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Recommendations for
the Management of Angina
Sandra L. Chase, BS, PharmD
Dr. Chase is a Clinical Pharmacy Specialist at Spectrum Health in Grand Rapids, MI, and an Adjunct Assistant Professor of Pharmacy at Ferris State University College of Pharmacy, in Big Rapids, MI.
After completing this continuing education article, the pharmacist should be able
to
:
1. Describe the etiology and pathogenesis of angina.
2. State the modes of therapy and their general mechanisms in the treatment of angina.
3. Explain the clinical use of the following agents in the treatment of angina: short- and long-acting nitrates, beta blockers, and calcium antagonists.
4. Identify potential adverse effects and drug interactions of the agents used in the treatment of angina.
5. Describe the role of the pharmacist in the management of patients with angina, including improving medication compliance and quality of life.
Angina, often described as discomfort in the chest, jaw, shoulder, back, or arm or chest pain, is the initial manifestation of ischemic heart disease (IHD) in approximately one half of patients who have this
disease.1 This is significant because IHD is a major public health problem. The American Heart Association (AHA) has estimated that more than 6 million Americans have chest pain; however, this may be a conservative
estimate.2 Although angina will be the focus of this review, an overview of IHD is necessary. IHD is important not only because of its prevalence, but also because of its associated morbidity and mortality. Despite the well-documented recent decline in cardiovascular
mortality,3 IHD remains the leading single cause of death in the United States and is responsible for 1 of every 4.8 deaths. In addition, each year more than 1 million patients with IHD have an acute myocardial infarction
(MI).4 Many more are hospitalized for unstable angina and evaluation and treatment of stable chest pain syndromes. Even if hospitalization is not required, many patients with chronic chest pain syndromes are temporarily unable to perform normal activities for hours or days, and thus, their quality of life is reduced.
The cost of chronic IHD is enormous when the direct and indirect costs of hospitalization, diagnostic tests, therapy, workdays lost, reduced productivity, long-term medication, and other associated effects are considered. The associated annual costs can easily exceed $10
billion.1
Recognizing the effect of IHD on patients and society and the lack of national clinical practice guidelines in this area, the AHA and the American College of Cardiology (ACC) developed guidelines for the management of patients with stable angina. Because angina is frequently encountered in the practice of internal medicine, the Task Force on Practice Guidelines invited the American College of Physicians-American Society of Internal Medicine (ACP-ASIM) to serve as a partner in this effort by naming four general internists to serve on the committee. The guidelines are referred to as the ACC/AHA/ACP-ASIM Guidelines for the Management of Patients with Chronic Stable
Angina.1 The guidelines are intended to assist physicians in clinical decision making by describing a range of generally accepted approaches for the diagnosis, management, and prevention of chronic stable angina. Patients with unstable angina who are considered at low risk and are not hospitalized but instead evaluated as
outpatients are indistinguishable from many patients with stable chest pain syndromes, and are, therefore, within the scope of the new guidelines. Patients whose recent unstable angina was satisfactorily treated by medical therapy who then present with a recurrence of symptoms with a stable pattern also fall within the scope of the guidelines. Similarly, patients who have had an MI and subsequently present with stable chest pain symptoms more than 30 days after the initial event are within the scope of the new
guidelines.1
Pharmacists should be aware of the new guidelines so that they can monitor patients’ therapy and assist physicians in providing optimal drug therapy for the management of chronic stable angina. Pharmacists have an excellent opportunity to become more involved in the care of patients with angina and to improve outcomes. This article will address the management of patients within the scope of the new guidelines, examining antianginal and anti-ischemic therapy (short- and long-acting nitrates, beta blockers, and calcium antagonists).
By understanding the pathophysiology of IHD, the pharmacist will be able to determine why certain medications are used in the management of angina. IHD has many clinical manifestations, including the following syndromes: (1) stable exertional angina; (2) unstable (rest, preinfarction, crescendo) angina; (3) silent myocardial ischemia; (4) acute coronary insufficiency; (5) coronary vasomotion or vasospasm associated with atypical, variant, or Prinzmetal’s angina; and (6) acute MI. The pathophysiology that underlies this disease process is dynamic, evolutionary, and complex. To better understand the rationale for the selection and use of pharmacotherapy for IHD, pharmacists must appreciate the importance of the determinants of myocardial oxygen demand, regulation of coronary blood flow, the effects of ischemia on the mechanical and metabolic function of the myocardium, and how ischemia may be recognized so that treatment can be instituted.
