Treatment Choices for Severe Hypertension
Primary Care Update
Brief summaries for Clinical Practice
Here, we will review the contemporary armamentarium for severe hypertension. The pros and cons of the drugs used to manage hypertensive crises will be highlighted.
In our article, "Extremely Elevated Blood Pressures: An Update on Hypertensive Urgencies and Emergencies," we defined a terminology for severe hypertension (eg, hypertensive urgency and emergency). We also offered treatment suggestions and outlined an appropriate workup for secondary causes of resistant hypertension in the ambulatory setting.
Mechanism of action. Oral clonidine stimulates central alpha-2 adrenergic receptors in the brain stem, which reduces sympathetic outflow. A rapid and immediate antihypertensive effect is obtained in 30 to 60 minutes with a peak effect in 2 to 4 hours. The duration of action for clonidine, however, is variable and lasts between 6 and 24 hours. This variability makes it difficult to titrate doses.1
Cautions. The use of clonidine in hypertensive urgencies is limited by its adverse-effect profile as well as its variable duration. While the hypotensive risk is small, the incidence of sedation can be significant.2 Clonidine should not be used in patients with heart failure or heart block or in those with hypertensive encephalopathy (sedation and confusion from the drug may complicate management).
Clonidine does have an important continuing role in the treatment of hypertensive urgencies consequent to clonidine withdrawal.
Mechanism of action. Nifedipine is a dihydropyridine calcium-channel blocker; this potent oral or sublingual agent has been used in hypertensive crises. Although it is not absorbed well from the buccal mucosa, the drug is rapidly absorbed in the GI tract and causes direct arteriolar vasodilation.3
Immediate-release formulations of nifedipine produce a rapid and significant reduction in blood pressure, usually within 5 to 20 minutes. Peak effects occur at 30 to 60 minutes, and the duration of action can last as long as 6 hours.4
Cautions. Nifedipine produces an unpredictable decline in blood pressure that can cause cerebral, renal, and cardiac ischemic events. These events have been associated with fatal outcomes. As a result, immediate-release nifedipine should be avoided for blood pressure control in acute episodes of severe hypertension.5
Mechanism of action. Sodium nitroprusside acts as a nitric oxide donor, causing vascular smooth muscle relaxation in both the venous and arterial vessels.
Cautions. Nitroprusside administration has been associated with decreased flow to areas of coronary ischemia; this is known as “the coronary steal effect.”6 In addition, nitroprusside may preferentially cause a decrease in systemic vascular resistance, generating an increase in blood flow to the systemic vasculature, which may result in decreased cerebral blood flow and increased intracranial pressure.7
Nitroprusside has been used to treat hypertensive emergencies for decades. Nitroprusside is as effective as fenoldopam in lowering blood pressure in hypertensive emergencies, but it is not as effective in improving renal function.8
As a result of its organ-specific detrimental pharmacological profile, nitroprusside should not be used in patients with CNS-associated end organ damage. Nitroprusside should also be avoided in the early treatment of hypertension (within 9 hours) in patients with an acute myocardial
infarction (MI).9 Because cyanide is released during its metabolism, nitroprusside should be avoided in patients with liver and kidney dys-function. Cyanide toxicity can result in cardiac arrest, coma, and encephalopathy. Lactic acidosis may be an early indication of toxicity.10
Although nitroprusside may not be the best choice to treat severe hypertension because of safety concerns, it may be used effectively in patients with hypertensive emergencies. It is recommended that the smallest dose and shortest duration be used.
Mechanism of action. Nitroglycerin is also a nitric oxide donor, resulting in smooth muscle vasodilation. This drug primarily acts on the veins but also affects arteries at high doses.11 Unlike nitroprusside, nitroglycerin can increase coronary blood flow to the coronary vessels.
Nitroglycerin may be considered for blood pressure control during an acute MI, heart failure, and hypertensive emergency with acute pulmonary edema.
