a collection of heart conditions caused by an acutely blocked coronary artery, including myocardial infarction and unstable angina.
chest pain or pressure. Stable angina is experienced by patients with ischemic heart disease. Unstable angina is the mildest form of acute coronary syndrome caused by temporary blockages of coronary arteries.
slower than normal heart rate, usually considered lower than 60 beats per minute. Seldom symptomatic until heart rate decreases below 50 beats per minute.
a diagnostic and/or therapeutic procedure in which a catheter is inserted into the heart and used to administer a dye to visualize the coronary arteries. If blockages are present, stents may be inserted to open blocked arteries.
the ability of the cardiac muscle to undergo the changes needed to cause a contraction.
movement of ions within a cell that leads to a change in the electrical charge of the cell.
Electrocardiogram (ECG or EKG)
a graphic representation of the electrical activity of the heart. The device used for this test is an electrocardiograph.
a condition in which cardiac output is reduced to the point where the blood supply can no longer meet the metabolic demands of the body.
related to cardiac contractility. Positive inotropic effects result in increased contractility while negative ones produce decreased contractility.
an imbalance between oxygen supply and demand.
Ischemic heart disease
a condition of lowered oxygen supply or increased oxygen demand of the heart, often caused by chronically blocked coronary arteries.
referring to the heart muscle.
an emergency caused by an acutely blocked coronary artery, leading to decreased oxygen supply to the heart and myocardial cell death.
a brief period of time after a depolarization during which a new depolarization cannot occur.
a state in which the body cannot provide the necessary materials to support metabolic function. Shock is characterized by its cause and may be
severe allergic reaction.
damage to the cardiovascular system.
loss of fluid from the vascular space.
traumatic brain injury.
After completing this chapter, you should be able to
Define ischemic heart disease, acute coronary syndrome, heart failure, arrhythmia, and shock and identify their causes, symptoms, and consequences.
List the nonpharmacologic treatments for the heart diseases above.
Identify the various pharmacological treatments used to treat heart diseases and their basic mechanisms of action.
Describe the common side effects caused by each of the medication classes used to treat heart diseases.
The heart lies at the center of the cardiovascular system, providing the force that circulates blood around the body. As discussed in Chapter 14, the heart is divided into four chambers, each separated by valves. Deoxygenated blood arriving at the right atrium passes into the right ventricle, which pumps it into the lungs. Upon its return to the heart, the blood enters the left side of the heart, passing through the left atrium before being pumped to the rest of the body by the left ventricle. Keeping the system pumping in synchrony is a complex electrical system and a continuous supply of oxygen delivered via the coronary arteries. These areas of the heart are vital to its proper function but are also vulnerable to a number of dysfunctions. If the coronary arteries are blocked, oxygen supply to the heart can be reduced, leading to ischemic heart disease. This condition may progress to an emergency known as an acute coronary syndrome, including myocardial infarctions, commonly known as heart attacks. In the long term, patients with decreased oxygen supply to the heart may develop a condition known as heart failure, a decreased ability of the heart to pump blood around the body. Finally, if the heart’s electrical systems are damaged, patients may develop life-threatening arrhythmias or abnormal heartbeats. Diseases of the heart can be particularly devastating, causing nearly 1 million deaths in the United States each year.1
A number of common heart diseases are discussed in this chapter, including ischemic heart disease, acute coronary syndromes, heart failure, arrhythmias, and shock. The causes, signs, symptoms, and diagnosis of each condition are reviewed, followed by a discussion of the most widely used pharmacological and nonpharmacological treatments.
Ischemic Heart Disease
The coronary arteries that surround the heart are responsible for delivering a constant supply of oxygen. This oxygen is used by the myocardial (heart muscle) cells, allowing the heart to pump ceaselessly throughout a lifetime. When there is an imbalance between oxygen supplied from the blood stream and demand of the cardiac cells, a patient is said to have ischemic heart disease.
G. S. is a 59-year-old man with a history of coronary artery disease. During a visit to his doctor’s office, he mentions that he has occasionally felt short of breath and a feeling “like something was sitting on my chest.” The symptoms tend to occur when he is shoveling snow from his driveway. His doctor explains that he is likely experiencing angina due to his ischemic heart disease.
Ischemia, or an imbalance between oxygen supply and demand, may be caused by a number of circumstances. In most cases, one underlying factor of ischemic heart disease is coronary artery disease. The process of developing coronary artery disease, or atherosclerosis, begins decades before symptoms or an acute event. Starting in small areas of vascular damage, deposits of cholesterol, called fatty streaks, begin lining the walls of a vessel. These deposits continue to grow over time and eventually spread into the layers beneath the vessel wall. Once the cholesterol has infiltrated these lower layers, white blood cells enter the area. In an effort to remove the cholesterol, the immune cells become activated, causing more irritation in the area and attracting additional white blood cells. This collection of cholesterol, white blood cells, and cellular debris, known as an atherosclerotic plaque, causes narrowing of the blood vessel, leading to a sharp drop in blood flow to the heart and a decline in oxygen supply. (This problem, and its treatment, is discussed extensively in Chapter 17.)
In addition to atherosclerosis, other factors can also affect myocardial oxygen balance. Some patients’ oxygen supply may be reduced as a result of vasospasms—an uncontrollable and unintended constriction of blood vessels that cause significant constriction of coronary arteries. Oxygen demand is determined by heart rate and contractility. Demand is higher when both are increased, such as during exercise. Typically, both supply and demand issues must occur to tip the oxygen balance in an unfavorable direction.
When oxygen concentration dwindles, the first signs of dysfunction are a decrease in the cardiac cell’s ability to cause a contraction. If the oxygen-depleted state lasts, the ischemic area widens. The larger the ischemic zone, the more likely the patient will experience the most common symptom of ischemic heart disease: angina or chest pain. Though descriptions of angina may vary from patient to patient, the typical presentation is a sensation of chest pressure or burning. This sensation may be coupled with radiation of the pain to the left arm, neck, and jaw. Patients may also complain of nausea, shortness of breath, and diaphoresis (sweating). It is important for clinicians to collect information about what the patient was doing at the time the angina began. This information can aid in the diagnosis of ischemic heart disease. Activities that cause increases in oxygen demand or decreases in oxygen supply can give rise to an anginal attack. These activities include exercise, cold temperatures, emotional upset, and eating a large meal, among others. It is also important to note that some patients, especially those with diabetes or certain nervous system disorders, may have ischemic heart disease and experience no symptoms whatsoever.
What situations led to G. S.’s angina symptoms? What other activities besides shoveling snow should G. S. avoid?
Since ischemic heart disease is a serious condition that indicates increased cardiovascular risk (the risk of having a cardiovascular event such as a heart attack or stroke), it is important that it is appropriately differentiated from other conditions that may present with similar symptoms. Anxiety, gastroesophageal reflux disease (GERD), and acute coronary syndromes can all present similarly, and a number of diagnostic tests can help clinicians obtain the correct diagnosis. One of the earliest tests ordered is the EKG, or electrocardiogram. This measures the electrical activity of the heart, producing a graphic record that can help clinicians decide if a patient is having angina or a myocardial infarction. For patients who have intermittent angina, a stress test, or exercise tolerance test, can be ordered to reproduce the conditions that caused the chest pain. In this test, patients are asked to run on a treadmill while attached to an EKG machine. If a patient has ischemic heart disease, the increased demand of exercising should cause a recurrence of chest pain. For patients who cannot exercise, agents such as adenosine (Adenoscan) and regadenoson (Lexi-Scan) can be administered to mimic the effect of exercise. The most invasive of tests is cardiac catheterization. In this procedure, a catheter (thin tube) is inserted into an artery and guided into the coronary arteries. A dye, such as iodixanol (Visipaque) or iohexol (Omnipaque), is injected and images are taken to give clinicians a clear view of the coronary arteries to aid in diagnosis. If extensive coronary artery disease is discovered, this procedure can also be used therapeutically, allowing physicians to insert stents to open clogged arteries. It is also possible to combine the exercise tolerance test with the imaging techniques of a catheterization to directly observe the effect of exercise on the coronary arteries. See Medication Table 16-1 for more information on diagnostic agents (Medication Tables are located at the end of the chapter).
The dyes that are commonly used during cardiac catheterizations can lead to serious side effects, such as anaphylactic reactions, drug interactions, and kidney failure, especially among patients sensitive to iodine-containing agents.
When used for cardiac catheterization, adenosine is dosed as a 140-mcg/kg/min infusion over 6 minutes, while regadenoson is given as a single 0.4-mg dose via intravenous (IV) push.
For patients who develop ischemic heart disease, the goal of treatment is to both relieve symptoms of angina and reduce the risk of future cardiac events. A number of medications, lifestyle modifications, and procedures can be used to reach these goals.
G. S.’s doctor would like to investigate his symptoms further. What noninvasive test can be used to help differentiate true ischemic heart disease from other conditions with similar symptoms?
