A Comprehensive Monograph on Hydralazine (DB01275): From Molecular Mechanisms to Clinical Applications

Introduction and Historical Context

Overview

Hydralazine (DrugBank ID: DB01275) is a small molecule, direct-acting peripheral arteriolar vasodilator that has occupied a distinct and evolving position in the cardiovascular pharmacopoeia for over seven decades.[1] Its primary therapeutic applications include the management of essential hypertension, particularly cases refractory to other agents; the treatment of severe hypertension, including hypertensive emergencies and crises associated with pregnancy (pre-eclampsia/eclampsia); and as a crucial component of adjunctive therapy in heart failure with reduced ejection fraction.[1] Despite its long history and proven efficacy in specific contexts, Hydralazine is no longer considered a first-line agent for most of these indications. Its clinical utility is tempered by a challenging side-effect profile, most notably a reflex sympathetic stimulation of the heart, and the development of newer, better-tolerated antihypertensive medications with more convenient dosing regimens.[1]

Discovery and Development

The discovery of Hydralazine is a classic example of serendipity in pharmaceutical research. In the late 1940s, scientists at the Swiss pharmaceutical company Ciba (later Ciba-Geigy, now part of Novartis) were investigating a series of hydrazine-phthalazine derivatives, initially in search of a novel treatment for malaria.[1] During this investigation, one compound, then designated C-5968, demonstrated potent blood pressure-lowering capabilities.[5] Recognizing its potential, Ciba repurposed the compound, filing a patent in 1945 which was issued in 1949.[5] The name "hydralazine" first appeared in the literature between 1950 and 1955.[6]

This pioneering work culminated in the landmark approval of Hydralazine Hydrochloride by the United States Food and Drug Administration (FDA) on January 15, 1953, under the brand name Apresoline®.[1] This approval was a significant milestone in medicine, as Hydralazine became one of the very first effective antihypertensive medications that could be administered orally, offering a transformative new option for managing a condition that was previously difficult to control.[5]

Evolution in Clinical Practice

Hydralazine's journey through clinical practice mirrors the broader evolution of cardiovascular medicine. Initially, as one of the few available oral agents, it enjoyed a prominent role. However, its primary mechanism—potent arteriolar vasodilation—was soon understood to trigger predictable and often problematic compensatory physiological responses. The drop in blood pressure elicits a baroreceptor-mediated reflex sympathetic stimulation, leading to tachycardia and increased cardiac output, and a separate neurohormonal response that increases plasma renin concentration, resulting in sodium and fluid retention.[3] To mitigate these effects, clinical practice evolved to co-administer Hydralazine with a beta-blocker to control heart rate and a diuretic to manage fluid retention, a strategy that remains relevant today.[3]

The advent of newer, more targeted antihypertensive drug classes—including beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium channel blockers—with more favorable side-effect profiles and simpler once-daily dosing, gradually displaced Hydralazine from its first-line position.[1] Its use became increasingly specialized, reserved for cases of resistant hypertension or specific clinical scenarios. A pivotal moment in its modern history came with the demonstration of its efficacy in combination with isosorbide dinitrate for treating heart failure, particularly in self-identified Black patients, leading to a specific, guideline-supported niche for the drug.[5]

This trajectory from a broadly applied first-in-class drug to a highly specialized niche therapy exemplifies a common lifecycle in pharmaceuticals. It is not a story of obsolescence, but of refinement, where decades of clinical experience and targeted research precisely define a drug's optimal place in the therapeutic armamentarium. Furthermore, the long-observed clinical variability in patient response and toxicity, particularly the risk of a drug-induced lupus syndrome, was eventually linked to a patient's genetic makeup. This makes Hydralazine a pioneering, albeit unintentional, case study in pharmacogenomics. The clinical challenges associated with its use in the mid-20th century were, in fact, an early, real-world demonstration of how a single gene polymorphism—in this case, affecting the N-acetyltransferase 2 (NAT2) enzyme—can dramatically alter a drug's risk-benefit profile, foreshadowing the modern era of personalized medicine.[8] Its continued importance is underscored by its inclusion on the World Health Organization's List of Essential Medicines and its significant prescription volume, with over 6 million prescriptions in the United States in 2023.[5]

Physicochemical Properties and Formulations

Chemical Identification and Structure

Hydralazine is a hydrazine derivative of phthalazine.[2] It is a small molecule with a well-defined chemical identity, crucial for its synthesis, formulation, and biological activity.

• Generic Name: Hydralazine [1]
• DrugBank ID: DB01275 [1]
• CAS Number: 86-54-4 [2]
• Chemical Formula: C8​H8​N4​ [2]
• Molecular Weight: Average: 160.1759 g/mol; Monoisotopic: 160.074896276 g/mol [1]
• IUPAC Name: phthalazin-1-ylhydrazine [2]
• Synonyms: 1-Hydrazinophthalazine, (1Z)-1(2H)-Phthalazinone hydrazone, Apresolin, Apressin, Hypophthalin, Hidralazina, Idralazina, and others.[1]

The molecule's structure consists of a phthalazine bicyclic ring system attached to a hydrazine group (−NHNH2​) at the 1-position. This reactive hydrazine moiety is central to both its metabolism and some of its toxicological properties.

Physical Characteristics

The physical properties of Hydralazine and its commonly used hydrochloride salt influence its formulation, stability, and biopharmaceutical behavior.

