What is the mechanism of action and drug class of hydralazine?

Hydralazine: Mechanism of Action and Drug Class

Hydralazine is a direct arterial vasodilator that lowers blood pressure by relaxing vascular smooth muscle through interference with calcium movements within smooth muscle cells, resulting in decreased peripheral vascular resistance. 1

Drug Class

• Hydralazine belongs to the class of direct-acting peripheral vasodilators 2, 3
• It is specifically classified as a direct arterial vasodilator, with preferential effects on arterioles compared to veins 4, 1

Primary Mechanism of Action

Vascular Smooth Muscle Effects

• Hydralazine directly relaxes vascular smooth muscle by altering cellular calcium metabolism, interfering with the calcium movements responsible for initiating or maintaining the contractile state 1
• The drug acts primarily by inhibiting IP₃-induced release of calcium from the sarcoplasmic reticulum in vascular smooth muscle cells 5
• This mechanism results in preferential dilatation of arterioles rather than veins, which minimizes postural hypotension and promotes increased cardiac output 1

Hemodynamic Consequences

• The peripheral vasodilation produces decreased arterial blood pressure (diastolic more than systolic) and decreased peripheral vascular resistance 1
• As a compensatory response, hydralazine triggers baroreceptor-mediated reflex sympathetic activation, leading to increased heart rate (reflex tachycardia), increased stroke volume, and increased cardiac output 2, 3
• The drug increases renin activity in plasma due to reflex sympathetic discharge, leading to angiotensin II production and subsequent aldosterone stimulation with sodium reabsorption 1

Additional Mechanisms (Research Context)

While the primary clinical mechanism involves calcium metabolism in smooth muscle, research has identified additional molecular targets:

• Hydralazine inhibits prolyl hydroxylase domain (PHD) enzymes, leading to HIF-1α stabilization and VEGF expression, which may contribute to pro-angiogenic effects 6
• At lower concentrations, hydralazine demonstrates endothelium-dependent vasorelaxation via cGMP accumulation, though this occurs through a mechanism distinct from nitric oxide or prostaglandin I₂ release 7
• The drug may have prejunctional effects on sympathetic nerve terminals, modulating neurotransmitter release 8, 9

Clinical Implications of Mechanism

Combination Therapy Rationale

• Hydralazine is typically combined with isosorbide dinitrate in heart failure because hydralazine provides arterial vasodilation while isosorbide dinitrate provides venous vasodilation, creating complementary hemodynamic effects 4, 2
• The American College of Cardiology recommends using hydralazine with background diuretic and beta-blocker therapy to counteract its effects of increasing sympathetic tone and causing sodium retention 3

Important Caveats

• Beta-blockers are essential when using hydralazine to minimize reflex tachycardia that results from its arterial vasodilation mechanism 3
• The American Heart Association notes that hydralazine should not be used as monotherapy in myocardial infarction due to the risk of provoking myocardial ischemia from reflex tachycardia 3
• Total daily doses should be kept below 150 mg to avoid drug-induced systemic lupus erythematosus 3