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Drug treatment of hypertensive emergencies Norman M Kaplan, MD Burton D Rose, MD UpToDate performs a continuous review of over 350 journals and other resources. Updates are added as important new information is published. The literature review for version 14.2 is current through April 2006; this topic was last changed on May 9, 2006. The next version of UpToDate (14.3) will be released in October 2006. INTRODUCTION — A hypertensive emergency is considered to be present when severe hypertension is associated with acute end-organ damage. Examples include malignant hypertension, with or without hypertensive encephalopathy, subarachnoid or intracerebral hemorrhage, acute pulmonary edema, aortic dissection, and rebound after withdrawal of antihypertensive medications. Immediate but careful reduction in blood pressure is indicated in these settings. However, an excessive hypotensive response is potentially dangerous, possibly leading to ischemic complications such as stroke, myocardial infarction or blindness in some cases. Thus, in patients who are severely hypertensive but asymptomatic, slower reductions in blood pressure should be provided with oral agents (see below). PARENTERAL DRUGS — A number of both parenteral and oral antihypertensive drugs can be used in these patients (show table 1A-1B) [1,2]. (See "Treatment of specific hypertensive emergencies" for a review of the approach to therapy in the different causes of severe hypertension). Nitroprusside — Nitroprusside dilates both arterioles and veins and is generally considered to be the most effective parenteral drug for most hypertensive emergencies. Nitroprusside, administered by intravenous infusion, begins to act within seconds and its effects disappear within minutes, thereby minimizing the risk of hypotension. Constant monitoring of the blood pressure is required. Nitroprusside and other nitrovasodilators (such as nitroglycerin) that provide nitric oxide appear to induce vasodilatation via generation of cyclic GMP which then activates calciumsensitive potassium channels in the cell membrane [3]. The major limitation to the use of nitroprusside is its metabolism to cyanide, possibly leading to the development of cyanide or rarely thiocyanate toxicity that may be fatal [4]. This problem, which is manifested by clinical deterioration, altered mental status, and lactic acidosis, can be minimized by using the lowest possible dose and by careful patient monitoring. Treatment for a prolonged period (>24 to 48 hours), underlying renal insufficiency, and the use of doses that exceed the capacity of the body to detoxify cyanide (more than 2 µg/kg per min) increase the risk of cyanide accumulation. The current FDA recommendation is that maximum doses of 10 µg/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 [4]. The recommended starting dose of nitroprusside is 0.25 to 0.5 µg/kg per minute. This can be increased as necessary to a maximum dose of 8 to 10 µg/kg per minute, although use of these higher doses should generally be avoided or limited to a maximum duration of 10 minutes [4]. Nitroprusside should not be given to pregnant women. Nitroglycerin — Nitroglycerin is also administered by intravenous infusion and is similar in action to nitroprusside except that it produces relatively greater venodilation than arteriolar dilation. It may be most useful in patients with symptomatic coronary disease and in those with hypertension following coronary bypass. The initial dose of nitroglycerin is 5 µg/min, which can be increased as necessary to a maximum of 100 µg/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 side effects. Cyanide accumulation does not occur. Nicardipine — Nicardipine is a dihydropyridine calcium channel blocker (like nifedipine) that can be given as an intravenous infusion. The initial dose is 5 mg/h and can be increased to a maximum of 15 mg/h. Initial experience with nicardipine has been very favorable when compared to nitroprusside [5]. The major limitation is a longer half-time, which precludes rapid titration. Fenoldopam — Fenoldopam is a peripheral dopamine-1 receptor agonist, and unlike other parenteral antihypertensive agents, maintains or increases renal perfusion while it lowers BP [6]. It maintains most of its efficacy for 48 hours of constant rate infusion without rebound hypertension when discontinued. Fenoldopam can be safely used in all hypertensive emergencies, and may be particularly beneficial in patients with renal insufficiency. After a starting dose of 0.1 µg/kg per min, the dose is titrated at 15 min intervals, depending on the BP response. Fenoldopam is contraindicated in patients with glaucoma [6]. Labetalol — Labetalol is a combined beta-adrenergic and alpha-adrenergic blocker. Its rapid onset of action (5 minutes or less) makes it the only ß-blocker that