spray) and follow with IV therapy in the event of persistent ischemia or hypertension.
• 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.
• Intravenous morphine sulfate—if pain is not relieved immediately by nitroglycerin, or if pulmonary congestion or severe agitation is present.
• An angiotensin-converting enzyme inhibitor—for patients with left ventricular dysfunction or congestive heart failure. Angiotensin receptor blockers are a reasonable alternative in patients who have intolerance to angiotensin-converting enzyme inhibitors.
Antiplatelet therapy, which should be started promptly, consists of:
• Aspirin—continue indefinitely.
• Clopidogrel [Plavix], prasugrel [Effient], or ticagrelor [Brilinta]—con- tinue for up to 2 months.
• 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 (e.g., enoxaparin [Lovenox]), direct thrombin inhibitors (bivalirudin [Angio- max]), factor Xa inhibitors (fondaparinux [Arixtra]), or IV 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.
Risk factors for stable angina should be corrected. Important among these are smoking, hypertension, hyperlipidemia, and a sedentary lifestyle. Patients should be strongly encouraged to quit smoking. Patients with a sedentary lifestyle should be encouraged to establish a regular program of aerobic exercise (e.g., 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 aggrega- tion, 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 2012, 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—2012 ACCF/AHA Focused Update Incorporated Into the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina and Non–ST-Segment Elevation Myocardial Infarction—is available free 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.
Prototype Drugs
DRUGS FOR ANGINA PECTORIS Organic Nitrates
Nitroglycerin Beta Blockers Metoprolol Propranolol
Calcium Channel Blockers Nifedipine
Verapamil
Drug That Increases Myocardial Efficiency Ranolazine
Nitroglycerin
Nitroglycerin has been used to treat angina since 1879. The drug is effective, fast acting, and inexpensive. Despite avail- ability 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.
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, nitro- glycerin 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 light-headedness and dizziness.
Patients should be instructed to sit or lie down if these occur.
Lying with the feet elevated promotes venous return and can 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, 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.
Nitroglycerin and the PDE5 inhibitors both increase cGMP (nitrates increase cGMP formation, and PDE5 inhibitors decrease The biochemical events that lead to vasodilation are outlined
in Fig. 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 so 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.
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.
Dephosphorylation of light-chain myosin
Activation of guanylyl cyclase
Nitrate (within VSM)
Sulfhydryl groups Mitochondrial
aldehyde dehydrogenase
Nitrate (extracellular)
Relaxation of VSM Cyclic GMP
Nitric oxide
Vasodilation
Fig. 51.2 ■ Biochemistry of nitrate-induced vasodilation.
Note that sulfhydryl groups are needed to catalyze the conver- sion of nitrate to its active form, nitric oxide. If sulfhydryl groups are depleted from VSM, tolerance to nitrates will occur.
as pain begins. Rapid-acting preparations can also be used for acute prophylaxis of angina. For this purpose, they are taken just before 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).
Brand names and dosages for nitroglycerin preparations are shown in Table 51.3.
Sublingual Tablets and Powder. When administered sublingually (beneath the tongue), nitroglycerin is absorbed directly through the oral mucosa into the bloodstream. Hence, unlike orally administered drugs, which must pass through the liver on their way to the systemic circulation, sublingual nitroglycerin bypasses the liver and thereby temporarily avoids inactivation. Because the liver is bypassed, sublingual doses can be low (between 0.3 and 0.6 mg). These doses are about 10 times lower than those required when nitroglycerin is dosed orally.
Effects of sublingual nitroglycerin begin rapidly—in 1 to 3 minutes—and persist up to 1 hour. Because sublingual administration works fast, this route is ideal for (1) terminating an ongoing attack and (2) short-term prophylaxis when exertion is anticipated.
To terminate an acute anginal attack, sublingual nitroglycerin should be administered as soon as pain begins. Administration should not be delayed until the pain has become severe. Accord- ing to current guidelines, if pain is not relieved in 5 minutes, the cGMP breakdown). Therefore, if these drugs are combined,
levels of cGMP can rise dangerously high, 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 tachy- cardia 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 mecha- nism 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 (e.g., 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 (e.g., sublingual nitroglyc- erin) 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 administra- tion by several routes. This proliferation of dosage forms reflects efforts to delay hepatic metabolism and 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 diminish in less than 1 hour. With three others, effects begin slowly but last several hours. Only one preparation—sublingual isosorbide dinitrate tablets—has both a rapid onset and a long duration.
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
Safety Alert
PHOSPHODIESTERASE TYPE 5 INHIBITORS As discussed in Chapter 66, PDE5 inhibitors—sildenafil [Viagra], tadalafil [Cialis], avanafil [Stendra], and vardenafil [Levitra]—are used for erectile dysfunction. All of these drugs can greatly intensify nitroglycerin-induced vasodilation. Life- threatening hypotension can result. Accordingly, concurrent use of PDE5 inhibitors with nitroglycerin is absolutely contraindicated.