Though some risk factors for the development of ischemic heart disease cannot be changed or avoided, such as male sex, family history, and genetics, there are a number of lifestyle modifications that can reduce the risk of cardiovascular events. Perhaps of the highest importance is the control of underlying conditions that increase cardiovascular risk, including hypertension and hyperlipidemia. Refer to Chapters 14 and 17, respectively, for discussions of these conditions and their treatment. Cigarette smoking is another important modifiable risk factor. Smoke exposure, both first and second hand, causes decreases in oxygen supply via vasoconstriction and increases in oxygen demand as the heart pumps against higher blood pressure. If a patient can quit smoking, cardiovascular risk falls significantly within 5 years of quitting.2 Finally, obesity significantly increases cardiovascular risks. Clinicians frequently recommend calorie-restricted diets and physical activity to bring patients down to normal weight.
The most commonly used agents in the treatment of ischemic heart disease are the beta antagonists (beta blockers), especially in patients who have more than one episode of chest pain per day. As discussed in Chapter 15, these medications block the ability of the catecholamines to cause increases in heart rate, contractility, and blood pressure. The resulting decreased oxygen demand helps restore oxygen balance, reducing the risk of angina attacks. In addition to decreasing the risk of developing angina, beta blockers have additional benefits in patients with coronary artery disease, such as blood pressure reduction, cutting the risk of heart attack, and protecting against arrhythmias.
Of the four subgroups of beta antagonists, the cardioselective agents are typically the drugs of choice in the treatment of angina. By selectively inhibiting the beta1 receptor, side effects, such as sexual dysfunction, hyperglycemia, and bronchospasm that are common with nonselective agents, can be minimized. Though certain side effects are reduced, the cardioselective beta blockers still have a number of troublesome effects. Bradycardia, dizziness, hypotension, and decreased exercise tolerance are common reactions that warrant a slow titration of these medications. For a complete discussion of the various beta antagonists and their typical dosing, refer to Chapter 15.
Calcium Channel Blockers
Calcium channel blockers, also discussed in Chapter 15, can improve the symptoms of ischemic heart disease by both decreasing oxygen demand and increasing supply. The dihydropyridines (eg, amlodipine, nifedipine) act primarily on the vasculature, causing vasodilation that can improve coronary blood flow and allow the heart to pump against lower levels of systemic vascular resistance. The nondihydropyridines (eg, diltiazem, verapamil), on the other hand, target the heart and cause a reduction in contractility and heart rate. Like the beta blockers, normalizing the oxygen balance improves chest pain and reduces the likelihood of future episodes of angina. Unlike the beta blockers, however, the calcium channel blockers may not have as many additional cardiovascular benefits. For this reason, the beta blockers remain the first-line therapy in ischemic heart disease. For patients with contraindications to beta blocker therapy or those who develop significant side effects, however, calcium channel blockers are appropriate alternatives. One exception to this rule is in patients who experience angina that is related to vasospasm. Studies have shown that calcium channel blockers are among the most efficacious medications in the treatment of this form of angina and should be used as first-line therapy in these cases.
Clinicians choosing between the two types of calcium channel blockers must take individual patient characteristics into consideration. For patients with concurrent atrial fibrillation or rapid heart rates, the mechanism of action of the nondihydropyridines may give added benefits beyond regulation of oxygen balance. For those patients with slow heart rates or heart failure, the dihydropyridines may be better agents. Regardless of the agent chosen, side effects must be closely monitored, with the nondihydropyridines likely to cause constipation and bradycardia, the dihydropyridines causing tachycardia and edema, and both groups likely to cause hypotension and dizziness. Chapter 15 contains an in-depth review of the calcium channel blockers, including agent names, dosing, and interactions.
Nitric oxide is a substance produced by the body that causes vasodilation. This effect can be mimicked with the administration of nitrates, medications that are broken down into nitric oxide–like compounds that cause a direct vasodilation. In ischemic heart disease, the vasodilation throughout the body produced by nitrates decreases oxygen demand of the heart while increasing oxygen supply by dilating coronary arteries. Many of the adverse effects experienced by patients taking nitrates are directly related to their mechanism of action. Headache, orthostatic hypotension, and reflex tachycardia are the most common side effects. In addition to the setting of acute ischemic heart disease, nitrates can be used alone to treat infrequent, predictable angina or in addition to beta blockers or calcium channel blockers to reduce the risk of future attacks.
For patients with acute chest pain, the most rapid-acting and widely used treatment is sublingual nitroglycerin (Nitro-Stat). Patients are typically instructed to place one nitroglycerin tablet (most often 0.4 mg) under the tongue at the onset of chest pain. Another dose may be administered every 5 minutes if the chest pain persists, up to a maximum of three tablets. Nearly 90% of patients with ischemic heart disease will have resolution of the acute symptoms with proper administration of nitroglycerin. If the symptoms are not relieved after two doses, the patient should seek immediate medical attention for the possibility of an acute coronary syndrome. In addition to the sublingual tablets, a number of other formulations of nitroglycerin are available. The lingual spray (Nitrolingual) is an alternative to the sublingual tablets in the treatment of acute angina attacks. It has a longer shelf life but higher cost. Intravenous (IV) nitroglycerin is available for use in a hospital setting.
Sublingual nitroglycerin tablets must be dispensed only in their original, amber glass container. They should be protected from light and heat to retain their effectiveness. Patients may need regular refill reminders, especially those with infrequent symptoms whose supply may go out of date before it is all used.
IV nitroglycerin interacts with many of the polyvinyl chloride (PVC) infusion sets routinely used in hospitals. Nonabsorbing tubing is available, and pharmacy technicians, as well as other personnel involved, must be aware that the dose administered through the nonabsorbing sets (5 mcg/min) is only 20% of that commonly given (25 mcg/min) if a regular PVC set is used. Be aware of your institution’s supplies and policies.
A number of nitrate medications are available for prophylaxis of ischemic heart disease symptoms, with a goal of reducing the number of angina attacks that patients experience. Nitroglycerin is available in a transdermal patch formulation (Minitran, Nitro-Dur) that can be applied once daily. Nitroglycerin ointment (Nitro-Bid) and oral capsules (Nitro-Time) can also be used for long-term prophylaxis of angina but are rarely used due to difficulty of administration, sometimes requiring as many as four doses per day.
While the chest is the preferred application site for transdermal nitroglycerin patches, any area of clean, dry, hairless skin will suffice as long as it is not below the knee or elbow. Hair that interferes with patch placement may be trimmed with scissors but not shaved.
Isosorbide mononitrate (Monoket) and dinitrate (Isordil) are oral nitrate therapies that are used solely for prophylaxis. These agents are available in sustained-release formulations that have longer half-lives and require dosing only one to three times daily. Refer to Medication Table 16-2 for available products and dosage forms.
Combining nitrates with erectile dysfunction drugs like sildenafil (Viagra) can cause a profound drop in blood pressure. Because patients may be seeing more than one physician, it is especially important to be alert to the patient’s medication history and profile when prescriptions are filled for medications in either of these classes (nitrates or erectile dysfunction drugs).
One important reminder for any patient on long-acting nitrate medications is the need for an 8–12-hour, nitrate-free interval. Without this interval, patients quickly develop a tolerance to the nitrate effect, losing all the benefit this type of therapy has to offer.
A number of other important therapies are initiated in patients with ischemic heart disease that will be discussed in later sections of this chapter. Aspirin or clopidogrel are antiplatelet therapies that have been proven to reduce mortality and the risk of heart attack and stroke. If a patient has an elevated cholesterol level or is otherwise at high risk of heart attack or stroke, treatment with statin medications (discussed in Chapter 17) is indicated, and the angiotensin-converting enzyme (ACE) inhibitors (Chapter 15) are another class of medications with proven benefit for reducing mortality in patients with coronary artery disease.
It is determined that G. S. is suffering from angina. Choose one possible pharmacological treatment and describe how it would help to relieve his symptoms.
For patients with advanced disease, physicians may decide to aggressively treat coronary artery disease with revascularization procedures to restore blood flow to an area of the heart with a blocked vessel. In percutaneous coronary intervention (PCI), a stent (small tube) is inserted into blocked arteries. Coronary artery bypass grafting (CABG) is the attachment of arteries from the patient’s arms or legs to the heart to allow blood to flow around blockages.
Acute Coronary Syndromes
For patients with ischemic heart disease, symptoms of angina are the result of chronic changes in oxygen supply and demand. When these changes are acute in nature, the risks are much greater, warranting a diagnosis of acute coronary syndrome. For the past 100 years, this life-threatening cardiovascular emergency has claimed more lives than any other heart disease in the United States.3
V. O. is a 76-year-old female brought to the emergency department by emergency medical services. She experienced sudden, severe chest pain that radiated to her neck and left arm. Her husband called 911 immediately.
