Drugs for angina pectoris

Angina pectoris is defined as sudden pain beneath the sternum, often radiating to the left shoulder, left arm, and jaw. Anginal pain is precipitated when the oxygen supply to the heart is insufficient to meet oxygen demand. Most often, angina occurs secondary to atherosclerosis of the coronary arteries. Hence, angina should be seen as a symptom of a disease and not as a disease in its own right. In the United States, over 7 million people have chronic stable angina; about 350,000 new cases develop annually.

Drug therapy of angina has two goals: (1) prevention of myocardial infarction (MI) and death and (2) prevention of myocardial ischemia and anginal pain. Two types of drugs are employed to decrease the risk of MI and death: cholesterol-lowering drugs and antiplatelet drugs. These agents are discussed in Chapters 50 and 52, respectively.

In this chapter, we focus on antianginal drugs (ie, drugs that prevent myocardial ischemia and anginal pain). There are three main families of antianginal agents: organic nitrates (eg, nitroglycerin), beta blockers (eg, propranolol), and calcium channel blockers (eg, verapamil). In addition, a fourth agent—ranolazine—can be combined with these dugs to supplement their effects. Most of the chapter focuses on the organic nitrates. Beta blockers and calcium channel blockers are discussed at length in previous chapters, and hence consideration here is limited to their use in angina.

Chronic stable angina (exertional angina)

Pathophysiology.

Stable angina is triggered most often by an increase in physical activity. Emotional excitement, large meals, and cold exposure may also precipitate an attack. Because stable angina usually occurs in response to strain, this condition is also known as exertional angina or angina of effort.

The underlying cause of exertional angina is coronary artery disease (CAD), a condition characterized by deposition of fatty plaque in the arterial wall. If an artery is only partially blocked by plaque, blood flow will be reduced and angina pectoris will result. However, if complete vessel blockage occurs, blood flow will stop and MI (heart attack) will result.

The impact of CAD on the balance between myocardial oxygen demand and oxygen supply is illustrated in Figure 51–1. As depicted, in both the healthy heart and the heart with CAD, oxygen supply and oxygen demand are in balance during rest. (In the presence of CAD, resting oxygen demand is met through dilation of arterioles distal to the partial occlusion. This dilation reduces resistance to blood flow and thereby compensates for the increase in resistance created by plaque.)

Figure 51–1 Effect of exertion on the balance between oxygen supply and oxygen demand in the healthy heart and the heart with CAD.
In the healthy heart, O₂ supply and O₂ demand are always in balance; during exertion, coronary arteries dilate, producing an increase in blood flow to meet the increase in O₂ demand. In the heart with CAD, O₂ supply and O₂ demand are in balance only during rest. During exertion, dilation of coronary arteries cannot compensate for the increase in O₂ demand, and an imbalance results.

The picture is very different during exertion. In the healthy heart, as cardiac oxygen demand rises, coronary arterioles dilate, causing blood flow to increase. The increase keeps oxygen supply in balance with oxygen demand. By contrast, in people with CAD, arterioles in the affected region are already fully dilated during rest. Hence, when exertion occurs, there is no way to increase blood flow to compensate for the increase in oxygen demand. The resultant imbalance between oxygen supply and oxygen demand causes anginal pain.

Treatment strategy.

The goal of antianginal therapy is to reduce the intensity and frequency of anginal attacks. Because anginal pain results from an imbalance between oxygen supply and oxygen demand, logic dictates two possible remedies: (1) increase cardiac oxygen supply or (2) decrease oxygen demand. Since the underlying cause of stable angina is occlusion of the coronary arteries, there is little we can do to increase cardiac oxygen supply. Hence, the first remedy is not a real option. Consequently, all we really can do is decrease cardiac oxygen demand. As discussed above, oxygen demand can be reduced with drugs that decrease heart rate, contractility, afterload, and preload.

Overview of therapeutic agents.

Stable angina can be treated with three main types of drugs: organic nitrates, beta blockers, and calcium channel blockers. As noted above, ranolazine can be combined with these drugs for additional benefit. All four groups relieve the pain of stable angina primarily by decreasing cardiac oxygen demand (Table 51–1). Please note that drugs only provide symptomatic relief; they do not affect the underlying pathology. To reduce the risk of MI, all patients should receive an antiplatelet drug (eg, aspirin) unless it is contraindicated. Other measures to reduce the risk of infarction are discussed later under Drugs Used to Prevent Myocardial Infarction and Death.