• Appearance: The base form of Hydralazine is a yellow crystalline solid or powder.[14] The hydrochloride salt (CAS: 304-20-1), which is more commonly used in pharmaceutical preparations, is described as white or yellow, odorless, crystalline powder.[16]
• Melting Point: The base melts at 172–173°C.[14] The hydrochloride salt has a much higher melting point of 273°C, at which it decomposes.[14]
• Solubility: Hydralazine exhibits poor water solubility, with a reported value of 4.8 mg/L at 22.5°C.[14] This property necessitates its formulation as a salt to improve solubility for parenteral administration.
• Biopharmaceutical Classification System (BCS): Hydralazine is classified as a BCS Class III drug, characterized by high solubility and low permeability.[14] This classification has profound implications for its pharmacokinetics. The high solubility ensures it readily dissolves in the gastrointestinal tract, but its low permeability means it is absorbed slowly across the intestinal wall. This slow absorption process increases its exposure time to metabolizing enzymes in the gut and liver, leading to a significant first-pass effect and providing the biopharmaceutical basis for the large inter-individual variability observed in its bioavailability.[18]

Commercial Formulations and Brand Names

Hydralazine is available in various forms to suit different clinical needs, both as a single agent and, more commonly, in combination products designed to optimize its therapeutic effect and mitigate its side effects.

• Dosage Forms: It is commercially available as oral tablets in strengths of 10 mg, 25 mg, 50 mg, and 100 mg; as an oral solution for patients who cannot swallow tablets; and as a parenteral solution (20 mg/mL) for intravenous (IV) or intramuscular (IM) injection in urgent clinical settings.[4]
• Single-Agent Brand Names: The most recognized brand name for single-agent Hydralazine is Apresoline®.[1] Other brand names include Dralzine®.[14]
• Combination Products: The formulation of Hydralazine in combination products is not merely a matter of convenience but a direct reflection of clinical strategy. Its primary vasodilatory action triggers predictable compensatory responses that can undermine its efficacy and tolerability. The combination products are specifically designed to counteract these effects.
• With Isosorbide Dinitrate: Marketed as BiDil®, this fixed-dose combination (37.5 mg hydralazine / 20 mg isosorbide dinitrate) is indicated for heart failure, particularly in Black patients. It provides balanced vasodilation, with Hydralazine reducing arterial afterload and the nitrate reducing venous preload.[1]
• With Hydrochlorothiazide: Marketed under brand names such as Hydra-Zide® and Apresazide®, this combination pairs Hydralazine with a thiazide diuretic. The diuretic counteracts the sodium and water retention that is a common consequence of Hydralazine-induced vasodilation.[25]
• With Hydrochlorothiazide and Reserpine: Marketed as Ser-Ap-Es® and Serpazide®, this triple combination adds reserpine, an agent that depletes catecholamines, to blunt the reflex tachycardia caused by Hydralazine, while hydrochlorothiazide manages fluid retention.[25]

Table 1: Physicochemical and Identification Data for Hydralazine
Identifier/Property	Value
Generic Name	Hydralazine 1
DrugBank ID	DB01275 1
CAS Number	86-54-4 2
IUPAC Name	phthalazin-1-ylhydrazine 2
Molecular Formula	C8​H8​N4​ 2
Average Molecular Weight	160.1759 g/mol 1
Appearance	Yellow solid/powder 14
Melting Point	172–173°C 14
Water Solubility	4.8 mg/L (at 22.5°C) 14
BCS Class	Class III (High Solubility, Low Permeability) 14

Comprehensive Pharmacological Profile

Pharmacodynamics (Mechanism of Action)

The pharmacological actions of Hydralazine are complex, encompassing a well-established primary mechanism responsible for its hemodynamic effects and more recently elucidated secondary pathways that suggest broader biological activity.

Primary Vasodilatory Mechanism

Hydralazine's principal therapeutic effect is achieved through direct relaxation of vascular smooth muscle, with a pronounced selectivity for resistance arterioles compared to veins.[1] This arteriolar specificity is responsible for the significant decrease in peripheral vascular resistance and afterload. While the precise molecular mechanism has been the subject of investigation for decades, it is widely accepted to involve the disruption of intracellular calcium (

Ca2+) homeostasis within smooth muscle cells.[1] Current theory posits that Hydralazine inhibits the inositol trisphosphate (

IP3​)-induced release of Ca2+ from the sarcoplasmic reticulum, the cell's primary intracellular calcium store.[3] It may also inhibit the phosphorylation of myosin, a critical step in the actin-myosin cross-bridging that generates contractile force.[3] By preventing the rise in intracellular free

Ca2+ required for contraction, Hydralazine effectively uncouples cellular stimulation from the mechanical response, leading to vasodilation.

Novel and Secondary Mechanisms

Beyond its direct action on calcium signaling, Hydralazine has been shown to engage with other fundamental cellular pathways, revealing a more complex pharmacological profile. A significant secondary mechanism involves the stabilization of Hypoxia-Inducible Factor 1-alpha (HIF-1α).[1] HIF-1α is a master transcription factor that is normally kept at low levels in oxygen-rich conditions through the action of prolyl hydroxylase domain (PHD) enzymes. These enzymes, which belong to the

Fe2+-dependent and 2-oxoglutarate-dependent dioxygenase family, hydroxylate HIF-1α, targeting it for rapid degradation.[12] Hydralazine is known to inhibit prolyl 4-hydroxylase (also called protocollagen prolyl hydroxylase) by competing for enzyme-bound iron.[1] By inhibiting the PHD enzymes, Hydralazine prevents the degradation of HIF-1α, causing it to accumulate even under normal oxygen conditions.[1]

The stabilization of HIF-1α has significant downstream consequences. It promotes the transcription of a suite of genes, most notably Vascular Endothelial Growth Factor (VEGF).[1] This leads to a pro-angiogenic phenotype, characterized by the proliferation of endothelial cells and the formation of new blood vessels, an effect that has been demonstrated in both cell culture and in vivo angiogenesis assays.[1] This dualistic pharmacology—acting as both an acute vasodilator and a potential modulator of gene expression and tissue remodeling—suggests that Hydralazine's biological effects may be more extensive than previously appreciated. The acute hemodynamic changes are explained by the calcium-mediated mechanism, while the HIF-1α pathway may contribute to longer-term vascular effects and opens avenues for investigational use in conditions involving ischemia or abnormal angiogenesis.