As seen in ischemic heart disease, the most important risk factor for the development of acute coronary syndrome is underlying coronary artery disease. When associated with acute coronary syndromes, symptoms of angina are not due to progressive changes in blood vessels but to an acute event known as a plaque rupture. This occurs when an unstable atherosclerotic plaque is damaged and breaks open. The body sees the ruptured plaque as an area of damage and attempts to form a blood clot at the site. Unfortunately, this attempt to remedy the situation only makes conditions worse. The clot that is formed ultimately causes either partial or complete blockage of the coronary artery, quickly diminishing blood flow to the heart. With the oxygen supply severely reduced or completely cut off, heart cells in the area begin to die. At this stage of cell death, a patient is said to be having a heart attack, or myocardial infarction, and typically experiences sudden, crushing chest pain, diaphoresis, nausea, and shortness of breath. Other patients, however, may be susceptible to a silent (without severe pain) myocardial infarction. This particularly dangerous form of heart attack, seen commonly in patients with diabetes and nerve disorders, may cause a patient to delay seeking medical attention until it is too late.
Acute coronary syndromes can be classified into three groups, depending on the extent of damage to the heart and the types of changes seen on an EKG. The mildest form is known as unstable angina in which cell death is minimal and most likely due to temporary interruptions in blood flow. Unstable angina differs from the chest pain seen in ischemic heart disease, often called stable angina, in that it occurs at rest, is more severe, has an uncharacteristic duration, or is not relieved with nitrate therapy. EKG strips of patients with unstable angina typically will not reveal any evidence of changes in the electrical conduction of the heart.
The second classification of acute coronary syndrome is called a non-ST-segment-elevation myocardial infarction, or NSTEMI. In these patients, coronary blood flow is obstructed to a degree that causes considerable cell death to occur. These effects are evident when clinicians obtain levels of troponin, an enzyme that is leaked from dying heart cells. However, because the area of damage seen in an NSTEMI does not traverse the entire thickness of the heart, EKGs obtained in these patients do not show an elevation in the ST segment of the tracing, a sign of cell death across the entire organ wall.
The most-deadly form of acute coronary syndrome is known as an ST-segment-elevation myocardial infarction, or STEMI. When the damage caused by an occluded coronary artery is severe enough to kill heart cells across the entire chamber wall, the electrical conduction is affected. This type of myocardial infarction gets its name from the characteristic changes in the EKG reading of the heart’s electrical activity, a rise in the ST segment of the tracing. In addition to these EKG changes, patients will also have high levels of troponins leaking from damaged cardiac cells. When both of these telltale signs are present, clinicians must work quickly to restore blood flow to the heart and minimize the long-term effects of ischemia.
Upon her arrival to the emergency department, V. O.’s blood sample has high levels of troponin and her EKG shows evidence of abnormal conduction. What type of acute coronary syndrome is V. O. likely having?
Early Treatment of Acute Coronary Syndromes
The first goal that must be reached in patients suffering from an acute coronary syndrome is to return blood flow to the area of the heart being damaged by ischemia. The earlier the revascularization, the less likely the patient will develop lasting consequences of a myocardial infarction, such as arrhythmias and congestive heart failure. Both pharmacological and nonpharmacological treatments play important roles in restoring oxygen supply to an area of infarction.
It has been established that the best way to restore circulation to occluded (blocked) vessels is to perform PCI or CABG. PCI is usually the preferred therapy for patients with coronary artery disease that is less extensive and contained to areas that can be reopened with stents. CABG, on the other hand, is reserved for the most severe cases of coronary artery disease, as the procedure is much more invasive and carries higher risks.
Glycoprotein IIB/IIIA Inhibitors
In both STEMI and NSTEMI patients who undergo PCI revascularization, glycoprotein IIB/IIIA (GP IIB/IIIA) inhibitors are important medications that lower the risk of occlusion of stents and the need to have additional PCI procedures. Agents in this class of medications, including abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat), are administered intravenously and bind to a receptor that is responsible for platelet adhesion, or the ability of platelets to stick together. With the function of platelets reduced, patients are less likely to develop blood clots that re-occlude stented vessels. Because they decrease platelet function, the major side effect of these agents is unwanted bleeding, especially when they are combined with other agents that interfere with platelet function or the body’s ability to form clots. If a patient has received fibrinolytic therapy (medication to dissolve blood clots, described next), has active bleeding, or has low numbers of platelets, these agents should be avoided. Dosing of GP IIB/IIIA inhibitors is based on a patient’s weight. See Medication Table 16-3 for dosing and adjustment information.
In some areas, access to life-saving PCI and CABG is limited. In these cases, patients with STEMI may receive fibrinolytic therapy to help restore blood supply to the heart. These IV agents, including alteplase (Activase), reteplase (Retavase), and tenecteplase (TNKase), bind to fibrin, an important component of blood clots. Once bound, the fibrinolytics begin to break down the clot and open the occluded coronary artery. Because of their mechanism of action, the fibrinolytics will dissolve clots throughout the body, not only those present in coronary arteries. For this reason, these agents should not be used in patients with active bleeding, a history of hemorrhagic stroke, extremely high blood pressure (higher than 180/110 mm Hg), or recent internal bleeding, among other contraindications. Finally, the use of fibrinolytics is also controversial in patients older than 75 years of age. Some studies suggest that patients treated may have higher mortality rates when compared to those who did not receive these agents. The dosing regimens for fibrinolytic therapies are complex and are listed in Medication Table 16-3.
Because the effectiveness of fibrinolytics decreases as time elapses after the onset of a cardiovascular event, it is important that therapy be initiated as soon as possible. When used to treat stroke, the window is only 3 hours from the onset of symptoms. Many emergency departments stock a fibrinolytic for ready use upon admission of a patient with suspected stroke or acute coronary syndrome.
Unfractionated and Low Molecular Weight Heparins
Unfractionated heparin and the low molecular weight heparins, enoxaparin (Lovenox) and dalteparin (Fragmin), are important anticoagulant medications that are typically administered in the early stages of an acute coronary syndrome. Unlike GP IIB/IIIA inhibitors, aspirin, and clopidogrel, which work on platelet function, these anticoagulants interfere with the body’s clotting cascade to inhibit clot formation. For a full discussion of their mechanism of action and dosing, refer to Chapter 27. Regardless of whether the patient has suffered a STEMI or NSTEMI, undergoing PCI or fibrinolytic therapy, heparins are typically administered for the first 24–48 hours of hospitalization to decrease the risk of additional clot formation. Like other agents that affect the body’s ability to form blood clots, these agents must be used cautiously in patients who have active bleeding, are taking other medications that interfere with the body’s clotting ability, or have a high risk of developing a bleed.
V. O. is taken to a community hospital emergency department that does not have the facilities to perform revascularization procedures, but she has a history of hemorrhagic stroke. Should she receive fibrinolytic therapy? Why or why not?
In addition to these important early treatments for STEMI and NSTEMI, a number of other supportive measures are also initiated. For some patients with oxygen saturation less than 90%, intranasal oxygen should be started. Nitroglycerin and morphine can be used together to control chest pain. Other therapies that are often started in the early treatment phase of an acute coronary syndrome, such as aspirin, beta blockers, and clopidogrel, are continued into the long-term treatment phase and are discussed below.
Long-term Treatment of Acute Coronary Syndromes
Once a patient is stabilized and revascularization is complete, the clinician’s primary focus is shifted to avoiding future cardiovascular events and preventing ventricular remodeling, or the stiffening of the chamber wall at the site of ischemia. A number of pharmacological agents have proven benefits for reducing mortality when used in the aftermath of a myocardial infarction and are typically initiated before a patient’s discharge from the hospital.
Unfractionated heparin carries an additional risk of causing heparin-induced thrombocytopenia (HIT), an immune reaction that destroys the body’s own platelets. If a patient has a history of this reaction, both heparin and low molecular weight heparins should be avoided, though the latter class of agents is associated with a much lower risk of causing this reaction.
Beta antagonists are typically initiated via the IV route in the early phase of treatment and later switched to an oral formulation and continued indefinitely. After a myocardial infarction, beta blockers have a proven survival benefit, reduce the risk of having a second event, and prevent ventricular remodeling. Their antihypertensive effects also help to control another important cardiovascular risk factor, elevated blood pressure. Similar to the agents chosen to treat ischemic heart disease, the cardioselective beta antagonists are the most commonly used subgroup. Clinicians must carefully monitor the side effects of hypotension and bradycardia as they can induce additional ischemic events or stoke. To avoid these issues, the beta blockers are initiated at lower doses and slowly increased toward target levels.
Esmolol (Brevibloc) is a very-short-acting IV beta blocker that must be administered via continuous infusion. Although its short duration of action limits its use for long-term therapy, it can be titrated rapidly to reach treatment goals in the short term.
