Chapter 9. Drugs Used in Heart Failure

Heart failure occurs when the cardiac output is inadequate to provide the oxygen needed by the body. Heart failure is a highly lethal condition, with a 5-year mortality rate conventionally said to be about 50%. In systolic failure, cardiac contractility and the ejection fraction of the heart are reduced. In diastolic failure, stiffening and loss of adequate relaxation plays a major role in reducing cardiac output, although the ejection fraction may be normal. Because other cardiovascular conditions such as myocardial infarction are now being treated more effectively, more patients are surviving long enough to develop heart failure. Thus, heart failure is increasing in prevalence. Although research suggests that the primary defect in early heart failure resides in the excitation-contraction coupling machinery of the heart, the clinical condition also involves many other processes and organs, including the baroreceptor reflex, the sympathetic nervous system, the kidneys, angiotensin II and other peptides, and death of cardiac cells. The most common cause of heart failure in the United States is coronary artery disease.

This chapter reviews normal cardiac contractility and the pathophysiology and major clinical manifestations of heart failure. Drugs used to treat heart failure include positive inotropic agents, vasodilators, diuretics, and several miscellaneous drug classes (Figure 9–1). The positive inotropic agents increase the contractility of the heart, whereas the vasodilators and miscellaneous drugs have effects at both cardiac and noncardiac sites. Several drugs acting at noncardiac sites, such as the vasculature, kidneys, and central nervous system, have been discussed in Chapters 6, 7, and 8.

The force of contraction of heart muscle is determined by several processes that lead to the movement of actin and myosin filaments in the cardiac sarcomere (Figure 9–2). During systole, contraction results from the interaction of calcium with the actin-troponin-tropomyosin system, thereby releasing the actin-myosin interaction from inhibition. The calcium involved in this interaction is released from the sarcoplasmic reticulum (SR). The amount released depends on the amount stored in the SR and on the amount of trigger calcium that enters the cell during the action potential.

Several factors related to intracellular calcium physiology have been proposed as key components for cardiac contractility and potential sites for pharmacologic manipulation. The first factor is sensitivity of the contractile proteins to calcium (Figure 9–2, Site 6). Increased sensitivity of these proteins to calcium improves cardiac contractility; however, the determinants of calcium sensitivity—the curve relating the shortening of cardiac myofibrils to the cytoplasmic calcium concentration—are incompletely understood. Next, increasing the amount of calcium stored and released from the SR improves cardiac contractility. The SR membrane contains a very efficient calcium uptake transporter (Figure 9–2, Site 4), which maintains free cytoplasmic calcium at very low levels during diastole by pumping calcium into the SR. The amount of calcium sequestered in the SR is determined in part by the amount available for transport into the SR. This in turn is dependent on the balance of calcium influx (Figure 9–2, Site 3), primarily through the voltage-gated membrane calcium channels, and calcium efflux, the amount removed from the cell primarily via the sodium-calcium exchanger (Figure 9–2, Site 2). The amount of calcium released from the sarcoplasmic reticulum (Figure 9–2, Site 5) is regulated in part by the calcium influx through the cell membrane at Site 3 in Figure 9–2. A small rise in free cytoplasmic calcium, brought about by calcium influx during the action potential, triggers the opening of calcium channels in the membrane of the SR, and results in the rapid release of a large amount of the ion into the cytoplasm in the vicinity of the actin-troponin-tropomyosin complex. The amount of calcium that enters the cell depends on the availability of L-type calcium channels and the duration of their opening. As described in Chapter 4, sympathetic stimulation of the heart increases calcium influx through an action on these L-type calcium channels.

The sodium-calcium exchanger uses the influx of extracellular sodium to move calcium against its concentration gradient from the cytoplasm to the extracellular space (Figure 9–2, Site 2). Under physiologic conditions, extracellular concentrations of these ions are much less labile than intracellular concentrations. The ability of the sodium-calcium exchanger to carry out this transport is thus strongly dependent on the intracellular concentrations of both calcium and sodium, especially sodium. By removing intracellular sodium, the Na+/K+ adenosine triphosphatase (ATPase) (Figure 9–2, Site 1) is the major determinant of sodium concentration in the cell. The sodium influx through voltage-gated channels, which occurs as a normal part of almost all cardiac action potentials, is another determinant. As described below, Na+/K+ ATPase appears to be the primary target of cardiac glycosides.

