Drugs used for the treatment of hypertensive emergencies

Authors:
William J Elliott, MD, PhD
Joseph Varon, MD, FACP, FCCP, FCCM, FRSM

Section Editors:
George L Bakris, MD
William B White, MD

Deputy Editor:
John P Forman, MD, MSc

INTRODUCTION

— A hypertensive emergency is present when severe hypertension is associated with acute end-organ damage.
Examples include hypertensive encephalopathy, acute pulmonary edema, aortic dissection, and rebound after abrupt
withdrawal of antihypertensive medications. Immediate but careful reduction in blood pressure is often indicated in
these settings. However, an excessive hypotensive response is potentially dangerous, possibly leading to ischemic
complications such as stroke, myocardial infarction, or blindness. Thus, in patients who are severely hypertensive but
asymptomatic, slower reductions in blood pressure may be achieved with oral agents. (See 'Oral drugs' below.)

The drugs that are used for the treatment of hypertensive emergencies are presented in this topic. The evaluation of
patients with severe hypertension and the blood pressure goals in patients with hypertensive emergencies are
presented elsewhere. (See "Evaluation and treatment of hypertensive emergencies in adults".)

PARENTERAL DRUGS

— A variety of parenteral and oral antihypertensive drugs are available for use in these patients (table 1) [1-7]. Few
studies have compared these agents with one another, and all are tolerated reasonably well [8,9]. Thus, the drug of
choice is often dictated by the type of hypertensive emergency and the local hospital formulary. (See "Moderate to
severe hypertensive retinopathy and hypertensive encephalopathy in adults" and "Evaluation and treatment of
hypertensive emergencies in adults".)

Nitrates
— Nitrovasodilators such as nitroprusside and nitroglycerin provide nitric oxide that induces vasodilatation (of both
arterioles and veins) via generation of cyclic GMP, which then activates calcium-sensitive potassium channels in the
cell membrane [10].

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

The recommended starting dose of nitroprusside is 0.25 to 0.5 mcg/kg per minute. This can be increased as necessary
to a maximum dose of 8 to 10 mcg/kg per minute, although use of these higher doses should generally be avoided or
limited to a maximum duration of 10 minutes [11].

Toxicities and limitations of nitroprusside include:

● Nitroprusside is metabolized to cyanide, possibly leading to the development of cyanide (or, rarely, thiocyanate)
toxicity that may be fatal [11]. This problem, which can manifest in as little as four hours, presents with altered
mental status and lactic acidosis. Risk factors for nitroprusside-induced cyanide poisoning include a prolonged
treatment period (>24 to 48 hours), underlying kidney function impairment, and the use of doses that exceed the
capacity of the body to detoxify cyanide (ie, more than 2 mcg/kg per minute). The risk of toxicity can be
minimized by using the lowest possible dose, avoiding prolonged use (ie, no more than two or three days), and by
careful patient monitoring (with special attention to unexplained acidemia or decreasing serum bicarbonate
concentrations).

In addition, doses of 10 mcg/kg per minute should never be given for more than 10 minutes. An infusion of
sodium thiosulfate can be used in affected patients to provide a sulfur donor to detoxify cyanide into thiocyanate
[11].

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

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

● The high cost of nitroprusside may limit its availability in some settings. (See "Nitroprusside: Drug information".)

Nitroglycerin
— Nitroglycerin is also administered by intravenous infusion and is similar in action and pharmacokinetics to
nitroprusside except that it produces relatively greater venodilation than arteriolar dilation. It has less
antihypertensive efficacy compared with other drugs used to treat hypertensive emergencies, and its effects on blood
pressure are variable from person to person and, potentially, from minute to minute. However, it may be useful in
patients with symptomatic coronary disease and in those with hypertension following coronary bypass. Prolonged
infusions are generally avoided to prevent tachyphylaxis. (See "Nitrates in the management of acute coronary
syndrome", section on 'Nitrate tolerance'.)

The initial dose of nitroglycerin is 5 mcg/min, which can be increased as necessary to a maximum of 100 mcg/min.
The onset of action is 2 to 5 minutes, while the duration of action is 5 to 10 minutes. Headache (due to direct
vasodilation) and tachycardia (resulting from reflex sympathetic activation) are the primary adverse effects. Cyanide
accumulation does not occur. Methemoglobinemia has been reported in patients receiving this agent for more than 24
hours [7].

