Hydralazine hydrochloride is a vasodilating agent.
Hydralazine is used in the management of moderate to severe hypertension. However, because of established clinical benefits (e.g., reductions in overall mortality and in adverse cardiovascular, cerebrovascular, and renal outcomes), current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics).502, 1200 Some experts state that direct vasodilators such as hydralazine may be considered as add-on therapy if goal blood pressure cannot be achieved with the recommended drugs.501, 502, 503, 504, 1200
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, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.
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).101, 102, 103, 104, 105, 108, 111, 112, 124, 542 (See Severe 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.542, 1200
Severe 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†.112, 540, 542, 1200 Recommendations for the management of such patients are based principally on experience in women with preeclampsia or gestational hypertension in the third trimester.112 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.112, 540 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).112, 139, 540 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.502, 542
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.135, 136, 137 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.524, 701, 703, 800 (See Uses: Heart Failure in Carvedilol 24:24 and in Sacubitril and Valsartan 24:32.92.) 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).524 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.524
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).135, 136, 137 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.135, 136, 137 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).135, 136, 137
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.135, 136, 137
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.135, 136, 137 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).135, 136, 137 Factors of age, gender, baseline disease, or concomitant medications appeared to have no effect on survival or rate of hospitalization.135 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.135, 136 However, the role of reduced blood pressure in the improved outcome of patients receiving the study medications has not been evaluated.135 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.135
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).113, 114 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,113 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.135
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).113, 115 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.135 In addition, concomitant therapy with the 2 vasodilators had more favorable effects on ventricular ejection fraction and exercise tolerance than those associated with enalapril.113
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.
Hydralazine hydrochloride usually is administered orally. In patients who are unable to take the drug orally or when a rapid decrease in blood pressure is required, the drug may be given IM or IV. Oral therapy with hydralazine should replace parenteral therapy as soon as possible.
Extemporaneously Compounded Oral Liquid
An extemporaneously compounded oral liquid formulation of hydralazine has been prepared using the commercially available tablets and a commercially available vehicle.106, 107
Standardized concentrations for an extemporaneously prepared oral liquid formulation of hydralazine have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 252Multidisciplinary expert panels were convened to determine recommended standard concentrations. 252Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 252 For additional information on S4S (including updates that may be available), see [Web].252
Concentration Standards |
|---|
4 mg/mL |
When hydralazine therapy is discontinued in patients with a marked reduction in blood pressure, withdrawal should be gradual to avoid a possible sudden increase in blood pressure. One study found 20-25 mg of IV hydralazine hydrochloride approximately equal to 75-100 mg of oral hydralazine hydrochloride.
Dosage of hydralazine must be adjusted according to the patient's blood pressure response and tolerance. Generally, dosage of hydralazine required for satisfactory blood pressure control is higher in rapid acetylators than in slow acetylators.
For the management of hypertension, an initial adult oral dosage of hydralazine hydrochloride of 10 mg 4 times daily for 2-4 days has been suggested. Dosage then can be increased to 25 mg 4 times daily for the remainder of the week. If necessary, dosage can be increased for the second and subsequent weeks to 50 mg 4 times daily. In a few patients, 300-400 mg daily may be required. Generally, slow acetylators should not receive more than 200 mg daily of oral hydralazine hydrochloride. For maintenance therapy, dosage is adjusted to the lowest effective level. Studies have shown hydralazine may be administered twice daily in many patients for maintenance therapy. Some experts state that the usual dosage range is 100-200 mg daily, administered in 2 or 3 divided doses.1200
Although the manufacturers state that pediatric dosage recommendations have not been established in controlled clinical trials,600, 601 there is experience with the use of hydralazine hydrochloride in pediatric patients.600, 601 Based on such experience, an initial oral hydralazine hydrochloride dosage of 0.75 mg/kg daily given in 4 divided doses has been suggested for treatment of hypertension.601 If necessary, oral dosage may be increased gradually over a period of 3-4 weeks up to a maximum of 7.5 mg/kg (or 200 mg) daily.601 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Blood Pressure Monitoring and Treatment Goals
Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved, the dosage may be increased or another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., ACE inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic) may be added; if target blood pressure is still not achieved with the use of 2 antihypertensive agents, a third drug may be added.1200, 1216 (See Uses: Hypertension.) In patients who develop unacceptable adverse effects with hydralazine, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1216
The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505, 506, 507, 508, 515, 523, 530, 1201, 1207, 1209, 1222 A 2017 multidisciplinary hypertension guideline from the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations generally recommends a blood pressure goal of less than 130/80 mm Hg in all adults, regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200, 1207 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200, 1220
For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.
