US Pharm. 2011;36(3):Epub.
Approximately 74 million people in the United States have hypertension, defined as a systolic blood pressure (BP) ≥140 mmHg or a diastolic BP ≥90 mmHg on at least two occasions.1,2 A severe, rapid elevation in BP is considered a hypertensive crisis. There are inconsistencies in the definition and the nomenclature of this condition. In addition, there is not an exact BP reading that constitutes a hypertensive crisis, although one report states that BP measurements >179/109 mmHg have been considered the threshold.3 It has been reported that approximately 27% of emergency room visits are due to hypertensive crises.4 This condition is divided into two categories based on the presence or absence of target organ damage.1 While end-organ damage occurs in a hypertensive emergency, a rapid and severe elevation in BP in the absence of organ injury is termed hypertensive urgency.
Clinical Presentation and Diagnosis
Patients presenting with hypertensive crisis typically have had either chronically elevated BP or may be completely unaware that they have hypertension. Subtherapeutic treatment regimens, nonadherence, and drug-induced etiologies have been attributed to its development.1,3,5,6 Being African American, elderly, male, and lacking a primary care physician have been identified as major risk factors for the development of hypertensive crisis.7,8 High grades of obesity, hypertensive heart disease, increased number of BP medications, and history of somatoform disorders have been identified as contributing factors; however, these factors should be studied further before concluding that they can increase the risk for development of a hypertensive crisis.5
Persons with hypertensive urgency may experience severe headache, shortness of breath, nosebleed, or anxiety.1 With hypertensive emergency, the clinical presentation will depend on the particular organ that is undergoing injury, in addition to other symptoms, such as headache.
A rapid but thorough assessment must be performed in order to differentiate between urgency and emergency. The clinician should inquire about use of all medications, including OTC and herbal therapies, and illicit drug use. Medication adherence, including time of last dose, should be evaluated in all patients previously diagnosed with hypertension. BP should be confirmed in both arms, using correct measurement techniques.9
Physical examination is an essential component of diagnosis. The examination should include assessment for signs indicative of heart failure, myocardial infarction, aortic dissection, hypertensive encephalopathy, cerebrovascular accident, renal failure, retinopathy, retinal hemorrhage, and papilledema.3 A CT scan, MRI, echocardiogram, or chest x-ray may also be necessary in assessing organ damage. Laboratory examination should include a metabolic panel, urinalysis, a complete blood count, and urine toxicology.
Treatment Approach: Hypertensive Urgency
Hypertensive urgencies may be treated in an outpatient facility with oral antihypertensives; treatment consists of a slow lowering of BP over 24 to 48 hours.10 A reduction in BP of no more than 25% within the first 24 hours has been suggested.10 Adjusting current medication regimens to improve adherence or increasing the doses of current agents may be a sufficient management approach.11 However, additional agents may be necessary to attain desired results. Follow-up with the primary care provider within a week of the episode is necessary.11
First-line agents to use in hypertensive urgencies have not been clearly elucidated.11,12 Captopril, clonidine, and labetalol (TABLE 1) have predominantly been used in this condition. Although used in the past, sublingual or oral nifedipine is no longer recommended due to its propensity to cause severe hypotension and organ ischemia.11
Treatment Approach: Hypertensive Emergency
Hypertensive emergency requires immediate medical attention, including admission to the intensive care unit. Continuous cardiac monitoring, frequent measurement of urine output, and neurologic assessment are all necessary. Treatment with IV antihypertensive agents (TABLE 2) is warranted in this setting. Drug selection should be based on specific characteristics of the drug (i.e., adverse effects) and patient-specific attributes, such as volume status and the presence of comorbidities.13 The primary goal would be to lower the mean arterial pressure by no more than 25% within the first hour, followed by BP reduction to 160/110-100 mmHg within the next 2 to 6 hours.1 BP reduction must be conducted in a controlled fashion in order to prevent organ hypoperfusion and subsequent ischemia or infarction.3 However, in patients with aortic dissection, BP must be aggressively lowered.3 Once the BP has stabilized and the risk of end-organ damage has dissipated, downward titration of the IV agent may begin, followed by conversion to oral therapy. The clinician should then attempt to ascertain causative factors for the event.
Labetalol and esmolol have been available for years and are preferred in most conditions.3 Nitroglycerin and sodium nitroprusside have also been widely available, but their use is limited primarily to individuals with myocardial ischemia and acute pulmonary edema or aortic dissection, respectively. The third-generation agent, clevidipine, represents the first agent for hypertensive emergency to be introduced to the market in over a decade. The agents trimethaphan and phentolamine have been largely supplanted by other, newer drugs; however, these may have utility in individuals with catecholamine-driven hypertensive crisis.
