Chapter 8. Drugs Used in the Treatment of Angina Pectoris

The name angina pectoris refers to a strangling or pressure-like pain caused by cardiac ischemia. Angina is the most common condition involving tissue ischemia in which vasodilatordrugs or cardiac depressants are used. The pain may be located substernally, radiating to the neck, in the left upper extremity, occasionally in the right upper extremity, or in the epigastrium. However, not all cardiac ischemia is associated with pain. Clinical conditions exist, such as silent myocardial infarction, in which myocardial ischemia or necrosis may occur without pain. Anginal pain is often atypical in women.

This chapter reviews the pathophysiology of angina and the therapeutic strategies for its treatment. Pharmacologic treatments are divided into vasodilators and cardiac depressants (Figure 8–1). In addition to the drugs discussed in this chapter, patients with angina are often treated with lipid-lowering drugs to minimize additional lipid plaque formation and antithrombotics or anticoagulants to control thrombosis at the site of these plaques. These drugs are discussed in Chapters 11 and 26.

The pharmacologic treatment of coronary insufficiency is based on physiologic factors that control the myocardial oxygen requirement. A major determinant of oxygen requirement is myocardial fiber tension. The higher the tension, the greater the oxygen requirement. Several variables contribute to fiber tension (Figure 8–2).

Among the diastolic factors, venous tone determines the capacity of the venous circulation and controls the amount of blood sequestered there versus the amount returned to the heart. Venous tone is maintained by sympathetic activity and increases when sympathetic activity increases. Venous tone and blood volume together determine preload, and preload is the major diastolic determinant of myocardial oxygen requirement.

The systolic factors include afterload, heart rate, contractility, and ejection time. Afterload is the pressure that the ventricle must overcome to eject blood into the arterial system. Afterload is determined by arterial blood pressure and large artery stiffness. Heart rate contributes to time-integrated fiber tension because at fast heart rates, fibers spend more time contracted at systolic tension levels. Because coronary perfusion is maximal during diastole, faster heart rates lead to decreased myocardial perfusion; that is, faster rates abbreviate the time spent in diastole and decrease myocardial perfusion. Systolic blood pressure and heart rate may be multiplied to yield the double product, a measure of cardiac work and, therefore, of oxygen requirement. In patients with atherosclerotic angina, effective drugs reduce the double product. Force of cardiac contraction is another systolic factor controlled mainly by sympathetic activity to the heart. Finally, ejection time for ventricular contraction is inversely related to force of contraction but is also influenced by impedance to outflow. Increased ejection time increases oxygen requirement.

Atherosclerotic angina is also known as exertional angina or classic angina. This type of angina is associated with atheromatous plaques that partially occlude one or more coronary arteries. When cardiac work increases, for example, during exercise, the obstruction to flow results in the accumulation of acidic metabolites and ischemic changes that stimulate myocardial pain fibers. Rest usually leads to relief of the pain within 5 to 15 minutes. Atherosclerotic angina constitutes about 90% of angina cases.

Vasospastic angina is also known as rest angina, variant angina, or Prinzmetal’s angina and accounts for less than 10% of cases. Vasospastic angina involves reversible spasm of large coronary arteries, usually at the site of an atherosclerotic plaque. Spasm may occur at any time, even during sleep. Vasospastic angina superimposed on atherosclerotic angina may deteriorate into unstable angina, also known as crescendo angina or acute coronary syndrome. This form of angina 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 defect that causes anginal pain is inadequate coronary oxygen delivery relative to the myocardial oxygen requirement. At present, this defect is corrected by either increasing oxygen delivery or by reducing the oxygen requirement (Figure 8–3).

Currently popular pharmacologic therapies include the nitrates, the calcium channel blockers, and the β-receptor antagonists. These drug classes all reduce the oxygen requirement in atherosclerotic angina. Nitrates and calcium channel blockers, but not β-receptor antagonists, can also increase oxygen delivery by reducing vasospasm, a useful effect only in vasospastic angina. Myocardial revascularization corrects coronary obstruction either by bypass grafting or by angioplasty (enlargement of the coronary lumen by means of a special catheter).

