Hydralazine

C02D - Arteriolar smooth muscle, agents acting on ATC C02DB02 Small molecule approved 1953 Oral Parenteral Natural product

JFDA label: Barolex 25mg

Mechanism of Action

Direct vasodilation of arterioles (with little effect on veins) with decreased systemic resistance

Indications

Approved

Hypertension

Off-label

Heart failure with reduced ejection fraction (HFrEF) (intolerance to an ACE inhibitor or angiotensin receptor blocker)
Heart failure with reduced ejection fraction (HFrEF) NYHA Class III-IV (African-American [self-identified] patients)
Hypertensive emergency in pregnancy
Postoperative hypertension

Contraindications

Source: Lexicomp

Hypersensitivity to hydralazine or any component of the formulation Absolute
coronary artery disease Absolute
mitral valve rheumatic heart disease Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (8)

Not Known Angina pectoris · circulatory shock · flushing · orthostatic hypotension · palpitations · paradoxical pressor response · peripheral edema · tachycardia

Nervous system disorders (9)

Not Known Anxiety · chills · depression · disorientation · dizziness · headache · increased intracranial pressure (IV; in patient with pre-existing increased intracranial pressure) · peripheral neuritis · psychotic reaction

Renal and urinary disorders (2)

Not Known Dysuria · impotence

Blood and lymphatic system disorders (6)

Not Known Agranulocytosis · decreased hemoglobin · decreased red blood cells · eosinophilia · hemolytic anemia · leukopenia

Gastrointestinal disorders (6)

Not Known Anorexia · constipation · diarrhea · nausea · paralytic ileus · vomiting

Skin and subcutaneous tissue disorders (4)

Not Known Diaphoresis · pruritus · skin rash · urticaria

Musculoskeletal and connective tissue disorders (5)

Not Known Lupus-like syndrome (dose related; fever, arthralgia, splenomegaly, lymphadenopathy, asthenia, myalgia, malaise, pleuritic chest pain, edema, positive ANA, positive LE cells, maculopapular facial rash · muscle cramps · rheumatoid arthritis · tremor · weakness

Eye disorders (2)

Not Known Conjunctivitis · lacrimation

General disorders and administration site conditions (1)

Not Known Fever

Respiratory, thoracic and mediastinal disorders (2)

Not Known Dyspnea · nasal congestion

Dosing

Source: Lexicomp

Hypertension: Oral: Initial: 10 mg 4 times daily for the first 2 to 4 days; increase to 25 mg 4 times daily for the balance of the first week; further increase to 50 mg 4 times daily; for maintenance, adjust dose to the lowest effective dose (up to 300 mg daily may be required in resistant patients) Heart failure (off-label use): Oral: Initial dose: 25 to 50 mg 3 or 4 times daily; use in combination with isosorbide dinitrate; maximum dose: 300 mg daily in divided doses (ACCF/AHA [Yancy, 2013]) Hypertensive emergency (off-label dose): Note: Use is generally not recommended due to unpredictable and prolonged antihypertensive effects (Marik, 2007): IM, IV: 10 to 20 mg every 4 to 6 hours as needed (Rhoney, 2009) Hypertensive emergency in pregnancy (systolic BP ≥160 mm Hg or diastolic BP ≥110 mm Hg) (off-label dose): IM, IV: Initial: 5 or 10 mg; may repeat dose in 20 to 40 minutes with 5 to 10 mg if blood pressure continues to exceed thresholds (ACOG, 2015; Magee, 2014; Too, 2013). Also refer to administration protocols developed by the American College of Obstetricians and Gynecologists (ACOG, 2015). A maximum total cumulative dose of 20 mg (IV) or 30 mg (IM) is recommended (Magee, 2014). Note: After the initial dose, may initiate a continuous infusion of 0.5 to 10 mg/hour instead of intermittent dosing (Magee, 2014). Perioperative hypertension (off-label dose): IV: 3 to 20 mg every 20 to 60 minutes as needed (Varon, 2008). Note: The lower end of the dosage range is preferred in the immediate perioperative period and in patients with renal failure. The use of hydralazine in this setting especially in patients with ischemic heart disease, aortic dissection, or an intracranial process is best avoided due to unpredictable and prolonged antihypertensive effects (Lien, 2012; Varon, 2008).

(For additional information see "Hydralazine: Pediatric drug information") Children and Adolescents: Note: Individualize dose; titrate gradually to patient response. Hypertension, chronic: Oral: Initial: 0.75 mg/kg/day in 2 to 4 divided doses, maximum initial dose: 10 mg/dose; may increase gradually over 3 to 4 weeks up to a maximum of 7.5 mg/kg/day in 2 to 4 divided doses not to exceed 200 mg/day (NHBPEP 2004; NHLBI 2012; Park 2014) Hypertensive emergency/urgency: IM, IV: Initial: 0.1 to 0.2 mg/kg/dose every 4 to 6 hours; increase as required to suggested usual range: 0.2 to 0.6 mg/kg/dose every 4 to 6 hours as needed; maximum dose: 20 mg/dose (NHBPEP 2004; Park 2014; Thomas 2011); manufacturer labeling suggests a dose range of 1.7 to 3.5 mg/kg/day divided in 4 to 6 doses

Refer to adult dosing.