Systemic Hemodynamic Effects

The direct arteriolar vasodilation produced by Hydralazine sets off a cascade of predictable systemic hemodynamic changes. The primary effect is a reduction in total peripheral resistance, which leads to a decrease in arterial blood pressure, with a more pronounced effect on diastolic than systolic pressure.[9] This fall in pressure is sensed by baroreceptors in the aortic arch and carotid sinuses, triggering a powerful compensatory reflex sympathetic nervous system discharge.[3] This sympathetic stimulation results in clinically significant increases in heart rate (tachycardia), myocardial contractility, stroke volume, and cardiac output.[5] This "hyperdynamic" circulatory state is responsible for many of the drug's common side effects (e.g., palpitations) and its most serious risks (e.g., myocardial ischemia in patients with coronary artery disease). Concurrently, the sympathetic discharge stimulates the renal juxtaglomerular cells to increase the secretion of renin, leading to increased plasma renin activity and subsequent activation of the renin-angiotensin-aldosterone system, which promotes sodium and water retention.[5]

Pharmacokinetics and Metabolism

The clinical use of Hydralazine is profoundly influenced by its complex pharmacokinetic profile, which is characterized by extensive metabolism and significant inter-individual variability driven by genetic factors.

Absorption

Following oral administration, Hydralazine is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations typically reached within 1 to 2 hours.[18] However, its systemic bioavailability is highly variable, ranging from approximately 22% to 69%.[18] This wide range is primarily determined by two factors: the extent of its pre-systemic (first-pass) metabolism, which is genetically determined, and the presence of food, which has been shown to increase its bioavailability.[1]

Distribution

Once in the systemic circulation, Hydralazine is highly bound to plasma proteins, with 87-90% bound to serum albumin.[17] It has a relatively small volume of distribution, reported as 0.5–0.9 L/kg, suggesting that its distribution is largely confined to the vascular and extracellular compartments.[17]

Metabolism

Hydralazine is subject to extensive and complex metabolism, primarily in the liver, with multiple competing pathways contributing to its clearance.[12]

• Acetylation: For the oral route, a critical metabolic pathway is N-acetylation, which is mediated by the N-acetyltransferase 2 (NAT2) enzyme.[8] This enzyme exhibits significant genetic polymorphism, which is the primary driver of the variability in Hydralazine's first-pass metabolism and bioavailability.
• Hydrazone Formation: Hydralazine's reactive hydrazine group can undergo rapid, non-enzymatic condensation reactions with endogenous α-keto acids, such as pyruvic acid and α-ketoglutarate, to form hydrazone metabolites.[1] The formation of hydralazine pyruvic acid hydrazone is a major pathway of systemic clearance and is independent of acetylator status, playing a more dominant role after intravenous administration.[12]
• Oxidation and Conjugation: Other significant pathways include aromatic hydroxylation of the phthalazine ring, followed by conjugation with glucuronic acid.[17] Oxidative metabolism can also precede acetylation, leading to the formation of metabolites like N-acetylhydrazinophthalazinone.[19]

The Central Role of NAT2 Polymorphism

The single most important factor governing the pharmacokinetics of oral Hydralazine is the genetic polymorphism of the NAT2 enzyme. The human population is broadly divided into two phenotypes based on NAT2 activity: "slow acetylators" (SA) and "rapid acetylators" (RA).[8] Approximately 50% of Caucasian and African American populations are slow acetylators.[8] This genetic difference has profound clinical consequences:

• Following a standard oral dose, slow acetylators have a significantly reduced capacity for first-pass acetylation. This results in a 2.2-fold greater systemic bioavailability, substantially higher peak plasma concentrations (Cmax​), and a 2.5-fold greater total drug exposure (Area Under the Curve, AUC) compared to rapid acetylators.[17]
• Conversely, rapid acetylators clear the drug more efficiently via acetylation, resulting in lower plasma levels and a shorter elimination half-life.[17]
• This pharmacokinetic disparity is the direct cause of the differential risk-benefit profile between the phenotypes. Slow acetylators achieve higher drug levels, which may lead to a greater therapeutic response but also places them at a much higher risk for developing dose-dependent adverse effects, most notably drug-induced lupus erythematosus.[8] Rapid acetylators, on the other hand, may be at risk for therapeutic inefficacy at lower doses.[8] This relationship establishes a clear causal chain: the NAT2 genotype dictates the pharmacokinetic profile (systemic exposure), which in turn dictates the likelihood of both efficacy and toxicity.