The fundamental physiologic defect in heart failure is a decrease in cardiac contractility. Decreased contractility results in cardiac output that is inadequate to maintain homeostasis. This is best shown by the ventricular function curve, also known as the Frank-Starling curve (Figure 9–3). The ventricular function curve reflects some compensatory responses of the body and may also be used to demonstrate the response to drugs. As ventricular ejection decreases, the end-diastolic fiber length increases as shown by the shift from point A to point B in Figure 9–3. Operation at point B is intrinsically less efficient than operation at shorter fiber lengths because of the increase in myocardial oxygen requirement associated with increased fiber stretch (Figure 8–2).

The compensatory responses of the body to depressed cardiac output are extremely important and are mediated mainly by the sympathetic nervous system and the renin-angiotensin-aldosterone system. They are summarized in Figure 9–4. The major responses include tachycardia, increased preload and afterload, and cardiomegaly. Tachycardia is an early manifestation of heart failure and is the result of increased sympathetic tone. Increased peripheral vascular tone results in increased preload and afterload, and is another early response of heart failure mediated by increased sympathetic activity. The activation of the renin-angiotensin-aldosterone system results in retention of salt and water by the kidney. This is also an early compensatory response and is facilitated by increased sympathetic activity. Finally, cardiomegaly, enlargement of the heart, is a slower compensatory response and is mediated at least in part by sympathetic activity. Angiotensin II also plays an important role in cardiomegaly, and may be directly responsible for these cardiac changes. Although these compensatory responses temporarily improve cardiac output, they also increase cardiac workload. Eventually, the increased load contributes to further long-term decline in cardiac function.

Heart failure presents with multiple clinical signs and symptoms. Patients may manifest varying degrees of impaired cardiac reserve and exercise tolerance. Tachycardia is usually present along with the potential for cardiac arrhythmias. Increased salt and water retention results in weight gain, edema in the lower extremities when in an upright position, and pulmonary congestion. The lower extremity edema manifests as pitting edema and patients’ complaints of heavy feet. Pulmonary congestion results in exertional dyspnea, positional orthopnea, and paroxysmal nocturnal dyspnea. When these clinical signs of congestion are present, the pathophysiology is described as congestive heart failure.

Clinically, heart failure may be divided into chronic “compensated” heart failure and acute “decompensated” heart failure. Chronic heart failure is further subdivided into four classes according to a scale suggested by the New York Heart Association. Class I failure is associated with no limitations on ordinary activities and symptoms that occur only with greater than ordinary exercise. Class II is characterized by some limitation of ordinary activities, which results in fatigue and palpitations. Class III presents with no symptoms at rest, but fatigue and other clinical manifestations appear with less than ordinary physical activity. Class IV is associated with symptoms even when the patient is at rest. In contrast, acute heart failure manifests as the fairly rapid (hours to days) development of worsening peripheral edema, respiratory distress with exertion and later at rest, and diaphoresis and cyanosis; acute failure requires urgent medical intervention.

Figure 9–1 presents the pharmacologic classes used in the treatment of acute and chronic heart failure. These drug classes include positive inotropic agents (cardiac glycosides, beta (β) agonists, and phosphodiesterase inhibitors), and vasodilators (nitrates and other direct vasodilators). Recent approval of nesiritide, a recombinant form of brain natriuretic peptide, has increased interest in the use of vasodilating and natriuretic peptides in heart failure. The miscellaneous drug category includes aldosteronereceptorantagonists, angiotensin inhibitors, loop and thiazide diuretics, and β-receptor antagonists.

Diuretics have long been considered first-line therapy for heart failure. Cardiac glycosides (digitalis) were also part of the traditional regimen, but careful studies indicate that digitalis has been greatly overused. Clinical results have shown that angiotensin-converting enzyme inhibitors, β-receptorantagonists, and aldosterone receptor antagonists are the only agents in current use that actually prolong life in patients with chronic heart failure. A summary of the treatment algorithm used in the treatment of heart failure is presented in Table 9–1.

