Anti-hypertensive agents

Aznan Lelo
Tri Widyawati
Dept. of Pharmacology & Therapeutic,
School of Medicine
Universitas Sumatera Utara
CVS 2009
 Hipertensi
Hipertensi adalah peningkatan tekanan darah di atas
140/90 mmHg secara terus- menerus.
Klasifikasi tekanan darah menurut JNC VII (The Joint
National Committee VII)

Klasifikasi TD TD sistolik TD diastolik

Normal <120 mmHg Dan >80 mmHg
Prehipertensi 120-139 mmHg Atau 80-89 mmHg
Hipertensi stage 1 140-159 mmHg Atau 90-99 mmHg
Hipertensi stage 2 ≥ 160 mmHg Atau ≥100 mmHg
 Blood Pressure Regulation

Cardiac output X Peripheral Resistence

LOCAL
Heart rate Ionic
CARDIAC Auto reg
BARORECEPTOR Contractility
NERVOUS
RENAL FLUID VOLUME SYMPATHETIC
• Sodium
• Minerokortikoid Constrictor Dilator
alpha beta
HUMORAL

VASOLIDATOR VASOCONSTRICTOR
Prostaglandins, KININ ANGIOTENSIN, Catechols
 Patho-physio-pharmacology
of hypertension
CNS BR

α2 β1 Heart
Sympathetic BP
Nerve
Ca++
α1 BV

Ag Retention
Kidney
Na & water
β1 Renin
A-I A-II Aldosteron
ACE
Anti-hypertensive agents
 Diuretic thiazides
 Alfa-blockers
 Beta-blockers
 ACE-inhibitors
 Angiotensin receptor blockers (ARB)
 Calcium antagonists
 Vasodilators, etc
 Antihypertensive agents
Diuretic Beta- Alfa- ACE- A-II Ca-Anta- etc
blocker blocker Inhibitor blocker gonist
HCT Propra- Prazosin Captopril Losartan Nifedipin Metil-
nolol dopa
Bume- Atenolol Doxa- Enalapril Cande- Diltiazem Cloni-
tanid zosin sartan dine
Furo- Labetalol Tera- Lisinopril Valsartan Vera- Hydra-
semid zosin pamil lazine
Spirono- Meto- Benaze- Telmi- Amlo- Nitro-
lacton prolol pril sartan dipin Prusside
Triam- Nadolol Fosino- Felo- Diazo-
teren pril dipin xide
Timolol Quinapril Nicar- Mino-
dipin xidil
Ramipril Nisol-
dipin
PHARMACOLOGY HYDROCHLOROTHIAZIDE

: Na & water retention, blood volume, COP

Combination with other antihypertensive:
ACE-I, beta-blocker
Mengganggu balans elektrolit, kadar K & Mg turun
Hyperuricemia (70%)
Hyperglycemia (10%)
JANGAN DIGUNAKAN pada penderita dengan:
• Diabetes
• Hyperlipidemia
 Diuretics as
antihypertensive agents
Potency Diuretics Drugs
++++ Thiazides and Hydrochlorothiazide
thiazides-like diuretics
Chlorthalidone
Indapamide
Metolazone
++ Aldosterone antagonists Spironolactone
+ Potassium sparing Amiloride
diuretics Triamterene
+ Loop diuretics Fuosemide
Bumetanide
Ethacrynic Acid
Torsemide
FARMAKOLOGI BETA-BLOCKER
Menurunkan:
HR & SV, COP
Sekresi RENIN, angiotensin II, aldosteron, dan
volume darah
Sering dibandingkan dengan PROPRANOLOL
Lebih efektif pada kulit putih dan dewasa muda
PROPRANOLOL, METOPROLOL mengalami
first-pass metabolism
JANGAN DIGUNAKAN pada penderita dengan:
• ASMA, PPOM
• bradikardi, gangguan seksual
Beta Blockers
 Mechanism of action
Beta Blocker

↓ activation of
Beta Blocker β1 receptor in ↓ CO
heart

↓BP
↓ Renin ↓ angiotensin II ↓PR

↓ aldosteron

↓ Na and
water ↓ blood
retention volume
 The Renin-Angiotensin system in
the development of high blood pressure
Non-ACE pathways ACE pathways
Angiotensinogen Kininogen
Non-renin
enzymes Renin Kallikrein