The therapy for unstable angina differs from that of exertional or vasospastic angina. Urgent angioplasty is the treatment of choice in most patients with unstable angina, and platelet clotting is the major target of drug therapy. The antithrombotics, eptifibatide and tirofiban, are used in this condition (Chapter 11). Intravenous nitroglycerin is sometimes of value.

Nitrates

The drugs of this pharmacologic class are sometimes referred to as “organic nitrates.” Nitroglycerin is the prototypical agent of this class and is the most important of the therapeutic nitrates. Nitroglycerin, also known as glyceryl trinitrate, is available in several forms (Table 8–1). Because treatment of acute attacks and prevention of attacks are both important aspects of therapy, the pharmacokinetics of these different dosage forms are clinically significant.

Glyceryl trinitrate is rapidly denitrated in the liver and in smooth muscle, first to glyceryl dinitrate and more slowly to glyceryl mononitrate. The dinitrate retains a significant vasodilating effect; the mononitrate is much less active. Because of the high enzyme activity in the liver, the first-pass effect for nitroglycerin is large—about 90%. The efficacy of 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 (Chapter 3). Other nitrates are similar to nitroglycerin in their pharmacokinetics and pharmacodynamics. Isosorbide dinitrate is another commonly used nitrate, and 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 of 4 to 6 hours. Parenteral passive transdermal delivery is also available. Patches or ointment containing nitroglycerin provide maintenance therapy by providing consistent blood levels for hours at a time.

Denitration of the nitrates within smooth muscle cells releases nitric oxide (NO), which stimulates guanylyl cyclase. Increased guanylyl cyclase activity increases the second messenger cyclic guanosine monophosphate (cGMP) and leads to smooth muscle relaxation by dephosphorylation of myosin light chain phosphate (Figure 8–4). This mechanism is identical to that of the direct-acting vasodilator nitroprusside (Chapter 7).

Physiologic Effect

The main beneficial effects of these drugs in the treatment of angina are on the cardiovascular system (Table 8–2); however, additional effects in other tissues are also observed. In the cardiovascular system, smooth muscle relaxation leads to peripheral venodilation, which results in reduced cardiac size and cardiac output through reduced preload. Reduced afterload, from arteriolar dilation, may contribute to an increase in ejection volume and a further decrease in cardiac size. The veins are the most sensitive to the action of nitrates, arteries less so, and arterioles are least sensitive. Venodilation leads to a decrease in venous return to the heart (preload) and subsequent reduction of intracardiac volume during diastole. The decrease in diastolic dilation reduces myocardial fiber tension. This decrease in fiber tension reduces myocardial oxygen demand. 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 for therapeutic benefit in atherosclerotic angina is reduction of the oxygen requirement. 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 a significant reflex tachycardia and increased force of contraction are predictable when nitroglycerin reduces the blood pressure. In 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 is sometimes used in unstable angina and has been demonstrated to reduce platelet aggregation. There are no significant effects on other tissues.

As previously stated, vasodilators used in hypertension such as nitroprusside and nitrates used in angina act by releasing nitric oxide. Nitroprusside and other drugs in this class are strong arteriolar vasodilators, in contrast to nitrates, which are relatively less effective dilators of arterioles. The more limited arteriolar vasodilation caused by nitrates ensures that excessive dilation will not occur in normal vessels to the detriment of flow through partially obstructed ones. Drugs such as nitroprusside would vasodilate both partially obstructed and normal coronary arterioles, and more so in the latter. Blood flow in the unobstructed arteriole then would increase disproportionately compared to the partially obstructed coronary arteriole, ultimately decreasing blood flow through the partially obstructed coronary arteriole and potentially exacerbating the tissue ischemia (coronary steal). For this reason, drugs such as nitrates that act primarily on veins are very useful in angina because they demonstrate minimal coronary steal.

Clinical Uses

As previously noted, nitroglycerin is available in several formulations (Table 8–1). The standard form for treatment of acute exertional anginal pain is the sublingual tablet, which has a duration of action of 10 to 20 minutes. Isosorbide dinitrate is similar or slightly longer in duration of action. Swallowed normal-release nitroglycerin has a duration of action of 4 to 6 hours. Sustained-release oral forms have a somewhat longer duration of action. Transdermal formulations, in ointment or patch, can maintain blood levels for up to 24 hours. Tolerance develops after 8 to 10 hours, however, with rapidly diminishing effectiveness thereafter. Therefore, conventional medical practice is to recommend that nitroglycerin patches be removed after 10 to 12 hours to allow recovery of sensitivity to the drug.