For the management of severe hypertension in hospitalized adults when there is an urgent need to lower blood pressure or when the drug cannot be given orally, the manufacturer states that the usual IM or IV dose of hydralazine hydrochloride is 20-40 mg, repeated as necessary; most patients can be transferred to oral therapy within 24-48 hours.600 Alternatively, some experts recommend an initial IV hydralazine hydrochloride dose of 10-20 mg, which may be repeated every 4-6 hours as needed, for the treatment of hypertensive emergencies in adults.1200 However, such experts state that hydralazine's unpredictability of response and prolonged duration of action make it an undesirable first-line agent for acute treatment in most patients.1200
If IV hydralazine is used in the management of a hypertensive emergency in adults with a compelling indication (e.g., aortic dissection, pheochromocytoma hypertensive crisis, severe preeclampsia or eclampsia), some experts state that systolic blood pressure should be reduced to less than 140 mm Hg during the first hour or, in patients with acute aortic dissection, to less than 120 mm Hg within the first 20 minutes.1200 If IV hydralazine is used in the management of a hypertensive emergency in adults without a compelling indication, such experts state that the initial goal of such therapy is to reduce mean systolic blood pressure by no more than 25% within the first hour, followed by further blood pressure reduction if stable to 160/110 or 160/100 mm Hg within the next 2-6 hours, avoiding excessive declines in pressure that could precipitate renal, cerebral, or coronary ischemia.1200 If this blood pressure is well tolerated and the patient is clinically stable, further gradual reductions toward normal blood pressure can be implemented in the next 24-48 hours.1200
Although the manufacturers state that pediatric dosage recommendations for hydralazine hydrochloride have not been established in controlled clinical trials, there is experience with the use of the drug in pediatric patients.600, 601 For the treatment of severe hypertension in pediatric patients when hydralazine hydrochloride cannot be administered orally or when urgent blood pressure reduction is needed, the manufacturer states that an IV or IM dosage of 1.7-3.5 mg/kg daily divided in 4-6 doses has been used.600 Alternatively, in pediatric patients with severe hypertension and life-threatening symptoms†, some experts have suggested an initial IV or IM hydralazine hydrochloride dose of 0.1-0.2 mg/kg per dose, which may be increased up to 0.4 mg/kg per dose; the drug may be given every 4 hours when administered by direct IV (“bolus”) injection.1150 Such experts suggest that blood pressure be reduced by no more than 25% of the planned blood pressure reduction over the first 8 hours, with the remainder of the planned reduction over the next 12-24 hours.1150 For pediatric patients with severe hypertension and non-life-threatening symptoms†, an oral hydralazine dose of 0.25 mg/kg per dose (up to 25 mg per dose) every 6-8 hours has been recommended.1150
Severe Hypertension during Pregnancy
For the urgent lowering of blood pressure in severely hypertensive pregnant women, the usual initial adult IV dose of hydralazine hydrochloride is 5 mg,101, 103, 105, 108, 112, 540 followed by IV doses of 5-10 mg every 20-40 minutes as necessary to achieve an adequate reduction in blood pressure;101, 102, 103, 104, 105, 108, 112, 540 a maximum total dose of 20 mg has been recommended.540 Alternatively, hydralazine hydrochloride has been infused IV at a rate of 0.5-10 mg/hour for the management of severe hypertension during pregnancy.112, 540 Blood pressure should be closely monitored when parenteral hydralazine is employed.
For the adjunctive treatment of heart failure in self-identified black patients, the recommended initial dosage of the fixed-combination preparation is 37.5 mg of hydralazine hydrochloride and 20 mg of isosorbide dinitrate (1 tablet of BiDil®) 3 times daily.135, 524 The dosage may be titrated to a maximum tolerated dosage, not to exceed 2 tablets (a total of 75 mg of hydralazine hydrochloride and 40 mg of isosorbide dinitrate) 3 times daily.135, 524 Although rapid titration (over 3-5 days) of dosage can be undertaken, slower titration may be needed in some patients who experience adverse effects.135 In patients who experience intolerable adverse effects, the dosage may be decreased to as little as one-half of the fixed-combination tablet 3 times daily; however, an attempt should be made to titrate the dosage up once the adverse effects subside.135
If the drugs are administered separately in the treatment of heart failure†, an initial dosage of hydralazine hydrochloride 25-50 mg 3 or 4 times daily, given concomitantly with isosorbide dinitrate 20-30 mg 3 or 4 times daily, is recommended by the American College of Cardiology Foundation (ACCF) and American Heart Association (AHA).524 Dosages of the drugs should be titrated to levels similar to those recommended for the fixed-combination preparation and administered at least 3 times daily.524 The maximum recommended dosages are hydralazine hydrochloride 300 mg daily and isosorbide dinitrate 120 mg daily.524
Patients with severe renal failure may require a lower dosage of hydralazine.
The most frequently occurring adverse effects of hydralazine are headache, palpitation, and tachycardia; these adverse effects can be minimized by starting with small doses and increasing dosage gradually to effective levels and by concomitant administration with other antihypertensive drugs such as propranolol. Patients should be instructed to consult a clinician if headache continues with repeated dosing.135 Generally, adverse effects of hydralazine are reversible when dosage is reduced, but in some cases it may be necessary to discontinue the drug.
Adverse GI disturbances such as anorexia, nausea, vomiting, and diarrhea may occur, especially with large doses. Constipation and adynamic ileus also have been reported. Cholecystitis has been reported occasionally in patients receiving fixed-combination therapy with hydralazine and isosorbide dinitrate.135
Hydralazine-induced tachycardia may precipitate angina pectoris and ECG effects characteristic of myocardial ischemia. The drug may accentuate specific cardiovascular abnormalities and has been implicated in the production of myocardial infarction. Orthostatic hypotension and dizziness may occur rarely, but are less pronounced with hydralazine than with guanethidine or ganglionic blockers. A paradoxical pressor response, edema, and palpitations also have been reported. IV administration of hydralazine in patients with preexisting increased intracranial pressure may produce increased cerebral ischemia.