is useful in the treatment of hypertensive emergencies. Labetalol is safe in patients with active coronary disease, since it does not increase the heart rate. On the other hand, labetalol should generally be avoided in patients with asthma, chronic obstructive lung disease, congestive heart failure, bradycardia, or greater than first-degree heart block. Labetalol can be given as an intravenous bolus or 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. Esmolol — Esmolol, a relatively cardioselective beta blocker, is rapidly metabolized by blood esterases and has a short (about 9 minutes) half-life and total duration of action (about 30 minutes). Its effects begin almost immediately, and it has found particular use during anesthesia to prevent postintubation hemodynamic perturbations. Hydralazine — 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 an aortic dissection, and a ß-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 and its current use is primarily limited to pregnant women. (See "Treatment of hypertension in pregnancy"). Hydralazine is given as an intravenous bolus. The initial dose is 10 mg, with the maximum dose being 20 mg. The fall in blood pressure begins within 10 to 30 minutes and lasts 2 to 4 hours. Enalaprilat — Enalaprilat is an intravenous preparation of the active form of the angiotensin converting enzyme (ACE) inhibitor enalapril. The response to enalaprilat is variable and not predictable, a reflection of the variable plasma volume and plasma renin activity in patients with a hypertensive emergency [7]. As an example, hypovolemic patients with a high plasma renin activity may have an excessive hypotensive response. In addition, ACE inhibitors are generally contraindicated in pregnancy. (See "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 [7]. 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 an alpha-adrenergic blocker, the use of which is limited to the treatment of severe hypertension due to increased catecholamine activity. Examples include pheochromocytoma and tyramine ingestion in a patient being treated with a monoamine oxidase inhibitor. (See "Clinical presentation and diagnosis of pheochromocytoma" and see "Treatment of pheochromocytoma in adults"). Phentolamine is given as an intravenous bolus. The usual dose is 5 to 10 mg every 5 to 15 minutes as necessary. ORAL DRUGS — Oral antihypertensive agents 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)" for a discussion of this issue, and see "Hypertensive emergencies: Malignant hypertension and hypertensive encephalopathy"). Use of UpToDate is subject to the Subscription and License Agreement. 1. 2. 3. 4. 5. 6. REFERENCES Chobanian, AV, Bakris, GL, Black, HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 report. JAMA 2003; 289:2560. Vaughan, CJ, Delanty, N. Hypertensive emergencies. Lancet 2000; 356:411. Archer, SL, Huang, JM, Hampl, V, et al. Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase. Proc Natl Acad Sci U S A 1994; 91:7583. Schulz, V. Clinical pharmacokinetics of nitroprusside, cyanide, thiosulphate and thiocyanate. Clin Pharmacokinet 1984; 9:239. Neutel, JM, Smith, DH, Wallin, D, et al. A comparison of intravenous nicardipine and sodium nitroprusside in the immediate treatment of severe hypertension. Am J Hypertens 1994; 7:623. Murphy, MB, Murray, C, Shorten, GD. Fenoldopam: a selective peripheral dopamine- receptor agonist for the treatment of severe hypertension. N Engl J Med 2001; 345:1548. 7. Hirschl, MM, Binder, M, Bur, A, et al. Clinical evaluation of different doses of intravenous enalaprilat in patients with hypertensive crises. Arch Intern Med 1995; 155:2217. GRAPHICS Drugs for HTV emergencies A Drugs for HTV emergencies B Treatment of specific hypertensive emergencies Norman M Kaplan, MD Burton D Rose, MD UpToDate performs a continuous review of over 350 journals and other resources. Updates are added as important new information is published. The literature review for version 14.2 is current through April 2006; this topic was last changed on May 8, 2006. The next version of UpToDate (14.3) will be released in October 2006. INTRODUCTION — Most patients with relatively severe hypertension (diastolic pressure 120 mmHg), have no acute, end-organ injury. Although some propose relatively rapid antihypertensive therapy in this setting (as with sublingual nifedipine or oral clonidine loading), there may be more risk than benefit from such an aggressive regimen. (See "Management of severe asymptomatic hypertension (hypertensive urgencies)"). There are, however, hypertensive emergencies in which rapid lowering of the BP is indicated. These disorders will be reviewed here with the exception of malignant hypertension and hypertensive encephalopathy, which are discussed separately. ( See "Hypertensive emergencies: Malignant hypertension and hypertensive encephalopathy"). ANTIHYPERTENSIVE