Cautions. Nitroglycerin should be avoided in patients with volume depletion because hypotension may result.Intravenous nitroglycerin may also be associated with increased intracranial pressure. Thus, it should be avoided in patients with CNS end organ damage.12
Mechanism of action. Fenoldo--pam, a peripheral dopamine type-1 receptor agonist, causes vasodilation of coronary, renal, mesenteric, and peripheral arteries.13 Through this mechanism of action, fenoldopam decreases blood pressure in a dose-related manner with a concomitant reflex tachycardia. Dopamine type-1 receptors are also located on renal tubular cells.
Fenoldapam causes vasodilation of the renal artery and afferent and efferent arterioles.14 An increase in renal blood flow and glomerular filtration rate can be seen with fenoldopam use.
Studies that compared fenoldopam with nitroprusside in the treatment of hypertensive emergencies showed no difference in time to goal blood pressure or mean arterial pressure.15 Although fenoldopam was not superior to nitroprusside in lowering blood pressure, its use was associated with greater improvement in urine output, sodium excretion, and creatinine clearance. Studies also support the use of fenoldopam in cardiac surgery patients with perioperative hypertension. The results demonstrated improved outcomes over both nifedipine and nitroprusside in the setting of coronary artery bypass graft surgery.16
With such a favorable renal profile, fenoldopam is a preferred treatment option in patients with
hypertensive emergency and renal dysfunction.
Cautions. Although fenoldopam’s pharmacological profile can be ideal for certain settings, it should probably be avoided in patients with CNS end organ damage or glaucoma. Dose-dependent increases in intraocular pressure have been observed in patients.17 Effects on intracranial pressure (ICP) are unknown. When dosing fenoldopam in elderly patients, it is best to start at a low dose and increase gradually.
Mechanism of action. Hydralazine is a direct arterial vasodilator that is associated with a reduction in afterload. This parenteral agent has been a mainstay in the treatment of eclampsia or preeclampsia most likely because it can improve uterine blood flow.
Hydralazine can be given intramuscularly or intravenously via injection or infusion. Given intravenously, the onset of action usually occurs in 5 to 15 minutes. Although the half-life of the drug is short, its pharmacological effect on blood pressure can last up to 12 hours or even longer.18
Cautions. As a result of this effect on blood pressure and the drug’s unpredictable hypotensive effect, it may be difficult to effectively titrate hydralazine. The adverse effects include reflex tachycardia, palpitations, headache, nausea, vomiting, flushing, and fluid retention. The reflex tachycardia and palpitations seen with this agent contraindicate its use in coronary artery disease and aortic dissection and may require the addition of a beta-blocker. In addition, the drug may raise ICP in patients with a preexisting
increase in ICP.19
Because of an unpredictable and prolonged response, hydralazine is not recommended for general treatment of hypertensive crises. Although it has long been the drug of choice for the treatment of preeclampsia and eclampsia, a meta-analysis has shown an increased risk of maternal hypotension, resulting in an excess of cesarean sections, placental abruptions, and low Apgar scores.20 As a result, it has been suggested that hydralazine no longer be recommended as the first-line agent in pregnancy.
Mechanism of action. Nicardipine is a non-dihydropyridine calcium-channel blocker that can be used for both hypertensive urgencies and emergencies. Intravenous and oral dosage forms are available. It is able to cross the blood-brain barrier and cause vasodilatation of cerebrovascular smooth muscle.21
Nicardipine is generally considered the drug of choice for hypertension in the setting of stroke. It is also used in perioperative hypertension, preeclampsia, eclampsia, hypertensive encephalopathy, and postoperative hypertension. Oral nicardipine can be used to treat hypertensive urgencies.
When compared with sodium nitroprusside, nicardipine was shown to be as effective, but without the risk of thiocyanate toxicity.22 Target blood pressure was also achieved faster with less variability in blood pressure than with sodium nitroprusside.
Mechanism of action. Clevidipine is a short-acting calcium-channel blocker used for hypertensive emergencies. It decreases
arterial blood pressure through a reduction in systemic vascular resistance. Clevidipine is not dependent on renal or hepatic metabolism
or clearance. Clevidipine has been studied in multiple settings for blood pressure reduction.23 It has been used successfully to treat severe hypertension and perioperative, preoperative, and postoperative hypertension.24
Cautions. Clevidipine should not be used in persons with aortic stenosis because it can decrease oxygen delivery to the myocardium. It can also cause heart failure as a result of its negative inotropic effects.