Sodium retention resulting in edema and weight gain has been reported in patients receiving hydralazine and can usually be controlled by concomitant administration with a thiazide diuretic.
In clinical trials in patients receiving hydralazine hydrochloride (37.5 mg) in fixed combination with isosorbide dinitrate (20 mg), chest pain and ventricular tachycardia have been reported.135
Hydralazine has produced a syndrome resembling systemic lupus erythematosus (SLE) or rheumatoid arthritis, characterized by fever, arthralgia, splenomegaly, glomerulonephritis,135 lymphadenopathy, asthenia, myalgia, malaise, pleuritic chest pain, edema, and the presence of antinuclear antibodies (ANA) and LE cells in the blood. Rash or maculopapular facial rash characteristic of SLE also has occurred. Patients with hydralazine-induced SLE may have a positive direct Coombs' test; Coombs'-positive hemolytic anemia without SLE has occurred rarely. One case of hydralazine-induced SLE associated with pericarditis and pericardial tamponade has been reported. Hydralazine-induced SLE syndrome probably represents a hypersensitivity reaction in which hydralazine antibodies and anti-DNA antibodies are formed. The incidence of hydralazine-induced SLE syndrome is greatest in patients receiving more than 200 mg of the drug daily for prolonged periods, but cases have occurred rarely in patients receiving 100 mg daily.
Other hypersensitivity reactions including urticaria, pruritus, chills, vascular collapse, and eosinophilia have occurred rarely. Hepatitis, including granulomatous hepatitis, has been reported rarely in patients receiving hydralazine. In clinical trials in patients receiving hydralazine hydrochloride (37.5 mg) in fixed combination with isosorbide dinitrate (20 mg), angioedema has been reported occasionally.135
Blood dyscrasias consisting of reduction in hemoglobin concentration and erythrocyte count, leukopenia, agranulocytosis, lymphadenopathy, thrombocytopenia with or without purpura, and splenomegaly have been reported rarely; if these abnormalities occur, hydralazine should be discontinued.
Peripheral neuritis characterized by paresthesia, numbness, and tingling has been reported rarely. These symptoms of peripheral neuritis may be caused by pyridoxine deficiency, and pyridoxine should be administered concomitantly with hydralazine if these symptoms occur.134 Headache, dizziness, and tremors have been reported with hydralazine.134
In clinical trials in patients receiving hydralazine hydrochloride (37.5 mg) in fixed combination with isosorbide dinitrate (20 mg), somnolence, malaise, and sweating have been reported.135
Nasal congestion, flushing, lacrimation, and conjunctivitis have occurred occasionally. Muscle cramps, weakness, asthenia, dyspnea, difficulty in micturition, and tremors also have been reported. In patients with severe hypertension and uremia, rapid increase in hydralazine dosage may produce a marked decrease in blood pressure, resulting in psychotic reactions such as anxiety, disorientation or depression, and coma. Impotence has been reported very rarely.
In clinical trials in patients receiving hydralazine and hydrochloride (37.5 mg) in fixed combination with isosorbide dinitrate (20 mg), bronchitis, sinusitis, rhinitis, hyperlipidemia, hypercholesterolemia, hyperglycemia, amblyopia, myalgia, tendon disorder, and alopecia have been reported.135
Precautions and Contraindications
When hydralazine is used in fixed combination with isosorbide dinitrate, the cautions, precautions, and contraindications associated with nitrates (see Cautions and Precautions and Contraindications in the Nitrates and Nitrites General Statement 24:12.08) should be considered in addition to those associated with hydralazine.135
Hydralazine generally is considered to be safe for use in patients with renal impairment, but the manufacturers state the drug should be used with caution in patients with severe renal impairment.
Patients who are slow acetylators of hydralazine may have a higher risk of developing drug-induced SLE than rapid acetylators; decreased renal function also increases risk. Patients receiving hydralazine should be instructed to report abnormalities such as joint or chest pain or fever to their physicians. If arthralgia, fever, chest pain, continued malaise, or other unexplained signs and symptoms occur during hydralazine therapy, appropriate laboratory studies such as complete blood counts and ANA titer determinations should be performed. Hydralazine should be discontinued in patients who develop this syndrome unless the potential benefit of antihypertensive therapy with the drug outweighs the potential risk. Signs and symptoms of hydralazine-induced SLE usually regress when the drug is discontinued, but residual effects have been detected years later; long-term treatment with corticosteroids may be necessary if symptoms do not regress.
Complete blood counts and ANA titer determinations should be performed before and periodically during prolonged hydralazine therapy, even in asymptomatic patients. The manufacturers state that a positive ANA titer requires that the implications of the test result be weighed against the benefits from therapy with the drug, but some experts state that an increase in ANA titer requires immediate discontinuance of the drug.
Some commercially available formulations of hydralazine may contain sulfites that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.
Patients who engage in potentially hazardous activities such as operating machinery or driving motor vehicles should be warned about possible faintness, dizziness, or weakness.
