clinical review  Intravenous therapy

clinical  review

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

H
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 prehyperten-
sive or hypertensive, according to the
seventh report of the Joint National
Committee on Prevention, Diag-
nosis 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. Hyper-
tensive emergencies are always as-
sociated 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 hyperten-
sive crisis annually. Hypertensive emergen-
cy 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 hy-
pertensive emergencies are, in general,
characterized by a short onset and offset
of action and predictable responses dur-
ing dosage adjustments to reach BP goals,
without excessive adjustment or extreme
fluctuations in BP. Nicardipine, nitroprus-
side, fenoldopam, nitroglycerin, enalaprilat,
hydralazine, labetalol, esmolol, and phen-
tolamine 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-
Detection, Evaluation, and Treatment of
High Blood Pressure. Since the publication
of these recommendations, another i.v. an-
tihypertensive agent, clevidipine, became
commercially available. The selection of
a specific agent should be based on the
agent’s pharmacology and patient-specific
factors, such as comorbidity and the pres-
ence of end-organ damage.
Conclusion. The rapid recognition and
initiation of therapy are key to minimiz-
ing end-organ damage in patients with
hypertensive emergency. Tailoring drug
selection according to individual patient
characteristics can optimize the manage-
ment and potential outcomes of patients
with hypertensive emergency.
Index terms: Clevidipine; Drugs; Emergen-
cies; 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 encephalopa-
thy, cerebral infarction, intracranial
hemorrhage, myocardial ischemia

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, 259 Mack Avenue, Detroit,
MI 48201 (drhoney@wayne.edu).
Dr. Rhoney has served on the scientific advisory boards or speak-
ers’ bureaus of or received research grants from PDL BioPharma
(now EKR Therapeutics), Astellas Pharma Inc., UCB Pharma Inc.,
and The Medicines Company. Dr. Peacock has served on the sci-
entific 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 Pharma-
cists, Inc. All rights reserved. 1079-2082/09/0801-1343$06.00.
DOI 10.2146/ajhp080348.p1

Am J Health-Syst Pharm—Vol 66 Aug 1, 2009 1343

 clinical review  Intravenous therapy
or infarction, acute left ventricular
dysfunction, acute pulmonary edema
(APE), aortic dissection, renal insuf-
ficiency, 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 hyperten-
sive patients experience a hyperten-
sive 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 hy-
pertensive emergency in a New York
City hospital.10 The mean age of this
cohort was 52 years (range, 22–87
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 clinical–surgical emer-
gencies.11 Of these, 60.4% were hy-
pertensive 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 31–60
years and in women age 21–60 years.
The rate of hypertensive emergencies
peaked in men age 41–70 years and in
women age 61–70 years.
Standard treatment for a hyper-
tensive 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 thera-
peutic goal is to lower the mean
arterial pressure (MAP) by 20–25%
within 60 minutes, avoiding a pre-
cipitous or excessive decrease in
BP that may cause iatrogenic renal,
cerebral, or coronary ischemia.1 This
recommendation is based on the
body’s ability to autoregulate tissue
perfusion in the brain, heart, and
kidneys, which lowers the prevail-
1344 Am J Health-Syst Pharm—Vol 66 Aug 1, 2009
ing BP by 20–25% under normal
conditions and during severe hy-
pertension.12 If the patient is stable,
SBP can be further reduced to 160
mm Hg and DBP can be reduced
to 100–110 mm Hg over the ensu-
ing 2–6 hours. A gradual reduction
to the patient’s baseline “normal”
BP is targeted over the initial 24–48
hours if the patient is stable, with
appropriate monitoring for signs or
symptoms of ischemia-related end-
organ 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 emergen-
cies. 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 hyper-
tensive 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 drug’s pharma-
cokinetic parameters and adverse
effects. In addition, due to the po-
tential for “overshoot” with agents
like nitroprusside, arterial BP moni-
toring is a requirement for the use
of some agents. Cost-effectiveness
is another important drug-specific
factor and should include consider-
ation of the length of hospital stay,
time spent in the ICU, and long-term
morbidity. Unfortunately, few stud-
ies have rigorously evaluated the
cost-effectiveness of pharmacologic
agents for the management of hyper-
tensive 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 (acces-
sible 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 pres-
ence 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 as-
sociated with high renin levels. Thus,
populations with traditionally low
renin levels (e.g., African Americans)
may experience smaller BP reduc-
tions 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 con-
siderations 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 hyperten-
sion, coronary artery disease (CAD),
and dysrhythmias. The available
CCBs are categorized into the three
structural classes: dihydropyridines
(e.g., nicardipine, clevidipine), phe-
nylalkylamines (e.g., verapamil), and
benzothiazepines (e.g., diltiazem).25

Although six types of calcium chan-
nels exist, the L-type and T-type
channels are relevant to cardiovas-
cular disease.26-28 The T-type channel
may be associated with significant
drug interactions and the potential
for life-threatening arrhythmia.26
The other channels—N-type (pain
management), P-type and Q-type
(migraine or epilepsy), and R-type
(diabetes mellitus)28—are not influ-
enced 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 conduc-
tion system cells and into intracel-
lular organelles. The loss of extra-
cellular calcium ion influx inhibits
intracellular phosphodiesterase,
which raises guanosine monophos-
phate (GMP) levels, inhibiting vas-
cular smooth muscle contractility,
myocardial contractility, and cardiac
conduction to different degrees, de-
pending on the particular drug’s af-
