A patient is started on hydralazine and isosorbide dinitrate combination for heart failure with reduced ejection fraction after failing ACE inhibitor and ARB due to intolerance. The mechanism of benefit is:
- A Nitrates reduce preload via venodilation; hydralazine reduces afterload via arteriolar smooth muscle dilation; together they reduce cardiac work and improve output, and hydralazine also attenuates nitrate tolerance by inhibiting reactive oxygen species generation ✓
- B Hydralazine primarily reduces preload via venodilation; nitrates primarily reduce afterload via arteriolar dilation
- C Both drugs are prodrugs activated by cardiac myocyte esterases to release nitric oxide at the myocardial level
- D Hydralazine activates the renin-angiotensin system and nitrates counteract this by inhibiting renin secretion
Correct answer: A. Nitrates reduce preload via venodilation; hydralazine reduces afterload via arteriolar smooth muscle dilation; together they reduce cardiac work and improve output, and hydralazine also attenuates nitrate tolerance by inhibiting reactive oxygen species generation
Explanation
Isosorbide dinitrate is a venodilator (reduces preload) via NO-mediated cGMP activation. Hydralazine is a direct arteriolar dilator (reduces afterload). The combination reduces ventricular wall stress from both directions. Crucially, hydralazine also scavenges reactive oxygen species (ROS) that oxidise tetrahydrobiopterin and deplete endothelial NOS cofactors — the main mechanism of organic nitrate tolerance — thereby prolonging nitrate efficacy.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.