Pharmacotherapeutic Agents
Captopril: The angiotensin-converting enzyme inhibitor (ACE-I) captopril has been used in oral and sublingual forms for the treatment of hypertensive urgency. Doses ranging from 6.25 to 50 mg have been reported in the literature.11,14-16 An initial effect is seen within approximately 5 to 15 minutes of administration, reaching a maximum reduction of BP within 30 minutes.11,14-16 The duration of effect has been reported to be at least 2 to 6 hours.11,15 Adverse effects include hyperkalemia and angioedema.11
Clonidine: The centrally-acting, alpha2-agonist clonidine has been used for hypertensive urgencies. Doses ranging from an 0.1 to 0.2 mg loading dose followed by 0.05 to 0.1 mg every hour until desired BP is reached, or the maximum dose of 0.8 mg is reached, have been reported in the literature.10,11 Clonidine has an onset of action of 15 to 30 minutes, and the reported duration of effect is approximately 2 to 8 hours.10,11 Adverse effects include dry mouth, sedation, orthostatic hypotension, and rebound hypertension, which can occur with abrupt discontinuation.10,11,15
Labetalol: The alpha1-selective, beta-nonselective antagonist labetalol has been used for both hypertensive urgencies and emergencies. An oral dosing regimen consisting of an initial dose of 200 mg followed by an additional 200 mg every hour to a maximum dose of 1,200 mg has been reported to be effective in hypertensive urgencies.15 The maximal BP-lowering effect is seen in approximately 2 hours, and the duration of effect lasts approximately 4 hours.15
For hypertensive emergencies, reported dosing regimens for IV labetalol include a loading dose of 20 mg followed by 20 to 80 mg doses repeated every 10 minutes until desired BP is attained, or the loading dose can be administered followed by a 1 to 2 mg/min continuous infusion; all regimens have a total effective dose of 300 mg.15 IV labetalol has an onset of action of 2 to 5 minutes and peaks within 5 to 15 minutes. Its duration of action is dose dependent, ranging from 2 to 18 hours. Although labetalol crosses the placenta, it is frequently utilized safely in pregnant women who develop hypertensive crisis.3 It should be avoided in patients with second- or third-degree heart block and severe bradycardia. Additionally, patients with severe bronchospastic disease or compensated heart failure could experience possible exacerbations of the disease state; thus, clinicians should weigh the risk of therapy against the potential benefits in these populations.
Esmolol: Esmolol is an extremely short-acting, cardioselective beta1-antagonist used in hypertensive emergencies. A recommended dose is 0.5 to 1 mg/kg bolus, followed by a continuous infusion of 50 to 300 mcg/kg/min.15 The onset of action can be as fast as 2 minutes, but it is quickest when a loading dose is administered. The drug has a reported duration of action of 10 to 30 minutes.3,15 Esmolol is a useful agent for conditions related to tachycardia and increased cardiac output and BP. Its use is not recommended in patients with decompensated heart failure, those who are already on beta-blocker therapy, or those with bradycardia. Esmolol should be used with caution in individuals with severe airway disease. Because it is metabolized by red blood cell esterases, the half-life of the agent may be prolonged in patients with anemia.17
Nicardipine: This drug is a second-generation dihydropyridine calcium channel blocker. The starting dose is 5 mg/h, increasing by 2.5 mg/h every 5 minutes until the desired reduction in BP is met or the maximum dose of 15 mg/h is reached.15 It has an onset of action of 5 to 15 minutes with a duration of 4 to 6 hours.17 It is a useful agent in patients with systolic heart failure and coronary artery disease. Recent guidelines recommend nicardipine in patients with ischemic stroke when systolic BP is >220 mmHg or diastolic BP is >120 mmHg.17
Clevidipine: Clevidipine is a third-generation dihydropyridine calcium channel blocker. It is indicated for the management of hypertension when oral treatment is not feasible or desirable.18 To date, clevidipine has been studied in patients with severe hypertension in the emergency department, intensive care unit, and various surgical settings.19 Its efficacy is comparable to traditional agents and may represent a viable option in certain patients. Adverse effects of clevidipine are similar to other vasodilatory dihydropyridines. Unlike other dihydropyridines, it generally does not produce reflex tachycardia. Additionally, patients should be monitored for rebound hypertension for at least 8 hours after the drug is discontinued. Because of its unique, oil-in-water emulsion formulation, strict aseptic technique is recommended when handling this product.13 Patients who have allergies to eggs, soybeans, or any product derived from these sources should not receive this product. If a patient is receiving exogenous lipid supplementation or has issues with lipid metabolism, the drug’s fat content must be taken into account in order to prevent hypertriglyceridemia.13,18 Metabolism occurs rapidly via blood esterases. Clevidipine can be initiated at 1 to 2 mg/h, and the dose can be doubled at 90-second intervals toward BP goals. The typical maintenance dose is 4 to 6 mg/h, and data are limited regarding infusion rates >32 mg/h and administration beyond 72 hours.18