Calcium channel blockers

Clevidipine
— Clevidipine is an ultra-short-acting dihydropyridine calcium channel blocker that is approved for intravenous use
to treat severe hypertension. The drug is hydrolyzed by serum esterases and has a serum elimination half-life of 5 to
15 minutes. It reduces blood pressure without affecting cardiac filling pressures but can cause reflex tachycardia
[1,12]. Clevidipine is contraindicated in patients with severe aortic stenosis (because it increases the risk of severe
hypotension), disordered lipid metabolism (because it is administered in a lipid-laden emulsion), or known allergies to
soy or eggs (because these are used to produce the emulsion). It has not been compared with other short-acting drugs,
such as nitroprusside and nitroglycerin in hypertensive emergencies, but it was as or more effective than nitroglycerin,
nitroprusside, and nicardipine in acutely hypertensive patients during and after cardiac surgery [13]. The initial dose
is 1 mg/hour, which can be increased as necessary to a maximum of 21 mg/hour.

Nicardipine
— Nicardipine is a dihydropyridine calcium channel blocker (like nifedipine) that can be given as an intravenous
infusion. The initial dose is 5 mg/hour and can be increased to a maximum of 15 mg/hour. Nicardipine has a better
safety profile and a similar antihypertensive effect when compared with nitroprusside [14]. The major limitations are
a longer onset of action, which precludes rapid titration, and a longer serum elimination half-life (three to six hours).

Dopamine-1 agonist

Fenoldopam
— Fenoldopam is a peripheral dopamine-1 receptor agonist which, unlike other parenteral antihypertensive agents,
maintains or increases kidney perfusion while it lowers blood pressure [15]. Fenoldopam may be particularly
beneficial in patients with kidney function impairment and, compared with nitroprusside, may increase glomerular
filtration rate, urine output, and sodium excretion [16,17]. After starting at 0.1 mcg/kg per minute, the dose can be
titrated at 15-minute intervals to 1.6 mcg/kg per minute, depending upon the blood pressure response. Some experts
have used doses as high as 2.0 mcg/kg per minute or higher without inducing toxicity.

Fenoldopam should be used cautiously or not at all in patients with glaucoma [15]. In addition, because this agent is
premixed in a solution containing sodium metabisulfite, caution is recommended for patients with sulfite sensitivity.

Adrenergic-blocking agents

Labetalol
— Labetalol is a combined beta-adrenergic and alpha-adrenergic blocker. Its rapid onset of action (five minutes or
less) makes it a useful intravenous medication for the treatment of hypertensive emergencies. However, one trial found
that labetalol has less antihypertensive efficacy as compared with nicardipine [18].

Labetalol is safe in patients with active coronary disease since it does not increase heart rate. However, labetalol
should be avoided in patients with asthma, chronic obstructive lung disease, heart failure, bradycardia, or greater than
first-degree heart block. In addition, labetalol should not be used without prior adequate alpha blockade in patients
with hyperadrenergic states, such as pheochromocytoma or cocaine or methamphetamine overdose, since unopposed,
inadequately blocked alpha-adrenergic activity can increase blood pressure if beta blockade is not complete. (See
"Cocaine: Acute intoxication".)

Labetalol can be given as a series of intravenous bolus injections or as a constant-dose infusion. The bolus dose is 20
mg initially, followed by 20 to 80 mg every 10 minutes to a total dose of 300 mg. The infusion rate is 0.5 to 2
mg/min. Higher total doses and higher infusion rates are sometimes used, particularly in patients who are overweight
or who have obesity.

Esmolol
— Esmolol, a relatively cardioselective beta blocker, is rapidly metabolized by blood esterases. Its effects begin almost
immediately, and it has both a short half-life (approximately 9 minutes) and a short total duration of action
(approximately 30 minutes), permitting rapid titration. Esmolol is often used during anesthesia to prevent
postintubation hemodynamic perturbations.

