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Anti

Hyperthensive
Drugs
Dr. Yogi P. R.
Medical Faculty
Swadaya Gunung Jati University
Cirebon 2009
Pathophysiology

= X

Blood Pressure Cardiac Output Total Peripheral


Resistance

Pathogenic mechanisms involve an increase in


CO or TPR or both.
Pathophysiology

Many age-related changes in physiology


contribute to BP
Age-Associated factors cause TPR 4
arterial vascular stiffness results in SBP
changes in renal function ( renal blood flow
and GFR)
Pathophysiology

Contributions to BP = combination of
genetic inheritance, psychological stress,
and dietary factors
Abnormalities in the ANS, baroreceptor
reflexes, the renin-angiotensin-
aldosterone system and the kidney (all
used in regulating BP).
Hypertension

Essential (primary) Secondary


- most (90-95 %) patients with - is secondary to some
persistent arterial hypertension distinct disease:
- genesis of hypertension unknown
- predisposing factors: Renal + renovascular desease

(artery stenosis)
susceptive
Hormonal defects
(obesity, stress, salt intake, lack of
(Cushings syndrome,
Mg2+, K+, Ca2+, ethanol dose,
phaeochromocytoma)
smoking)
Mechanical defect
(coarctation of aorta)
non-susceptive Hypertension in pregnancy
(positive family history, insulin Drug-induced hypertension
resistance, age, sex, defect of (sympatomimetics,
local vasomotoric regualtion) glucocorticoids)
Neurologic desease
Classification
JNC-VII
JNC VI
Stages of Hypertension
Stage Diastolic Range (mm Systolic Range (mm
Hg) Hg)

High Normal 85-89 130-139

Stage 1 90-99 140-159

Stage 2 100-109 160-179

Stage 3 > 109 >179


THERAPY OF HYPERTENSION

A. Non-pharmacological - lifestyle

- decrease of salt intake


- reduction of body weight
- restriction of smoking and drinking excessive
amounts of alcohol
- regular physical activity and relaxation, lack of stress

*BNF 51th edition, 2006


Drug treatment of hypertension

The choice of antihypertensive drug will depend on the


relevant indications or contra-indications for the individual
patient:
1. Diuretics
2. Drugs influencing sympathetic nerves
3. Vasodilators
4. Angiotensin-converting enzyme inhibitors
(ACEI), blockers of AT1 receptor

*BNF 51th edition, 2006


1. DIURETICS
- Obat lini pertama untuk pasien dengan hipertensi ringan
- Bisa dikombinasi dengan obat hipertensi lainnya pd hipertensi
sedang dan berat

THIAZIDES
hydrochlorothiazide, clopamid, chlorthalidone
indapamid, metipamid

- Dipilih utk hipertensi tanpa komplikasi


- Diberikan secara oral 1x sehari pagi hari
- Mulai bekerja dlm 1-2 jam dan selama 12-24 jam
Mechanism of action:

-Menurunkan tekanan darah dgn mengurangi volume darah

- Menghambat transport Na dan Cl pd tubulus distal


natriuresis, menurunkan preload and cardiac output -
renal effect

- Secara perlahan menurunkan total peripheral resistance


extrarenal effects
Adverse effects:
- Metabolic and electrolyte changes
Hyponatremia
Hypokalemia
Hypomagnesemia
Hyperuricemia
Hyperglycemia
Hypercalcemia
Hypercholesterolemia (a small in plasma
cholesterol concentration)
Gangguan fungsi seksual
LOOP DIURETICS
furosemid

- Digunakan pada hipertensi sedang hingga berat atau adanya


gangguan ginjal berat, atau dgn hypertensive heart failure.
- Relatif singkat (diuresis muncul dalam 4 jam)

Mechanism of action:
- Menghambat transport Na+, K+ dan Cl-
- of Ca2+ and Mg2+ excretion
- Memiliki efek vasodilatasi pembuluh darah pulmo (unknown
mechanism)
Adverse Effect :
- hypokalemic metabolic alkalosis (increased
excretion of K+)
- ototoxicity (dose dependent, reversible)
- decrease of Mg2+ plasma concentration
(hypomagnesemia)
- hyperuricemia
- risk of dehydration (> 4 L urine/ 24 h)
DIURETICS HEMAT KALIUM
Spironolacton

- Diuretik lemah
- Digunakan dgn diuretik lain utk mencegah
atau mengurangi hipokalemia dr diuretik lain

Mechanism of action:
- Antagonis spesifik dari aldosteron pilihan
utama utk hiperaldosteronisme primer
Adverse Effect :
Ginekomastia
Mastodinia
Menstruasi tidak teratur
Berkurangnya libido pd pria
2. Drugs influencing sympathetic nerves

a) -adrenoreceptor antagonists
Mechanism of action:
- Vasodilatasi dan menurunkan BP dgn menghambat noradrenalin
pd 1 receptors (vascular smooth muscle)

competitive with:
a. short-term action:
non-selective - phentolamine
selective - prazosin, uradipil,
b. long-acting
antagonists - doxazosin, terazosin

non-competitive with long-term action, non-selective - phenoxybenzamin


Side effects of 1-
adrenoceptor blockers
First dose phenomenon (- drowsiness,
weakness, orthostatic
hypotension )
Nasal congestion
GI effects (rare)
Adverse Effects of Non
Specific -Adrenoceptor
Blockers
Postural hypotension
Reflex tachycardia
Fluid retention
2. Drugs influencing sympathetic nerves

b) -adrenoreceptor antagonists
Mechanism of action:
1. Mengurangi denyut jantung dan kontraktilitas myocard CO
berkurang
2. Menghambat pelepasan NE melalui hambatan reseptor 2
prasinaps
3. Menghambat sekresi renin melalui hambatan 1 di ginjal
4. Efek sentral
-adrenoreceptor antagonists
cardio-selective:
blockers atenolol, metoprolol
blockers with ISA acebutol
blockers labetalol, carvedilol

cardio non-selective:
blockers metiprolol, propranolol,
nadolol
blockers with ISA pindolol, bopindolol