DRUGS — An overview of the mechanism of action, doses, and routes of administration of the antihypertensive drugs that may be used in this setting is provided in Table 1 (show Table 1A-1B) [1,2]. Intravenous furosemide or other potent diuretics are often needed to enhance the efficacy of these agents. The pharmacology and side effects of these drugs are discussed elsewhere. ( See "Drug treatment of hypertensive emergencies"). As will be described below, the choice of antihypertensive drug varies with the clinical setting. Nitroprusside has been the gold standard for many hypertensive emergencies because it begins to act within seconds and its effects disappear within minutes, thereby minimizing the risk of hypotension. The major limitations to the use of nitroprusside are the need for constant monitoring and its metabolism to cyanide, possibly leading to the development of cyanide or rarely thiocyanate toxicity that may be fatal. Nitroprusside — an arteriolar and venous dilator, given as an intravenous infusion. Initial dose: 0.25 to 0.5 µg/kg per min; maximum dose: 8 to 10 µg/kg per min which should be continued for no more than 10 minutes. Nitroglycerin — a venous and, to a lesser degree, arteriolar dilator, given as an intravenous infusion. Initial dose: 5 µg/min; maximum dose: 100 µg/min. Labetalol — an alpha- and ß-adrenergic blocker, given as an intravenous bolus or infusion. Bolus: 20 mg initially, followed by 20 to 80 mg every 10 minutes to a total dose of 300 mg. Infusion: 0.5 to 2 mg/min. Nicardipine — a calcium channel blocker, given as an intravenous infusion. Initial dose: 5 mg/h; maximum dose: 15 mg/h. Fenoldopam — a peripheral dopamine-1 receptor agonist, given as an intravenous infusion. Initial dose: 0.1 µg/kg per min; the dose is titrated at 15 min intervals, depending upon the blood pressure response. Hydralazine — an arteriolar dilator, given as an intravenous bolus. Initial dose: 10 mg given every 20 to 30 minutes; maximum dose: 20 mg. Propranolol — a ß-adrenergic blocker, given as an intravenous infusion and then followed by oral therapy. Dose: 1 to 10 mg load, followed by 3 mg/h. Phentolamine — an a-adrenergic blocker, given as an intravenous bolus. Dose: 5 to 10 mg every 5 to 15 minutes. Enalaprilat — an angiotensin converting enzyme inhibitor, given as an intravenous bolus. Dose: 1.25 mg every six hours. In general, nitroprusside is most rapid and potent. It acts within seconds and has a duration of action of only 2 to 5 minutes. Thus, hypotension can be easily reversed by temporarily discontinuing the infusion. The major limitation to the use of this drug is the development of cyanide toxicity in patients treated with high doses, for a prolonged period (>24 to 48 hours), or with underlying renal insufficiency. Alternatives to nitroprusside include intravenous labetalol, nicardipine, and fenoldopam; hypotension is uncommon with these drugs and cyanide toxicity is not an issue. Intravenous fenoldopam, a dopamine agonist that acts at the vasodilator DA1 receptors, is as effective and short-acting as nitroprusside [3]; however, it has the advantages of increasing renal blood flow and sodium excretion, of not being associated with the accumulation of toxic metabolites, and of not requiring shielding from light. TREATMENT — The optimal therapy varies with the type of hypertensive emergency. In addition to malignant hypertension, which is discussed elsewhere, the BP may be markedly elevated in the presence of cardiovascular or neurologic symptoms in a number of other clinical conditions [1,2]. (See "Hypertensive emergencies: Malignant hypertension and hypertensive encephalopathy"). Ischemic stroke or subarachnoid or intracerebral hemorrhage — The benefit of reducing the BP in these disorders must be weighed against possible worsening of cerebral ischemia induced by the thrombotic lesion or by cerebral vasospasm. This issue is discussed in detail separately. (See "Treatment of hypertension following a stroke"). These cerebrovascular events are characterized by the abrupt onset of usually focal neurologic findings. This is in contrast to the typically insidious onset of headache, nausea, vomiting, and confusion seen in hypertensive encephalopathy, a disorder in which rapid lowering of the BP generally leads to resolution of the symptoms within 24 to 48 hours. (See "Hypertensive emergencies: Malignant hypertension and hypertensive encephalopathy"). Acute pulmonary edema — Hypertension in patients with acute left ventricular failure due to systolic dysfunction should be principally treated with vasodilators. Nitroprusside or nitroglycerin with a loop diuretic is the regimen of choice for this problem. Drugs that increase cardiac work (hydralazine) or decrease cardiac contractility (labetalol or other beta blocker) should be avoided. (See "Acute decompensated heart failure (cardiogenic pulmonary edema)"). Angina pectoris or acute myocardial infarction — Acute coronary insufficiency frequently increases the systemic blood pressure. Intravenous parenteral vasodilators, principally nitroprusside and nitroglycerin, are effective and reduce mortality in patients with acute myocardial infarction, with or without hypertension [4]. Labetalol is also effective in this setting. Drugs that increase cardiac work (hydralazine) are contraindicated. (See "Overview of the management of acute ST elevation (Q wave) myocardial infarction" and see "Overview of the management of unstable angina and acute non-ST elevation (non-Q wave) myocardial infarction"). Aortic dissection — With acute aortic dissection, the stresses that damage the vessel wall are related to the mean pressure, the width of the pulse pressure, and the maximal rate of rise of the pressure (dp/dt). Drugs that diminish dp/dt are the optimal agents to treat a dissection [5]. The initial aim of medical therapy in such patients is to decrease both the systemic BP (to a systolic pressure of 100 to 120 mmHg if tolerated) and cardiac contractility. These combined goals are usually achieved by the combination of nitroprusside and an intravenous beta blocker such as propranolol or labetalol. Nitroprusside should not be given without a beta blocker. ( See "Management of aortic dissection"). Withdrawal of antihypertensive therapy — Abrupt discontinuation of a short-acting sympathetic blocker (such as clonidine or propranolol) can lead to severe hypertension and coronary ischemia due to upregulation of sympathetic receptors. Control of the BP can be achieved in this setting by readministration of the discontinued drug and, if necessary, phentolamine, nitroprusside, or labetalol. (See "Withdrawal syndromes with antihypertensive therapy"). Acute increase in sympathetic activity — In addition to drug withdrawal, increased adrenergic activity can lead to severe hypertension in a variety of other clinical settings. These include: (1) pheochromocytoma; (2) autonomic dysfunction, as in the Guillain-Barré syndrome or post-spinal cord injury; and (3) the use of sympathomimetic drugs, such as phenylpropanolamine, cocaine, amphetamines, phencyclidine, or the combination of an MAO (monoamine oxidase) inhibitor and the ingestion of tyramine-containing foods (such as most fermented cheeses, smoked or aged meats, Chianti, champagne, and avocados) [2,6]. (See "Designer drugs in adults"). The rise in BP seen in the last setting is due to an MAO inhibitor-induced decline in intestinal tyramine metabolism, followed by increased tyramine absorption and a subsequent tyramine-induced release of endogenous catecholamines. ( See "Clinical presentation and diagnosis of pheochromocytoma" for a more complete list of possibly dangerous foods). Control of the hypertension in these disorders can be achieved with phentolamine, labetalol, or nitroprusside. Administration of a ß-blocker alone is contraindicated, since inhibition of ß-receptor-induced vasodilation results in unopposed alpha-adrenergic vasoconstriction and a further rise in BP [7,8]. Pregnancy — Intravenous hydralazine is the treatment of choice in pregnant women with severe hypertension (usually due to preeclampsia or preexistent hypertension); nicardipine or labetalol are alternatives in patients who do not achieve adequate BP control with hydralazine. In contrast, nitroprusside (which may cause cyanide intoxication in the fetus), angiotensin converting enzyme inhibitors (which can impair renal function in the fetus), and angiotensin II receptor blockers are contraindicated in this setting. (See "Treatment of hypertension in pregnancy"). Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES Kaplan, NM. Management of hypertensive emergencies. Lancet 1994; 344:1335. 2. Vaughan CJ, Delanty N. Hypertensive emergencies. Lancet 2000; 356:411. 3. Murphy, MB, Murray, C, Shorten, GD. Drug therapy: Fenoldopam - A selective peripheral dopamine-receptor agonist for the treatment of severe hypertension. N Engl J Med 2001; 345:1548. 4. Lau, J, Antman, EM, Jimenez-Silva, J, Kupelnick, B. Cumulative meta-analysis of therapeutic trials for myocardial infarction. N Engl J Med 1992; 327:248. 5. Pretre, R, Von Segesser, LK. Aortic dissection. Lancet 1997; 349:1461. 6. Kaplan, NM. Hypertensive crises in clinical hypertension, 8th ed. Lippincott, Williams & Wilkins, Philadelphia, 2002, pg. 339. 7. Prichard, BN, Ross, EJ. Use of propranolol in conjunction with alpha-receptor blocking drugs in pheochromocytoma. Am J Cardiol 1966; 18:394. 1. 8. Brown, H, Goldberg, PA, Selter, JG, et al. Hemorrhagic pheochromocytoma associated with systemic corticosteroid therapy and presenting as myocardial infarction with severe hypertension. J Clin Endocrinol Metab 2005; 90:563. GRAPHICS Drugs for HTV emergencies A Drugs for HTV emergencies B