This stark difference is less pronounced with intravenous administration because the first-pass effect is bypassed, and non-acetylation pathways (like hydrazone formation) account for a larger proportion of systemic clearance.[12]

Table 2: Comparative Pharmacokinetic Parameters by NAT2 Acetylator Status (Oral Administration)
Pharmacokinetic Parameter	Slow Acetylators (SA)	Rapid Acetylators (RA)
Systemic Bioavailability	~30-35%; 2.2-fold greater than RA 17	~10-16% 19
Total Drug Exposure (AUC)	Substantially greater; 2.5-fold greater than RA 17	Lower 17
Peak Plasma Concentration (Cmax​)	Substantially higher 17	Lower 17
Elimination Half-life (t1/2​)	2.0–5.8 hours 1	2.2–7.8 hours (Note: variability exists across studies) 1

Excretion

The metabolites of Hydralazine are predominantly eliminated via the kidneys, with 65-90% of an administered dose being recovered in the urine.[1] A smaller fraction, typically less than 10%, is excreted in the feces.[1]

Clinical Efficacy and Therapeutic Applications

The clinical utility of Hydralazine is well-defined, with applications spanning the management of various hypertensive states and a specific role in heart failure. Its use is guided by decades of clinical experience and evidence from key clinical trials.

Management of Hypertension

Essential Hypertension

In the management of chronic essential hypertension, Hydralazine is positioned as a second- or third-line agent.[3] It is typically reserved for patients whose blood pressure is not adequately controlled by a multi-drug regimen of first-line agents (e.g., thiazide diuretics, ACE inhibitors, angiotensin receptor blockers, or calcium channel blockers).[1] Its relegation from first-line therapy is due to its significant side-effect profile, particularly reflex tachycardia and fluid retention, and its demanding dosing frequency of two to four times daily, which can pose a challenge for long-term patient adherence.[3]

Hypertensive Emergencies

Parenteral (IV or IM) Hydralazine is indicated when there is an urgent need to lower blood pressure, such as in a hypertensive crisis.[1] However, its use in this setting has become less common and is often considered controversial. The primary concerns are its unpredictable and occasionally prolonged hypotensive response, which can be difficult to titrate, and the potent reflex tachycardia it induces, which can be detrimental in patients with underlying cardiac conditions.[3] Consequently, other parenteral agents with more predictable pharmacokinetics and less cardiac stimulation (e.g., labetalol, nicardipine, esmolol) are now generally preferred for the management of most hypertensive emergencies.[32]

Hypertensive Disorders of Pregnancy

Hydralazine has a long and established history in the management of severe hypertension during pregnancy, including pre-eclampsia and eclampsia.[1] It remains a viable option for acute blood pressure control in this population. Its efficacy and safety have been directly compared against other agents, notably labetalol, in randomized controlled trials such as NCT01538875 and NCT02050529.[33] While effective, some evidence suggests that intravenous Hydralazine may be associated with a higher incidence of maternal and perinatal adverse effects compared to labetalol, such as maternal hypotension and tachycardia.[7] This has led to its positioning as a suitable second-line agent in many clinical guidelines for this indication.[7]

Treatment of Heart Failure with Reduced Ejection Fraction (HFrEF)

Adjunctive Therapy with Nitrates (H-ISDN)

The combination of Hydralazine with a nitrate, typically isosorbide dinitrate (ISDN), serves as a cornerstone of its modern use in cardiology. This combination provides a balanced approach to vasodilation for patients with HFrEF.[1] Hydralazine, as a direct arteriolar vasodilator, primarily reduces systemic vascular resistance (afterload), decreasing the impedance against which the failing left ventricle must eject blood.[10] Isosorbide dinitrate is predominantly a venodilator, which increases venous capacitance and reduces venous return to the heart (preload), thereby decreasing ventricular filling pressures and alleviating congestive symptoms.[10]

The African-American Heart Failure Trial (A-HeFT)

The role of H-ISDN was solidified by the landmark African-American Heart Failure Trial (A-HeFT). This randomized, double-blind, placebo-controlled trial specifically enrolled self-identified Black patients with NYHA class III or IV heart failure who were already receiving standard therapy. The trial was stopped early due to a striking mortality benefit in the treatment group. A-HeFT demonstrated that the addition of a fixed-dose combination of H-ISDN (marketed as BiDil®) resulted in a 43% reduction in all-cause mortality, a 39% reduction in the rate of first hospitalization for heart failure, and significant improvements in quality of life compared to placebo.[5] These powerful results led to the strong recommendation by the American College of Cardiology/American Heart Association and other major cardiology societies for the use of H-ISDN as part of standard therapy for HFrEF in this specific patient population.[3]

Comparative Efficacy and Real-World Data

The evidence for Hydralazine in heart failure is nuanced. An earlier study, the Hydralazine Captopril Trial (Hy-C), directly compared a regimen of hydralazine and nitrates against the ACE inhibitor captopril in patients with severe heart failure. The results showed that captopril conferred a superior survival benefit, primarily by reducing the rate of sudden cardiac death.[36] This established ACE inhibitors as a foundational therapy for HFrEF.

More recently, the impressive results of A-HeFT have been tempered by observations from real-world clinical practice. An analysis of data from the large Get With The Guidelines-Heart Failure (GWTG-HF) registry revealed a significant "efficacy-effectiveness gap." The study found that guideline-recommended initiation of H-ISDN therapy at hospital discharge was uncommon, and long-term patient adherence to the regimen was low.[11] In this large observational cohort, the survival benefit demonstrated so clearly in the controlled setting of A-HeFT was not observed.[11] This discrepancy highlights a critical challenge in translating clinical trial evidence into practice; the benefits of a proven therapy can be negated by practical barriers such as complex dosing schedules, side effects, and cost, which lead to low rates of prescription and poor adherence.