Angina, as noted earlier, is a clinical syndrome characterized by discomfort in the chest, jaw, shoulder, back, or arm. Various adjectives have been used by patients to describe the quality of their anginal pain: “squeezing,” “griplike,” “pressurelike,” “suffocating,” and “heavy” are common. Patients will often insist that their symptom is a “discomfort” but not “pain.” Angina is almost never sharp or stabbing, and it usually does not change with position or respiration. This clinical syndrome is typically aggravated by exertion or emotional stress and relieved by nitroglycerin within 30 seconds to several minutes. Angina usually occurs in patients with coronary artery disease (CAD) involving one or more large epicardial arteries. However, angina can also occur in patients with valvular heart disease, hypertrophic cardiomyopathy, or uncontrolled hypertension. It may also be present in patients with normal coronary arteries and myocardial ischemia related to spasm or endothelial dysfunction. Angina is also a symptom in patients with noncardiac conditions of the esophagus, chest wall, or lungs. The clinical assessment of patients will determine if the patient has a cardiac or a noncardiac condition. A detailed discussion of clinical assessment and diagnosis is beyond the scope of this article (Refer to Gibbons RJ et al.
J Am Coll Cardiol 1999;33:2092-2197 for more details).
Ischemia may be defined as lack of oxygen and decreased or no blood flow in the myocardium. It may also be painless or “silent” in 60% to 100% of patients depending on the series cited and the patient
population.5,6 In patients with myocardial ischemia, approximately 70% of the episodes of documented ischemia are painless as determined by ambulatory electrocardiogram (ECG) monitoring, and the ST segment changes associated with these episodes can be ST elevation or depression. The mechanism of silent ischemia is unclear, but studies have shown that patients not experiencing pain have altered pain perception, with the threshold and tolerance for pain being higher than that of patients who have pain more frequently. Reduced endorphin release, adenosine, and substance P release and that the threshold for pain owing to exertion is fixed in some patients and variable in others (which can change over time) are possible
explanations.7
Ischemia occurs when there is an imbalance between myocardial oxygen supply and myocardial oxygen demand. Anginal symptoms are experienced by the patient when cardiac work and myocardial oxygen demand exceed the ability of the coronary arteries to supply adequate oxygen.
Myocardial oxygen demand is directly related to heart rate, the degree of ventricular filling (preload), the force of myocardial contractions, and the resistance to ventricular ejection of blood from the heart (afterload). Increases in any of these factors will result in an increase in myocardial oxygen demand. Therapeutic maneuvers that decrease the myocardial oxygen demand (nitrates, beta blockers, and calcium antagonists) act to slow the heart rate, reduce preload, depress myocardial contractility, and reduce after-load.
The myocardial oxygen supply is diminished in IHD that resulted from an obstruction or narrowing of the coronary arteries by atherosclerosis. Less frequently encountered causes of reductions in myocardial oxygen supply include coronary artery spasm (variant angina), valvular heart disease, pulmonary hypertension, and myocardial hypertrophy.
The types of angina have been identified from their clinical characteristics. Stable angina is often referred to as classic or effort-induced angina. In this type of angina, discomfort is precipitated by physical activity or emotional stress and is relieved by rest. Each episode of symptoms lasts about 3 to 5 minutes and is characterized by chest pain or discomfort with radiation to the neck, jaw, back, shoulders, or arms. Pain above the mandible, below the epigastrium, or localized to a small area over the left lateral chest wall is rarely anginal. Nausea, diaphoresis, palpitations, or shortness of breath may be present. Stable angina is usually predictable and reproducible at a given workload and results from an increase in myocardial oxygen demand beyond that which can bypass narrowed coronary arteries.
Unstable angina, also referred to as crescendo, accelerated, and preinfarction angina, describes chest pain that occurs with increasing intensity and frequency. This type of angina is associated with decreasing levels of work and is characterized by a decrease in the responsiveness to treatment. Unstable angina is operationally defined as angina that presents in one of the three principal ways: rest angina, severe new-onset angina, or increasing
angina.1
Unstable angina may signal the prodrome of acute MI and requires urgent diagnosis and treatment. The mechanism contributing to unstable angina is an increased myocardial oxygen demand in the presence of severe coronary artery stenosis, thrombosis, or spasm.
