Antianginal Drugs



Antianginal Drugs


Objectives


When you reach the end of this chapter, you will be able to do the following:



Drug Profiles



Key Terms


Angina pectoris Chest pain that occurs when the heart’s supply of blood carrying oxygen is insufficient to meet the demands of the heart. (p. 369)


Atherosclerosis A common form of arteriosclerosis involving deposits of fatty, cholesterol-containing material (plaques) within arterial walls. (p. 369)


Chronic stable angina Chest pain that is primarily caused by atherosclerosis, which results in a long-term but relatively stable level of obstruction in one or more coronary arteries. (p. 369)


Coronary arteries Arteries that deliver oxygen to the heart muscle. (p. 369)


Coronary artery disease (CAD) Any one of the abnormal conditions that can affect the arteries of the heart and produce various pathologic effects, especially a reduced supply of oxygen and nutrients to the myocardium. (p. 369)


Ischemia Poor blood supply to an organ. (p. 369)


Ischemic heart disease Poor blood supply to the heart via the coronary arteries. (p. 369)


Myocardial infarction (MI) Necrosis of the myocardium following interruption of blood supply; it is almost always caused by atherosclerosis of the coronary arteries and is commonly called a heart attack. (p. 369)


Reflex tachycardia A rapid heartbeat caused by a variety of autonomic nervous system effects, such as blood pressure changes, fever, or emotional stress. (p. 371)


Unstable angina Early stage of progressive coronary artery disease. (p. 369)


Vasospastic angina Ischemia-induced myocardial chest pain caused by spasms of the coronary arteries; also referred to as Prinzmetal or variant angina. (p. 369)


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Anatomy, Physiology, and Pathophysiology Overview


The heart is a very efficient organ that pumps blood to all the tissues and organs of the body. It is very demanding in an aerobic sense because it requires a large supply of oxygen to meet the incredible demands placed on it. The heart’s much-needed oxygen supply is delivered to the heart muscle by means of the coronary arteries. When the heart’s supply of blood carrying oxygen and energy-rich nutrients is insufficient to meet the demands of the heart, the heart muscle (or myocardium) aches. This is called angina pectoris, or chest pain. Poor blood supply to an organ is referred to as ischemia. When the heart is involved, the condition is called ischemic heart disease.


Ischemic heart disease is the number-one killer in the United States today. The primary cause is a disease of the coronary arteries known as atherosclerosis (fatty plaque deposits in the arterial walls). When atherosclerotic plaques project from the walls into the lumens of these vessels, the vessels become narrow. The supply of oxygen and energy-rich nutrients needed for the heart to meet its demand is then decreased. This disorder is called coronary artery disease (CAD). An acute result of CAD and of ischemic heart disease is myocardial infarction (MI), or heart attack. An MI occurs when blood flow through the coronary arteries to the myocardium is completely blocked so that part of the heart muscle cannot receive any of the blood-borne nutrients (especially oxygen). If this process is not reversed immediately, that area of the heart will die and become necrotic (dead or nonfunctioning). Damage to a large enough area of the myocardium can be disabling or fatal.


The rate at which the heart pumps and the strength of each heartbeat (contractility) influence oxygen demands on the heart. There are many substances and situations that can increase heart rate and contractility and thus increase oxygen demand. These include caffeine, exercise, and stress, among others, and result in stimulation of the sympathetic nervous system, which leads to increased heart rate and contractility. In a patient with CAD who has an already overburdened heart, this stimulation can worsen the balance between myocardial oxygen supply and demand and result in angina. Some of the drugs used to treat angina are aimed at correcting the imbalance between myocardial oxygen supply and demand by decreasing heart rate and contractility.


The pain of angina is a result of the following process: Under ischemic conditions when the myocardium is deprived of oxygen, the heart shifts to anaerobic metabolism to meet its energy needs. One of the byproducts of anaerobic metabolism is lactic acid. Accumulation of lactic acid and other metabolic byproducts causes the pain receptors surrounding the heart to be stimulated, which produces the heart pain known as angina. This is the same pathophysiologic mechanism responsible for causing the soreness in skeletal muscles after vigorous exercise.


