilation TPR .
- membentuk neurotransmiter
palsu : Methyldopa
 Mekanisme Kerja
Clonidin dan Methyldopa
 Blok Adrenergik
di Ganglion Otonom
Contoh : Hexamethonium
Mekanisme kerja :
memblok reseptor nikotinik di ganglion
Blok Adrenergik di Ujung Saraf

Contoh : Reserpin, inhibit uptake of NE into

Guanethidin storage vesicle (also DA,
Mekanisme kerja : 5-HT) leads to
- menghambat transport depletion of transmitter
NE ke vesikel sinap : stores (peripheral & CNS
reserpin action)
ES: sedation, mental
- mengosongkan dan
memblok pelepasan NE depression, Parkinsonism,
dari tempat gastric acid secretion
penyimpanannya : ulcer
guanethidin
 Blok Adrenergik di
Reseptor Adrenergik
 Blok Adrenergik di Reseptor - 1

Contoh : Prazosin, Oxazosin, Terazosin

Site of action : otot polos vaskuler perifer

Mekanisme kerja :
memblok reseptor -1 relaksasi otot polos
vaskulerdilatasi vaskulerresistensi vaskuler .
Efek pd COP <<</(-)
 ES : nausea, postural reflex tachycardia (-);
hipotensi s.d synkope Awali dg dosis kecil
KI : hipersensitif Pilihan utk : pt dg DM,
asma dg / tanpa
hiperkolesterol, mild-
moderate HT
Sering dikombinsi dg
diuretic, antagonist
 Blok Adrenergik di Reseptor-

blocker non selektif : Propranolol

1blocker selektif : Atenolol, Metoprolol
Mekanisme kerja :
Blok reseptor 1 di jantung HR dan kontraktilitas jantung
CO TD
Blok reseptor 1 di ginjal release renin
Blok reseptor 2 presinap release NE
Blok reseptor di CNS aliran simpatis tonus vaskuler
Efek samping :
insomnia, unpleasant dreams (bisa nembus BBB), erectile
dysfunction, akral dingin (hambat vasodilatasi 2), TG dan HDL
(hambat metabolisme lemak di hepar),arritmia, hipoglikemia
Kontraindikasi :
asthma,bradycardia berat, AV block, severe unstable LV failure,
diabetes
 Vasodilator

Calcium Channel Blocker

Vasodilator Oral : hidralazin, minoksidil
Vasodilator parenteral
 Calcium Channel Blocker

Contoh : Nifedipine, Verapamil, Diltiazem

Mekanisme kerja : memblok kanal Ca type-L hambat
influk Ca ke intrasel kadar Ca intrasel *
kontraktilitas sel otot polos vaskular vasodilatasi
resistensi perifer
*pd otot jantung kontraktilitas, HR
 Vasodilator : release NO
hidralazin (p.o),
EDRF / Nitric oxide (NO) /
cGMPinvolvement
dilate arterioles but not veins
TPR, BPreflex tachycardia
ES :
-reflectory symp activation
-headache, nausea, sweating,
flushing
-palpitations, HR angina
-lupus reaction (mainly in slow
acetylators)
nitroprussid (i.v)
melepaskan NO stimulasi
guanilil siklase cGMP di otot
polos relaxation of vascular
smooth
dilates arterial ( TPR) and
venous vessels
venous return , reflex tachy
Indikasi : hypertensive
emergency, acute CHF
ES : metab acidosis,
arrhythmias, severe hypotensio
 Vasodilator : open K-channel
minoksidil (p.o),
membuka kanal K+
hiperpolarisasi , stabilisasi
membran saat resting
potensial relaksasi otot
polos vask
dilates arterioles, not veins
ES : reflex sympathetic
stimulation, fluid retention
(value in combination
therapy), hypertrichosis
diazoksid (i.v)
dilates arteriolar vessels
TPR reflex HRCO
inhibits insulin release (via
opening K beta cell
membrane)
similar structure as
thiazidediuretics but no
diuretic effect
Sistem Renin-Aldosteron Angiotensin

29

29
Katzung 9ed
 ACE Inhibitor

Contoh : Captopril , Enalapril , Quinapril ,

Ramipril
Mekanisme kerja :
hambat Angiotensin Converting Enzyme shg :
hambat pembentukan AII AII merupakan salah
satu vasokonstriktor kuat.
kadar bradikinin menstimulasi release NO dan
prostasiklin vasodilatasi.
Keuntungan : respon kompensasi (-)
mencegah remodelling jantung dan vaskuler
Angiotensin II Receptor Blocker (ARB)

Contoh : Irbesartan, Losartan , Valsartan

Mekanisme kerja : menduduki R/ AII (AT1).
AT1 tdpt di otot polos vaskuler, korteks adrenal, ginjal, dan otak.
Obat ini tidak mempunyai efek pada metabolisme bradykinin.
Menghambat AII lebih kuat dp ACE inhibitors karena ada enzim
lain yang juga bisa menghasilkan AII.
ES ACE- Inhibitor & ARB
ACE INHIBITOR ARB
 Direct Renin Inhibition
Inhibits the Entire Renin System1-4 Aliskiren
Class PRA Ang I Ang II

ACEI

ARB

Direct Renin Inhibitor (DRI)

Increased peptide levels have not been shown to overcome the blood pressurelowering effect of these agents.
ACEI, angiotensin-converting enzyme inhibitor; Ang, angiotensin; ARB, angiotensin receptor blocker;
PRA, plasma renin activity.

