Antihypertensive Drugs

Dr Khaled M Hasan, MD,MSc, Mphil, PhD

Pharmacology and Clinical Pharmacology
University of London, UK
Dr Khaled M Hasan
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Dr Khaled M Hasan
 I. OVERVIEW
• Hypertension (HT) is defined as either a sustained systolic
blood pressure (SBP) of greater than 140 mm Hg or a
sustained diastolic blood pressure (DBP) of greater than 90
mm Hg.
• Hypertension results from increased peripheral vascular
smooth muscle tone, which leads to increased arteriolar
resistance and reduced capacitance of the venous system.
• Hypertension is common disorder, affecting 15% of the
population of the USA (60 million). Although many of these
individuals have no symptoms, chronic HT- either systolic
or diastolic-can lead to congestive heart failure, myocardial
infarction, renal damage, and cerebrovascular accidents.
Dr Khaled M Hasan
• The incidence of morbidity and mortality significantly decreases
when hypertension is diagnosed early and is properly treated.

• Classification of hypertension
• Normal (SBP/DBP, <120/<80)
• Prehypertension (SBP/DBP, 120-139/80-89)
• Stage 1 hypertension (SBP/DBP, 140-159/90-99)
• Stage 2 hypertension (SBP/DBP ≥ 160/≥100)

Dr Khaled M Hasan
 II. ETIOLOGY OF HYPERTENSION
• Although hypertension may occur secondary to other
disease processes, more than 90% of patients have
essential hypertension, a disorder of unknown origin
affecting the blood pressure regulating mechanism. A
family history of hypertension increases the likelihood that
an individual will develop hypertensive disease.

• Essential hypertension is four-fold more frequent among

blacks than among whites, and it occurs more often among
middle-aged males than among middle-aged females.

• Environmental factors, such as a stressful lifestyle, high

dietary intake of sodium, obesity, and smoking, all further
predispose an individual to the occurrence of hypertension.
Dr Khaled M Hasan
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Fig. 13.116 Digital subtraction angiography, showing
typical unilateral atheromatous renal artery stenosis
with post-stenotic dilatation (Kumar).

Dr Khaled M Hasan
 III. Mechanisms for Controlling Blood Pressure
• Arterial blood pressure is regulated within a narrow range to
provide adequate perfusion of the tissues without causing damage
to the vascular system, particularly the arterial intima.

• Arterial blood pressure is directly proportional to the product of

the cardiac output and the peripheral vascular resistance.

Dr Khaled M Hasan
 III. Mechanisms for Controlling Blood Pressure
• In both normal and hypertensive individuals, cardiac output and
peripheral resistance are controlled mainly by two overlapping
control mechanisms:

• Baroreflexes, which are mediated by the sympathetic nervous

system
• Reninangiotensin-aldosterone system (RAAS)

• Most antihypertensive drugs lower blood pressure by reducing

cardiac output and/or decreasing peripheral resistance.

Dr Khaled M Hasan
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 A. Baroreceptors and the sympathetic nervous system
• Baroreflexes involving the sympathetic nervous system are
responsible for the rapid, moment-to-moment regulation of blood
pressure.

• A fall in blood pressure causes pressure-sensitive neurons

(baroreceptors in the aortic arch and carotid sinuses) to send
fewer impulses to cardiovascular centers in the spinal cord.

• This prompts a reflex response of increased sympathetic and

decreased parasympathetic output to the heart and vasculature,
resulting in vasoconstriction and increased cardiac output.
• These changes result in a compensatory rise in blood pressure
(Fig).

