What is the mechanism of action of hydralazine?

Mechanism of Action of Hydralazine

Hydralazine primarily acts as a direct arterial vasodilator by relaxing vascular smooth muscle through interference with cellular calcium metabolism, which affects calcium movements responsible for maintaining vascular contractility. 1

Primary Mechanism

• Hydralazine exerts a peripheral vasodilating effect through direct relaxation of vascular smooth muscle, preferentially dilating arterioles compared to veins 1
• The drug interferes with calcium movements within vascular smooth muscle cells that are responsible for initiating or maintaining the contractile state 1
• Hydralazine primarily inhibits inositol 1,4,5 trisphosphate (IP₃)-induced release of calcium from the sarcoplasmic reticulum in vascular smooth muscle cells 2
• It has greater potency in inhibiting IP₃-mediated contractions compared to caffeine-evoked contractions, suggesting specificity for certain calcium release pathways 2

Hemodynamic Effects

• The vasodilatory action results in:
  • Decreased arterial blood pressure (with greater effect on diastolic than systolic pressure) 1
  • Decreased peripheral vascular resistance 1
  • Increased heart rate, stroke volume, and cardiac output due to reflex sympathetic stimulation 1, 3
• The preferential dilation of arterioles versus veins minimizes postural hypotension while promoting increased cardiac output 1
• Hydralazine maintains or increases renal and cerebral blood flow 1

Secondary Effects

• Hydralazine typically increases plasma renin activity due to increased secretion from renal juxtaglomerular cells in response to reflex sympathetic discharge 1
• This increased renin activity leads to angiotensin II production, which stimulates aldosterone and consequent sodium reabsorption 1
• Unlike some other vasodilators, hydralazine does not act through guanylate cyclase activation or endothelium-dependent mechanisms 4
• The drug has no significant effect on membrane potential or potassium currents in vascular smooth muscle cells 2

Additional Mechanisms

• Beyond its vasodilatory effects, hydralazine has been identified to have potential antioxidative properties 5
• It may also have DNA demethylation and anti-inflammatory abilities that contribute to its effects in certain disease states 5
• When combined with nitrates (such as isosorbide dinitrate), hydralazine may help prevent nitrate tolerance 6

Clinical Implications of Mechanism

• The direct arterial vasodilation with minimal venous effects explains why hydralazine is often combined with venodilators (like nitrates) in heart failure treatment 6
• The reflex sympathetic activation and fluid retention caused by hydralazine's mechanism necessitates combination with beta-blockers and diuretics in clinical practice 3
• The pharmacokinetics are affected by acetylator status, with slow acetylators generally having higher plasma levels and requiring lower doses 1

Understanding hydralazine's mechanism helps explain both its therapeutic effects and common side effects such as headache, tachycardia, and fluid retention, which are direct consequences of its vasodilatory action and the resulting compensatory mechanisms.