Angiotensin I Bradykinin
CAGE
t-PA Chymase ACE
Cathepsin G Cathepsin G
Chymase
Angiotensin II Inactive
Cathepsin G
peptides

AT1 AT2 NO
PG
• vasoconstriction • Vasodilation (?) vasodilation
• aldosterone release, Na • Bradykinin, NO and
and fluid retention cGMP release
• cell proliferation, • Antiproliferation,
hypertrophy apoptosis stimulation,
• Sympathetic activation tissue regeneration
CAGE= Chymotrypsin like
Adapted from Hollerberg NK. Am J Med Care,1998;A(suppl7)5384-5387
Angiotensin Generating Enzyme
FARMAKOLOGI ACE-INHIBITOR
Menurunkan: produksi angiotensin,
• Output sistem saraf simpatis
• Vasodilatasi
• Retensi Na & air, volume darah, COP
Meninggikan: Kadar bradikinin -> batuk kering
Sering digunakan pada penderita dengan CHF
menimbulkan FIRST-DOSE SYNCOPE
Mengganggu balans elektrolit, HYPERKALEMIA
JANGAN DIGUNAKAN bersamaan dengan:
• SPIRONOLAKTON
• OAINS
ACE-inhibitor
Golongan sulfhidril : captopril
Golongan karboksil :
- prodrug: enalapril – enalaprilat
perindopril – perindoprilat
ramipril – ramiprilat
- active : lisinopril
Golongan fosforil : fosinopril

Masa kerja: = Singkat : captopril

= Panjang : lisinopril
Angiotensin Receptor Blocker
(ARB)
AII-A
(Angiotensin II Receptor Antagonist)
 AT1 Antagonist
(Angiotensin Receptor Blockers)
• Commonly substitued for ACE-I in
patients with drug induced cough
 Pharmacodynamic of ARB sartans

Lo- Val- Irbe- Cande- Telmi- Epro-

Initial dosage
(mg/day)
50 80 150 8-16 40 600
Dosing frequency q.d. / b.i.d. q.d. q.d. q.d. / b.i.d. q.d. q.d.
Maintenance
dosage (mg/day)
50-100 80-320 150-300 8-32 20-80 600-?
Dose-response No data
plateau (mg)
50 80 300 32 40-80
T:P ratio (%) 58-78 69-76 > 60 80 ≥ 97 67
50-100 mg 80-160 mg ≥ 150 mg 8-16 mg 20-80 mg 600 mg
Equivalent No data
dosage (mg)
50 80 150 8 40
Dosage adjustment
Clcr < 30 ml/min No No No No No No
Hepatic failure initial dose No No No No No
by 50%
Song JC, White CM. Pharmacologic, pharmacokinetic, and therapeutic differences
among Angiotensin II Receptor Antagonists. Pharmacotherapy 20(2):130-9, 2000
 Pharmacokinetic of ARB sartans
Lo- Val- Irbe- Cande- Telmi- Epro-
Candesartan
Prodrug No No No cilexetil
No No
Active Candesartan
EXP3174 No No No No
metabolite

Elimination
Fecal (%) 60 83 80 67 > 98 90
Urinary (%) 35 13 20 33 7
Onset of BP 2-3 2 2 2-4 3 No data
effect (hrs)
Maximum BP 6 4-6 3-6 6-8 3-9 3
effect (hrs)
Hemodialyzable No No No No No No
Drug interaction
Food-drug No No No No No No
Drug-drug Rifampin, Digoxin
fluconazole
 FARMAKOLOGI Ca-ANTAGONIST

Menghambat masuknya ion Ca ke dalam sel otot

Vasodilatasi
Sering dikombinasikan dengan beta-blocker
Mengganggu kontraksi otot:
• Konstipasi (10%)
• Kelelahan/fatigue
• Edema mata kaki
Verapamil JANGAN DIGUNAKAN pada penderita
dengan CHF
t1/2 paling panjang: amlodipin, felodipin
 Calcium Antagonist
 Derivat DIHYDROPYRIDINE
– Masa kerja singkat : nifedipin
– Masa kerja panjang : amlodipin, felodipin
 Derivat BENZOTHIAZEPINE (ex. diltiazem)
 Derivat DIPHENYLALKYLAMINE (ex. verapamil,
gallopamil)

