isosorbide dinitrate

MECHANISM: Isosorbide dinitrate (ISDN) is a prodrug that is denitrated (via mitochondrial aldehyde dehydrogenase, ALDH2) to release nitric oxide (NO). NO activates guanylate cyclase, which raises cGMP. Increased cGMP activates protein kinase G, which causes dephosphorylation of myosin light chain, and that produces smooth muscle relaxation. Effect is predominantly VENODILATION at low doses (and arteriolar dilation at higher doses). Venodilation decreases venous return (preload), which lowers LV end-diastolic volume and wall tension and therefore myocardial O2 demand. It also dilates epicardial coronary arteries and relieves coronary vasospasm (useful in Prinzmetal/variant angina).

CLINICAL USES: - Chronic stable angina prophylaxis (oral ISDN, isosorbide mononitrate; not for acute attacks - sublingual nitroglycerin is used for acute relief). - HFrEF: ISDN + hydralazine. Indicated in self-identified Black patients with NYHA III-IV HFrEF on optimal therapy (A-HeFT trial showed mortality benefit), and in patients who cannot tolerate ACEi/ARB/ARNI (e.g., renal insufficiency, hyperkalemia). Nitrate reduces preload; hydralazine reduces afterload (arteriolar dilator). Hydralazine also may help prevent nitrate tolerance (antioxidant effect). - Esophageal spasm (less common).

PHARMACOKINETICS: Oral bioavailability is low and variable because of extensive first-pass hepatic metabolism. Active metabolites include isosorbide-5-mononitrate (also available as its own drug, with ~100% bioavailability and no first-pass effect) and isosorbide-2-mononitrate. ISDN has a longer duration than nitroglycerin.

ADVERSE EFFECTS: Throbbing headache (meningeal vessel dilation), flushing, dizziness, orthostatic hypotension, and reflex tachycardia (blunted by co-administration of a beta-blocker, which is why combination therapy is used in angina). Methemoglobinemia is rare (more with high-dose nitrites/nitrates). - Tolerance: continuous exposure causes loss of efficacy (depletion of sulfhydryl groups, oxidative stress, neurohormonal activation). Prevented by a nitrate-free interval of about 10-14 hours (typically overnight). - Monitoring: Avoid abrupt withdrawal because of rebound angina.

CONTRAINDICATIONS / KEY INTERACTIONS: - PDE-5 inhibitors (sildenafil, tadalafil, vardenafil) and riociguat: both increase cGMP, so the combination causes severe, potentially fatal hypotension. - Hypertrophic obstructive cardiomyopathy (reduced preload worsens outflow obstruction). - Severe aortic stenosis (preload-dependent, risk of syncope/hypotension). - Right ventricular infarction (preload-dependent). - Elevated intracranial pressure (venodilation of cerebral vessels can increase ICP) and hypotension.

BOARD PEARLS: - Nitrates: ↓ preload (venodilation) → ↓ LV wall tension → ↓ O2 demand. Beta-blocker + nitrate has a synergistic effect on lowering O2 demand (beta-blocker prevents reflex tachycardia; nitrate prevents the increase in end-diastolic volume caused by beta-blockade). - Nitrates do not improve mortality in stable CAD, only symptoms (exceptions: the ISDN/hydralazine combination in HFrEF improves survival in Black patients). - Nitrate-free interval prevents tolerance. - "Monday disease" in nitrate-exposed munitions workers: tolerance develops during the week, then loss of tolerance over the weekend causes headache, dizziness, and tachycardia on re-exposure; withdrawal can cause angina or sudden death. - Cyanide toxicity is associated with nitroprusside, not organic nitrates.