Chapter 12. Drugs Used in the Treatment of Angina Pectoris

Angina pectoris refers to a strangling or pressure-like pain caused by cardiac ischemia. The pain is usually located substernally but is sometimes perceived in the neck, shoulder and arm, or epigastrium. Women develop angina at a later age than men and are less likely to have classic substernal pain. Drugs used in angina exploit two main strategies: reduction of oxygen demand and increase of oxygen delivery to the myocardium.

Types of Angina

Atherosclerotic Angina

Atherosclerotic angina is also known as angina of effort or classic angina. It is associated with atheromatous plaques that partially occlude one or more coronary arteries. When cardiac work increases (eg, in exercise), the obstruction of flow and inadequate oxygen delivery results in the accumulation of acidic metabolites and ischemic changes that stimulate myocardial pain endings. Rest usually leads to complete relief of the pain within 15 min. Atherosclerotic angina constitutes about 90% of angina cases.

Vasospastic Angina

Vasospastic angina, also known as rest angina, variant angina, or Prinzmetal's angina, is responsible for less than 10% of cases. It involves reversible spasm of coronaries, usually at the site of an atherosclerotic plaque. Spasm may occur at any time, even during sleep. Vasospastic angina may deteriorate into unstable angina.

Unstable Angina

A third type of angina—unstable or crescendo angina, also known as acute coronary syndrome—is characterized by increased frequency and severity of attacks that result from a combination of atherosclerotic plaques, platelet aggregation at fractured plaques, and vasospasm. Unstable angina is thought to be the immediate precursor of a myocardial infarction and is treated as a medical emergency.

The pharmacologic treatment of coronary insufficiency is based on the physiologic factors that control myocardial oxygen requirement. A major determinant is myocardial fiber tension (the higher the tension, the greater the oxygen requirement). Several variables contribute to fiber tension (Figure 12–1), as discussed next. Note that several of these variables are increased by sympathetic discharge.

Preload (diastolic filling pressure) is a function of blood volume and venous tone. Venous tone is mainly controlled by sympathetic outflow. Afterload is determined by arterial blood pressure and large artery stiffness. It is one of the systolic determinants of oxygen requirement.

Heart rate contributes to total fiber tension because at fast heart rates, fibers spend more time at systolic tension levels. Furthermore, at faster rates, diastole is abbreviated, and diastole constitutes the time available for coronary flow (coronary blood flow is low or nil during systole). Heart rate and systolic blood pressure may be multiplied to yield the double product, a measure of cardiac work and therefore of oxygen requirement. As intensity of exercise (eg, running on a treadmill) increases, demand for cardiac output increases, so the double product also increases. However, the double product is sensitive to sympathetic tone, as is cardiac oxygen demand (Figure 12–1). In patients with atherosclerotic angina, effective drugs reduce the double product by reducing cardiac work without reducing exercise capacity.

Force of cardiac contraction is another systolic factor controlled mainly by sympathetic outflow to the heart. Ejection time for ventricular contraction is inversely related to force of contraction but is also influenced by impedance to outflow. Increased ejection time (prolonged systole) increases oxygen requirement.

The defect that causes anginal pain is inadequate coronary oxygen delivery relative to the myocardial oxygen requirement. This defect can be corrected—at present—in 2 ways: by increasing oxygen delivery and by reducing oxygen requirement (Figure 12–2). Traditional pharmacologic therapies include the nitrates, the calcium channel blockers, and the β blockers.

A newer strategy attempts to increase the efficiency of oxygen utilization by shifting the energy substrate preference of the heart from fatty acids to glucose. Drugs that may act by this mechanism are termed partial fatty acid oxidation inhibitors (pFOX inhibitors) and include ranolazine and trimetazidine. However, more recent evidence suggests that the major mechanism of action of ranolazine is inhibition of late sodium current (see below). Another new group of antianginal drugs selectively reduces heart rate with no other detectable hemodynamic effects. These investigational drugs (ivabradine is the prototype) act by inhibition of the sinoatrial pacemaker current, If.