Nitroglycerin: This agent is commonly used as an adjunctive agent in patients with hypertensive emergency with acute coronary syndrome or acute pulmonary edema. The onset of action is immediate, and the duration of action 3 to 5 minutes. The initial dose is 5 mcg/min by continuous infusion and is increased every 5 minutes until 20 mcg/min is reached. If response is inadequate, then the dose is increased by 10 to 20 mcg/min every 5 minutes until a maximum dose of 200 mcg/min is attained. Tolerance could develop regardless of appropriate dose titration. The preload reduction that occurs with this agent typically is followed by a decrease in cardiac output; this can pose a detriment to patients who already have compromised coronary, cerebral, or renal blood flow. Reflex tachycardia and hypotension may develop in volume-depleted individuals. Headache is the most common adverse effect, and tolerance can develop within 24 hours of administration. Prolonged treatment could result in methemoglobinemia, where hemoglobin contains ferric oxide, thus hindering appropriate oxygen transportation.20
Sodium Nitroprusside: Sodium nitroprusside possesses potent vasodilatory effects on venous and arterial systems. The initial dose for the management of hypertensive emergency is 0.25 mcg/kg/min, titrating by 0.25 mcg/kg/min every 5 to 10 minutes until the desired effect is noted.15 The effects are immediate, and the drug has a duration of action of 2 to 5 minutes. This agent should be used cautiously or avoided in patients with cerebral ischemia, coronary artery disease, and hepatic and renal dysfunction due to the potential for increased intracranial pressure, reduction of blood flow due to coronary steal, and increased risk of cyanide intoxication, respectively. Once cyanide is released from the nitroprusside ion, thiosulfate converts it to thiocyanide. Although this metabolite is 100-fold less toxic than cyanide, it may still result in harm if sufficiently accumulated. Signs of thiocyanide toxicity include hyperreflexia, delirium, and psychosis. Cyanide toxicity can occur at infusion rates >4 mcg/kg/min within several hours.20 Because of its potent activity and the potential for toxicity, use of sodium nitroprusside is limited to those with acute pulmonary edema and/or severe left ventricular dysfunction and to patients with aortic dissection.
Fenoldopam: Fenoldopam is a selective dopamine-1 receptor agonist.21 Doses between 0.1 and 0.5 mcg/kg/min have been reported in the literature.15 It has an onset of action of about 5 minutes and a duration of action between 30 and 60 minutes. Fenoldopam has demonstrated a benefit to overall renal function by improving creatinine clearance, urine flow rates, and sodium excretion in hypertensive patients.22
Hydralazine: This antihypertensive is a direct arterial vasodilator, which results in a decrease in systemic resistance. Its onset of action is 5 to 20 minutes, but precipitous falls in BP can occur and can last up to 12 hours. Hydralazine can be dosed at 10 to 20 mg every 6 hours as needed. Its use can result in reflex tachycardia and increased intracranial pressure; thus, caution should be exercised in those individuals with coronary heart disease or pre-existing increased intracranial pressure.13 Because its response can be unpredictable, hydralazine is not generally used as a first-line agent in hypertensive emergency.20
Enalaprilat: Enalaprilat is currently the only ACE-I that is commercially available in a parenteral formulation. It has an onset of action of 15 minutes and a duration of action of 12 to 24 hours, which may be advantageous for those who are in need of prolonged BP control. However, this property makes titration difficult, and hypotension can potentially develop in some individuals. Lower starting doses should be considered for patients who are receiving concomitant diuretic therapy, experience volume depletion, or have hyponatremia. Enalaprilat should be avoided in those with decompensated heart failure or acute myocardial infarction and is contraindicated in patients who have bilateral renal artery stenosis or are pregnant.6
Summary
A rapid and severe elevation in BP is considered a hypertensive crisis. The presence or absence of target organ damage is the guiding factor in classification of the crisis and ultimately the manner in which the crisis is treated. Hypertensive urgencies may be treated on an outpatient basis, by gradually reducing BP using oral antihypertensives. Hypertensive emergencies, on the other hand, require more immediate treatment with IV antihypertensives in an inpatient setting.
Pharmacists can play an integral role in the prevention and management of hypertensive crises. Proper patient education that includes the importance of medication adherence can help prevent the development of hypertensive urgencies. Additionally, pharmacists can assist in the selection of drug therapy that is cost-effective and has relatively few adverse effects, thus reducing the potential for nonadherence stemming from the patient’s inability to afford drug therapy. A review of medication therapy as well as concurrent medical conditions by the pharmacist can assist in selecting the optimal regimen for the patient while minimizing the risk of adverse events.
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