Hydralazine (Apresoline) tablets/ injections are used in the treatment of hypertension. The drug acts as a vasodilator and reduces blood pressure by causing arteriolar vasodilation.

Indications of Hydralazine:

• Hypertension:

  • The therapy of moderate to severe hypertension is indicated.

Note: For the initial management of hypertension, not advised.

• Off Label Use of Hydralazine in Adults:

  • Decreased ejection fraction in heart failure.
  • Emergency hypertension during pregnancy or after delivery (including preeclampsia/eclampsia-related acute-onset hypertension).

Hydralazine dosage in adults:

Hydralazine dose for treating heart failure with reduced ejection fraction (off-label):

Note: It can be administered as a supplemental medication to patients with persistent NYHA class III or IV heart failure who cannot tolerate an ACE inhibitor, ARB, or angiotensin II-neprilysin inhibitor or who do not improve on these treatments.

• Initial: 25 to 50 mg per mouth, three or four times per day, in conjunction with three or four doses of isosorbide dinitrate; titrate dose every two to four weeks.
• 300 mg per day in divided doses is the maximum dose.
• Some experts start taking isosorbide dinitrate at a dose of 25 mg three times every day.
• When combined with isosorbide dinitrate, evaluate every two to four weeks and gradually titrate as tolerated to a target dose of 75 mg three times per day.
• Note: Instead of using the two drugs separately, an isosorbide dinitrate/hydralazine fixed-dose combination can be employed.

Hydralazine dose as an alternative agent in the treatment of Hypertension:

Note: It can be administered to individuals who do not respond well to combination therapy with preferred medications, but it is not advised as a first-line treatment.

• Initial: 10 mg orally titration based on response to 50 mg four times daily after taking 25 mg four times daily for the remainder of the week (manufacturer's labelling)
• The typical dosage range is divided doses of 100 to 200 mg per day.
• The manufacturer's labelling states that the maximum dose is 300 mg/day; however, doses greater than 200 mg/day should typically be avoided due to a higher risk of a lupus-like reaction.
• For the purpose of avoiding the reflex tachycardia and fluid retention brought on by hydralazine, a beta-blocker and/or diuretic can be administered.

Hydralazine Dose as an alternative agent in the treatment of Hypertensive emergency:

Note: Due to its unexpected and protracted antihypertensive effects, hydralazine should not be used in cases of severe hypertension that are accompanied by new or increasing target-organ damage.

• IM, IV:
  • Some experts advise a maximum of 20 mg/dose, while others propose 10 to 20 mg every 4 to 6 hours as needed. If necessary, the amount may be increased to a maximum of 40 mg/dose.
  • To prevent reflex tachycardia associated with hydralazine, it should be given with a beta-blocker

Hydralazine Dose in the treatment of Hypertensive emergency in pregnancy or postpartum (including acute-onset hypertension in preeclampsia/eclampsia) (off-label):

Note: for severe, chronic, and quick-onset (e.g., within 15 minutes) hypertension.

• IM, IV: Initial:
  • 5 or 10 mg;
  • If, with a cumulative total dose of 20 to 30 mg, either the systolic blood pressure or the diastolic blood pressure remains above the threshold, an alternative medication should be administered.

Hydralazine dose in the treatment of Perioperative hypertension (as an alternative treatment):

Note: 

• Patients with persistent hypertension should begin oral treatments as soon as possible before surgery after they are hemodynamically stable.
• Hydralazine's antihypertensive effects can result in reflex tachycardia and are less predictable than those of other parenteral antihypertensives.
• According to some professionals, 5 to 20 mg should be administered as needed.
  • IV: Every 4 to 6 hours at the lowest amount possible.

Hydralazine dosage in children:

Note: Dose should be individualized and titrated to patient response.

Hydralazine dose in the treatment of heart failure, afterload reduction: Limited data available:

Note: It should be given in combination with beta-blockers as it can lead to reflex tachycardia.

• Infants: IV:

  • 1 to 0.5 mg/kg/dose every 6 to 8 hours.
  • maximum dose: 2 mg/kg/dose.

• Children and Adolescents:

  • 15 to 0.2 mg/kg/dose every 4 to 6 hours.
  • maximum dose: 20 mg/dose.

• Infants, Children, and Adolescents:Oral:

  • 75 to 3 mg/kg/day divided every 6 to 12 hours.
  • maximum daily dose: 7 mg/kg/day or 200 mg/day whichever is less.