Investigational and Off-Label Uses

Beyond its approved indications, Hydralazine's unique mechanisms of action have prompted investigation into other potential therapeutic areas.

• Intracerebral Hemorrhage: As part of a multi-drug strategy for intensive blood pressure reduction, Hydralazine was included as a potential agent in the INTERACT2 trial (NCT00226096) for patients with acute cerebral hemorrhage.[37]
• Left Ventricular Dysfunction / Acute Heart Failure: A Phase 3 trial (NCT01822808) is evaluating the efficacy of a hydralazine/nitrate combination versus placebo in African patients admitted with acute heart failure, extending the investigation of this therapy to the acute setting.[38]
• Polycystic Kidney Disease (PKD): A fascinating area of research explores Hydralazine's potential as an epigenetic modulator. A Phase 0 basic science trial (NCT03423810) was conducted to assess its effect on DNA methyltransferase 1 in patients with PKD.[39] This line of inquiry is based on evidence that Hydralazine can inhibit DNA methylation, a key epigenetic mechanism, and potentially reactivate the expression of silenced tumor suppressor genes.[14] This represents a potential paradigm shift for the drug, moving beyond its hemodynamic effects to target the fundamental molecular pathology of certain diseases.

Table 3: Summary of Landmark and Representative Clinical Trials Involving Hydralazine
Trial Acronym/Identifier	Indication	Comparison Arms	Primary Endpoint	Key Finding	Source
A-HeFT	HFrEF (NYHA III-IV) in Black patients	Fixed-dose H-ISDN vs. Placebo (on top of standard therapy)	Composite score of mortality, HF hospitalization, and quality of life	H-ISDN significantly reduced mortality by 43% and HF hospitalization by 39%.	11
Hy-C	Severe CHF (NYHA III-IV)	Captopril vs. Hydralazine/Nitrates	Mortality	One-year survival was significantly better with Captopril (81%) vs. H-ISDN (51%), driven by a reduction in sudden death.	36
NCT01538875	Hypertensive Disorders of Pregnancy	Hydralazine (IV) vs. Labetalol (IV)	Control of hypertensive crisis	A randomized trial to compare the efficacy of two standard treatments.	34
NCT03423810	Polycystic Kidney Disease (PKD)	Dose-response study of Hydralazine	Effect on DNA methyltransferase 1	Basic science trial exploring potential epigenetic modulating effects.	39

Safety, Tolerability, and Risk Management

The clinical application of Hydralazine requires a thorough understanding of its safety profile, which is characterized by a range of adverse effects stemming from both its primary pharmacological action and its unique chemical properties.

Adverse Drug Reactions

The adverse effects of Hydralazine can be broadly categorized into two groups: acute, predictable effects related to its vasodilatory mechanism, and more delayed, idiosyncratic effects related to its interaction with the immune and metabolic systems.

Common Side Effects (>1% frequency)

These reactions are largely extensions of the drug's intended pharmacology and the body's compensatory responses.

• Cardiovascular: Palpitations, tachycardia (rapid heart rate), flushing, and hypotension are very common, resulting directly from vasodilation and the reflex sympathetic stimulation.[3] Angina pectoris (chest pain) can be precipitated or worsened, particularly in patients with underlying coronary artery disease.[21]
• Gastrointestinal: Nausea, vomiting, diarrhea, and anorexia (loss of appetite) are frequently reported.[21]
• Neurological: Headache is a very common side effect, likely related to the rapid dilation of cerebral blood vessels.[5]
• Other: Nasal congestion, lacrimation (excessive tearing), and conjunctivitis can also occur.[21]

Serious Adverse Events

• Drug-Induced Lupus Erythematosus (DILE): This is the most well-known and significant long-term risk associated with Hydralazine therapy. Prolonged treatment can induce a clinical syndrome that mimics systemic lupus erythematosus (SLE), which may include severe complications like glomerulonephritis and can be fatal if not recognized and treated by discontinuing the drug.[1] Symptoms include arthralgia (joint pain), fever, skin rashes (including the characteristic butterfly-shaped rash on the face), chest pain, and persistent malaise.[24] The risk of developing DILE is strongly correlated with the daily dose (higher risk with doses >200 mg/day), the duration of therapy, and, most importantly, the patient's NAT2 acetylator status. Slow acetylators, due to their higher systemic drug exposure, are at a significantly greater risk.[5]
• Myocardial Ischemia and Infarction: The reflex tachycardia and increased myocardial contractility significantly increase the heart's oxygen demand. In patients with pre-existing coronary artery disease (CAD), where oxygen supply is limited by stenotic arteries, this mismatch can provoke myocardial ischemia, angina, and even acute myocardial infarction.[3]
• Peripheral Neuritis: Some patients may develop symptoms of peripheral neuropathy, including paresthesia (tingling), numbness, and pain in the extremities.[21] This is believed to result from an antipyridoxine (Vitamin B6) effect, as Hydralazine can interfere with its metabolism. These symptoms can often be prevented or treated with pyridoxine supplementation.[29]
• Hematologic Dyscrasias: Although rare, serious blood disorders have been reported, including reduction in hemoglobin and red cell count (anemia), leukopenia (low white blood cell count), agranulocytosis (a severe lack of granulocytes), and purpura (easy bruising). If these abnormalities are detected, therapy should be discontinued immediately.[9]
• Hypersensitivity Reactions: These can manifest as skin rash, urticaria (hives), pruritus (itching), fever, and chills. Rarely, drug-induced hepatitis has been reported.[21]

Contraindications and Precautions

The use of Hydralazine is strictly prohibited or requires significant caution in certain patient populations where its known effects are likely to be harmful.