The nitrates, calcium blockers, and β blockers all reduce the oxygen requirement in atherosclerotic angina. Nitrates and calcium channel blockers (but not β blockers) can also increase oxygen delivery by reducing spasm in vasospastic angina. Myocardial revascularization corrects coronary obstruction either by bypass grafting or by angioplasty (enlargement of the lumen by means of a special catheter). Therapy of unstable angina differs from that of stable angina in that urgent angioplasty is the treatment of choice in most patients and platelet clotting is the major target of drug therapy. A variety of platelet inhibitors are used in this condition (see Chapter 34). Intravenous nitroglycerin is sometimes of value.

Classification and Pharmacokinetics

Nitroglycerin (the active ingredient in dynamite) is the most important of the therapeutic nitrates and is available in forms that provide a range of durations of action from 10–20 min (sublingual for relief of acute attacks) to 8–10 h (transdermal for prophylaxis) (see the Drug Summary Table at the end of the chapter). Nitroglycerin (glyceryl trinitrate) is rapidly denitrated in the liver and in smooth muscle—first to the dinitrate (glyceryl dinitrate), which retains a significant vasodilating effect; and more slowly to the mononitrate, which is much less active. Because of the high enzyme activity in the liver, the first-pass effect for nitroglycerin is about 90%. The efficacy of oral (swallowed) nitroglycerin probably results from the high levels of glyceryl dinitrate in the blood. The effects of sublingual nitroglycerin are mainly the result of the unchanged drug because this route avoids the first-pass effect (see Chapters 1 and 3).

Other nitrates are similar to nitroglycerin in their pharmacokinetics and pharmacodynamics. Isosorbide dinitrate is another commonly used nitrate; it is available in sublingual and oral forms. Isosorbide dinitrate is rapidly denitrated in the liver and smooth muscle to isosorbide mononitrate, which is also active. Isosorbide mononitrate is available as a separate drug for oral use. Several other nitrates are available for oral use and, like the oral nitroglycerin preparation, have an intermediate duration of action (4–6 h). Amyl nitrite is a volatile and rapid-acting vasodilator that was used for angina by the inhalational route but is now rarely prescribed.

Mechanism of Action

Nitrates release nitric oxide (NO) within smooth muscle cells, probably through the action of the mitochondrial enzyme aldehyde dehydrogenase-2 (ALD2). NO stimulates guanylyl cyclase and causes an increase of the second messenger cGMP (cyclic guanosine monophosphate); the latter results in smooth muscle relaxation by dephosphorylation of myosin light-chain phosphate (Figure 12–3). Note that this mechanism is identical to that of nitroprusside (see Chapter 11).

Organ System Effects

Cardiovascular

Smooth muscle relaxation by nitrates leads to an important degree of venodilation, which results in reduced cardiac size and cardiac output through reduced preload. Relaxation of arterial smooth muscle may increase flow through partially occluded epicardial coronary vessels. Reduced afterload, from arteriolar dilation of resistance vessels, may contribute to an increase in ejection and a further decrease in cardiac size. Some studies suggest that of the vascular beds, the veins are the most sensitive, arteries less so, and arterioles least sensitive. Venodilation leads to decreased diastolic heart size and fiber tension. Arteriolar dilation leads to reduced peripheral resistance and blood pressure. These changes contribute to an overall reduction in myocardial fiber tension, oxygen consumption, and the double product. Thus, the primary mechanism of therapeutic benefit in atherosclerotic angina is reduction of the oxygen requirement. A secondary mechanism—namely, an increase in coronary flow via collateral vessels in ischemic areas—has also been proposed. In vasospastic angina, a reversal of coronary spasm and increased flow can be demonstrated. Nitrates have no direct effects on cardiac muscle, but significant reflex tachycardia and increased force of contraction are common results when nitroglycerin reduces the blood pressure. These compensatory effects result from the baroreceptor mechanism shown in Figure 6–4.

Other Organs

Nitrates relax the smooth muscle of the bronchi, gastrointestinal tract, and genitourinary tract, but these effects are too small to be clinically useful. Intravenous nitroglycerin (sometimes used in unstable angina) reduces platelet aggregation. There are no clinically useful effects on other tissues.