finity 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 myo-
cardium 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. Intra-
coronary administration of diltiazem
and verapamil decreases myocardial
contractility and induces conduction
system abnormalities.30,31
Nicardipine. Nicardipine may have
unique benefits in cerebrovascular
clinical review  Intravenous therapy
disease based on its pharmacologic
profile. It crosses the blood-brain
barrier and acts to vasorelax cerebro-
vascular smooth muscle. At the acidic
pH of ischemic cerebral tissue, nicar-
dipine is almost 100% protonated,
allowing for rapid accumulation in
ischemic tissue, localized vasodila-
tion, and a reduction in vasospasm
seen in patients with acute suba-
rachnoid 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 oxy-
gen balance. However, nicardipine
is contraindicated in patients with
advanced aortic stenosis. 33-35 The
most common adverse events associ-
ated 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 ni-
cardipine is 5 mg/hr, increasing
by 2.5 mg/hr every 5 minutes to
a maximum of 30 mg/hr, adjust-
able as needed. Once the target BP
is achieved, downward adjustment
by 3 mg/hr should be attempted as
tolerated. Its onset of action is 5–15
minutes, and the duration of action
is 4–6 hours. Steady-state concentra-
tions are achieved after 24–48 hours
of continuous infusion. Nicardipine’s
terminal elimination half-life is 14.4
hours.35,36 The steady-state pharma-
cokinetics 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 arte-
rioles and reduces afterload without
affecting cardiac-filling pressures
Am J Health-Syst Pharm—Vol 66 Aug 1, 2009
or causing reflex tachycardia. Cle-
vidipine has a rapid onset (~ – 2–4
minutes) and offset of action (~– 5–15
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 bio-
availability via antioxidative actions.
Thus, clevidipine may diminish the
severity of low-flow myocardial isch-
emia, preserve coronary endothelial
function, reduce infarct size,39 and
maintain renal function by preserv-
ing splanchnic blood flow.40
The starting dose of clevidipine is
1–2 mg/hr.14 The dose can be doubled
every 90 seconds until BP approaches
the target, then increased by less than
double every 5–10 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 commer-
cially 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 me-
tabolism, such as pathological hy-
perlipemia, 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 clevid-
ipine 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
1345
 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 clevid-
ipine have included 852 patients over
the age of 65 years, with no differenc-
es in safety or effectiveness observed
compared with younger patients.
However, doses should be adjusted
cautiously for elderly patients, usu-
ally 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 endovascu-
lar 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 ar-
eas of ischemia toward nonischemic
myocardium with dilated coronary
arteries) results in reduced coro-
nary perfusion pressure.41 A recent
study that compared the cerebral
hemodynamic effects of sodium
nitroprusside with those of labetalol
in patients with malignant hyperten-
sion suggested that a “cerebral steal-
like 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 nitroprus-
side in patients with brain injury
and subsequent altered intracranial
compliance (alterations in intrac-
ranial vault volume). Case reports
and studies have shown a direct cor-
relation between increased ICP and
sodium nitroprusside infusion.43-45
Information regarding the effect of
sodium nitroprusside on cerebral
1346 Am J Health-Syst Pharm—Vol 66 Aug 1, 2009
blood flow is conflicting, with many
studies conducted in the operating
suite while patients were under the
influence of various anesthetic regi-
mens 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 pres-
sure (calculated by subtracting ICP
from MAP). Patients with altered
cerebral autoregulation or intracra-
nial compliance may be extremely
susceptible to the sudden variations
in MAP and cerebral vasodilation
induced by sodium nitroprusside.
Although vasodilators are gener-
ally contraindicated in aortic steno-
sis, sodium nitroprusside is safe in
selected patients with aortic stenosis
and left ventricular systolic dys-
function.46 The drug should not be
administered to patients with hyper-
tensive emergency in the setting of
acute myocardial infarction (MI), as
it was associated with increased mor-
tality 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 ni-
troprusside is 0.3–0.5 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 dimin-
ished baroreceptor reflex activity, re-
sistance of cardiac adrenergic recep-
tors to catecholamine stimulation, or
variations in the direct vasodilating
effects of sodium nitroprusside.48 It
has an immediate onset and a dura-
tion of effect of two to three  min-
utes.22 Intraarterial BP monitoring is
recommended when using sodium
nitroprusside because of the poten-
tial for “overshoot.” In addition, tac-
hyphylaxis 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 cen-
ter complexed with five cyanide moi-
eties and a nitrosyl group and is 44%
cyanide by weight. Each molecule
releases five cyanide radicals, which
may react with methemoglobin and
produce cyanomethemoglobin. Nor-
mal methemoglobin concentrations
can bind the cyanide released from
18 mg of sodium nitroprusside. The
total dose of sodium nitroprusside
required to cause 10% methemo-
globinemia is >10 mg/kg (>10 mg/
kg/min for more than 16 hours). Be-
cause the remaining cyanide radicals
are converted to thiocyanate by tran-
sulfuration in the liver and excreted
by the kidneys, the drug should be
avoided whenever possible in pa-
tients with hepatic or renal failure.49
Normally, adults can detoxify 50 mg
of sodium nitroprusside using exist-
ing 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 phos-
phorylation, 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 instabil-
ity, and increasing metabolic acidosis
should be assessed for cyanide toxic-
ity, 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

available at many institutions, limit-
ing its everyday clinical utility, which
leaves the clinician to assess for meta-
bolic acidosis and conduct a clinical
examination.