There are three classic types of chest pain, or angina pectoris. Chronic stable angina has atherosclerosis as its primary cause. Classic angina and effort angina are other names for it. Chronic stable angina can be triggered by exertion or other stress (e.g., cold, emotions). The nicotine in tobacco as well as alcohol, coffee, and other drugs that stimulate the sympathetic nervous system can also exacerbate it. The pain of chronic stable angina is commonly intense but subsides within 15 minutes of either rest or appropriate antianginal drug therapy. Unstable angina is usually the early stage of progressive coronary artery disease (CAD). It often ends in an MI in subsequent years. For this reason, unstable angina is also called preinfarction angina. Another term for this type of angina is crescendo angina, because the pain increases in severity, as does the frequency of attacks. In later stages, pain may even occur while the patient is at rest. Vasospastic angina results from spasms in the layer of smooth muscle that surrounds atherosclerotic coronary arteries. In contrast to chronic stable angina, this type of pain often occurs at rest and without any precipitating cause. It does seem to follow a regular pattern, however, usually occurring at the same time of day. This type of angina is also called Prinzmetal angina or variant angina. Dysrhythmias and electrocardiogram (ECG) changes often accompany these different types of anginal attacks.


Pharmacology Overview


The three main classes of drugs used to treat angina pectoris are the nitrates and nitrites, the beta blockers, and the calcium channel blockers (CCBs). Their various therapeutic effects are summarized and compared in Table 23-1. There are three main therapeutic objectives of antianginal drug therapy: (1) minimize the frequency of attacks and decrease the duration and intensity of the anginal pain; (2) improve the patient’s functional capacity with as few adverse effects as possible; and (3) prevent or delay the worst possible outcome, myocardial infarction. The overall goal of antianginal drug therapy is to increase blood flow to ischemic myocardium, decrease myocardial oxygen demand, or both. Figure 23-1 illustrates how drug therapy works to alleviate angina. Evidence exists to suggest that drug therapy may be at least as effective as angioplasty in treating angina.




Nitrates And Nitrites


Nitrates have long been the mainstay for both the prophylaxis and treatment for angina and other cardiac problems. Today there are several chemical derivatives of the early precursors, all of which are organic nitrate esters. They are available in a wide variety of preparations, including sublingual and oral tablets; capsules; ointments; patches; a translingual spray; and intravenous solutions. The following are the rapid- and long-acting nitrates available for clinical use:



Mechanism of Action and Drug Effects


Medicinal nitrates and nitrites, more commonly referred to simply as nitrates, dilate all blood vessels. They predominantly affect venous vascular beds; however, they also have a dose-dependent arterial vasodilator effect. These vasodilatory effects are the result of relaxation of the smooth muscle cells that are part of the wall structure of veins and arteries. The nitrates have a potent dilating effect on the large and small coronary arteries. This causes redistribution of blood and oxygen to previously ischemic myocardial tissue and reduction of anginal symptoms. By causing venous dilation, the nitrates reduce venous return and, in turn, reduce the left ventricular end-diastolic volume (or preload), which results in a lower left ventricular pressure. Left ventricular systolic wall tension is thus reduced, as is myocardial oxygen demand. These and other drug effects are summarized in Table 23-1.


Coronary arteries that have been narrowed by atherosclerosis can still be dilated as long as smooth muscle surrounding the coronary artery and the atherosclerotic plaque does not completely obstruct the arterial lumen. Exercise-induced spasms in atherosclerotic coronary arteries can also be reversed or prevented by administration of nitrates, which encourages healthy physical activity in patients.


Indications


The nitrates are used to treat stable, unstable, and vasospastic (Prinzmetal) angina. Long-acting dosage forms are used more for prevention of anginal episodes. Rapid-acting dosage forms, most often sublingual nitroglycerin tablets, or an intravenous drip in the hospital setting, are used to treat acute anginal attacks.


Contraindications


Contraindications to the use of nitrates include known drug allergy, as well as severe anemia, closed-angle glaucoma, hypotension, and severe head injury. This is because the vasodilatory effects of nitrates can worsen these latter conditions. In anemia, a drug-induced hypotensive episode can further compromise already reduced tissue oxygenation. Nitrates are also contraindicated with the use of the erectile dysfunction drugs sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) (see Chapter 35).


Adverse Effects


Nitrates are well tolerated, and most adverse effects are usually transient and involve the cardiovascular system. The most common undesirable effect is headache, which generally diminishes soon after the start of therapy. Other cardiovascular effects include tachycardia and postural hypotension. If nitrate-induced vasodilation occurs too rapidly, the cardiovascular system overcompensates and increases the heart rate, a condition referred to as reflex tachycardia.This may occur with significant vasodilation that involves the systemic veins. There is a large shift in blood volume toward the systemic venous circulation and away from the heart. Baroreceptors (blood pressure receptors) in the heart then falsely sense that there has been a dramatic loss of blood volume. At this point, the heart begins beating more rapidly to move the apparently smaller volume of blood more quickly throughout the body, especially toward the vital organs (including the heart itself). However, the same baroreceptors soon sense that there has not been a loss of blood volume but that the volume of blood missing in the heart is now in the periphery (e.g., venous system), and the heart rate slows back to normal.


Topical nitrate dosage forms can produce various types of contact dermatitis (skin inflammation), but these are actually reactions to the dosage delivery system and not to the nitroglycerin itself; thus, it is not a true drug allergy. It is important for the nurse to document the type of allergic reaction, so that clinicians do not avoid this important drug class if the reaction is only a contact dermatitis.


Tolerance to the antianginal effects of nitrates can occur surprisingly quickly in some patients, especially those taking long-acting formulations or taking nitrates around the clock. In addition, cross-tolerance can arise when a patient receives more than one nitrate dosage form. To prevent this, a regular nitrate-free period is arranged to allow certain enzymatic pathways to replenish themselves. A common regimen with transdermal patches is to remove them at night for 8 hours and apply a new patch in the morning. This has been shown to prevent tolerance to the beneficial effects of nitrates. However, some studies have questioned the advisability of this practice.


Interactions


Nitrate antianginal drugs can produce additive hypotensive effects when taken in combination with alcohol, beta blockers, calcium channel blockers, phenothiazines, and erectile-dysfunction drugs such as sildenafil, tadalafil, and vardenafil. In fact, numerous deaths have been reported due to interactions with erectile-dysfunction drugs.


Dosages


The organic nitrates are available in an array of forms and doses. For dosage information, see the table on this page.



Drug Profiles


♦ isosorbide dinitrate


Isosorbide dinitrate (Isordil) is an organic nitrate. It exerts the same effects as the other nitrates. When isosorbide dinitrate is metabolized in the liver, it is broken down into two active metabolites, both of which have the same therapeutic actions as isosorbide dinitrate itself. This drug is available in rapid-acting sublingual tablets, immediate-release tablets, and long-acting oral dosage forms.



♦ isosorbide mononitrate


Isosorbide mononitrate (Imdur) is one of the two active metabolites of isosorbide dinitrate, but it has no active metabolites itself. Because of these qualities, it produces a more consistent, steady therapeutic response, with less variation in response within the same patient and between patients. It is available in both immediate- and sustained-release oral dosage forms but is most commonly used in the sustained-release form.