Pharmacologic therapies for heart failure include the removal of retained salt and water with diuretics, direct treatment of the depressed heart with positive inotropicdrugs such as cardiac glycosides, reduction of preload and afterload with vasodilators, and reduction of afterload and retained salt and water by angiotensin inhibitors. In addition, considerable evidence suggests that angiotensin inhibitors diminish pathologic structural cardiac changes that often follow myocardial infarction and lead to failure. Current clinical evidence suggests that acute heart failure should be treated with a loop diuretic, a prompt-acting positive inotropic agent such as a β agonist or phosphodiesterase inhibitor, and vasodilators as required to optimize filling pressures and blood pressure. In contrast, evidence suggests that therapy directed at noncardiac targets may be more valuable in chronic heart failure than traditional drugs such as digitalis that focus on improving cardiac contractility. Thus, chronic failure is best treated with diuretics plus an angiotensin-converting enzyme (ACE) inhibitor and, if tolerated, a β-receptor antagonist. Positive inotropic drugs such as cardiac glycosides reduce symptoms in chronic failure if systolic dysfunction is prominent.

Positive Inotropic Agents

Cardiac Glycosides

The cardiac glycosides are often called “digitalis” because several come from the digitalis (foxglove) plant. Digoxin is the prototypic agent and the only one commonly used in the United States. A very similar molecule, digitoxin, which also comes from the foxglove, is no longer available in the United States. Inhibition of Na+/K+–ATPase of the cell membrane by digitalis is well documented and is considered to be the primary biochemical mechanism of action of digitalis (Figure 9–2, Site 1). Translation of this effect into an increase in cardiac contractility involves the Na+/Ca2+ exchange mechanism (Figure 9–2, Site 2). Inhibition of Na+/K+–ATPase results in a small increase in intracellular sodium. The increased sodium alters the driving force for sodium-calcium exchange so that less calcium is removed from the cell. The increased intracellular calcium is stored in the sarcoplasmic reticulum (Figure 9–2, Site 4) and, upon release, (Figure 9–2, Site 5) increases contractile force (Figure 9–2, Site 6). Other mechanisms of action for digitalis have been proposed but these are probably not as important as the inhibition of ATPase. The consequences of Na+/K+–ATPase inhibition are seen in both the mechanical and the electrical function of the heart. Digitalis also has a cardioselective parasympathomimetic effect. This action involves sensitization and increased firing of the baroreceptors resulting in decreased efferent sympathetic activity and increased vagal stimulation. Muscarinic transmission in atrial and atrioventricular (AV) nodal cells is also facilitated.

Physiologic Response

The cardiovascular response to digitalis is mediated by both the direct effect on cardiac cells and the indirect effect mediated through the parasympathetic system (Table 9–2). These effects are divided into mechanical and electrical effects. The mechanical effects include an increase in contractility resulting in increased ventricular ejection, decreased end-systolic and end-diastolic dilation, increased cardiac output, and increased renal perfusion. These beneficial effects permit a decrease in the compensatory sympathetic and renal responses previously described. The decrease in sympathetic tone is especially beneficial: reduced heart rate, preload, and afterload permit the heart to function more efficiently (Figure 9–3, point C).

The electrical effects include early cardiac parasympathomimetic responses and later detrimental arrhythmogenic responses. An increased PR interval, caused by the decrease in AV conduction velocity, and flattening of the T wave are often seen. The effects on the atria and AV node are largely parasympathetic in origin. The increase in the AV nodal refractory period is particularly important when atrial flutter or fibrillation is present because the refractoriness of the AV node determines the ventricular rate in these arrhythmias. The effect of digitalis is to slow the ventricular rate. Shortened QT, inversion of the T, and ST depression may occur later.

Clinical Uses

Digitalis is the traditional positive inotropic agent used in the treatment of chronic heart failure. However, careful clinical studies indicate that while digitalis improves functional status by reducing symptoms, it does not prolong life. As discussed later, other agents such as diuretics, ACE inhibitors, and vasodilators may be equally effective and less toxic in some patients, and some of these alternative therapies do prolong life. In atrial flutter and fibrillation, reduction of the conduction velocity, or increasing the refractory period of the atrioventricular node, is desirable so that the ventricular rate is controlled at a level compatible with efficient filling and ejection. The parasympathomimetic action of digitalis often accomplishes this therapeutic objective, although high doses may be required. Alternative drugs for rate control include β-receptor antagonists and calcium channel blockers, but these drugs have negative inotropic effects. Because the half-lives of cardiac glycosides are long, the drugs accumulate significantly in the body, and dosing regimens must be carefully designed and monitored. The therapeutic and toxic concentrations are presented in Table 9–3.