Aspirin is another agent that is typically initiated in the early stages of an acute coronary syndrome, regardless of the type of event. The primary benefit of this agent is platelet inhibition. Within 10 minutes of administration, aspirin irreversibly binds to cyclooxygenase-1 (COX1), the enzyme responsible for the production of thromboxane A2, an important factor in platelet aggregation and adhesion. It is also theorized that aspirin’s anti-inflammatory effects may play a role in risk reduction. With platelet function diminished and the immune system tempered, the risk of forming additional clots, occluding a stent, and having future cardiovascular events is reduced. Like other antiplatelet therapies, the major side effect of aspirin therapy is a risk of bleeding, particularly of the gastrointestinal tract. To help reduce this risk, the lowest effective dose of aspirin is used. In the early phase of treatment, an initial 162-mg dose is administered followed by 81 mg daily, thereafter.
Though controversial, some studies have identified a drug interaction between clopidogrel and proton pump inhibitors (PPIs) used to treat gastrointestinal conditions. These agents inhibit liver enzymes that are responsible for converting clopidogrel into its active form and may increase the risk of coronary events when used together.
Platelet Aggregation Inhibitors
Another type of antiplatelet therapy that may be considered in acute coronary syndrome are the platelet aggregation inhibitors. These agents (clopidogrel, prasugrel, and ticagrelor) inhibit platelet function by binding to receptors that normally play a role in platelet aggregation. For patients who have undergone PCI with stenting, they can help to prevent stent occlusion. Depending on the type of stent inserted, patients may be treated with platelet aggregation inhibitors daily for several months up to an indefinite period of time. Clopidogrel is also used as an alternative to aspirin in patients with contraindications to its use. Because of bleeding risk, clopidogrel and prasugrel are not administered to patients who may require CABG. If CABG is needed in patients who have received this medication, a 5-day wash-out period must pass before the procedure can be performed. (This appears to be less of an issue with ticagrelor.) When these agents are used in combination with aspirin, bleeding risk is increased. To reduce this risk, only low-dose aspirin (100 mg or less) is usually used in combination with platelet aggregation inhibitors.
After being transported to another institution for revascularization, V. O. is being discharged on clopidogrel and aspirin. What is an appropriate dose of aspirin for this patient?
Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers
In the first 24 hours following a myocardial infarction, treatment with an oral angiotensin-converting enzyme (ACE) inhibitor is usually started and continued indefinitely. Many studies have shown improved survival and reduced re-infarctions when these agents are initiated in the early phase of treatment. The body releases angiotensin II and aldosterone after ischemic events in an attempt to maintain appropriate blood pressure. In the long term, however, these substances are actually harmful to the heart, increasing the rate and degree of cardiac remodeling. An ACE inhibitor can reduce the levels of these substances. If a patient exhibits symptoms of heart failure, which are discussed below, ACE inhibitor therapy has been shown to be even more beneficial. For patients with contraindications or side effects while on ACE inhibitor therapy, angiotensin II receptor blockers (ARBs) may be a good alternative option. The common side effects of ACE inhibitor and ARB therapy include elevations of potassium levels, decreases in kidney function, and low blood pressure. For a complete discussion of ACE inhibitor and ARB medications, refer to Chapter 15.
The statins are a group of medications used to reduce cholesterol levels in the blood. As described above, high levels of cholesterol increase a patient’s risk of developing atherosclerotic plaques and coronary artery disease. Statin therapy can reduce cholesterol levels significantly and, in turn, reduce the risk of cardiovascular disease. In patients with existing coronary artery disease or a myocardial infarction, it is theorized that statins have additional benefits, called pleiotropic effects, that go beyond their cholesterol-lowering effects. One hypothesis is that statins help to stabilize plaques, making unstable plaques less likely to rupture and cause future myocardial infarctions. The anti-inflammatory effects of statins may decrease cardiovascular risks, as well. For a full discussion of statins and other lipid-lowering medications, see Chapter 17.
One of the most devastating long-term consequences of an acute coronary syndrome is known as heart failure. When a significant area of the heart becomes ischemic and dies off, its pumping ability can be reduced. When the heart can no longer pump blood at a rate sufficient to meet the oxygen demands of the body, a diagnosis of heart failure is made.
B. R. is a 52-year-old male with a history of myocardial infarction. Ever since his acute coronary syndrome incident, B. R. has been excessively tired performing tasks that were previously easy for him. He has also noticed that it is difficult to put on his shoes due to swelling in his legs. His physician fears he has developed heart failure.
In a normally functioning heart, the amount of blood ejected during each heartbeat, called the stroke volume, is determined by three factors: preload, afterload, and contractility. Preload is defined as the amount of blood in the ventricle before the contraction begins. As more blood is forced into the ventricle, the preload increases and allows for a greater stroke volume. This effect, however, only improves stroke volume to a point. Beyond it, additional fluid in the ventricle is no longer beneficial. Afterload is described as the forces that impede the ejection of blood out of the ventricle. These include systemic vascular resistance and the physical shape of the ventricle wall. As afterload increases, it becomes more difficult for the heart to pump blood, decreasing the stroke volume. Finally, contractility is defined simply as the ability of the heart’s cells to cause a contraction. If myocardial cells are replaced by scar tissue after an event such as a myocardial infarction, contractility and, as a result, stroke volume are decreased.
To upset the natural balance among the three factors that make up stroke volume, one or more inciting events must take place. As discussed earlier in the chapter, the most common of these events is an acute coronary syndrome; however, other causes of heart failure include longstanding hypertension, heart valve diseases, arrhythmias, fluid overload, or certain medications. After one of these events initially reduces stroke volume, the body attempts to compensate. Increased levels of aldosterone and vasopressin cause retention of sodium and water. The additional fluid in the vasculature allows for extra blood to fill the ventricle, increasing preload. As a result of declines in stroke volume, blood pressure is also reduced. In an effort to maintain tissue perfusion, the body activates the renin-angiotensin-aldosterone system and the autonomic nervous system, resulting in vasoconstriction, increased blood pressure, and increases in afterload. Finally, the increased workload on the heart and the numerous hormones released in an attempt to compensate cause changes to the heart tissue called ventricular hypertrophy, or a thickening of the ventricular walls.
Taken as a whole, these compensatory changes help the heart maintain adequate circulation in the short term, all while leading to heart failure in the future. To review, decreased stroke volume and blood pressure lead to the release of a number of hormones that temporarily improve stroke volume and tissue perfusion. To truly compensate, however, these hormones must increase systemic vascular resistance and afterload, making it harder for the heart to eject blood. These conditions cause remodeling that further reduces stroke volume and restarts the cycle.
The types of symptoms a patient experiences depend largely on what areas of the heart are damaged. If the left side of the heart is affected, decreases in cardiac output cause a backing up of blood into the lungs. In these patients, many of the resulting symptoms are lung-related, including wheezing, cough, pulmonary edema, and tachypnea, or rapid breathing. When the right side of the heart is damaged, blood backs up into the systemic circulation and patients suffer from symptoms such as lower leg edema, bloating, cold extremities, and liver damage. All patients with heart failure, regardless of the side of the heart affected, can expect to have symptoms of fatigue, weakness, fluid overload, and decreased quality of life due to decreased cardiac output.
If B. R.’s symptoms are primarily lower-leg edema and cold extremities, what side of the heart is likely compromised?
Treatment of Chronic Heart Failure
The goals of treating heart failure include relief of symptoms and improving quality of life in the short term, but focus on improving survival and slowing progression of the disease in the long term. To accomplish these goals, treatment focuses on halting and reversing the harmful compensatory mechanisms. Medications and lifestyle changes are started that reduce preload to near-normal levels, decrease afterload, and disrupt the barrage of harmful hormones and proteins that eventually worsen the condition.
The body’s normal response to decreased stroke volume is to retain sodium and water. This harmful response to heart failure is made even worse if a patient consumes large quantities of salt in the diet. Most experts recommend a sodium restriction to less than 2 g each day. This lifestyle modification can significantly decrease the risk of heart failure exacerbations and reduce the doses of medicines needed to control the disease. It is also important for heart failure patients to remain active. Though overexertion can worsen heart function, mild to moderate exercise has been proven to be an important piece of many treatment regimens. Finally, clinicians focus heavily on improving patient adherence to the medication regimen. It has been shown that nonadherence is the most common cause of hospitalization for heart failure exacerbation. Educating patients about pillboxes, simplifying drug regimens, and reducing other barriers to adherence are of utmost importance.
One teaspoon of table salt contains more than the 2 g daily allowance in the sodium-restricted diet described above.
In the past, the beta antagonists were a class of medications avoided in patients with heart failure. It was not until a number of recent trials showed a significant improvement in patient mortality and decreases in hospitalizations for heart failure that these agents became routinely used components of heart failure treatment regimens. It is theorized that the benefit of beta blockers lies in their ability to stop the effects of catecholamines on the heart, decrease oxygen demand, or stop ventricular remodeling. Because of their tendency to reduce contractility and cause heart failure symptoms, however, these agents are only started in patients with stable heart failure and at very low doses. Dose increases are performed in 2-week intervals and monitored closely. If a patient experiences worsening heart failure, the dose is immediately reduced to previously tolerated levels and only increased after another 2-week interval has passed.
