Continuing Education Activity

Hydralazine is a direct vasodilator used orally to treat essential hypertension, among other diseases, and intravenously to rapidly reduce blood pressure in hypertensive urgency or emergency. Per JNC 8 guidelines, it is not a first-line agent for the treatment of essential hypertension. This is due to hydralazine’s stimulation of the sympathetic nervous system, among several other adverse effects that make the current newer first-line agents more efficacious. This activity outlines the indications, mechanism of action, administration, contraindications, and adverse effects of hydralazine.

Objectives:

• Identify the indications for initiating hydralazine therapy.
• Summarize the theorized mechanism of action of hydralazine.
• Discuss the parameters of hydralazine administration.
• Outline how an interprofessional team can coordinate the use and monitoring of hydralazine to obtain the best patient outcomes.

Indications

Hydralazine is primarily used to treat hypertension and hypertensive urgency/emergency.[1] It has also been utilized in the treatment of eclampsia along with heart failure with reduced ejection fraction (HFrEF) when in combination with isosorbide dinitrate.[2] 

In current practice, oral hydralazine is used in essential hypertension refractory to other therapeutic agents.[2] Studies comparing its effects as an add-on medication to multidrug treatment for hypertension have proved effective but not as efficacious as other multi-modal first-line therapies (calcium channel blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, thiazides).[2] Per the JNC 8 guideline algorithm, hydralazine can be considered if initiation of first-line therapy titrated to its maximum dose and/or the addition of a second first-line agent does not meet blood pressure reduction goals. In these guidelines, hydralazine is categorized with other medications, including beta-blockers and aldosterone antagonists, that have more compelling additional indications when compared to hydralazine, such as their use in heart failure and pregnancy.[3]   

IV hydralazine has had increased off-label use in the setting of hypertensive emergencies. It is often given to hospitalized patients but has little evidence of improved outcomes. Reasons for this include highly variable blood pressure changes and adverse hypotensive episodes.[4]

IV hydralazine along with IV labetalol are considered first-line therapy for the treatment of acute-onset, severe hypertension in pregnancy and during the postpartum period. Either of these medications should be administered during the intrapartum or postpartum period if severe blood pressure persists for greater than 15 minutes.[5] 

For African-American patients with severe heart failure (New York Heart Association Class III and IV) with reduced ejection fraction (HFrEF), the American Heart Association recommends ACE inhibitors and beta-blockers as first-line therapy.[6] Within this population, the use of hydralazine in combination with isosorbide dinitrate has demonstrated a mortality benefit, although more recent studies have shown less robust efficacy.[7] Per the 2019 American College of Cardiology expert consensus guidelines, fixed-dose long-acting nitrates, and hydralazine can be added to African American people already receiving an ACE inhibitor, ARB, or ARNI plus a beta-blocker.[8]

Mechanism of Action

Hydralazine is a direct arteriole vasodilator. Although the mechanism is not completely understood, it is theorized to be associated with intracellular calcium homeostasis. Specifically, it acts to inhibit inositol trisphosphate (IP3)-induced release of calcium from the smooth muscle cells' sarcoplasmic reticulum and inhibits myosin phosphorylation within the arterial smooth muscle.[2] This reduces peripheral vascular resistance and leads to a compensatory baroreceptor-mediated release of epinephrine and norepinephrine, which, as a result, increases venous return and cardiac output. Given hydralazine’s stimulation of the sympathetic nervous system, it consequently leads to tachyphylaxis and tachycardia. It is sometimes given with a beta-blocker or diuretic for better patient tolerance.[2]

Hydralazine is metabolized by the liver. It undergoes polymorphic acetylation. Slow acetylators require lower doses of the drug. Both the acetylated drug and unchanged drug are excreted in the urine and feces.[1]

For intravenous dosing, the blood-pressure-lowering effects occur within 5 to 30 minutes with a total duration of 2 to 6 hours. For oral dosing, the blood-pressure-lowering effects occur within 20 to 30 minutes with a total duration of 2 to 4 hours.[2]

Administration

For the treatment of hypertensive emergencies, hydralazine should be administered at a dosage of 10 mg via slow IV infusion with a maximum initial dose of 20 mg. This can be repeated every 4-6 hours as needed. Due to its unpredictable response and prolonged duration of action, hydralazine is not a desirable first-line agent for acute treatment.[9]

To treat essential hypertension, hydralazine should be initiated at a dosage of 10 mg orally four times daily for the first 2 to 4 days, then increased to 25 mg four times daily to complete 1 week of treatment. It can then be increased to 50 mg four times daily for maintenance therapy. The oral dosage maximum is 300 mg per day.[9] 