Hydralazine dose for chronic hypertension:

• Children and Adolescents:

  • Initial: 0.75 mg/kg/day per oral in 2 to 4 divided doses.
  • maximum initial dose: 10 mg/dose;
  • Increases up to 7.5 mg/kg/day in 2 to 4 divided doses, not to exceed 200 mg/day, may be made gradually over 3 to 4 weeks.

Hydralazine dose for hypertensive emergency/urgency:

• Infants, Children, and Adolescents:

  • IM, IV: Initial:
    • 0.1 to 0.2 mg/kg/dose every 4 to 6 hours;
    • Raise as necessary to the recommended typical range: 0.2 to 0.6 mg/kg/dose given as needed every 4 to 6 hours.
    • The maximum dose: 20 mg/dose,
    • The dosage range, according to the manufacturer's labelling, is 1.7 to 3.5 mg/kg/day, split into 4 to 6 doses.

Hydralazine Pregnancy Risk Factor C

• Some studies on animal reproduction revealed negative outcomes. Hydralazine can cross the placenta.
• Preeclampsia or postpartum is when intravenous hydroalazine can be used to treat acute onset, severe hypertension.
• Negative outcomes for the mother, child, and foetus can result from persistent maternal hypertension that is not managed.
• For the treatment of pregnancy-related hypertension, alternative oral agents are preferable.

Hydralazine use during breastfeeding:

• Breast milk contains hydralazine.
• In comparison to an oral infant therapeutic dose of 0.7 to 3 mg/kg/day, the relative infant dose (RID) of hydralazine ranges from 0.777% to 3% when computed from the highest breastfeeding concentration.
• When the RID of a medication falls below 10%, breastfeeding is generally acceptable.
• Hydralazine's RID was calculated using a milk content of 0.0016 mg/mL (792 nmol/L).
• Accordingly, 0.023 mg/kg/day is the anticipated daily newborn dose given through breastfeeding.
• This milk concentration was attained following the three-time daily oral delivery of 50 mg of hydralazine to the mother.
• Both baby serum and hydralazine metabolites were discovered in breast milk.
• Hydralazine should not be given to a nursing woman unless it is prescribed by the manufacturer.
• Hydralazine can be used in conjunction with breastfeeding. However, there isn't enough information available after long-term use.

Hydralazine Dose adjustment in renal disease:

The manufacturer's labelling does not mention dosage changes, although the following ones have been suggested:

Note: Recommendations for renally adjusted dosages are based on doses of 25 to 50 mg per 8 hours.

• GFR ≥10 mL/minute:
  • Administer every 8 hours.
• GFR <10 mL/minute:
  • Administer every 8 to 16 hours.
• Intermittent hemodialysis:
  • Dose after dialysis.
• Peritoneal dialysis:
  • Administer every 8 to 16 hours.
• Continuous renal replacement therapy:
  • Administer every 8 hours.

Hydralazine Dose adjustment in liver disease:

The manufacturer's labelling does not mention dosage changes, however hydralazine goes through a significant amount of hepatic metabolism.

Side effects of hydralazine:

• Cardiovascular:

  • Peripheral Edema
  • Orthostatic Hypotension
  • Circulatory Shock
  • Palpitations
  • Flushing
  • Paradoxical Pressor Response
  • Tachycardia
  • Angina Pectoris

• Central Nervous System:

  • Headache
  • Chills
  • Peripheral Neuritis
  • Depression
  • Increased Intracranial Pressure (IV; In Patient With Preexisting Increased, Intracranial Pressure)
  • Dizziness
  • Disorientation
  • Psychotic Reaction
  • Anxiety

• Dermatologic:

  • Pruritus
  • Urticaria
  • Skin Rash
  • Diaphoresis

• Gastrointestinal:

  • Nausea
  • Constipation
  • Paralytic Ileus
  • Diarrhea
  • Vomiting
  • Anorexia

• Genitourinary:

  • Impotence
  • Dysuria

• Hematologic & Oncologic:

  • Eosinophilia
  • Decreased Hemoglobin
  • Hemolytic Anemia
  • Decreased Red Blood Cells
  • Leukopenia
  • Agranulocytosis

• Neuromuscular & Skeletal:

  • Tremor
  • Arthralgia
  • Maculopapular Facial Rash
  • Lymphadenopathy
  • Pericardial Tamponade)
  • Asthenia
  • Malaise
  • Positive ANA
  • Pleuritic Chest Pain
  • Positive LE Cells
  • Positive Direct Coombs' Test
  • Myalgia
  • Pericarditis
  • Muscle Cramps
  • Splenomegaly
  • Rheumatoid Arthritis
  • Edema
  • Weakness
  • Lupus-Like Syndrome (Dose Related; Fever

• Ophthalmic:

