Hydralazine

Hydralazine is a Vasodilator.

Hydralazine is an antihypertensive agent used to manage essential hypertension or severe hypertension associated with conditions requiring immediate action, heart failure, and pre-eclampsia or eclampsia.

Taking oral hydralazine with food improves the bioavailability of the drug. The volume of distribution is 1.34±0.79L/kg in congestive heart failure patients and 1.98±0.22L/kg in hypertensive patients. Acetylation is a minor metabolic pathway for hydralazine; the major pathway is hydroxylation, followed by glucuronidation.

The common side effects are Headache, pounding/fast heartbeat, loss of appetite, nausea, vomiting, diarrhea, or dizziness may occur.

Hydralazine is available in the form of dosage form such as tablets and injection solution.

Hydralazine is available in China, Germany, India, Japan, U.S

Hydralazine may interfere with calcium transport in vascular smooth muscle by an unknown mechanism to relax arteriolar smooth muscle and lower blood pressure. The interference with calcium transport may be by preventing the influx of calcium into cells, preventing calcium release from intracellular compartments, directly acting on actin and myosin, or a combination of these actions. This decrease in vascular resistance leads to increased heart rate, stroke volume, and cardiac output.

Hydralazine also competes with procollagen prolyl hydroxylase (cph) for free iron. This competition inhibits cph-mediated hydroxylation of hif-1α, preventing the degradation of his-1α. Induction of hif-1α and VEGF promote proliferation of endothelial cells and angiogenesis.

Hydralazine interferes with calcium transport to relax arteriolar smooth muscle and lower blood pressure. Hydralazine has a short duration of action of 2-6h.This drug has a wide therapeutic window, as patients can tolerate doses of up to 300mg

The Tmax was 208.4 ± 56.9 SD ng/ml and 2.8 ± 2.5 h, respectively

Hydralazine is available in the form of tablets and injection solution.

Hydralazine is indicated alone or adjunct to standard therapy to treat essential hypertension. A combination product with isosorbide dinitrate is indicated as an adjunct therapy in the treatment of heart failure.

Hydralazine is an antihypertensive agent used for the management of essential hypertension or severe hypertension associated with conditions requiring immediate action, heart failure, and pre-eclampsia or eclampsia.

Hydralazine is a hydrazine derivative vasodilator used alone or as adjunct therapy in the treatment of hypertension and only as adjunct therapy in the treatment of heart failure. Hydralazine is no longer a first line therapy for these indications since the development of newer antihypertensive medications

Hydralazine is approved for use in the following clinical indications

• Severe Essential Hypertension

10 mg taken orally for every 6 hour for 2-4 days; 25 mg q6hr daily for the first week; increase to 50 mg q6hr from second week on; adjust dose to lowest effective levels

20-40 mg IM/IV; repeat as necessary

Dosing considerations

Change to oral therapy as soon as possible

Hypertension (Chronic)

Initial: 10 mg taken orally for every 6 hour for 2-4 days; may increase gradually by 10-25 mg/dose every 2-5 days up to 50 mg taken orally for every 6hr (some patients require 300 mg/day)

• Hypertensive Crisis

10-40 mg IV/IM; not to exceed 20 mg/dose; repeat PRN

Pregnancy-associated

5-10 mg IV/IM initially, THEN 5-10 mg q20-30min PRN, OR

0.5-10 mg/hr IV infusion

• Congestive Heart Failure

Initial dose: 10-25 mg taken orally for every 6-8hr; titrate dose q2-4weeks

Maintenance dose: 225-300 mg/day taken orally divided for every 6-8 hour.

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

Hydralazine is available in various dosage strengths of 10mg, 25mg, 50mg, 100mg, 20 mg/ml.

Hydralazine is available in the form tablets amd injection solution

Hydralazine is an antihypertensive agent used for the management of essential hypertension or severe hypertension associated with conditions requiring immediate action, heart failure, and pre-eclampsia or eclampsia.

Hypertension: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

The dietary restriction should be individualized as per the patient requirements.

Hydralazine may be contraindicated in the following

• Coronary artery disease
• Stroke
• Low blood pressure
• Condition with symptoms that resemble lupus
• High pressure within the skull
• Decreased blood volume
• Slow acetylator

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

Warnings

In a few patients hydralazine may produce a clinical picture simulating systemic lupus erythematosus including glomerulonephritis. In such patients hydralazine should be discontinued unless the benefit-to-risk determination requires continued antihypertensive therapy with this drug. Symptoms and signs usually regress when the drug is discontinued but residua have been detected many years later. Long-term treatment with steroids may be necessary.

Precautions

General

Myocardial stimulation produced by hydralazine can cause anginal attacks and ECG changes of myocardial ischemia. The drug has been implicated in the production of myocardial infarction. It must, therefore, be used with caution in patients with suspected coronary artery disease.

The “hyperdynamic" circulation caused by hydralazine may accentuate specific cardiovascular inadequacies. For example, hydralazine may increase pulmonary artery pressure in patients with mitral valvular disease. The drug may reduce the pressor responses to epinephrine. Postural hypotension may result from hydralazine but is less common than with ganglionic blocking agents. It should be used with caution in patients with cerebral vascular accidents.

