Hydralazine

Article Author:
Linda Herman
Article Editor:
Vijai Tivakaran
Updated:
3/3/2019 8:48:48 AM
PubMed Link:
Hydralazine

Indications

Hydralazine is used orally as a therapeutic agent to treat essential hypertension and intravenously to lower blood pressure urgently or emergently. FDA-approved hydralazine is usually not used as a first-line agent for the treatment of essential hypertension due to the stimulation of the sympathetic system.  It is used in combination with other hypertensives to treat persistently elevated blood pressure. [1] [2]

Hydralazine is one of three drugs that can be used in eclampsia to control severe hypertension after magnesium is administered. [3][4]

The Vasodilator Heart Failure Study (V-HeFT),  a prospective study performed in 1986, did not demonstrate a decrease in the mortality of patients receiving vasodilator therapy. Certain subgroups were reexamined, and the A-HeFT (African-American Heart Failure Trial), published in 2004, demonstrated a significantly decreased mortality for African Americans that were on a fixed dose of isosorbide dinitrate and hydralazine for severe congestive heart failure (New York Heart Association Class III and IV). These studies have been replicated, and the results continue to demonstrate a decrease in mortality for African-American patients with known heart failure and a reduced ejection fraction who are prescribed both isosorbide dinitrate and hydralazine. The results have been criticized because the study was performed before the benefits of ACE-inhibitors and beta-blockers were known. The Americal Heart Association does recommend ACE-inhibitors and beta-blockers as first-line therapy for patients with congestive heart failure. For African Americans that cannot tolerate ACE-inhibitors and/or beta-blockers, hydralazine and isosorbide are used. [5][6][7][8][9][10][11]

Mechanism of Action

Hydralazine directly relaxes the arteriolar smooth muscle but not venous smooth muscle. The mechanism is not fully known but is theorized to be due to an interference of calcium movement in the vascular smooth muscle which is responsible for vasoconstriction. This results in lowering of blood pressure. Lowering of blood pressure improves cardiac output. Also, hydralazine stimulates the sympathetic system which can cause tachyphylaxis and tachycardia. Patients tend to tolerate this medication better when the hydralazine is given with a beta-blocker and/or diuretic. [1]

The drug is metabolized in the liver.  Hydralazine undergoes polymorphic acetylation. Those that are slow acetylators require lower doses of the drug. Both the acetylated drug and unchanged drug are excreted in the urine and feces.[2]

The hypotensive effects occur 5 to 30 minutes after an intravenous dose. The duration is approximately 2 to 6 hours. The hypotensive effect occurs in 20 to 30 minutes after an oral dose, and the duration is approximately 2 to 4 hours. [1][2]

Administration

Dosage is 20 to 40 mg intravenously when treating emergent or urgent elevations of blood pressure. Dosage is 10 to  50 mg four times a day by mouth as part of a therapeutic plan in the treatment of essential hypertension. The initial dose orally should be 10 mg 4 times a day.   After 3 to 4 days, it can be increased to 25 mg for another 4 days. If the blood pressure is still not controlled, the hydralazine can be increased to 50 mg 4 times a day. Oral dosage maximum is 300 mg/day. After the maximum dosage is obtained, the drug frequency can be changed to twice a day.[12][13]

Adverse Effects

Patients may experience a headache, nausea, flushing, hypotension, palpitations, tachycardia, dizziness, and angina due to stimulation of the sympathetic system. The reflex tachycardia is a concern when given intravenously to patients that already have elevated heart rate.  [14]

Immune phenomenon such as drug-induced lupus erythematosus (DILE), serum sickness, hemolytic anemia, vasculitis, and glomerulonephritis are associated with the use of hydralazine. Usually, the lupus syndrome occurs after the patient has been ingesting the drug for approximately 6 months.