Adverse Effects

The most common adverse effects of nitrates are the responses evoked by vasodilation (Table 8–2). These include tachycardia from the baroreceptor reflex, orthostatic hypotension as 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. Both classes of drugs increase cGMP in vascular smooth muscle causing a synergistic relaxation of vascular smooth muscle with potentially dangerous hypotension and hypoperfusion of critical organs (Figure 8–4).

β-Receptor Antagonists

These drugs are described in detail in Chapter 6. All β-receptor antagonists are effective in the prophylaxis of atherosclerotic angina attacks.

Physiologic Effects

Beneficial effects include decreases in heart rate, cardiac contractility, and blood pressure. Like the nitrates and calcium channel blockers, the β-receptor antagonists reduce the double product.

Clinical Use

β-receptorantagonists are used only for prophylactic therapy of angina, but are extremely important in this application. They are of no value in an acute attack. These drugs are effective in preventing exertional angina, but are ineffective against the vasospastic form. The combination of β-receptor antagonists with nitrates is useful in the treatment of angina because the adverse compensatory effects discussed below are minimized.

Adverse Effects

Adverse cardiac effects caused by β-receptorantagonists include increased end diastolic pressure and increased ejection time. For additional adverse effects, see Chapter 6.

Calcium Channel Blockers

These drugs were discussed in the treatment of hypertension (Chapter 7). Several of the calcium channel blockers are approved for use in angina (Table 8–3). These drugs may be divided into two main classes: dihydropyridines and miscellaneous agents. Nifedipine is the prototypical dihydropyridine, whereas diltiazem and verapamil are familiar examples of the miscellaneous class. Although calcium channel blockers differ markedly in structure, all are orally active and most have half-lives of 3 to 6 hours.

These drugs block voltage-gated L-type calcium channels, which are the calcium channels most important in cardiac and smooth muscle. These agents decrease calcium influx during action potentials in a frequency- and voltage-dependent manner. As a result of the reduced intracellular calcium, cardiac and vascular smooth muscle contractility is decreased. None of these L-type channel blockers interfere with calcium-dependent neurotransmission or hormone release because those processes do not utilize L-type channels.

Physiologic Effects

Calcium channel blockers decrease cardiac contractility, relax blood vessels, and, to a lesser extent, relax the uterus, bronchi, and gut. The physiologic response to these drugs varies with the specific agent (Table 8–3). Diltiazem and verapamil have a greater inhibitory effect on cardiac rate and contraction compared to their vasodilatory effect. Because they block calcium-dependent conduction in the atrioventricular (AV) node, verapamil and diltiazem may be used to treat AV nodal arrhythmias (Chapter 10). Nifedipine and other dihydropyridines evoke greater vasodilation, and the resulting sympathetic reflex prevents bradycardia and may actually increase the heart rate. All the calcium channel blockers reduce blood pressure and reduce the double product in patients with angina.

Clinical Use

Calcium channel blockers are effective as prophylactic therapy in both exertional and vasospastic angina. Nifedipine has also been used to abort acute anginal attacks. In atherosclerotic angina, these drugs are particularly valuable when combined with nitrates. In addition to well-established uses in angina, hypertension, and supraventricular tachycardia, some of these agents are used in the treatment of migraine headaches, preterm labor, and Raynaud’s phenomenon (Table 8–3). Finally, nimodipine, another dihydropyridine, is approved only for the management of stroke associated with subarachnoid hemorrhage.

Adverse Events

A summary of the adverse events related to calcium channel blockers when used alone is presented in Table 8–3. These drugs cause constipation, pretibial edema, nausea, flushing, and dizziness. More serious adverse effects include heart failure, atrioventricular blockade, and sinoatrial node depression; these are more common with verapamil than with the dihydropyridines.

A summary of the beneficial effects compared to the adverse effects of nitrates, calcium channel blockers, or β-receptor antagonists used alone, or in combination with each other, is presented in Table 8–4. Each drug class used alone has some undesirable effects. These adverse effects are mitigated when used in combination. Thus, the combined use of nitrates with calcium channel blockers or β-receptor antagonists enhances their clinical benefits by decreasing net myocardial oxygen requirement, and minimizes adverse events.

