Dihydralazine

Usage

Dihydralazine, commonly referred to as hydralazine, is primarily prescribed for the treatment of moderate to severe essential hypertension (high blood pressure), either alone or in combination with other antihypertensive medications. It is also used to manage hypertensive crisis (extremely high blood pressure) and heart failure. Its pharmacological classification is a direct-acting vasodilator. It works by directly relaxing the smooth muscles in the walls of arterioles (small arteries), leading to a decrease in peripheral vascular resistance and lowering of blood pressure.

Alternate Names

While “dihydralazine” might be encountered, the standard generic name is hydralazine. It is marketed under various brand names, including Apresoline.

How It Works

Pharmacodynamics: Hydralazine’s primary action is the direct relaxation of arterial smooth muscle, predominantly in arterioles. This leads to vasodilation, reducing peripheral vascular resistance, and ultimately decreasing blood pressure. It also increases renal and cerebral blood flow.

Pharmacokinetics: Hydralazine is well-absorbed orally, with a bioavailability of 30-50% influenced by individual acetylator status. It undergoes extensive hepatic metabolism via acetylation, with “fast acetylators” showing lower plasma concentrations and shorter half-lives compared to “slow acetylators”. Hydralazine and its metabolites are primarily excreted via the kidneys.

Mode of Action: Hydralazine’s precise mechanism at the cellular level isn’t fully elucidated, but it involves interference with calcium influx into vascular smooth muscle cells, ultimately reducing their ability to contract. It is thought to activate nitric oxide formation, leading to vasodilation. It doesn’t directly bind to adrenergic receptors. The elimination is primarily renal, with a minor hepatic component. The involvement of specific CYP enzymes in its metabolism requires further clarification, though some sources suggest CYP2E1 may play a role.

Dosage

Standard Dosage

Adults:

Oral: Initial dose is typically 10 mg four times daily for 2-4 days, then increased to 25 mg four times daily. The dose can be further titrated up to 50 mg four times a day, with a maximum of 200mg/day.

Children:

Oral: A starting dose of 0.75 mg/kg/day divided into four doses is recommended. The dose may be gradually increased over several weeks, not exceeding 7.5 mg/kg/day or a maximum of 200 mg/day.

Special Cases:

• Elderly Patients: Start with a lower dose and titrate cautiously due to potential age-related decline in renal function.
• Patients with Renal Impairment: Dose adjustments are necessary based on creatinine clearance.
• Patients with Hepatic Dysfunction: Start with a lower dose due to the drug’s extensive hepatic metabolism.
• Patients with Comorbid Conditions: Careful monitoring is essential, especially for those with heart failure or coronary artery disease.

Clinical Use Cases

• Intubation: Hydralazine is not typically used during intubation.
• Surgical Procedures: Not routinely used during surgery.
• Mechanical Ventilation: Not indicated for this purpose.
• Intensive Care Unit (ICU) Use: May be used for severe hypertension management, particularly in a hypertensive crisis. Parenteral administration is often preferred in such scenarios.
• Emergency Situations (e.g., hypertensive crisis): Intravenous administration, with initial doses ranging from 5-20 mg, repeated as needed.

Dosage Adjustments

Dose reductions are required for renal impairment, and possibly hepatic impairment. Adjustments may be necessary for patients with slow acetylator status.

Side Effects

Common Side Effects

Headache, dizziness, nausea, vomiting, diarrhea, palpitations, tachycardia, and flushing.

Rare but Serious Side Effects

Drug-induced lupus erythematosus, hypotension, myocardial ischemia, peripheral neuropathy, and blood dyscrasias.

Long-Term Effects

Drug-induced lupus and peripheral neuropathy.

Adverse Drug Reactions (ADR)

Hypotension, lupus-like syndrome, and severe allergic reactions.

Contraindications

Hypersensitivity to hydralazine, coronary artery disease, mitral valvular rheumatic heart disease, and dissecting aortic aneurysm.

Drug Interactions

Hydralazine interacts with other antihypertensives (additive hypotensive effect), nonsteroidal anti-inflammatory drugs (NSAIDs) (reduced antihypertensive effect), and monoamine oxidase inhibitors (MAOIs) (risk of severe hypotension). It also interacts with beta-blockers, diuretics, nitrates, and other cardiovascular drugs.

Pregnancy and Breastfeeding

Pregnancy Category C: Use with caution. Hydralazine crosses the placenta and can cause fetal distress. It is excreted in breast milk, and while not contraindicated, infants should be monitored for side effects like drowsiness and hypotension.

Drug Profile Summary

• Mechanism of Action: Direct-acting vasodilator, relaxing arterial smooth muscle.
• Side Effects: Headache, dizziness, nausea, palpitations, lupus-like syndrome, hypotension.
• Contraindications: Coronary artery disease, mitral valve rheumatic heart disease, dissecting aortic aneurysm.
• Drug Interactions: Other antihypertensives, NSAIDs, MAOIs.
• Pregnancy & Breastfeeding: Category C, use with caution; excreted in breast milk.
• Dosage: Adults: Starting 10 mg four times daily, titrated up to 200 mg/day; Children: 0.75 mg/kg/day divided into four doses, titrated up to 7.5mg/kg/day or 200 mg/day
• Monitoring Parameters: Blood pressure, heart rate, renal function, signs of lupus-like syndrome.

Popular Combinations

Hydralazine is often combined with nitrates (like isosorbide dinitrate) in heart failure, especially in self-identified Black patients. It’s also commonly used with beta-blockers and diuretics for hypertension management.

Precautions

• General Precautions: Monitor blood pressure, heart rate, and renal function closely.
• Specific Populations:
  • Pregnant Women: Use with caution, monitor fetal well-being.
  • Breastfeeding Mothers: Monitor infant for adverse effects.
  • Children & Elderly: Careful dose titration is required.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for hydralazine?

A: Adults: 10mg four times a day initially, titratable up to 200mg/day. Children: 0.75 mg/kg/day in four divided doses, titratable to a maximum of 7.5mg/kg/day or 200 mg/day.

Q2: How does hydralazine differ from other antihypertensives?

A: It is a direct-acting vasodilator, unlike many other antihypertensives that work through different mechanisms (e.g., beta-blockers, ACE inhibitors).

Q3: What are the serious side effects to watch out for?

A: Drug-induced lupus erythematosus, severe hypotension, and myocardial ischemia.

Q4: Can hydralazine be used during pregnancy?

A: It’s a Pregnancy Category C drug, meaning use with caution if benefits outweigh risks. Fetal heart rate monitoring is crucial.

Q5: How should hydralazine be administered?

A: It can be administered orally or intravenously/intramuscularly depending on the situation.

Q6: What if a patient misses a dose?

A: Take the missed dose as soon as remembered unless it is almost time for the next dose. Do not double the dose.

Q7: Does food affect hydralazine absorption?

A: It can be taken with or without food, though some sources suggest taking it with food may reduce gastrointestinal upset.

Q8: What are the signs of hydralazine overdose?

A: Severe hypotension, reflex tachycardia, headache, dizziness, and potentially cardiac arrhythmias.

Q9: How should hydralazine be discontinued?

A: Gradual tapering is recommended to avoid rebound hypertension.

Q10: What is the role of acetylator status in hydralazine therapy?

A: Patients categorized as “slow acetylators” metabolize the drug slower, leading to higher plasma levels and potentially increased risk of side effects. Lower doses may be needed in this population.