Clevidipine is contraindicated in patients with egg, egg product, soybean, and soybean product allergy; as well as persons with defective lipid metabolism.
Mechanism of action. Labetalol is an alpha-1 and nonselective
beta-adrenergic receptor antagonist used in the treatment of hypertensive urgencies and emergencies. Beta-blockade is more prevalent than alpha-blockade in a 3-10:1 ratio.25 Labetalol lowers blood pressure by reducing systemic vascular resistance without decreasing total peripheral blood flow. It has very
little effect on cerebral, renal, or coronary vasculature.26
Labetalol has been used to treat hypertension in ischemic and hemorrhagic stroke, hypertensive encephalopathy, aortic dissection, acute MI, catecholamine excess, postoperative hypertension, and preeclampsia and eclampsia.27 Labetolol does not appear to induce fetal distress in the treatment of eclampsia.28
Mechanism of action. Esmolol is a beta-1 selective adrenergic receptor antagonist with negative inotropic and chronotropic effects that is used to treat hypertensive emergencies. Administration should be accompanied by invasive blood pressure monitoring.
Esmolol has been used in the treatment of hypertension after
MI as well as perioperative and postoperative hypertension, during repair of coarctation, and in acute aortic dissection (given with sodium nitroprusside).29-31 Esmolol is the beta-antagonist of choice in aortic dissection.32
Cautions. Esmolol can exacerbate heart failure.
Mechanism of action. Phentolamine, a competitive peripheral alpha-1 and alpha-2 receptor antagonist, has been used to treat hypertension associated with catecholamine excess. It is most commonly used in the alpha-blockade phase of pheochromocytoma treatment and is the drug of choice for adrenergic crises only.33 It has been used to treat hypertension related to cocaine toxicity, amphetamine overdose, clonidine withdrawal, and monoamine oxidase inhibitor interactions with food and other drugs.10
Cautions. In patients with coronary artery disease, phentolamine use has induced angina and MIs.
Mechanism of action. Enalaprilat is an angiotensin-converting enzyme (ACE) inhibitor with effects identical to those of captopril. The drug is administered intravenously at an initial dosage of 1.25 mg over 5 minutes every 4 to 6 hours. This initial dosage may be titrated in 1.25-mg increments at 12 to 24 hour intervals to a maximum of 5 mg every 6 hours. The onset of action varies from 10 to 60 minutes with a duration of action from 2 to 6 hours or more. Because enalaprilat does not impair cerebral blood flow, it may be indicated for patients with severe hypertension and heart failure or high levels of angiotensin II, as well as patients at risk for cerebral hypotension.34
Cautions. Enalaprilat can lead to rapid untoward decreases in blood pressure in patients who are hypovolemic and in those with bilateral renal artery stenosis. Note that these agents are contraindicated in pregnancy, bilateral renal artery
stenosis, and acute MI. Because of the delayed peak, long duration of action, and varied response, enalaprilat is not ideal for the rapid titration of blood pressure needed in the emergency setting. ACE inhibitors should also be used cautiously in hyperkalemic patients.■
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6. Mann T, Cohn PF, Holman LB, et al. Effect of nitroprusside on regional myocardial blood flow in coronary blood flow in coronary artery disease. Circulation. 1978;57:732-738.
7. Immink RV, van den Born BJ, van Montfrans GA, et al. Cerebral hemodynamics during treatment with sodium nitroprusside versus labetalol in malignant hypertension. Hypertension. 2008;52:236-240.
8. Panacek EA, Bednarczyk EM, Dunbar LM, et al. Randomized prospective trial of fenoldopam vs. sodium nitroprusside in the treatment of acute severe hypertension. Acad Emerg Med. 1995;2:959-965.
9. Cohn JN, Franciosa JA, Francis GS, et al. Effect of short-term infusion of sodium nitroprusside on mortality rate in acute myocardial infarction complicated by left ventricular failure: results of a Veteran’s Administration Cooperative Study. N Engl J Med. 1982;306:1129-1135.
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