PHARMACOTHERAPY

OF HYPERTENSION

By
Jastria Pusmarani, S. Farm., M. Sc., Apt.
 Definition
Hypertension  defined as persistently
elevated arterial blood pressure (BP).
Isolated systolic hypertension is diastolic blood
pressure (DBP) values less than 90 mm Hg and
systolic blood pressure (SBP) values of 140 mm
Hg or more.
 Blood Pressure
 Systolic BP (SBP)During systole the left ventricle
contracts, ejecting blood systemically into the arteries,
causing a sharp rise in arterial BP.
 This is the The left ventricle then relaxes during
diastole, and arterial BP decreases to a trough value as
blood returns to the right atria and ventricle of the heart from
the venous system.
 When recording BP (e.g., 120/76 mmHg), the numerator refers
to SBP and the denominator refers to DBP.
Classification and Management of
Blood Pressure (BP) in Adults
 Types of Hypertension
 Essential Hypertension
Most patients with hypertension have essential hypertension
(also known as primary hypertension), with no identifiable cause
for their disorder
 Secondary Causes of Hypertension
Chronic Kidney Disease
Drug-Induced or Drug-Related
Adrenal steroids
Alcohol in excess
Erythropoietin
Nonsteroidal anti-inflammatory drugs and COX-2 inhibitors
Oral contraceptives
Oral decongestants (e.g., pseudoephedrine)
 PATHOPHYSIOLOGY
The renin–angiotensin–aldosterone system (RAAS),
natriuretic hormone, or insulin resistance and
hyperinsulinemia;
Abnormalities in renal or tissue autoregulatory processes
for sodium excretion, plasma volume, and arteriolar
constriction;
Deficiency in synthesis of vasodilating substances in
vascular endothelium (prostacyclin, bradykinin, and
nitric oxide) or excess vasoconstricting substances
(angiotensin II, endothelin I);
High sodium intake
 Renin is produced and stored in the juxtaglomerular
cells of the kidney, and its release is stimulated by
impaired renal perfusion, salt depletion, and
β1-adrenergic stimulation.
 The role of the RAAS in primary hypertension is
supported by the presence of high levels of renin
 In hypertensive individuals, this theory proposes a shift in the
control mechanism preventing the normalization of blood
pressure.
 The mechanisms behind the resetting of the pressure-
natriuresis curve may include afferent arteriolar
vasoconstriction, decreased glomerular ultrafiltration, or an
increase in tubular sodium reabsorption.
 Peripheral Resistance
 Elevated peripheral arterial resistance is a hallmark of
primary hypertension.
 The increase in peripheral resistance typically observed
may be due to a reduction in the arterial lumen size
as a result of vascular remodeling.
 This remodeling, or change in vascular tone, may be
modulated by various endothelium derived vasoactive
substances, growth factors, and cytokines.
 This increase in arterial stiffness or reduced compliance
results in the observed increase in systolic blood pressure.
NON PHARMACOLOGIC THERAPY
 Lifestyle modifications
 weight loss if overweight,
 dietary sodium restriction ideally to 1.5 g/day (3.8 g/day
sodium chloride)
 regular aerobic physical activity,
 moderate alcohol consumption (two or fewer drinks per
day),
 smoking cessation.
 PHARMACOLOGIC THERAPY
Angiotensin-converting enzyme (ACE) inhibitors,
angiotensin II receptor blockers (ARBs),
calcium channel blockers (CCBs), and
Loop Diuretic
Diuretik hemat kalium
thiazide diuretics
β-Blockers
 Angiotensin-Converting Enzyme
Inhibitors
 MA inhibitors block conversion of angiotensin I to
angiotensin II, a potent vasoconstrictor and stimulator of
aldosterone secretion.
 ACE inhibitors decrease aldosterone and can increase
serum potassium concentrations.
 Side Effect Hyperkalemia
 A persistent dry cough occurs in up to 20% of patients 
inhibition of bradykinin breakdown.
 ACE inhibitors (as well as ARBs and direct renin inhibitors)
are contraindicated in pregnancy.
 Obat Golongan ACEI
 Benazepril
 Captopril
 Enalapril
 Fosinopril
 Lisinopril
 Moexipril
 Perindopril
 Quinapril
 Ramipril
 Angiotensin II Receptor Blockers
Unlike ACE inhibitors, ARBs do not block bradykinin
breakdown.
Like ACE inhibitors, they may cause renal
insufficiency, hyperkalemia, and orthostatic
hypotension.
ARBs  contraindicated in pregnancy.