TABLE 51–1

Mechanisms of Antianginal Action

	Mechanism of Pain Relief
Drug Class	Stable Angina	Variant Angina
Nitrates	Decrease oxygen demand by dilating veins, which decreases preload	Increase oxygen supply by relaxing coronary vasospasm
Beta Blockers	Decrease oxygen demand by decreasing heart rate and contractility	Not used
Calcium Channel Blockers	Decrease oxygen demand by dilating arterioles, which decreases afterload (all calcium blockers), and by decreasing heart rate and contractility (verapamil and diltiazem)	Increase oxygen supply by relaxing coronary vasospasm
Ranolazine	Appears to decrease oxygen demand, possibly by helping the myocardium generate energy more efficiently	Not used

Nondrug therapy.

Patients should attempt to avoid factors that can precipitate angina. These include overexertion, heavy meals, emotional stress, and exposure to cold.

Risk factors for stable angina should be corrected. Important among these are smoking, obesity, hypertension, hyperlipidemia, and a sedentary lifestyle. Patients should be strongly encouraged to quit smoking. Overweight patients should be given a restricted-calorie diet; the diet should be low in saturated fats (less than 7% of total caloric intake), and total fat content should not exceed 30% of caloric intake. The target weight is 110% of ideal or less. Patients with a sedentary lifestyle should be encouraged to establish a regular program of aerobic exercise (eg, walking, jogging, swimming, biking). Hypertension and hyperlipidemia are major risk factors and should be treated. These disorders are discussed in Chapters 47 and 50, respectively.

Variant angina (prinzmetal’s angina, vasospastic angina)

Pathophysiology.

Variant angina is caused by coronary artery spasm, which restricts blood flow to the myocardium. Hence, as in stable angina, pain is secondary to insufficient oxygenation of the heart. In contrast to stable angina, whose symptoms occur primarily at times of exertion, variant angina can produce pain at any time, even during rest and sleep. Frequently, variant angina occurs in conjunction with stable angina. Alternative names for variant angina are vasospastic angina and Prinzmetal’s angina.

Treatment strategy.

The goal is to reduce the incidence and severity of attacks. In contrast to stable angina, which is treated primarily by reducing oxygen demand, variant angina is treated by increasing cardiac oxygen supply. This makes sense in that the pain is caused by a reduction in oxygen supply, rather than by an increase in demand. Oxygen supply is increased with vasodilators, which prevent or relieve coronary artery spasm.

Overview of therapeutic agents.

Vasospastic angina is treated with two groups of drugs: calcium channel blockers and organic nitrates. Both relax coronary artery spasm. Beta blockers and ranolazine, which are effective in stable angina, are not effective in variant angina. As with stable angina, therapy is symptomatic only; drugs do not alter the underlying pathology.

Unstable angina

Pathophysiology.

Unstable angina is a medical emergency. Symptoms result from severe CAD complicated by vasospasm, platelet aggregation, and transient coronary thrombi or emboli. The patient may present with either symptoms of angina at rest, new-onset exertional angina, or intensification of existing angina. Unstable angina poses a much greater risk of death than stable angina, but a smaller risk of death than MI. The risk of dying is greatest initially and then declines to baseline in about 2 months.

Treatment.

In March of 2002, the American College of Cardiology (ACC) and the American Heart Association (AHA) issued updated guidelines for the diagnosis and management of unstable angina. The document—ACC/AHA 2002 Guideline Update for the Management of Patients with Unstable Angina and Non–ST-Segment Elevation Myocardial Infarction—is available free online at www.acc.org and www.americanheart.org. According to the guideline, the treatment strategy is to maintain oxygen supply and decrease oxygen demand. The goal is to reduce pain and prevent progression to MI or death. All patients should be hospitalized. Acute management consists of anti-ischemic therapy combined with antiplatelet and anticoagulation therapy.

Anti-ischemic therapy consists of

• Nitroglycerin—give the first dose sublingually (tablet or spray) and follow with IV therapy.

• A beta blocker—give the first dose IV if chest pain is ongoing. If beta blockers are contraindicated, substitute a nondihydropyridine calcium channel blocker (verapamil or diltiazem).

