CHAPTER 26 Antianginal Drugs
Angina pectoris (from the Latin, literally meaning “pain in the chest”) is usually manifested as severe, transient, retrosternal pain that sometimes radiates to the left arm, back, or jaw. It is frequently accompanied by fear, anxiety, feelings of suffocation, and a sensation of tightening of the chest. There is a wide variation among individuals in the intensity and quality of the pain, and some ischemic episodes may occur without prominent symptoms. The pain and associated changes in the electrocardiogram (e.g., depressed ST segment) result from ischemia (hypoxia) of some area of the myocardium, usually a subendocardial area. The most frequent pathologic cause of angina is epicardial coronary artery atherosclerosis leading to compromised blood flow and reduced oxygen delivery to a region of the myocardium. Angina may also result from vasospasm; the coronary vasoconstriction frequently occurs at an atherosclerotic site on the artery.
As shown in Figure 26-1, the normal response to increased myocardial oxygen demand is satisfied by vasodilation of the small coronary resistance vessels, increased blood flow, and increased oxygen supply. In contrast, in the classic anginal patient with exertional (exercise-induced) episodes, significant sclerosis (>70% narrowing of the luminal diameter) of the large conductance arteries precludes increased vasodilation in response to increased myocardial work because the poststenotic resistance vessels are already dilated, and the resultant demand for oxygen cannot be met. Cardiac determinants of oxygen consumption and factors that can precipitate changes in these determinants are also shown in Figure 26-1.
The intraventricular pressure is important in determining flow in subendocardial regions because of compression of blood vessels in the involved area. Coronary blood flow occurs primarily during diastole, when the intraventricular pressure is least. Increased heart rate decreases the diastolic time more than the systolic and requires increased oxygen supply in concert with the increased rate of metabolism. Alterations of ventricular size also cause concurrent changes in ventricular work and oxygen demand. Finally, the inotropic state of the myocardium is also a factor in determining oxygen consumption. An important control of myocardial contractility is exerted by the sympathetic nervous system through catecholamine release.
It is beyond the scope of this chapter to consider in detail the specific changes in the cardiac determinants of myocardial oxygen consumption caused by each of the factors that may precipitate an anginal attack. It is sufficient to say that any factor that compromises the balance between oxygen demand and oxygen supply may cause an attack of angina. Anginal pain may follow exercise, emotional upset, or exposure to cold or may occur after meals or smoking. Certain individuals have nocturnal attacks of angina, probably because recumbent posture can increase venous return to the heart and cardiac work. Anginal attacks in susceptible patients may also result from self-medication with various drugs, such as cocaine and cold remedies that contain sympathomimetic agents.
There are three types of angina pectoris: chronic stable angina (classic exertional angina), variant (Prinzmetal’s) angina, and unstable angina (also known as preinfarction angina, intermediate coronary syndrome, acute coronary insufficiency, and accelerated angina). Chronic stable angina occurs in patients who have fixed atherosclerotic coronary artery disease. Pain in these individuals occurs when the myocardial oxygen requirement reaches a given stable value. Variant angina occurs as a result of coronary artery spasm and a subsequent decrease in coronary blood flow and oxygen supply. These patients usually also exhibit coronary atherosclerosis, although it may be minimal in some. Variant angina is characterized by chest pain occurring at rest and, frequently, during sleep. The third type, unstable angina, refers to a new onset of severe, frequent angina, anginal pain at rest, or a sudden worsening of pain in a patient with previously stable exertional angina.18 The cause of unstable angina is often sudden platelet aggregation or plaque emboli in coronary vessels. Most of these patients have severe coronary artery disease; coronary spasm may also be involved. Of patients with chest pain, 30% have unstable angina, and it was estimated that 20% of these patients will have a myocardial infarct within a year and most within a month.11 More recent studies suggest that compared with conservative management, early invasive treatment of patients with unstable angina using coronary angiography with or without revascularization reduces mortality and myocardial infarction at 2 and 5 years.10
Six classes of drugs are used extensively in the treatment of angina pectoris; Figure 26-2 shows the sites of action of β-adrenergic receptor blockers, Ca++ channel blockers (CCBs), and nitrates/nitrites. The first class, organic nitrites and nitrates, comprises drugs (e.g., sublingual nitroglycerin) that provide immediate relief from anginal symptoms or provide prophylaxis of an attack and nitrate formulations (e.g., topical nitroglycerin, oral isosorbide dinitrate) that are promoted for long-term protection from anginal episodes.