Unstable angina patients can be subdivided by their short-term risk. Patients at high or moderate risk often have coronary artery plaques that have recently ruptured. Such patients’ risk of death is intermediate; thus, their risk is in between that of patients with acute MI and patients with stable angina. The initial evaluation of high- or moderate-risk patients with unstable angina is best carried out in the inpatient setting. However, low-risk patients with unstable angina have a short-term risk not substantially different from those with stable angina. Their evaluation can be accomplished safely in an outpatient setting. The recommendations made in the guidelines for the management of patients with chronic stable angina do not apply to high- and moderate-risk unstable angina, but are applicable to the low-risk angina
group.1
Variant angina, or Prinzmetal’s angina, is characterized by recurrent chest pain at rest and an ECG showing ST segment elevation during pain. The pain associated with variant angina differs from stable angina; it may be of longer duration, is usually not precipitated by exertion, and may occur only at certain times of day. Decreased blood flow in this type of angina results from coronary artery spasm. Variant angina is usually treated with calcium antagonists.
There are two major reasons for treating angina. The first is to prevent acute MI and death and, thereby, increase the “quantity” of life. The second is to reduce symptoms of angina and occurrence of ischemia, which should improve the quality of life
(Table 1).1 Therapy directed toward preventing death has the higher priority. When two different therapeutic strategies are equally effective in relieving symptoms of angina, the therapy with a definite or very probable advantage in preventing death should be recommended (e.g., coronary artery bypass surgery versus medical management in a patient with significant left main CAD).
Table 1.
From the patient’s perspective, reducing symptoms is of greater concern. The cardinal symptom of stable CAD is anginal chest pain or equivalent symptoms such as exertional dyspnea. Patients suffer not only from the discomfort of these symptoms but also from limitations of their activities and the anxiety caused by the symptoms. For some patients, the predominant symptoms of CAD may be palpitations or syncope that are caused by arrhythmias or fatigue, or edema or orthopnea caused by heart failure. Because there is a variation in symptom complexes among patients, it is difficult to create a definition of treatment success that is accepted by all. The committee that developed the guidelines agreed that the goal of treatment should be complete, or nearly complete, elimination of anginal chest pain, a return to normal activities, and a functional capacity whereby ordinary physical activity (e.g., walking, climbing stairs) does not cause angina or when angina occurs only with strenuous, rapid, or prolonged exertion at work or
recreation.1 This goal should be accomplished with minimal adverse effects of therapy. Pharmacists have a wonderful opportunity to monitor patients to ascertain if therapy is successful and to aid other health care professionals in choosing therapy that does not cause adverse effects.
The initial treatment of the patient with angina should include the following elements: (1) aspirin and antianginal therapy, (2) beta blocker and blood pressure reduction, (3) cigarette smoking cessation and cholesterol management, (4) diet and diabetes control, and (5) education and exercise. These are outlined in a mnemonic developed by the Committee on the Management of Patients with Chronic Stable Angina. The mnemonic is intended to highlight the 10 treatment elements that the committee considered most important
(Table 2).1 Pharmacists can use this mnemonic to contribute to patient education and when evaluating patients’ therapy to be sure those patients are receiving adequate treatment.
Table 2
The flow diagram that was developed to describe the treatment process is divided into two parts: (1) antianginal treatment and (2) education and risk-factor modification
(Figure 1). Aspirin was assigned to the education and risk-factor component of the flow diagram
because it has no known benefit in preventing angina but reduces the risk of a subsequent heart attack and
death.1
Medications (e.g., immediate-release calcium antagonists, sympathomimetics) or conditions (e.g., hypertension, anxiety, tachycardia, anemia, asthma) that are known to provoke or exacerbate angina must be recognized and treated appropriately. This may be enough to relieve the patient’s angina and no further antianginal therapy would be required. Usually, anginal symptoms improve but are not relieved by the treatment of such conditions. If such is the case, further therapy should then be initiated.
All patients with anginal symptoms should receive a prescription for sublingual nitroglycerin (tablets or spray). Pharmacists should educate patients on the proper use and storage of nitroglycerin. To ensure that patients are not reluctant to take their medication, pharmacists should make it very clear that nitroglycerin is a short-acting drug with no known long-term consequences.
Figure 1
If the patient’s history has a prominent feature of rest and nocturnal angina suggesting vasospasm, initiation of therapy with long-acting nitrates or calcium antagonists is appropriate.