Dr Khaled M Hasan
 B. Renin-angiotensin-aldosterone system (RAAS)
• Kidney provides for long-term control of blood pressure
by altering blood volume.
• Baroreceptors in kidney respond to reduced arterial
pressure (and to sympathetic stimulation of
adrenoceptors) by releasing the enzyme renin (Fig).
• This peptidase converts angiotensinogen to angiotensin
I, which is converted in turn to angiotensin II in presence
of (ACE). Angiotensin II is the body's most potent
circulating vasoconstrictor, causing an increase in blood
pressure. Furthermore, angiotensin II stimulates
aldosterone secretion, leading to increased renal sodium
reabsorption and increased blood volume, which
contribute to a further increase in blood pressure.
Dr Khaled M Hasan
 TREATMENT STRATEGIES
• The goal of antihypertensive therapy is to reduce
cardiovascular and renal morbidity and mortality.
• Pre hypertension emphasizes need for decreasing BP in the
general population by education and adoption of blood pressure-
lowering behaviors.
• Mild hypertension can often be controlled with a single drug.
Current treatment recommendations are to initiate therapy with
a thiazide diuretic unless there are compelling reasons to employ
other drug classes (Fig).
• If BP is inadequately controlled, a second drug is added, with the
selection based on minimizing the adverse effects of the
combined regimen. A beta-blocker is usually added if the initial
drug was a diuretic, or a diuretic is usually added if the first drug
was a β-blocker. A vasodilator can be added as a third step for
those patients who still fail to respond.
Dr Khaled M Hasan
• A. Individualized care
• Black patients respond well to diuretics and
calcium channel blockers, but therapy with β-
blockers or ACE inhibitors is often less effective.

• Elderly respond well to calcium channel blockers,

ACE inhibitors, and diuretics, whereas β-blockers
and αantagonists are less well tolerated.

• Furthermore, hypertension may coexist with

other diseases that can be aggravated by some
of the antihypertensive drugs.
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Hasan
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Compelling indications
for individual drug classes.
Dr Khaled M Hasan
The main drugs for treating hypertension can
usefully be grouped as:
A: angiotensin-converting enzyme inhibitors
(ACEI) and angiotensin AT1 receptor antagonists
(sartans);
B: beta-adrenoceptor antagonists;
C: calcium channel antagonists;
D: diuretics.

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Hasan
 Initiating and titrating
antihypertensive
drug treatment, 2011

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Dr Khaled M Hasan
Algorithm for treatment of hypertension

Dr Khaled M Hasan
•Diuretics may aggravate diabetes
•Beta-blockers worsen glucose
intolerance and mask symptoms of
hypoglycaemia

•Both diuretics and beta-blockers

disturb the lipid profile

•Verapamil and diltiazem may

exacerbate heart failure, although
amlodipine appears to be safe

•Patients with peripheral vascular

disease may also have renal artery
stenosis; therefore ACE inhibitors
should be used cautiously
Dr Khaled M Hasan
• B. Patient compliance in antihypertensive therapy
• Lack of patient compliance is the most common reason for
failure of antihypertensive therapy. The hypertensive patient is
usually asymptomatic and is diagnosed by routine screening
before the occurrence of overt end-organ damage.
• Thus, therapy is generally directed at preventing disease
sequelae (that occur in the future), rather than in relieving the
patient's present discomfort.

• The adverse effects associated with the hypertensive therapy

may influence the patient more than the future benefits. For
example, β-blockers can decrease libido and induce impotence
in males, particularly middleaged and elderly men. This drug-
induced sexual dysfunction may prompt the patient to
discontinue therapy. Thus, it is important to enhance
compliance by carefully selecting a drug regimen that both
reduces adverse effects and minimizes the number of doses
required daily.
Dr Khaled M Hasan
 V. DIURETICS
• Diuretics are currently recommended as the first-line drug
therapy for hypertension unless there are compelling reasons to
chose another agent. Low-dose diuretic therapy is safe and
effective in preventing stroke, myocardial infarction, and
congestive heart failure, all of which can cause mortality.
• Recent data suggest that diuretics are superior to β-blockers in
older adults.

• A. Thiazide diuretics
• B. Loop diuretics

Dr Khaled M Hasan
A. Thiazide diuretics
Thiazides have found the most widespread
use.
Spironolactone, a potassiumsparing
diuretic, is used with thiazides.
Spironolactone has the additional benefit
of diminishing the cardiac remodeling that
occurs in heart failure.
1.Actions: Thiazide diuretics lower BP
initially by increasing sodium and water
excretion. This causes a decrease in
extracellular volume, resulting in a
decrease in cardiac output .
With long-term treatment, plasma volume
approaches a normal value, but
peripheral resistance decreases.
Dr Khaled M Hasan
(a) Ventricular
remodelling
after acute
infarction

(b) Ventricular
remodelling
in diastolic
and systolic
heart
failure

Dr Khaled M Hasan
• 2. Therapeutic uses: Thiazide diuretics decrease BP
in both supine and standing positions.
• These agents counteract the sodium and water retention
observed with other agents used in treatment of
hypertension (e.g, hydralazine).

• Thiazides are useful in combination therapy with β-

blockers and ACE inhibitors. Thiazide diuretics are useful
in the treatment of black or elderly patients.

• They are not effective in patients with inadequate

kidney function (creatinine clearance <50 mL/min). Loop
diuretics may be required in these patients.
Dr Khaled M Hasan
• B. Loop diuretics
• The loop diuretics act promptly, even in patients with
poor renal function or who have not responded to
thiazides or other diuretics.

• The loop diuretics cause decreased renal vascular

resistance and increased renal blood flow.

Dr Khaled M Hasan
Dr Khaled M
Hasan
 β-Adrenoceptor-blocking Agents
• β-Blockers are currently recommended as first-line drug therapy for
hypertension when indicated-for example, with heart failure.

• A. Actions
• The Beta-blockers reduce BP primarily by decreasing cardiac output (Fig).
They may also decrease sympathetic outflow from CNS and inhibit the
release of renin from the kidneys, thus decreasing the formation of
angiotensin II and secretion of aldosterone.
• Prototype β-blocker is propranolol, which acts at both β1 and β2
receptors.
• Selective blockers of β1 receptors, such as metoprolol and atenolol, are
among the most commonly prescribed β-blockers.

• The selective β-blockers may be administered cautiously to hypertensive

patients who also have asthma, for which propranolol is contraindicated
due to its blockade of β2-mediated bronchodilation.

Dr Khaled M Hasan
Dr Khaled M Hasan
• B. Therapeutic uses
• The β-blockers are more effective for treating
hypertension in white than in black patients, and in young
compared to elderly patients.

• Conditions that discourage the use of β-blockers (for

example, severe chronic obstructive lung disease, chronic
congestive heart failure, or severe symptomatic occlusive
peripheral vascular disease) are more commonly found in
the elderly and in diabetics.

• 2. Hypertensive patients with concomitant diseases: The

β-blockers are useful in treating conditions that may
coexist with hypertension, such as supraventricular
tachyarrhythmia, previous myocardial infarction, angina
pectoris, chronic heart failure, and migraine headache.

Dr Khaled M Hasan
• C. Pharmacokinetics
• The β-blockers are orally active. The β-blockers may take several
weeks to develop their full effects.
• D. Adverse effects
• Bradycardia, fatigue, lethargy, insomnia, and hallucinations,
hypotension, decrease libido, impotence. Drug-induced sexual
dysfunction can severely reduce patient compliance.
• Decrease HDL and increase plasma triacylglycerol.
• 3. Drug withdrawal: Abrupt withdrawal may cause rebound
hypertension, probably as a result of up-regulation of β-receptors.
Removal from β-blocker therapy should therefore be tapered to
avoid precipitation of arrhythmias.
• The β-blockers should be employed cautiously in the treatment of
patients with asthma, acute heart failure, or peripheral vascular
disease.
Dr Khaled M Hasan
 VII. ACE Inhibitors
• The ACE inhibitors, such as
enalapril or lisinopril, are
recommended when the
preferred first-line agents
(diuretics or β-blockers) are
contraindicated or
ineffective.
Dr Khaled M Hasan
 ACE Inhibitors
Alacepril, Lisinopril,
Benazepril, Moexipril,
Captopril, Perindopril,
Cilazapril, Quinapril,
Delapril, Ramipril,
Enalapril, Spirapril,
Enalaprilat, Temocapril,
Fosinopril, Teprotide,
Imidapril, Trandolapril
, Zofenopril,
Dr Khaled M Hasan
• A. Actions
• The ACE inhibitors lower blood pressure by reducing peripheral
vascular resistance without reflexively increasing cardiac output,
rate, or contractility. These drugs block the ACE that cleaves AngI
to form the potent vasoconstrictor AngII (Fig).

• The converting enzyme is also responsible for the breakdown of

bradykinin. Vasodilation occurs as a result of the combined effects
of lower vasoconstriction caused by diminished levels of
angiotensin II and the potent vasodilating effect of increased
bradykinin.

