What is the mechanism of action of hydralazine?

Mechanism of Action of Hydralazine

Hydralazine primarily works as a direct arterial vasodilator by relaxing vascular smooth muscle through interference with calcium movements within the cells that maintain vascular contractility. 1

Primary Mechanism

Hydralazine exerts its antihypertensive effects through:

• Direct relaxation of vascular smooth muscle 1
• Preferential dilation of arterioles rather than veins, which minimizes postural hypotension 1
• Interference with cellular calcium metabolism that maintains vascular contractility 1
• Inhibition of IP₃-induced calcium release from the sarcoplasmic reticulum in vascular smooth muscle cells 2

Hemodynamic Effects

The vasodilatory action of hydralazine produces several hemodynamic changes:

• Decreased arterial blood pressure (with greater effect on diastolic than systolic) 1
• Decreased peripheral vascular resistance 1
• Increased heart rate, stroke volume, and cardiac output due to reflex sympathetic activation 1, 3
• Maintenance or increase in renal and cerebral blood flow 1

Secondary Physiological Responses

Hydralazine administration triggers several compensatory mechanisms:

• Increased plasma renin activity due to increased secretion from renal juxtaglomerular cells in response to reflex sympathetic discharge 1
• Production of angiotensin II leading to aldosterone stimulation and sodium reabsorption 1
• Baroreflex-mediated venoconstriction increasing venous return to the heart 3
• Catecholamine-mediated positive inotropic and chronotropic cardiac stimulation 3

Endothelial Involvement

Research findings on endothelial involvement are mixed:

• At clinically relevant concentrations (<10 μM), hydralazine's effects in splanchnic resistance vasculature are primarily endothelial in origin 4
• However, other studies suggest hydralazine's vascular relaxation is independent of endothelium 5

Pharmacokinetics

• Rapid absorption after oral administration 1
• Peak plasma levels reached at 1-2 hours 1
• Half-life of 3-7 hours 1
• Extensive hepatic metabolism with excretion mainly as metabolites in urine 1
• Subject to polymorphic acetylation (slow acetylators generally have higher plasma levels and require lower doses) 1

Clinical Considerations

• Hydralazine is often combined with a sympathetic inhibitor (like beta-blockers) to prevent reflex tachycardia and with a diuretic to prevent sodium retention 3
• In heart failure patients, hydralazine increases cardiac output and stroke volume while decreasing vascular resistance 6
• When combined with isosorbide dinitrate, it has shown particular efficacy in African American patients with heart failure, presumed to be related to enhanced nitric oxide bioavailability 7, 8

Common Pitfalls

• Reflex tachycardia can occur without concomitant beta-blocker use 3
• Fluid retention may develop without diuretic therapy 3
• Headache is common, especially early in therapy 3
• Lupus-like syndrome risk with high doses and long-term use 3
• Gastrointestinal complaints are common adverse effects, particularly when combined with isosorbide dinitrate 8

Understanding hydralazine's mechanism as a direct arterial vasodilator that interferes with calcium handling in vascular smooth muscle explains both its therapeutic effects and side effect profile.