clinical review Intravenous therapy

clinical review

Intravenous therapy
for hypertensive emergencies, part 1
Denise Rhoney and W. Frank Peacock

ypertension is a global problem,

affecting 50 million people in
the United States and 1 billion
people worldwide.1,2 In the United
States, as many as 60% of adults over
age 18 years are either prehypertensive or hypertensive, according to the
seventh report of the Joint National
Committee on Prevention, Diagnosis and Treatment of High Blood
Pressure (JNC-7) guidelines.1-3 The
Framingham Heart Study found that
individuals who are normotensive at
age 55 years have a 90% lifetime risk
of developing hypertension.4
Supplementary material is available
with the full text of this article
at www.ajhp.org.

Hypertensive crises include both

urgencies and emergencies. Hypertensive emergencies are always associated with end-organ damage, not
with a specific level of blood pressure
(BP). Hypertensive emergencies are
associated with severe elevations in

Purpose. Intravenous antihypertensive

agents for the treatment of hypertensive
emergencies are reviewed.
Summary. An estimated 500,000 people in
the United States experience a hypertensive crisis annually. Hypertensive emergency is associated with significant morbidity
in the form of end-organ damage. Rapid
controlled reduction of blood pressure (BP)
may be necessary to prevent or minimize
end-organ damage. I.V. antihypertensive
agents available for the treatment of hypertensive emergencies are, in general,
characterized by a short onset and offset
of action and predictable responses during dosage adjustments to reach BP goals,
without excessive adjustment or extreme
fluctuations in BP. Nicardipine, nitroprusside, fenoldopam, nitroglycerin, enalaprilat,
hydralazine, labetalol, esmolol, and phentolamine are i.v. antihypertensive agents
recommended for use in hypertensive
emergency by the seventh report of the
Joint National Committee on Prevention,

BP (systolic BP [SBP] level of >180

mm Hg or diastolic BP [DBP] level
of >120 mm Hg) in the presence of
impending or progressive end-

Denise Rhoney, Pharm.D., FCCP, FCCM, is Associate Professor,

Department of Pharmacy Practice, Eugene Applebaum College of
Pharmacy and Health Sciences, Wayne State University, Detroit,
MI. W. Frank Peacock, M.D., is Vice Chair, Institute of Emergency
Medicine, The Cleveland Clinic Foundation, Cleveland, OH.
Address correspondence to Dr. Rhoney at the Department of
Pharmacy Practice, Eugene Applebaum College of Pharmacy and
Health Sciences, Wayne State University, 259Mack Avenue, Detroit,
MI 48201 (drhoney@wayne.edu).
Dr. Rhoney has served on the scientific advisory boards or speakers bureaus of or received research grants from PDL BioPharma
(now EKR Therapeutics), Astellas Pharma Inc., UCB Pharma Inc.,

Detection, Evaluation, and Treatment of

High Blood Pressure. Since the publication
of these recommendations, another i.v. antihypertensive agent, clevidipine, became
commercially available. The selection of
a specific agent should be based on the
agents pharmacology and patient-specific
factors, such as comorbidity and the presence of end-organ damage.
Conclusion. The rapid recognition and
initiation of therapy are key to minimizing end-organ damage in patients with
hypertensive emergency. Tailoring drug
selection according to individual patient
characteristics can optimize the management and potential outcomes of patients
with hypertensive emergency.
Index terms: Clevidipine; Drugs; Emergencies; Enalaprilat; Esmolol; Fenoldopam;
Hydralazine; Hypertension; Hypotensive
agents; Injections; Labetalol; Nicardipine;
Nitroglycerin; Nitroprusside; Phentolamine
Am J Health-Syst Pharm. 2009; 66:1343-52

organ damage, such as neurologic

changes, hypertensive encephalopathy, cerebral infarction, intracranial
hemorrhage, myocardial ischemia

and The Medicines Company. Dr. Peacock has served on the scientific advisory boards or speakers bureaus of or received research
grants from Abbott, BAS, Beckman-Coulter, Biosite, Brahms, CHF
Solutions, Heartscape, Inovise, Inverness, Otsuka, Ortho Clinical
Diagnostics, PDL BioPharma (now EKR Therapeutics), Scios, The
Medicines Company, and Vital Sensors.
Part 2 of this article will appear in the August 15, 2009, issue.
Copyright 2009, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/09/0801-1343$06.00.
DOI 10.2146/ajhp080348.p1

