Official reprint from UpToDate

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Drugs used for the treatment of hypertensive emergencies

Authors
Section Editors
William J Elliott, MD, PhD
George L Bakris, MD
Joseph Varon, MD, FACP, FCCP, Norman M Kaplan, MD
FCCM, FRSM

Deputy Editor
John P Forman, MD, MSc

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2016. | This topic last updated: Nov 03, 2014.

INTRODUCTION A hypertensive emergency is present when severe hypertension is associated with

acute end-organ damage. Examples include hypertensive encephalopathy, acute pulmonary edema, aortic
dissection, and rebound after abrupt withdrawal of antihypertensive medications. Immediate but careful
reduction in blood pressure is often indicated in these settings. However, an excessive hypotensive
response is potentially dangerous, possibly leading to ischemic complications such as stroke, myocardial
infarction, or blindness. Thus, in patients who are severely hypertensive but asymptomatic, slower
reductions in blood pressure may be achieved with oral agents. (See 'Oral drugs' below.)
The drugs that are used for the treatment of hypertensive emergencies are presented in this topic. The
evaluation of patients with severe hypertension and the blood pressure goals in patients with hypertensive
emergencies are presented elsewhere. (See "Evaluation and treatment of hypertensive emergencies in
adults".)
PARENTERAL DRUGS A variety of parenteral and oral antihypertensive drugs are available for use in
these patients (table 1) [1-5]. Few studies have compared these agents with one another, and all are
tolerated reasonably well [6,7]. Thus, the drug of choice is often dictated by the type of hypertensive
emergency and the local hospital formulary. (See "Moderate to severe hypertensive retinopathy and
hypertensive encephalopathy in adults" and "Evaluation and treatment of hypertensive emergencies in
adults".)
Nitrates Nitrovasodilators such as nitroprusside and nitroglycerin provide nitric oxide that induces
vasodilatation (of both arterioles and veins) via generation of cyclic GMP, which then activates calciumsensitive potassium channels in the cell membrane [8].

Nitroprusside Sodium nitroprusside, when administered by intravenous infusion, begins to act within
one minute or less, and once discontinued, its effects disappear within 10 minutes or less. Frequent
monitoring is required since this drug can produce a sudden and drastic drop in blood pressure.

The recommended starting dose of nitroprusside is 0.25 to 0.5 mcg/kg per minute. This can be increased as
necessary to a maximum dose of 8 to 10 mcg/kg per minute, although use of these higher doses should
generally be avoided or limited to a maximum duration of 10 minutes [9].
Toxicities and limitations of nitroprusside include:

Nitroprusside is metabolized to cyanide, possibly leading to the development of cyanide (or, rarely,
thiocyanate) toxicity that may be fatal [9]. This problem, which can manifest in as little as four hours,
presents with altered mental status and lactic acidosis. Risk factors for nitroprusside-induced cyanide
poisoning include a prolonged treatment period (>24 to 48 hours), underlying renal impairment, and
the use of doses that exceed the capacity of the body to detoxify cyanide (ie, more than 2 mcg/kg per
minute). The risk of toxicity can be minimized by using the lowest possible dose, avoiding prolonged
use (ie, no more than two or three days), and by careful patient monitoring (with special attention to

unexplained acidemia or decreasing serum bicarbonate concentrations).

In addition, doses of 10 mcg/kg per minute should never be given for more than 10 minutes. An
infusion of sodium thiosulfate can be used in affected patients to provide a sulfur donor to detoxify
cyanide into thiocyanate [9].

Nitroprusside can result in dose-related declines in coronary, renal, and cerebral perfusion.

Nitroprusside should not be given to pregnant women, patients with Lebers optic atrophy, or patients
with tobacco amblyopia. In addition, nitroprusside should be avoided, if possible, in patients with
impaired renal function. (See 'Fenoldopam' below.)