Beta blockers, in the absence of contraindications, are considered the initial drug of choice. The evidence for the use of beta blockers is strongest in the presence of prior MI because this class of drugs has been shown to reduce mortality post MI. These agents have also been shown to reduce mortality in the
treatment of isolated hypertension and, therefore, are considered initial therapy in patients with isolated systolic hypertension in the absence of prior
MI.1
Calcium antagonists should be administered if serious contraindications to beta blockers exist, unacceptable adverse effects occur with beta blocker use, or angina persists despite the use of beta blockers.
Long-acting nitrate therapy should be prescribed if serious contraindications to calcium antagonists exist, unacceptable adverse effects occur, or angina persists despite the use of calcium antagonists.
Low-risk patients should be treated with at least two and preferably all three available classes of drugs before medical therapy is considered a failure. At that point, patients should be considered for coronary revascularization. However, at any point, depending on the patient’s anatomy, severity of symptoms, and patient preferences, a patient can be considered for
revascularization.1
As with any therapy, the primary consideration in the choice of pharmacologic agents for treatment of chronic stable angina should be to improve prognosis. Aspirin and lipid-lowering therapy have been shown to reduce the risk of death and nonfatal MI in both primary and secondary prevention trials (these agents will not be further discussed here because they are beyond the scope of this article). These data suggest that cardiac events also will be reduced among patients with chronic stable angina.
Cardiac events have been reduced by beta blockers when used as secondary prevention in postinfarction patients. Beta blockers have also been shown to reduce morbidity and mortality among patients with hypertension. Because of their beneficial effects on morbidity and mortality, beta blockers are recommended as initial therapy for chronic stable
angina.1 However, they are underutilized in the treatment of this
condition.8 Pharmacists have an opportunity to increase the use of beta blockers in appropriate patients and reduce patients’ morbidity and mortality. Nitrates have not been shown to reduce mortality in patients with acute MI or CAD. Immediate-release or short-acting dihydropyridine calcium antagonists have been reported to increase adverse cardiac events. However, long-acting or slow-release dihydropyridines (amlodipine, felodipine) or nondihydropyridines (diltiazem, verapamil) have the potential to relieve symptoms in patients with chronic stable angina without increasing the risk of adverse cardiac events. It has not been determined whether long-acting nitrates or calcium antagonists are superior for long-term treatment for symptomatic relief of angina. Calcium antagonists offer the benefit of a sustained
24-hour effect. The choice of agents will be influenced by the patient’s clinical situation and by the physician’s preferences.
Special clinical situations may also influence which agent is utilized for the management of angina
(Table 3).1 Newer generation, vasoselective, long-acting dihydropyridine calcium antagonists, such as amlodipine or felodipine, can be used in patients with depressed left ventricular (LV) systolic function. Beta blockers or heart-rate modulating calcium antagonists (e.g., diltiazem, verapamil) should be avoided in patients who have sinus node dysfunction, rest bradycardia, or atrioventricular (AV) block. In patients with type 1 or type 2 diabetes who rely on insulin therapy for control, beta blockers should be used with caution because they can mask hypoglycemic symptoms (e.g., increase in heart rate). Pharmacists should inform patients to monitor blood glucose closely when therapy is initiated and to watch for other symptoms of hypoglycemia (e.g., sweating, nausea). Beta blockers and calcium antagonists may be used in patients with mild peripheral vascular disease. However, the use of beta blockers should be avoided in patients with severe peripheral vascular disease with ischemic symptoms at rest; calcium antagonists are preferred. The use of nitrates and dihydropyridine calcium antagonists should be avoided in patients with hypertrophic obstructive cardiomyopathy; beta blockers or heart-rate modulating calcium antagonists may be useful. If a patient has severe aortic stenosis, all vasodilators, including nitrates, should be used cautiously because of the risk of inducing hypotension and syncope. Patients with angina may have other cardiac conditions, such as heart failure, which require additional medications, such as diuretics and angiotensin-converting enzyme (ACE) inhibitors.9 Continuing and new clinical trials may also change the way in which these patients are
treated.10 Table 3
Antianginal and anti-ischemic drug therapy consists of nitrates, beta blockers, and calcium antagonists. Other drugs, including ACE inhibitors, “metabolic agents,” amiodarone, and nonconventional therapy, have also been used in select patient populations with chronic stable angina, but their clinical effectiveness has not been confirmed.
Although nitroglycerin has been used for more than 100 years in the treatment of angina, advances in its administration and its increasing clinical applications have revolutionized its use. Before the development of innovative drug delivery systems, the high degree of volatility and short duration of action of nitroglycerin were major limiting factors.