Hydralazine should be used with caution in patients with cerebrovascular accidents or with severe renal damage. Because of the risk of orthostatic hypotension, preparations containing hydralazine should be used with caution in patients who may be volume depleted, those with preexisting hypotension, or those receiving other hypotensive agents.135 In addition, patients receiving hydralazine in fixed combination with isosorbide dinitrate should be advised that inadequate fluid intake or excessive fluid loss due to diarrhea, vomiting, or perspiration may result in excessive hypotension, possibly leading to lightheadedness or even syncope.135 If syncope occurs, the fixed-combination therapy with hydralazine and isosorbide dinitrate should be discontinued and the patient's clinician should be notified as soon as possible.135 Because of the risk of developing hypotension and tachycardia, careful clinical and hemodynamic monitoring is recommended when preparations containing hydralazine are used in patients with acute myocardial infarction.135 Patients receiving hydralazine in fixed-dose combination with isosorbide dinitrate should be cautioned against concomitant use of phosphodiesterase type 5 (PDE type 5) inhibitors (e.g., sildenafil [Viagra®, Revatio®], tadalafil [Cialis®]), vardenafil [Levitra®].135 (See: Drug Interactions: Organic Nitrates and Nitrites, in Sildenafil 24:12.12.)
Hydralazine also should be used with caution, if at all, in patients with known or suspected coronary artery disease and is contraindicated in patients with mitral valve rheumatic heart disease or hypersensitivity to the drug.
Safety and efficacy of hydralazine alone or in fixed combination with isosorbide dinitrate in children have not been established.134, 135 However, there is some experience with use of hydralazine in children.134 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
Clinical studies of hydralazine in fixed combination with isosorbide dinitrate did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.135 Although other clinical experience has not revealed age-related differences in response or tolerance, drug dosage generally should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range.135 The greater frequency of decreased hepatic and/or renal function and of concomitant disease and drug therapy observed in the elderly also should be considered.135 Hydralazine may be eliminated more slowly in geriatric patients.135
Mutagenicity and Carcinogenicity
Hydralazine has been shown to be mutagenic in bacterial systems.134, 135 In addition, hydralazine was positive for mutagenicity in the in vitro rat and rabbit hepatocyte DNA repair assays.134, 135 However, there was no evidence of mutagenicity or clastogenicity when hydralazine was tested with additional in vivo and in vitro studies, including mouse fibroblasts and lymphoma or germinal cells, Chinese hamster bone marrow cells, and human cell line fibroblasts.134, 135
In a lifetime study in Swiss albino mice, there was a statistically significant increase in the incidence of lung tumors (adenomas and adenocarcinomas) in female and male mice receiving hydralazine hydrochloride 250 mg/kg daily (approximately 6 or 80 times the maximum recommended human dosage daily, given as hydralazine hydrochloride in fixed combination with isosorbide dinitrate [on a body surface area basis] or alone, respectively).134, 135 In addition, in a 2-year carcinogenicity study in rats that used hydralazine hydrochloride oral gavage dosages of 15, 30, and 60 mg/kg daily (up to 3 or 5-20 times, the maximum recommended human dosage daily, given as hydralazine hydrochloride in fixed combination with isosorbide dinitrate [on a body surface area basis] or alone, respectively), there was a small but statistically significant increase in benign neoplastic nodules in male (high-dosage group) and female (high- and intermediate-dosage groups) rats.135 A statistically significant increase in benign interstitial cell tumors of the testes also was observed in the high-dosage group.134 135
The relevance of these findings to humans currently is not fully known.134 The manufacturer states that although long-term clinical observation has not suggested an association between carcinogenicity in humans and administration of hydralazine, there is insufficient experience from epidemiologic studies to draw definitive conclusions.134
Pregnancy, Fertility, and Lactation
Safe use of hydralazine in pregnancy has not been established. Hydralazine is teratogenic in mice and possibly in rabbits but not in rats. Teratogenic effects in animals have included cleft palate and malformation of facial and cranial bones.
A meta-analysis of randomized, controlled trials comparing hydralazine with other antihypertensive agents for the treatment of severe hypertension during pregnancy showed that hydralazine was associated with a higher incidence of maternal hypotension, placental abruption, cesarean sections, and oliguria, as well as a higher incidence of lower Apgar scores and adverse effects on fetal heart rate than the other hypotensive drugs.135 In one study in 13 pregnant women with long-standing hypertension during 15 pregnancies who received combination therapy with hydralazine and propranolol, 14 live births and one unexplained stillbirth were reported.135 The only neonatal complications observed were 2 cases of mild hypoglycemia.135 In patients receiving hydralazine during pregnancy, the drug and its metabolites have been detected in maternal and umbilical plasma using a nonselective assay.135 The manufacturers state that although clinical experience with the drug does not indicate any positive evidence of adverse effect on the human fetus to date, hydralazine should not be used during pregnancy unless the possible benefits outweigh the potential risks to the fetus.
It is not known whether hydralazine is distributed into breast milk.134, 135 Because many drugs are distributed into milk, the drug should be used with caution in nursing women.134
Diuretics and Hypotensive Agents
When hydralazine is administered with diuretics or other hypotensive agents, the hypotensive effect of hydralazine may be increased. This effect is usually used to therapeutic advantage, but careful adjustment of dosage is necessary when these drugs are used concomitantly. When parenteral hydralazine and parenteral diazoxide (parenteral formulation no longer commercially available in the US) are used concomitantly, profound hypotensive episodes may occur. When other potent parenteral hypotensive agents are used in combination with hydralazine, patients should be continually observed for several hours for any excessive reduction in blood pressure.
The manufacturers state that monoamine oxidase (MAO) inhibitors should be used with caution in patients receiving hydralazine, since these drugs have a synergistic effect resulting in a marked decrease in blood pressure.
Hydralazine may reduce the pressor response to epinephrine.