For sodium nitroprusside infu-
sions of ≥4–10 mg/kg/min14 or dura-
tions longer than 30 minutes, thiosul-
fate can be coadministered at a 10:1
sodium nitroprusside to thiosulfate
ratio to avoid cyanide toxicity, par-
ticularly during surgical procedures
that require intraoperative hypoten-
sion 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 cy-
anide poisoning. The starting dose is
5 g (available as 2.5-g vials) adminis-
tered 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 ni-
troprusside were chromaturia (red
urine) and erythema (skin redness).
Hydroxycobalamine also has the
potential to cause photosensitivity
and can interfere with colorimetric
determinations of certain labora-
tory 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 ex-
cretion, with a half-life of 3–7 days.
Sodium nitroprusside infusions of
2–5 mg/kg/min for 7–14 days may
be needed to generate thiocyanate
toxicity. Nonspecific symptoms of
thiocyanate toxicity include fatigue,
tinnitus, nausea, and vomiting; clini-
cal signs include hyperreflexia, con-
fusion, psychosis, and miosis.
Nitroglycerin. Nitroglycerin is pri-
marily a venodilator, though dilation
of arterial smooth muscle also occurs
clinical review  Intravenous therapy
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 relax-
ation, 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 unde-
sirable in patients with compromised
myocardial, cerebral, or renal perfu-
sion. Severe hypotension and reflex
tachycardia have been reported in
volume-depleted patients within
minutes of initiating nitroglycerin
infusion.18
For the treatment of hyperten-
sion, 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 3–5 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 3–5 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 2–5 min-
utes, and the duration of action is
5–10 minutes,22 with a half-life of
1–3 minutes. Tolerance to the hemo-
dynamic effects of nitroglycerin may
limit its clinical usefulness.53 Head-
ache is the most common adverse
effect, and methemoglobinemia is a
rare complication of prolonged ni-
troglycerin therapy.1 Administration
of low-dose nitroglycerin (≈60 mg/
min) as an adjunct to other i.v. an-
tihypertensive therapy may be ben-
eficial for patients with hypertensive
emergencies associated with acute
coronary syndromes or APE.51
Hydralazine. Hydralazine is a pe-
ripheral vasodilator that causes relax-
ation of arteriolar smooth muscle by
inhibiting calcium ion release from
the sarcoplasmic reticulum. The
specific mechanism of action is not
known, but proposed mechanisms
Am J Health-Syst Pharm—Vol 66 Aug 1, 2009
include blocking the release of inosi-
tol trisphosphate-induced calcium
and reducing calcium turnover. 54
The vasodilation reduces cardiac
afterload and may improve cardiac
function in patients with heart fail-
ure. 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 in-
clude membrane hyperpolarization,
generation of nitric oxide, elevation
of intracellular cGMP, or inhibition
of oxidase formation.20,56,57
Recent evidence suggests that hy-
dralazine induces hypoxia-inducible
factor-1a, which upregulates mul-
tiple 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 sympa-
thetic 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 4–6
hours as needed. Repeated bolus
doses via slow i.v. infusion gener-
ally do not exceed 20 mg, although
they may be increased to 40 mg.
BP begins to decrease within 10–30
minutes, and the fall lasts 2–4 hours.
Hydralazine may also be given intra-
muscularly.22 Onset of action after
i.v. administration is 10–20 minutes,
with a duration of 1–4 hours.1 While
hydralazine’s half-life is 1.5 hours, its
effect on BP generally persists for 2–4
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 relax-
ing factor.63 The unpredictability of
1347
 clinical review  Intravenous therapy
response and prolonged duration
of action do not make hydralazine
a desirable first-line agent in most
patients with hypertensive emergen-
cies. 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 com-
petitive antagonist of peripheral a1-
and a2-receptors, is generally used
to treat hypertensive emergencies
induced by catecholamine excess,
such as pheochromocytoma, interac-
tions between monoamine oxidase
inhibitors and other drugs or food,
cocaine toxicity, amphetamine over-
dose, or clonidine withdrawal.1,64,65
Phentolamine is given as an i.v. bolus
dose of 5–15 mg. The onset of action
is 1–2 minutes, with a duration of
10–30 minutes.1 It should be used
cautiously in patients with CAD, as it
can induce angina or MI.66 Tachycar-
dia, flushing, and headache are also
common adverse effects.1 Compen-
satory 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 vasodila-
tory actions.
Typically, the drug is given as a
0.5–1.0-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 dura-
tion of action of 10–20 minutes.67,68
Concomitant anemia may prolong
esmolol’s short duration of effect due
to the metabolic pathway.