The basic action of nitroglycerin is relaxation of vascular smooth muscle throughout the body. The
therapeutic action of nitrates may be attributed to their potent vasodilating effects in both the venous system (capacitance vessels) and, to a lesser extent, on the arterial circulation (resistance vessels). The venous dilation decreases venous return, reduces cardiac filling (preload), and decreases tension on the walls of the heart. Blood shifts from the central to the peripheral circulation, and the heart becomes smaller. The arteriolar dilation causes reduced systemic vascular resistance, leading to reduced pressure against which the left ventricle must pump to eject blood (reduced afterload). Both of these effects reduce myocardial oxygen demand. A reflex increase in heart rate occurs as a result of the reduced vagal tone, which is caused by the reduction in blood pressure.
The effects of nitroglycerin on the coronary vessels and their contribution to this drug’s pharmacologic action are controversial. Nitrates have been shown to cause redistribution of coronary flow and an increase in collateral circulation to augment blood flow to ischemic regions of the myocardium. However, this redistribution of blood flow does not necessarily imply that the drugs act directly on the coronary vasculature. Although nitrates dilate normal coronary arteries, they do not increase total coronary flow in the patient with CAD.
Nitroglycerin is available in various forms —
nasal inhalant; translingual spray; sublingual, transmucosal, oral, and chewable tablets; oral capsules; parenteral (intravenous) injection; topical ointment; and transdermal preparations
(Table 4). Many newer preparations have a longer duration of action, making their use more convenient and suitable as a prophylactic agent.
Table 4
Nitroglycerin by nasal inhalation is available as amyl nitrite. Amyl nitrite is relatively expensive, inconvenient to use, has an unpleasant odor, and a high incidence of adverse effects such as headache and tachycardia. Although it is seldom used for acute angina, amyl nitrite is used as an adjunct in the treatment of cyanide poisoning.
Sublingual nitroglycerin is used commonly for acute relief of angina. Unsuitable for chronic prophylaxis because of its short duration of action, sublingual tablets or the translingual spray (0.4 mg glyceryl trinitrate per spray) may be used for immediate relief of effort or rest
angina.1 Patients should be started with one low-strength (1/200 grain 0.3 mg) tablet sublingually or one metered spray onto the oral mucosa. If chest pain is not relieved, the dose may be repeated every 3 to 5 minutes to a maximum of three doses. Continued chest pain may indicate unstable angina or an acute MI; patients should be instructed to seek emergency aid. Sublingual nitroglycerin or the translingual spray may be used prophylactically 5 to 10 minutes before engaging in activities that might precipitate an acute attack (such as climbing stairs, walking uphill, walking in cold weather, or sexual
activity).1
Pharmacists should counsel patients regarding the correct use and storage of nitroglycerin tablets and spray. Patients should be instructed to keep nitroglycerin tablets in the original, tightly closed glass container and to avoid mixing the tablets with other medications, because mixing may reduce nitroglycerin absorption and vaporization. Additional counseling should emphasize that nitroglycerin is not an analgesic but rather it partially corrects the underlying problem and that repeated use is not harmful or addicting. Patients should also be aware that enhanced venous pooling in the sitting or standing positions may improve the effect as well as the symptoms of postural hypotension, and that inadequate saliva may slow or prevent tablet disintegration and dissolution. In the situation of inadequate saliva, the lingual spray would be a good alternative.
The lingual spray has other advantages over nitroglycerin tablets, including a shelf-life of 2 years from the date of manufacture compared with only 3 to 6 months for a newly opened bottle of tablets. Patients should be informed that the expiration date can be found on the bottom of the bottle. Use of the spray may translate into a more cost-effective alternative. The results of a recent study demonstrated that over a 2-year period, total drug acquisition cost and drug wastage for the lingual spray were lower than for the sublingual nitroglycerin tablet, regardless of disease
severity.11
Differences in total drug acquisition costs and drug wastage were greatest among mild angina patients (defined as one episode per week). For these patients, the total 2-year drug acquisition cost for sublingual nitroglycerin tablets was determined to be more than three times that of the lingual spray. The drug wastage was estimated to be 85% of the total number of tablets provided. The tablet stability was considered the key cost driver at all levels of
severity.11 In addition, patients may continue to use out-of-date medication, which may not be effective when needed. Patient surveys have also found that more patients received faster relief and experienced less headaches with the
spray.12 And because there is no medicine bottle to open, the spray may be easier to use for patients with arthritis in their hands or fingers.