The fixed-combination preparation containing hydralazine should not be used concomitantly with phosphodiesterase type 5 (PDE type 5) inhibitors (e.g., sildenafil, vardenafil, tadalafil).135 See Drug Interactions: Organic Nitrates and Nitrites, in Sildenafil 24:12.12.
Overdosage of hydralazine may produce hypotension, tachycardia, headache, and generalized skin flushing. Myocardial ischemia and cardiac arrhythmias may develop; profound shock can occur in severe overdosage.
There is no specific antidote for the treatment of hydralazine overdosage.134, 135 Support of the cardiovascular system is most important for the treatment of hydralazine overdosage. Evacuation of gastric contents using adequate precautions to protect the airway and prevent aspiration should be done only after cardiovascular status has been stabilized, since this procedure may precipitate cardiac arrhythmias or increase the depth of shock. Activated charcoal may be instilled if the cardiovascular system is stable. Shock should be treated with plasma volume expanders without the use of vasopressor drugs if possible. If a vasopressor drug is necessary, a drug that is least likely to precipitate or aggravate cardiac arrhythmias (e.g., methoxamine or phenylephrine) should be used. Digitalization may be necessary. Renal function should be monitored and supported if necessary. Experience with hemodialysis or peritoneal dialysis has not been reported.
Hydralazine reduces peripheral resistance and blood pressure as a result of a direct vasodilatory effect on vascular smooth muscle; the effect on arterioles is greater than on veins. It has been postulated that cyclic 3',5'-adenosine monophosphate (cyclic AMP) mediates, at least partly, the relaxation of arterial smooth muscle by the drug probably by stimulation of a calcium-binding process. Diastolic blood pressure is usually decreased more than systolic pressure. The drug decreases blood pressure in both the supine and standing positions, and there is little orthostatic hypotension.
In hypertensive patients, the hydralazine-induced decrease in blood pressure is accompanied by increased heart rate, cardiac output, and stroke volume, probably because of a reflex response to decreased peripheral resistance. The drug has no direct effect on the heart. Changes in blood pressure do not correlate well with the degree of increase in cardiac output. Increased cardiac output partially offsets the hypotensive effect of arteriolar dilation and limits the antihypertensive effectiveness of the drug. Hydralazine may increase pulmonary arterial pressure. Coronary, splanchnic, cerebral, and renal blood flows usually increase. Glomerular filtration rate, renal tubular function, and urine volume are not consistently affected by the drug. Hydralazine causes sodium and water retention and expansion of plasma volume. Tolerance to the antihypertensive effect of the drug develops during prolonged therapy, especially if a diuretic is not administered concurrently. Hydralazine usually increases plasma renin activity. Parenteral administration of the drug usually causes respiratory stimulation.
In patients with heart failure, hydralazine markedly decreases systemic vascular resistance and increases cardiac output. Systemic blood pressure, pulmonary venous pressure, and right atrial pressure are slightly decreased or unchanged in these patients; pulmonary vascular resistance may be decreased and heart rate may be slightly increased or unchanged. Increased cardiac output may be accompanied by increased renal blood flow and decreased renal vascular resistance. In patients with heart failure precipitated or exacerbated by mitral or aortic regurgitation, hydralazine may increase cardiac output and decrease regurgitant volume.
In a small number of patients with heart failure, administration of single doses of hydralazine 75 mg with isosorbide dinitrate 20 mg resulted in a substantially greater decrease in pulmonary wedge pressure compared with that observed with hydralazine alone.135 However, the increase in cardiac output, renal blood flow, and limb blood flow associated with the combination was similar to that observed with hydralazine alone.135
In some patients with unexplained pulmonary hypertension, hydralazine may decrease systemic and pulmonary vascular resistance and increase cardiac output, resulting in improved hemodynamic status; however, in other patients with this condition, only systemic vascular resistance may be decreased, and the drug may produce hazardous hemodynamic effects (e.g., symptomatic hypotension).
Although hydralazine has little effect on nonvascular smooth muscle, animal studies indicate that the drug decreases the frequency of uterine contractions and may decrease blood flow to the uterus in toxemia of pregnancy.
Because assay methods used in many published pharmacokinetic studies were nonspecific and measured inactive metabolites, the accuracy of the reported values for various pharmacokinetic parameters (e.g., bioavailability) of hydralazine has been questioned.