Obat golongan ARB
 candesartan
 eprosartan
 irbesartan
 losartan
 olmesartan
 telmisartan
 valsartan
 ACE-I

ARB
Calcium Channel Blockers
 Calcium Channel Blockers
 Calcium channel blockers (CCBs)  relaxation of cardiac and
smooth muscle by blocking voltage-sensitive calcium channels,
thereby reducing entry of extracellular calcium into cells.
 This leads to vasodilation and a corresponding reduction in BP.
 Dihydropyridine calcium channel antagonists may cause reflex
sympathetic activation, and all agents (except amlodipine and
felodipine) may have negative inotropic effects.
 Dihydropyridines do not decrease AV node conduction and are not
effective for treating supraventricular tachyarrhythmias.
 Diltiazem and verapamil can cause cardiac conduction
abnormalities such as bradycardia, AV block, and HF.
 Both can cause anorexia, nausea, peripheral edema, and
hypotension.
Diuretics
 Thiazide diuretics
 Loop diuretics
 Potassium-sparing diuretics
 Aldosterone antagonists (spironolactone and
eplerenone)
 Next…
 Acutely, diuretics lower blood pressure by causing diuresis.
 The reduction in plasma volume and stroke volume associated with
diuresis decreases cardiac output and, consequently, blood pressure.
 The initial drop in cardiac output causes a compensatory increase in
peripheral vascular resistance.
 With chronic diuretic therapy, the extracellular fluid volume and
plasma volume return almost to pretreatment levels, and peripheral
vascular resistance falls below its pretreatment baseline.
 The reduction in peripheral vascular resistance is responsible for the
long-term hypotensive effects.
 Thiazides lower blood pressure by mobilizing sodium and water from
arteriolar walls, which may contribute to decreased peripheral
vascular resistance.
 When diuretics are combined with other antihypertensive
agents, an additive hypotensive effect is usually observed
because of independent mechanisms of action.
 Furthermore, many nondiuretic antihypertensive agents
induce salt and water retention, which is counteracted by
concurrent diuretic use.
 Thiazide diuretics
 Thiazide diuretics are the • Side effects of thiazides include
preferred type of diuretic for • hypokalemia,
most hypertensive patients. • hypomagnesemia,
 Mechanism of Action  Inhibits • hypercalcemia,
sodium reabsorption in the
distal tubules causing increased • hyperuricemia,
excretion of sodium and water • hyperglycemia,
as well as potassium and • hyperlipidemia, and
hydrogen ions • sexual dysfunction.
 They mobilize sodium and • Loop diuretics have less effect
water from arteriolar walls, on serum lipids and glucose,
which may contribute to but hypocalcemia may occur.
decreased peripheral vascular • Hypokalemia and
resistance and lowered BP. hypomagnesemia may cause
muscle fatigue or cramps.
Loop Diuretik
 Serious cardiac arrhythmias may occur, especially in
patients receiving digitalis therapy, patients with left
ventricular hypertrophy, and those with ischemic heart
disease. Low-dose therapy (e.g., 25 mg
hydrochlorothiazide or 12.5 mg chlorthalidone daily)
rarely causes significant electrolyte disturbances.
 Mechanism of Action Inhibits reabsorption of sodium
and chloride in the ascending loop of Henle and distal
renal tubule, interfering with the chloride-binding
cotransport system, thus causing increased excretion of
water, sodium, chloride, magnesium, and calcium
Aldosterone antagonists
 Aldosterone antagonists are also potassium-sparing
diuretics but are more potent antihypertensives with
a slow onset of action (up to 6 weeks with
spironolactone).
 Potassium-sparing diuretics
 Potassium-sparing diuretics are weak antihypertensives
when used alone and provide minimal additive effect
when combined with a thiazide or loop diuretic.
 Their primary use is in combination with another diuretic to
counteract potassium-wasting properties.
 Next…
 Potassium-sparing diuretics may cause hyperkalemia,
especially in patients with CKD or diabetes and in patients
receiving concurrent treatment with an ACE inhibitor, ARB,
direct renin inhibitor, or potassium supplement.
 Eplerenone has an increased risk for hyperkalemia and is
contraindicated in patients with impaired renal function or
type 2 diabetes with proteinuria.
 Spironolactone may cause gynecomastia in up to 10% of
patients; this effect occurs rarely with eplerenone.
β-Blockers
 Atenolol
 Betaxolol
 Bisoprolol
 Metoprolol
 Nadolol
 Propranolol
 Timolol
Next…
 β-Blockers are only considered appropriate first-line
agents to treat specific compelling indications
(eg, post-MI [myocardial infarction], coronary artery
disease).
 Their hypotensive mechanism may involve
decreased cardiac output through negative
chronotropic and inotropic effects on the heart and
inhibition of renin release from the kidney
 Atenolol, betaxolol, bisoprolol, and metoprolol are
cardioselective at low doses and bind more avidly to β1-
receptors than to β2-receptors.