It is important to note that not all beta blockers are approved for use in heart failure. To date, three beta blockers have proven benefit. These are bisoprolol (Zebeta), carvedilol (Coreg), and metoprolol succinate (Toprol XL).
Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers
The ACE inhibitors are considered the cornerstone of heart failure treatment. By inhibiting the renin-angiotensin-aldosterone system, these medications have numerous benefits. Preload is reduced when aldosterone release is inhibited, afterload is decreased when angiotensin II production declines, and ventricular remodeling can be halted or reversed. Studies have shown that the ACE inhibitors not only reduce the risk of heart failure exacerbations, but they also improve survival. For those patients who develop a cough due to ACE inhibitor exposure, the ARBs can be substituted. Though they are not as well studied as the ACE inhibitors, these medications do have some evidence to support their use. The ARB valsartan may be used in combination with sacubitril, a neprilysin inhibitor, to further reduce the risk of death in patients with heart failure (Medication Table 16-4).
Hydralazine and Isosorbide Dinitrate
Before renin-angiotensin-aldosterone system–mediating medications were widely available, another combination of vasodilators was commonly used to treat heart failure. Studies predating the ACE inhibitors and ARBs shed light on the favorable effects of the combination of hydralazine (Apresoline) and isosorbide dinitrate (Isordil) on both mortality and hospitalizations due to worsening heart failure. Hydralazine is a potent direct arterial vasodilator that reduces afterload, while the isosorbide dilates veins and reduces preload. Today, ACE inhibitors and ARBs are first- and second-line agents with considerably better efficacy and safety evidence. However, for some populations, especially African Americans, the combination of hydralazine and isosorbide dinitrate can still be an important treatment option. Though both agents are available generically, a name brand combination tablet (BiDil) is available combining 37.5 mg of hydralazine and 20 mg of isosorbide dinitrate, dosed one to two tablets three times daily. Despite their efficacy in select patients, side effects still limit the overall use of this combination. Headaches, rebound tachycardia, and the potential to cause drug-induced lupus require close monitoring.
Another group of medications that have proven risk reduction and mortality benefits is the aldosterone antagonists. Though these agents fall under the class of potassium-sparing diuretics, it is their antialdosterone effects that are responsible for their benefit in heart failure. As described in Chapter 14, aldosterone causes retention of water and sodium, increasing preload initially, but worsening symptoms of pulmonary and lower-extremity edema in the long term. Aldosterone may also have a direct effect on heart tissue, increasing the rate of ventricular remodeling. Spironolactone (Aldactone) has been studied extensively in heart failure and shows the greatest benefit in patients with severe heart failure. Eplerenone (Inspra) is an alternative in male patients who experience spironolactone-induced gynecomastia (painful breast enlargement).
Accumulating fluid and edema are a constant concern for heart failure patients. To help treat these symptoms, patients are usually prescribed a diuretic. Though these medications have no mortality benefit, they are used to improve quality of life. Thiazide diuretics are considered too weak to adequately control edema related to heart failure. For this reason, loop diuretics, including bumetanide (Bumex), furosemide (Lasix), and torsemide (Demadex) are the drugs of choice. Close attention must be paid to ensure proper dosing, as over-diuresis may be harmful. Clinicians often instruct patients to use their body weight as a guide for diuretic dosing, increasing the dose if weight increases and vice versa.
Digoxin (Lanoxin) comes from a class of medications known as the cardiac glycosides. In the past, it was theorized that the main benefit of adding this medication was a positive inotropic effect, meaning an increase in contractility. Today, it is thought that low doses of digoxin actually improve heart failure symptoms by blocking a number of the harmful proteins and hormones that cause ventricular remodeling. This agent is available in two doses, 0.125 mg and 0.25 mg, is available generically, and is dosed once daily. Over the years, a number of conflicting studies caused debate about whether digoxin should be used in heart failure, at all. The evidence suggests that digoxin may reduce heart failure symptoms and the risk for hospitalization, but it does not improve survival. Experts generally agree that the lack of a mortality benefit and serious side effects such as nausea, dizziness, bradycardia, or other arrhythmias make this drug difficult to use. What was once a first-line therapy for heart failure has now become the last-line agent, only used when all other treatments are maximized and a patient is still having exacerbations.
A blood test can be performed to monitor digoxin levels. If a patient overdoses, a dose of IV digoxin antibodies, digoxin immune fab (Digibind), can be given to neutralize the drug and reduce the concentration to nontoxic levels. Digoxin antibodies are dosed based on the amount of digoxin ingested or a measurement of the amount of digoxin in the blood.
Treatment of Acute Exacerbations of Heart Failure
When heart failure symptoms become suddenly worse, a patient is said to be having an exacerbation. The usual cause of an exacerbation is nonadherence to lifestyle changes or medications, but it may also be caused by progression of the underlying disease. The end result is usually worsening edema, decreased profusion, and hospitalization. The following agents are used to help bring these worsening symptoms under control.
To help reduce pulmonary and lower-extremity edema, high doses of diuretics are started upon hospital admission. IV loop diuretic therapy is usually initiated. If the loop diuretic is not sufficient on its own to improve symptoms, a thiazide-like diuretic, such as metolazone, can be added for a synergistic effect. When the acute exacerbation has resolved, the patient can be returned to oral loop diuretics.
When drugs are dosed on the basis of mg/kg/min or mcg/kg/min, care must be taken to be sure that patient weights expressed in pounds are converted to their kg equivalent and that infusion rates in mL/hr have been adjusted for the factor of 60 minutes per hour.
The positive inotropes are medications that increase heart contractility. These agents are used temporarily to boost stroke volume until the exacerbation can be controlled. One mechanism by which this action is accomplished is by activation of cardiac beta1 receptors. Dobutamine, an IV synthetic catecholamine, is the most commonly used beta1 agonist in the treatment of acute exacerbations of heart failure. This agent is relatively selective for the beta1 receptors, leading to minimal side effects through alpha1 and beta2 activation. Doses are typically started at 2.5–5 mcg/kg/min and slowly increased to a maximum of 20 mcg/kg/min.
Long-term, beta blocker use may decrease the effectiveness of dobutamine and some patients may require higher than normal doses.
Another mechanism by which contractility is increased is inhibition of an enzyme called phosphodiesterase III (PDE3). Under normal conditions, this enzyme plays a role in regulating calcium concentration in heart cells. When it is inhibited, calcium levels rise and contractility is increased. The effect, however, is not limited to cardiac tissue. PDE3 inhibition in the vasculature causes vasodilation and reductions in preload and afterload, effects that contribute to improved stroke volume. Milrinone is the most commonly used PDE3 inhibitor. It is dosed intravenously at a rate of 0.5 mcg/kg/min but must be adjusted if patients have renal failure. Because it does not act on beta receptors, patients on beta blocker therapy will not have a reduction in effect, but side effects such as hypotension, arrhythmias, and headache are still a possibility.
Regardless of which positive inotrope is chosen, two important factors must be considered. With long-term use, both of these medications, and others with similar mechanisms of action, cause an increase in mortality. They must be used for the shortest time possible, and, when they are discontinued, it must be done carefully to avoid a return of heart failure symptoms. The doses must be slowly decreased to ensure the patient can tolerate their withdrawal.
In acutely ill heart failure patients, fluid retention causes large increases in preload and afterload. Clinicians use potent IV vasodilators to return these factors to normal levels. They are categorized by their predominant effect: arterial or venous vasodilation.
Nitroglycerin in its IV formulation is an important heart failure treatment. It acts primarily on the venous side of the vasculature, with only minimal dilation of arteries. Preload reductions with a subsequent improvement in pulmonary edema are its main benefit. Doses of 0.5–3 mcg/kg/min are administered via continuous infusion, starting at the lower end of the range and titrated upward to effect and tolerability. The most commonly reported side effects in this setting are headache and hypotension due to excessive vasodilation. As seen when it is used in ischemic heart disease, tolerance to these effects may develop when nitroglycerin is used for extended periods.
Nitroprusside (Nitropress) is a mixed vasodilator, affecting both the arterial and venous systems. It causes dilation by increasing production of nitric oxide, one of the body’s natural vasodilators. The result is a decrease in both preload and afterload. Doses of 0.5–3 mcg/kg/min are administered as continuous infusions starting at lower doses that are increased every 5–10 minutes. Beside the expected side effects of hypotension, dizziness, and headache, nitroprusside has a unique adverse event: cyanide and thiocyanate toxicity. High levels of cyanide affect the body’s ability to transport oxygen, leading to confusion, weakness, and syncope (feeling faint or passing out). Though this effect is rare at typical doses, patients with kidney failure are at higher risk.
When damage is done to the electrical system of the heart, the potential for arrhythmias, or abnormal heartbeats, increases. Though ischemia is only one cause among many, including longstanding hypertension, heart failure, certain medications, and structural defects of the heart, it is one of the most common. The consequences of these abnormal heartbeats are as varied as the number of arrhythmias possible, ranging from asymptomatic to life threatening, and the treatments are just as numerous.