  • Lacrimation
  • Conjunctivitis

• Respiratory:

  • Nasal Congestion
  • Dyspnea

• Miscellaneous:

  • Fever

Contraindications to Hydralazine:

• Rheumatic heart disease caused by the mitral valve
• Coronary artery disease
• Hypersensitivity to hydralazine and any component of the formulation

Canadian labeling: Additional contraindications not in US labeling

• High cardiac output and severe tachycardia (HF)
• Mechanical obstruction can cause myocardial insufficiency (eg, mitral or aortic stenosis, constrictive pericarditis).
• Pulmonary hypertension causing isolated right-ventricular failure
• Aneurysm of aorta in acute dissection
• Idiopathic systemic Lupus Erythematosus (or related disease)

Warnings and precautions

• Drug-induced lupus-like symptoms:

  • Patients who have taken larger dosages of hydralazine have been reported to develop glomerulonephritis, one of the symptoms associated with drug-induced lupus.
  • You can treat it with long-term steroid therapy.
  • This syndrome should not be treated unless there is a clear benefit to the patient.
  • The condition will usually disappear after the treatment is stopped, although residua may still be present many years later.

• Hematologic effects

  • Hydralazine can cause blood dyscrasias such as reduced hemoglobin, red blood cell count, leukopenia and agranulocytosis.
  • Hematologic effects should prompt the termination of therapy.

• Hypotension

  • Hypotension can occur.

• Peripheral neuritis:

  • Because of the antipyridoxine properties of hydralazine peripheral neuritis may occur. This can include paresthesia, numbness and tingling.
  • In the case of these symptoms, pyridoxine therapy should be given.

• Cardiovascular disease

  • It is recommended that patients with coronary artery disease avoid using the medication.
  • It should not be given to patients suffering from cerebral vascular accidents or suspected CAD. 
  • Hydralazine can cause myocardial stimulation, which can lead to angina attacks or ECG changes in myocardial ischemia.
  • The American Heart Association/American College of Cardiology/American Society of Hypertension (2015) recommended against using hydralazine in patients with CAD/heart failure (with lower ejection %).

• Mitral valvular Disease:

  • Increased pulmonary arterial pressure may result from hydralazine use. When administering it, patients with mitral valve disease should exercise caution.
  • Patients with mitral valve dysfunction or rheumatic hearts disease should not use this medication.

• Renal impairment

  • Patients with advanced renal disease need to be cautious. Dose reduction may be necessary.

Monitoring parameters:

• Blood pressure
• Pulse rate
• Complete blood cell count
• Antinuclear antibody (ANA) titer

The 2017 Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Confirmed hypertension and known CVD or 10-year ASCVD risk ≥10%:

• Target blood pressure <130/80 mm Hg is recommended.

Confirmed hypertension without markers of increased ASCVD risk:

• Target blood pressure <130/80 mm Hg may be reasonable.

How to administer Hydralazine?

Oral.

• It can be taken orally with or without food.
• However, administering it consistently with relation to meals increases its bioavailability.
   

Injection:

• It is necessary to titrate gently in accordance with response because some patients may have an unpredictably or slowly unfolding reaction.
• IM:
  • It should be given undiluted as an IM injection.
• IV:
  • It should be given undiluted as a slow IV push.

Mechanism of action of Hydralazine:

It works by lowering systemic resistance and immediately vasodilating the arterioles (with minimal impact on veins).

The onset of action: IV:

• 10 to 80 minutes

Duration: IM, IV:

• Up to 12 hours.

Note: Duration depends on the acetylation status of the patient. Hypotension due to hydralazine may last longer even though the circulating half-life is much short.

Absorption: Oral:

• Rapidly absorbed

Protein binding:

• 87%

Metabolism:

• Hepatically acetylated; extensive first-pass effect (oral)

Bioavailability:

• Increased with food

Half-life elimination:

• 3 to 7 hours

Time to peak, plasma:

• Oral: 1 to 2 hours

Excretion:

• Urine (as metabolites)

International Brand Names of Hydralazine:

• APO-HydrALAZINE
• Apresoline
• JAMP-HydrALAZINE
• MINT-HydrALAZINE
• PMS-HydrALAZINE
• Ademan
• Alphapress
• Aprelazine
• Apresol
• Apresolin
• Apresolina
• Apresoline
• Aprezin
• Apulon
• Ardiolazin
• Cesoline Y
• Cesoline-W
• Hidral
• Hydrapres
• Hylazine
• Hyperphen
• Hyperphen-50
• Hyperzine
• Slow-Apresoline
• Stable

Hydralazine Brand Names in Pakistan: