Hydralazine


Article Author:
Linda Herman


Article Editor:
Vijai Tivakaran


Editors In Chief:
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Joseph Nahas
CHOKKALINGAM SIVA


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Phillip Hynes
Sandeep Sekhon


Updated:
10/7/2019 2:49:04 PM

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.[5][6][7][8] For African Americans that cannot tolerate ACE-inhibitors and/or beta-blockers, hydralazine and isosorbide are used.  [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]

Enhancing Healthcare Team Outcomes

Hydralazine is prescribed as an antihypertensive by nurse practitioners, obstetricians, internists, emergency department physicians, and intensivists. While the drug is relatively safe, it is important to be aware that in the rare patient it may cause a lupus-like syndrome. This syndrome usually reverses upon discontinuation of the drug.

Hydralazine is never the first choice for patients with essential hypertension but may be selected in African Americans who fail to respond to other antihypertensives.


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Hydralazine - Questions

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A 59-year-old male was recently prescribed an addition to his anti-hypertensive medications to control his blood pressure. He presents stating that he has been having palpitations and pressure-like chest pain. Which of the listed anti-hypertensive agents is responsible for his symptoms?



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Which of the following mechanisms is responsible for the vasodilatory effect of hydralazine?



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Which of the following is the antihypertensive drug associated with systemic lupus?



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A 62-year-old male with known history of hypertension and hyperlipidemia presents with complaints of palpitations. He is presently taking hydralazine, hydrochlorothiazide, and rosuvastatin. Vital signs show blood pressure162/82 mmHg, heart rate 106 bpm, respiratory rate 16, and he is afebrile. His physical exam is normal. What medication should be added to his regimen at this time?



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A 44-year-old female with known history of hypertension presents with complaints of fatigue and a rash on the bridge of the nose and cheeks. Her vital signs are within normal limits. The physical exam is normal except for the rash. Her BUN is 45 and creatinine is 2.2. Which of the following medications is responsible for these findings?



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Which drug causes a lupus-like syndrome?



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Which of the following is the mechanism by which hydralazine exerts its antihypertensive action?



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A 48-year old male presents to the clinician with symptoms of joint pain, joint swelling, cough, fever, and excessive fatigue. Further history reveals that he has been diagnosed with high blood pressure 8 months ago. After further evaluation and laboratory findings, a diagnosis of drug-induced lupus is made. Which one of the following drugs is the most likely etiological agent?



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Hydralazine falls into which of the following drug classifications?



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Hydralazine - References

References

Hydralazine Induced Lupus Syndrome Presenting with Recurrent Pericardial Effusion and a Negative Antinuclear Antibody., Iyer P,Dirweesh A,Zijoo R,, Case reports in rheumatology, 2017     [PubMed]
Direct Vasodilators and Sympatholytic Agents., McComb MN,Chao JY,Ng TM,, Journal of cardiovascular pharmacology and therapeutics, 2016 Jan     [PubMed]
Hydralazine-induced lupus syndrome presenting with large pericardial effusion., Chamsi-Pasha MA,Bassiouny M,Kim ES,, QJM : monthly journal of the Association of Physicians, 2014 Apr     [PubMed]
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]
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]
Clinical Effectiveness of Hydralazine-Isosorbide Dinitrate in African-American Patients With Heart Failure., Ziaeian B,Fonarow GC,Heidenreich PA,, JACC. Heart failure, 2017 Sep     [PubMed]
A case report of hydralazine-induced skin reaction: Probable toxic epidermal necrolysis (TEN)., Mahfouz A,Mahmoud AN,Ashfaq PA,Siyabi KH,, The American journal of case reports, 2014     [PubMed]
Hydralazine-induced toxic epidermal necrolysis in a patient on continuous ambulatory peritoneal dialysis., Chan JC,Yap DY,Yeung CK,, Journal of clinical pharmacy and therapeutics, 2014 Jun     [PubMed]
Hydralazine-induced pauci-immune glomerulonephritis: intriguing case series with misleading diagnoses., Babar F,Posner JN,Obah EA,, Journal of community hospital internal medicine perspectives, 2016     [PubMed]
Hydralazine associated pauci-immune glomerulonephritis., Suneja M,Baiswar S,Vogelgesang SA,, Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases, 2014 Mar     [PubMed]
Hydralazine-Induced Autoimmune Hepatitis Precipitated by the Blood Transfusion., Amjad W,John G,Gulru S,, American journal of therapeutics, 2017 Oct 16     [PubMed]
Acute Cholestatic Liver Injury From Hydralazine Intake., Harati H,Rahmani M,Taghizadeh S,, American journal of therapeutics, 2016 Sep-Oct     [PubMed]
The Paradox in Demonstrating Hydralazine-Nitrate Efficacy., Cohn JN,, JACC. Heart failure, 2017 Sep     [PubMed]
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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]
Cohn JN,Archibald DG,Ziesche S,Franciosa JA,Harston WE,Tristani FE,Dunkman WB,Jacobs W,Francis GS,Flohr KH, Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. The New England journal of medicine. 1986 Jun 12;     [PubMed]
Cohn JN,Archibald DG,Francis GS,Ziesche S,Franciosa JA,Harston WE,Tristani FE,Dunkman WB,Jacobs W,Flohr KH, Veterans Administration Cooperative Study on Vasodilator Therapy of Heart Failure: influence of prerandomization variables on the reduction of mortality by treatment with hydralazine and isosorbide dinitrate. Circulation. 1987 May;     [PubMed]
Loeb HS,Johnson G,Henrick A,Smith R,Wilson J,Cremo R,Cohn JN, Effect of enalapril, hydralazine plus isosorbide dinitrate, and prazosin on hospitalization in patients with chronic congestive heart failure. The V-HeFT VA Cooperative Studies Group. Circulation. 1993 Jun;     [PubMed]
KIRKENDALL WM,PAGE EB, Polyneuritis occurring during hydralazine therapy; report of two cases and discussion of adverse reactions to hydralazine. Journal of the American Medical Association. 1958 May 24;     [PubMed]
Yancy CW,Jessup M,Bozkurt B,Butler J,Casey DE Jr,Colvin MM,Drazner MH,Filippatos GS,Fonarow GC,Givertz MM,Hollenberg SM,Lindenfeld J,Masoudi FA,McBride PE,Peterson PN,Stevenson LW,Westlake C, 2017 ACC/AHA/HFSA Focused 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. Journal of the American College of Cardiology. 2017 Aug 8;     [PubMed]
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Whelton PK,Carey RM,Aronow WS,Casey DE Jr,Collins KJ,Dennison Himmelfarb C,DePalma SM,Gidding S,Jamerson KA,Jones DW,MacLaughlin EJ,Muntner P,Ovbiagele B,Smith SC Jr,Spencer CC,Stafford RS,Taler SJ,Thomas RJ,Williams KA Sr,Williamson JD,Wright JT Jr, 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 (Dallas, Tex. : 1979). 2018 Jun;     [PubMed]

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