Nitrates are also useful in the treatment of the acute coronary syndrome of unstable angina, but the precise mechanism for their beneficial effects is not clear. Because both increased coronary vascular tone and increased myocardial oxygen demand can precipitate rest angina in these patients, nitrates may exert their beneficial effects both by dilating the epicardial coronary arteries and by simultaneously reducing myocardial oxygen demand. As previously noted, nitroglycerin also decreases platelet aggregation, and this effect may be of importance in unstable angina.
Clinical Use of Nitrates
Some of the forms of nitroglycerin and its congeners and their doses are listed in Table 12–3. Because of its rapid onset of action (1–3 minutes), sublingual nitroglycerin is the most frequently used agent for the immediate treatment of angina. Because its duration of action is short (not exceeding 20–30 minutes), it is not suitable for maintenance therapy. The onset of action of intravenous nitroglycerin is also rapid (minutes), but its hemodynamic
TABLE 12–3 Nitrate and nitrite drugs used in the treatment of angina.
effects are quickly reversed when the infusion is stopped. Clinical use of intravenous nitroglycerin is therefore restricted to the treatment of severe, recurrent rest angina. Slowly absorbed preparations of nitroglycerin include a buccal form, oral preparations, and several transdermal forms. These formulations have been shown to provide blood concentrations for long periods but, as noted above, this leads to the development of tolerance.
The hemodynamic effects of sublingual or chewable isosorbide dinitrate and the oral organic nitrates are similar to those of nitroglycerin given by the same routes. Although transdermal administration may provide blood levels of nitroglycerin for 24 hours or more, the full hemodynamic effects usually do not persist for more than 8–10 hours. The clinical efficacy of slow-release forms of nitroglycerin in maintenance therapy of angina is thus limited by the development of tolerance. Therefore, a nitrate-free period of at least 8 hours between doses of long-acting and slow-release forms should be observed to reduce or prevent tolerance.
Nicorandil is a nicotinamide nitrate ester that has vasodilating properties in normal coronary arteries but more complex effects in patients with angina. Recent studies in isolated myocytes indicate that the drug activates an Na+/Ca2+ exchanger and reduces intracellular Ca2+ overload. Clinical studies suggest that it reduces both preload and afterload. It also provides some myocardial protection via preconditioning by activation of cardiac KATP channels. One large trial showed a significant reduction in relative risk of fatal and nonfatal coronary events in patients receiving the drug. Nicorandil is currently approved for use in the treatment of angina in Europe and Japan but has not been approved in the USA. Molsidomine is a prodrug that is converted to a nitric oxide–releasing metabolite. It is said to have efficacy comparable to that of the organic nitrates and is not subject to tolerance. Recent studies suggest that it may reduce cerebral vasospasm in stroke. It is not available in the USA.
It has been known since the late 1800s that transmembrane calcium influx is necessary for the contraction of smooth and cardiac muscle. The discovery of a calcium channel in cardiac muscle was followed by the finding of several different types of calcium channels in different tissues (Table 12–4). The discovery of these channels made possible the measurement of the calcium current, ICa, and subsequently, the development of clinically useful blocking drugs. Although the blockers currently available for clinical use in cardiovascular conditions are exclusively L-type calcium channel blockers, selective blockers of other types of calcium channels are under intensive investigation. Certain antiseizure drugs are thought to act, at least in part, through calcium channel (especially T-type) blockade in neurons (see Chapter 24).