Adverse Effects

Increased automaticity, caused by intracellular calcium overload, is the most important manifestation of toxicity. This increase in calcium results in delayed after-depolarizations, which may evoke extrasystoles, tachycardia, or fibrillation in any part of the heart. In the ventricles, the extrasystoles are recognized as premature ventricular contractions (PVCs). When PVCs are coupled to normal beats in a 1:1 fashion, the rhythm is called bigeminy. Cardiac glycosides also have significant drug interactions which, when combined with its narrow therapeutic window, often result in adverse events. Quinidine causes a well-documented reduction in digoxin clearance and can increase the serum digoxin level if digoxin dosage is not adjusted. Digitalis effects are inhibited by extracellular potassium and magnesium and facilitated by extracellular calcium. Loop diuretics and thiazides, often used in treating heart failure, may induce hypokalemia and hypomagnesemia, and thus precipitate digitalis toxicity. Digitalis-induced vomiting may induce hypomagnesemia and similarly facilitate toxicity. These ion interactions are important in treating digitalis toxicity. The major signs of digitalis toxicity are arrhythmias, nausea, vomiting, and diarrhea. Rarely, confusion or hallucinations and visual aberrations may occur. The treatment of digitalis arrhythmias is important because this manifestation of digitalis toxicity is common and dangerous. Chronic intoxication is characterized by increased automaticity and the arrhythmias noted in Table 9–2. Acute severe intoxication is caused by suicidal or accidental extreme overdose and results in cardiac depression leading to cardiac arrest rather than tachycardia or fibrillation.

β Agonists

Dobutamine and dopamine are useful in many cases of acute failure in which systolic function is markedly depressed. These agents stimulate cardiac β1 adrenoreceptors and enhance calcium influx (Figure 9–2, Site 3). The increased calcium influx increases cardiac contractility with, in heart failure, minimal increase in heart rate. However, they are not appropriate for chronic failure because of tolerance and lack of oral efficacy. Manifestations of toxicity include significant arrhythmogenic effects and angina.

Phosphodiesterase Inhibitors

Inamrinone and milrinone are the major representatives of this infrequently used group. These drugs increase cyclic adenosine monophosphate (cAMP) by inhibiting its breakdown by phosphodiesterase, and cause an increase in cardiac intracellular calcium similar to that produced by β1 adrenoceptor agonists (Figure 9–2, Site 3). Again, the increase in contractility occurs with, in heart failure, a minimal increase in heart rate. Phosphodiesterase inhibitors also cause vasodilation, which may be responsible for a major part of their beneficial effect. At sufficiently high concentrations, these agents may also increase the sensitivity of the contractile protein system to calcium (Figure 9–2, Site 6). These agents are used in the treatment of acute heart failure, and should not be used in chronic failure because they have been shown to increase morbidity and mortality. Manifestations of toxicity include nausea, vomiting, thrombocytopenia, hepatic and bone marrow toxicities, and arrhythmias.

Vasodilators

Vasodilators, including nitrate and other direct-acting drugs, were previously discussed in Chapters 7 and 8. Vasodilator therapy with nitroprusside or nitroglycerin is often used for acute severe heart failure with congestion. The use of these vasodilator drugs is based on the reduction in cardiac size and improved efficiency that can be realized with proper adjustment of venous return and reduction of resistance to ventricular ejection. Vasodilator therapy can be dramatically effective, especially in cases in which increased afterload is a major factor in causing the failure, such as in continuing hypertension in an individual who has just had a myocardial infarct. Chronic heart failure sometimes responds favorably to oral vasodilators such as hydralazine or isosorbide dinitrate, especially in African Americans.