In hypertensive patients with normal kidneys who are treated with hydralazine , there is evidence of increased renal blood flow and a maintenance of glomerular filtration rate. In some instances where control values were below normal, improved renal function has been noted after administration of hydralazine. However, as with any antihypertensive agent, hydralazine should be used with caution in patients with advanced renal damage.

Peripheral neuritis, evidenced by paresthesia, numbness, and tingling, has been observed. Published evidence suggests an antipyridoxine effect, and that pyridoxine should be added to the regimen if symptoms develop. The hydralazine (100 mg) contain FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who are also hypersensitive to aspirin.

• Information for Patients

Patients should be informed of possible side effects and advised to take the medication regularly and continuously as directed.

• Laboratory Tests

Complete blood counts and antinuclear antibody titer determinations are indicated before and periodically during prolonged therapy with hydralazine even though the patient is asymptomatic. These studies are also indicated if the patient develops arthralgia, fever, chest pain, continued malaise, or other unexplained signs or symptoms.

Consumption of alcohol is not recommended while receiving this medicine as it may increase the risk of adverse effects and lowers the blood pressure.

Hydralazine use in breastfeeding patients is not recommended.

Pregnancy Category C

Animal studies indicate that hydralazine is teratogenic in mice at 20 to 30 times the maximum daily human dose of 200 to 300 mg and possibly in rabbits at 10 to 15 times the maximum daily human dose, but that it is nonteratogenic in rats. Teratogenic effects observed were cleft palate and malformations of facial and cranial bones.

There are no adequate and well-controlled studies in pregnant women. Although clinical experience does not include any positive evidence of adverse effects on the human fetus, hydralazine should be used during pregnancy only if the expected benefit justifies the potential risk to the fetus

Limit caffeine intake (examples: coffee, teas, colas, chocolate and some herbal supplements) while taking Hydralazine. Also avoid medicines containing additional Caffeine whenever possible.

The adverse reactions related to molecule Hydralazine can be categorized as

• Common Adverse effects:

Hemodynamic compromise, Dizziness, peripheral ischemia, dry mouth,asthenia, and somnolence.

• Less Common adverse effects:

Asymptomatic and symptomatic hypotension, burning, crawling, itching, numbness.

• Rare adverse effects:

Bradycardia, decompensated heart failure, cardiac arrest, and heart block.

The clinically relevant drug interactions of Hydralazine is briefly summarized here.

• Taking MAO inhibitors with this medication may cause a serious (possibly fatal) drug interaction.
• Avoid taking MAO inhibitors (isocarboxazid, linezolid, metaxalone, methylene blue, moclobemide, phenelzine, procarbazine, rasagiline, safinamide, selegiline, tranylcypromine) during treatment with this medication.
• Concomitant use with adrenergic blocking agents (e.g., phentolamine), phenothiazine drugs (e.g., chlorpromazine) and amiodarone may cause antagonistic effects.
• May potentiate pressor effects of oxytocic drugs and CV depressant effects of inhalational anaesthetics (e.g. cyclopropane, halothane).
• May increase risk of arrhythmias with cardiac glycosides and quinidine. May enhance the effects of anticholinergic drugs (e.g., TCAs).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Symptoms:

Pronounced hypotension and tachycardia, headache, flushing, myocardial ischaemia, cardiac arrhythmias, shock, coma.

Management:

Symptomatic and supportive treatment. Perform gastric lavage or give emetic treatment in conscious patients as soon as possible. Administer IV fluids or plasma expander as needed. May administer angiotensin or norepinephrine IV to raise blood pressure with caution, avoiding precipitation or aggravation of cardiac arrhythmia or tachycardia.

Pharmacodynamics:

● Hydralazine interferes with calcium transport to relax arteriolar smooth muscle and lower blood pressure.

● Hydralazine has a short duration of action of 2-6h. This drug has a wide therapeutic window, as patients can tolerate doses of up to 300mg. Patients should be cautioned regarding the risk of developing systemic lupus erythematosus syndrome

Pharmacokinetics:

• Absorption:

Taking oral hydralazine with food improves the bioavailability of the drug.

The Cmax of oral hydralazine is 0.12-1.31µM depending on the acetylator status of patients

• Distribution:

The volume of distribution is 1.34±0.79L/kg in congestive heart failure patients and 1.98±0.22L/kg in hypertensive patients

• Metabolism:

Acetylation is a minor metabolic pathway for hydralazine; the major pathway is hydroxylation followed by glucuronidation. There are identified metabolic pathways for hydralazine.

Hydralazine can be metabolized to phthalazine or α-ketoglutarate hydrazone. These metabolites can be further converted to phthalazinone or hydralazine can be metabolized directly to phthalazinone.

Hydralazine can undergo a reversible converstion to the active hydralazine acetone hydrazone

• Excretion:

The majority of hydralazine clearance is extrahepatic- 55% for rapid acetylators and 70% for slow acetylators

<10% of hydralazine is recovered in the feces; 65-90% is recovered in the urine

1. https://www.webmd.com/drugs/2/drug-8941/hydralazine-injection/details/list-contraindications
2. https://go.drugbank.com/drugs/DB01275
3. https://www.accessdata.fda.gov/drugsatfda_docs/anda/97/040136_hydralazine_toc.cfm