Myocardial revascularization can be achieved by coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). The latter procedure includes both percutaneous transluminal coronary angioplasty (PTCA) to dilate the vessel and the placement of an intraluminal stent to maintain the patency. These procedures are extremely important in the treatment of severe angina. They are the only methods capable of consistently increasing coronary flow in atherosclerotic angina and increasing the double product.

Exercise is a well-recognized component of cardiac rehabilitation following a myocardial infarction. Such exercise programs yield physical, psychological, and financial benefits to the patient. Additionally, a regular moderate exercise program also appears to reduce the potential for subsequent myocardial infarction, and may do so at a reduced financial cost to the patient and the health-care system. Such exercise programs are not limited to use of the treadmill, but may also utilize upper body activities or functional activities related to returning to work in order to achieve the same goal. These programs are currently being safely supervised by physical therapists. Therefore, therapists require an understanding of the potential benefits and liabilities of antianginal drug effects during periods of increased functional activity or exercise.

Patients may experience angina as the sole manifestation or as a component of a larger cardiovascular pathophysiologic presentation. To prevent or reduce angina, antianginal drugs are prescribed. Physical therapists must take into account the antianginal drugs being taken by patients during assessments and treatments. The therapist must know whether the drug is being taken prophylactically or on an as-needed basis by the patient. In the former case, the therapist must affirm that the patient has taken the drug regularly prior to participating in the rehabilitation activity. In the latter case, the therapist must affirm that the patient has the drug at hand during the assessment or treatment time because it may be needed. Many activities in rehabilitation can increase sympathetic stimulation of the heart, resulting in an anginal attack. Therapists recognize that exercise or functional and strength conditioning can increase the incidence of anginal attacks; in addition, activities such as painful wound treatment or apprehension at ambulation following a stroke or orthopedic surgery can also induce such an attack.

Finally, the therapist should remember that not all antianginal drugs enhance exercise tolerance in patients. Passive nitroglycerin may benefit the patient during functional activity. In contrast, β-receptor antagonists may reduce bronchodilation or cause bronchoconstriction and adversely affect cardiac responses to exercise. Calcium channel blockers and nitrates may induce orthostatic hypotension.

Adverse Drug Reactions

Many of the drugs clinically used for angina pectoris are also used in the treatment of hypertension and the adverse effects are similar to those discussed in Chapter 7.

• Orthostatic hypotension is a common problem with several classes of antianginal drugs.
• Bronchoconstriction is a problem with the β-receptor antagonists.
• Beta-receptor antagonists blunt the early manifestations of hypoglycemia.
• Several antianginal drugs depress cardiac rate.
• Several antianginal drugs depress cardiac contractility.
• Nitrates cause reflex tachycardia.

Effects Interfering with Rehabilitation

• Orthostatic hypotension may cause patients to faint when transferring from a sitting or supine position to standing, exiting from a warm aquatherapy area, or if aerobic exercise is terminated without an appropriate cool-down period.
• Dyspnea may limit the aerobic capacity of patients.
• Cardiac output may be depressed by these drugs, further limiting aerobic activities.
• Manifestations of hypoglycemia occurring during aerobic activities may be diminished in patients taking β-receptor antagonists.
• Heart rate cannot be used as a marker of exertion for patients taking β-receptor antagonists.

Possible Therapy Solutions

• Check blood pressure and heart rate prior to and following aerobic activities.
• Monitor heart rate during aerobic activities.
• Have patients check glucose levels prior to aerobic activities if the patients are taking hypoglycemic drugs.
• To prevent fainting associated with orthostatic hypotension, assist patients with positional changes and when exiting a warm pool. Always provide a cool-down period following a period of exercise.
• Allow increased time to complete aerobic tasks to prevent dyspnea.
• Use perceived exertion (Borg Rating of Perceived Exertion Scale) when determining aerobic activity in patients being treated with β-receptor antagonists.

Potentiation of Functional Outcomes Secondary to Drug Therapy

• Patients with exertional angina may experience chest pain prior to aerobic activities or painful treatments such as wound debridement. Administration of drugs such as nitrates prior to the activity can help prevent chest pain.