Natriuretic Peptides

The atria and other tissues of mammals contain a family of peptides consisting of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). The release of both ANP and BNP appears to be related to blood volume. ANP and BNP exhibit similar natriuretic, diuretic, and hypotensive activities. CNP has less natriuretic and diuretic activity than ANP and BNP, but is a potent vasodilator. The physiologic role of CNP is unclear. Several factors increase the release of ANP from the heart. These include atrial stretch, volume expansion, changing from the standing to the supine position, and exercise. In each case, the increase in ANP release is probably due to increased atrial stretch. Increased sympathetic stimulation (of α1A adrenoceptors) and release of glucocorticoids and vasopressin also stimulate ANP release. Plasma ANP concentration increases in various pathologic states including heart failure, primary aldosteronism, chronic renal failure, and a syndrome of inappropriate antidiuretic hormone (SIADH) release. Natriuretic peptides participate in the physiologic regulation of sodium excretion and blood pressure. Administration of ANP to normal subjects produces prompt and marked increases in sodium excretion and urine flow. Secretion of renin, aldosterone, and vasopressin is inhibited by ANP. These changes may also increase sodium and water excretion. ANP decreases arterial blood pressure. This hypotensive action is due to vasodilation, resulting from relaxation of vascular smooth muscle via guanylyl cyclase activity. ANP also reduces sympathetic tone to the peripheral vasculature and antagonizes the vasoconstrictor action of angiotensin II and other vasoconstrictors. These actions may contribute to the hypotensive action of the peptide. Patients with heart failure have high plasma levels of ANP and BNP, which have emerged as diagnostic and prognostic markers in this condition. Plasma BNP concentration has been shown to be closely correlated with the New York Heart Association functional class of symptomatic heart failure. The clinical benefits of the recombinant BNP (nesiritide) appear mainly to be due to vasodilation, although its natriuretic effects may also contribute. Nesiritide is given by IV bolus or infusion for acute failure only. Excessive hypotension is the most common adverse effect, and renal damage is also of serious concern.

Miscellaneous Category

Loop, thiazide, and aldosteroneantagonist diuretics, angiotensin inhibitors, and β-receptorantagonists have been discussed in Chapters 6 and 7. This discussion will focus on the clinical benefit of these medications in the treatment of heart failure. Diuretics are usually used in heart failure treatment before any other drugs are considered. Furosemide, a loop diuretic, is a very useful agent for immediate reduction of the pulmonary congestion and severe edema associated with acute heart failure or severe chronic failure. Thiazides, such as hydrochlorothiazide, are sometimes sufficient for mild chronic failure. Clinical studies suggest that spironolactone and eplerenone, which are both aldosterone antagonist diuretics, have significant long-term benefits in chronic failure. ACE inhibitors, such as captopril, have been shown to reduce morbidity and mortality in chronic heart failure. Although they have no direct positive inotropic action, these agents reduce aldosterone secretion, salt and water retention, and vascular resistance. They are now considered, along with diuretics, among the first-line drugs for chronic heart failure. The angiotensin receptor antagonists such as losartan appear to have the same benefits as ACE inhibitors, although experience with these newer drugs is not as extensive as with ACE inhibitors. Finally, certain β-receptor antagonists (carvedilol, labetalol, and metoprolol) have been shown in long-term studies to reduce progression of chronic heart failure. The benefit of these agents had long been recognized in patients with hypertrophic cardiomyopathy, but has now been shown to occur also in patients without cardiomyopathy. The β-receptor antagonists are not of value in acute failure and may be detrimental if systolic dysfunction is marked.

Exercise programs for patients with congestive heart failure result in improved exertion tolerance, endurance, and improved quality of life. Effective formats for these programs may include hydrotherapy, aerobic activities, strengthening, or a combination of both strengthening and aerobic activities. Many exercise programs involving physical therapists are hospital based, although non-hospital-based programs are also safe and effective. The therapist should be aware of the interactions between the drugs, patients, and their exercise programs.

Drugs used to improve cardiac performance or decrease cardiac workload improve patient participation in these programs. However, prescription drug effects may result in adverse events previously discussed. Additional care should also be taken by therapists when aerobic activities such as hydrotherapy are combined with drugs that produce orthostatic hypotension. Finally, appropriate cool-down periods are required following aerobic activities in patients taking these drugs to prevent syncope due to peripheral distribution of blood.