♦ nitroglycerin


Nitroglycerin is the prototypical nitrate and is manufactured by many pharmaceutical companies; therefore, it goes by many different trade names (e.g., Nitro-Bid, Nitrostat). It is often abbreviated as NTG or TNG. It has traditionally been the most important drug used in the symptomatic treatment of ischemic heart conditions such as angina. When given orally, nitroglycerin goes to the liver to be metabolized before it can become active in the body. During this process, a very large amount of the nitroglycerin is removed from the circulation. This is called a large first-pass effect (see Chapter 2). For this reason, nitroglycerin is administered by other routes to avoid the first-pass effect. Tablets administered by the sublingual route are used for the treatment of chest pain or angina of acute onset. They are also used for the prevention of angina when patients find themselves in situations likely to provoke an attack. Use of these routes is advantageous for relieving these acute conditions because the area under the tongue and inside the cheek is highly vascular. This means that the nitroglycerin is absorbed quickly and directly into the bloodstream, and hence its therapeutic effects occur rapidly. Sublingual nitroglycerin tablets must be stored in their original container, because exposure to air and moisture can inactivate the drug. Nitroglycerin also comes as a metered-dose aerosol that is sprayed under the tongue. Nitroglycerin is available in an intravenous form that is used for blood pressure control in hypertensive patients perioperatively; for the treatment of ischemic pain, heart failure, and pulmonary edema associated with acute MI; and in hypertensive emergency situations. Oral and topical dosage formulations are used for the long-term prophylactic management of angina pectoris. The topical formulation offers the same advantages as the sublingual formulation in that it also bypasses the liver and the first-pass effect. This formulation allows for the continuous slow delivery of nitroglycerin, so that a steady dose of nitroglycerin is supplied to the patient. See the Safety: Preventing Medication Errors box on p. 372.



Beta Blockers


The beta-adrenergic blockers, more commonly referred to as beta blockers, have become the mainstay in the treatment of several cardiovascular diseases. These include angina, MI, hypertension (see Chapter 22), and dysrhythmias (see Chapter 25). Most available beta blockers demonstrate antianginal efficacy, although not all have been approved for this use. Those beta blockers approved as antianginal drugs are atenolol, metoprolol, nadolol, and propranolol.



image SAFETY AND QUALITY IMPROVEMENT: PREVENTING MEDICATION ERRORS


Understanding Rate Versus Dose


The Institute for Safe Medication Practices (ISMP) reported an incident in which a nitroglycerin intravenous drip was set to infuse at 60 mL/hr rather than 60 mcg/min. With the medication concentration used (50 mg/250 mL) the patient actually received 200 mcg/min instead of the ordered 60 mcg/min. Investigation of this incident revealed that the nurses were using a handwritten, nonstandard dosing table rather than one that corresponded to the available concentrations of premixed solutions in the hospital. According to the report, the patient became hypotensive but recovered.


It is crucial to understand the difference between “mL/hr” and “mcg/min” when programming infusion pumps; rates are not interchangeable with ordered doses! In addition, using standardized dosing charts that correspond to available concentrations of solutions is important. Some facilities also require double-checking of infusion pump settings before medication therapy is begun.


For more information, see Improvised dosing charts can cause errors, Nurse Advise-ERR 3(6):3, 2005, available at http://www.ismp.org/Newsletters/nursing/Issues/NurseAdviseERR200506.pdf.


Mechanism of Action and Drug Effects


The primary effects of the beta blockers are related to the cardiovascular system. As discussed in Chapters 19 and 22, the predominant beta-adrenergic receptors in the heart are the beta1 receptors. Beta1 receptors are located in the heart’s conduction system and throughout the myocardium. The beta receptors are normally stimulated by the binding of the neurotransmitters epinephrine and norepinephrine. These catecholamines are released in greater quantities during times of exercise or other stress to stimulate the heart muscle to contract more strongly. At the normal heart rate of 60 to 80 beats/min, the heart spends 60% to 70% of its time in diastole. As the heart rate increases during stress or exercise, the heart spends more time in systole and less time in diastole. The physiologic consequence is that the coronary arteries receive increasingly less blood, and eventually the myocardium becomes ischemic.


