A clinically significant additive hypotensive effect may occur when hydralazine is used in combination with other drugs that cause hypotension. Fatalities have been reported in patients treated with the combination of hydralazine and diazoxide, so this combination should be avoided if possible, or used with extreme caution.
Dosage and Administration
| Indication | Route | Initial Dose | Dose Titration | Usual Dose | Maximum Dose | Clinical Comment | Hypertension
(Not an approved use in Canada) | Oral | 0.75 mg/kg/day in 4 divided doses; initial oral dose should not exceed 25 mg/dose | May be increased slowly to a dose of 7 mg/kg/day over a period of 3 to 4 weeks | 0.75 to 7 mg/kg/day in
4 divided doses | 200 mg/day | | Hypertension
(Not an approved use in Canada) | IM/IV | 1.7 to 3.5 mg/kg/day in 4 to 6 divided doses; not to exceed
20 mg/dose | | | 20 mg/dose | When administered by continuous infusion the initial recommended dose is 1.5 µg/kg/min. |
| Indication | Route | Initial Dose | Dose Titration | Usual Dose | Maximum Dose | Clinical Comment | | Hypertensiona | Oral | 10 mg QID | After 2–4 days, may be increased to 25 mg QID for remainder of first week of therapy; then, may increase by 25 mg per day at 1-week intervals up to 50 mg QID | 50 mg QID; has also been used at doses of 25 to 150 mg BID | Rarely, doses up to 300 to 400 mg daily may be required to control blood pressure | Patients with the slow acetylator phenotype should receive a daily dose of no more than 200 mg. | | Acute Hypertension | IV | 10 to 20 mg repeated as necessary at 20 to 30 minute intervals to achieve desired blood pressure response | | | | May also be administered as a continuous infusion at an initial dose of 200 to 300 µg/min, titrated to achieve desired blood pressure; usual maintenance dose 50 to 150 µg/minute.b | | Hypertensive Emergencies during Pregnancy | IV | 5 to 10 mg initially, followed by 5 to 10 mg every 20 to 30 minutes as necessary | | | | For severe hypertension, may be infused at a rate of 0.5 to 10 mg/hour.b | Heart Failure
(Not an approved use in Canada) | Oral | 50 to 100 mg Q8H | | 200 to 600 mg/day divided every 4 to 12 hours | | Used in conjunction with isosorbide dinitrate. | a. Canadian guidelines on the management of hypertension are published [ Can J Cardiol 2008;24(6):465-75] or available at www.hypertension.ca. b. Patients started on intravenous hydralazine should be switched to oral therapy as soon as is practical; an intravenous dose of 25 to 50 mg has been reported to be equivalent to an oral dose of 75 to 100 mg.
No specific dosage adjustment recommended for older individuals. Use same dosage as for adult patients. Wait until next dose. Do not take a double dose. Reduce the dose in patients with hepatic dysfunction. Patients may be slow or fast acetylator phenotype; related to intestinal activity of N-acetyl transferase. No specific recommendations. It is not known whether hydralazine is dialyzable. In patients with creatinine clearance <10 mL/minute the dosage interval should be extended to 8 to 16 hours (12 to 24 hours in slow acetylators).
