Parenteral hydralazine should be considered an intermediate treatment between oral
agents and more aggressive therapy with such agents as fenoldopam or nitroprusside.
It can be given IV or intramuscularly. The onset of action develops slowly over 20 to
40 minutes, thus minimizing the risk of acute hypotension. Parenteral doses are
considerably lower than oral doses because of increased bioavailability.
Enalaprilat, the active metabolite of the oral prodrug enalapril, is approved by the
U.S. Food and Drug Administration for the treatment of hypertension when oral
therapy is not feasible. However, enalaprilat has been used to treat severe
112–117 The initial dose is 0.625 to 1.25 mg IV and can be repeated every
6 hours, if necessary. To minimize the risk of hypotension, the initial doses should
not exceed 0.625 mg in patients receiving diuretics or in patients with clinical
evidence of hypovolemia. The onset of action is within 15 minutes, but the maximal
effect may take several hours. Because only 60% of the patients respond to BP
reduction within 30 minutes, it cannot be reliably used to acutely lower pressure in
115 Although higher initial doses have been successfully
116 some evidence indicates that doses greater than 0.625
mg do not significantly alter the magnitude of enalaprilat’s antihypertensive effect.
Enalaprilat is also beneficial in patients with HF. Precautions for the use of
enalaprilat are similar to those of captopril (see Case 16-1, Question 5). Because of
the prolonged time required to achieve an adequate response, limited clinical
experience, and variable response rates (especially in African Americans),
enalaprilat cannot be recommended for the routine treatment of patients with
Intravenous Calcium-Channel Blockers
Postoperative hypertension is typically short lived and is most commonly seen after
neurosurgical, head and neck, vascular, and cardiothoracic procedures (as is the case
with H.C.). Treatment is typically only required for 6 hours postoperatively, and up
24 to 48 hours for some who may have persistent hypertension. Adequate control of
BP postoperatively is necessary to minimize the risk of cardiovascular, neurologic,
or surgical-site complications such as bleeding.
118 When selecting an agent, one
should consider therapies with a quick onset and short duration of action as well as
established efficacy and safety in the postoperative setting.
Nicardipine is a potent cerebral and systemic vasodilator and a useful therapeutic
option in the management of severe hypertension. Its onset of action is within 1 to 2
minutes, and its elimination half-life is 40 minutes.
demonstrated that IV nicardipine significantly decreased mean arterial pressure and
systemic vascular resistance and significantly increased cardiac index with little or
120 As a dihydropyridine, nicardipine has less negative
inotropic activity compared with nondihydropyridines. Titratable IV nicardipine has
been studied extensively for use in controlling postoperative hypertension
In the treatment of postoperative hypertension,
IV nicardipine was administered
as an infusion titrated in the following manner: 10 mg/hour for 5 minutes, 12.5
mg/hour for 5 minutes, and 15 mg/hour for 15 minutes, followed by a maintenance
infusion of 3 mg/hour thereafter. The mean response time and infusion rate were 11.5
minutes and 12.8 mg/hour, respectively. The most commonly reported adverse effects
included hypotension, tachycardia, and nausea and vomiting.
In studies of patients receiving nicardipine versus nitroprusside for postoperative
hypertension after cardiac endarterectomy and coronary artery bypass grafting,
breakthrough BP was controlled more rapidly with nicardipine and required fewer
overall dose titrations. In addition, nicardipine was well tolerated and did not lead to
an increased risk of complications.
Nicardipine is an appropriate choice of therapy for H.C. in the postoperative
setting because this agent has a rapid onset of action, and provides sustained BP
control during the infusion period. It is easily titratable, with a predictable response,
and is relatively free of severe adverse effects. Therapy should be titrated to achieve
a BP approximately 10% higher than the patient’s baseline. In addition to
nicardipine, nitroprusside, nitroglycerin, and labetalol are most commonly used to
manage postoperative hypertension.
118 Finally, nicardipine may be useful in patients
with cerebral insufficiency or peripheral vascular disease. Because of the potential
for reflex tachycardia, it should be used with caution in patients with ongoing
Nicardipine has been proven effective in multiple studies of populations with
hypertensive emergencies, and, as a dihydropyridine, has less negative inotropic
activity compared with nondihydropyridines.
In contrast, the nondihydropyridines parenteral verapamil and diltiazem, although
clinically effective for prompt lowering of BP, have not been extensively studied in
patients with hypertensive emergencies. Clevidipine, a third-generation
dihydropyridine, has also been shown to be useful in controlling BP in hypertensive
emergencies and in the perioperative setting.
CASE 16-5, QUESTION 2: What other IV forms of calcium-channel blockers are available? Would any of
these agents be an appropriate choice of therapy for H.C.?
IV verapamil (5–10 mg) produces a significant reduction in BP, which occurs within
15 minutes and persists for 6 to 8 hours. As a cardiovascular drug, it is primarily
used as a rate-controlling agent in the treatment of supraventricular tachycardias.
IV diltiazem is approved for temporary control of the ventricular rate in atrial
fibrillation or atrial flutter and for rapid conversion of paroxysmal supraventricular
130–132 Parenteral diltiazem has also been used to control hypertension that
occurs intraoperatively and postoperatively,
133,134 and in patients with an acute
135,136 However, published experience with the use of IV diltiazem
for the treatment of severe hypertension is limited.