It is not known whether impaired renal or hepatic function has an effect on the pharmacokinetics of hydralazine.135
Hydralazine hydrochloride is rapidly absorbed from the GI tract and is extensively metabolized in the GI mucosa during absorption and on first pass through the liver. Following oral administration of a single 50-mg dose of 14C-hydralazine to patients with hypertension, about 66% of the dose was absorbed.135 With fixed dosage, there are large interindividual variations in the plasma concentrations of hydralazine; however, with a given dosage, plasma concentrations generally remain constant in individual patients. Acetylation phenotype is an important determinant of the plasma concentration of hydralazine; slow acetylators have been shown to have higher plasma concentrations of the drug than rapid acetylators when the same dose of hydralazine is administered orally. A mean absolute bioavailability of 10-26% has been reported in patients with heart failure receiving a single 75-mg oral hydralazine dose; the higher bioavailability values were observed in slow acetylators.135
Following oral administration of 100 mg of 14C-hydralazine to healthy adults in one study, peak plasma concentrations of the drug and metabolites occurred in 2 hours and plasma concentrations of the unchanged drug ranged from 1.6-3.2 mcg/mL. When escalating doses of hydralazine (75 mg to 1 g) were administered 3 times daily in patients with congestive heart failure, up to a ninefold increase in dose-normalized area under the plasma-concentration time curve (AUC) values was observed; this nonlinear pharmacokinetic pattern is likely to be associated with saturable first-pass metabolism.135 After oral administration of a single dose of hydralazine, the antihypertensive effect begins in 20-30 minutes and lasts 2-4 hours. In one study, plasma hydralazine concentrations were similar after IV administration in both slow and rapid acetylator phenotype adults; the plasma concentrations of hydralazine in these patients 3 hours after IV administration of 20-25 mg of the drug ranged from 0.11-0.33 mcg/mL. Following IV administration of hydralazine, the hypotensive effect begins within 5-20 minutes, is maximum in 10-80 minutes, and lasts 2-6 hours. After IM administration of 20 mg of the drug to healthy individuals, peak plasma concentrations of 0.16-0.61 mcg/mL occur within 1 hour. The hypotensive effect begins within 10-30 minutes and lasts 2-6 hours after IM administration.
Following oral administration of a single 75-mg dose of hydralazine hydrochloride given in fixed combination with 40 mg of isosorbide dinitrate (2 tablets of BiDil®) in 19 healthy adults, peak plasma hydralazine concentrations of 88 ng/mL per 65 kg were reached in 1 hour.135
Administration of hydralazine with food has been reported to result in higher plasma concentrations of the drug.134 The effect of food on the bioavailability of hydralazine administered in fixed combination with isosorbide dinitrate is not known.135
Animal studies indicate that hydralazine is widely distributed into body tissues. In rats, highest concentrations of the drug are found in the kidneys, plasma, and liver; lower concentrations are present in the brain, lungs, muscle, heart, and fat. Radioisotope studies indicate hydralazine has a high affinity for arterial walls. A steady-state volume of distribution of 2.2 L/kg has been reported in patients with congestive heart failure receiving a 0.3-mg/kg IV hydralazine dose.135
Hydralazine appears to readily cross the placenta. In patients receiving hydralazine during pregnancy, the drug and its metabolites have been detected in maternal and umbilical plasma using a nonselective assay.135 The drug appears to be distributed into milk; limited data suggest that milk concentrations of the drug would be clinically unimportant.
Approximately 85-87% of hydralazine in the blood is bound to plasma proteins following administration of usual doses.
The plasma half-life of hydralazine generally is 2-4 hours, but may be up to 8 hours in some patients. Plasma concentrations are increased and possibly prolonged in patients with impaired renal function. In one study, the plasma half-life was the same in both rapid and slow acetylators.
Hydralazine is metabolized extensively in the GI mucosa during absorption and in the liver by acetylation, hydroxylation, and conjugation with glucuronic acid. Four metabolites have been identified, and they apparently have no therapeutic activity. A small amount of hydralazine is reportedly converted to a hydrazone, which may be responsible for some toxic effects. Following oral administration of the drug, the main circulating metabolites of hydralazine are hydralazine pyruvate hydrazone and methyltriazolophthalazine.135 First-pass acetylation in the GI mucosa and liver is related to genetic acetylator phenotype. The rate of acetylation is genetically determined and varies among individuals; however, it is constant for each person. Slow acetylation is an autosomal recessive trait and results from a relative deficiency of the hepatic enzyme N -acetyl transferase. About 50% of American blacks and whites and the majority of American Indians, Native Alaskans, and Asians are rapid acetylators of hydralazine. The metabolism of hydralazine appears to be similar in healthy individuals and in patients with systemic lupus erythematosus (SLE); however, patients with hydralazine-induced SLE are usually slow acetylators.
Hydralazine is rapidly excreted in urine, mainly as metabolites. The major identified metabolite of hydralazine present in the urine is acetylhydrazinophthalazinone.135 Negligible amounts of unchanged drug are excreted in the urine.135 Approximately 10% of an oral dose is excreted in feces. The rate of excretion of the drug is apparently unrelated to acetylator phenotype. It is not known whether hydralazine is dialyzable.
Hydralazine hydrochloride is a phthalazine-derivative antihypertensive agent. Hydralazine hydrochloride occurs as a white to off-white, crystalline powder and has solubilities of approximately 40 mg/mL in water and 2 mg/mL in alcohol at 25°C. The drug has a pKa of 7.3. Commercially available hydralazine hydrochloride injection has a pH of 3.4-4.
Commercially available preparations of hydralazine hydrochloride should be stored at a temperature less than 40°C, preferably at 15-30°C; freezing of the injection should be avoided. Hydralazine hydrochloride tablets should be stored in tight, light-resistant containers. Commercially available fixed-combination tablets of hydralazine and isosorbide dinitrate should be stored in tight, light-resistant containers at a controlled room temperature of 25°C but may be exposed to temperatures ranging from 15-30°C.135
When hydralazine hydrochloride injection is diluted with most IV infusion solutions, a color change develops. Generally, color changes over a period of 8-12 hours do not indicate loss of potency when the solution is stored at 30°C or lower. Hydralazine hydrochloride injection has been reported to be physically incompatible with some drugs. Specialized references should be consulted for specific compatibility information.