For the treatment of Stage C Heart Failure with Reduced Ejection Fraction (HFrEF), the recommended fixed initial dose combination of hydralazine and isosorbide dinitrate is 37.5 mg hydralazine/20 mg isosorbide dinitrate 3 times daily with a maximum dose of 75 mg hydralazine/40 mg isosorbide dinitrate 3 times daily.[10]

Adverse Effects

Hydralazine has been reported to cause headaches, nausea, flushing, hypotension, palpitations, tachycardia, dizziness, and angina.[11]

Immune phenomena such as drug-induced lupus erythematosus (DILE), serum sickness, hemolytic anemia, vasculitis, and glomerulonephritis have been reported using hydralazine.[12]

Hydralazine-related DILE, also known as hydralazine-induced lupus syndrome (HILS), usually occurs with greater than 6 months of exposure, and roughly 5-8% of hydralazine users are at risk of developing DILE.[12] The incidence of HILS is dose-dependent. The syndrome typically manifests with arthralgias, myalgias, serositis, and fevers; cardiac involvement is rare [13]. The risk factors for developing DILE include slow acetylator phenotype, family history of autoimmune disease, and decreased renal function. There have also been associations between DILE occurrence and certain human leukocyte antigens (HLA). Discontinuation of hydralazine usually resolves the lupus-like syndrome.[12]

Cases of drug-induced liver injury (DILI) have also been reported with the use of hydralazine. Symptoms of DILI are consistent with hepatitis and include nausea, vomiting, dark urine, jaundice, abdominal pain, and pruritus. Treatment entails discontinuation of hydralazine.[14]

There have been rare cases of toxic epidermal necrolysis (TEN) reported in association with hydralazine.[15][16]

There have also been rare cases reported of polyneuritis that are amenable to pyridoxine supplements.[17] 

Contraindications

Coronary artery disease: this is due to hydralazine’s stimulation of the sympathetic nervous system. This leads to increased cardiac output and oxygen demand, which can provoke myocardial ischemia.[18]

Lactation: use caution in breastfeeding women as it is unknown if hydralazine is excreted in human milk[19]

Aortic dissection:  it can increase aortic wall shear stress 

Monitoring

A complete blood count (CBC) and an antinuclear antibody (ANA) titer should be obtained prior to initiating therapy and periodically during therapy. In 95-100% of HILS, the serum ANA titer is positive. Abnormal hematologic findings to be aware of in HILS includes anemia, leukopenia, and/or agranulocytosis.[20] Risks versus benefits must be discussed with the patient with positive ANA titers before initiating therapy with hydralazine.[11]

If the patient develops arthralgias, fever, chest pain, continued malaise, hematologic findings mentioned above, or other unexplained signs or symptoms related to DILE, the drug should be discontinued immediately, and corticosteroids and/or immunosuppressive therapy should be considered in life-threatening cases.[13]

Toxicity

Published reports of toxicity with acute use of hydralazine are uncommon. Signs of toxicity include hypotension, tachycardia, headaches, and generalized flushing.[21] Chronic toxicity could lead to DILE.[22] There is no specific treatment for an overdose other than supportive therapy. Fluids should be given initially, followed by vasopressors should fluids fail to improve the hypotension. Tachycardia or ischemia can be treated with beta-blockers with attention to blood pressure prior to administration.[22]

Enhancing Healthcare Team Outcomes

Hydralazine should not be considered a first-line agent for essential hypertension but can be considered in hypertension refractory to other first-line medications. The newer hypertensive medications are more efficacious with fewer adverse effects. The recommended dosing of three to four times daily makes hydralazine patient compliance a challenge. Patients tend to tolerate this medication better when the hydralazine is given with a beta-blocker and/or diuretic.[2]

IV hydralazine has had increased off-label use for the treatment of hypertensive urgency or emergency.[4] However, it should not be considered for first-line therapy due to tachyphylaxis, highly variable blood pressure, and adverse hypotension.[2]

For African Americans with HFrEF, the combination of hydralazine and isosorbide dinitrate can be added to medication therapy if the patient is already receiving an ACE inhibitor, ARB, or ARNI and a beta-blocker.[6] In clinical practice, this combination has been used in heart failure patients as a preload and afterload reducer, especially in patients who cannot tolerate beta-blockers and ACE inhibitors or ARBs and would benefit from therapy reducing their systolic blood pressure.[8]

While hydralazine is relatively safe, it is important to be aware of some of its adverse effects, which, although rare, include triggering lupus-like syndrome.[11] This can usually be reversed upon discontinuation of the drug.[13] 

An interprofessional team approach involving clinicians, mid-level practitioners, and specialists, plus the nursing staff and pharmacists, can help monitor the patient's therapeutic results, watch for potential adverse events, provide patient medication counseling regarding dosing and signs of toxicity, check for drug-drug interactions, and alert the prescriber. These types of interprofessional strategies will result in improved outcomes from hydralazine therapy. [Level 5]