Clinical Uses

As previously noted, nitroglycerin is available in several formulations (see Drug Summary Table). The standard form for treatment of acute anginal pain is the sublingual tablet or spray, which has a duration of action of 10–20 min. Sublingual isosorbide dinitrate is similar with a duration of 30 min. Oral (swallowed) normal-release formulations of nitroglycerin and isosorbide dinitrate have durations of action of 4–6 h. Sustained-release oral forms have a somewhat longer duration of action. Transdermal formulations (ointment or patch) can maintain blood levels for up to 24 h. Tolerance develops after 8–10 h, however, with rapidly diminishing effectiveness thereafter. It is therefore recommended that nitroglycerin patches be removed after 10–12 h to allow recovery of sensitivity to the drug.

Toxicity of Nitrates and Nitrites

The most common toxic effects of nitrates are the responses evoked by vasodilation. These include tachycardia (from the baroreceptor reflex), orthostatic hypotension (a direct extension of the venodilator effect), and throbbing headache from meningeal artery vasodilation.

Nitrates interact with sildenafil and similar drugs promoted for erectile dysfunction. These agents inhibit a phosphodiesterase isoform (PDE5) that metabolizes cGMP in smooth muscle (Figure 12–4). The increased cGMP in erectile smooth muscle relaxes it, allowing for greater inflow of blood and more effective and prolonged erection. This effect also occurs in vascular smooth muscle. As a result, the combination of nitrates (through increased production of cGMP) and a PDE5 inhibitor (through decreased breakdown of cGMP) causes a synergistic relaxation of vascular smooth muscle with potentially dangerous hypotension and inadequate perfusion of critical organs.

Nitrites are of significant toxicologic importance because they cause methemoglobinemia at high blood concentrations. This same effect has a potential antidotal action in cyanide poisoning (see later discussion). The nitrates do not cause methemoglobinemia. In the past, the nitrates were responsible for several occupational diseases in munitions factories in which workplace contamination by these volatile chemicals was severe. The most common of these diseases was "Monday disease," that is, the alternating development of tolerance (during the work week) and loss of tolerance (over the weekend) for the vasodilating action and its associated tachycardia and resulting in headache (from cranial vasodilation), tachycardia, and dizziness (from orthostatic hypotension) every Monday.

Nitrites in the Treatment of Cyanide Poisoning

Cyanide ion rapidly complexes with the iron in cytochrome oxidase, resulting in a block of oxidative metabolism and cell death. Fortunately, the iron in methemoglobin has a higher affinity for cyanide than does the iron in cytochrome oxidase. Nitrites convert the ferrous iron in hemoglobin to the ferric form, yielding methemoglobin. Therefore, cyanide poisoning can be treated by a 3-step procedure: (1) immediate exposure to amyl nitrite, followed by (2) intravenous administration of sodium nitrite, which rapidly increases the methemoglobin level to the degree necessary to remove a significant amount of cyanide from cytochrome oxidase. This is followed by (3) intravenous sodium thiosulfate, which converts cyanomethemoglobin resulting from step 2 to thiocyanate and methemoglobin. Thiocyanate is much less toxic than cyanide and is excreted by the kidney. (It should be noted that excessive methemoglobinemia is fatal because methemoglobin is a very poor oxygen carrier.) Recently, hydroxocobalamin, a form of vitamin B12, has become the preferred method of treating cyanide poisoning (see Chapter 58).

Classification and Pharmacokinetics

Several types of calcium channel blockers are approved for use in angina; these drugs are typified by nifedipine, a dihydropyridine, and several other dihydropyridines; diltiazem; and verapamil. Although calcium channel blockers differ markedly in structure, all are orally active and most have half-lives of 3–6 h.

Mechanism of Action

Calcium channel blockers block voltage-gated L-type calcium channels, the calcium channels most important in cardiac and smooth muscle, and reduce intracellular calcium concentration and muscle contractility. None of these channel blockers interferes with calcium-dependent neurotransmission or hormone release because these processes use different types of calcium channels that are not blocked by these agents. Nerve ending calcium channels are of the N-, P-, and R-types. Secretory cells use L-type channels, but these channels are less sensitive to the calcium blockers than are cardiac and smooth muscle L-type channels.

