Hydralazine targets vascular smooth muscle cells, where it causes vasodilation by relaxing the arterial smooth muscle. The exact mechanism of action is not fully understood, but it is believed to involve the inhibition of inositol trisphosphate (IP3)-mediated calcium release from the sarcoplasmic reticulum in smooth muscle cells, leading to reduced intracellular calcium and muscle relaxation. It may also activate guanylate cyclase, increasing cGMP levels, which contributes to vasodilation. The compound primarily affects arterioles rather than veins, reducing afterload and lowering blood pressure. It may also have antioxidant and anti-inflammatory effects.

In vitro, hydralazine causes relaxation of isolated arterial smooth muscle preparations. In vascular smooth muscle cells, it inhibits calcium release from intracellular stores and reduces contractile responses to vasoconstrictors such as angiotensin II and norepinephrine. It activates guanylate cyclase in some cell types, increasing cGMP levels. It shows antioxidant activity by scavenging reactive oxygen species and may inhibit the formation of advanced glycation end-products (AGEs). It has been shown to inhibit the proliferation of vascular smooth muscle cells, which may contribute to its beneficial effects in preventing vascular remodeling.

In vivo, hydralazine is an effective antihypertensive agent that lowers blood pressure by reducing peripheral vascular resistance. Following oral or intravenous administration, it causes rapid and sustained vasodilation, leading to decreased systolic and diastolic blood pressure. It also increases cardiac output and heart rate due to reflex sympathetic activation. It is used for the management of essential hypertension, hypertensive emergencies, and as an adjunct in heart failure treatment. In patients with heart failure, it is often used in combination with isosorbide dinitrate to reduce mortality. Its effects are dose-dependent and reversible upon discontinuation.

In vitro enzyme assays for hydralazine focus on its antioxidant properties and effects on vascular enzymes. For antioxidant activity, DPPH radical scavenging, ABTS, or FRAP assays are used. For effects on guanylate cyclase, the enzyme is incubated with hydralazine in assay buffer (50 mM Tris-HCl, pH 7.4, 1 mM DTT, 1 mM MgCl₂) with GTP as substrate, and cGMP production is measured by ELISA. For effects on calcium signaling, calcium mobilization assays using fluorescent indicators (Fura-2) are performed in vascular smooth muscle cells. For inhibition of AGE formation, the compound is incubated with glucose and protein, and AGE formation is measured by fluorescence.

In vitro cell-based assays for hydralazine use vascular smooth muscle cells (e.g., A7r5 rat aortic smooth muscle cells or human coronary artery smooth muscle cells). Cells are cultured in appropriate media (DMEM with 10% FBS, 37°C, 5% CO₂) and treated with hydralazine at various concentrations (0.1-1000 μM) for 1-48 hours. Cell proliferation is measured by MTT or [³H]-thymidine incorporation assays. Calcium mobilization is assessed using Fluo-4 or Fura-2 following stimulation with vasoconstrictors. cGMP levels are measured by ELISA. Reactive oxygen species production is assessed using DCFH-DA. Apoptosis is evaluated by caspase-3/7 activation. Cytotoxicity is determined by LDH release assays. Anti-inflammatory effects are assessed by measuring cytokine production.

In vivo animal studies for hydralazine are conducted in hypertensive animal models. Spontaneously hypertensive rats (SHR) are administered hydralazine orally or intraperitoneally at doses of 5-50 mg/kg. Blood pressure is monitored by tail-cuff plethysmography or telemetry before and after administration. Heart rate is also measured to assess reflex tachycardia. For pharmacokinetic studies, blood samples are collected at multiple time points for drug concentration analysis. In heart failure models (e.g., after myocardial infarction), hydralazine is administered alone or in combination with isosorbide dinitrate, and survival, cardiac function, and hemodynamic parameters are assessed. Vascular reactivity studies are performed using isolated aortic rings.