FIGURE 26-2 Sites of action of β-adrenergic receptor blockers, Ca++ channel blockers (CCBs), and nitrates/nitrites. β Blockers reduce the rate and contractility of the heart, reducing energy and oxygen demand of the heart. CCBs reduce vasoconstriction in coronary and noncoronary vessels, increasing coronary blood flow and reducing cardiac load. The nitrates/nitrites act primarily on systemic blood vessels to reduce cardiac load. The effect on coronary arteries is less a factor in alleviating classic angina but plays a major role in variant angina. Three anatomic levels are shown: cardiac anatomy, cell layers of the blood vessel walls, and a blood vessel smooth muscle cell membrane showing a Ca++ channel and the effect of CCBs in preventing Ca++ entry.
The second class contains β-adrenergic receptor–blocking agents (β blockers). These drugs are administered on a long-term basis, frequently in conjunction with organic nitrates, to decrease the frequency and severity of anginal attacks.
The third class of drugs useful in the management of angina comprises calcium channel blockers (CCBs). This class includes verapamil, diltiazem, nifedipine, and others. These agents, similar to the β blockers, are used prophylactically in angina therapy.
The fourth class of drugs targets blood-clotting mechanisms and comprises aspirin, other antiplatelet drugs, and anticoagulants. Aspirin is used to treat stable and unstable angina. The pharmacologic features of aspirin are discussed in detail in Chapter 21. It acts by inhibiting platelet aggregation through irreversible inhibition of cyclooxygenase.
The fifth class is represented by ranolazine, which was approved by the U.S. Food and Drug Administration in 2006 for the treatment of chronic angina in patients who have failed to respond to other angina therapy. The sixth class is represented by trimetazidine, a novel anti-ischemic drug with properties unrelated to changes in myocardial oxygen supply/demand ratio.3 Trimetazidine is considered to be a metabolic agent that modifies substrate use in chronic heart failure.1 This drug can lessen oxidation of free fatty acids via inhibition of the enzyme long-chain 3-ketoacyl coenzyme A thiolase, which is crucial in the β-oxidation pathway. Trimetazidine has a favorable side-effect profile and exhibits no notable vasodilator properties at rest or during dynamic exercise.15 It is not discussed further.
Amyl nitrite was introduced for use in angina pectoris in 1867, and nitroglycerin (glyceryl trinitrate) was introduced in 1879. Since then, nitroglycerin has remained the drug of choice for the relief of acute symptoms of angina pectoris. Nitroglycerin is administered sublingually as a tablet or aerosol spray and has a quick onset and short duration of action. Various organic nitrates and sustained-release forms of nitroglycerin have been developed in attempts to find a suitable, long-lasting preparation for the control and prevention of anginal pain. Amyl nitrite is used by inhalation for angina pectoris. Its use in the treatment of cyanide poisoning is discussed in Chapter 52.
Nitroglycerin is chemically a simple compound. Figure 26-3 shows its structure and, for comparison, the structures of some of the other organic nitrates marketed for oral, topical, sublingual, buccal, inhalant, or intravenous administration. All nitrites and nitrates with antianginal activity are esters of nitrous or nitric acid. Organic nitrites and nitrates are capable of being metabolized to yield the free radical nitric oxide (NO). Research in this area led to the Nobel Prize for Physiology/Medicine being awarded in 1998 to Robert Furchgott, Louis Ignarro, and Ferid Murad for their discovery of NO as a signaling molecule in the cardiovascular system. Previous studies had identified a vasodilator substance released from endothelial cells and referred to as endothelium-derived relaxing factor. Experimental evidence from several laboratories indicates that endothelium-derived relaxing factor is NO.12 NO is the active intermediate of vasoactive nitrites and nitrates, which are appropriately referred to collectively as nitrovasodilators. (See Figure 8-3 for further information on NO.)
FIGURE 26-3 Structural formulas and methods of administration of selected organic nitrates and amyl nitrite. B, Buccal (transmucosal) tablet; C, sustained-release capsule or tablet; D, transdermal disk; Inh, inhalant; IV, intravenous injection; O, ointment; S, lingual spray; T, sublingual tablet; TC, chewable tablet; TO, oral tablet or capsule.
The pharmacologic effects of all the members of this class are similar and result from actions of NO released by denitration reactions of the parent drugs in the tissues. It is likely that mitochondrial aldehyde dehydrogenase plays an essential role in the synthesis of NO from nitroglycerin bioactivation, resulting in dilation of blood vessels.6 NO has been shown to stimulate the synthesis of cyclic 3′,5′-guanosine monophosphate (cGMP) by a direct action on cytosolic guanylyl cyclase or indirectly by being converted to S-nitrosothiols, which stimulate the enzyme (Figure 26-4; see also Figure 8-3). cGMP initiates a cascade of reactions involving cGMP-dependent protein kinases leading to the various cellular responses that relax vascular smooth muscle.