Drug and
Dosage Form Onseta Durationb
NITROGLYCERIN
Sublingual tablets Rapid (1–3 min) Brief (30–60 min) Sublingual powder 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)c 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) TABLE 51.2 ■ Organic Nitrates: Time Course
of Action
aNitrates with a rapid onset have two uses: (1) termination of an ongoing anginal attack and (2) short-term prophylaxis before anticipated exertion. Of the rapid-acting nitrates, nitroglycerin (sublingual tablet, sublingual powder, or translingual spray) is preferred to the others for terminating an ongoing attack.
bLong-acting nitrates are used for sustained prophylaxis (prevention) of anginal attacks. All cause tolerance if used without interruption.
cAlthough patches can release nitroglycerin for up to 24 hours, they should be removed after 12 to 14 hours to avoid tolerance.
IR, Immediate release; SR, sustained release.
Transdermal Delivery Systems. Nitroglycerin patches contain a reservoir from which nitroglycerin is slowly released.
Following release, the drug is absorbed through the skin and then into the blood. The rate of release is constant and, depend- ing on the patch used, can range from 0.1 to 0.8 mg/hr. Effects begin within 30 to 60 minutes and persist as long as the patch remains in place (up to 14 hours). Patches are applied once daily to a hairless area of skin. The site should be rotated to avoid local irritation.
Tolerance develops if patches are used continuously (24 hours a day every day). Accordingly, a daily “patch-free” interval of 10 to 12 hours is recommended. This can be accomplished by applying a new patch each morning, leaving it in place for 12 to 14 hours, and then removing it in the evening.
Because of their long duration, patches are well suited for sustained prophylaxis. Since patches have a delayed onset, they cannot be used to abort an ongoing attack.
Translingual Spray. Nitroglycerin can be delivered to the oral mucosa using a metered-dose spray device. Each activation delivers a 0.4-mg dose.
Indications for nitroglycerin spray are the same as for sublingual tablets:
suppression of an acute anginal attack and prophylaxis of angina when exertion is anticipated. As with sublingual tablets, no more than three doses should be administered within a 15-minute interval. Instruct patients not to inhale the spray.
Topical Ointment. Topical nitroglycerin ointment is used for sustained protection against anginal attacks. The ointment is applied to the skin of the chest, back, abdomen, or anterior thigh. (Since nitroglycerin acts primarily by dilating peripheral veins, there is no mechanistic advantage to applying topical nitroglycerin directly over the heart.) Following topical application, nitroglycerin is absorbed through the skin and then into the blood. Effects begin in 20 to 60 minutes and may persist up to 12 hours.
patient should call 911 or report to an emergency department, since anginal pain that does not respond to nitroglycerin may indicate MI. While awaiting emergency care, the patient can take 1 more tablet, and then a third tablet 5 minutes later.
Sublingual administration is unfamiliar to most patients.
Accordingly, education is needed. The patient should be instructed to place the tablet or empty the powder packet under the tongue and leave it there while it dissolves. Nitroglycerin tablets and powder formulated for sublingual use are ineffective if swallowed.
Nitroglycerin tablets available today have good chemical stability. When stored properly, they should remain effective until the expiration date on the container. To ensure good stability, the tablets should be stored moisture free at room temperature in their original container, which should be closed tightly after each use.
Sustained-Release Oral Capsules. Sustained-release oral capsules are intended for long-term prophylaxis only; these formulations cannot act fast enough to terminate an ongoing anginal attack. Sustained-release capsules contain a large dose of nitroglycerin that is slowly absorbed across the GI wall. In theory, doses are large enough so that amounts of nitroglycerin sufficient to produce a therapeutic response will survive passage through the liver. Because they produce sustained blood levels of nitroglycerin, these formulations can cause tolerance. To reduce the risk of tolerance, these products should be taken only once or twice daily. Patients should be instructed to swallow sustained-release capsules intact.
Drug and Formulation Brand Name Usual Dosage NITROGLYCERIN
Sublingual tablets Nitrostat 0.3–0.6 mg as needed every 5 min for maximum of three doses Sublingual powder GONITRO 1–2 packets (400 mcg/packet, up to three packets in a 15-min period) 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 Nitro-Dur 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 4–6 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 Generic only 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 daily; do not crush or chew
ISOSORBIDE DINITRATE
Sublingual tablets Generic only 2.5–5 mg before activities that may cause angina. For acute angina, 2.5–5 mg every 5 min for maximum of three doses. Do not crush or chew
Oral tablets, IR Isordil Oral Titradose 10–40 mg 2 or 3 times daily; to avoid tolerance, take 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)
TABLE 51.3 ■ Organic Nitrates: Brand Names and Dosages
IR, Immediate release; SR, sustained release.