1348 Am J Health-Syst Pharm—Vol 66 Aug 1, 2009
One of the major indications for
esmolol is to decrease the sympa-
thetic discharge seen with severe
postoperative hypertension, when
cardiac output, heart rate, and BP
are increased.69-74 Esmolol is indi-
cated for perioperative hypertension
and is safe in the setting of myocar-
dial is­chemia or infarction.75 Patients
should be monitored for bradycar-
dia, which may be more problem-
atic 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 discon-
tinuation. Esmolol reduces cardiac
index and may worsen or exacerbate
symptoms in patients with heart fail-
ure.1,73 Although esmolol is cardiose-
lective, 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, result-
ing in both fatalities and permanent
disability, have been reported.77 Bolus
doses in the range of 625 mg to 2.5
g (12.5–50 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 periph-
eral arterial vasoconstriction if given
unopposed.78 Unopposed b-blockade
may induce a-storm (i.e., unopposed
a-stimulation), with increased drug-
induced 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
of 1:7 when given intravenously.7 The
a1-blocking component minimizes
reductions in cardiac output ob-
served 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 circu-
lation 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 syn-
dromes.65 Because it is a nonselective
b-blocker, labetalol is contraindi-
cated in patients with reactive airway
disease or chronic obstructive pul-
monary disease. It may worsen or ex-
acerbate 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 2–5
minutes, with a duration of action
lasting 2–4 minutes.14 Incremental
doses of 20–80 mg at 10-minute in-
tervals continue until the target BP
is reached. An infusion of 1–2 mg/
min, adjusted until the target BP is
achieved is an effective alternative
regimen. Bolus-dose injections of
1–2 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 2–4 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 vascu-
lature, lowering BP and total periph-
eral resistance while preserving renal
blood flow.82
Although fenoldopam increases
intraocular pressure, very little in-
formation is available regarding

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 as-
sessed 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 Fenoldo-
pam was associated with a lower risk
of the need for renal replacement
therapy (odds ratio [OR], 0.54; 95%
confidence interval [CI], 0.34–0.84;
p = 0.007), inhospital death (OR,
0.64; 95% CI, 0.45–0.91; p = 0.01),
and acute kidney injury (OR, 0.43;
95% CI, 0.32–0.59; p < 0.001) in
patients at risk for acute renal im-
pairment. 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 0.1–0.3 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 maxi-
mal 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 experi-
ence has not identified differences
in responses between the elderly and
younger patients. In general, dos-
age 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, tachycar-
dia, dizziness, and a dose-related in-
crease in intraocular pressure. Thus,
fenoldopam should be administered
with caution or avoided in patients
with glaucoma.1,82 The drug prepara-
tion contains sodium metabisulfate
and should be avoided in patients
with a sulfite allergy.
clinical review  Intravenous therapy
Enalaprilat. Enalaprilat is an
i.v. angiotensin-converting-enzyme
(ACE) inhibitor that blocks the
conversion of angiotensin I to angio-
tensin II, a potent vasoconstrictor. Its
vasodilatory properties are due to the
decreased production of angiotensin
II.86 Bradykinin‑induced vasodilation
may also play a role, since ACE is
responsible for bradykinin degrada-
tion, and bradykinin levels increase
after administration of ACE inhibi-
tors.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 in-
travenously 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 subse-
quent doses may exceed those of the
first. The onset of enalaprilat occurs
in 15–30 minutes, and its duration of
action is 12–24 hours.1,7 In contrast
to shorter-acting vasodilators for hy-
pertensive 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 concen-
tration of angiotensin II and plasma
renin activity.89 In general, ACE in-
hibitors 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. Enal-
aprilat should be avoided in patients
with acute MI and in patients with
bilateral renal artery stenosis. In ad-
dition, ACE inhibitors are contrain-
dicated in pregnancy86 and should
not be used to treat preeclampsia or
eclampsia.
Am J Health-Syst Pharm—Vol 66 Aug 1, 2009
For patients on diuretic therapy,
the recommended starting dose
is 0.625 mg administered over 5
minutes.86 Clinical response is usu-
ally 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 six-
hour 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 recombi-
nant 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, im-
proves 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 associat-
ed 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 sub-
sequent large, prospective, random-
ized trial investigated the adjunctive
administration of nesiritide on an
1349
 clinical review  Intravenous therapy

5. Aggarwal M, Khan IA. Hypertensive cri-

Table 1. sis: hypertensive emergencies and urgen-
Agents for Treating Hypertensive Emergencies with cies. Cardiol Clin. 2006; 24:135-46.
Comorbidities1,5,8,12,14,17,51,64,66,91,a 6. Kincaid-Smith P, McMichael J, Murphy
EA. The clinical course and pathology of
Comorbidity Preferred Agent(s) hypertension with papilloedema (malig-
nant hypertension). Q J Med. 1958; 27:
Acute aortic dissection Esmolol b
117-53.
Acute congestive heart failure Nesiritide,c nitroglycerin, nitroprusside 7. Kitiyakara C, Guzman NJ. Malignant
Acute intracerebral hemorrhage Labetalol, nicardipine hypertension and hypertensive emergen-
Acute ischemic stroke Labetalol, nicardipine cies. J Am Soc Nephrol. 1998; 9:133-42.
8. Varon J, Marik PE. The diagnosis and
Acute myocardial infarction Clevidipine,d esmolol, labetalol, management of hypertensive crises.
  nicardipine,d nitroglycerin Chest. 2000; 118:214-27.
Acute pulmonary edema Nesiritide,c nitroglycerin, nitroprusside 9. Zampaglione B, Pascale C, Marchisio M
Acute renal failure Clevidipine, fenoldopam, nicardipine et al. Hypertensive urgencies and emer-
gencies. Prevalence and clinical presenta-
Eclampsia or preeclampsia Hydralazine, labetalol, nicardipine
tion. Hypertension. 1996; 27:144-7.