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clinical review Intravenous therapy

or infarction, acute left ventricular

dysfunction, acute pulmonary edema
(APE), aortic dissection, renal insufficiency, or eclampsia.1,2,5 Although
data collected in the current era are
limited, reports from as far back as
the 1950s6 have consistently shown
that approximately 1% of hypertensive patients experience a hypertensive crisis.7,8 One study of emergency
department admissions found that
hypertensive crises accounted for
27.5% of all medical emergencies
and urgencies in patients arriving at
an emergency department, with 77%
of these patients having a history of
hypertension.9 A study examined 100
cases of hospital admissions for hypertensive emergency in a New York
City hospital.10 The mean age of this
cohort was 52 years (range, 2287
years), and 66 patients were male. A
retrospective review of cases in one
hospital in Brazil found 452 patients
with hypertensive crisis, representing
0.5% of all clinicalsurgical emergencies.11 Of these, 60.4% were hypertensive urgencies and 39.6% were
hypertensive emergencies; 62% of
hypertensive urgencies and 44.7% of
hypertensive emergencies occurred
in women. The rate of hypertensive
urgencies peaked in men age 3160
years and in women age 2160 years.
The rate of hypertensive emergencies
peaked in men age 4170 years and in
women age 6170 years.
Standard treatment for a hypertensive emergency generally includes
admission to an intensive care unit
(ICU), continuous BP monitoring,
and parenteral administration of
an antihypertensive agent. Based on
JNC-7 guidelines, the general therapeutic goal is to lower the mean
arterial pressure (MAP) by 2025%
within 60 minutes, avoiding a precipitous or excessive decrease in
BP that may cause iatrogenic renal,
cerebral, or coronary ischemia.1 This
recommendation is based on the
bodys ability to autoregulate tissue
perfusion in the brain, heart, and
kidneys, which lowers the prevail1344

ing BP by 2025% under normal

conditions and during severe hypertension.12 If the patient is stable,
SBP can be further reduced to 160
mm Hg and DBP can be reduced
to 100110 mm Hg over the ensuing 26 hours. A gradual reduction
to the patients baseline normal
BP is targeted over the initial 2448
hours if the patient is stable, with
appropriate monitoring for signs or
symptoms of ischemia-related endorgan system deterioration that may
accompany changes in SBP, DBP, or
MAP.1,2
A number of agents in a variety
of drug classes are available for the
treatment of hypertensive emergencies. This review discusses the i.v.
antihypertensive drugs and provides
insights and evidence to support
their respective clinical applicability
in managing emergent hypertensive
conditions.
Rationale for i.v. antihypertensive
selection
In general, the multiple agents
available for the treatment of hypertensive emergencies rapidly lower BP
in patients at imminent risk of or
during evolving end-organ damage.1
The goal of drug therapy is to reduce
BP in a controlled and predictable
manner, while weighing the potential
adverse effects of each drug on an
individual basis. Both drug-specific
and patient-specific factors must be
considered to ensure the selection of
an appropriate agent. Drug-specific
factors include the drugs pharmacokinetic parameters and adverse
effects. In addition, due to the potential for overshoot with agents
like nitroprusside, arterial BP monitoring is a requirement for the use
of some agents. Cost-effectiveness
is another important drug-specific
factor and should include consideration of the length of hospital stay,
time spent in the ICU, and long-term
morbidity. Unfortunately, few studies have rigorously evaluated the
cost-effectiveness of pharmacologic

Am J Health-Syst PharmVol 66 Aug 1, 2009

agents for the management of hypertensive emergencies. Thus, treatment

decisions cannot currently be based
on perceived cost-effectiveness. A
detailed description of important
drug-specific factors of each agent is
available in eTables 1 and 2 (accessible online at www.ajhp.org).
Patient-specific factors that must
be considered when selecting an
appropriate drug and dose include
patient age, race, pregnancy status,
and volume status and the presence of end-organ disease and other
comorbidities. In general, elderly
patients may be more responsive
to the hypotensive effects of these
agents; for this reason, it is a good
practice to start with a lower dose
or infusion rate of these agents in
patients over age 65 years. Race may
be an important consideration for
the use of many antihypertensives.
For example, i.v. enalaprilat is most
effective in treating hypertension associated with high renin levels. Thus,
populations with traditionally low
renin levels (e.g., African Americans)
may experience smaller BP reductions than patients with high renin
values. Similarly, patients with high
renin levels may have large and rapid
decreases in BP and should be closely
monitored. Both hepatic and renal
function status are important considerations with agents that rely on
these organ systems for elimination
or whose toxic metabolites may need
elimination, such as with sodium
nitroprusside.
Clinical pharmacology of i.v.
antihypertensives
Calcium-channel blockers.
Calcium-channel blockers (CCBs)
are a heterogeneous class of drugs
used in the treatment of hypertension, coronary artery disease (CAD),
and dysrhythmias. The available
CCBs are categorized into the three
structural classes: dihydropyridines
(e.g., nicardipine, clevidipine), phenylalkylamines (e.g., verapamil), and
benzothiazepines (e.g., diltiazem).25