Absolute Contraindications

• Hypersensitivity: Known allergy to Hydralazine or any of its components.[29]
• Coronary Artery Disease (CAD): Hydralazine is contraindicated in patients with CAD because the inevitable reflex tachycardia and increased myocardial work can precipitate dangerous myocardial ischemia or infarction.[3]
• Mitral Valvular Rheumatic Heart Disease: In patients with this condition, the increased cardiac output caused by Hydralazine can exacerbate pulmonary hypertension, making it contraindicated.[5]

The contraindications for Hydralazine are not arbitrary; they represent clinical scenarios where the drug's predictable side effects are amplified into life-threatening events due to the patient's underlying disease. In a patient with CAD, the "side effect" of increased cardiac oxygen demand becomes the primary mechanism of harm. Similarly, in a patient with mitral valve disease, the "side effect" of increased cardiac output predictably worsens their specific hemodynamic problem.

Precautions and Warnings

• Renal Impairment: Hydralazine should be used with caution in patients with advanced renal damage, as impaired kidney function can reduce drug clearance and increase systemic exposure, potentially heightening the risk of toxicity.[5]
• Cerebrovascular Accidents (Stroke): Caution is advised in patients with a history of stroke, as significant fluctuations in blood pressure can be detrimental.[9]
• Pregnancy and Lactation: Hydralazine is classified as FDA Pregnancy Category C. Animal studies have shown teratogenic effects at high doses, but there are no adequate and well-controlled studies in pregnant women. Its use in pregnancy should be reserved for situations where the potential benefit to the mother justifies the potential risk to the fetus.[5] Studies suggest that the risk to a nursing infant is minimal.[27]
• Carcinogenesis: A lifetime study in Swiss albino mice administered high doses of Hydralazine in their drinking water showed a statistically significant increase in the incidence of lung tumors.[9] The relevance of this finding to humans at therapeutic doses is unclear.

Overdosage

Signs and Symptoms

Acute overdose of Hydralazine manifests as an exaggeration of its pharmacological effects. Symptoms include profound hypotension, severe tachycardia, headache, and generalized skin flushing. Serious complications can ensue, including myocardial ischemia leading to infarction, cardiac arrhythmias, and profound shock, which can be life-threatening.[1]

Management

There is no specific antidote for Hydralazine overdose. Treatment is entirely supportive and aimed at stabilizing the cardiovascular system. Management strategies include:

• Gastric evacuation (e.g., lavage) and administration of activated charcoal may be considered if the ingestion was recent and the patient's cardiovascular status is stable.
• The primary focus is on treating shock with intravenous fluids and plasma expanders.
• Vasopressors should be avoided if possible, as they may precipitate or worsen cardiac arrhythmias. If required, they must be used with extreme caution.
• Tachycardia and arrhythmias can be managed with beta-blockers.
• Renal function should be monitored and supported as needed.[1]

The highest known oral dose survived by an adult is 10 grams.21

Drug and Disease Interactions

The therapeutic effects and safety profile of Hydralazine can be significantly altered by concomitant medications, food, and underlying patient conditions. A comprehensive understanding of these interactions is essential for safe prescribing.

Pharmacodynamic Interactions

These interactions occur when two drugs have additive or opposing effects on the body.

• Additive Hypotensive Effects: The most common pharmacodynamic interaction is an additive effect on blood pressure. When Hydralazine is co-administered with other antihypertensive agents—including other vasodilators, diuretics, ACE inhibitors, calcium channel blockers, and beta-blockers—the risk of hypotension is increased. This effect is often leveraged therapeutically to achieve blood pressure goals but requires careful dose titration. Other drug classes, such as tricyclic antidepressants and major tranquilizers, can also potentiate the hypotensive effect.[5] Concomitant use with the potent parenteral vasodilator diazoxide can lead to profound and dangerous hypotensive episodes.[47]
• Ethanol (Alcohol): Consumption of alcohol can enhance the blood pressure-lowering effect of Hydralazine, increasing the risk of symptoms like dizziness, lightheadedness, and orthostatic hypotension.[5]
• Sympathomimetics: Hydralazine can increase the heart rate-accelerating effects of sympathomimetic agents like epinephrine (adrenaline), potentially leading to excessive tachycardia.[5]
• Monoamine Oxidase (MAO) Inhibitors: These drugs should be used with caution in patients receiving Hydralazine due to the potential for unpredictable interactions affecting blood pressure.[44]

Pharmacokinetic Interactions

These interactions occur when one drug affects the absorption, distribution, metabolism, or excretion of another.