1. Johnston CI. Blood Press Suppl. 2000;1:9(suppl 1):9-13.

2. Widdop RE et al. Hypertension. 2002;40:516-520.
3. Fabiani ME et al. Angiotensin II Receptor Antagonists. 2001:263-278.
4. Lin C et al. Am Heart J. 1996;131:1024-1034.
 JNC 7:
Algorithm for Treatment of Hypertension

Prehypertension (SBP 120-139 mm Hg or DBP 80-89 mm Hg)

LIFESTYLE MODIFICATIONS

Not at Goal BP (<140/90 mm Hg, or <130/80 mm Hg for patients with

Prehypertension
diabetes or chronic kidney disease)

INITIAL DRUG CHOICES

Without Compelling Indications With Compelling Indications

Stage 1 Hypertension Stage 2 Hypertension Drug(s) for compelling indications

(SBP 140-159 or DBP 90-99 mm Hg)
Thiazide-type diuretics for most;
may consider ACEI, ARB, BB,
CCB, or combination.
(SBP 160 or DBP 100 mm Hg)
Other antihypertensive drugs
2-drug combinations for most
(diuretic, ACEI, ARB, BB, CCB)
(usually thiazide-type diuretics and
as needed.
ACEI, or ARB, or BB, or CCB).

If not at goal BP, optimize dosages or add additional drugs until

goal BP is achieved. Consider consultation with hypertension specialist.

AdaptedPartners in Healthcare
from NHBPEPCC. 2003. NIH Publication No. 03-5233. 36
Education, LLC 2009
 Compelling indications:
Ischemic Heart Disease
Recent ST Segment Elevation-MI or non-
ST Segment Elevation-MI
Left Ventricular Systolic Dysfunction
Cerebrovascular Disease
Left Ventricular Hypertrophy
Non Diabetic Chronic Kidney Disease
Renovascular Disease
Smoking
 JNC 7: Classification and Management of
Blood Pressure for Adults
Initial Drug Therapy

Without With
BP SBP* DBP* Lifestyle Compelling Compelling
Classification (mm Hg) (mm Hg) Modification Indications Indications
Normal <120 and <80 Encourage
Drug(s) for
Prehypertensio No antihypertensive compelling
120139 or 8089 Yes
n drug indicated. indications.
Thiazide-type diuretic
for most. May Drug(s) for
Stage 1
140159 or 9099 Yes consider ACEI, ARB, compelling
hypertension indications.
BB, CCB,
or combination.
Two-drug
combination Other
Stage 2 for most (usually antihypertensive
160 or 100 Yes thiazide-type diuretic drugs (diuretic,
hypertension
and ACEI or ARB or ACEI, ARB, BB,
JNC 7. May 2003. NIH publication 03-5233. BB or CCB). CCB) as needed.
39

39
 JNC 7: Compelling Indications for Individual
Antihypertensive Drug Classes
Recommended Drugs
Compelling Aldo
Indication* DIURETIC BB ACEI ARB CCB ANT
Heart failure
Post-MI
High coronary disease
risk

Diabetes
Chronic kidney disease
Recurrent stroke
prevention

*Compelling indications for antihypertensive drugs are based on benefits from outcome studies or existing clinical guidelines; the compelling indication is managed parallel with the BP.
ACEI = angiotensin converting
Partners inenzyme inhibitor; ARB = angiotensin receptor blocker; Aldo ANT = aldosterone
Healthcare 40antagonist; BB = beta-blocker; CCB = calcium channel blocker.
Adapted from NHBPEPCC.
Education, 2003. NIH 2009
LLC Publication No. 03-5233.
 Perkembangan Terapi Antihypertensi

Effective but As effective and As effective and even

poorly tolerated better tolerated better tolerated
1940s 1950 1957 1960s 1970s 1980s 1990s 2007

Direct ACE ARBs

vasodilators inhibitors
Peripheral Thiazides -blockers
sympatholytics diuretics
Central 2
Ganglion
agonists Calcium
blockers
antagonists-
Calcium
Veratrum DHPs
antagonists-
alkaloids
non DHPs
-blockers
Penggunaan Dual Combinations

Kolom 1 Kolom 2
Thiazide diuretic Beta adrenergic blocker
Long-acting calcium channel ACE Inhibitor
blocker *
ARB

Tujuan : meningkatkan efek hipotensif

kombinasikan obat pada kolom 1 dengan obat pd kolom 2
 Terapi Antihipertensi Kombinasi

1990
1950 1960 1970 1980
s-
s s s s
2000s

Ser-Ap-Es
(reserpine/hydralazine/ ACE inhibitor/thiazide
hydrochlorothiazide)
Methyldopa/thiazide

Butiserpine (reserpine/butalbital) ACE inhibitor/CCB

Hyphex ARB/thiazide
(hexamethonium/hydralazine) Thiazide/K+-sparing Low-dose
Hypotensin A, B, & C diuretic blocker/thiazide
(pentolinium/hydralazine/resperi blocker/thiazide
ne) Clonidine/thiazide
Renir (reserpine/ephedrine)
Verapene (rauwolfia/veratrum)
Penyebab Kurangnya Respon terhadap
Terapi Hipertensi
Pseudoresisten : salah diagnosa, pseudohipertensi
pada lansia, salah pemeriksaan
Penderita tidak patuh dalam menjalani terapi (biaya,
instruksi tdk jelas, ESO, pemakaian tdk praktis)
Volume overload (asupan garam berlebih, kerusakan
ginjal yg berat, retensi cairan akibat penurunan TD,
terapi diuretik tidak adekuat.
Kondisi tertentu : perokok, obesitas, resistensi
insulin, peminum alkohol, serangan cemas/panik
Obat : dosis terlalu rendah, kombinasi tdk cocok
Interaksi obat : simpatomimetik, nasal decongestan,
apetite suppressan, kokain, kafein, kontrasepsi oral,
steroid adrenal,antidepressan, NSAID
Mekanisme Gagal Terapi Hipertensi
akibat Respon Kompensasi
Krisis Hipertensi

Hipertensi Gawat (Emergency)

Hipertensi Darurat (Urgency)
Hipertensi Emergensi
 Penatalaksanaan HT Emergensi

TD harus turun dalam hitungan menit, ok

ada ancaman kerusakan target organ
Obat parenteral (i.v):
- sodium nitroprussid
- nitrogliserin
- diltiazem HCl
- hidralazin
 Hypertensive Emergency
Drug Dose Onset Duration Adverse Effects Special Indications
(min) (min)
Sodium 0.2510 mcg/kg/min Immediate 12 Nausea, vomiting, muscleMost hypertensive
nitroprusside intravenous infusion twitching, sweating, emergencies; caution
(requires special thiocyanate and cyanide with high intracranial
delivery system) intoxication pressure, azotemia, or in
chronic kidney disease
Nicardipine 515 mg/h 510 1530; may Tachycardia, headache, Most hypertensive
hydrochloride intravenous exceed 240 flushing, local phlebitis emergencies except
acute heart failure;
caution with coronary
ischemia
Clevidipine 1-2 mg/h intravenous 2-4 5-15 Headache, syncope, Most hypertensive
butyrate infusion; may double dyspnea, nausea, vomiting emergencies except
dose every 90 sec severe aortic stenosis;
initially; maximum: caution with heart
32 mg/h; typical failure
maintenance dose: 4
to 6 mg/h
Fenoldopam 0.10.3 mcg/kg/min <5 30 Tachycardia, headache, Most hypertensive
mesylate intravenous infusion nausea, flushing emergencies; caution
with glaucoma
49
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com/
 Hypertensive Emergency
Drug Dose
Nitroglycerin 5100 mcg/min
intravenous infusion
Hydralazine 1220 mg intravenous 1020
hydrochloride 1050 mg intramuscular 2030
Labetalol 2080 mg intravenous
hydrochloride bolus every 10 min; 0.5
2.0 mg/min intravenous
infusion
Esmolol 250500 mcg/kg/min
hydrochloride intravenous bolus, then
50100 mcg/kg/min
intravenous infusion;
may repeat bolus after 5
min or increase infusion
to 300 mcg/min
Onset Duration Adverse Effects Special
(min) (min) Indications
25 510 Headache, vomiting, Coronary
methemoglobinemia, ischemia
tolerance with prolonged use
60240 Tachycardia, flushing, Eclampsia
240360 headache vomiting,
aggravation of angina
510 180360 Vomiting, scalp tingling, Most hypertensive
bronchoconstriction, dizziness, emergencies
nausea, heart block, except acute
orthostatic hypotension heart failure
12 1020 Hypotension, nausea, Aortic dissection;
asthma, first-degree heart perioperative
block, heart failure

50
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com/
 Hipertensi Urgensi

Penanganan
- dalam hitungan jam
- Obat HT diberikan secara per oral, sublingual
 Monitoring Antihypertensives

Class Parameters
Diuretics blood pressure
BUN/serum creatinine
serum electrolytes (K+, Mg2+, Na+)
uric acid (for thiazides)
-Blockers blood pressure
heart rate
Aldosterone antagonists blood pressure
ACE inhibitors BUN/serum creatinine
Angiotensin II receptor blockers serum potassium
Direct Renin inhibitors
Calcium channel blockers blood pressure
heart rate

52
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy:A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com/
RESUME
Horee.. Selesaiii