Nitroglycerin Nitroglycerin is also administered by intravenous infusion and is similar in action and
pharmacokinetics to nitroprusside except that it produces relatively greater venodilation than arteriolar
dilation. It has less antihypertensive efficacy compared with other drugs used to treat hypertensive
emergencies, and its effects on blood pressure are variable from person to person and, potentially, from
minute to minute. However, it may be useful in patients with symptomatic coronary disease and in those with
hypertension following coronary bypass.
The initial dose of nitroglycerin is 5 mcg/min, which can be increased as necessary to a maximum of 100
mcg/min. The onset of action is 2 to 5 minutes, while the duration of action is 5 to 10 minutes. Headache
(due to direct vasodilation) and tachycardia (resulting from reflex sympathetic activation) are the primary
adverse effects. Cyanide accumulation does not occur. Methemoglobinemia has been reported in patients
receiving this agent for more than 24 hours.
Calcium channel blockers

Clevidipine Clevidipine is an ultra short-acting dihydropyridine calcium channel blocker that is

approved for intravenous use to treat severe hypertension. The drug is hydrolyzed by serum esterases and
has a serum elimination half-life of 5 to 15 minutes. It reduces blood pressure without affecting cardiac filling
pressures but can cause reflex tachycardia [1,10]. Clevidipine is contraindicated in patients with severe
aortic stenosis (because it increases the risk of severe hypotension), disordered lipid metabolism (because it
is administered in a lipid-laden emulsion), or known allergies to soy or eggs (because these are used to
produce the emulsion). It has not been compared with other short-acting drugs, such as nitroprusside and
nitroglycerin. The initial dose is 1 mg/hour, which can be increased as necessary to a maximum of 21
mg/hour.
Nicardipine Nicardipine is a dihydropyridine calcium channel blocker (like nifedipine) that can be
given as an intravenous infusion. The initial dose is 5 mg/hour and can be increased to a maximum of 15
mg/hour. Nicardipine has a better safety profile and a similar antihypertensive effect when compared with
nitroprusside [11]. The major limitations are a longer onset of action, which precludes rapid titration, and a
longer serum elimination half-life (three to six hours).
Dopamine-1 agonist

Fenoldopam Fenoldopam is a peripheral dopamine-1 receptor agonist which, unlike other parenteral
antihypertensive agents, maintains or increases renal perfusion while it lowers blood pressure [12].
Fenoldopam may be particularly beneficial in patients with renal impairment. After starting at 0.1 mcg/kg per
minute, the dose can be titrated at 15-minute intervals to 1.6 mcg/kg per minute, depending upon the blood
pressure response. Some experts have used doses as high as 2.0 mcg/kg per minute or higher without
inducing toxicity.

Fenoldopam should be used cautiously or not at all in patients with glaucoma [12]. In addition, because this
agent is premixed in a solution containing sodium metabisulfite, caution is recommended for patients with
sulfite sensitivity.
Adrenergic-blocking agents

Labetalol Labetalol is a combined beta-adrenergic and alpha-adrenergic blocker. Its rapid onset of
action (five minutes or less) makes it a useful intravenous medication for the treatment of hypertensive
emergencies. However, one trial found that labetalol has less antihypertensive efficacy as compared with
nicardipine [13].

Labetalol is safe in patients with active coronary disease since it does not increase heart rate. However,
labetalol should be avoided in patients with asthma, chronic obstructive lung disease, heart failure,
bradycardia, or greater than first-degree heart block. In addition, labetalol should not be used without prior
adequate alpha blockade in patients with hyperadrenergic states, such as pheochromocytoma or cocaine or
methamphetamine overdose, since unopposed, inadequately blocked alpha-adrenergic activity can increase
blood pressure if beta blockade is not complete. (See "Cocaine: Acute intoxication", section on 'Use of beta
blockers'.)
Labetalol can be given as a series of intravenous bolus injections or as a constant-dose infusion. The bolus
dose is 20 mg initially, followed by 20 to 80 mg every 10 minutes to a total dose of 300 mg. The infusion rate
is 0.5 to 2 mg/min.
Esmolol Esmolol, a relatively cardioselective beta blocker, is rapidly metabolized by blood esterases.
Its effects begin almost immediately, and it has both a short half-life (about 9 minutes) and a short total
duration of action (about 30 minutes), permitting rapid titration. Esmolol is often used during anesthesia to
prevent postintubation hemodynamic perturbations.
Other agents

Hydralazine Hydralazine is a direct arteriolar vasodilator with little or no effect on the venous
circulation. Thus, precautions are needed in patients with underlying coronary disease or aortic dissection,
and a beta blocker should be given concurrently to minimize reflex sympathetic stimulation. The hypotensive
response to hydralazine is less predictable than that seen with other parenteral agents. The use of
parenteral hydralazine is primarily limited to pregnant women, although a reduction in the utero-placental
blood flow has been reported in such patients. (See "Management of hypertension in pregnant and
postpartum women".)
Hydralazine can be given as an intravenous bolus. The initial dose is 10 mg, with the maximum dose being
20 mg. The fall in blood pressure can be sudden and begins within 10 to 30 minutes and lasts two to four
hours.

