Hydralazine is used in the management of moderate to severe hypertension. Although other antihypertensive drug classes (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics) are preferred for the initial management of hypertension in adults, direct vasodilators such as hydralazine may be considered as add-on therapy if goal blood pressure cannot be achieved with the recommended drugs.
Hydralazine generally is used in conjunction with a diuretic and another hypotensive agent. The use of a diuretic may prevent tolerance to hydralazine and also the sodium retention and increased plasma volume that may occur after prolonged hydralazine therapy. Use of hydralazine in conjunction with other hypotensive agents also may permit a reduction in the dosage of each drug and minimizes adverse effects while maintaining blood pressure control.
(See Drug Interactions: Diuretics and Hypotensive Agents.)Adverse effects such as tachycardia and precipitation of angina may be minimized by administering the drug in conjunction with a β-adrenergic blocking agent (β-blocker).
For additional information on overall principles and expert recommendations for treatment of hypertension,
Parenteral hydralazine may be used for the management of severe hypertension when the drug cannot be given orally or when blood pressure must be lowered immediately. Because hydralazine has a less predictable hypotensive effect and greater cardiac stimulating effects, other agents (e.g., labetalol, esmolol, fenoldopam, nicardipine, sodium nitroprusside) usually are preferred for the management of severe hypertension or hypertensive emergencies when a parenteral hypotensive agent is employed. In addition, because of potential adverse effects on cerebrovascular circulation, hydralazine generally is not recommended for the management of severe hypertension or hypertensive emergencies associated with cerebrovascular accidents or in patients with cerebral edema and encephalopathy. However, IV or IM hydralazine has been used effectively and historically has been considered the parenteral hypotensive agent of choice for the management of hypertensive emergencies associated with pregnancy (e.g., preeclampsia, eclampsia).
(See Hypertension During Pregnancy under Uses: Hypertension.)Excessive falls in blood pressure should be avoided in any hypertensive crisis since they may precipitate renal, cerebral, or coronary ischemia.
Hypertension during Pregnancy
Hydralazine has been used parenterally in the hospital setting for urgent lowering of blood pressure in severely hypertensive pregnant women, including those with preeclampsia. Recommendations for the management of such patients are based principally on experience in women with preeclampsia or gestational hypertension in the third trimester. Delivery is the preferred method of management for women with severe preeclampsia; however, use of antihypertensive drugs is recommended in such women who have severely elevated blood pressures (sustained systolic blood pressure of at least 160 mm Hg or diastolic blood pressure of at least 110 mm Hg) to prevent potentially life-threatening cardiovascular, renal, and cerebrovascular complications. Results of several randomized clinical trials evaluating antihypertensive therapy in women with severe hypertension during pregnancy suggest that IV hydralazine, IV labetalol, or oral nifedipine are appropriate antihypertensives for urgently lowering blood pressure in such patients; choice of therapy should be based on clinician experience and preference as well as patient-specific-factors (e.g., concomitant medical conditions or therapies) and drug-related factors (e.g., route of administration, adverse effects, contraindications, local availability, cost). Although hydralazine historically has been considered the agent of choice for management of hypertensive emergencies associated with pregnancy, some clinicians now prefer IV labetalol for its more rapid onset, shorter duration of action, and more predictable hypotensive effect. If antihypertensive therapy is considered for the management of preeclampsia, it should be recognized that such therapy is employed solely for maternal benefit; it does not improve perinatal outcomes and may adversely affect uteroplacental flow.
Hydralazine is used in fixed combination with isosorbide dinitrate (BiDil) as an adjunct to standard therapy for the treatment of heart failure in self-identified black patients to improve survival, decrease rate of hospitalization for worsened heart failure, and improve patient-reported functional status. Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure. ( and .) The combination of hydralazine and isosorbide dinitrate is recommended by the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA) for self-identified black patients with New York Heart Association (NYHA) functional class III or IV heart failure and reduced ejection fraction who are receiving optimal therapy with ACE inhibitors and β-blockers (unless contraindicated). The ACCF and AHA also state that combined therapy with hydralazine and isosorbide dinitrate may be considered in patients with current or prior symptomatic heart failure with reduced ejection fraction who cannot receive an ACE inhibitor or angiotensin II receptor antagonist because of drug intolerance, hypotension, or renal insufficiency.