clinical review Intravenous therapy

Although six types of calcium channels exist, the L-type and T-type
channels are relevant to cardiovascular disease.26-28 The T-type channel
may be associated with significant
drug interactions and the potential
for life-threatening arrhythmia.26
The other channelsN-type (pain
management), P-type and Q-type
(migraine or epilepsy), and R-type
(diabetes mellitus)28are not influenced by the CCBs discussed in this
article and are the subject of ongoing
clinical investigation.
L-type CCBs inhibit the influx of
extracellular calcium ions through
calcium channels located in cellular
membranes of myocardial, vascular
smooth muscle, or cardiac conduction system cells and into intracellular organelles. The loss of extracellular calcium ion influx inhibits
intracellular phosphodiesterase,
which raises guanosine monophosphate (GMP) levels, inhibiting vascular smooth muscle contractility,
myocardial contractility, and cardiac
conduction to different degrees, depending on the particular drugs affinity for a particular L-type channel
receptor and the type of cell affected.
The dihydropyridines (nicardipine
and clevidipine) are selective for
vascular smooth muscle over myocardium in the order of cerebral,
coronary, peripheral muscle, and
renal vascular smooth muscle,29 with
little if any activity in cardiac muscle
or the sinoatrial node; thus, they have
little effect on heart rate and no effect
on myocardial contractility.29,30 The
vascular smooth muscle relaxation
induced by the dihydropyridines
causes vasodilation and a reduction
of systemic BP. In contrast, diltiazem
and verapamil have a predilection for
the cardiac conduction systems and
myocardial calcium channels. Intracoronary administration of diltiazem
and verapamil decreases myocardial
contractility and induces conduction
system abnormalities.30,31
Nicardipine. Nicardipine may have
unique benefits in cerebrovascular

disease based on its pharmacologic

profile. It crosses the blood-brain
barrier and acts to vasorelax cerebrovascular smooth muscle. At the acidic
pH of ischemic cerebral tissue, nicardipine is almost 100% protonated,
allowing for rapid accumulation in
ischemic tissue, localized vasodilation, and a reduction in vasospasm
seen in patients with acute subarachnoid hemorrhage.29,32 Although
nicardipine is a cerebral vasodilator,
it dilates small-resistance arterioles,
so there are no significant changes in
intracranial volume or intracranial
pressure (ICP).32
Nicardipine also reduces cardiac
ischemia, increases stroke volume
and coronary blood flow, and has a
favorable effect on myocardial oxygen balance. However, nicardipine
is contraindicated in patients with
advanced aortic stenosis. 33-35 The
most common adverse events associated with nicardipine are related to
vasodilation and include headache,
hypotension, nausea, vomiting, and
tachycardia.35
For hypertensive emergencies,
the initial i.v. infusion rate for nicardipine is 5 mg/hr, increasing
by 2.5 mg/hr every 5 minutes to
a maximum of 30 mg/hr, adjustable as needed. Once the target BP
is achieved, downward adjustment
by 3 mg/hr should be attempted as
tolerated. Its onset of action is 515
minutes, and the duration of action
is 46 hours. Steady-state concentrations are achieved after 2448 hours
of continuous infusion. Nicardipines
terminal elimination half-life is 14.4
hours.35,36 The steady-state pharmacokinetics of nicardipine are similar
between elderly hypertensive patients
(over age 65 years) and young healthy
adults.
Clevidipine. Clevidipine, the first
third-generation dihydropyridine
CCB, recently received marketing
approval in the United States. 13
Clevidipine specifically dilates arterioles and reduces afterload without
affecting cardiac-filling pressures

or causing reflex tachycardia. Clevidipine has a rapid onset (~

24
minutes) and offset of action (~
515
minutes).37,38 It undergoes rapid ester
hydrolysis by arterial blood esterases
to form inactive metabolites. This
unique metabolism terminates the
action of clevidipine, independent of
renal or hepatic functional status. The
initial phase half-life (measured in
cardiac surgery patients) is less than
one minute, and its terminal half-life
is approximately four minutes.37,38
Clevidipine has the potential to
protect against organ reperfusion
injury through its ability to hamper
oxygen free radical-mediated toxicity
and cellular calcium overload and to
augment endothelial nitric oxide bioavailability via antioxidative actions.
Thus, clevidipine may diminish the
severity of low-flow myocardial ischemia, preserve coronary endothelial
function, reduce infarct size,39 and
maintain renal function by preserving splanchnic blood flow.40
The starting dose of clevidipine is
12 mg/hr.14 The dose can be doubled
every 90 seconds until BP approaches
the target, then increased by less than
double every 510 minutes. There is
limited experience with doses higher
than 32 mg/hr or any dose given
longer than 72 hours. This agent is
insoluble in water and is commercially available in a lipid emulsion.
Clevidipine is contraindicated in
patients with allergies to soybeans,
soy products, eggs, or egg products.
Clevidipine is also contraindicated
in patients with defective lipid metabolism, such as pathological hyperlipemia, lipoid nephrosis, or acute
pancreatitis, if it is accompanied by
hyperlipidemia. Due to lipid-load
restrictions, no more than 1000 mL
or an average of 21 mg/hr of clevidipine infusion is recommended per
24-hour period.13 Clinicians must
account for the calories infused from
the lipid emulsion and adjust the
nutrition regimen as needed and
monitor triglyceride levels during
prolonged administration. Since this

