Which of the following antianginal drugs acts primarily by inhibiting mitochondrial aldehyde dehydrogenase, leading to nitrate tolerance with continuous use?

Explanation

## Mechanism of Nitrate Tolerance **Key Point:** Organic nitrates (isosorbide dinitrate, isosorbide mononitrate, nitroglycerin) require bioconversion by mitochondrial aldehyde dehydrogenase (mtALDH) to release nitric oxide (NO), the active vasodilator. ### Nitrate Tolerance Pathophysiology Continuous exposure to nitrates leads to: 1. **Enzyme inhibition** — mtALDH becomes inactivated by oxidative stress and depletion of sulfhydryl cofactors (cysteine, glutathione) 2. **Loss of bioconversion** — organic nitrate cannot be metabolized to NO 3. **Clinical consequence** — loss of antianginal efficacy despite continued dosing ### Prevention Strategy **High-Yield:** A **nitrate-free interval** (10–14 hours daily) is mandatory to allow enzyme regeneration and prevent tolerance. This is why long-acting nitrates are dosed asymmetrically (e.g., 8 AM and 2 PM, not round-the-clock). **Clinical Pearl:** Concomitant use of ACE inhibitors or statins may reduce tolerance risk by preserving endothelial function and reducing oxidative stress. ## Comparison with Other Antianginals | Drug | Mechanism | Tolerance Risk | | --- | --- | --- | | **Isosorbide dinitrate** | mtALDH-dependent NO release | High (requires nitrate-free interval) | | **Diltiazem** | L-type Ca²⁺ channel blockade | None | | **Ivabradine** | If channel inhibition (heart rate reduction) | None | | **Ranolazine** | Late Na⁺ current inhibition | None | **Warning:** Continuous nitrate dosing without a nitrate-free interval rapidly leads to complete loss of antianginal effect — a common clinical pitfall.