Patients who have used a lingual spray in the past should be informed that the original white, pressurized metal canister has been replaced with a clear red pump-action bottle. This was done for two reasons: (1) the pressurized gas (chlorofluorocarbons) has been eliminated so the canister is environmentally safe, and (2) the new bottle is see-through so that patients know exactly how much solution is
left.13 Patients must be informed that because there is no gas in the bottle, they will need to prime the spray before it is used for the first time, or if they have not used it for 6 weeks or more. Pharmacists should counsel patients to point the spray away from themselves and depress the nozzle one time to get the pump working properly. When they use the spray, patients should hold the container upright with their forefinger on top of the grooved button and then spray the medication onto or under the tongue. The medication should not be spit out or rinsed out of the mouth for 5 to 10 minutes following administration. Pharmacists should also tell patients that the spray is a solution and does not need to be shaken.
Longer acting nitrates, such as oral sustained-release formulations of nitroglycerin and several synthetic nitrate esters, have been used to
obtain prolonged antianginal effects. Hepatic clearance of oral isosorbide dinitrate (ISDN) is extensive, and variable doses are needed to obtain a therapeutic effect. Longer duration is obtained with higher doses, but the titration to very high doses is limited by adverse effects (orthostasis and headache). The development of isosorbide mononitrate (ISMN) has made dosing of the longer acting nitrates easier and more consistent. ISDN is metabolized to ISMN, which is well absorbed, has a half-life of about 5 hours, and may be given once or twice daily depending on the product. The twice-daily products must be given 8 hours apart to ensure a nitrate-free period. This may not be compatible with some patients’ schedules and thus may affect adherence to therapy. Pharmacists are in a good position to discuss this with their patients and assess whether a once-daily ISMN product may be better.
The use of cutaneous nitroglycerin was first described in 1955 but did not become popular until the 1970s. Administered doses of nitroglycerin ointment are large, often up to 30 mg. Absorption is variable from different sites and is probably related to cutaneous blood flow, with the least absorption from the extremities. The ointment must be carefully measured to ensure similar doses, it must be used several times daily, and it may be greasy and stain clothing. These factors may limit compliance.
Several different slow-release transdermal preparations of nitroglycerin are available. Each preparation consists of a nitroglycerin reservoir that permits even, gradual absorption. Although each preparation differs in reservoir material, nitroglycerin content, appearance, and size, all appear to be functionally similar. The most important property in comparing dosage strengths is the amount of drug delivered over 24 hours. The pharmacist can be an excellent resource for this information if a patient is switched to another transdermal product (ie, because of changes in insurance, availability). Patients should be counseled to place the patch only on intact skin and remove the patch after 10 to 12 hours to avoid nitrate tolerance.
Transdermal preparations are indicated for the treatment of angina, but because of a longer onset of action, patients need to have sublingual nitroglycerin tablets or spray available for acute attacks.
Intravenous nitroglycerin is established in the treatment of ischemic chest pain when other antianginal drugs have failed to provide relief. Administration is by continuous intravenous infusion with careful hemodynamic monitoring (e.g., heart rate, blood pressure).
The first-line pharmacologic agent in the management of angina is nitroglycerin. Because the individual response to nitrates is unpredictable, patients should be started on low doses, and the dose should be altered to the patient’s response. Palpitations may be bothersome to some patients. Doses may be increased according to patient tolerance over a period of several days or weeks to a maximum dose.
Nitroglycerin and nitrates are relatively contraindicated in hypertrophic obstructive cardiomyopathy. In these patients, nitrates can increase left ventricular outflow tract obstruction and severity of mitral regurgitation and can precipitate presyncope or syncope. In patients with severe aortic valve stenosis, nitroglycerin should be avoided because of the risk of inducing syncope. However, nitroglycerin can be used for relief of angina. Pharmacists must warn patients of the potentially serious consequences of taking sildenafil within 24 hours after taking a nitrate preparation, including sublingual nitroglycerin or the lingual spray. The coadministration of nitrates and sildenafil significantly increases the risk of potentially life-threatening hypotension.
Headache is a common adverse effect but should not be used as the therapeutic end point. The headache, usually throbbing, disappears after several days to 2 weeks of nitrate therapy. Temporary
reduction of the dose and mild analgesics, such as aspirin or acetaminophen, may be used to relieve headache initially.