Absorption, Distribution and Excretion
Oral administration of hydralazine with food improves its bioavailability. After intravenous injection of 0.3 mg/kg, the AUC is 17.5-29.4 µMmin; after oral administration of 1 mg/kg, the AUC is 4.0-30.4 µMmin. The Cmax of oral hydralazine is 0.12-1.31 µM, depending on the patient's acetylation status. 10% of hydralazine is excreted in feces; 65-90% is excreted in urine. The volume of distribution is 1.34 ± 0.79 L/kg in patients with congestive heart failure and 1.98 ± 0.22 L/kg in patients with hypertension. The clearance of hydralazine primarily occurs extrahepatically—55% in patients with rapid acetylation and 70% in patients with slow acetylation. The mean clearance rate in patients with congestive heart failure was 1.77 ± 0.48 L/kg/h, while the mean clearance rate in hypertensive patients was 42.7 ± 8.9 mL/min/kg. Metabolism/Metabolites Acetylation is a minor metabolic pathway for hydralazine; the major metabolic pathway is hydroxylation, followed by glucuronidation. Five metabolic pathways for hydralazine have been identified. Hydralazine can be metabolized to phthalazine or α-ketoglutarate hydrazone. These metabolites can be further converted to phthalazinones, or hydralazine can be directly metabolized to phthalazinones. Hydralazine can be reversibly converted to the active product hydralazine-acetylasinone. Hydralazine can spontaneously convert to the active product pyruvate hydrazone or its tricyclic dehydration product; these metabolites can interconvert between these two forms. Hydralazine can be converted to hydrazylphthalazinone, which can be further converted to the active product acetylhydrazylphthalazinone. The final metabolic pathway of hydralazine involves conversion to an unnamed hydralazine metabolite, which is further metabolized to 3-methyltriazolamide (MTP). MTP can be metabolized to 9-hydroxymethyltriazolamide or 3-hydroxymethyltriazolamide; the latter can be converted to triazolamide. Known metabolites of hydralazine include the N-acetyl group. The half-life of hydralazine is 2.2–7.8 hours in rapid acetylated individuals and 2.0–5.8 hours in slow acetylated individuals. In patients with heart failure, the half-life of hydralazine is 57–241 minutes, with an average of 105 minutes; in hypertensive patients, the half-life is 200 minutes in rapid acetylated individuals and 297 minutes in slow acetylated individuals. Hydralazine exhibits polymorphic acetylation; slow acetylated individuals typically have higher plasma concentrations of hydralazine, thus requiring lower doses to control blood pressure. However, other factors, such as acetylation, which is a secondary metabolic pathway of hydralazine, can also lead to differences in elimination rates.
Hydralazine is rapidly absorbed after oral administration, with peak plasma concentrations achieved within 1-2 hours. It undergoes extensive first-pass metabolism in the liver, primarily through acetylation (N-acetylation) and hydroxylation. The compound has a plasma half-life of approximately 2-4 hours, but its antihypertensive effect lasts longer due to tissue binding. It is metabolized by N-acetyltransferase, and the rate of acetylation is genetically determined (slow vs. fast acetylators), which affects its pharmacokinetics and clinical response. It is excreted primarily in urine as metabolites. It crosses the placenta and is secreted in breast milk. Dose adjustments may be needed in patients with renal impairment.

Hepatotoxicity
Elevated serum transaminases are uncommon during hydralazine treatment. However, hydralazine has been definitively linked to acute liver injury with jaundice and delayed lupus-like syndrome. Two clinical patterns of liver injury have been described, associated with short latency periods (2 to 6 weeks) or long latency periods (2 months to over a year). Clinically apparent liver injury is usually hepatocellular, but cholestatic patterns have also been reported (Case 1). In short-latency cases, rash, fever, and eosinophilia are common; onset is typically abrupt and severe, but recovery is rapid. In long-latency cases (Case 2), onset is usually more insidious; liver biopsy may resemble chronic hepatitis and show fibrosis, and autoantibodies are often present. Late-stage hepatitis may also be accompanied by lupus-like syndrome induced by hydralazine, especially with high-dose use for 6 months or longer. Recovery may be prolonged. In patients with hepatotoxicity caused by the structure-related antihypertensive drug dihydrozirconium (available in Europe but not in the US), autoantibodies against the P450 system (CYP 1A2) isoenzyme have been identified, and the incidence of hepatotoxicity with dihydrozirconium is higher than with hydralazine.
Probability score: A (Etiology of clinically confirmed liver injury).
Pregnancy and lactation effects
◉ Overview of use during lactation
Limited data on milk and infant serum concentrations, along with a long history of use in postpartum mothers, suggest that hydralazine is an acceptable antihypertensive drug for lactating mothers, including mothers of newborns.
◉ Effects on breastfed infants
No adverse reactions were reported in an 8-week-old breastfed infant.
◉ Effects on lactation and breast milk
No relevant published information found. Found as of the revision date.
Protein binding
hydralazine has a protein binding rate of 87% in serum and may bind to human serum albumin.
Hydralazine is generally well-tolerated but has potential side effects. Common adverse effects include headache, flushing, palpitations, tachycardia, dizziness, and gastrointestinal disturbances (nausea, vomiting, diarrhea). These are often dose-related and may be managed by dose titration and combination with other agents (e.g., beta-blockers). More serious but less common side effects include drug-induced lupus erythematosus (especially in slow acetylators), which is usually reversible upon discontinuation. Other rare side effects include peripheral neuropathy, hepatitis, and blood dyscrasias. Hydralazine is contraindicated in patients with coronary artery disease, rheumatic heart disease, and certain other conditions. Regular monitoring is recommended during therapy.

[1]. Hydralazine inhibits human peritoneal mesothelial cell proliferation and collagen synthesis . Nephrology Dialysis Transplantation, 1996, 11(11): 2276-2281.