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Tablets | 10 mg* | ||
25 mg* | hydrALAZINE Hydrochloride Tablets | |||
50 mg* | hydrALAZINE Hydrochloride Tablets | |||
100 mg* | hydrALAZINE Hydrochloride Tablets | |||
Parenteral | Injection | 20 mg/mL* |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
101. Pritchard J, Stone SR. Clinical and laboratory observations on eclampsia. Am J Obstet Gynecol . 1967; 99:754-65. [PubMed 5301234]
102. Pritchard JA, Pritchard SA. Standardized treatment of 154 consecutive cases of eclampsia. Am J Obstet Gynecol . 1975; 123:543-51. [PubMed 1180300]
103. Nissen JC. Treatment of hypertensive emergencies of pregnancy. Clin Pharm . 1982; 1:334-43. [PubMed 6764393]
104. Lubbe WF. Hypertension in pregnancy: pathophysiology and management. Drugs . 1984; 28:170-88. [PubMed 6147240]
105. Lindheimer MD, Katz AI. Current concepts: hypertension in pregnancy. N Engl J Med . 1985; 313:675-80. [PubMed 3894964]
106. Nahata MC, Pai VB. Pediatric Drug Formulations. 6 th ed. Cincinnati, OH: Harvey Whitney Book; 2011
107. Allen LV Jr, Erickson MA III. Stability of alprazolam, chloroquine phosphate, cisapride, enalapril maleate, and hydralazine hydrochloride in extemporaneously compounded oral liquids. Am J Health-Syst Pharm. 1998; 55:1915-20
108. National High Blood Pressure Education Program Working Group. National High Blood Pressure Education Program Working Group report on high blood pressure in pregnancy. Am J Obstet Gynecol . 1990; 163:1689-1712.
109. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health; 1997 Nov. (NIH publication No. 98-4080.)
110. Kaplan NM. Choice of initial therapy for hypertension. JAMA . 1996; 275:1577-80. [PubMed 8622249]
111. Rey E, LeLorier J, Burgess E et al. Report of the Canadian Hypertension Society consensus conference: 3. pharmacologic treatment of hypertensive disorders in pregnancy. CMAJ . 1997; 157:1245-54. [PubMed 9361646]
112. ACOG task force on hypertension in pregnancy: hypertension in pregnancy. Washington, DC: American College of Obstetricians and Gynecologists; 2013.
113. Anon. Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. Part II. Management of heart failure: approaches to the prevention of heart failure. Am J Cardiol . 1999; 83:9A-38A.
114. Cohn JN, Archibald DG, Ziesche S et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engl J Med . 1986; 314:1547-52. [PubMed 3520315]
115. Cohn JN, Johnson G, Ziesche et al. A comparison of enalapril with hydralazine—isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med . 1991; 325:303-10. [PubMed 2057035]
116. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension . 2000; 35:1021-4. [PubMed 10818056]
117. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension . 2000; 35:1019-20. [PubMed 10818055]
118. Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis . 2000; 36:646-61. [PubMed 10977801]
119. Hansson L, Zanchetti A, Carruthers SG et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet . 1998; 351:1755-62. [PubMed 9635947]
122. Appel LJ. The verdict from ALLHAT—thiazide diuretics are the preferred initial therapy for hypertension. JAMA . 2002; 288:3039-60. [PubMed 12479770]
123. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA . 2002; 288:2981-97. [PubMed 12479763]
124. National High Blood Pressure Education Program.. Report of the National High Blood Pressure Education Program Working Group on high blood pressure in pregnancy. Am J Obstet Gynecol . 2000; 183:S1-22.
125. Whelton PK, Appel LJ, Espeland MA et al. for the TONE Collaborative Research Group. Sodium reduction and weight loss in the treatment of hypertension in older persons: a randomized controlled trial of nonpharmacologic interventions in the elderly (TONE). JAMA . 1998; 279:839-46. [PubMed 9515998]
127. Psaty BM, Smith NL, Siscovick DS et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA . 1997; 277:739-45. [PubMed 9042847]
130. The Guidelines Subcommittee of the WHO/ISH Mild Hypertension Liaison Committee. 1999 guidelines for the management of hypertension. J Hypertension . 1999; 17:392-403.
132. Carter B for the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Personal communication.
134. Par Pharmaceutical., Inc. Hydralazine hydrochloride tablets prescribing information. Spring Valley, NY; 2003 Jun.
135. NitroMed, Inc. BiDil (isosorbide dinitrate and hydralazine hydrochloride) tablets prescribing information. Lexington, MA; 2005 Jun 23.