If nitrates are used without a beta blocker, the optimum dose can be selected by the effect on blood pressure and heart rate. The greatest attainable decrease in blood pressure without symptoms of hypotension, intolerable headache, or an increase in resting heart rate greater than 10 to 15 beats per minute indicates optimum nitrate therapy. Pharmacists can monitor a patient’s response to therapy by subjective assessment methods, including reduction in the number of painful episodes and the amount of nitroglycerin consumed. Objective assessment includes the resolution of ECG changes at rest, during exercise, or with ambulatory ECG monitoring.
Nine oral beta blockers and two combined alpha- and beta-blocking agents (carvedilol and labetalol) are currently available in the United States. Many additional agents are under investigation. Propranolol, nadolol, metoprolol, and atenolol are the beta blockers approved for use in angina, but all beta blockers appear to be effective in angina. By inhibiting the sympathetic nervous system, beta blockers decrease heart rate, blood pressure, and the velocity of cardiac conduction. Thus, myocardial oxygen demand is significantly decreased and exercise tolerance is improved.
As discussed earlier, beta blockers should be strongly considered as initial therapy for chronic stable angina in patients who require more than sublingual nitroglycerin. Patients with angina who do not adequately respond to nitrate therapy may be started on beta blockers, provided these patients have no contraindications to the use of beta blockers. Sublingual nitroglycerin therapy should be continued, as needed, for acute attacks of chest pain.
Small doses of beta blockers should be used to initiate treatment. The dose may be increased every few days until a desired response is attained. The patient may be monitored for a reduction in chest pain, improved exercise tolerance, reduction in sublingual nitroglycerin use, and development of adverse effects. A resting heart rate of 55 to 60 beats per minute is desired. In patients with more severe angina, heart rate can be reduced to < 50 beats per minute, provided there are no symptoms associated with bradycardia and heart block does not
develop.1 The effective dose of beta blockers for angina varies with each patient and must be individualized.
The absolute cardiac contraindications for the use of beta blockers are severe bradycardia (heart rate <50 beats per minute with symptoms of dizziness and syncope), preexisting high degree of AV block, sick sinus syndrome, and severe, unstable LV failure (mild-to-moderate heart failure is an indication for beta blockers, and severe failure may be an indication in the future). Asthma and bronchospastic disease, severe depression, and peripheral vascular disease are relative contraindications. Most patients with diabetes will tolerate beta blockers, although, as noted earlier, these drugs should be used cautiously in patients who require insulin.
Adverse effects are usually related to consequences of beta blockade and include heart failure, bronchospasm, bradycardia, and Raynaud’s phenomenon. Fatigue, inability to perform exercise, lethargy, insomnia, nightmares, and impotence are frequently experienced adverse effects.
Abrupt withdrawal of beta blockers in patients with underlying IHD has been associated with increased severity and number of pain episodes and MI. Dosage reduction should be made gradually over 2 days or more while monitoring the patient for signs and symptoms of angina.
Beta blockers are frequently combined with nitrate therapy to provide additive antianginal effects. Used together, these cardiac drugs are complementary. The increase in heart rate induced by the nitrates is offset by the decrease in heart rate resulting from beta blockade. Beta blockers may depress myocardial contractility and increase LV size; nitrates produce opposite effects. The overall resultant effects are beneficial to the patient.
In more severe cases of angina, calcium antagonists have been combined with beta blockers, nitrates, or both to further reduce myocardial oxygen demand. This combination requires close monitoring to avoid decreases in contractility, AV block, and hypotension. The beta blockers differ in pharmacologic action, pharmacokinetic properties, and adverse effects
(Table 5). Patient compliance and liver and renal function are important considerations in selecting a beta blocker.
Table 5
The selection of a beta blocker also depends on the patient’s other concurrent medical conditions. For example, in an asthmatic patient, a cardioselective beta blocker, such as metoprolol or atenolol, may be preferred. However, the cardioselectivity is not absolute and is dose-dependent. Cardioselective agents may still cause bronchial constriction in some patients at low doses and in many asthmatic patients in high doses. Pharmacists should be aware of patients’ concomitant medical conditions and medications so that they can assess their patients for appropriate therapy.
The calcium antagonists are a pharmacologically unique group of drugs that are generally equally as effective as beta blockers in relieving angina and improving exercise time to onset of angina or
ischemia.1 Whereas the specific mechanisms may vary among calcium antagonists, the drugs all alter the slow inward currents of calcium at specific membrane sites, blocking contraction of smooth and cardiac muscle. The sites and relative intensity of effects vary among the agents
(Table 6). Table
6
All calcium antagonists are vasodilators because of their effects on smooth muscle. They produce their antianginal effects via vasodilation and prevention of coronary artery vasospasm. This results in improved myocardial oxygen
supply. In various degrees, the calcium antagonists decrease the force of contraction (especially verapamil and diltiazem). The negative inotropic effects may aid in the control of angina but may precipitate heart failure in susceptible patients. Myocardial oxygen demand is also reduced by reducing peripheral vascular resistance (afterload) and heart rate.