• By reducing circulating angiotensin II levels, ACE inhibitors also

decrease the secretion of aldosterone, resulting in decreased
sodium and water retention.

Dr Khaled M Hasan
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Hasan
• B. Therapeutic uses
• Like β-blockers, ACE inhibitors are most effective in hypertensive patients who are
white and young. However, when used in combination with a diuretic, the
effectiveness of ACE inhibitors is similar in white and black patients with
hypertension.

• Along with the angiotensin receptor blockers, ACE inhibitors slow the progression of
diabetic nephropathy and decrease albuminuria.
• ACE inhibitors are also effective in the management of patients with chronic heart
failure. ACE inhibitors are a standard in the care of a patient following a myocardial
infarction.

• C. Adverse effects
• Common side effects include dry cough, rash, fever, altered taste, hypotension (in
hypovolemic states), and hyperkalemia.
• The dry cough, which occurs in about 10% of patients, is thought to be due to
increased levels of bradykinin in the pulmonary tree.
• Potassium levels must be monitored, and potassium supplements or
spironolactone
are contraindicated.
• Angioedema is a rare but potentially life-threatening reaction and may also be due to
increased levels of bradykinin. Because of the risk of angioedema and first-dose
syncope, ACE inhibitors are first administered in the physician's office with close
observation.
• Reversible renal failure can occur in patients with severe renal artery stenosis. ACE
inhibitors are feto-toxic and shouldDrnot beMused
Khaled Hasan by women who are pregnant.
Angiotensin-converting enzyme inhibitors
• CAPTOPRIL
• CILAZAPRIL
• ENALAPRIL MALEATE
• FOSINOPRIL SODIUM
• IMIDAPRIL HYDROCHLORIDE
• LISINOPRIL
• MOEXIPRIL HYDROCHLORIDE
• PERINDOPRIL ERBUMINE
• QUINAPRIL
• RAMIPRIL
• RAMIPRIL WITH FELODIPINE
• TRANDOLAPRIL

Dr Khaled M Hasan
 VIII. Angiotensin II-receptor Antagonists
• The Ang- II-receptor blockers (ARBs) are alternatives to the
ACE inhibitors.
• Losartan, is the prototypic ARB; currently, there are six additional
ARBs. Their pharmacologic effects are similar to those of ACE
inhibitors in that they produce vasodilation and block aldosterone
secretion, thus lowering blood pressure and decreasing salt and
water retention.

• ARBs decrease the nephrotoxicity of diabetes, making them an

attractive therapy in hypertensive diabetics. Their adverse
effects are similar to those of ACE inhibitors, although the risks of
cough and angioedema are significantly decreased. They are
feto-toxic.
•

Dr Khaled M Hasan
 Angiotensin-II receptor antagonists
• CANDESARTAN CILEXETIL
• EPROSARTAN
• IRBESARTAN
• LOSARTAN POTASSIUM
• OLMESARTAN MEDOXOMIL
• TELMISARTAN
• VALSARTAN

Dr Khaled M Hasan
 IX. Calcium Channel Blockers (CCB)
• CCBs are recommended when the preferred firstline
agents are contraindicated or ineffective.
• They are effective in treating hypertension in patients
with angina or diabetes. High doses of short-acting
CCBs should be avoided because of increased risk of
myocardial infarction.
• Classes of calcium channel blockers
• Verapamil
• Diltiazem
• Dihydropyridines (nifedipine, amlodipine, felodipine,
isradipine, nicardipine, and nisoldipine)

Dr Khaled M Hasan
• Verapamil is the least selective of any calcium channel
blocker, and has significant effects on both cardiac and
vascular smoothmuscle cells. It is used to treat angina,
supraventricular tachyarrhythmias, and migraine
headache.
•
• Diltiazem, like verapamil, diltiazem affects both cardiac
and vascular smoothmuscle cells; however, it has a less
pronounced negative inotropic effect on heart compared
to that of verapamil. Diltiazem has a favorable side-effect
profile.

Dr Khaled M Hasan
• Dihydropyridines include nifedipine, amlodipine,
felodipine, isradipine, nicardipine, and nisoldipine.
• These new-generation calcium channel blockers differ in pharmacokinetics, approved uses, and drug
interactions.