• Supplemental oxygen—for patients with cyanosis or respiratory distress.

• IV morphine sulfate—if pain is not relieved immediately by nitroglycerin, or if pulmonary congestion or severe agitation is present.

• An angiotensin-converting enzyme inhibitor—but only for patients with persistent hypertension, and only if they have left ventricular dysfunction or congestive heart failure.

Antiplatelet therapy, which should be started promptly, consists of

• Aspirin—continue indefinitely.

• Clopidogrel [Plavix]—continue for at least 1 month.

• Abciximab [ReoPro], a glycoprotein IIb/IIIa inhibitor—but only if angioplasty is planned.

• Eptifibatide [Integrilin] or tirofiban [Aggrastat] (both are glycoprotein IIb/IIIa inhibitors)—but only in high-risk patients with continuing ischemia, and only if angioplasty is not planned.

Anticoagulant therapy consists of subcutaneous low-molecular-weight heparin (eg, dalteparin [Fragmin]) or intravenous unfractionated heparin.

Organic nitrates

The organic nitrates are the oldest and most frequently used antianginal drugs. These agents relieve angina by causing vasodilation. Nitroglycerin, the most familiar organic nitrate, will serve as our prototype.

Nitroglycerin

Nitroglycerin has been used to treat angina since 1879. The drug is effective, fast acting, and inexpensive. Despite availability of newer antianginal agents, nitroglycerin remains the drug of choice for relieving an acute anginal attack.

Vasodilator actions

Nitroglycerin acts directly on vascular smooth muscle (VSM) to promote vasodilation. At usual therapeutic doses, the drug acts primarily on veins. Dilation of arterioles is only modest.

The biochemical events that lead to vasodilation are outlined in Figure 51–2. The process begins with uptake of nitrate by VSM, followed by conversion of nitrate to its active form: nitric oxide. As indicated, conversion requires the presence of sulfhydryl groups. Nitric oxide then activates guanylyl cyclase, an enzyme that catalyzes the formation of cyclic GMP (cGMP). Through a series of reactions, elevation of cGMP leads to dephosphorylation of light-chain myosin in VSM. (Recall that, in all muscles, phosphorylated myosin interacts with actin to produce contraction.) As a result of dephosphorylation, myosin is unable to interact with actin, and hence VSM relaxes, causing vasodilation. For our purposes, the most important aspect of this sequence is the conversion of nitrate to its active form—nitric oxide—in the presence of a sulfhydryl source.

Figure 51–2 Biochemistry of nitrate-induced vasodilation.
Note that sulfhydryl groups are needed to catalyze the conversion of nitrate to its active form, nitric oxide. If sulfhydryl groups are depleted from VSM, tolerance to nitrates will occur.

Mechanism of antianginal effects

Stable angina.

Nitroglycerin decreases the pain of exertional angina primarily by decreasing cardiac oxygen demand. Oxygen demand is decreased as follows: By dilating veins, nitroglycerin decreases venous return to the heart, and thereby decreases ventricular filling; the resultant decrease in wall tension (preload) decreases oxygen demand.

In patients with stable angina, nitroglycerin does not appear to increase blood flow to ischemic areas of the heart. This statement is based on two observations. First, nitroglycerin does not dilate atherosclerotic coronary arteries. Second, when nitroglycerin is injected directly into coronary arteries during an anginal attack, it does not relieve pain. Both observations suggest that pain relief results from effects of nitroglycerin on peripheral blood vessels—not from effects on coronary blood flow.

Variant angina.

In patients with variant angina, nitroglycerin acts by relaxing or preventing spasm in coronary arteries. Hence, the drug increases oxygen supply. It does not reduce oxygen demand.

Pharmacokinetics

Absorption.

Nitroglycerin is highly lipid soluble and crosses membranes with ease. Because of this property, nitroglycerin can be administered by uncommon routes (sublingual, buccal, transdermal) as well as by more conventional routes (oral, intravenous).

Metabolism.

Nitroglycerin undergoes rapid inactivation by hepatic enzymes (organic nitrate reductases). As a result, the drug has a plasma half-life of only 5 to 7 minutes. When nitroglycerin is administered orally, most of each dose is destroyed on its first pass through the liver.