Efficacy of the hydralazine/isosorbide dinitrate fixed-combination preparation was evaluated in a multicenter, randomized, placebo-controlled, double-blind trial (the African-American Heart Failure Trial; A-HeFT trial) in 1050 self-identified black adults (mean age: 57 years) with stable moderate-to-severe heart failure (NYHA functional class III in over 95% of patients) secondary to left ventricular dysfunction (ejection fraction 35% or less). Patients were randomized to receive the fixed-combination preparation containing hydralazine and isosorbide dinitrate (initially, 37.5 mg of hydralazine hydrochloride and 20 mg of isosorbide dinitrate 3 times daily and titrated [as tolerated] to a target dosage of 75 mg of hydralazine hydrochloride and 40 mg of isosorbide dinitrate 3 times daily) or placebo for up to 18 months. Patients also received standard therapy (e.g., diuretics [mainly loop diuretics], β-blockers, ACE inhibitors, angiotensin II receptor antagonists, cardiac glycosides, and/or aldosterone antagonists).
The A-HeFT trial was terminated early (after a mean follow-up period of 10-12 months) primarily because of a significant reduction (43%) in all-cause mortality in patients receiving the fixed-combination preparation containing hydralazine and isosorbide dinitrate; mortality rate was about 10.2 or 6.2% in patients receiving placebo or the fixed combination, respectively.
The primary end point of the study (a mean primary composite score consisting of all-cause mortality, first hospitalization for worsening of heart failure, and improvement of quality of life [as assessed by responses to the Minnesota Living with Heart Failure questionnaire]) also showed substantial differences between drug therapy and placebo. Patients receiving the fixed combination containing hydralazine and isosorbide dinitrate experienced a significant reduction (33%) in the rate of first hospitalization for heart failure (16.4 or 24.4% for those receiving the drug or placebo, respectively) and a significant improvement in response to the Minnesota Living with Heart Failure questionnaire (a self-report of functional status). Factors of age, gender, baseline disease, or concomitant medications appeared to have no effect on survival or rate of hospitalization. The fixed combination containing hydralazine and isosorbide dinitrate had a slight but significant blood pressure-lowering effect; a mean decrease of 1.9 and 2.4 mm Hg from baseline in systolic and diastolic blood pressure, respectively, was observed in patients receiving the drugs, while an increase of 1.2 and 0.8 mm Hg from baseline in systolic and diastolic blood pressure, respectively, was observed in patients receiving placebo. However, the role of reduced blood pressure in the improved outcome of patients receiving the study medications has not been evaluated. The manufacturer states that there is no adequate clinical experience with hydralazine hydrochloride or isosorbide dinitrate as separate agents† or with dosages of the drugs other than those used in the A-HeFT trial for the treatment of heart failure.
In another randomized, placebo-controlled, comparative, long-term (median 2.3 years; range: 6-68 months) study (Vasodilator Heart Failure Trial [V-HeFT I]) in patients with chronic congestive heart failure (associated with ischemic or nonischemic cardiomyopathy) who were receiving conventional therapy (cardiac glycosides and diuretics, without an ACE inhibitor), addition of hydralazine hydrochloride (up to 300 mg daily) given concomitantly with isosorbide dinitrate (up to 160 mg daily) resulted in a 25-30% decrease in overall mortality rates after 2 years when compared with conventional therapy and placebo or prazosin (up to 20 mg daily). However, despite substantial increases in ejection fraction, the combination of the 2 vasodilators was not associated with decreased hospitalizations and many patients discontinued therapy during follow-up, although retrospective analysis of such data indicate that there was a trend favoring the administration of the 2 vasodilators, which was attributed to an effect observed in black patients.
In a subsequent randomized, comparative, long-term (median 2.5 years; range: 6-68 months) study (V-HeFT II) in patients with ischemic or nonischemic cardiomyopathy and mild to moderate heart failure (NYHA functional class II and III) who were receiving conventional therapy (cardiac glycosides and diuretics), addition of enalapril maleate (up to 20 mg daily) resulted in a 28% decrease in overall mortality rates after 2 years when compared with conventional therapy and concomitant use of hydralazine hydrochloride (up to 300 mg daily) with isosorbide dinitrate (up to 160 mg daily). Retrospective analysis of the data indicates that such decreases in mortality rates in patients receiving enalapril in conjunction with conventional therapy were not observed in black patients. In addition, concomitant therapy with the 2 vasodilators had more favorable effects on ventricular ejection fraction and exercise tolerance than those associated with enalapril.
Hydralazine has produced hemodynamic and clinical improvement in some patients with unexplained pulmonary hypertension; however, the drug does not produce consistent results and may cause serious adverse reactions (e.g., symptomatic hypotension, severe dyspnea) in patients with this condition. Further studies are needed to determine the safety, efficacy, and role of hydralazine in the treatment of unexplained pulmonary hypertension. The drug should be used for the treatment of this condition only with careful hemodynamic monitoring and clinical evaluation.