• Beta-Blockers: Hydralazine can increase the bioavailability of certain beta-blockers that undergo extensive first-pass metabolism, such as propranolol and metoprolol. This is thought to be due to Hydralazine-induced increases in hepatic blood flow, which reduces the efficiency of first-pass extraction. This can lead to higher plasma concentrations of the beta-blocker, potentially enhancing both its therapeutic and adverse effects.[5]
• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): NSAIDs, such as aspirin and ibuprofen, can antagonize the antihypertensive effect of Hydralazine. They do so by inhibiting the synthesis of renal prostaglandins, which play a role in maintaining renal blood flow and promoting sodium excretion, thereby counteracting the blood pressure-lowering effect.[22]

Food and Supplement Interactions

• Food: The bioavailability of oral Hydralazine is significantly enhanced when taken with food.[18] To ensure consistent drug exposure and a predictable therapeutic response, patients should be counseled to take Hydralazine in a consistent manner, either always with food or always on an empty stomach.[40]
• Vitamin B6 (Pyridoxine): As previously noted, Hydralazine can act as a pyridoxine antagonist, leading to a deficiency that may manifest as peripheral neuropathy. Patients on long-term therapy, particularly those who are malnourished or have other risk factors, may benefit from pyridoxine supplementation.[29]

Disease State Interactions

The presence of certain underlying medical conditions can significantly increase the risks associated with Hydralazine therapy. Key disease interactions include:

• Coronary Artery Disease and Valvular Heart Disease: These are contraindications, as discussed previously.[46]
• Systemic Lupus Erythematosus (SLE): Patients with a history of SLE may be at increased risk of a flare-up, and Hydralazine can induce a lupus-like syndrome.[46]
• Renal Dysfunction: Advanced renal disease can impair the clearance of Hydralazine and its metabolites, increasing the risk of toxicity. Dose adjustments may be necessary.[46]
• Cerebral Vasculopathy: In patients with cerebrovascular disease, caution is required to avoid excessive or rapid drops in blood pressure that could compromise cerebral perfusion.[46]
• Bone Marrow Suppression: Patients with pre-existing bone marrow suppression may be at higher risk for the rare hematologic adverse effects of Hydralazine.[46]

Table 4: Clinically Significant Drug and Disease Interactions with Hydralazine
Interacting Agent/Disease	Nature of Interaction	Clinical Consequence	Management Recommendation	Source
Other Antihypertensives, Alcohol	Pharmacodynamic	Additive hypotension, dizziness, orthostatic hypotension.	Monitor blood pressure closely. Titrate doses carefully. Counsel patient on alcohol use and orthostatic precautions.	5
NSAIDs (e.g., Ibuprofen, Aspirin)	Pharmacodynamic	Antagonism of antihypertensive effect.	Monitor for reduced blood pressure control. Consider alternative analgesics if possible.	22
Beta-Blockers (e.g., Propranolol)	Pharmacokinetic	Increased bioavailability of the beta-blocker.	Monitor for signs of excessive beta-blockade (bradycardia, hypotension). Dose adjustment of the beta-blocker may be needed.	5
Food	Pharmacokinetic	Increased bioavailability of Hydralazine.	Advise patient to take Hydralazine consistently, either always with food or always without, to ensure stable drug levels.	18
Coronary Artery Disease (CAD)	Disease Interaction	Reflex tachycardia increases myocardial oxygen demand, risking ischemia/infarction.	Contraindicated.	45
Renal Dysfunction	Disease Interaction	Decreased drug clearance, leading to increased systemic exposure and toxicity risk.	Use with caution. Dose reduction may be necessary. Monitor for adverse effects.	46

Dosing, Administration, and Clinical Monitoring

The safe and effective use of Hydralazine is contingent upon careful dose initiation and titration according to individual patient response, appropriate administration, and diligent clinical and laboratory monitoring.

Recommended Dosage Regimens

Dosage must be individualized. The following are general guidelines for different indications and patient populations.

Adult Dosing

• Chronic/Essential Hypertension (Oral): Therapy should be initiated at a low dose and gradually increased. A typical starting regimen is 10 mg taken four times daily for the first 2 to 4 days. This can be increased to 25 mg four times daily for the remainder of the first week. For the second and subsequent weeks, the dosage can be increased to 50 mg four times daily. The maintenance dose should be adjusted to the lowest effective level. In some resistant cases, daily doses up to 300 mg may be required, but the risk of adverse effects, particularly DILE, increases significantly at these higher doses.[3]
• Hypertensive Crisis (Parenteral): For urgent blood pressure reduction, a dose of 10 to 20 mg can be administered by slow intravenous injection or intramuscularly. This dose can be repeated every 4 to 6 hours as needed. For pregnancy-associated hypertensive emergencies, an initial dose of 5 to 10 mg IV/IM is recommended, which can be repeated every 20 to 30 minutes if blood pressure remains uncontrolled.[3]
• Heart Failure with Reduced Ejection Fraction (Oral): When used in combination with isosorbide dinitrate, the fixed-dose combination tablet (BiDil®) is typically started at one tablet (37.5 mg Hydralazine / 20 mg Isosorbide Dinitrate) three times daily.[10] When using individual components, Hydralazine is often initiated at 10 to 25 mg three or four times daily and titrated every 2 to 4 weeks, with a target maintenance dose of 225-300 mg daily, divided into 3-4 doses, as tolerated.[22]

Pediatric Dosing

• Chronic Hypertension (Oral): The initial dose is typically 0.75 mg/kg of body weight per day, divided into two to four doses. The dose can be gradually increased over 3 to 4 weeks as needed. The maximum dose for children over 1 year is 7.5 mg/kg/day or 200 mg/day, whichever is less.[4]
• Hypertensive Crisis (Parenteral): The initial dose for infants and children is 0.1 to 0.2 mg/kg per dose, administered IV or IM every 4 to 6 hours as needed. The dose can be increased up to a usual range of 1.7-3.5 mg/kg/day divided into 4-6 doses, not to exceed 20 mg per dose.[22]

Administration

• Oral: Tablets should be taken consistently, either always with meals or always on an empty stomach, to minimize variability in absorption.[40] The oral solution formulation can be mixed with fruit juice or applesauce for easier administration, particularly in pediatric patients, and should be consumed immediately after mixing.[4]
• Parenteral: Intravenous administration should be performed slowly to avoid a precipitous drop in blood pressure. Intramuscular injection is an alternative when IV access is not available.[3]

Patient Monitoring

Regular and comprehensive monitoring is critical to ensure efficacy and detect adverse effects early.