Adverse effects

Nitroglycerin is generally well tolerated. Principal adverse effects—headache, hypotension, and tachycardia—occur secondary to vasodilation.

Headache.

Initial therapy can produce severe headache. This response diminishes over the first few weeks of treatment. In the meantime, headache can be reduced with aspirin, acetaminophen, or some other mild analgesic.

Orthostatic hypotension.

Relaxation of VSM causes blood to pool in veins when the patient assumes an erect posture. Pooling decreases venous return to the heart, which reduces cardiac output, causing blood pressure to fall. Symptoms of orthostatic hypotension include lightheadedness and dizziness. Patients should be instructed to sit or lie down if these occur. Lying with the feet elevated promotes venous return, and can thereby help restore blood pressure.

Reflex tachycardia.

Nitroglycerin lowers blood pressure—primarily by decreasing venous return, and partly by dilating arterioles. By lowering blood pressure, the drug can activate the baroreceptor reflex, thereby causing sympathetic stimulation of the heart. The resultant increase in both heart rate and contractile force increases cardiac oxygen demand, which negates the benefits of therapy. Pretreatment with a beta blocker or verapamil (a calcium channel blocker that directly suppresses the heart) can prevent sympathetic cardiac stimulation.

Drug interactions

Hypotensive drugs.

Nitroglycerin can intensify the effects of other hypotensive agents. Consequently, care should be exercised when nitroglycerin is used concurrently with beta blockers, calcium channel blockers, diuretics, and all other drugs that can lower blood pressure, including inhibitors of phosphodiesterase type 5 (PDE5). Also, patients should be advised to avoid alcohol.

Phosphodiesterase type 5 inhibitors.

As discussed in Chapter 66, PDE5 inhibitors—sildenafil [Viagra], tadalafil [Cialis], and vardenafil [Levitra]—are used for erectile dysfunction. All three drugs can greatly intensify nitroglycerin-induced vasodilation. Life-threatening hypotension can result. Accordingly, concurrent use of PDE5 inhibitors with nitroglycerin is absolutely contraindicated.

What’s the mechanism of the interaction? Nitroglycerin and the PDE5 inhibitors both increase cGMP (nitrates increase cGMP formation and PDE5 inhibitors decrease cGMP breakdown). Hence, if these drugs are combined, levels of cGMP can rise dangerously high, thereby causing excessive vasodilation and a precipitous drop in blood pressure.

Beta blockers, verapamil, and diltiazem.

These drugs can suppress nitroglycerin-induced tachycardia. Beta blockers do so by preventing sympathetic activation of beta₁-adrenergic receptors on the heart. Verapamil and diltiazem prevent tachycardia through direct suppression of pacemaker activity in the sinoatrial node.

Tolerance

Tolerance to nitroglycerin-induced vasodilation can develop rapidly (over the course of a single day). One possible mechanism is depletion of sulfhydryl groups in VSM: In the absence of sulfhydryl groups, nitroglycerin cannot be converted to nitric oxide, its active form. Another possible mechanism is reversible oxidative injury to mitochondrial aldehyde dehydrogenase, an enzyme needed to convert nitroglycerin into nitric oxide. Patients who develop tolerance to nitroglycerin display cross-tolerance to all other nitrates and vice versa. Development of tolerance is most likely with high-dose therapy and uninterrupted therapy. To prevent tolerance, nitroglycerin and other nitrates should be used in the lowest effective dosages; long-acting formulations (eg, patches, sustained-release preparations) should be used on an intermittent schedule that allows at least 8 drug-free hours every day, usually during the night. If pain occurs during the nitrate-free interval, it can be managed with sparing use of a short-acting nitrate (eg, sublingual nitroglycerin) or by adding a beta blocker or calcium channel blocker to the regimen. Tolerance can be reversed by withholding nitrates for a short time.

Preparations and routes of administration

Nitroglycerin is available in several formulations for administration by several routes. This proliferation of dosage forms reflects efforts to delay hepatic metabolism, and thereby prolong therapeutic effects.

All nitroglycerin preparations produce qualitatively similar responses; differences relate only to onset and duration of action (Table 51–2). With two preparations, effects begin rapidly (in 1 to 5 minutes) and then fade in less than 1 hour. With three others, effects begin slowly but last several hours. Only one preparation—sublingual tablets—has both a rapid onset and long duration.