• All dihydropyridines have a much greater affinity for

vascular calcium channels than for calcium channels in
the heart. They are therefore particularly attractive in
treating hypertension.

• Newer agents, such as amlodipine and nicardipine, have

the advantage that they show little interaction with
other cardiovascular drugs, such as digoxin or warfarin,
which are often used concomitantly with calcium
channel blockers.
Dr Khaled M Hasan
Dr Khaled M Hasan
 Calcium-channel blockers
• AMLODIPINE
• DILTIAZEM HYDROCHLORIDE
• FELODIPINE
• ISRADIPINE
• LACIDIPINE
• LERCANIDIPINE HYDROCHLORIDE
• NICARDIPINE HYDROCHLORIDE
• NIFEDIPINE
• NIMODIPINE
• NISOLDIPINE
• VERAPAMIL HYDROCHLORIDE

Dr Khaled M Hasan
• B. Actions
• The intracellular concentration of calcium plays an important role in
maintaining the tone of smooth muscle and in the contraction of the
myocardium.
• Calcium enters muscle cells through special voltagesensitive calcium channels. This triggers release of
calcium from the sarcoplasmic reticulum and mitochondria, which further increases the cytosolic level
of calcium.
• Calcium channel antagonists block the inward movement of calcium by
binding to L-type calcium channels in the heart and in smooth muscle of
the coronary and peripheral vasculature. This causes vascular smooth
muscle to relax, dilating mainly arterioles.
•
• C. Therapeutic uses
• Calcium channel blockers have an intrinsic natriuretic effect and, therefore,
do not usually require the addition of a diuretic. These agents are useful in
the treatment of hypertensive patients who also have asthma, diabetes,
angina, and/or peripheral vascular disease (Fig). Black hypertensives
respond well to calcium channel blockers.

Dr Khaled M Hasan
• D. Pharmacokinetics
• Most of these agents have short half-lives (3-8 hours).
Treatment is required three times a day to maintain good
control of hypertension. Sustained-release preparations permit
less frequent dosing.
•
• E. Adverse effects
• Infrequent side effects: constipation 10%, as dizziness,
headache, and a feeling of fatigue caused by a decrease in
blood pressure, edema (Fig).

• Verapamil should be avoided in patients with congestive heart

failure due to its negative inotropic effects.

Dr Khaled M Hasan
 Alpha(α )-Adrenoceptor-blocking Agents
• Prazosin, doxazosin, and terazosin produce a competitive block of α-
adrenoceptors.
• They decrease the peripheral vascular resistance and lower the
arterial blood pressure by causing relaxation of both arterial and
venous smooth muscle.
• These drugs cause only minimal changes in cardiac output, renal
blood flow, and glomerular filtration rate. Therefore, long-term
tachycardia does not occur, but salt and water retention does.

• Postural hypotension may occur in some individuals. Reflex

tachycardia and first-dose syncope are almost universal adverse
effects. Concomitant use of a beta-blocker may be necessary to
blunt the short-term effect of reflex tachycardia.
Dr Khaled M Hasan
• DOXAZOSIN
• INDORAMIN
• PRAZOSIN
• TERAZOSIN

• Prostatic hyperplasia
• Alfuzosin, doxazosin, indoramin, prazosin,
tamsulosin, and terazosin are indicated for benign
prostatic hyperplasia

Dr Khaled M Hasan
 Centrally Acting Adrenergic Drugs
A. Clonidine
• This α2 agonist diminishes central adrenergic outflow. Clonidine
is used primarily for the treatment of mild to moderate
hypertension that has not responded adequately to treatment
with diuretics alone. Clonidine does not decrease renal blood
flow or glomerular filtration and, therefore, is useful in the
treatment of hypertension complicated by renal disease.

• Clonidine is absorbed well after oral administration and is

excreted by the kidney. Because it causes sodium and water
retention, clonidine is usually administered in combination with a
diuretic.
• Side effects: mild (sedation, drying nasal mucosa)
• Rebound HT occurs followinDrgKhaaedl bMrHuapsant withdrawal of clonidine
 B. α-Methyldopa
• This α2-agonist is converted to methylnorepinephrine
centrally to diminish the adrenergic outflow from the
CNS, leading to reduced total peripheral resistance
and a decreased blood pressure.
• Cardiac output is not decreased and blood flow to
vital organs is not diminished. Because blood flow to
the kidney is not diminished by its use, α-methyldopa
is especially valuable in treating HT patients with renal
insufficiency.
• Side effects : sedation and drowsiness.

