Читать книгу Practical Cardiovascular Medicine - Elias B. Hanna - Страница 199

1 Nitrates are venodilators and thus reduce ischemia primarily by reducing preload. They also improve coronary flow by reducing intramyo- cardial diastolic tension, i.e., LVEDP. They are also, to a lesser extent, arterial vasodilators and thus reduce afterload.The dilatation of epicardial coronary arteries is a less important anti-ischemic mechanism than preload reduction, but dilatation of collaterals may be particularly useful. Vasodilators, in general, may worsen myocardial ischemia in critical CAD as they increase flow through the normal coronary arteries at the expense of the abnormal artery that cannot further increase its flow, creating a coronary steal phenomenon through collaterals (e.g., adenosine). This, however, does not usually happen with nitrates as they do not drastically affect the microvascular tone, and thus do not drastically increase coronary flow to the normal myocardium.

2 While sublingual nitroglycerin (NTG) is used as needed (during angina or before exertion) and has a short effect <5 min, long-acting formulations are used as adjunct to background β-blocker or calcium channel blocker therapy:Isosorbide dinitrate (ISDN) 10–40 mg TID, isosorbide mononitrate (ISMN) 30–240 mg Qday, NTG paste 0.5–2 inches TID, NTG patch 0.2–0.6 mg/h Q24h.

3 Tolerance to nitrates develops quickly, within 24 hours of therapy. It is minimized by providing nitrate-free intervals (e.g., administer ISDN at 8 a.m., 2 p.m., and 8 p.m., with 10–14 hours free interval; administer ISMN once daily; or place NTG patch for 12 out of 24 hours every day). However, rebound ischemia may occur during the nitrate-free intervals.

4 Nitrates are metabolized into NO by large arteries. NO promotes the release of cGMP, a smooth muscle relaxant. In contrast to large arteries, arterioles cannot metabolize nitrates into NO.

Nitrate tolerance occurs as the beneficial NO eventually gets metabolized into reactive oxygen species, which reduce NO generation and NO effect and increase the vascular sensitivity to vasoconstrictors; nitrates may, in fact, impair endothelial function.⁴⁷ Neurohormonal activa- tion may also contribute to nitrate tolerance. The same phenomenon leads to vasoconstriction and rebound ischemia in the first 4 hours after nitrate withdrawal in a tolerant patient. Several studies have shown that statin, ACE-I (and possibly ARB), hydralazine, and carvedilol reduce nitrate tolerance as they reduce the production of reactive oxygen species and counteract the neurohormonal activation.^47–50 Thus, with the contemporary drug regimens, nitrate tolerance and rebound are minimized.