Basic Actions of Ca Antagonist on CVS

Vaso- Suppression
Drug dilation automaticity conductivity
contractility (SA) (AV)
Nifedipine 5 1 1 0
Diltiazem 3 2 5 4
Verapamil 4 4 5 5
 Farmakokinetik
- ‘ First-pass metabolism’ dan protein binding tinggi
-Sebagian besar CCB digunakan untuk mengatasi angina  aktif dalam waktu 30 menit setelah
pemberian oral (t1/2 beberapa jam)

Obat Bioav oral Mula kerja (rute) T1/2 (jam) Disposisi

> 90%%pp, metab.
Amlodipine 65-90 Tidak ada data 30-50
Luas
Felodipine > 90% pp, metab
15-20 2-5 jam (oral) 11-16
luas

90% pp, dimetab

jadi lactic acid
< 1 menit (IV), 5-20 menit
Nifedipine 45-70 4 80% obat &
(sublingual,oral)
metabolit dieksresi
dlm urin

>99% pp, metab

Bepridil 60 60 menit (oral) 24-40
luas

< 3 menit, > 30 menit 70-80% pp, eksresi

Diltiazem 40-65 3-4
(oral) feses

90% pp, 70%

<1,5 menit (IV), 30 menit
Verapamil 20-35 6 eliminasi di ginjal,
(oral)
15 % oleh sl. cerna
 Table. Relative Cardiovascular Effects of Prototypical Calcium Channel Blockers
(adapted from Goodman and Gilman (9th ed.) and Massie, Am. J. Cardiol. 80(9A)23I-32I(1997)).

V’dilatasi Penekanan kontraktilitas Penekanan Penekanan

Senyawa
koroner jantung SA Node AV Node

Verapamil ++++ ++++ +++++ +++++

Diltiazem +++ ++ +++++ ++++

Nifedipine +++++ + + 0

Nicardipine +++++ 0 + 0

Bepridil (+++) (+++) (+++++) (++++)

Mibefradil (++++) (0) (++++) (++++)

Bepridil , similar in structure to verapamil, has a longer duration of action but greater
cardiovascular toxicity than the other CCB
 Cardiac vs. Vascular
Selectivity of Ca Antagonist
 FARMAKOLOGI ALFA-BLOCKER

Berkompetisi dengan Nadr pada reseptor alfa-1

Menurunkan resistensi pembuluh darah perifer
Reflex takikardi pada pemberian pertama
Sering dikombinasikan dengan beta-blocker
Mengganggu kontraksi otot polos pembuluh darah
• postural hypotension
• first-dose syncope
NILAI PLUS bila DIGUNAKAN pada penderita
dengan BPH (benign prostate hypertrophy)
FARMAKOLOGI SIMPATOLITIK SENTRAL

CLONIDIN
Menghambat bebasnya NAdr dari ujung syaraf
Tidak mengganggu aliran darah ginjal
Sering dikombinasikan dengan diuretika
• sedasi
• kering mukosa hidung
HATI-HATI dengan REBOUND PHENOMENON

ALFA-METHYLDOPA
 NORADRENALIN

Re-uptake

2 PRE-
SYNAP
- +
2

2 COMT
2
POST-SYNAPTIC
EFFECTOR

= noradrenalin
FARMAKOLOGI VASODILATOR

HYDRALAZIN
MINOXIDIL
• Vasodilatasi langsung
• Reflex takikardi pada pemberian pertama
Sering dikombinasikan dengan beta-blocker

SODIUM NITROPRUSSIDE
DIAZOXIDE
LABETALOL (alfa- dan beta- blocker)
 Activators of NO/guanylate cyclase pathway
Hydralazine ?
1 – Adrenoreceptor Nitroprusside
Nitroglycerin Ca2+ - channel blockers
antagonists
Doxazosin Dihydropiridines
Prazosin Verapamil
NO Diltiazem

Ca2+

VSMCs

Ang II receptor
antagonists K+
Losartan K+ - channels activators
Minoxidile
Diazoxide Peripheral
Vasodilators
 K+ Channel Openers
• Arterial vasodilator
• Minoxidil and hydralazine
• Adverse effects: (more severe:minoxidil )
- retention of Na+ and H2O
- reflex tachycardia
• Hydralazine:
- tolerance
- tacyphylaxis
- a drug-induced lupus syndrome
 African Americans with HTN
Minority Populations:
• Elderly African-Americans (>60 yo) show best responses to
monotherapy with Diuretics or CCB, and decreased response with B-
Blockers, ACE-Inhibitors, or ARBs compared.
• Angioedema from ACE-I occurs 2 – 4 times more frequently in the
African-American population
 Causes of
Resistant Hypertension
 Improper BP measurement
 Excess sodium intake
 Inadequate diuretic therapy
 Medication
• Inadequate doses
• Drug actions and interactions (e.g., NSAIDs, illicit drugs,
sympathomimetics, oral contraceptives)
• Over-the-counter (OTC) drugs and herbal supplements
 Excess alcohol intake
 Identifiable causes of HTN
First-line antihypertensive drugs
Diuretics