Long-acting calcium antagonists, including slow-release and long-acting dihydropyridines and nondihydropyridines, are effective in relieving symptoms in patients with chronic stable angina. They should be used in combination with beta blockers when initial treatment with a beta blocker is not successful, or as a substitute for a beta blocker when initial treatment leads to unacceptable adverse effects, or when use of a beta blocker is contraindicated.
Short-acting dihydropyridine calcium antagonists have the potential to enhance the risk of adverse cardiac events and should be avoided. However, even long-acting calcium antagonists have had negative outcomes in clinical trials.
Calcium antagonists have some advantages over beta blockers in the treatment of angina. They can prevent the vasospastic component of angina and improve coronary blood flow. Unlike beta blockers, they do not produce fatigue and depression as adverse effects and may be used in patients with concurrent pulmonary diseases, diabetes mellitus, or peripheral vascular diseases.
Adverse effects from the pharmacologic activity of the calcium antagonists include vasodilation, negative inotropy, and conduction disturbances. The incidence of each of these effects varies with the drug. Vasodilation can manifest as headache, dizziness, vertigo, flushing, and hypotension. Negative inotropic effects are minimal in patients with good cardiac function but may be significant in patients with cardiac abnormalities such as heart failure, cardiac hypertrophy, or valvular disease. Verapamil has the greatest effect on myocardial depression and AV conduction disturbances. Diltiazem causes minimal myocardial depression but may depress sinoatrial node function. The dihydropyridine calcium antagonists can cause a reflex increase in heart rate secondary to their vasodilator effects on the peripheral circulation.
Gastrointestinal symptoms may occur but do not require
discontinuation of therapy. Nausea and indigestion may be minimized by
administration of calcium antagonists with meals. Constipation occurs more commonly with verapamil. Pharmacists can recommend a stool softener to prevent the constipation.
Ankle edema, unrelated to the cardiac effects of these drugs, has been reported. Diuretic therapy may be helpful, but persistence of edema requires discontinuation of the drug and careful evaluation to rule out drug-induced heart failure.
Frequently combined with calcium antagonists, beta blockers must be used cautiously (especially with
Verapamil and diltiazem) to avoid excessive depression of AV node function and myocardial contractility. Antihypertensive drugs with vasodilator and strong hypotensive effects can be additive to those effects caused by calcium antagonists. Disopyramide has myocardial depressant effects and should be avoided in patients taking
Verapamil. The concurrent use of digoxin with calcium antagonists requires close monitoring. The use of
Verapamil in a patient taking digoxin may result in significant increases in digoxin plasma concentrations and additive pharmacodynamic effects to slow AV conduction. Verapamil is thought to reduce the renal and nonrenal digoxin clearance from the body. The overall effects of nifedipine and diltiazem on digoxin deposition are minimal and are not likely to be of clinical importance. Nicardipine does not appear to significantly alter digoxin levels. A long QT interval is a contraindication for the use of
bepridil.
Patients receiving calcium antagonists should be monitored for a reduced incidence and duration of anginal pain, reduced use of
sublingual nitroglycerin, and improved exercise tolerance. Patients with heart failure, bradyarrhythmias, or
conduction disturbances are at risk for drug toxicity and should be closely
monitored. For agents with extensive first-pass metabolism, diseases such as cirrhosis may enhance
bioavailability, necessitating dosage reduction. In addition to problems unique to specific calcium antagonists, blood pressure, heart rate, symptoms of heart failure, and constipation should be monitored by the pharmacist.
Failure to control angina with maximum dosages of specific antianginal drugs warrants the trial of combination drug therapy. Because each of the three major antianginal drug categories act through different mechanisms, appropriately selected drug combinations may act synergistically when single-agent drug therapy is inadequate.
Role of the Pharmacist
Pharmacists can make significant contributions to the care of the patient with angina. Patients benefit from education about their condition and the role of various medications. Pharmacists should counsel patients on the proper use and storage of nitroglycerin products. Patients should also be monitored for
adequate response to therapeutic interventions and for potential drug interactions.
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[Introduction]
[References]
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