• Hemodynamic Monitoring: Blood pressure and heart rate must be checked regularly, especially during dose initiation and titration. Patients may be asked to keep a home blood pressure log to help guide therapy.[24] In the acute setting, continuous monitoring may be necessary.
• Laboratory Tests:
• For Drug-Induced Lupus: For patients on long-term or high-dose therapy (>200 mg/day), it is prudent to obtain a baseline Antinuclear Antibody (ANA) titer. These tests should be repeated if the patient develops any unexplained signs or symptoms suggestive of DILE, such as arthralgia, fever, chest pain, or persistent malaise.[9]
• For Hematologic Effects: A baseline and periodic Complete Blood Count (CBC) should be performed to screen for the rare but serious adverse effects of anemia, leukopenia, and agranulocytosis.[29]
• Clinical Assessment: Patients should be regularly questioned about and examined for signs of:
• Peripheral Neuropathy: Numbness, tingling, or burning sensations in the hands or feet.[24]
• Fluid Retention: Edema (swelling) in the lower extremities or a sudden increase in body weight.[49]
• Myocardial Ischemia: New or worsening chest pain (angina).[49]
• Orthostatic Hypotension: Dizziness or lightheadedness upon standing.[40]

Table 5: Comprehensive Dosing and Monitoring Guidelines for Hydralazine
Indication	Patient Population	Route	Starting Dose	Titration/Maintenance	Essential Monitoring
Essential Hypertension	Adult	Oral	10 mg, 4 times daily	Titrate up to 50 mg, 4 times daily (max 300 mg/day)	BP, HR. Periodically check CBC and ANA (if on long-term/high-dose).
	Pediatric	Oral	0.75 mg/kg/day, divided 2-4 times	Titrate up to 7.5 mg/kg/day (max 200 mg/day)	BP, HR.
Hypertensive Crisis	Adult	IV/IM	10-20 mg	Repeat every 4-6 hours PRN	Continuous BP and HR monitoring.
	Pediatric	IV/IM	0.1-0.2 mg/kg/dose	Repeat every 4-6 hours PRN	Continuous BP and HR monitoring.
Heart Failure (HFrEF)	Adult	Oral	10-25 mg, 3-4 times daily (with ISDN)	Titrate to maintenance of 225-300 mg/day, divided	BP, HR, signs of fluid retention, symptoms of DILE.

Conclusion and Future Perspectives

Synthesis of Hydralazine's Clinical Profile

Hydralazine remains a potent and clinically useful direct-acting arteriolar vasodilator, but its role in modern medicine is that of a specialized tool rather than a first-line agent. Its seven-decade history has precisely defined both its strengths and its significant limitations. It retains an enduring, albeit niche, place in the management of treatment-resistant hypertension, certain hypertensive emergencies such as those in pregnancy, and most notably, as a component of life-saving therapy for heart failure with reduced ejection fraction in self-identified Black patients. However, its overall clinical utility is fundamentally constrained by a challenging adverse effect profile dominated by reflex sympathetic activation, a high risk of drug-induced lupus erythematosus in susceptible individuals, an inconvenient multi-daily dosing schedule that hampers adherence, and profound inter-individual pharmacokinetic variability. The decision to use Hydralazine requires a careful weighing of these factors against the potential benefits for a specific patient.

The Imperative of Pharmacogenomics

The single most critical factor influencing the risk-benefit profile of oral Hydralazine is the genetic polymorphism of the N-acetyltransferase 2 (NAT2) enzyme. The vast difference in systemic drug exposure between slow and rapid acetylators is the direct, mechanistic cause for the observed variability in both efficacy and toxicity. The evidence strongly suggests that prescribing Hydralazine without knowledge of a patient's acetylator status is an incomplete approach to risk management. A future in which genotype-guided dosing becomes standard practice is not only plausible but necessary for the optimal use of this drug. Such a strategy would involve prescribing lower initial and maintenance doses for known slow acetylators to minimize the risk of DILE, while ensuring that rapid acetylators receive adequate doses to achieve a therapeutic effect. Implementing this personalized approach would transform Hydralazine from a drug with unpredictable toxicity to one with a more manageable and predictable safety profile.

Future Research Directions

While its role in cardiovascular medicine is well-established, the most exciting future for Hydralazine may lie outside of its hemodynamic effects. The discovery of its non-vasodilator mechanisms, particularly its ability to inhibit prolyl hydroxylase to stabilize HIF-1α and its capacity to act as a DNA methyltransferase inhibitor, opens up compelling new avenues for research and therapeutic development.[14] These properties suggest that Hydralazine could be repurposed as an epigenetic modulator. Future investigations should focus on these pathways, exploring its potential in oncology for reactivating silenced tumor suppressor genes, in genetic disorders like Polycystic Kidney Disease, or in ischemic conditions where promoting angiogenesis via the HIF-1α pathway could be beneficial. The ultimate goal of such research could be the development of novel analogues of Hydralazine that retain these valuable epigenetic or pro-angiogenic activities while being devoid of the potent vasodilatory effects and their associated cardiovascular liabilities, potentially giving this very old drug a new and impactful life in 21st-century medicine.

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