Adverse Drug Reactions

• Cardiac glycosides can cause arrhythmias.
• Thiazide and loop diuretics can cause hypokalemia.
• Hypokalemia can exacerbate the toxic effects of cardiac glycosides.
• Drugs that cause hyperkalemia inhibit the effects of cardiac glycosides.
• Drugs that inhibit the renin-angiotensin-aldosterone system including aldosterone receptor antagonists can cause hyperkalemia.
• Bronchoconstriction is a problem with the β-receptor antagonists, especially in asthmatics.
• Beta-receptor antagonists blunt the early manifestations of hypoglycemia in diabetics.
• Beta-receptor antagonists can depress cardiac contractility.
• Beta-receptor antagonists can depress cardiac rate.
• Vasodilators and loop diuertics can cause orthostatic hypotension.
• Vasodilators can cause reflex tachycardia.

Effects Interfering with Rehabilitation

• Orthostatic hypotension may cause patients to faint when transferring from a sitting or supine position to standing, exiting from warm aquatherapy area, or if aerobic exercise is terminated without an appropriate cool-down period.
• Dyspnea may decrease the aerobic capacity of patients.
• Heart rate should not be used as a marker of exertion for patients taking β-receptor antagonists.
• Cardiac output may be depressed during aerobic activities.
• Manifestations of hypoglycemia occurring during aerobic activities may be delayed.
• Altered plasma potassium levels can cause paresthesia, decrease skeletal muscle function, and increase cramps.
• Aerobic activities may initiate cardiac arrhythmias.

Possible Therapy Solutions

• Check blood pressure and heart rate prior to and following aerobic activities.
• Monitor heart rate during aerobic activities.
• To prevent fainting associated with orthostatic hypotension, assist patients with positional changes and when exiting a warm pool. Always provide a cool-down period following a period of exercise.
• To prevent dyspnea and to account for depressed cardiac activity, allow increased time to complete aerobic tasks.
• Use perceived exertion (Borg Rating of Perceived Exertion Scale) when determining aerobic activity in patients being treated with β-receptor antagonists.
• Have patients check glucose levels prior to aerobic activities if the patients are taking hypoglycemic drugs.
• Note clinical manifestations of altered plasma potassium levels and determine if patients are prescribed medications which may alter these levels.

Potentiation of Functional Outcomes Secondary to Drug Therapy

• Effective therapy improves cardiac function and reserve in many patients with heart failure, allowing them to participate in aerobic activities associated with rehabilitation.

Brief History: The patient is a 65-year-old male with a history of congestive heart failure resulting from long-standing cardiomyopathy. The patient has a history of coronary artery disease including a triple coronary artery bypass graft 5 years ago. The patient has a body mass index of 30 and a 40-year plus history of smoking cigarettes. The patient quit smoking 10 years ago.

Current Medical Status and Drug Therapy: The patient was hospitalized recently for orthopedic surgery involving a right total knee replacement. The patient spent 3 days in acute care followed by a transfer to a rehabilitation facility where he spent 5 days. The patient was discharged from the rehabilitation setting with minimal assistance and household ambulation in a quad-walker. Current drugs include nadolol, benazepril, furosemide, and spironolactone. Opiate analgesic medication is provided for as-needed pain relief.

Rehabilitation Setting: The patient was referred to the outpatient clinic to continue ambulation training and endurance and for re-evaluation of assistive devices. The patient was initially evaluated 2 days ago at the clinic. At that time, his vital signs were blood pressure 120/70 mm Hg and heart rate 68 beats per minute (bpm). The patient arrives today at 10:30 for his second appointment, ambulating with a quad-walker approximately 15 feet from the car into the general treatment area. The patient appears pale while seated prior to beginning ambulation training, but states that he has consistently been taking all drugs on a regular basis on the preceding days. His vital signs are 145/90 mm Hg and heart rate is 70 bpm. The physical therapist is concerned. Prior to beginning the ambulation training with a cane, while attaching the gait belt, the physical therapist notices 3+/5 pitting edema at the ankles. During this process that patient talks about the new barbecue restaurant that recently opened, and that he had a barbecue platter with French fries and ice tea for dinner there last night. The patient is assisted to standing and begins ambulation with the cane for approximately 35 feet. The patient becomes extremely dyspneic with labored breathing and wheezing, lips appear cyanotic, and diaphoresis is noted about the head, neck, and hands. A chair is immediately brought, and the patient is assisted into seating. His vital signs are now 160/94 mm Hg for blood pressure and 86 bpm.