T. B. is a 46-year-old female having a routine checkup with her family physician. She does not have any worrisome symptoms at this time; however, the nurse notices an irregular pulse when checking her heart rate. The physician orders an EKG to help diagnose T. B.’s arrhythmia.
Review of Normal Conduction
As described in Chapter 14, a normal heartbeat originates from the sinoatrial (SA) node, located near the right atrium. This group of cells, often called the heart’s pacemaker, has leaky membranes that allow electrolytes to cross freely, causing depolarization and the start of a contraction. The depolarization spreads outward from the SA node, leading to contraction of the atria. When the depolarization reaches the junction between the atria and ventricles, another important group of cells, called the atrioventricular (AV) node, allow the depolarization to cross over into the lower half of the heart. To ensure the ventricles contract from the bottom up, the depolarization travels from the AV node down the left and right bundle branches to the Purkinje fibers at the bottom of the heart. From there, the depolarization can move upward, allowing efficient contractions of the ventricles. When the cycle is complete, the leaky cells of the SA node are ready to depolarize once more and start another contraction.
When the heart undergoes normal depolarization, the EKG tracing will have a predictable pattern for each beat of the heart, going from a small P wave to a large QRS complex and finishing with a T wave, as shown in Figure 16-1. The small P wave is a representation of the depolarization and contraction of the atria. The large QRS complex corresponds to the electrical charge moving toward the AV node and passing into the ventricles, causing ventricular contraction. Finally, as the ventricles repolarize after contraction, the T wave appears on the EKG tracing. Figure 16-2 illustrates a normal sinus rhythm, which would be expected in a patient without heart abnormalities. Figure 16-3 shows the ST segment elevation (raised above the baseline), which alerts physicians to a STEMI acute coronary syndrome.
Overall, the various arrhythmias that have the potential to occur can be divided into two groups. The first are those caused when cells outside of the SA node take over as the pacemaker of the heart. The second type of arrhythmia begins when a pathway is opened up to allow the wave of depolarization to travel along an abnormal route. The most common types of arrhythmias are discussed below.
Atrial fibrillation is characterized by rapidly beating atria. It is thought that this abnormal heartbeat occurs when an extra pathway opens to allow depolarization to reenter the atria and restart an unneeded contraction. If this dysfunction occurs, the atria will contract at a rate of 400–600 beats per minute, well above the normal rate of 60–100 beats per minute. Though this is extremely fast, many patients have no symptoms and can be in atrial fibrillation for years before a clinician discovers it. The lack of symptoms is due to regulation by the AV node, the gateway to the ventricles. When it is functioning properly, the AV node will not allow all of the 400–600 depolarizations to be transmitted to the lower half of the heart. If this ability is lost, however, patients will often begin to complain of “skipped heartbeats” or palpitations. When clinicians listen to the patient’s heart with a stethoscope, they will discover an irregularly irregular heartbeat as the atria and ventricles beat out of sync.
EKG tracings performed on patients with atrial fibrillation will display one major difference when compared to a normal EKG. In these cases, the typical P wave is replaced with many jagged, erratic waves or no P wave, at all. For an example of an EKG tracing of atrial fibrillation, see Figure 16-4.
The EKG performed on T. B. reveals atrial fibrillation. Why has T. B. felt no symptoms?
The consequences of atrial fibrillation can vary greatly. Some patients may have the condition for many years and not develop serious complications. In other cases, however, the outcome may be the onset of heart failure, atrial enlargement, or, the most worrisome result, a stroke. When the atria beat at a very high rate, blood cannot be pumped effectively. If it is allowed to pool, clots will begin to form in the atrium. A dislodged blood clot may travel to the brain and cause a stroke, an event that happens in 5% to 7% of atrial fibrillation patients each year.4 To reduce this risk, these patients are often started on warfarin (Coumadin), dabigatran (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), or edoxaban (Savaysa). These medications interfere with the production of important clotting factors, inhibiting the formation of a clot. For a full discussion of these agents and the clotting cascade, refer to Chapters 26 and 27.
Ventricular Tachycardia and Fibrillation
Often the result of ischemic damage to the heart after an acute coronary syndrome, ventricular tachycardia and fibrillation are very dangerous rhythms with dire consequences. Ventricular tachycardia is defined as heartbeats originating in the ventricle that occur at a rate faster than 100 beats per minute. When large areas of the heart die, the electrical system can become badly damaged. This leads to the formation of reentry pathways in the ventricles that allow depolarization to occur chaotically along abnormal routes. The result is a rapidly beating ventricle, unguided by the timely depolarization of the SA node. In contrast to atrial fibrillation, fast heart rates in the ventricle are considered life threatening, as blood cannot be pumped to the body effectively.
If it is allowed to progress, ventricular tachycardia may lead to ventricular fibrillation, or complete disarray of the electrical system of the heart. This lethal condition is the cause of death in 50% of myocardial infarctions. When the ventricle is in fibrillation, no coherent heartbeats occur, only minor quivering of the chamber. Unless it is rapidly treated, all blood flow stops and the risk of death is extremely high.
EKG tracings of ventricular tachycardia and fibrillation lose all resemblance to the normal EKG tracing discussed above, due to the extreme disarray of the electrical system of the heart. In ventricular tachycardia, the disorganized, rapid contraction of the ventricles appears as a series of repetitive narrow or wide spikes, completely lacking P waves, QRS complexes, or T waves. If this condition progresses to ventricular fibrillation, this repetitive pattern is lost to a chaotic, jagged tracing that mirrors the quivering of the fibrillating ventricle. See Figures 16-5 and 16-6 for examples of ventricular tachycardia and fibrillation tracings.
Torsades de Pointes
Torsades de pointes is translated to mean twisting of the points, a description of what this arrhythmia looks like on an EKG (as seen in Figure 16-7). Like ventricular fibrillation, torsades de pointes is a life-threatening abnormal heartbeat. It arises during the phase of rest after each depolarization, called the refractory period, when electrical conduction is limited. In normally functioning hearts, this resting phase is in place to help avoid having a new contraction begin before the heart has fully recovered from the previous one. After this period is over, repolarization is complete and the heart cells are ready for another contraction. Certain medical conditions, electrolyte imbalances, genetic defects, or medications can delay repolarization. This weakens the ability of the myocardial cells in the refractory period to ward off early contractions. If a new wave of depolarization happens during this weakened refractory period, the patient can develop torsades. Clinicians monitor the chance for developing torsades by examining the section of an EKG called the QT interval. If this segment of the tracing is prolonged, there is an increased risk of developing this life-threatening arrhythmia. Much like ventricular fibrillation, torsades causes an ineffective heartbeat, leading to impaired circulation of blood. If left untreated, death is a very common result. For a list of the common medications that can cause or contribute to torsades, see Table 16-1.
Selected Medications That May Cause Torsades de Pointes
In addition to rapid heart rates, arrhythmias can also come in the form of abnormally slow heartbeats. Called bradyarrhythmias, these slowed rhythms come in many types and range from the common sinus bradycardia, a slow heartbeat seen in athletes, to troubling AV blocks and escape rhythms. AV block is the result of a malfunctioning AV node. Though the atria contract normally, the wave of depolarization occasionally is not transmitted past the AV node, meaning the ventricles miss a beat. In its mildest form, no treatment is necessary, but symptoms can develop as the dropped beats become more frequent.
Escape rhythms are the heart’s way of replacing a damaged pacemaker. If the SA node is unable to perform its functions, the responsibility of initiating each heartbeat falls to the surrounding atrial tissue. When this happens, however, the heart rate is slightly slower. If the atrial tissue is also damaged, the responsibility falls to the AV node and the resting heart rate is even slower. If even the AV node cannot fulfill the duties of the pacemaker, the ventricular tissue itself can depolarize spontaneously, though the rate is as low as 30 beats per minute.
The treatment of the various arrhythmias has changed significantly in recent years, as most clinicians move away from antiarrhythmic drugs that have troublesome side effects toward nonpharmacological treatments. In addition to a wealth of new surgical and mechanical interventions, the incidence of new arrhythmias has been declining, thanks to rapid treatment of acute coronary syndromes and other precipitating events.
Depending on the arrhythmia, clinicians can choose among a wide variety of nonpharmacological interventions. When acute arrhythmias threaten a patient’s life, the treatment of choice is often direct current cardioversion, using electrical current to reset the heart’s conduction system. As made famous by numerous medical dramas, patients are sedated, paddles are placed on the chest, and electrical current is applied to the heart. For patients suffering from severe bradyarrhythmias, pacemakers have become popular treatment options. These small devices, implanted into the pectoral (chest) area, are attached to electrodes embedded into the cardiac tissue. Sophisticated software can sense the patient’s heartbeat and take over if the physiologic electrical system can no longer perform its duties. Similar to pacemakers, implantable automatic cardioverter-defibrillators (ICDs) can be used in patients at risk of developing sudden cardiac death. Like the paddles used in acute treatment of arrhythmias, these devices can sense the onset of ventricular tachycardia or fibrillation and deliver an electrical shock to return the heart to a normal rhythm. Finally, ablation is a surgical procedure used to destroy abnormal conduction pathways that can be sources of arrhythmias. Using a special EKG, the exact location of the abnormal circuit can be discovered and destroyed using radio waves.