Adverse Reactions
| Body System | Effect | Clinical Comment | | Cardiovascular | Palpitations, tachycardia, flushing, sodium and water retention, hypotension, paradoxical hypertension, heart failure, angina | Often administered with a β-blocker to counteract reflex tachycardia, and a diuretic to counteract sodium and water retention. | | Central Nervous System | Headache, dizziness, anxiety, disorientation, agitation, depression, hallucinations, sleep disturbances, cerebral ischemia or hypoperfusion | Mild CNS effects usually do not require medical attention and resolve over time. | | Dermatologic | Rash, urticaria, pruritus | | | Gastrointestinal | Anorexia, diarrhea, constipation, nausea, vomiting, gastrointestinal distress, paralytic ileus | Gastrointestinal effects usually do not require medical attention and resolve over time. | | Genitourinary | Proteinuria, hematuria, uremia, glomerulonephritis, acute renal failure, urinary retention, difficult micturition, increased serum creatinine concentration | Microhematuria and/or proteinuria in the presence of elevated ANA titres may result from immune-complex glomerulonephritis and be associated with SLE-like syndrome. | | Hematologic | Anemia, leukopenia (agranulocytosis and thrombocytopenia), Coomb's-test positive hemolytic anemia, leukocytosis, lymphadenopathy, pancytopenia, splenomegaly, antinuclear antibodies | A positive ANA does not correlate with the onset of the SLE-like syndrome; serial measurement of ANA titre is not recommended. | | Hepatic | Jaundice, liver enlargement, elevated liver enzymes, hepatocellular necrosis and granulomatous hepatitis | Monitor transaminase levels. | | Hypersensitivity | SLE-like syndrome, chills, eosinophilia, cutaneous and systemic vasculitis, pruritus, urticaria, hepatitis, fever, vascular collapse | Clinical manifestations of the syndrome are usually reversible upon stopping hydralazine. | | Neuromuscular | Peripheral neuritis with paresthesia, numbness and tingling, polyneuritis, tremor, muscle cramps, weakness | Peripheral neuritis may respond to pyridoxine administration. | | Ocular | Lacrimation, conjunctivitis, blurred vision | | | Respiratory | Nasal congestion, dyspnea, pleural pain, pulmonary hemorrhage, pulmonary edema, pulmonary hypertension | Nasal congestion usually resolves with time. Pleuropulmonary symptoms occur in 30% of patients with SLE-like syndrome. | | Other | Weight decrease, malaise, impotence, decreased libido, sweating | | Abbreviations: ANA=antinuclear antibodies; SLE=systemic lupus erythematosis.
| Test | Effect | Clinical Comment | | Antinuclear antibodies | Positive | Possible SLE-like syndrome (see Warnings and Precautions, Hypersensitivity) | | Coomb's test | Positive | Hemolytic anemia | | Serum liver enzymes | Elevated | Possible hepatotoxicity |
Indications and Clinical UseHealth Canada-approved indication is:
Uses Not Approved in Canada: Hydralazine has been used in the treatment of heart failure when used in combination with isosorbide dinitrate.
Hypertension: For the management of hypertension, hydralazine is recommended only in patients who do not respond adequately to a combination of first-line antihypertensive agents (e.g., a thiazide diuretic and a β-blocker and/or an ACE inhibitor or calcium channel blocking agent or angiotensin II antagonist).
Hydralazine, in combination with isosorbide dinitrate, can be considered in patients with hypertension and heart failure if first line agents cannot be tolerated. Guidelines recommend that hydralazine should be avoided in patients with hypertension and left ventricular hypertrophy [Can J Cardiol 2008;24(6):465-75]. Hydralazine has not been shown to produce regression of left ventricular hypertrophy, therefore other agents are preferred.
Hydralazine is generally administered in combination with a thiazide diuretic and a β-blocker. This reduces the hydralazine-induced sodium and water retention and reflex tachycardia, permits use of lower dosages of each drug and minimizes the probability of adverse effects.