In an ischemic heart, the increased oxygen demand from increasing contractility (systole) also leads to increasing degrees of ischemia and chest pain. The physiologic act of systole requires energy in the form of adenosine triphosphate (ATP) and oxygen. Therefore, any decrease in the energy demands on the heart is beneficial for alleviating conditions such as angina. When beta receptors are blocked by beta blockers, the rate at which the pacemaker (sinoatrial [SA] node) fires decreases, and the time it takes for the node to recover increases. The beta blockers also slow conduction through the atrioventricular (AV) node and reduce myocardial contractility (negative inotropic effect). Both of these effects serve to slow the heart rate (negative chronotropic effect). These effects reduce myocardial oxygen demand, which aids in the treatment of angina by reducing the workload of the heart. Slowing the heart rate is also beneficial in patients with ischemic heart disease, because the coronary arteries have more diastolic time to fill with oxygen- and nutrient-rich blood and deliver these substances to the myocardial tissues.


The beta blockers also have many therapeutic effects after an MI. Following an MI, there is a high level of circulating catecholamines (norepinephrine and epinephrine). These catecholamines will produce harmful consequences if their actions go unopposed. They cause the heart rate to increase, which leads to a further imbalance in the supply-and-demand ratio, and they irritate the conduction system of the heart, which can result in potentially fatal dysrhythmias. The beta blockers block all of these harmful effects, and their use has been shown to improve the chances for survival in patients after MI. Unless strongly contraindicated, beta blockers are given to all patients in the acute stages after an MI.


The beta blockers also suppress the activity of the hormone renin, which is the first step in the renin-aldosterone-angiotensin system. Renin is a potent vasoconstrictor released by the kidneys when they sense that they are not being adequately perfused. When beta blockers inhibit the release of renin, blood vessels to and in the kidney dilate, causing reduced blood pressure (see Chapter 22).


Indications


The beta blockers are most effective in the treatment of exertional angina (i.e., that caused by exercise). This is because the usual physiologic effects of an increase in the heart rate and systolic blood pressure that occurs during exercise or stress are blunted by the beta blockers, thereby decreasing the myocardial oxygen demand. For an individual (often elderly) with significant angina, “exercise” may simply be carrying out the activities of daily living, such as bathing, dressing, cooking, or housekeeping. Performing such activities with significant angina can become a major stressor for these patients. The beta blockers are also approved for the treatment of MI, hypertension (see Chapter 22), cardiac dysrhythmias (see Chapter 25), and essential tremor. Some uses that are common but are not U.S. Food and Drug Administration (FDA) approved are treatment of migraine headache and, in low dosages, even treatment of the tachycardia associated with stage fright.


Contraindications


There are a number of contraindications to the use of beta blockers, including systolic heart failure and serious conduction disturbances, because of the effects of beta blockade on heart rate and myocardial contractility. These drugs should be used with caution in patients with bronchial asthma, because any level of blockade of beta2 receptors can promote bronchoconstriction. These contraindications are relative rather than absolute and depend on patient-specific risks and expected benefits of this drug therapy. Other relative contraindications include diabetes mellitus (due to masking of hypoglycemia-induced tachycardia) and peripheral vascular disease (the drug may further compromise cerebral or peripheral blood flow).


Adverse Effects


The adverse effects of the beta blockers result from their ability to block beta-adrenergic receptors (beta1 and beta2 receptors) in various areas of the body. Blocking of beta1 receptors may lead to a decrease in heart rate, cardiac output, and cardiac contractility. Blocking of beta2 receptors may result in bronchoconstriction and increased airway resistance in patients with asthma or chronic obstructive pulmonary disease. Beta blockers may lead to cardiac rhythm problems, decreased SA and AV nodal conduction, a decrease in systolic and diastolic blood pressures, and possible peripheral receptor blockade and/or decreased renin release from the kidneys. Beta blockers can mask the tachycardia associated with hypoglycemia, and diabetic patients may not be able to tell when their blood sugar falls too low. Fatigue, insomnia, and weakness may occur because of the negative effects on the cardiac and central nervous systems. The beta blockers can also cause both hypoglycemia and hyperglycemia, which is of particular concern in diabetic patients. Other common beta blocker–related adverse effects are listed in Table 23-2.


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May 9, 2017 | Posted by in NURSING | Comments Off on Antianginal Drugs

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