Other agents

Hydralazine
— Although not a preferred agent for hypertensive emergencies, hydralazine is a direct arteriolar vasodilator with
little or no effect on the venous circulation. Thus, precautions are needed in patients with underlying coronary disease
or aortic dissection, and a beta blocker should be given concurrently to minimize reflex sympathetic stimulation. The
hypotensive response to hydralazine is less predictable than that seen with other parenteral agents. Although
intravenous hydralazine is often given to hospitalized patients when blood pressures exceeding arbitrary thresholds,
there is little evidence that this practice improves outcomes, and it can be associated with hypotension [19]. The most
evidence-based use of parenteral hydralazine is primarily limited to pregnant women, although a reduction in the
utero-placental blood flow has been reported in such patients. (See "Treatment of hypertension in pregnant and
postpartum patients".)

Hydralazine can be given as an intravenous bolus. The initial dose is 10 mg, with the maximum dose being 20 mg. The
fall in blood pressure can be sudden and begins within 10 to 30 minutes and lasts two to four hours.

Enalaprilat
— Enalaprilat is the intravenously active, des-ethyl ester of the angiotensin-converting enzyme (ACE) inhibitor,
enalapril. The hypotensive response to enalaprilat is unpredictable and depends upon the plasma volume and plasma
renin activity in individual patients with a hypertensive emergency [20]. Typically, hypovolemic patients with a high
plasma renin activity are most likely to have an excessive hypotensive response. In addition, ACE inhibitors are
contraindicated in pregnancy, severe renal artery stenosis with kidney ischemia, and severe hyperkalemia. (See
"Adverse effects of angiotensin-converting enzyme inhibitors and receptor blockers in pregnancy".)

The usual initial dose is 1.25 mg. As much as 5 mg may be given every six hours as necessary [20]. The onset of action
begins in 15 minutes, but the peak effect may not be seen for four hours. The duration of action ranges from 12 to 24
hours.

Phentolamine
— Phentolamine is a nonselective alpha-adrenergic blocker, the use of which is limited to the treatment of severe
hypertension due to increased catecholamine activity. Examples include pheochromocytoma or tyramine ingestion in a
patient being treated with a monoamine oxidase inhibitor. However, it is not more effective than other alpha-
adrenergic blockers, and its availability may be limited in many centers. (See "Clinical presentation and diagnosis of
pheochromocytoma" and "Treatment of pheochromocytoma in adults".)

Phentolamine is given as an intravenous bolus. The usual dose is 5 to 15 mg every 5 to 15 minutes as necessary.
Patients receiving this agent who do not require intravenous therapy can be converted to oral phenoxybenzamine.

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

SOCIETY GUIDELINE LINKS

— Links to society and government-sponsored guidelines from selected countries and regions around the world are
provided separately. (See "Society guideline links: Hypertension in adults".)

INFORMATION FOR PATIENTS

— UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient
education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five
key questions a patient might have about a given condition. These articles are best for patients who want a general
overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for
patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics
to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info"
and the keyword(s) of interest.)

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

SUMMARY AND RECOMMENDATIONS

● Hypertensive emergency – A hypertensive emergency is defined as severe hypertension that is associated with
acute end-organ damage. (See 'Introduction' above.)

Immediate but careful reduction in blood pressure is indicated in hypertensive emergencies; an excessive
hypotensive response may lead to ischemic complications. A variety of parenteral and oral antihypertensive drugs
are available for use in these patients (table 1). (See 'Introduction' above and 'Parenteral drugs' above.)

Parenteral drugs include nitroprusside, nitroglycerin, clevidipine, nicardipine, fenoldopam, labetalol, esmolol,
hydralazine, enalaprilat, and phentolamine. (See 'Parenteral drugs' above.)

● Severe asymptomatic hypertension – Among patients who are severely hypertensive but asymptomatic, slower
reductions in blood pressure may be provided with oral agents. (See 'Oral drugs' above.)

REFERENCES

1. Padilla Ramos A, Varon J. Current and newer agents for hypertensive emergencies. Curr Hypertens Rep 2014;
16:450.
2. Vaughan CJ, Delanty N. Hypertensive emergencies. Lancet 2000; 356:411.
3. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension:
the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and