There are no dosage adjustments provided in the manufacturer's labeling; however, the following adjustments have been recommended (Aronoff 2007): Children and Adolescents: Note: Renally adjusted dose recommendations are based on doses: Oral: 0.75 to 1 mg/kg/day divided every 6 to 12 hours; IV: 0.1 to 0.2 mg/kg/dose every 6 hours: GFR >50 mL/minute/1.73 m2: No adjustment necessary GFR 10 to 50 mL/minute/1.73 m2: Administer every 8 hours GFR 2: Administer every 12 to 24 hours Intermittent hemodialysis: Administer every 12 to 24 hours Peritoneal dialysis: Administer every 12 to 24 hours Continuous renal replacement therapy: Administer every 8 hours Adults: Note: Renally adjusted dose recommendations are based on doses of 25 to 50 mg every 8 hours: GFR ≥10 mL/minute: Administer every 8 hours. GFR Intermittent hemodialysis: Dose after dialysis Peritoneal dialysis: Administer every 8 to 16 hours Continuous renal replacement therapy: Administer every 8 hours

There are no dosage adjustments provided in the manufacturer's labeling. However, hydralazine undergoes extensive hepatic metabolism.

Warnings & Precautions

Source: Lexicomp

Drug-induced lupus-like syndrome

May cause a drug-induced lupus-like syndrome including glomerulonephritis, especially in patients receiving higher doses. If this syndrome occurs, discontinue therapy unless the benefit-to-risk requires continued therapy. Signs and symptoms usually regress after discontinuation of therapy, but residua have been detected many years later. Long-term treatment with steroids may be necessary.

Hematologic effects

Blood dyscrasias (eg, reduction in hemoglobin and red blood cell count, leukopenia, agranulocytosis, purpura) may occur; discontinue therapy if these hematologic effects occur.

Hypotension

Postural hypotension may occur.

Peripheral neuritis

Hydralazine has been associated with peripheral neuritis (eg, paresthesia, numbness, and tingling), possibly due to an antipyridoxine effect. Pyridoxine therapy should be initiated with onset of such symptoms. Disease-related concerns:

Cardiovascular disease

Use is contraindicated in patients with coronary artery disease (CAD). Use with caution in patients with cerebral vascular accidents and suspected CAD; myocardial stimulation produced by hydralazine can cause anginal attacks and electrocardiogram (ECG) changes of myocardial ischemia; has been implicated in the production of myocardial infarction. According to the American Heart Association/American College of Cardiology/American Society of Hypertension 2015 scientific statement for the treatment of hypertension in patients with CAD, hydralazine (without a concomitant nitrate [eg, isosorbide dinitrate]) should be avoided for the treatment of hypertension in patients with heart failure (with reduced ejection fraction) of ischemic origin (AHA/ACC/ASH [Rosendorff, 2015]).

Mitral valvular disease

Use with caution in patients with mitral valvular disease; may increase pulmonary artery pressure in these patients. Use is contraindicated in patients with mitral valve rheumatic heart disease.

Renal impairment

Use with caution in patients with advanced renal impairment; dosage adjustment recommended. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Dosage forms related issues:

Tartrazine sensitivity

May contain tartrazine, which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of tartrazine sensitivity in the general population is low, it is frequently seen in patients who are also hypersensitive to aspirin.

Pregnancy & Lactation

Pregnancy

FDA category C

Safe

IV hydralazine or IV labetalol are first-line for acute severe hypertension in pregnancy

Lactation

Hydralazine is excreted in breast milk. In a case report, following a maternal dose of hydralazine 50 mg 3 times daily, exposure to the infant was calculated to be 0.013 mg per 75 mL of breast milk (Liedholm, 1982). The manufacturer recommends that caution be used if administered to a breast-feeding woman.

Monitoring

Clinical pearl	Blood pressure (monitor closely with IV use), standing and sitting/supine, heart rate, complete blood cell count (CBC), antinuclear antibody (ANA) titer

Chemistry & Properties

Formula	C8H8N4
Molecular weight	160.18 g/mol
IUPAC name	phthalazin-1-ylhydrazine
CAS	86-54-4
PubChem CID	3637
InChIKey	`RPTUSVTUFVMDQK-UHFFFAOYSA-N`
logP	0.92 (XLogP 0.7)
Polar surface area	63.83 Å²
H-bond acceptors / donors	4 / 2
Drug-likeness (QED)	0.48
Lipinski violations	0

SMILES

NNc1nncc2ccccc12

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	0.951 h
Volume of distribution	1.393 L/kg
Protein binding	78.5%
BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP1A2	Inhibitor	—
CYP2C8	Inhibitor	—

Transporters

BCRP (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)OCT1 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Acetylsalicylic acid	moderate
Adalimumab	moderate
Aldesleukin	moderate
Alimemazine	moderate
Amifostine	moderate
Benznidazole	moderate
Betamethasone	moderate
Bortezomib	moderate
Brentuximab vedotin	moderate
Brimonidine (ophthalmic)	moderate
Brimonidine (topical)	moderate
Budesonide	moderate
Bupropion	moderate
Cabazitaxel	moderate
Canagliflozin	moderate
Carboplatin	moderate
Carfilzomib	moderate
Certolizumab pegol	moderate
Chloramphenicol	moderate
Chloroquine	moderate
Cisplatin	moderate
Codeine	moderate
Corticotropin	moderate
Crizotinib	moderate
Dapagliflozin	moderate
Dapsone	moderate
Deflazacort	moderate
Dexamethasone	moderate
Diazoxide	moderate
Diclofenac	moderate
Dinutuximab	moderate
Diphenhydramine	moderate
Disulfiram	moderate
Docetaxel	moderate
Doxepin	moderate
Doxepin (topical)	moderate
Dronabinol	moderate
Elotuzumab	moderate
Empagliflozin	moderate
Epoprostenol	moderate

Showing 40 of 100+.

Registered Products (3)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Barolex	Tablet 25 mg	30 tab	Al-Taqqadom Pharmaceutical Industries	4.370
Barolex	Tablet 50 mg	30 tab	Al-Taqqadom Pharmaceutical Industries	4.370
Hydralazine Hydrochloride	Ampoule 20 mg/ml	10 amp	مستودع أدوية جاودة الدولي	—