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clinical review Intravenous therapy

agent does not contain preservatives

but contains phospholipids that can
support microbial growth, the vial
must be changed every 4 hours once
punctured. Clinical trials of clevidipine have included 852 patients over
the age of 65 years, with no differences in safety or effectiveness observed
compared with younger patients.
However, doses should be adjusted
cautiously for elderly patients, usually starting at the low end of the
dosing range.
Nitric oxide vasodilators. Sodium
nitroprusside. Sodium nitroprusside
is a nitric oxide donor. Free-radical
nitric oxide activates endovascular guanyl cyclase, causing myosin
dephosphorylation and vascular
smooth muscle relaxation. The drug
acts on arteriolar and venous smooth
muscle, reducing both preload and
afterload. However, in patients with
CAD, the theoretical coronary steal
(i.e., redistribution of oxygenated
blood away from nonvasodilating areas of ischemia toward nonischemic
myocardium with dilated coronary
arteries) results in reduced coronary perfusion pressure.41 A recent
study that compared the cerebral
hemodynamic effects of sodium
nitroprusside with those of labetalol
in patients with malignant hypertension suggested that a cerebral steallike effect, with a preferential blood
flow to the low-resistance systemic
vascular bed rather than the cerebral
vascular bed, was found with sodium
nitroprusside.42 Unpredictable shifts
in BP are often seen in patients with
hypovolemia or diastolic dysfunction
due to the effects of venodilation.36
There are potential concerns
with the use of sodium nitroprusside in patients with brain injury
and subsequent altered intracranial
compliance (alterations in intracranial vault volume). Case reports
and studies have shown a direct correlation between increased ICP and
sodium nitroprusside infusion.43-45
Information regarding the effect of
sodium nitroprusside on cerebral
1346

blood flow is conflicting, with many

studies conducted in the operating
suite while patients were under the
influence of various anesthetic regimens that also affect cerebral blood
flow. Unlike the dihydropyridine
CCBs, sodium nitroprusside dilates
large-capacitance vessels, including
cerebral vessels that may increase
cerebral blood volume, leading to
an increase in ICP and a subsequent
decrease in cerebral perfusion pressure (calculated by subtracting ICP
from MAP). Patients with altered
cerebral autoregulation or intracranial compliance may be extremely
susceptible to the sudden variations
in MAP and cerebral vasodilation
induced by sodium nitroprusside.
Although vasodilators are generally contraindicated in aortic stenosis, sodium nitroprusside is safe in
selected patients with aortic stenosis
and left ventricular systolic dysfunction.46 The drug should not be
administered to patients with hypertensive emergency in the setting of
acute myocardial infarction (MI), as
it was associated with increased mortality when administered within nine
hours of the onset of chest pain in
patients with acute MI and elevated
left ventricular filling pressure.47
The initial dose of sodium nitroprusside is 0.30.5 mg/kg/min,
with increases in increments of
0.5 mg/kg/min to reach the desired
hemodynamic effect. The duration
of treatment should be as short as
possible, and it is best to avoid doses
exceeding 2 mg/kg/min. The dosage
requirement in elderly patients is
lower than in younger patients.48 The
exact mechanism of this increased
sensitivity is largely unknown but is
hypothesized to be related to diminished baroreceptor reflex activity, resistance of cardiac adrenergic receptors to catecholamine stimulation, or
variations in the direct vasodilating
effects of sodium nitroprusside.48 It
has an immediate onset and a duration of effect of two to three minutes.22 Intraarterial BP monitoring is

Am J Health-Syst PharmVol 66 Aug 1, 2009

recommended when using sodium

nitroprusside because of the potential for overshoot. In addition, tachyphylaxis may develop while using
this agent.15
A major concern regarding the
use of sodium nitroprusside is the
accumulation of toxic metabolites.
Cyanide toxicity results in cellular
hypoxia and is clinically manifested
by irreversible neurologic changes
and cardiac arrest.14 Sodium nitro
prusside comprises a ferrous ion center complexed with five cyanide moieties and a nitrosyl group and is 44%
cyanide by weight. Each molecule
releases five cyanide radicals, which
may react with methemoglobin and
produce cyanomethemoglobin. Normal methemoglobin concentrations
can bind the cyanide released from
18 mg of sodium nitroprusside. The
total dose of sodium nitroprusside
required to cause 10% methemoglobinemia is >10 mg/kg (>10 mg/
kg/min for more than 16 hours). Because the remaining cyanide radicals
are converted to thiocyanate by transulfuration in the liver and excreted
by the kidneys, the drug should be
avoided whenever possible in patients with hepatic or renal failure.49
Normally, adults can detoxify 50 mg
of sodium nitroprusside using existing stores of sulfur, but malnutrition,
surgery, diuretic use, or other factors
can reduce this capacity. Because free
cyanide radicals may bind to and
inactivate tissue cytochrome oxidase,
thereby preventing oxidative phosphorylation, an increase in cyanide
concentrations may also cause tissue
anoxia, anaerobic metabolism, and
lactic acidosis. Patients receiving
sodium nitroprusside who show
subsequent central nervous system
dysfunction, cardiovascular instability, and increasing metabolic acidosis
should be assessed for cyanide toxicity, and sodium nitroprusside should
be discontinued.49 Monitoring for
cyanide toxicity is difficult. The use
of the red blood cell cyanide level is
a sensitive method but not readily

clinical review Intravenous therapy

available at many institutions, limiting its everyday clinical utility, which

leaves the clinician to assess for metabolic acidosis and conduct a clinical
examination.
For sodium nitroprusside infusions of 410 mg/kg/min14 or durations longer than 30 minutes, thiosulfate can be coadministered at a 10:1
sodium nitroprusside to thiosulfate
ratio to avoid cyanide toxicity, particularly during surgical procedures
that require intraoperative hypotension for longer than 30 minutes.50
As an alternative, hydroxycobalamin
(vitamin B12a) received marketing
approval in 2006 from the Food and
Drug Administration (FDA) for the
treatment of known or suspected cyanide poisoning. The starting dose is
5 g (available as 2.5-g vials) administered by i.v. infusion over 15 minutes.
The safety of coadministration with
other cyanide antidotes has not been
established. Because of its dark red
color, the two most common adverse
reactions reported with sodium nitroprusside were chromaturia (red
urine) and erythema (skin redness).
Hydroxycobalamine also has the
potential to cause photosensitivity
and can interfere with colorimetric
determinations of certain laboratory values. Hydroxycobalamine is
unstable and should be stored in a
dry place and protected from light.
Cyanocobalamin (vitamin B12) is
completely ineffective as a cyanide
antidote.14
Thiocyanate can cause toxicity,
although it is 100-fold less toxic than
cyanide. It is eliminated by renal excretion, with a half-life of 37 days.
Sodium nitroprusside infusions of
25 mg/kg/min for 714 days may
be needed to generate thiocyanate
toxicity. Nonspecific symptoms of
thiocyanate toxicity include fatigue,
tinnitus, nausea, and vomiting; clinical signs include hyperreflexia, confusion, psychosis, and miosis.
Nitroglycerin. Nitroglycerin is primarily a venodilator, though dilation
of arterial smooth muscle also occurs

with high doses.51 Once nitroglycerin

is converted to nitric oxide, it activates
guanylate cyclase and stimulates the
production of cyclic GMP (cGMP).
This produces smooth muscle relaxation, mainly in the venous system,
and reduces myocardial preload.52 In
volume-depleted patients, typical of
hypertensive emergencies other than
APE, a reduced myocardial preload
reduces cardiac output and is undesirable in patients with compromised
myocardial, cerebral, or renal perfusion. Severe hypotension and reflex
tachycardia have been reported in
volume-depleted patients within
minutes of initiating nitroglycerin
infusion.18
For the treatment of hypertension, the initial dose of nitroglycerin
is 5 mg/min by i.v. infusion. The dose
may be increased in increments of
5 mg/min every 35 minutes to a
maximum rate of 20 mg/min. If the
BP response is inadequate at 20 mg/
min, the dose may be increased by
10 mg/min every 35 minutes, up
to a maximum rate of 200 mg/min.
When a partial response is achieved,
dosing increments are made more
carefully.22
Drug onset is within 25 minutes, and the duration of action is
510 minutes,22 with a half-life of
13minutes. Tolerance to the hemodynamic effects of nitroglycerin may
limit its clinical usefulness.53 Headache is the most common adverse
effect, and methemoglobinemia is a
rare complication of prolonged nitroglycerin therapy.1 Administration
of low-dose nitroglycerin (60 mg/
min) as an adjunct to other i.v. antihypertensive therapy may be beneficial for patients with hypertensive
emergencies associated with acute
coronary syndromes or APE.51
Hydralazine. Hydralazine is a peripheral vasodilator that causes relaxation of arteriolar smooth muscle by
inhibiting calcium ion release from
the sarcoplasmic reticulum. The
specific mechanism of action is not
known, but proposed mechanisms

include blocking the release of inositol trisphosphate-induced calcium

and reducing calcium turnover. 54
The vasodilation reduces cardiac
afterload and may improve cardiac
function in patients with heart failure. There is also evidence of a direct
myocardial effect from increased
sarcolemma calcium influx. This
may be partly due to the stimulation
of b-adrenergic receptors.55 Other
proposed mechanisms of action include membrane hyperpolarization,
generation of nitric oxide, elevation
of intracellular cGMP, or inhibition
of oxidase formation.20,56,57
Recent evidence suggests that hydralazine induces hypoxia-inducible
factor-1a, which upregulates multiple endothelial cell growth factors
that induce cGMP.58 Small increases
in ICP associated with hydralazine
use have been reported in patients
with defective or absent cerebral
autoregulation. Hydralazine causes
a reflex stimulation of the sympathetic nervous system that can result
in increases in pulse rate and ICP59;
however, this effect can be blunted
by coadministration of b-receptor
antagonists.60-62
The initial dose of hydralazine in
acute hypertension is a 10-mg bolus
via slow i.v. infusion (maximum
initial bolus dose, 20 mg) every 46
hours as needed. Repeated bolus
doses via slow i.v. infusion generally do not exceed 20 mg, although
they may be increased to 40 mg.
BP begins to decrease within 1030
minutes, and the fall lasts 24 hours.
Hydralazine may also be given intramuscularly.22 Onset of action after
i.v. administration is 1020 minutes,
with a duration of 14 hours.1 While
hydralazines half-life is 1.5 hours, its
effect on BP generally persists for 24
hours. However, a pharmacologic
effect on BP exceeds 100 hours.22,23
The prolonged effect may be due to
active metabolites, tissue binding
in the arteriolar wall, or a sustained
effect on endothelium-derived relaxing factor.63 The unpredictability of

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clinical review Intravenous therapy

response and prolonged duration

of action do not make hydralazine
a desirable first-line agent in most
patients with hypertensive emergencies. As with all i.v. antihypertensives,
the transition to oral therapy should
begin as soon as possible after BP
stabilization.
Adrenergic-receptor antagonists.
Phentolamine. Phentolamine, a competitive antagonist of peripheral a1and a2-receptors, is generally used
to treat hypertensive emergencies
induced by catecholamine excess,
such as pheochromocytoma, interactions between monoamine oxidase
inhibitors and other drugs or food,
cocaine toxicity, amphetamine overdose, or clonidine withdrawal.1,64,65
Phentolamine is given as an i.v. bolus
dose of 515 mg. The onset of action
is 12 minutes, with a duration of
1030 minutes.1 It should be used
cautiously in patients with CAD, as it
can induce angina or MI.66 Tachycardia, flushing, and headache are also
common adverse effects.1 Compensatory tachycardia is managed with
an i.v. b-blocker.
Esmolol. Esmolol is a b1-adrenergic
antagonist with a rapid onset and
a very short duration of action. Its
negative inotropic and chronotropic
profiles and b1-cardioselectivity pair
well with a direct-acting a-adrenergic
vasodilator such as phentolamine,
since esmolol has no direct vasodilatory actions.
Typically, the drug is given as a
0.51.0-mg/kg loading dose over
1 minute, followed by a 50-mg/kg/
min infusion. For additional dosing,
the bolus dose is repeated and the
infusion increased in 50-mg/kg/min
increments as needed to a maximum
of 300 mg/kg/min.14,67 The onset of
action is approximately 1 minute.14
The drug is rapidly metabolized by
erythrocyte esterases, with a terminal
half-life of 9 minutes and a duration of action of 1020 minutes.67,68
Concomitant anemia may prolong
esmolols short duration of effect due
to the metabolic pathway.
1348

One of the major indications for

esmolol is to decrease the sympathetic discharge seen with severe
postoperative hypertension, when
cardiac output, heart rate, and BP
are increased.69-74 Esmolol is indicated for perioperative hypertension
and is safe in the setting of myocardial ischemia or infarction.75 Patients
should be monitored for bradycardia, which may be more problematic in the elderly, who may be more
sensitive to the bradycardiac effects.
If bradycardia occurs, the effects of
esmolol on heart rate are eliminated
within 20 minutes after drug discontinuation. Esmolol reduces cardiac
index and may worsen or exacerbate
symptoms in patients with heart failure.1,73 Although esmolol is cardioselective, patients with reactive airway
disease should be monitored closely,
even though several studies have
shown esmolol to be well tolerated
in patients with pulmonary disease.76
Current contraindications to the
use of esmolol include concurrent
b-blocker therapy, bradycardia, and
decompensated heart failure.
Massive accidental overdosages of
esmolol due to dilution errors, resulting in both fatalities and permanent
disability, have been reported.77 Bolus
doses in the range of 625 mg to 2.5
g (12.550 mg/kg) have been fatal.
Premixed injection solutions are
available and may help reduce dosage
errors.
I.V. b -blockers, often used as
monotherapy for ischemic CAD,
will potentiate sympathomimetic,
drug-induced, coronary and peripheral arterial vasoconstriction if given
unopposed.78 Unopposed b-blockade
may induce a-storm (i.e., unopposed
a-stimulation), with increased druginduced toxicity and physiological
decompensation that may lead to
death.11
Labetalol. Labetalol is a combined
a1- and nonselective b-adrenergic
blocker. Its pharmacodynamic action
is primarily mediated by b-blockade,
with an a- to b-receptor activity ratio

Am J Health-Syst PharmVol 66 Aug 1, 2009

of 1:7 when given intravenously.7 The

a1-blocking component minimizes
reductions in cardiac output observed with b-blockers alone.7 Unlike
esmolol, labetalol reduces systemic
vascular resistance without reducing
total peripheral blood flow. Labetalol
has very little effect on cerebral circulation and is thus not associated with
increased ICP in the normal brain.79
The drug may be particularly useful
when the hypertensive emergency
is caused by hyperadrenergic syndromes.65 Because it is a nonselective
b-blocker, labetalol is contraindicated in patients with reactive airway
disease or chronic obstructive pulmonary disease. It may worsen or exacerbate heart failure and should not
be used in patients with second- or
third-degree atrioventricular block
or bradycardia.1,66
A loading dose of labetalol 20
mg i.v. typically precedes either an
infusion or ongoing bolus doses of
labetalol. Labetalol as a single bolus
dose has an onset of action of 25
minutes, with a duration of action
lasting 24 minutes.14 Incremental
doses of 2080 mg at 10-minute intervals continue until the target BP
is reached. An infusion of 12 mg/
min, adjusted until the target BP is
achieved is an effective alternative
regimen. Bolus-dose injections of
12 mg/kg have produced precipitous
decreases in BP and should therefore
be avoided.80 The duration of effect
with repeated sequential bolus doses
or infusions is 24 hours, with an
elimination half-life of 5.5 hours.81
Fenoldopam. Fenoldopam is a
peripheral dopamine type 1 (D1)
agonist. It has no activity on do
pamine type 2 receptors. Stimulation
of postsynaptic D1 receptors causes
vasodilation of peripheral arteries
and the renal and mesenteric vasculature, lowering BP and total peripheral resistance while preserving renal
blood flow.82
Although fenoldopam increases
intraocular pressure, very little information is available regarding

clinical review Intravenous therapy

the effects of fenoldopam on the

cerebral vasculature, so it should
be avoided in patients at risk for
increased intraocular pressure and
increased ICP. The effects of this
agent on renal function were assessed in a meta-analysis involving
1290 patients from 16 randomized
controlled trials evaluating the renal
protective properties of fenoldopam
in a variety of settings.83 Fenoldopam was associated with a lower risk
of the need for renal replacement
therapy (odds ratio [OR], 0.54; 95%
confidence interval [CI], 0.340.84;
p = 0.007), inhospital death (OR,
0.64; 95% CI, 0.450.91; p = 0.01),
and acute kidney injury (OR, 0.43;
95% CI, 0.320.59; p < 0.001) in
patients at risk for acute renal impairment. However, the data for the
use of this agent as prophylaxis for
contrast-induced nephropathy have
not been robust.84,85
After a starting dose of 0.10.3 mg/
kg/min, the fenoldopam dosage may
be increased in increments of 0.05
0.1 mg/kg/min every 15 minutes until
the target BP is reached.22 The maximal infusion rate reported in clinical
studies was 1.6 mg/kg/min. There is
limited information on the use of
fenoldopam in patients age 65 years
or older, although anecdotal experience has not identified differences
in responses between the elderly and
younger patients. In general, dosage selection for an elderly patient
should be cautious, usually starting at
the low end of the dosing range. The
onset of action of i.v. fenoldopam is
<5 minutes, with a duration of 30
minutes. The half-life of the drug is
9.8 minutes.1,7,82 Common adverse
events associated with fenoldopam
include headache, flushing, tachycardia, dizziness, and a dose-related increase in intraocular pressure. Thus,
fenoldopam should be administered
with caution or avoided in patients
with glaucoma.1,82 The drug preparation contains sodium metabisulfate
and should be avoided in patients
with a sulfite allergy.

Enalaprilat. Enalaprilat is an
i.v. angiotensin-converting-enzyme
(ACE) inhibitor that blocks the
conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. Its
vasodilatory properties are due to the
decreased production of angiotensin
II.86 Bradykinininduced vasodilation
may also play a role, since ACE is
responsible for bradykinin degradation, and bradykinin levels increase
after administration of ACE inhibitors.87 In patients with hypertension,
administration of ACE inhibitors is
associated with a decrease in total
peripheral resistance but with little
change in heart rate, cardiac output,
or pulmonary occlusion pressures.88
For hypertension, enalaprilat 1.25
mg is administered every 6 hours intravenously over a 5-minute period.86
A clinical response is usually seen
within 15 minutes. Peak effects after
the first dose may not occur for up
to 4 hours after administration. The
peak effects of the second and subsequent doses may exceed those of the
first. The onset of enalaprilat occurs
in 1530 minutes, and its duration of
action is 1224 hours.1,7 In contrast
to shorter-acting vasodilators for hypertensive emergency, the enalaprilat
dosage is not easily adjusted. Once a
bolus dose is given, a longer time is
needed before the clinical effects are
seen. If hypotension occurs, the long
duration of action is not a favorable
property. The degree of BP lowering
associated with ACE inhibitors is
related to the pretreatment concentration of angiotensin II and plasma
renin activity.89 In general, ACE inhibitors are more effective in patients
with high renin levels, although these
patients may have drastic drops in
BP and should be closely monitored
after receiving i.v. enalaprilat. Enalaprilat should be avoided in patients
with acute MI and in patients with
bilateral renal artery stenosis. In addition, ACE inhibitors are contraindicated in pregnancy86 and should
not be used to treat preeclampsia or
eclampsia.

