What are the advantages and disadvantages of administering hydralazine (antihypertensive medication) once daily?

From the Guidelines

Hydralazine is not recommended for once-daily dosing due to its short half-life, which necessitates multiple daily doses for effective blood pressure control. The main disadvantage of once-daily hydralazine is inadequate 24-hour blood pressure coverage, leading to periods of uncontrolled hypertension and potential blood pressure fluctuations, as seen in the 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 1. This can increase cardiovascular risk and reduce the medication's effectiveness. Additionally, attempting to use a larger single daily dose may increase side effects like headache, dizziness, reflex tachycardia, and fluid retention without providing consistent blood pressure control.

The standard dosing for hydralazine is typically 25-100 mg taken two to four times daily, with a maximum daily dose of 300 mg, as recommended in the seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure 1. For patients who strongly prefer once-daily dosing, alternative antihypertensive medications with longer half-lives such as amlodipine, chlorthalidone, or olmesartan would be more appropriate choices. The only potential benefit of once-daily hydralazine might be improved medication adherence for some patients, but this advantage is outweighed by the pharmacokinetic limitations and reduced efficacy.

Some key points to consider when prescribing hydralazine include:

• Hydralazine is associated with sodium and water retention and reflex tachycardia, and should be used with a diuretic and beta blocker, as noted in the 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline 1.
• Hydralazine is associated with drug-induced lupus-like syndrome at higher doses, as seen in the same guideline 1.
• The fixed-dose combination of hydralazine and isosorbide dinitrate can be initiated at a dose of 1 tablet containing 37.5 mg of hydralazine hydrochloride and 20 mg of isosorbide dinitrate 3 times daily, and increased to 2 tablets 3 times daily for a total daily dose of 225 mg of hydralazine hydrochloride and 120 mg of isosorbide dinitrate, as recommended in the 2013 ACCF/AHA guideline for the management of heart failure 1.

Overall, the risks and limitations of once-daily hydralazine dosing outweigh any potential benefits, and alternative medications with longer half-lives should be considered for patients who require once-daily dosing.

From the FDA Drug Label

DOSAGE AND ADMINISTRATION Initiate therapy in gradually increasing dosages; adjust according to individual response. Start with 10 mg four times daily for the first 2 to 4 days, increase to 25 mg four times daily for the balance of the first week. For the second and subsequent weeks, increase dosage to 50 mg four times daily. The pros of hydralazine once daily are not mentioned in the label, and the cons include a higher incidence of toxic reactions, particularly the L. E. cell syndrome, with large doses.

• The label does not support once daily dosing.
• The recommended dosing is four times daily. 2

From the Research

Hydralazine Once Daily Pros

• Hydralazine once daily has been shown to maintain blood pressure control in well-controlled hypertension 3
• A significant blood pressure reduction was achieved in 72% of patients with inadequately controlled hypertension 3
• Normotension was reached in 53% of patients 3
• Slow-release hydralazine administered once daily maintained blood pressure control with no discrepancy between once- and twice-daily administration 4

Hydralazine Once Daily Cons

• Sixteen patients discontinued treatment due to symptoms probably related to hydralazine 3
• Acetylator phenotyping showed that slow acetylators predominated in the group of patients discontinuing hydralazine due to side-effects 3
• Larger single doses of hydralazine may be required with slow-release hydralazine, which could potentially increase the risk of side effects 4
• Hydralazine may induce a systemic lupus-like erythematosus syndrome, although this is not as common as with other vasodilators 5

Comparison with Other Treatments

• Cadralazine has been shown to have a similar blood pressure lowering effect to hydralazine in patients not controlled by beta-blocker and/or diuretic 5
• Hydralazine is often used in combination with beta-adrenergic blockers and diuretics as a step III drug in the treatment of hypertension 6
• Other vasodilators, such as minoxidil and captopril, are typically reserved for hypertensive patients whose blood pressure is not controlled by standard antihypertensive drugs 6