[2]. Hydralazine protects the heart against acute ischaemia/reperfusion injury by inhibiting Drp1-mediated mitochondrial fission . Cardiovascular Research, 2022, 118(1): 282-294.

[3]. The antihypertensive drug hydralazine activates the intrinsic pathway of apoptosis and causes DNA damage in leukemic T cells . Oncotarget, 2016, 7(16): 21875.

[4]. Hydralazine plays an immunomodulation role of pro-regeneration in a mouse model of spinal cord injury . Experimental Neurology, 2023, 363: 114367.

[5]. Hydralazine reduces leukocyte migration through different mechanisms in spontaneously hypertensive and normotensive rats . European journal of pharmacology, 2008, 589(1-3): 206-214.

Hydralazine is a 1-hydrazine derivative of phthalazine, a direct-acting vasodilator used as an antihypertensive drug. It is both an antihypertensive and a vasodilator. Hydralazine belongs to the phthalazine, aza-aromatic, ortho-fused aza-aromatic, and hydrazine classes. Initially developed in the 1950s for the treatment of malaria, hydralazine quickly demonstrated antihypertensive effects and was repurposed for treating other diseases. Hydralazine is a hydrazine derivative vasodilator that can be used alone or as adjunctive therapy for hypertension, but only as adjunctive therapy for heart failure. With the advent of newer antihypertensive drugs, hydralazine is no longer a first-line treatment for these diseases. Hydralazine hydrochloride was approved by the U.S. Food and Drug Administration (FDA) on January 15, 1953. Hydralazine is a small artery vasodilator. Its physiological action is achieved by dilating small arteries. Hydralazine is a commonly used oral antihypertensive drug whose mechanism of action is through inducing peripheral vasodilation. Hydralazine is associated with various acute liver injuries and lupus-like syndromes. Hydralazine has been reported in Achillea pseudopectinata, and relevant data are available. Hydralazine is an phthalazine derivative with antihypertensive effects. It exerts its vasodilatory effect by altering the contractile state of arterial smooth muscle, thereby changing intracellular calcium release and interfering with calcium influx into smooth muscle cells. This drug can also inhibit myosin phosphorylation or chelate trace metals required for smooth muscle contraction, thereby increasing heart rate, stroke volume, and cardiac output. It is a direct-acting vasodilator used as an antihypertensive drug. See also: hydralazine hydrochloride (salt form). Drug Indications Hydralazine can be used alone or as adjunctive therapy for the treatment of essential hypertension. Combination formulations with isosorbide dinitrate can be used as adjunctive therapy for the treatment of heart failure. Mechanism of Action Hydralazine may relax arteriole smooth muscle and lower blood pressure by interfering with calcium transport in vascular smooth muscle through an unknown mechanism. Interference with calcium transport may be achieved by preventing calcium inflow into cells, preventing calcium release from cells, acting directly on actin and myosin, or a combination of these actions. The reduction in vascular resistance leads to an increase in heart rate, stroke volume, and cardiac output. Hydralazine also competes with procollagen prolyl hydroxylase (CPH) for free iron. This competition inhibits CPH-mediated HIF-1α hydroxylation, thereby preventing HIF-1α degradation. Induction of HIF-1α and VEGF promotes endothelial cell proliferation and angiogenesis. Pharmacodynamics Hydralazine relaxes arteriole smooth muscle and lowers blood pressure by interfering with calcium ion transport. The duration of action of hydralazine is short, ranging from 2 to 6 hours. It has a wide therapeutic window, and patients can tolerate doses up to 300 mg. Patients should be informed of the risk of developing systemic lupus erythematosus syndrome.
Hydralazine Hydrochloride (CAS# 304-20-1) is a medication used for the treatment of hypertension (high blood pressure). It is a vasodilator that acts directly on arterial smooth muscle to cause relaxation and dilation. It is available as oral tablets and as an injectable formulation for intravenous use. It is approved for clinical use and is available by prescription. It is used for essential hypertension, hypertensive emergencies, and as an adjunct in heart failure treatment. In heart failure, it is often used in combination with isosorbide dinitrate. Regular monitoring of blood pressure and heart rate is recommended during therapy. This product is for human therapeutic use under medical supervision.

C8H8N4.HCL

196.63686

196.051

304-20-1

Hydralazine;86-54-4

3637

White to off-white solid powder

491.9ºC at 760 mmHg

273°C

251.3ºC

1.724

2

4

1

12

150

0

C1=CC=C2C(=C1)C=NN=C2NN.Cl

Hydralazine Hydrochloride; Aiselazine; 1-Hydrazinophthalazine hydrochloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O : ~25 mg/mL (~127.14 mM)
DMSO : ~25 mg/mL (~127.14 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (10.58 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (10.58 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: 8.33 mg/mL (42.36 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication (<60°C).

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 (Please use freshly prepared in vivo formulations for optimal results.)