Perioperative hypertension Clevidipine, esmolol, nicardipine, 10. Bennett NM, Shea S. Hypertensive
  nitroglycerin, nitroprusside emergency: case criteria, sociodemo-
Sympathetic crisis or catecholamine Clevidipine, fenoldopam, nicardipine, graphic profile, and previous care of
toxicity   phentolamine 100 cases. Am J Public Health. 1988; 78:
636-40.
a
Agents listed in alphabetical order, not in order of preference. 11. Martin JF, Higashiama E, Garcia E et al.
b
May be used in combination with a vasodilatorlike dihydropyridine calcium-channel blocker or nitroprusside; Hypertensive crisis profile. Prevalence
however, b-blockade must precede administration of these agents. and clinical presentation. Arq Bras Car-
c
Use is controversial. diol. 2004; 83:125-36.
d
May be used in patients with heart rate of <70 beats/min. 12. Flanigan JS, Vitberg D. Hypertensive
emergency and severe hypertension: what
to treat, who to treat, and how to treat.
Med Clin North Am. 2006; 90:439-51.
outpatient basis for advanced heart vals, the dosage may be increased by 13. Cleviprex (clevidipine butyrate) inject-
failure.93 A total of 300 patients re- 0.005 mg/kg/min after a bolus dose able emulsion package insert. Parsippany,
NJ: The Medicines Company; 2008.
ceived once-weekly infusions and of 1.0 mg/kg, up to a maximum of 14. Varon J, Marik PE. Clinical review: the
300 received twice-weekly infusions 0.03 mg/kg/min.22 Its half-life is 18 management of hypertensive crises. Crit
of nesiritide for three months; all minutes, it is metabolized predomi- Care. 2003; 7:374-84.
15. Nitropress (sodium nitroprusside) pack-
were followed for an additional three nately by endothelial receptors, and age insert. Lake Forest, IL: Hospira, Inc.;
months. Nesiritide was administered 60–70% of the drug’s effect is seen 2006.
as a bolus dose of 2 mg/kg, followed within 15 minutes. 16. GlobalRPH. Nitroglycerin. www.global
rph.com/nitroglycerin_dilution.htm
by an infusion of 0.01 mg/kg/min for Table 1 lists the agents for treat- (accessed 2008 Oct 20).
4–6 hours. No effect on mortality was ing hypertensive emergencies with 17. Cardene i.v. (nicardipine) package insert.
found. A study is currently recruiting comorbidities. Fremont, CA: PDL BioPharma; 2006.
18. Elkayam U, Kulick D, McIntosh N et al.
patients to assess rehospitalization Incidence of early tolerance to hemody-
References
due to heart failure and all-cause namic effects of continuous infusion of
1. Chobanian AV, Bakris GL, Black HR et nitroglycerin in patients with coronary
mortality through day 30 and dysp- al. Seventh report of the Joint National artery disease and heart failure. Circula-
nea symptoms at 6 and 24 hours after Committee on Prevention, Detection, tion. 1987; 76:577-84.
nesiritide initiation.94 Nesiritide in- Evaluation, and Treatment of High 19. Cheung AT, Guvakov DV, Weiss SJ et al.
Blood Pressure. Hypertension. 2003; 42: Nicardipine intravenous bolus dosing for
fusions lasting longer than 24 hours 1206-52. acutely decreasing arterial blood pressure
appear to be associated with elevated 2. National Heart Lung and Blood Institute. during general anesthesia for cardiac
markers of worsening renal function The seventh report of the Joint National operations: pharmacokinetics, pharma-
Committee on Prevention, Detection, codynamics, and associated effects on left
in patients with acute decompen- Evaluation, and Treatment of High Blood ventricular function. Anesth Analg. 1999;
sated congestive heart failure.95 Pressure. www.nhlb.nih.gov/guidelines/ 89:1116-23.
For i.v. treatment of adult patients hypertension/jnc7full.pdf (accessed 2009 20. Hermsmeyer K, Trapani A, Abel PW et al.
Jun 22). Effect of hydralazine on tension and mem-
with acute decompensated conges- 3. Wang Y, Wang QJ. The prevalence of pre- brane potential in the rat caudal artery. J
tive heart failure, nesiritide is given hypertension and hypertension among Pharmacol Exp Ther. 1983; 227:322-6.
as a 2-mg/kg bolus dose (over one US adults according to the new Joint Na- 21. Franklin C, Nightingale S, Mamdani B.
minute), then a continuous infusion tional Committee guidelines: new chal- A randomized comparison of nifedipine
lenges of the old problem. Arch Intern and sodium nitroprusside in severe hy-
of 0.01 mg/kg/min.22 The medication Med. 2004; 164:2126-34. pertension. Chest. 1986; 90:500-3.
is reconstituted, and the bolus dose 4. Vasan RS, Beiser A, Seshadri S et al. Resid- 22. GlobalRPh Inc. Vasodilators. www.global
withdrawn directly from the bag. ual lifetime risk for developing hyperten- rph.com/vasodilators.htm (accessed 2008
sion in middle-aged women and men: the Feb 7).
Higher initial doses are not recom- Framingham Heart Study. JAMA. 2002; 23. O’Malley K, Segal JL, Israili ZH et al.
mended. However, at 3-hour inter- 287:1003-10. Duration of hydralazine action in hy-

1350 Am J Health-Syst Pharm—Vol 66 Aug 1, 2009


pertension. Clin Pharmacol Ther. 1975;
18:581-6.
24. Boehrer JD, Moliterno DJ, Willard JE
et al. Influence of labetalol on cocaine-
induced coronary vasoconstriction in
humans. Am J Med. 1993; 94:608-10.
25. Grossman E, Messerli FH. Calcium an-
tagonists. Prog Cardiovasc Dis. 2004; 47:
34-57.
26. Levine TB, Bernink PJ, Caspi A et al.
Effect of mibefradil, a T-type calcium
channel blocker, on morbidity and mor-
tality in moderate to severe congestive
heart failure: the MACH-1 study. Mor-
tality Assessment in Congestive Heart
Failure Trial. Circulation. 2000; 101:
758-64.
27. Vermeulen LC, Dunham DB. Mibefradil
and an effective formulary system. Am
J Health-Syst Pharm. 1998; 55:1934-5.
Letter.
28. Triggle DJ. Calcium channel antagonists:
clinical uses—past, present and future.
Biochem Pharmacol. 2007; 74:1-9.
29. Sabbatini M, Strocchi P, Amenta F. Ni-
cardipine and treatment of cerebrovas-
cular diseases with particular reference to
hypertension-related disorders. Clin Exp
Hypertens. 1995; 17:719-50.
30. Fugit MD, Rubal BJ, Donovan DJ. Effects
of intracoronary nicardipine, diltiazem
and verapamil on coronary blood flow. J
Invasive Cardiol. 2000; 12:80-5.
31. Vi j aya l a k s h m i K , Wh i t t a ker V J,
Kunadian B et al. Prospective, ran-
domised, controlled trial to study the
effect of intracoronary injection of vera-
pamil and adenosine on coronary blood
flow during percutaneous coronary inter-
vention in patients with acute coronary
syndromes. Heart. 2006; 92:1278-84.
32. Gaab MR, Czech T, Korn A. Intracranial
effects of nicardipine. Br J Clin Pharma-
col. 1985; 20(suppl 1):67S-74S.
33. Silke B, Verma SP, Hussain M et al. Com-
parative haemodynamic effects of nicar-
dipine and verapamil in coronary artery
disease. Herz. 1985; 10:112-9.
34. Silke B, Verma SP, Nelson GI et al. Hae-
modynamic dose-response effects of i.v.
nicardipine in coronary artery disease.
Br J Clin Pharmacol. 1984; 18:717-24.
35. Curran MP, Robinson DM, Keating GM.
Intravenous nicardipine: its use in the
short-term treatment of hypertension
and various other indications. Drugs.
2006; 66:1755-82.
36. Halpern NA, Alicea M, Krakoff LR et al.
Postoperative hypertension: a prospec-
tive, placebo-controlled, randomized,
double-blind trial, with intravenous ni-
cardipine hydrochloride. Angiology. 1990;
41:992-1004.
37. Nordlander M, Sjoquist PO, Ericsson H
et al. Pharmacodynamic, pharmacoki-
netic and clinical effects of clevidipine, an
ultrashort-acting calcium antagonist for
rapid blood pressure control. Cardiovasc
Drug Rev. 2004; 22:227-50.
38. Kieler-Jensen N, Jolin-Mellgard A,
Nordlander M et al. Coronary and
systemic hemodynamic effects of cle-
clinical review  Intravenous therapy
vidipine, an ultra-short-acting calcium
antagonist, for treatment of hypertension
after coronary artery surgery. Acta Anaes-
thesiol Scand. 2000; 44:186-93.
39. Segawa D, Sjoquist PO, Wang QD et al.
Calcium antagonist protects the myocar-
dium from reperfusion injury by interfer-
ing with mechanisms directly related to
reperfusion: an experimental study with
the ultrashort-acting calcium antagonist
clevidipine. J Cardiovasc Pharmacol.
2000; 36:338-43.
40. Stephens CT, Jandhyala BS. Effects of
fenoldopam, a dopamine D-1 agonist,
and clevidipine, a calcium channel an-
tagonist, in acute renal failure in anes-
thetized rats. Clin Exp Hypertens. 2002;
24:301-13.
41. Mann T, Cohn PF, Holman LB et al. Effect
of nitroprusside on regional myocardial
blood flow in coronary artery disease. Re-
sults in 25 patients and comparison with
nitroglycerin. Circulation. 1978; 57:732-
8.
42. Immink RV, van den Born BJ, van
Montfrans GA et al. Cerebral hemody-
namics during treatment with sodium
nitroprusside versus labetalol in malig-
nant hypertension. Hypertension. 2008;
52:236-40.
43. Cottrell JE, Patel K, Turndorf H et al.
Intracranial pressure changes induced by
sodium nitroprusside in patients with in-
tracranial mass lesions. J Neurosurg. 1978;
48:329-31.
44. Griswold WR, Reznik V, Mendoza SA.
Nitroprusside-induced intracranial hy-
pertension. JAMA. 1981; 246:2679-80.
45. Anile C, Zanghi F, Bracali A et al. Sodium
nitroprusside and intracranial pressure.
Acta Neurochir. 1981; 58:203-11.
46. Khot UN, Novaro GM, Popovic ZB et al.
Nitroprusside in critically ill patients with
left ventricular dysfunction and aortic
stenosis. N Engl J Med. 2003; 348:1756-
63.
47. Libby P, Bonow R, Mann DL, eds.
Braunwald’s heart disease: a textbook of
cardiovascular medicine, 8th ed. Phila-
delphia, PA: Elsevier; 2008:1007–8.
48. Wood M, Hyman S, Wood AJ. A clinical
study of sensitivity to sodium nitro­
prusside during controlled hypotensive
anesthesia in young and elderly patients.
Anesth Analg. 1987; 66:132-6.
49. Friederich JA, Butterworth JF 4th. So-
dium nitroprusside: twenty years and
counting. Anesth Analg. 1995; 81:152-62.
50. Hall VA, Guest JM. Sodium nitroprusside-
induced cyanide intoxication and preven-
tion with sodium thiosulfate prophylaxis.
Am J Crit Care. 1992; 1:19-25.
51. Varon J. Treatment of acute severe hyper-
tension: current and newer agents. Drugs.
2008; 68:283-97.
52. Ignarro LJ. After 130 years, the molecular
mechanism of action of nitroglycerin is
revealed. Proc Natl Acad Sci U S A. 2002;
99:7816-7.
53. Hirai N, Kawano H, Yasue H et al. At-
tenuation of nitrate tolerance and oxida-
tive stress by an angiotensin II receptor
Am J Health-Syst Pharm—Vol 66 Aug 1, 2009
blocker in patients with coronary spastic
angina. Circulation. 2003; 108:1446-50.
54. Gurney AM, Allam M. Inhibition of
calcium release from the sarcoplasmic
reticulum of rabbit aorta by hydralazine.
Br J Pharmacol. 1995; 114:238-44.
55. Azuma J, Sawamura A, Harada H et al.
Mechanism of direct cardiostimulating
actions of hydralazine. Eur J Pharmacol.
1987; 135:137-44.
56. Munzel T, Kurz S, Rajagopalan S et
al. Hydralazine prevents nitroglycerin
tolerance by inhibiting activation of a
membrane-bound NADH oxidase. A new
action for an old drug. J Clin Invest. 1996;
98:1465-70.
57. Wei S, Kasuya Y, Yanagisawa M et al.
Studies on endothelium-dependent va-
sorelaxation by hydralazine in porcine
coronary artery. Eur J Pharmacol. 1997;
321:307-14.
58. Knowles HJ, Tian YM, Mole DR et al.
Novel mechanism of action for hydrala-
zine: induction of hypoxia-inducible
factor-1 alpha, vascular endothelial
growth factor, and angiogenesis by in-
hibition of prolyl hydroxylases. Circ Res.
2004; 95:162-9.
59. Rhoney DH, Liu-DeRyke X. Effect of va-
soactive therapy on cerebral circulation.
Crit Care Clin. 2006; 22:221-43.
60. Overgaard J, Skinhoj E. A paradoxical
cerebral hemodynamic effect of hydrala-
zine. Stroke. 1975; 6:402-10.
61. Skinhoj E, Overgaard J. Effect of dihy-
dralazine on intracranial pressure in
patients with severe brain damage. Acta
Med Scand Suppl. 1983; 678:83-7.
62. James DJ, Bedford RF. Hydralazine for
controlled hypotension during neuro-
surgical operations. Anesth Analg. 1982;
61:1016-9.
63. Powers DR, Papadakos PJ, Wallin JD.
Parenteral hydralazine revisited. J Emerg
Med. 1998; 16:191-6.
64. Elliott WJ. Clinical features in the
management of selected hypertensive
emergencies. Prog Cardiovasc Dis. 2006;
48:316-25.
65. Phillips RA, Greenblatt J, Krakoff LR.
Hypertensive emergencies: diagnosis and
management. Prog Cardiovasc Dis. 2002;
45:33-48.
66. Grossman E, Ironi AN, Messerli FH.
Comparative tolerability profile of hyper-
tensive crisis treatments. Drug Saf. 1998;
19:99-122.
67. Gray RJ. Managing critically ill patients
with esmolol. An ultra short-acting
beta-adrenergic blocker. Chest. 1988;
93:398-403.
68. Singh PP, Dimich I, Sampson I et al. A
comparison of esmolol and labetalol for
the treatment of perioperative hyper-
tension in geriatric ambulatory surgical
patients. Can J Anaesth. 1992; 39:559-
62.
69. Balser JR, Martinez EA, Winters BD et
al. Beta-adrenergic blockade accelerates
conversion of postoperative supraven-
tricular tachyarrhythmias. Anesthesiology.
1998; 89:1052-9.
1351
 clinical review  Intravenous therapy
70. Platia EV, Michelson EL, Porterfield JK et
al. Esmolol versus verapamil in the acute
treatment of atrial fibrillation or atrial
flutter. Am J Cardiol. 1989; 63:925-9.
71. Smerling A, Gersony WM. Esmolol for
severe hypertension following repair of
aortic coarctation. Crit Care Med. 1990;
18:1288-90.
72. Gray RJ, Bateman TM, Czer LS et al. Use
of esmolol in hypertension after cardiac
surgery. Am J Cardiol. 1985; 56:49F-
56F.
73. Gray RJ, Bateman TM, Czer LS et al. Com-
parison of esmolol and nitroprusside for
acute post-cardiac surgical hypertension.
Am J Cardiol. 1987; 59:887-91.
74. Muzzi DA, Black S, Losasso TJ et al.
Labetalol and esmolol in the control of
hypertension after intracranial surgery.
Anesth Analg. 1990; 70:68-71.
75. Mooss AN, Hilleman DE, Mohiuddin
SM et al. Safety of esmolol in patients
with acute myocardial infarction treated
with thrombolytic therapy who had rela-
tive contraindications to beta-blocker
therapy. Ann Pharmacother. 1994; 28:
701-3.
76. Sheppard D, DiStefano S, Byrd RC et al.
Effects of esmolol on airway function in
patients with asthma. J Clin Pharmacol.
1986; 26:169-74.
77. Brevibloc (esmolol hydrocholoride)
package insert. Deerfield, FL: Baxter;
2005.
78. Lange RA, Cigarroa RG, Flores ED et al.
Potentiation of cocaine-induced coro-
nary vasoconstriction by beta-adrenergic
blockade. Ann Intern Med. 1990; 112:897-
903.
79. Olsen KS, Svendsen LB, Larsen FS et al.
Effect of labetalol on cerebral blood flow,
oxygen metabolism and autoregulation
in healthy humans. Br J Anaesth. 1995;
75:51-4.
1352 Am J Health-Syst Pharm—Vol 66 Aug 1, 2009
80. Rosei EA, Trust PM, Brown JJ et al. Intra-
venous labetalol in severe hypertension.
Lancet. 1975; 2:1093-4.
81. Medscape. Labetalol hydrochloride.
www.medscape.com/druginfo/monogra
ph?cid=med&drugid=8798&drugname
=Labetalol+IV&monotype=monograph
(accessed 2008 Oct 20).
82. Murphy MB, Murray C, Shorten GD.
Fenoldopam: a selective peripheral
dopamine-receptor agonist for the treat-
ment of severe hypertension. N Engl J
Med. 2001; 345:1548-57.
83. Landoni G, Biondi-Zoccai GG, Tumlin
JA et al. Beneficial impact of fenoldopam
in critically ill patients with or at risk for
acute renal failure: a meta-analysis of
randomized clinical trials. Am J Kidney
Dis. 2007; 49:56-68.
84. Ng TM, Shurmur SW, Silver M et al.
Comparison of N-acetylcysteine and
fenoldopam for preventing contrast-
induced nephropathy (CAFCIN). Int J
Cardiol. 2006; 109:322-8.
85. Pannu N, Wiebe N, Tonelli M. Prophy-
laxis strategies for contrast-induced
nephropathy. JAMA. 2006; 295:2765-79.
86. Vasotec (enalapril maleate) i.v. package
insert. Bridgewater, NJ: Biovail Pharma-
ceuticals; 2007.
87. Barbe F, Su JB, Guyene TT et al. Bradyki-
nin pathway is involved in acute hemody-
namic effects of enalaprilat in dogs with
heart failure. Am J Physiol. 1996; 270:
H1985-92.
88. McAreavey D, Robertson JI. Angiotensin
converting enzyme inhibitors and moder-
ate hypertension. Drugs. 1990; 40:326-45.
89. Hirschl MM, Binder M, Bur A et
al. Impact of the renin-angiotensin-
aldosterone system on blood pressure
response to intravenous enalaprilat in
patients with hypertensive crises. J Hum
Hypertens. 1997; 11:177-83.
90. Publication Committee for the VMAC
Investigators (Vasodilation in the Man-
agement of Acute CHF). Intravenous ne-
siritide vs nitroglycerin for treatment of
decompensated congestive heart failure: a
randomized controlled trial. JAMA. 2002;
287:1531-40. [Erratum, JAMA. 2002;
288:577.]
91. Hunt S, Abraham W, Chin M et al. ACC/
AHA 2005 guideline update for the
diagnosis and management of chronic
heart failure in the adult. A report of
the American College of Cardiology/
American Heart Association Task Force
on Practice Guidelines (Writing Com-
mittee to Update the 2001 Guidelines
for the Evaluation and Management of
Heart Failure). J Am Coll Cardiol. 2005;
46:1116-43.
92. Sackner-Bernstein JD, Kowalski M, Fox
M et al. Short-term risk of death after
treatment with nesiritide for decom-
pensated heart failure: a pooled analysis
of randomized controlled trials. JAMA.
2005; 293:1900-5.
93. Yancy C, on behalf of the FUSION II
Steering Committee and FUSION II In-
vestigators. Results of the follow-up serial
infusions of nesiritide for the manage-
ment of patients with [advanced] heart
failure. FUSION II Trial. Presented at
ACC Scientific Session. New Orleans, LA;
2007 Mar 25.
94. ClinicalTrials.gov. A study testing the
effectiveness of nesiritide in patients
with acute decompensated heart failure.
http://clinicaltrials.gov/ct2/show/NCT00
475852?term=nesiritide+ascend&rank=1
(accessed 2008 Oct 20).
95. Chow SL, Peng JT, Okamoto MP et al.
Effect of nesiritide infusion duration on
renal function in acutely decompensated
heart failure patients. Ann Pharmacother.
2007; 41:556-61.