Effects and Clinical Use

Calcium blockers relax blood vessels and, to a lesser extent, the uterus, bronchi, and gut. The rate and contractility of the heart are reduced by diltiazem and verapamil. Because they block calcium-dependent conduction in the atrioventricular (AV) node, verapamil and diltiazem may be used to treat AV nodal arrhythmias (see Chapter 14). Nifedipine and other dihydropyridines evoke greater vasodilation, and the resulting sympathetic reflex prevents bradycardia and may actually increase heart rate. All the calcium channel blockers reduce blood pressure and reduce the double product in patients with angina.

Calcium blockers are effective as prophylactic therapy in both effort and vasospastic angina; nifedipine has also been used to abort acute anginal attacks but use of the prompt-release form is discouraged (see Skill Keeper). In severe atherosclerotic angina, these drugs are particularly valuable when combined with nitrates (Table 12–1). In addition to well-established uses in angina, hypertension, and supraventricular tachycardia, some of these agents are used in migraine, preterm labor, stroke, and Raynaud's phenomenon.

Toxicity

The calcium channel blockers cause constipation, pretibial edema, nausea, flushing, and dizziness. More serious adverse effects include heart failure, AV blockade, and sinus node depression; these are most common with verapamil and least common with the dihydropyridines.

(See Chapter 6)

A pair of studies during the 1990s suggested that use of nifedipine was associated with an increased risk of myocardial infarction. What effects of nifedipine might lead to this result? The Skill Keeper Answer appears at the end of the chapter.

Classification and Mechanism of Action

These drugs are described in detail in Chapter 10. Because they reduce cardiac work (and oxygen demand), all β blockers are effective in the prophylaxis of atherosclerotic angina attacks.

Effects and Clinical Use

Actions include both beneficial antianginal effects (decreased heart rate, cardiac force, blood pressure) and detrimental effects (increased heart size, longer ejection period; Table 12–1). Like nitrates and calcium channel blockers, β blockers reduce cardiac work, the double product, and oxygen demand.

Beta blockers are used only for prophylactic therapy of angina; they are of no value in an acute attack. They are effective in preventing exercise-induced angina but are ineffective against the vasospastic form. The combination of β blockers and nitrates is useful because the adverse undesirable compensatory effects evoked by the nitrates (tachycardia and increased cardiac force) are prevented or reduced by β blockade (Table 12–1).

Toxicity

See Chapter 10.

Ranolazine appears to act mainly by reducing a late, prolonged sodium current in myocardial cells. The decrease in intracellular sodium causes an increase in calcium expulsion via the Na/Ca transporter (see Chapter 13) and a reduction in cardiac force and work. As noted previously, it may also alter cardiac metabolism. Ranolazine is moderately effective in angina prophylaxis. Ivabradine, an investigational drug, inhibits the If sodium current in the sinoatrial node. The reduction in this hyperpolarization-induced inward pacemaker current results in decreased heart rate and consequently decreased cardiac work.

Myocardial revascularization by coronary artery bypass grafting (CABG) and percutaneous transluminal coronary angioplasty (PTCA) are extremely important in the treatment of severe angina. These are the only methods capable of consistently increasing coronary flow in atherosclerotic angina and increasing the double product.

(See Chapter 6)

Several studies have suggested that patients receiving prompt-release nifedipine may have an increased risk of myocardial infarction. Slow-release formulations do not seem to impose this risk. These observations have been explained as follows: Rapid-acting vasodilators—such as nifedipine in its prompt-release formulation—cause significant and sudden reduction in blood pressure. The drop in blood pressure evokes increased sympathetic outflow to the cardiovascular system and increases heart rate and force of contraction as shown in Figure 6–4. These changes can markedly increase cardiac oxygen requirement. If coronary blood flow does not increase sufficiently to match the increased requirement, ischemia and necrosis can result.

When you complete this chapter, you should be able to:

• □ Describe the pathophysiology of effort angina and vasospastic angina and the major determinants of cardiac oxygen consumption.
• □ List the strategies and drug targets for relief of anginal pain.
• □ Contrast the therapeutic and adverse effects of nitrates, β blockers, and calcium channel blockers when used for angina.
• □ Explain why the combination of a nitrate with a β blocker or a calcium channel blocker may be more effective than either alone.
• □ Explain why the combination of a nitrate and sildenafil is potentially dangerous.
• □ Contrast the effects of medical therapy and surgical therapy of angina.