Type I Antiarrhythmics
The medications used to treat arrhythmias are divided into four general classes, depending on the electrolyte channels they affect. The type I agents primarily slow the transport of sodium into cardiac cells. Type II agents, the beta blockers, do not directly affect any electrolyte channels but reduce arrhythmic potential by blocking the effect of catecholamines on the SA and AV nodes. Type III agents block the influx of potassium into heart cells, and Type IV agents slow calcium transport.
The type I antiarrhythmic agents are further divided into three subgroups. The type Ia agents include quinidine, procainamide, and disopyramide (Norpace), and all are available generically. In addition to slowing the transport of sodium into cardiac cells, the type Ia agents also prolong the refractory period. As discussed with torsades de pointes, delaying this segment of the depolarization cycle actually increases the risk of developing arrhythmias. In addition to increasing the risk of the very condition they are attempting to treat, low success rates in the treatment of both ventricular and atrial arrhythmias limit the use of these agents significantly. Each agent in this class has unique side effects. Quinidine is notorious for causing severe gastrointestinal complaints, including vomiting, diarrhea, and abdominal cramping. Procainamide has been implicated as a cause of systemic lupus erythematosus, a serious immune disorder that can damage the skin, joints, kidneys, or other organs (see Chapter 14). Disopyramide causes dry mouth, blurry vision, constipation, and urinary retention, as it blocks cholinergic receptors.
Though procainamide itself is not entirely eliminated by the kidney, it is metabolized to an active compound that can accumulate if the kidneys are not functioning properly. It must be used with caution in patients with renal failure.
The Type Ib agents include generic lidocaine (Xylocaine) and mexiletine (Mexitil) and cause a shortening of the refractory period while slowing sodium influx. These agents are used in the treatment of ventricular arrhythmias. Though it works well, IV lidocaine is limited to the treatment of ventricular arrhythmias in the hospital setting; there is no oral or injectable product suitable for outpatient use. Mexiletine, on the other hand, is available in a tablet formulation but is rarely used due to severe gastrointestinal side effects and poor efficacy.
Type Ic agents slow sodium transport into cardiac cells dramatically and have no impact on the refractory period. These agents, including flecainide and propafenone (Rythmol), are available as oral tablets and can be used to treat both atrial and ventricular arrhythmias. Though the refractory period is not shortened, their potent blockade of sodium transport causes an increased risk of arrhythmias via other mechanisms. Both of the type Ic agents are negative inotropes, meaning they decrease the contractility of the heart. For this reason, this subgroup of antiarrhythmic agents cannot be used in patients with heart failure.
Type II Antiarrhythmics
The type II antiarrhythmic agents are the beta antagonists. In addition to their other therapeutic actions; the beta antagonists can reduce the risk of developing both ventricular and atrial arrhythmias. In the ventricles, these medications block the potentially proarrhythmic (arrhythmia promoting) effects of catecholamines. In atrial arrhythmias, they block the AV node, decreasing the risk of transmitting unwanted contractions to the ventricles. For a full discussion of beta blockers, see Chapter 15.
Type III Antiarrhythmics
Though the use of most antiarrhythmics is limited by either severe side effects or an increased risk of developing arrhythmias, the type III agents are some of the most commonly used treatments. Medications in this subgroup, including amiodarone (Pacerone), dofetilide (Tikosyn), dronedarone (Multaq), ibutilide (Corvert), and sotalol (Betapace), act primarily by slowing the transport of potassium into cardiac cells, though some agents in the class have additional effects.
Amiodarone is available in an injectable dosage form as well as generic oral tablets and is one of the most effective treatments for ventricular and atrial arrhythmias. It has a mixed mechanism of action that borrows from many different classes of antiarrhythmics. The largest drawback with this agent is its numerous side effects. Patients can develop such varying reactions as dizziness, confusion, thyroid problems, eye problems, liver toxicity, bradycardia, or pulmonary fibrosis, a severe and sometimes fatal condition. Clinicians must carefully monitor all patients receiving amiodarone for the many potential side effects. In an effort to discover a safer drug with amiodarone’s efficacy, dronedarone was developed. It does lack many of the side effects of amiodarone but may increase mortality in patients with heart failure and is significantly less effective.
T. B. has been started on a regimen of amiodarone for her atrial fibrillation. What types of side effects might be expected?
Sotalol’s mechanism of action includes both type II and type III properties. This injection or generic oral medication can be used to treat many arrhythmias, but its main use is in atrial fibrillation. Because of its beta blocker effects, patients must be monitored for low blood pressure, bradycardia, and other side effects of that class of medications. Perhaps more concerning, however, is the chance of prolonging the QT interval of the EKG and causing torsades de pointes. The risk is even higher if patients have kidney failure as this can lead to sotalol accumulation.
Dofetilide and ibutilide, oral and IV medications, respectively, are type III antiarrhythmic agents used to convert atrial fibrillation to a normal heart rhythm. Ibutilide and dofetilide are available as generic options. With either agent, clinicians must monitor patients’ electrolyte levels closely. If potassium or magnesium levels are low, there is a significant risk for developing torsades de pointes. To avoid this side effect, many experts recommend pretreating all patients with potassium and magnesium supplementation.
Type IV Antiarrhythmics
Calcium channel blockers, discussed at length as antihypertensives in Chapter 15, make up the type IV antiarrhythmic agents. In atrial fibrillation, these agents block the AV node, similar to the beta blockers. They may also play a role in decreasing the risk of developing ventricular arrhythmias caused by increased exertion or catecholamine release. In general, the nondihydropyridines are the agents of choice to treat arrhythmias, as they are more selective for the cardiac tissue. (See Medication Table 16-5.)
At its most basic level, shock is defined as a state of abnormal cellular metabolism. It is a condition where the body cannot provide the materials necessary to keep cells alive and functioning normally. The causes of shock are numerous, spanning a number of body systems and dysfunctions, but all have one issue in common: regardless of its cause, once shock sets in, mortality rates are extremely high and a return to baseline function is very difficult to achieve. In fact, shock is often described as the end stage of all disease states, the ultimate cause of death in nearly every illness.
J. S. is a 39-year-old male who has suffered a massive myocardial infarction. He is currently in the intensive care unit because his blood pressure is dropping, his heart rate is elevated, and it appears his cardiac output is not high enough to circulate blood around his body. The cardiologist is concerned that J. S. may be developing shock.
When cells are deprived of oxygen or glucose, abnormal routes of metabolism must be used to supply energy. If these states are temporary, very little damage is done and cells can resume their usual function after resolution of the deficiency. Under other circumstances, however, oxygen and glucose may be depleted for extended periods of time. The result is an accumulation of the toxic byproducts of abnormal metabolism. When released into the bloodstream, the toxins cause damage that further impedes the normal delivery of oxygen and glucose to the cells. As neighboring cells are affected and the damage spreads, entire organs begin to shut down and, eventually, the body, as a whole, ceases to function.
Types of Shock
Shock is the root cause of death in many disease states, and the types of shock are numerous. When shock is due to a loss of fluid from the bloodstream, a patient is said to have hypovolemic shock. This condition may arise from a lack of adequate water ingestion, excessive sweating, vomiting, or diarrhea. A subtype of hypovolemic shock is known as hemorrhagic shock. In these cases, shock sets in due to loss of blood. If the body cannot keep enough volume in its blood vessels, the heart cannot circulate the blood through the vasculature and oxygen cannot be delivered to the tissues.
Severe infections can also cause a patient to develop shock. When the immune system is fighting a foreign invader, the response may be so strong that surrounding tissues become damaged along with the bacteria. To make matters worse, some bacteria can release toxins of their own to damage blood vessels and hasten the onset of septic shock. Yet another immune system–related cause of shock is severe allergic reactions. These patients are said to develop anaphylactic shock, when an outside trigger causes a vigorous immune response that damages the vasculature. In both cases, vascular damage leads to leaky blood vessels and impaired circulation, interfering with oxygen and nutrient delivery.
Other common causes of shock are the result of direct damage to the heart or central nervous system. Cardiogenic shock may be one consequence of severe ischemia after a myocardial infarction. If large areas of the heart are dead, cardiac output can drop to the point where it cannot provide sufficient blood flow to the rest of the body. Traumatic brain injuries lead to a neurogenic shock, where the nervous system can no longer maintain vasoconstriction. When widespread vasodilation occurs, blood pressure can drop so far that tissue perfusion suffers.
Regardless of the cause of shock, treatment focuses on restoring blood pressure to appropriate levels. One strategy for raising blood pressure is to administer fluids to the patient. This is typically the first treatment initiated and can lower mortality significantly if started early. Next, clinicians may choose to administer vasopressors, drugs that cause constriction of the blood vessels to raise blood pressure.