Enalaprilat Enalaprilat is the intravenously active, des-ethyl ester of the angiotensin-converting

enzyme (ACE) inhibitor, enalapril. The hypotensive response to enalaprilat is unpredictable and depends
upon the plasma volume and plasma renin activity in individual patients with a hypertensive emergency [14].
Typically, hypovolemic patients with a high plasma renin activity are most likely to have an excessive
hypotensive response. In addition, ACE inhibitors are contraindicated in pregnancy, severe renal artery
stenosis with global ischemia, and severe hyperkalemia. (See "Angiotensin converting enzyme inhibitors
and receptor blockers in pregnancy".)
The usual initial dose is 1.25 mg. As much as 5 mg may be given every six hours as necessary [14]. The
onset of action begins in 15 minutes, but the peak effect may not be seen for four hours. The duration of
action ranges from 12 to 24 hours.

Phentolamine Phentolamine is a nonselective alpha-adrenergic blocker, the use of which is limited to

the treatment of severe hypertension due to increased catecholamine activity. Examples include
pheochromocytoma or tyramine ingestion in a patient being treated with a monoamine oxidase inhibitor.
(See "Clinical presentation and diagnosis of pheochromocytoma" and "Treatment of pheochromocytoma in
adults".)
Phentolamine is given as an intravenous bolus. The usual dose is 10 to 15 mg every 5 to 15 minutes as
necessary. Patients receiving this agent who do not require intravenous therapy can be converted to oral
phenoxybenzamine.

ORAL DRUGS Oral antihypertensive agents usually lower the blood pressure more slowly than
parenteral drugs. Thus, they are primarily used when parenteral agents are not available or when there is
severe hypertension without serious acute end-organ damage; see Management of severe asymptomatic
hypertension (hypertensive urgencies) in adults for a discussion of this issue, and see Moderate to severe
hypertensive retinopathy and hypertensive encephalopathy in adults.

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Basics topics (see "Patient information: High blood pressure emergencies (The Basics)")

SUMMARY AND RECOMMENDATIONS

A hypertensive emergency is defined as severe hypertension that is associated with acute end-organ
damage. (See 'Introduction' above.)
Immediate but careful reduction in blood pressure is indicated in hypertensive emergencies; an
excessive hypotensive response may lead to ischemic complications. A variety of parenteral and oral
antihypertensive drugs are available for use in these patients (table 1). (See 'Introduction' above and
'Parenteral drugs' above.)
Parenteral drugs include nitroprusside, nitroglycerin, clevidipine, nicardipine, fenoldopam, labetalol,
esmolol, hydralazine, enalaprilat, and phentolamine. (See 'Parenteral drugs' above.)

Among patients who are severely hypertensive but asymptomatic, slower reductions in blood pressure
may be provided with oral agents. (See 'Oral drugs' above.)
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REFERENCES
1. Varon J. Treatment of acute severe hypertension: current and newer agents. Drugs 2008; 68:283.
2. Vaughan CJ, Delanty N. Hypertensive emergencies. Lancet 2000; 356:411.

3. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for the management of arterial
hypertension: the Task Force for the management of arterial hypertension of the European Society of
Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013; 31:1281.
4. Cherney D, Straus S. Management of patients with hypertensive urgencies and emergencies: a
systematic review of the literature. J Gen Intern Med 2002; 17:937.

5. Perez MI, Musini VM. Pharmacological interventions for hypertensive emergencies: a Cochrane
systematic review. J Hum Hypertens 2008; 22:596.

6. Grossman E, Ironi AN, Messerli FH. Comparative tolerability profile of hypertensive crisis treatments.
Drug Saf 1998; 19:99.
7. Peacock F, Amin A, Granger CB, et al. Hypertensive heart failure: patient characteristics, treatment,
and outcomes. Am J Emerg Med 2011; 29:855.

8. Archer SL, Huang JM, Hampl V, et al. Nitric oxide and cGMP cause vasorelaxation by activation of a
charybdotoxin-sensitive K channel by cGMP-dependent protein kinase. Proc Natl Acad Sci U S A
1994; 91:7583.
9. Schulz V. Clinical pharmacokinetics of nitroprusside, cyanide, thiosulphate and thiocyanate. Clin
Pharmacokinet 1984; 9:239.

10. Aronson S, Dyke CM, Stierer KA, et al. The ECLIPSE trials: comparative studies of clevidipine to
nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac
surgery patients. Anesth Analg 2008; 107:1110.
11. Neutel JM, Smith DH, Wallin D, et al. A comparison of intravenous nicardipine and sodium
nitroprusside in the immediate treatment of severe hypertension. Am J Hypertens 1994; 7:623.