Problem/Clinical Options: The physical therapist should immediately contact the referring physician’s office to determine whether the patient should be transferred to emergency facilities or to the office of the referring physician. This patient’s medical history and current medical problems are extensive. Progression through prior ambulation training was probably delayed because of the high body mass index, age, and congestive heart failure. The current adverse event at this rehabilitation treatment session was probably precipitated by the previous evening’s activities. The dinner the previous evening included a significant amount of sodium and water, exceeding the diuretic’s action, resulting in both systemic and pulmonary edema. Nadolol, a nonselective β-receptor antagonist, may have exacerbated the dyspnea by preventing bronchodilation. Although not documented, the patient probably suffers from chronic obstructive pulmonary disease due to the 40-year plus history of cigarette smoking. This comorbidity also exacerbated the dyspnea. Finally, the opiate drug for pain may have decreased respiratory drive. See Chapter 20 for additional information on these drugs.

Digitalis

Digoxin* (Generic, Lanoxicaps, Lanoxin)

Oral: 0.125-, 0.25-mg tablets; 0.05-, 0.1-, 0.2-mg capsules*; 0.05 mg/mL elixir

Parenteral: 0.1, 0.25 mg/mL for injection

*Digoxin capsules (Lanoxicaps) have greater bioavailability than digoxin tablets.

Sympathomimetics Most Commonly Used in Congestive Heart Failure

Dobutamine (Generic, Dobutrex)

Parenteral: 12.5 mg/mL for IV infusion

Dopamine (Generic, Intropin)

Parenteral: 40, 80, 160 mg/mL for IV injection; 80, 160, 320 mg/dL in 5% dextrose for IV infusion

Angiotensin-Converting Enzyme Inhibitors Labeled for Use in Congestive Heart Failure

Captopril (Generic, Capoten)

Oral: 12.5-, 25-, 50-, 100-mg tablets

Enalapril (Vasotec, Vasotec I.V.)

Oral: 2.5-, 5-, 10-, 20-mg tablets

Parenteral: 1.25 mg enalaprilat/mL

Fosinopril (Monopril)

Oral: 10-, 20-, 40-mg tablets

Lisinopril (Prinivil, Zestril)

Oral: 2.5-, 5-, 10-, 20-, 40-mg tablets

Quinapril (Accupril)

Oral: 5-, 10-, 20-, 40-mg tablets

Ramipril (Altace)

Oral: 1.25-, 2.5-, 5-, 10-mg capsules

Trandolapril (Mavik)

Oral: 1-, 2-, 5-mg tablets

Angiotensin Receptor Blockers

Candesartan (Atacand)

Oral: 4-, 8-, 16-, 32-mg tablets

Eprosartan (Teveten)

Oral: 400-, 800-mg tablets

Irbesartan (Avapro)

Oral: 75-, 150-, 300-mg tablets

Losartan (Cozaar)

Oral: 25-, 50-, 100-mg tablets

Olmesartan (Benicar)

Oral: 5-, 20-, 40-mg tablets

Telmisartan (Micardis)

Oral: 20-, 40-, 80-mg tablets

Valsartan (Diovan)

Oral: 40-, 80-, 160-, 320-mg tablets

β Blockers That Have Reduced Mortality in Heart Failure

Bisoprolol (Zebeta, Unlabeled Use)

Oral: 5-, 10-mg tablets

Carvedilol (Coreg)

Oral: 3.125-, 6.25-, 12.5-, 25-mg tablets

Metoprolol (Lopressor, Toprol XL)

Oral: 50-, 100-mg tablets; 25-, 50-, 100-, 200-mg extended-release tablets

Parenteral: 1 mg/mL for IV injection

Phosphodiesterase Inhibitors

Inamrinone (Generic)

Parenteral: 5 mg/mL for IV injection

Milrinone (Generic, Primacor)

Parenteral: 1 mg/mL for IV injection; 200 mcg/mL premixed for IV infusion

Natriuretic Peptide

Nesiritide (Natrecor)

Parenteral: 1.5 mg lyophilized reconstituted for IV bolus or infusion

Diuretics

See Chapter 7