The most important action of nitrovasodilators is the direct relaxation of vascular smooth muscle by the metabolite NO, resulting in vasodilation first in veins at low doses and then in arteries at higher doses. Nitroglycerin has been shown to cause varying degrees of change in coronary flow in normal and diseased mammalian hearts. Its efficacy in the various types of angina is attributed in part to a preferentially increased oxygen supply to ischemic areas, with variable actions on total coronary blood flow. More important, through a reduction in venous tone, there is a reduction in venous pressure, pulmonary arterial pressure, and end-diastolic filling pressure. These actions lead to a decrease in ventricular volume, producing a decrease in intramyocardial tension and a decline in myocardial oxygen demand. Nitrovasodilators tend to cause redistribution of coronary blood flow to the more ischemic areas. As implied earlier, arterial smooth muscle is relaxed by these drugs, although to a lesser degree than venous smooth muscle. The efficacy of nitrates and nitrites in relieving variant angina probably stems from a direct alleviation of coronary artery spasm.
Nitrates and nitrites also relax nonvascular smooth muscle. Bronchial, biliary, and gastrointestinal smooth muscle is relaxed. This action is the basis for the use of nitrates such as isosorbide dinitrate for the treatment of esophageal spasms. The major use of these drugs is based, however, on their cardiovascular actions.
Nitroglycerin is rapidly absorbed after sublingual administration (onset 1 to 3 minutes, duration 30 to 60 minutes). An advantage of the aerosol spray over the sublingual tablet is the better absorption in patients with dry mucous membranes. Nitroglycerin has a much slower onset when applied topically to the skin in a patch or ointment, but has a comparably longer duration of action. Although organic nitrates administered orally are readily absorbed, they are extensively metabolized during the first pass through the liver.
In addition to undergoing denitration reactions in tissues, nitrates are metabolized in the liver by glutathione–organic nitrate reductase. The products of hepatic biotransformation, including the released nitrite ions, are much less effective than the parent compound; they are subsequently excreted in the urine, at least in part, in the form of glucuronide conjugates. Isosorbide dinitrate is exceptional because its principal metabolite, the mononitrate, is responsible for most of its action and is now available separately for clinical use.
Although sublingual nitroglycerin is highly effective for the treatment of acute anginal episodes, its short duration of action makes it unsuitable for long-term prophylaxis. Several nitrates formulated for oral administration have been marketed for many years for the prevention of anginal attacks. The vasodilatory effects of isosorbide dinitrate were discovered in the 1930s, and the drug was introduced in the 1960s as an oral preparation. When administered sublingually, isosorbide dinitrate (see Figure 26-3) was shown to be comparable to nitroglycerin. When administered orally in recommended dosages, this compound offered no protection against exercise-induced angina. Subsequent investigations showed, however, that large doses of isosorbide dinitrate (and nitroglycerin) improve exercise tolerance in patients with angina. There is a concomitantly increased possibility of drug toxicity.
Newer long-acting mononitrates, which are major active metabolites of isosorbide dinitrate, offer the advantage of improved bioavailability because they avoid first-pass hepatic elimination. Isosorbide-5-mononitrate, which is at least as effective as isosorbide dinitrate, is available as immediate-release tablets and as a sustained-release formulation for once-daily administration. The clinical efficacy of a single dose of isosorbide mononitrate formulated as a 30% immediate-release/70% sustained-release formulation is observed within a few minutes to increase work and exercise capacity.2 More recent evidence indicates that nitrates reduce platelet aggregation and adhesion in patients with acute myocardial infarction. This finding suggests a possible added benefit of nitrates.9
To avoid the first-pass phenomenon that plagues orally administered nitrates, nitroglycerin has been prepared in several other forms. The first of these, nitroglycerin ointment, is effective prophylactically, but it must be administered every 3 to 4 hours. A further development is the nitroglycerin transdermal system, which comes in the form of an adhesive patch. When applied to the skin, the transdermal patch slowly releases nitroglycerin over a 24-hour period. This system minimizes the potential for toxicity inherent in large-dose oral administration, and it overcomes the inconvenience and frequency of application associated with the ointment. Nitroglycerin is also marketed in a transmucosal preparation. Supplied in a matrix, the drug is made available in a sustained-release fashion when placed between the upper lip and teeth. Swallowing or chewing increases the rate of absorption and could lead to toxicity. The advantages of this preparation are its rapid onset and extended action.
One problem shared by all the long-acting preparations is the development of tolerance. In vitro studies suggest that the causes include volume expansion and tissue tolerance resulting partly from enzyme changes. Such tolerance is not observed with the intermittent administration of sublingual nitroglycerin. Intermittent transdermal administration (12 hours on, 12 hours off) has been used to avoid the development of tolerance; however, questions still remain concerning the increased risk of precipitating unstable angina and myocardial infarction during the nontreated periods, especially if they occur during the early morning hours.
Nitrates have a place in the prophylactic treatment of patients with angina pectoris because their efficacy is not in doubt. Some practical problems are associated with their use, however, such as unreliable absorption, short duration />