β– blockers ACE inhibitors

α1–blockers Ca antagonists

Angiotensin II antagonists
 Combination Therapies
 -adrenergic blockers and diuretics
 ACE inhibitors and diuretics
 Angiotensin II receptor antagonists and
diuretics
 Calcium antagonists and ACE inhibitors
 Other combinations
 Obat vasodilator sebagai
antihipertensi NHNH2

1. Hidralazin  mendilatasi arteriol, bukan vena. N

2. Minoksidil  vasodilator oral yang mendilatasi

arteriol, bukan vena.
3. Diazoksid  vasodilator arteriol parenteral efektif dgn masa
kerja relatif panjang.

4. Natrium nitroprusid  vasodilator parenteral yg sangat kuat. NO+

Mendilatasi arteriol dan vena. CN- CN-

Fe+
+
CN- CN-

CN-
 Farmakokinetik
Hidralazin Minoksidil Diazoksid Natrium
nitroprussid
Absorbsi Cepat setelah Baik di saluran Intravena lebih Intravena lebih
pemberian oral, cerna baik (digunakan baik (digunakan
puncak plasma pd kedaruratan pd kedaruratan
level 1-2 jam hipertensi) hipertensi)
Distribusi Berikatan Tidak Berikatan dengan Ke dalam cairan
dengan protein berikatan albumin, waktu
plasma 87%, dengan paruh 24 jam ekstra seluler
waktu paruh 3-7 protein, waktu
jam paruh 4 jam
Metabolisme First pass Terutama Tidak diketahui Dengan cara
metabolisme dengan secara jelas ambilan ke sel-sel
konjugasi dalam darah merah,
dihati hati, metabolit metabolitnya
aktifnya minoxidil cyanide dan
thiocyanate
sulfate

Ekskresi Ginjal Ginjal 1/3 ginjal Lambat diginjal

2/3 metabolisme
hati
 Farmakodinamik
Hidralazin Minoksidil Diazoksid Natrium
nitroprusid

Indikasi Hipertensi essensial Hipertensi Hipertensi darurat, Kedaruratan

akselerasi, Hipertensi hipertensi, penyakit
Hipertensi maligna Ensefalopati, jantung kongestif
Hipertensi maligna

Mekanisme Menurunkan tahanan Mendilatasi Mencegah kontraksi Meningkatkan GMP

pembuluh darah dan arteriol,membuka otot polos vaskular intraselular yang
kerja mendilatasikan arteri kanal kalium diotot dgn membuka kanal merelaksasikan otot
polos kalium polos vaskular

Efek samping Sakit Efusi perikardial, Hipotensi, Hipotensi,aritmia

kepala,mual,palpitasi, angina pektoris menimbulkan
berkeringat dan flushing hiperglikemi

Kontraindikasi Hipersensitif dengan Penyakit ginjal, Insufisiensi Koroner Hiperglikemia

hidralazin, penyakit artesi Pheochromocytom atau Serebral
koroner, penyakit jantung a, Angina Pektoris
rematik katub mitral
 Posologi obat
Hidralazine HCl tablet 10, 25, 50,100 mg
Dosis: 40-200 mg/hari
Terapi awal:4x 10 mg/hari selama 2-4 hari

1. Hidralazin Ditingkatkan sampai 4x 25 mg/hari selama 1

minggu pertama
Minggu selanjutnya sampai 4x50 mg/hari

2. Minoksidil Terapi awal: 5 atau 10 mg/hari dlm 2 dosis

Ditingkatkan bertahap menjadi 40 mg/hari

Dosis: 300 mg diinjeksikan cepat

3. Diazoksid

Dosis: 0,5-10 µg/kg/menit.

4. Natrium nitroprusid
 Interaksi Obat
• Hidralazin
Diuretik: retensi cairan yg disebabkan hidralazin akan
dihambat.
-blocker: refleks takikardi thdp vasodilatasi akan
dihambat.
MAO-inhibitor: makin poten menurunkan TD.