12. Murphy MB, Murray C, Shorten GD. Fenoldopam: a selective peripheral dopamine-receptor agonist
for the treatment of severe hypertension. N Engl J Med 2001; 345:1548.

13. Peacock WF, Varon J, Baumann BM, et al. CLUE: a randomized comparative effectiveness trial of IV
nicardipine versus labetalol use in the emergency department. Crit Care 2011; 15:R157.
14. Hirschl MM, Binder M, Bur A, et al. Clinical evaluation of different doses of intravenous enalaprilat in
patients with hypertensive crises. Arch Intern Med 1995; 155:2217.
Topic 3840 Version 15.0

GRAPHICS

Parenteral drugs for treatment of hypertensive emergencies in

adults*
Drug
Vasodilators
Clevidipine

Dose
range

1 to 2
mg/hour as
IV infusion
with rapid
titration.

Onset of
action

Duration
of action

Adverse
effects

Role*

(minutes)

(minutes)

2 to 4

5 to 15

Atrial fibrillation,
nausea, lipid
formulation contains
potential allergens
(eg, soy, egg)

Hypertensive
emergencies
including
postoperative
hypertension.

15 to 30

~6 to >12
hours

Precipitous fall in
pressure in highrenin states;
variable response,
headache, dizziness

Acute left
ventricular failure.

Most patients
respond to 4
to 6 mg/hour
and are
treated with
maximum
doses of 16
mg/hour or
less.

Enalaprilat

Fenoldopam

NOTE:
Delivered in
lipid
emulsion.
1000 mL
maximum
per 24 hours
(equivalent
to 21
mg/hour)
due to lipid
load
restriction.

1.25 to 5 mg
every six
hours IV

5 to 10

30 to 60

Due to slow onset

and long duration
of effect, rarely
used.
Avoid use in AMI,
renal impairment,
or pregnancy.

0.1 mcg/kg

Tachycardia,

per minute
as IV

headache, nausea,
flushing

infusion
titrated to a
maximum of
1.6 mcg/kg
per minute

Hydralazine

10 to 20 mg
IV
10 to 40 mg
IM

Nicardipine

5 to 15
mg/hour as
IV infusion.

emergencies,
including aortic
dissection.

Use caution or
avoid with

10 to 20 IV
20 to 30 IM

5 to 15

1 to 4 hours
IV
4 to 6 hours
IM

~1.5 to 4
hours

Some

patients may
require up to
30 mg per
hour.

Sudden precipitous
drop in blood
pressure,
tachycardia,
flushing, headache,
vomiting,
aggravation of
angina
Tachycardia,
headache, dizziness,
nausea, flushing,
local phlebitis,
edema

glaucoma or
increased
intracranial
pressure.

In general,
hydralazine should
be avoided due to
its prolonged and
unpredictable
hypotensive effect.

Labetalol and
nicardipine are
generally preferred
Most hypertensive
choices for
emergencies,
treatment of
including aortic
eclampsia.
dissection and
pregnancyinduced.
Avoid use in acute
heart failure.

Nitroglycerin
(glyceryl
trinitrate)

5 to 100
mcg/minute
as IV
infusion

2 to 5

5 to 10

Nitroprusside

0.25 to 10
mcg/kg per
minute as IV
infusion.

0.5 to 1

1 to 10

To minimize
risk of
cyanide
toxicity,
infusion
duration

Most hypertensive

Hypoxemia,
tachycardia (reflex
sympathetic
activation),
headache, vomiting,
flushing,
methemoglobinemia,
tolerance with
prolonged use
Elevated intracranial
pressure, decreased
cerebral blood flow,
reduced coronary
blood flow in CAD,
cyanide and
thiocyanate toxicity,
nausea, vomiting,
muscle spasm,
flushing, sweating

Caution with
coronary ischemia.

Potential adjunct to
other IV
antihypertensive
therapy in patients
with coronary
ischemia (ACS) or
acute pulmonary
edema.
In general,
nitroprusside
should be avoided
due to its toxicity.

If other
appropriate agents
(eg, nicardipine,
fenoldopam) are
unavailable, can be
used for treating

should be as

aortic dissection

not exceed 2
mcg/kg per
minute.

beta blockade.

short as
possible and

after control of
heart rate with

Nitroprusside
should be avoided

Patients who
receive
higher doses
(ie, >500

in patients with
AMI, CAD, CVA or
elevated
intracranial

mcg/kg at a
rate
exceeding 2
mcg/kg per
minute)
should
receive

pressure, renal or
hepatic
impairment.

sodium
thiosulfate
infusion to
avoid
cyanide
toxicity.