The risk factors for developing this side effect are slow acetylator phenotype, family history of autoimmune disease, and decreased renal function. Patients with the genotype of HLA-DR4 with slow acetylator hepatic status are considered more prone to DILE. Discontinuing the hydralazine usually cures the lupus-like syndrome. Patients with DILE test positive for antinuclear antibodies (ANA) and anti-neutrophil cytoplasmic antibodies (ANCA). Discontinuation of hydralazine is the treatment of DILE and other auto-immune phenomena that accompany DILE. Immunosuppression with prednisone and other immunosuppressants, such as cyclophosphamide, are controversial but have been attempted.[15][16][17][18][19][18]

Drug-induced liver injury (DILI) has also been noted to occur with the use of hydralazine. This adverse reaction can occur with the lupus syndrome or in isolation. Symptoms of DILI are those of hepatitis: nausea, vomiting, dark urine, jaundice, abdominal pain, and pruritis.  The treatment is similar to that of DILE. [20][21]

There have been rare cases of toxic epidermal necrolysis (TEN) reported in association with ingestion of hydralazine. [22][23]

Paresthesias, numbness, and tingling of peripheral neuritis have been reported that are amenable to pyridoxine supplements. [24]

Contraindications

Contraindications include:

  • Allergy to the medication.
  • Coronary artery disease due to the increased oxygen demand by the heart due to stimulation of the sympathetic system.  There have been reports of angina and myocardial ischemia.[25]
  • Mitral valve rheumatic heart disease because hydralazine can increase pulmonary artery pressure.

Pregnancy risk category C: Hydralazine has not been studied in pregnant women. In rats, it has been known to cause cleft palate and malformations of facial and cranial bones. [26]

Lactation: It is not known if hydralazine is excreted in human milk. [26]

Monitoring

A complete blood count (CBC) and an antinuclear antibody (ANA)  titer determination should be performed before and periodically during therapy. A positive ANA titer must be considered before the patient starts this medication. Risks versus benefits must be discussed with the patient before initiating therapy with hydralazine.  [14]

If the patient develops arthralgias, fever, chest pain, continued malaise, or other unexplained signs or symptoms related to DILE, a complete blood count and ANA titer should be performed immediately, and the drug should be discontinued. [19][15]

If anemia, leukopenia, agranulocytosis, and/or purpura develop, the drug should be discontinued immediately. 

Toxicity

Toxicity symptoms include hypotension, tachycardia, headache, and generalized skin flushing. Patients have developed myocardial ischemia and subsequent myocardial infarction, cardiac arrhythmia, and shock from ingestion of the drug. There is no specific treatment for an overdose other than supportive therapy. Fluids should be given, and if unsuccessful in restoring blood pressure to an adequate level, vasopressors can be administered. Tachycardia can be treated with beta-blockers with attention to the blood pressure before administration. No known recent deaths have been associated with this medication. [25]


References

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[3] ACOG Committee Opinion No. 767: Emergent Therapy for Acute-Onset, Severe Hypertension During Pregnancy and the Postpartum Period. Obstetrics and gynecology. 2019 Feb;     [PubMed PMID: 30575639]
[4] ACOG Committee Opinion No. 767 Summary: Emergent Therapy for Acute-Onset, Severe Hypertension During Pregnancy and the Postpartum Period. Obstetrics and gynecology. 2019 Feb;     [PubMed PMID: 30681541]
[5] Combination of isosorbide dinitrate and hydralazine in blacks with heart failure., Taylor AL,Ziesche S,Yancy C,Carson P,D'Agostino R Jr,Ferdinand K,Taylor M,Adams K,Sabolinski M,Worcel M,Cohn JN,, The New England journal of medicine, 2004 Nov 11     [PubMed PMID: 15533851]
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[16] Hydralazine-induced anti-neutrophil cytoplasmic antibody-positive renal vasculitis presenting with a vasculitic syndrome, acute nephritis and a puzzling skin rash: a case report., Keasberry J,Frazier J,Isbel NM,Van Eps CL,Oliver K,Mudge DW,, Journal of medical case reports, 2013 Jan 14     [PubMed PMID: 23316942]
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