For patients on diuretic therapy,

the recommended starting dose
is 0.625 mg administered over 5
minutes.86 Clinical response is usually seen within 15 minutes, although
peak response may not occur until
four hours after administration.
The 0.625-mg dose may be repeated
after one hour if there is inadequate
clinical response. Additional doses
of 1.25 mg may be given at sixhour intervals. For patients with a
creatinine clearance of 30 mL/min
(serum creatinine concentration of 3
mg/dL), the starting dose should be
0.625 mg, which may be repeated
after one hour if the clinical response
is inadequate. Additional doses of
1.25 mg may be given at six-hour
intervals.
Nesiritide. Nesiritide, a recombinant B-type natriuretic peptide, is a
venous, an arterial, and a coronary
vasodilator.90 It reduces preload and
afterload, increases cardiac output
without direct inotropic effects, improves echocardiographic indexes
of diastolic function, and decreases
dyspnea when used in the setting
of decompensated congestive heart
failure with APE. It is structurally
identical to the peptide produced by
cardiac ventricles in response to the
increased wall stress, hypertrophy,
and volume overload commonly
seen in APE.
Nesiritide use is controversial
at this time. 91 One meta-analysis
of pooled data from existing trials
found that nesiritide may be associated with a statistically nonsignificant
trend of mortality within the first
month after its use for the treatment
of decompensated congestive heart
failure; however, the analysis was
not based on an adequately powered
prospective trial.92 Instead, data from
pooled trials were analyzed, allowing
the authors to qualify their results as
hypothesis generating rather than as
conclusive evidence of harm. A subsequent large, prospective, randomized trial investigated the adjunctive
administration of nesiritide on an

Am J Health-Syst PharmVol 66 Aug 1, 2009

1349

clinical review Intravenous therapy

Table 1.

Agents for Treating Hypertensive Emergencies with

Comorbidities1,5,8,12,14,17,51,64,66,91,a
Comorbidity

Preferred Agent(s)

Acute aortic dissection

Esmolol
Acute congestive heart failure
Nesiritide,c nitroglycerin, nitroprusside
Acute intracerebral hemorrhage
Labetalol, nicardipine
Acute ischemic stroke
Labetalol, nicardipine
Acute myocardial infarction
Clevidipine,d esmolol, labetalol,
nicardipine,d nitroglycerin
Acute pulmonary edema
Nesiritide,c nitroglycerin, nitroprusside
Acute renal failure
Clevidipine, fenoldopam, nicardipine
Eclampsia or preeclampsia
Hydralazine, labetalol, nicardipine
Perioperative hypertension
Clevidipine, esmolol, nicardipine,
nitroglycerin, nitroprusside
Sympathetic crisis or catecholamine
Clevidipine, fenoldopam, nicardipine,
toxicity phentolamine
b

Agents listed in alphabetical order, not in order of preference.

May be used in combination with a vasodilatorlike dihydropyridine calcium-channel blocker or nitroprusside;
however, b-blockade must precede administration of these agents.
c
Use is controversial.
d
May be used in patients with heart rate of <70 beats/min.
a

outpatient basis for advanced heart

failure.93 A total of 300 patients received once-weekly infusions and
300 received twice-weekly infusions
of nesiritide for three months; all
were followed for an additional three
months. Nesiritide was administered
as a bolus dose of 2 mg/kg, followed
by an infusion of 0.01 mg/kg/min for
46 hours. No effect on mortality was
found. A study is currently recruiting
patients to assess rehospitalization
due to heart failure and all-cause
mortality through day 30 and dyspnea symptoms at 6 and 24 hours after
nesiritide initiation.94 Nesiritide infusions lasting longer than 24 hours
appear to be associated with elevated
markers of worsening renal function
in patients with acute decompensated congestive heart failure.95
For i.v. treatment of adult patients
with acute decompensated congestive heart failure, nesiritide is given
as a 2-mg/kg bolus dose (over one
minute), then a continuous infusion
of 0.01 mg/kg/min.22 The medication
is reconstituted, and the bolus dose
withdrawn directly from the bag.
Higher initial doses are not recommended. However, at 3-hour inter1350

vals, the dosage may be increased by

0.005 mg/kg/min after a bolus dose
of 1.0 mg/kg, up to a maximum of
0.03 mg/kg/min.22 Its half-life is 18
minutes, it is metabolized predominately by endothelial receptors, and
6070% of the drugs effect is seen
within 15 minutes.
Table 1 lists the agents for treating hypertensive emergencies with
comorbidities.
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