Adrenergic inhibitors
Esmolol

Labetalol

250 to 500
mcg/kg
loading dose
over one
minute; then
initiate IV
infusion at
25 to 50
mcg/kg per
minute;
titrate
incrementally
up to

1 to 2

Initial bolus
of 20 mg IV
followed by
20 to 80 mg
IV bolus
every 10
minutes

5 to 10

maximum of
300 mcg/kg
per minute

10 to 30

2 to 4 hours

Nausea, flushing,
bronchospasm, firstdegree heart block,
infusion site pain;
half-life prolonged in
setting of anemia

Aortic dissection,
perioperative
hypertension.

Nausea/vomiting,
paresthesias (eg,
scalp tingling),
bronchospasm,
dizziness, nausea,
heart block

Most hypertensive
emergencies
including
myocardial
ischemia, aortic
dissection,
hypertensive
encephalopathy,

Avoid use in acute

decompensated
heart failure.

(maximum

pregnancy, and

300 mg)

postoperative
hypertension.

OR

Avoid use in acute

decompensated
heart failure.

0.5 to 2
mg/minute
as IV
infusion
following an
initial 20 mg

Metoprolol

Phentolamine

IV bolus
(maximum
300 mg per
24 hours)

Use cautiously in
obstructive or
reactive airway.

Initially 1.25
to 5 mg IV
followed by
2.5 to 15 mg
IV every
three to six
hours

20

5 to 15 mg
IV bolus
every 5 to 15
minutes

1 to 2

5 to 8 hours

10 to 30

Refer to labetalol

Tachycardia,
flushing, headache,
nausea/vomiting

Aortic dissection,
myocardial
ischemia,
perioperative
hypertension.

Avoid use in acute

decompensated
heart failure.

Alternative option
for catecholamine
excess (eg,
adrenergic crisis
secondary to
pheochromocytoma
or cocaine
overdose).

AMI: acute myocardial infarction; CAD: coronary artery disease; CVA: cerebrovascular accident.
* Intravenous short-acting agents for treatment of hypertensive emergency should be administered
immediately by clinicians who are trained and experienced in their titration using continuous noninvasive electronic monitoring of blood pressure, heart rate, and ECG. Patients should be admitted
to an intensive care unit as rapidly as possible. A combination of IV agents is often selected
depending upon the acute indication. Refer to topic(s) for suggested combinations.
Hypotension may occur with all agents.

References:
1. Marik PE, Varon J. Hypertensive crises: Challenges and management. Chest 2007;
131:1949.
2. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on
Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension
2003; 42:1206.
3. Varon J. Treatment of acute severe hypertension: Current and newer agents. Drugs 2008;
68:283.
NOTE: Recommendations for parenteral treatment of hypertensive emergencies were not given in
either the JNC 8 guideline (James PA, Oparil S, Carter BL, et al. 2014 Evidence-based guideline for
the management of high blood pressure in adults: Report from the panel members appointed to the

Eighth Joint National Committee [JNC 8]. JAMA 2014; 311:507) or the Joint ASH/ISH guidelines
(Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of
hypertension in the community: A statement by the American Society of Hypertension and the
International Society of Hypertension [ASH/ISH]. J Hypertens 2014; 32:3).
Graphic 64066 Version 26.0

Contributor Disclosures

William J Elliott, MD, PhD Consultant/Advisory Board: Insyght Interactive [Hyperkalemia (Patiromer)].
Other Financial Interest: Elsevier; Springer [Hypertension (book, journal)]. Joseph Varon, MD, FACP,
FCCP, FCCM, FRSM Nothing to disclose. George L Bakris, MD Grant/Research/Clinical Trial Support:
Bayer, Boehringer Ingelheim, Relypsa, Vascular Dynamics, Medtronic [Diabetic neuropathy, diabetes,
hypertension (Empagliflozin, patiromer)]. Consultant/Advisory Boards: AstraZeneca, Arbor Pharmaceuticals,
Bayer, Boehringer Ingelheim, Relypsa, Vascular Dynamics, Medtronic [Diabetic neuropathy, diabetes,
hypertension (Empagliflozin, patiromer)]. Norman M Kaplan, MD Nothing to disclose. John P Forman, MD,
MSc Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
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