From what type of shock is J. S. likely suffering?
IV 0.9% sodium chloride, also known as normal saline, solution, lactated Ringer’s, or 5% dextrose solutions are collectively called the crystalloids. These fluids are usually the agents of choice to restore vascular volume because studies show they are as effective as other treatments but cause fewer side effects and are less costly. In some cases, clinicians turn to fluids called colloids, such as 5% albumin, hetastarch, or dextran. In theory, these solutions, which contain larger molecules than those found in crystalloids, should remain in the vasculature for longer periods of time before diffusing out into the tissues. In practice, however, studies comparing the crystalloids and colloids do not show a significant difference in survival, despite their theoretical advantages and higher cost.
What are the theoretical benefits of using colloid fluids to treat J. S.’s shock?
The most common intravenously administered vasopressors used to treat shock include dopamine, dobutamine, norepinephrine (Levophed), epinephrine (Adrenalin), and phenylephrine, all of which activate the receptors of the autonomic nervous system to cause vasoconstriction, increases in contractility, and increases in stroke volume. The use of vasopressors to increase blood pressure in patients experiencing shock requires close monitoring and careful dose titrations. A balance must be obtained that allows for extra vasoconstriction that supports blood pressure but not excessive constriction that cuts off blood supply entirely. This becomes especially difficult, as extremely high doses of these agents are often required to counteract the symptoms of shock. If patients are stabilized on a vasopressor regimen, care must also be exercised when trying to discontinue these medications. Abrupt withdrawal often results in sudden deterioration of symptoms, so patients are typically weaned off of vasopressors very slowly (see Medication Table 16-6).
Advanced Cardiovascular Life Support Medications
When the heart stops, circulation is no longer maintained and cells begin to die throughout the body. If nothing is done to maintain cardiovascular activity, the patient’s situation will deteriorate to the point where life cannot continue. Stopping this series of events is known as life support. Basic life support (BLS) consists mainly of cardiopulmonary resuscitation (CPR) techniques and is the mainstay of rescue for patients whose hearts have stopped for whatever reason.5 CPR is a skill that can be acquired even by people with no other healthcare education; it is widely taught in schools and community settings, as well as in hospitals and healthcare organizations, and it has been shown to be of value when applied in cardiac arrest. The sooner the patient receives CPR, the more likely recovery becomes.
In hospitals and among emergency response personnel, the use of medications and other techniques to augment the BLS activities is termed advanced cardiac life support (ACLS). It involves advanced assessment and monitoring techniques (such as the EKG), placement of airway and IV access devices, and administration of medications. When performed in a hospital setting, it is often called a code (or some variation, such as code blue) and the personnel responding (physicians, nurses, pharmacists, respiratory therapists) make use of a specialized kit of medications and devices often termed a crash cart or code cart, that is maintained in readiness to enable a quick response to a potentially fatal patient condition.
Most of the medications kept in the crash cart and used in ACLS have been described in this or other chapters. Administration is generally via the IV route, although if a patient’s condition makes placement of an IV line difficult they are sometimes given via the endotracheal route (via a tube placed through the throat and into the tracheal entrance to the lung) or even intraosseously (injected into a bone, usually in the lower leg).
Medications most likely to be used in ACLS include vasopressors (drugs to increase blood pressure), including epinephrine and vasopressin; drugs to control heart rate (adenosine, atropine); and various antiarrhythmics (especially amiodarone, beta antagonists, diltiazem, and lidocaine). Additionally, most code kits or crash carts will include electrolytes such as calcium chloride and magnesium sulfate, along with concentrated (50%) dextrose injection. Because they must be immediately available, these medications are frequently packaged in single-use syringes with specialized needles.
Not every life-threatening emergency originates as a cardiac problem, so crash carts frequently carry medications to treat anaphylaxis (allergic reactions) or medication (particularly narcotic or sedative) overdose, which can also result in fatalities, sometimes by respiratory depression. Epinephrine, antihistamines, corticosteroids, and inhaled beta-adrenergic agents (such as albuterol) have a place in anaphylactic emergencies. Doses of naloxone (Narcan) and flumazenil can sometimes reverse the effects of narcotics and benzodiazepines, respectively. A list of medications typically kept in an emergency kit or cart can be found in Medication Table 16-7.
Most healthcare organizations have many crash carts ready and placed in various strategic locations so that there is always one close by when an emergency occurs. While maintenance of defibrillators and other equipment and supplies on these carts may vary from one institution to another, maintaining the supply and integrity of the medications is uniformly the responsibility of the pharmacy department. Special packaging, correct (and varied) doses, and even medication placement (so personnel in an emergency situation don’t have to be searching for what the patient needs) are vital, and technicians generally stock and restock these supplies, which are checked by the pharmacist before being sealed in a cart certified for use in emergencies.
Because crash carts and their contents are placed throughout the building and are used with varying (but irregular) frequency, ensuring that all items are in date is an important task. Carts are generally assigned a beyond-use date that corresponds to the earliest expiration date of any medication contained within it. Pharmacy technicians are frequently given a regular (weekly or monthly) assignment of checking the dates on all the carts on the premises and returning any at or near their beyond-use dates to the pharmacy for restocking.
When the function of the heart is compromised, the consequences are far-reaching and life-threatening. The coronary arteries and the electrical systems of the heart are especially vulnerable to various dysfunctions. The root cause of many of these heart diseases is atherosclerosis. Atherosclerotic plaques can reduce blood flow to the heart, causing damage to the muscle and reducing its ability to function. When oxygen supply is reduced chronically over time, patients develop ischemic heart disease and suffer from chest pain. If the drop in oxygen supply is sudden, patients may experience acute coronary syndromes, an emergent situation that requires immediate attention to restore blood flow and minimize permanent damage to the myocardium. When a significant area of the heart is damaged, however, cardiac output can be reduced or damage can be done to the electrical system of the heart. These circumstances may lead to heart failure and arrhythmias, respectively. In the worst of cases, patients may lose the ability to maintain adequate blood pressure for tissue perfusion, culminating in multiorgan failure and shock. Though numerous treatment strategies exist to help reduce the damage caused by these various heart diseases, prevention remains the best way to ensure a healthy cardiovascular system.
RothGA, AbateD, AbateKH, et al.Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1736–1788.
RothGA, AbateD, AbateKH, et al.Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392:1736–1788.)| false
PanchalAR, BergKM, HirschKG, et al.2019 American Heart Association focused update on advanced cardiovascular life support: Use of advanced airways, vasopressors, and extracorporeal cardiopulmonary resuscitation during cardiac arrest: An update to the American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2019;140:e881–e894.
PanchalAR, BergKM, HirschKG, et al.2019 American Heart Association focused update on advanced cardiovascular life support: Use of advanced airways, vasopressors, and extracorporeal cardiopulmonary resuscitation during cardiac arrest: An update to the American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2019;140:e881–e894.)| false
Used to treat ventricular arrhythmias caused by exercise or catecholamines; also useful in blocking the AV node in atrial fibrillation
(bis OH proe lol)
2.5–10 mg once daily
(KAR ve dil ol)
12.5–50 mg twice daily
20–80 mg once daily
(la BET a lole)
200–800 mg twice daily
(me toe PROE lole)
100–400 mg twice daily
(me TOE proe lole)
50–200 mg once daily
(NAY doe lole)
40–120 mg once daily
(proe PRAN oh lole)
160–480 mg twice daily
Inderal LA, InnoPran XL
80–320 mg once daily
(TYE moe lole)
10–40 mg once daily
(a MEE oh da rone)
Atrial fibrillation: 10 g load then 200–400 mg once daily; Ventricular arrhythmias: 800–1600 mg 1–2 times daily for 1 mo then 400 mg daily
Amiodarone and sotalol may be used in both atrial and ventricular arrhythmias; dronedarone is used in atrial fibrillation only; Ibutilide and dofetilide are used to convert atrial fibrillation to a normal heartbeat
1.2–1.8 g daily until 10 g is administered
(doe FET il ide)
500 mcg twice daily
(droe NE da rone)
400 mg twice daily
(i BYOO ti lide)
1 mg over 10 min
(SOE ta lole)
75–150 mg twice daily
80–160 mg 2–3 times daily
(am LOE di peen)
2.5–10 mg once daily
Used to treat ventricular arrhythmias caused by exercise or catecholamines; also useful in blocking the AV node in atrial fibrillation
(dil TYE a zem)
180–360 mg twice daily
Cardizem CD, Cartia XT, Tiazac, others
120–480 mg once daily
120–540 mg once daily
(fe LOE di peen)
5–20 mg once daily
(iz RA di peen)
5–10 mg twice daily
(nye KAR de peen)
60–120 mg twice daily
(nye FED i peen)
Adalat CC, Procardia XL
30–90 mg once daily
(ver AP a mil)
180–480 mg 1–2 times daily
180–420 mg at bedtime
100–400 mg at bedtime
AV = atrioventricular; IM = intramuscular; IV = intravenous.