A 58-year-old man with stable angina pectoris is prescribed an antianginal drug. He develops tolerance to the drug within 2 weeks of continuous use. Which of the following antianginal agents is most commonly associated with the development of tolerance?

Explanation

## Nitrate Tolerance: The Clinical Problem **Key Point:** Organic nitrates (isosorbide dinitrate, isosorbide mononitrate, nitroglycerin) are the antianginal agents most commonly associated with the development of tolerance when used continuously without a nitrate-free interval. ### Mechanism of Nitrate Tolerance Nitrates require bioconversion by mitochondrial enzymes (particularly mitochondrial aldehyde dehydrogenase, mtALDH) to generate nitric oxide (NO), which activates guanylate cyclase and causes vasodilation. Continuous nitrate exposure leads to: 1. Depletion of sulfhydryl donors (cysteine, glutathione) needed for bioconversion 2. Oxidative stress and increased production of superoxide anion 3. Inactivation of mtALDH enzyme 4. Uncoupling of endothelial NO synthase (eNOS), producing superoxide instead of NO ### Prevention of Nitrate Tolerance **High-Yield:** A **nitrate-free interval of 10–14 hours daily** is essential to prevent tolerance. This allows regeneration of sulfhydryl cofactors and recovery of mtALDH activity. **Clinical Pearl:** Patients on long-acting nitrates (e.g., isosorbide dinitrate 40 mg TDS) should use a dosing schedule such as 8 AM, 1 PM, and 8 PM (with 10 hours nitrate-free from 8 PM to 8 AM) rather than uniform dosing. ### Comparison with Other Antianginals | Agent | Tolerance Risk | Mechanism | Nitrate-Free Interval Needed | |-------|----------------|-----------|------------------------------| | Isosorbide dinitrate | **Very High** | Requires continuous bioconversion | **Yes (10–14 hrs)** | | Isosorbide mononitrate | High | Partially metabolized; still requires mtALDH | Yes | | Nitroglycerin | Very High | Requires bioconversion | Yes | | Amlodipine (CCB) | None | Direct vasodilation; no enzyme dependency | No | | Atenolol (β-blocker) | None | Reduces heart rate/contractility | No | | Ivabradine | None | Selective I~f~ inhibitor; no tolerance | No | **Warning:** Patients often report that "the drug stopped working" after 1–2 weeks of continuous use — this is nitrate tolerance, not treatment failure. Reintroduction of a nitrate-free interval restores efficacy. ## Why Isosorbide Dinitrate? Isosorbide dinitrate is a long-acting organic nitrate that, when dosed without a nitrate-free interval, rapidly depletes the enzymatic capacity for bioconversion. It is the **most commonly encountered cause of antianginal tolerance** in clinical practice because: - It is widely prescribed for stable angina - Many patients (and some prescribers) are unaware of the need for a nitrate-free interval - Continuous dosing is a common prescribing error [cite:KD Tripathi 8e Ch 31]