136. Taylor AL, Ziesche S, Yancy C et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med . 2004; 351:2049-57. [PubMed 15533851]
137. Anon. BiDil for Heart Faillure. Med Lett Drugs Ther . 2005; 47:77-8. [PubMed 16186789]
139. Duley L, Meher S, Jones L. Drugs for treatment of very high blood pressure during pregnancy. Cochrane Database Syst Rev . 2013; 7:CD001449. [PubMed 23857334]
252. ASHP. Standardize 4 Safety: compounded oral liquid standards. Updated 2024 Mar. From ASHP website. Updates may be available at ASHP website. [Web]
501. James PA, Oparil S, Carter BL et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA . 2014; 311:507-20. [PubMed 24352797]
502. 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 of the European Society of Cardiology (ESC). J Hypertens . 2013; 31:1281-357. [PubMed 23817082]
503. Go AS, Bauman MA, Coleman King SM et al. An effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and Prevention. Hypertension . 2014; 63:878-85. [PubMed 24243703]
504. Weber MA, Schiffrin EL, White WB et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich) . 2014; 16:14-26. [PubMed 24341872]
505. Wright JT, Fine LJ, Lackland DT et al. Evidence supporting a systolic blood pressure goal of less than 150 mm Hg in patients aged 60 years or older: the minority view. Ann Intern Med . 2014; 160:499-503. [PubMed 24424788]
506. Mitka M. Groups spar over new hypertension guidelines. JAMA . 2014; 311:663-4. [PubMed 24549531]
507. Peterson ED, Gaziano JM, Greenland P. Recommendations for treating hypertension: what are the right goals and purposes?. JAMA . 2014; 311:474-6. [PubMed 24352710]
508. Bauchner H, Fontanarosa PB, Golub RM. Updated guidelines for management of high blood pressure: recommendations, review, and responsibility. JAMA . 2014; 311:477-8. [PubMed 24352759]
515. Thomas G, Shishehbor M, Brill D et al. New hypertension guidelines: one size fits most?. Cleve Clin J Med . 2014; 81:178-88. [PubMed 24591473]
523. Fihn SD, Gardin JM, Abrams J et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation . 2012; 126:e354-471.
524. WRITING COMMITTEE MEMBERS, Yancy CW, Jessup M et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation . 2013; 128:e240-327.
526. Kernan WN, Ovbiagele B, Black HR et al. Guidelines for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke . 2014; :. [PubMed 24788967]
530. Myers MG, Tobe SW. A Canadian perspective on the Eighth Joint National Committee (JNC 8) hypertension guidelines. J Clin Hypertens (Greenwich) . 2014; 16:246-8. [PubMed 24641124]
536. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl . 2012: 2: 337-414.
540. Magee LA, Pels A, Helewa M et al., for the Canadian Hypertensive Disorders of Pregnancy (HDP) Working Group. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. Pregnancy Hypertens . 2014; 4:105-45. [PubMed 26104418]
542. Marik PE, Varon J. Hypertensive crises: challenges and management. Chest . 2007; 131:1949-62. [PubMed 17565029]
600. Akorn., Inc. Hydralazine hydrochloride injection prescribing information. Lake Forest, IL; 2016 Jun.
601. Nivagen Pharmaceuticals. Hydralazine hydrochloride tablets prescribing information. Sacramento, CA; 2016 Aug.
701. Ponikowski P, Voors AA, Anker SD et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J . 2016; :.
703. Ansara AJ, Kolanczyk DM, Koehler JM. Neprilysin inhibition with sacubitril/valsartan in the treatment of heart failure: mortality bang for your buck. J Clin Pharm Ther . 2016; 41:119-27. [PubMed 26992459]
800. Yancy CW, Jessup M, Bozkurt B et al. 2016 ACC/AHA/HFSA Focused Update on New Pharmacological Therapy for Heart Failure: An Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation . 2016; :.
1150. Flynn JT, Kaelber DC, Baker-Smith CM et al. Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics . 2017; 140 [PubMed 28827377]
1200. Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension . 2018; 71:el13-e115. [PubMed 29133356]
1201. Bakris G, Sorrentino M. Redefining hypertension - assessing the new blood-pressure guidelines. N Engl J Med . 2018; 378:497-499. [PubMed 29341841]
1202. Carey RM, Whelton PK, 2017 ACC/AHA Hypertension Guideline Writing Committee. Prevention, detection, evaluation, and management of high blood pressure in adults: synopsis of the 2017 American College of Cardiology/American Heart Association hypertension guideline. Ann Intern Med . 2018; 168:351-358. [PubMed 29357392]
1207. Burnier M, Oparil S, Narkiewicz K et al. New 2017 American Heart Association and American College of Cardiology guideline for hypertension in the adults: major paradigm shifts, but will they help to fight against the hypertension disease burden?. Blood Press . 2018; 27:62-65. [PubMed 29447001]
1209. Qaseem A, Wilt TJ, Rich R et al. Pharmacologic treatment of hypertension in adults aged 60 years or older to higher versus lower blood pressure targets: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med . 2017; 166:430-437. [PubMed 28135725]
1210. SPRINT Research Group, Wright JT, Williamson JD et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med . 2015; 373:2103-16. [PubMed 26551272]
1216. Taler SJ. Initial treatment of hypertension. N Engl J Med . 2018; 378:636-644. [PubMed 29443671]
1220. Cifu AS, Davis AM. Prevention, detection, evaluation, and management of high blood pressure in adults. JAMA . 2017; 318:2132-2134. [PubMed 29159416]
1222. Bell KJL, Doust J, Glasziou P. Incremental benefits and harms of the 2017 American College of Cardiology/American Heart Association high blood pressure guideline. JAMA Intern Med . 2018; 178:755-7. [PubMed 29710197]
1223. LeFevre M. ACC/AHA hypertension guideline: what is new? what do we do?. Am Fam Physician . 2018; 97(6):372-3. [PubMed 29671534]
1224. Brett AS. New hypertension guideline is released. From NEJM Journal Watch website. Accessed 2018 Jun 18. [Web]
1229. Ioannidis JPA. Diagnosis and treatment of hypertension in the 2017 ACC/AHA guidelines and in the real world. JAMA . 2018; 319(2):115-6. [PubMed 29242891]