Note: Partial agonist activity (intrinsic sympathomimetic activity ISA) - may be an


advantage in treating patients with asthma because these drugs will cause
bronchodilation; they have moderate (lower) effect on lipid metabolism, cause lesser
vasospasms and negative inotropic effect
Adverse effects

Cardiovascular adverse effects, which are extension of the beta


blockade, include:
- bradycardia
- antrioventricular blockade
- congestive heart failure (unstable)
- asthmatic attacks (in patients with airway disease)
- premonitory symptoms of hypoglycemia from insulin overdosage
(eg, tachycardia, tremor and anxiety, may be marked)
- CNS adverse effects - sedation, fatigue, and sleep alterations.
2. Drugs influencing sympathetic nerves

c) Centrally acting drugs


2-agonist actions
Methyldopa
false transmitter
Clonidine, Moxonidine
direct 2-agonist

- Penggunaannya terbatas
- methyldopa hypertension saat kehamilan
- methyldopa menyebabkan gejala pusing dan kelelahan
Adverse effects:

- drowsiness, fatigue (esp. methyldopa), depression,


nightmares (methyldopa - rarely extrapyramidal
features)
- nasal congestion, anticholinergic symptoms (constipation,
bradycardia)
- dry mouth
- sexual dysfunction, salt and water retention
- hypertensive rebound associated with anxiety, sweating,
tachycardia and extrasystoles (rarely hypertensive crisis)
3. Vasodilators

* Pengeluaran nitric oxide


(NO merangsang guanylyl cyclase dan meningkatkan cGMP pada otot
polos mengurangi cytoplasmic Ca2+ dgn menyebabkan Ca2+
sekuestrasi pada endoplasmic reticulum relaksasi arterioles dan
venous

* Block kanal kalsium


(Menurunkan konsentrasi kalsium di intraseluler relaksasi otot polos
arteriol, mengurangi tahanan perifer)

* Membukanya kanal kalium


(Memicu hiperpolarisasi dan relaksasi otot polos vaskuler)
3. Vasodilators

A) DIRECT ACTING

minoxidil, diazoxide, sodium nitroprusside, hydralazine

Minoxidil
- Membuka kanal kalium
- Lebih berefek pd arteriol dibanding pd vena
- Adverse: oedemas, hypertrichosis, breast tenderness
3. Vasodilators

Diazoxide
- Membuka kanal kalium
- adverse: Na+ and water retention, hyperglycaemia, hirsutism

Hydralazine
- arteriolar resistance
- Bermanfaat untuk hypertensive crisis selama kehamilan
- AE: Na+ and water retention, systemic lupus erythematosus

*BNF 51th edition, 2006


B) INDIRECT ACTING - CALCIUM CHANNEL-BLOCKING AGENTS

1. dihydropyridine (nifedipine, nicardipine, amlodipine)


2. non- dihydropyridine (diltiazem, verapamil)

-Memblok kanal kalium


relaksasi otot polos
vasodilation
mengurangi resistensi
vaskuler perifer
menurunkan BP
Adverse effects of calcium channel-blocking agents
Drug Effect on Adverse effects
heart rate

Nifedipine Headache, flushing, ankle swelling

Amlodipine Ankle swelling

Nimodipine Flushing, headache


Diltiazem Generally mild
Verapamil Constipation, marked negative
inotropic action
4. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS (ACEI)


Captopril, enalapril, quinapril, lisinopril, perindopril, ramipril

Indikasi :

-hypertension saat didptkan kontraindikasi thiazide diuretics dan beta-


blockers
-Bermanfaat pada pasien hipertensi dgn gagal jantung
-diabetic nephropathy
Mechanism of action:

Converting enzyme inhibitors menurunkan BP dgn menghambat


angiotensin II, dan juga meningkatkan bradykinin yg
merupakan vasodilator

Dilatation of arteriol reduction of peripheral vascular


resistance, blood pressure and afterload

Increase of Na+ and decrease of K+ excretion in kidney

Decrease noradrenaline release reduction of sympathetic


activity

menghambat sekresi aldosteron

mempengaruhi remodelling jantung


Adverse effects and contraindications of ACEI:

-are generally well tolerated. Adverse effects include:

First dose hypotension.


Dry cough
(5-30%) symptom
Urticaria and angioneurotic edema
- kinin concentrations urticarial reactions and angioneurotic
edema)
Functional renal failure
Hyperkalemia monitor !!
Fetal injury
- contraindication in pregnancy
4. Angiotensin-converting enzyme inhibitors (ACEI), blockers of AT1 rc.

B) BLOCKERS OF AT1 RECEPTOR (Angiontensin Receptor Blocker/ARB)


losartan, valosartan, irbesartan
Sebagian besar efek angiotensin II - termasuk vasoconstriction
dan aldosterone release dimediasi reseptor AT1
AT1-blockers tdk memblock AT2 receptor
ARB lebih efektif karena sifatnya yg selektif
Insiden efek samping dr akumulasi bradykinin lebih rendah
dibanding ACE inhibitor (cough, angioneurotic oedema)
menyebabkan fetal renal toxicity (seperti ACE inhibitors)