TABLE 51–2

Organic Nitrates: Time Course of Action

Drug and Dosage Form	Onset*	Duration^†
Nitroglycerin
Sublingual tablets	Rapid (1–3 min)	Brief (30–60 min)
Translingual spray	Rapid (2–3 min)	Brief (30–60 min)
Oral capsules, SR	Slow (20–45 min)	Long (3–8 hr)
Transdermal patches	Slow (30–60 min)	Long (24 hr)^‡
Topical ointment	Slow (20–60 min)	Long (2–12 hr)
Isosorbide Mononitrate
Oral tablets, IR	Slow (30–60 min)	Long (6–10 hr)
Oral tablets, SR	Slow (30–60 min)	Long (7–12 hr)
Isosorbide Dinitrate
Sublingual tablets	Rapid (2–5 min)	Long (1–3 hr)
Oral tablets, IR	Slow (20–40 min)	Long (4–6 hr)
Oral tablets, SR	Slow (30 min)	Long (6–8 hr)
Oral capsules, SR	Slow (30 min)	Long (6–8 hr)

IR = immediate release, SR = sustained release.

^*Nitrates with a rapid onset have two uses: (1) termination of an ongoing anginal attack and (2) short-term prophylaxis prior to anticipated exertion. Of the rapid-acting nitrates, nitroglycerin (sublingual tablet or translingual spray) is preferred to the others for terminating an ongoing attack.

^†Long-acting nitrates are used for sustained prophylaxis (prevention) of anginal attacks. All cause tolerance if used without interruption.

^‡Although patches can release nitroglycerin for up to 24 hours, they should be removed after 12 to 14 hours to avoid tolerance.

Applications of specific preparations are based on their time course. Preparations with a rapid onset are employed to terminate an ongoing anginal attack. When used for this purpose, rapid-acting preparations are administered as soon as pain begins. Rapid-acting preparations can also be used for acute prophylaxis of angina. For this purpose, they are taken just prior to anticipated exertion. Long-acting preparations are used to provide sustained protection against anginal attacks. To provide protection, they are administered on a fixed schedule (but one that permits at least 8 drug-free hours each day).

Trade names and dosages for nitroglycerin preparations are summarized in Table 51–3.

TABLE 51–3

Organic Nitrates: Trade Names and Dosages

Drug and Formulation	Trade Name	Usual Dosage
Nitroglycerin
Sublingual tablets	Nitrostat	0.3–0.6 mg as needed
Translingual spray	Nitrolingual Pumpspray, NitroMist	1–2 sprays (up to 3 sprays in a 15-min period)
Oral capsules, SR	Nitro-Time	2.5–6.5 mg 3 or 4 times daily; to avoid tolerance, administer only once or twice daily; do not crush or chew
Transdermal patches	Minitran, Nitro-Dur, Transderm Nitro, Trinipatch	1 patch a day; to avoid tolerance, remove after 12–14 hr, allowing 10–12 patch-free hours each day. Patches come in sizes that release 0.1–0.8 mg/hr
Topical ointment	Nitro-Bid	1–2 inches (7.5–40 mg) every 4–8 hr
Intravenous	Generic only	5 mcg/min initially, then increased gradually as needed (max 200 mcg/min); tolerance develops with prolonged continuous infusion
Isosorbide Mononitrate
Oral tablets, IR	ISMO, Monoket	20 mg twice daily; to avoid tolerance, take the first dose upon awakening and the second dose 7 hr later
Oral tablets, SR	Imdur	60–240 mg once a day; do not crush or chew
Isosorbide Dinitrate
Sublingual tablets	Generic only	2.5–15 mg every 4–6 hr; do not crush or chew
Oral tablets, IR	Isordil Titradose	5–80 mg every 6 hr; to avoid tolerance, take only 2 or 3 times daily, with the last dose no later than 7:00 pm
Oral tablets, SR	Generic only	40 mg every 6–12 hr; to avoid tolerance, take only once or twice daily (at 8:00 am and 2:00 pm)
Oral capsules, SR	Dilatrate-SR	40 mg every 6–12 hr; to avoid tolerance, take only once or twice daily (at 8:00 am and 2:00 pm)
Amyl Nitrite
Inhalant	Generic only	0.18 or 0.3 mL