ORGANICNITRATES

Biological Functions

The oxygen requirements of the myocardial tissues are related to the workload (oxygen demand) of the heart, which is, in part, a function of the heart rate, the systolic pressure, and the peripheral resistance of the blood flow (oxygen supply). Myocardial ischemia occurs when the oxygen supply is insufficient to meet the myocardial oxygen demand. This can occur, as explained previously, because of atherosclerotic narrowing of the coronary circulation (typical) or vasospasm of the coronary artery (variant). The nitrates have been shown to be effective in treating angina resulting from either cause. The vasodilating effect of organic nitrates on the veins leads to pooling of the blood in the veins and decreased venous return to the heart (decreased preload), whereas vasodilation of the coronary arterioles decreases the resistance of the peripheral tissues (decreased afterload). The decrease in both preload and afterload results in a generalized decrease in the myocardial workload, which translates into a reduced oxygen demand by the myocardium. Organic nitrates restore the balance between oxygen supply by venous dilation and oxygen demand by decreasing the myocardial workload.

Mechanism of action

The organic nitrates are pharmacological sources of nitric oxide (NO) for the body. In the cardiovascular system, NO is naturally produced by vascular endothelial cells. This endothelialderived NO has several important functions, including relaxation of vascular smooth muscle, inhibiting platelet aggregation (antithrombotic), and inhibiting leukocyte-endothelial interactions (anti-inflammatory). These actions involve NO-stimulated formation of cyclic guanosine monophosphate (cGMP). Nitrodilators are drugs that mimic the actions of endogenous NO by releasing NO or forming NO within tissues. Free tissue sulfhydryl groups play a key role in the venodilation effect of nitroglycerin, which is supported by experimental evidence showing that prior administration of N-acetylcysteine, which should increase the availability of free sulfhydryl groups, resulted in an increase in the venodilating effect of organic nitrates. Similarly, pretreatment with reagents that react with free sulfhydryl groups, such as ethacrynic acid, blocked glyceryl trinitrate venodilation in vitro. A more complex mechanism for nitrate venodilation, however, was proposed by Ignarro et al.. They suggested that the nitrates act indirectly, by stimulating the enzyme guanylate (also known as guanylyl) cyclase and, thereby, producing elevated levels of cGMP, which in turn leads to venodilation. The initial stimulation of soluble guanylate cyclase is believed to be mediated by a nitrate-derived nitrosothiol metabolite produced intracellularly.

Clinical Use

Organic nitrates are used for both treatment and prevention of painful anginal attacks. The therapeutic approaches to achieve these two goals, however, are distinctly different. For the treatment of acute anginal attacks (i.e., attacks that have already begun), a rapid-acting preparation is required. In contrast, preventative therapy requires a long-acting preparation with more emphasis on duration and less emphasis on onset. The onset of organic nitrate action is influenced not only by the specific agent chosen but also by the route of administration. Sublingual administration is used predominantly for a rapid onset of action. The duration of nitrate action is strongly influenced by rate of metabolism. All of the organic nitrates are subject to rapid first-pass metabolism not only by the action of glutathione-nitrate reductase in the liver, but also in extrahepatic tissues, such as the blood vessel walls themselves. In addition, rapid uptake into the vessel walls plays a significant role in the rapid disappearance of organic nitrates from the bloodstream. Sublingual, transdermal, and buccal administration routes have been used in an attempt to avoid at least some of the hepatic metabolism.

Side effects

Most patients tolerate the nitrates fairly well. Headache and postural hypotension are the most common side effects of organic nitrates. Dizziness, nausea, vomiting, rapid pulse, and restlessness are among the additional side effects reported. These symptoms may be controlled by administering low doses initially and then gradually increasing the dose. Fortunately, tolerance to nitrate-induced headache develops after a few days of therapy. Because postural hypotension may occur in some individuals, advise the patient to sit down when taking a rapid-acting nitrate preparation for the first time. An effective dose of nitrate usually produces a fall in upright systolic pressure of 10 mm Hg and a reflex rise in heart rate of 10 beats per minute.
Another concern associated with prophylactic nitrate use is the development of tolerance. Tolerance, usually in the form of shortened duration of action, is commonly observed with chronic nitrate use. The clinical importance of this tolerance is, however, a matter of controversy. Because tolerance to nitrates has not been reported to lead to a total loss of activity, some physicians feel that it is not clinically relevant. In addition, an adjustment in dosage can compensate for the reduced response. It also has been reported that intermittent use of long-acting and sustained-release preparations may limit the extent of tolerance development.

Drug interactions

The most significant interactions of organic nitrates are with those agents that cause hypotension, such as other vasodilators, alcohol, and tricyclic antidepressants, in which the potential for orthostatic hypotension may arise. On the other hand, concurrent administration with sympathomimetic amines, such as ephedrine and norepinephrine, may lead to a decrease in the antianginal efficacy of the organic nitrates.

Metabolism

Acute angina most frequently is treated with sublingual glyceryl trinitrate. This sublingual preparation is rapidly absorbed from the sublingual, lingual, and buccal mucosa and usually provides relief within 2 minutes. The duration of action also is short (~30 minutes). Other treatments include amyl nitrite by inhalation and sublingual isosorbide dinitrate. Amyl nitrite is by far the fastest-acting preparation, with an onset of action in approximately 15 to 30 seconds, but the duration of action is only approximately 1 minute. Isosorbide dinitrate, although usually used as a long-acting agent, may be used to treat acute angina. Sublingually administered isosorbide dinitrate has a somewhat slower onset than glyceryl trinitrate (~3 minutes), but its action may last for 4 to 6 hours. Although the onset appears to be almost as rapid as that of glyceryl trinitrate, waiting an additional minute for relief may be deemed unacceptable by some patients.