Brief History: The patient is a 52-year-old male with a 14-year history of hypertension and coronary artery disease, and is a union pipe fitter employed at a private shipyard. Job description includes climbing on scaffolding for activities performed in the process of ship construction. Three days ago, while at his job, the patient fell 8 feet off a platform, striking a raised object with the right leg in the area of the thigh. The impact resulted in a compound fracture to the right femur. Other relevant history includes moderate alcohol intake, 25 plus year history of smoking one-half pack of cigarettes a day, and a body mass index of 28.

Current Medical Status and Drug Therapy: The compound fracture of the femur was reduced with internal fixation by means of a medullary rod during orthopedic surgery 2 days ago. The patient was listed as stable following surgery. The chart states initial evaluation of upper body strength and trunk control unremarkable and patient is independent in transfer from bed to chair. Evaluation of patient was carried out in his room during the previous day prior to scheduling for rehabilitation in the acute care facilities gym today. Patient is scheduled today for ambulation assessment in parallel bars prior to determination and training for the type of ambulation assistive device required. The most recent blood pressure listed in the chart was 135/88 mm Hg, and heart rate was 60 bpm at rest. The current drugs include metoprolol, hydrochlorothiazide, and quinapril for chronic treatment of hypertension and additional drugs for pain control. The patient is also prescribed sublingual nitroglycerin as needed.

Rehabilitation Setting: The patient arrives in rehabilitation at 11:00 in a wheelchair. The patient expresses apprehension about standing and attempting to walk due to fear of excessive pain. The physical therapist convinces the patient to attempt standing in the parallel bars with use of a gait belt and two assistants. The patient stands with both hands on the parallel bars for assistance in rising. Prior to taking his first step, the patient begins to complain of chest pain on the left side and radiating down the left arm. The patient is quickly seated again, and the following vital signs recorded: blood pressure is 145/92 mm Hg, heart rate is 78 bpm and regular, and diaphoresis and paleness were also noted. A decision is made to return the patient to his room, and to inform the nursing staff of the changes in his status. The patient declines an afternoon session when contacted on the same day.

Problem/Clinical Options: Upon rising, the patient probably experienced pain due to the right femur injury. This resulted in increased sympathetic discharge to the heart. The combined increase in pain-associated sympathetic discharge and exertional activity of rising from the chair resulted in increased cardiac oxygen demand and ischemia. This increased oxygen demand clinically manifested as exertional angina. To minimize a recurrence of this exertional angina at the next scheduled session, the therapist should recommend to the nursing staff that sublingual nitroglycerin be given to the patient to carry with him to the session. The patient could then take the drug 5 to 10 minutes prior to beginning the exertion. The therapist should remember that a maximum of three nitroglycerin tablets may be taken at no longer than 5-minute intervals if pain occurs. If three tablets do not relieve the pain, medical evaluation for possible myocardial infarction is advisable.

Nitrates and Nitrites

Isosorbide Dinitrate (Generic, Isordil, Sorbitrate)

Oral: 5-, 10-, 20-, 30-, 40-mg tablets; 5-, 10-mg chewable tablets

Oral sustained-release (generic, Sorbitrate SA, Iso-Bid): 40-mg tablets and capsules

Sublingual: 2.5-, 5-, 10-mg sublingual tablets

Isosorbide Mononitrate (Ismo, Others)

Oral: 10-, 20-mg tablets; extended-release 30-, 60-, 120-mg tablets

Nitroglycerin

Sublingual: 0.3-, 0.4-, 0.6-mg tablets; 0.4 mg/ metered dose aerosol

Oral sustained-release (generic, Nitrong): 2.6-, 6.5-, 9-mg tablets; 2.5-, 6.5-, 9-, 13-mg capsules

Buccal (Nitrogard): 2-, 3-mg buccal tablets

Parenteral (Nitro-Bid IV, Tridil, generic): 0.5, 5 mg/mL for IV administration

Transdermal patches (Minitran, Nitro-Dur, Transderm-Nitro): to release at rates of 0.1, 0.2, 0.3, 0.4, 0.6, or 0.8 mg/h.

Topical ointment (generic, Nitrol): 20 mg/mL ointment (1 inch, or 25 mm, of ointment contains about 15 mg nitroglycerin)

Calcium Channels Blockers

See Chapter 7.

Beta Receptor Antagonists

See Chapter 6.