isosorbide mononitrate

**Class/Mechanism:** Organic nitrate (vasodilator). Metabolized in vascular smooth muscle to nitric oxide (NO) → activates guanylate cyclase → ↑cGMP → ↓intracellular Ca2+ and dephosphorylation of myosin light chain → smooth muscle relaxation. Predominantly venodilation (↓preload, ↓LV wall tension, ↓myocardial O2 demand); at higher doses also dilates arterioles (↓afterload) and epicardial coronary arteries (relieves vasospasm, e.g., Prinzmetal angina).

**Pharmacokinetics:** Active metabolite of isosorbide dinitrate, so it has no first-pass hepatic metabolism. ~100% oral bioavailability and a longer half-life (~4-5 h) than isosorbide dinitrate or nitroglycerin. It is dosed once daily (extended-release) or BID (asymmetric dosing, e.g., 8 AM and 3 PM). It is NOT used for acute angina attacks because onset is too slow. Use sublingual nitroglycerin for acute attacks.

**Clinical uses:** Chronic stable angina prophylaxis (reduces frequency of attacks; no proven mortality benefit). Vasospastic angina. Isosorbide dinitrate + hydralazine is used in HFrEF, with proven mortality benefit in self-identified African American patients (A-HeFT). Nitrates do not improve survival in CAD.

**Adverse effects:** Headache (meningeal vessel dilation; the most common), flushing, orthostatic hypotension, reflex tachycardia (often combined with β-blocker to blunt this), dizziness. Methemoglobinemia is rare (more with other nitrates/nitrites).

**Tolerance:** Continuous exposure leads to tolerance (depleted sulfhydryl groups, neurohormonal activation, ↑oxidative stress). Prevent with a nitrate-free interval of 8-12 h (usually overnight).

**Contraindications/interactions:** - PDE-5 inhibitors (sildenafil, tadalafil, vardenafil): both ↑cGMP, causing profound hypotension. Avoid within 24 h of sildenafil/vardenafil and 48 h of tadalafil. - Riociguat (sGC stimulator). - Caution with hypertrophic obstructive cardiomyopathy, severe aortic stenosis, right ventricular infarct (preload dependent), and increased intracranial pressure.

**Board pearls:** - Nitrates + β-blockers: the β-blocker counteracts reflex tachycardia, and nitrates counteract the β-blocker's increase in end-diastolic volume. - Nitrates ↓ preload, so they ↓ end-diastolic volume and ↓ wall tension (law of Laplace), reducing O2 demand. - Compared with nitroglycerin: nitroglycerin is used for acute attacks (sublingual) and IV for ACS/hypertensive emergency/acute HF. Isosorbide mononitrate and dinitrate are used for chronic prophylaxis. - Nitroprusside is a different drug (NO donor for hypertensive emergency; risk of cyanide toxicity).