Heart Failure: The combination of a beta-blocking agent and an ACE inhibitor is considered to be first line treatment for heart failure. The combination of hydralazine and isosorbide dinitrate is recommended as an alternative in patients who cannot tolerate first line agents. In addition, hydralazine and isosorbide dinitrate in combination should be considered as additional therapy for black patients [Can J Cardiol 2006;22(1):23-45]. Warnings and PrecautionsHydralazine is associated with the development of antinuclear antibodies (ANA) and a potentially fatal SLE-like syndrome that manifests most often as fever, arthralgia, asthenia, myalgia, malaise, lymphadenopathy, splenomegaly, pleuritic chest pain and edema. Development of ANA does not necessarily predict the onset of the SLE-like syndrome, as approximately 30–60% of patients develop a positive ANA titre after 3 years of therapy with hydralazine. The SLE-like syndrome has been estimated to occur in 7-13% of patients taking hydralazine [Ann N Y Acad Sci 2007;1108:166-182]. It is thought to be a type of hypersensitivity reaction in which hydralazine-directed antibodies and anti-DNA antibodies arise. The SLE-like syndrome most often develops with the use of doses >200 mg/day although it has been reported with lower doses. The onset usually is 1 month to 5 years after the start of therapy with hydralazine and usually manifests as arthralgia and arthritis (95% of patients), fever and myalgia (50%) and as pleuropulmonary symptoms (30% of patients; pleurisy, pleural effusions, pulmonary infiltrates). The clinical syndrome usually resolves after withdrawal of hydralazine. Hydralazine readily crosses the placenta, and serum concentrations in the fetus are similar to maternal levels of the drug. Hydralazine has not been associated with any congenital defects and the drug is used to manage hypertension during pregnancy. The American Academy of Pediatrics considers hydralazine to be compatible with breast-feeding. The manufacturer recommends that prescribers obtain a complete blood count, ANA titre, lupus erythematosus cell preparation and urinalysis at baseline and after 6 months of treatment, and if arthralgia, fever, chest pain or malaise occur during treatment with hydralazine.
Storage and StabilityDry powder ampoules should be stored at room temperature (15 to 30°C). Tablets should be protected from heat and humidity, below 30°C. Action and Clinical PharmacologyHydralazine is widely distributed in body tissues. Approximately 85% of the drug in circulation is bound to plasma proteins. Hydralazine crosses the placenta and is excreted in breast milk. Hydralazine is rapidly absorbed from the gastrointestinal tract after oral administration. Peak plasma concentrations were achieved 2 hours after oral administration of a single 100 mg dose of 14C-hydralazine in healthy adults. There are large interindividual differences in plasma concentrations, but plasma concentrations are generally fairly constant in individuals receiving a fixed dose. Acetylator phenotype is an important determinant of plasma concentrations. Higher concentrations occur in slow acetylators. Administration with food may increase oral absorption. Hydralazine has a direct vasodilatory effect that leads to a reduction in peripheral vascular resistance. The effect is greater in arterioles than in veins, results in a greater reduction in diastolic than systolic blood pressure and produces little orthostatic hypotension. The decrease in peripheral resistance is usually accompanied by reflex tachycardia with an accompanying increase in cardiac output and stroke volume. Sodium and water retention with an expansion of plasma volume occur and may be counteracted by administration of a diuretic. The major portion of a dose is rapidly eliminated in urine as inactive metabolites. Approximately 10% of an orally administered dose is excreted in feces. It is not known if the drug is dialyzable. The serum elimination half-life is about 2 to 4 hours, but may range up to 8 hours. The plasma elimination half-life is the same in slow and fast acetylators. Hydralazine is metabolized in the gastrointestinal mucosa and the liver (including extensive first-pass metabolism). Metabolism occurs by acetylation, hydroxylation and conjugation with glucuronic acid. Four pharmacologically inactive metabolites have been identified. The extent of first-pass acetylation in the gastric mucosa and liver is affected by acetylator phenotype. Slow acetylation is an autosomal recessive trait and is attributable to a relative deficiency in N-acetyl transferase. Approximately 50% of black and white patients and the majority of East Asian and North American Aboriginal patients are fast acetylators.
ContraindicationsHypersensitivity to hydralazine or to any ingredient in the formulation or component of the container.
Acute dissecting aortic aneurysm
Cor pulmonale
Mitral valve rheumatic heart disease
Myocardial insufficiency due to mechanical obstruction (e.g., aortic or mitral stenosis or constrictive pericarditis)
Severe tachycardia and heart failure with high cardiac output (i.e., thyrotoxicosis)
Systemic lupus erythematosus (SLE) OverdoseFor management of a suspected drug overdose, CPhA recommends that you contact your regional Poison Control Centre. See the eCPS Directories section for a list of Poison Control Centres.
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