Atrioventricular nodal conduction abnormalities can occur during administration
of IV verapamil or diltiazem. Patients receiving either of these therapies require
continuous monitoring by electrocardiogram and frequent BP checks. IV verapamil
and diltiazem should be avoided in patients with sick sinus syndrome or advanced
degrees of heart block. Until additional information is available, caution should be
exercised in using either agent parenterally to lower BP acutely. In addition, use of
nondihydropyridines should be avoided when acutely treating any hypertensive
patient with concomitant systolic HF owing to their negative inotropic effects.
CASE 16-5, QUESTION 3: What factors should clinicians consider before recommending the use of
139 Clevidipine is quickly metabolized in
extravascular tissue and blood by esterases, leading to a short elimination half-life of
140 and complete resolution of hemodynamic effects within 10 minutes after
the end of a 24-hour continuous infusion.
141 Clevidipine demonstrates a quick onset of
142 These pharmacokinetic and pharmacodynamic properties
make it an attractive agent for managing hypertensive emergencies. Clevidipine
demonstrated efficacy in the treatment of hypertension in both preoperative and
postoperative cardiac surgery patients.
In this setting, therapy was initiated at a
rate of 0.4 mcg/kg/minute. Target BP was a reduction of at least 15% from baseline.
The dose was titrated every 90 seconds by doubling the dose up to an infusion rate of
3.2 mcg/kg/minute, then increasing the dose by 1.5 mcg/kg/minute to a maximum rate
of 8 mcg/kg/minute. Clevidipine demonstrated a median time of effectiveness within
6 minutes in greater than 90% of the patients who received the study medication.
Clevidipine has been compared with nitroglycerin, nitroprusside, and nicardipine
in the management of perioperative hypertension in cardiac surgery patients.
Clevidipine was more effective in maintaining patients within a predefined BP target
range when compared individually with nitroglycerin and nitroprusside, but this did
not translate to differences in clinical outcomes. Clevidipine was equivalent to
nicardipine in keeping patients within a prespecified BP range. The incidence and
severity of adverse events were similar among patients who received clevidipine
Based on the limited data, nondihydropyridines would not be an appropriate
choice of therapy for H.C. Additionally, IV verapamil has a long duration of action,
which is not an ideal characteristic in the setting of postoperative hypertension.
Clevidipine, however, has a rapid onset of action and short duration of action and is
effective in controlling BP in the perioperative setting.
Clevidipine infusions can induce reflexive tachycardia with an increased heart rate
by up to approximately 20 beats/minute.
141 Clevidipine is formulated in a 20% lipid
emulsion, so it should be avoided in patients with serum triglycerides greater than
400 mg/dL, and any remaining drug should be discarded after 4 hours of use.
Clevidipine is contraindicated in patients with allergies to soybeans, soy products,
eggs, or egg products. This agent is also contraindicated in those with defective lipid
metabolism or acute pancreatitis (if accompanied by hyperlipidemia), and in patients
QUESTION 1: B.S., a 68-year-old Caucasian man with a long history of hypertension and nonadherence,
hypertrophy, but no acute changes are noted. The chest radiograph is significant for widening of the
What antihypertensive medication(s) would be most appropriate for B.S., and why?
Dissection of the aorta occurs when the innermost layer of the aorta (the intima) is
torn such that blood enters and separates its layers. The ultimate treatment for this
type of hypertensive emergency depends on its location and severity; however, the
first principle of therapy is to control any existing hypertension with agents that do
not increase the force of cardiac contraction or heart rate. This lessens the force that
the cardiac impulse transmits to the dissecting aneurysm.
The aim of antihypertensive therapy in aortic dissection is to lessen the pulsatile
load or aortic stress by lowering the BP. Reducing the force of left ventricular
contractions, and consequently the rate of rise of aortic pressure, retards the
propagation of the dissection and aortic rupture.
145,146 The treatment of choice for
aortic dissection has classically been a vasodilatory agent such as sodium
nitroprusside, fenoldopam, or nicardipine in combination with a β-blocker titrated to
a heart rate of 55 to 65 beats/minute.
145,147 Labetalol monotherapy has been used as an
148 These drugs decrease BP, venous return, and cardiac contractility, thus
decreasing sheer stress to the aorta.
One common regimen is a combination of IV sodium nitroprusside (0.5–2
mcg/kg/minute) plus IV esmolol.
20,146 This combination can be used as initial therapy
for B.S. The concurrent administration of a β-blocking agent with a vasodilator is
desirable because the latter may induce reflex tachycardia in response to
Esmolol is a parenteral cardioselective β1
-blocker with a rapid onset and short
duration of action. For the management of hypertension, esmolol should be given as a
loading dose of 250 to 500 mcg/kg over 1 minute, followed by a maintenance
infusion of 50 to 300 mcg/kg/minute. Irritation, inflammation, and induration at the
infusion site occur in 5% to 10% of patients.
Hypotension is the most commonly reported adverse event and is directly related
to the duration of esmolol administration.
149 However, because of the short half-life,
resolution of hypotension occurs within 30 minutes of discontinuing the infusion.
Direct vasodilators such as hydralazine should be avoided because they increase
stroke volume and left ventricular ejection rate. These effects augment the pulsatile
flow and accentuate the sharpness of the pulse wave. This increases mechanical
stress on the aortic wall and may lead to further dissection.
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