• Minoksidil
Diuretik: menghambat retensi cairan
-blocker: mencegah refleks takikardi
 Interaksi obat
• Diazoksid
Diuretik: menghambat retensi cairan
-blocker: efek hipotensi akan lebih besar

• Natrium nitroprussid
REBOUND PHENOMENON
dijumpai pada pemakai:
• Beta-blocker
• Clonidine

GAWAT HIPERTENSI
dapat diterapi dengan:
• SODIUM NITROPRUSSIDE
• DIAZOXIDE
• LABETALOL
• CLONIDINE (drip)
 Penggunaan Antihipertensi
Pada Pasien Dengan Penyakit
Penyakit
Penyerta
Vasodilator Diuretik  Blocker Ca Channel Ace inhibitor
penyerta Blocker

Diabetes  x x  

Dyslipidaemia  x x  

CHD     

Heart failure   x x 

Asthma/COPD   x  / x

Peripheral   x  x
vascular disease

Renal artery     x
stenosis
Penyakit Antihipertensi yang selalu digunakan
penyerta

Asma, D ACE-I Ca-A

PPOM
Angina D B-B ACE-I Ca-A
pectoris

DM ACE-I Ca-A

Hyper- ACE-I Ca-A

lipidemia

JANGAN
GUNAKAN
CHF D ACE-I Ca-A
Old-MCI D B-B ACE-I Ca-A

Ggg. Ginjal D B-B ACE-I Ca-A

kronis
Classification of Blood Pressure for Adults Aged >/= 18 Years: JNC 7 vs JNC 6
JNC 7 Blood Pressure JNC 6 Blood SBP and/or DBP
Category Pressure (mm Hg) (mm Hg)
Category
Normal Optimal < 120 and < 80
Prehypertension 120-139 or 80-89
-- Normal < 130 and < 85
-- High-normal 130-139 or 85-89
Hypertension: Hypertension:
Stage 1 Stage 1 140-159 or 90-99
Stage 2 >/= 160 or >/= 100
-- Stage 2 160-179 or 100-109
-- Stage 3 >/= 180 or >/= 110
Types of hypertension
Essential hypertension
90%
No underlying cause
Secondary hypertension
Underlying cause
BLOOD PRESSURE = CARDIAC OUTPUT x PERIPHERAL
RESISTANCE
Hypertension = increased CO and/or Increased PR

 preload  contracitilty Functional Structural

Constriction hypertension

 Fluid Volume
volume redistribution

Hyper-
Cell insulinemia
Renal Decreased Sympathetic Renin Memberane
Sodium Filtration Nervous Angiotension Alteration
Retention Surface Over Activity Excess

Genetic Obesity
Alteration
Excess
Genetic
Sodium Stress Alteration Endothelium
intake
Derived factors
Consequences of Hypertension1-4

Brain Stroke, dementia

Hypertension MI, heart failure,

Heart
sudden death

End-stage
Kidney renal disease
1. Weir et al. Am J Hypertens 1999;12:205S-213S. 2. Beers MH, Berkow R, eds. The Merck Manual of
Diagnosis and Therapy. 17th ed. 1999:1629-1648. 3. Francis CK. In: Izzo JL Jr, Black HR, eds. Hypertension
Primer: The Essentials of High Blood Pressure. 2nd ed. 1999:175-176. 4. Hershey LA. In: Izzo JL Jr, Black
HR, eds. Hypertension Primer: The Essentials of High Blood Pressure. 2nd ed. 1999:188-189.
46
 Compelling Indications for
Individual Drug Classes
Compelling
Indication Initial Therapy Options
Thiazide-type diuretic, beta-blocker, ACE inhibitor,
Heart failure ARB, aldosterone antagonist

Post MI Beta-blocker, ACE inhibitor, aldosterone antagonist

Thiazide-type diuretic, beta-blocker, ACE inhibitor,
High CVD risk CCB
Thiazide-type diuretic, beta-blocker, ACE inhibitor,
Diabetes ARB, CCB
Chronic kidney
disease ACE inhibitor, ARB
Recurrent stroke
prevention Thiazide-type diuretic, ACE inhibitor
Pathophysiology of hypertension
 Cardiac function
 Vascular function
 Renal function
 Neuroendocrine function