 β1-receptors ada di jantung, β2-receptors di paru-
paru
 As a result, they are less likely to provoke bronchospasm
and vasoconstriction and may be safer than nonselective
β-blockers in patients with asthma, chronic obstructive
pulmonary disease (COPD), diabetes, and peripheral
arterial disease (PAD).
 Cardioselectivity is a dose-dependent phenomenon, and
the effect is lost at higher doses.
 Next…
 Acebutolol, carteolol, penbutolol, and pindolol possess
intrinsic sympathomimetic activity (ISA) or partial β-receptor
agonist activity.
 When sympathetic tone is low, as in resting states, β-receptors
are partially stimulated, so resting heart rate, cardiac output,
and peripheral blood flow are not reduced when receptors are
blocked.
 Theoretically, these drugs may have advantages in patients
with HF or sinus bradycardia.
 Unfortunately, they do not reduce CV events as well as other β-
blockers and may increase risk after MI or in those with high
coronary disease risk. Thus, agents with ISA are rarely needed.
α1-Receptor Blockers
 Prazosin, terazosin, and  Because doxazosin (and
doxazosin are selective α1- probably other α1-receptor
receptor blockers that inhibit blockers) may not be as
catecholamine uptake in protective against CV events
smooth muscle cells of as other therapies, they
peripheral vasculature, should be reserved as
resulting in vasodilation. alternative agents for unique
 Sodium and water retention situations, such as men with
can occur; these agents are benign prostatic hyperplasia.
most effective when given  If used to lower BP in this
with a diuretic to maintain situation, they should only be
antihypertensive efficacy and used in combination with
minimize edema. first-line antihypertensives.
Central α2-Agonists
 Clonidine, guanabenz, guanfacine, and
methyldopa lower BP primarily by stimulating α2-
adrenergic receptors in the brain, which reduces
sympathetic outflow from the vasomotor center and
increases vagal tone.
 Stimulation of presynaptic α2-receptors peripherally may
contribute to reduced sympathetic tone.
 Consequently, there may be decreases in heart rate,
cardiac output, total peripheral resistance, plasma renin
activity, and baroreceptor reflexes.
 Chronic use results in sodium and fluid retention.
 Other side effects include depression, orthostatic hypotension,
dizziness, and anticholinergic effects.
 Methyldopa rarely causes hepatitis or hemolytic anemia.
 A transient elevation in hepatic transaminases occasionally occurs.
 Discontinue therapy if persistent increases in liver function tests
occur
 For these reasons, methyldopa has limited usefulness except in
pregnancy.
Reserpine
 Reserpine depletes dosing, but it may take 2 to 6
norepinephrine from weeks before the maximal
sympathetic nerve endings and antihypertensive effect is seen.
blocks transport of  Reserpine can cause significant
norepinephrine into storage sodium and fluid retention, and
granules. it should be given with a
 When the nerve is stimulated, diuretic (preferably a thiazide).
less than the usual amount of  Reserpine’s strong inhibition of
norepinephrine is released sympathetic activity results in
into the synapse. parasympathetic activity, which
 This reduces sympathetic is responsible for side effects of
tone, decreasing peripheral nasal stuffiness, increased gastric
vascular resistance and BP. acid secretion, diarrhea, and
 Reserpine has a long half-life bradycardia.
that allows for once-daily
 Direct Arterial Vasodilators
 Hydralazine and minoxidil cause
direct arteriolar smooth muscle
relaxation.
 Compensatory activation of baroreceptor
reflexes results in increased sympathetic
outflow from the vasomotor center,
increasing heart rate, cardiac output,
and renin release.
 Consequently, hypotensive
effectiveness of direct vasodilators
diminishes over time unless the patient
is also taking a sympathetic inhibitor
and a diuretic.
 Patients taking these drugs for long-term
hypertension therapy should first receive 
both a diuretic and a β-blocker.
 The diuretic minimizes the side effect of
sodium and water retention.
 Direct vasodilators can precipitate angina
in patients with underlying coronary
artery disease unless the baroreceptor
reflex mechanism is completely
 blocked with a β-blocker.
Nondihydropyridine CCBs can be used as
an alternative to
 β-blockers in patients with
contraindications to β-blockers.
 • Hydralazine may cause dose-related,
reversible lupus-like syndrome, which is
more
 common in slow acetylators. Lupus-like
reactions can usually be avoided by using
total daily doses less than 200 mg.
Because of side effects, hydralazine has
limited
 usefulness for chronic hypertension
management.
JNC 8 Hypertension Management
Algorithm