Dr Khaled M Hasan
Dr Khaled M
Hasan
 Vasodilators
• Direct-acting smooth muscle relaxants: hydralazine ,minoxidil.
• Vasodilators produce relaxation of vascular smooth muscle,
which decreases resistance and therefore decreases blood
pressure.

• These agents produce reflex stimulation of the heart, resulting in

the competing symptoms of increased myocardial contractility,
heart rate, and oxygen consumption. These actions may prompt
angina pectoris, myocardial infarction, or cardiac failure in
predisposed individuals.

• Vasodilators also increase plasma renin concentration,

resulting in sodium and water retention. These undesirable side
effects Dr Khaled M Hasan can be
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A. Hydralazine
• Hydralazine is used to treat moderately severe HT. It is
almost always administered in combination with a beta-
blocker such as propranolol (to balance the reflex
tachycardia) and a diuretic (to decrease sodium
retention). Together, the three drugs decrease cardiac
output, plasma volume, and peripheral vascular
resistance.

• A lupus-like syndrome can occur with high dosage, but it

is reversible on discontinuation of the drug.

Dr Khaled M Hasan
B. Minoxidil
• This drug causes dilation of resistance vessels
(arterioles) but not of capacitance vessels (venules).
• Minoxidil is administered orally for treatment of severe
to malignant hypertension that is refractory to other
drugs.

• Minoxidil causes serious sodium and water retention,

leading to volume overload, edema, and congestive
heart failure.
• Minoxidil treatment also causes hypertrichosis (growth
of body hair). This drug is now used topically to treat
male pattern baldness.
Dr Khaled M Hasan
 Hypertensive Emergency
• Hypertensive emergency is a rare but life-
threatening situation in which the DBP is either >150
mm Hg (with SBP >210 mm Hg) in an otherwise
healthy person, or a DBP of 130 mm Hg in an
individual with preexisting complications, such as
encephalopathy, cerebral hemorrhage, left-ventricular
failure, or aortic stenosis.
• The therapeutic goal is to rapidly reduce blood
pressure.
• A. Sodium nitroprusside
• B. Labetalol
• C. Fenoldopam
Dr Khaled M Hasan
•
A. Sodium nitroprusside
• Nitroprusside is administered intravenously, and causes prompt
vasodilation with reflex tachycardia. It is capable of reducing
blood pressure in all patients regardless of the cause of
hypertension (Fig).
• The drug has little effect outside the vascular system, acting
equally on arterial and venous smooth muscle.
• Because nitroprusside also acts on the veins, it can reduce cardiac preload.
Nitroprusside is metabolized rapidly (halflife of minutes) and requires continuous
infusion to maintain its hypotensive action.
• Adverse effects: hypotension caused by overdose. Nitroprusside
metabolism results in cyanide ion production.
• Although cyanide toxicity is rare, it can be effectively treated with an infusion of
sodium thiosulfate to produce thiocyanate, which is less toxic and is eliminated by the
kidneys. [Note: Nitroprusside is poisonous if given orally because of its hydrolysis to
cyanide.]

Dr Khaled M Hasan
• B. Labetalol
• Labetalol is both an (alpha- and a beta-blocker and is given as an intravenous
bolus or infusion in hypertensive emergencies. Labetalol does not cause reflex
tachycardia. Labetalol carries the contraindications of a nonselective beta-
blocker. The major limitation is a longer half-life, which precludes rapid titration.

• C. Fenoldopam
• Fenoldopam is a peripheral dopamine-1 receptor agonist that is given as an
intravenous infusion. Unlike other parenteral antihypertensive agents,
fenoldopam maintains or increases renal perfusion while it lowers blood
pressure. Fenoldopam can be safely used in all hypertensive emergencies and
may be particularly beneficial in patients with renal insufficiency.

• D. Nicardipine
• Nicardipine, a calcium channel blocker, can be given as an intravenous
infusion.

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