Drugs Used in Heart Failure: Introduction
Heart failure results when cardiac output is inadequate for the needs of the body. A defect in cardiac contractility is complicated by multiple compensatory processes that further weaken the failing heart. The drugs used in heart failure fall into 3 major groups with varying targets and actions.
High-Yield Terms to Learn
Bigeminy An arrhythmia consisting of normal sinus beats coupled with ventricular extrasystoles, that is, "twinned" beats (Figure 13-4) End-diastolic fiber length The length of the ventricular fibers at the end of diastole; a determinant of the force of the following contraction Heart failure A condition in which the cardiac output is insufficient for the needs of the body. Low-output failure may be due to decreased stroke volume (systolic failure) or decreased filling (diastolic failure) PDE inhibitor Phosphodiesterase inhibitor; a drug that inhibits one or more enzymes that degrade cAMP (and other cyclic nucleotides). Examples: high concentrations of theophylline, inamrinone Premature ventricular beats An abnormal beat arising from a cell below the AV node—often from a Purkinje fiber, sometimes from a ventricular fiber Sodium pump (Na+ /K+ ATPase)
A transport molecule in the membranes of all vertebrate cells; responsible for the maintenance of normal low intracellular sodium and high intracellular potassium concentrations; it uses ATP to pump these ions against their concentration gradients Sodium-calcium exchanger A transport molecule in the membrane of many cells that pumps one calcium atom outward against its concentration gradient in exchange for three sodium ions moving inward down their concentration gradient Ventricular function curve The graph that relates cardiac output, stroke volume, etc, to filling pressure or end-diastolic fiber length; also known as the Frank-Starling curve Ventricular tachycardia An arrhythmia consisting entirely or largely of beats originating below the AV node
Pathophysiology
Heart failure is an extremely serious cardiac condition associated with a high mortality rate. The fundamental physiologic defect in heart failure is a decrease in cardiac output relative to the needs of the body, and the major manifestations are dyspnea and fatigue. The causes of heart failure are still not completely understood. In some cases, it can be ascribed to simple loss of functional myocardium, as in myocardial infarction. It is frequently associated with chronic hypertension, valvular disease, coronary artery disease, and a variety of cardiomyopathies. In about one third of cases of heart failure, the primary defect is a reduction of cardiac contractile force and ejection fraction that is detected during systole (systolic failure). In another third, the primary defect is stiffening or other changes of the ventricles that prevent adequate filling during diastole; ejection fraction may be normal even though stroke volume is decreased (diastolic failure). The remainder of cases can be attributed to a combination of systolic and diastolic dysfunction. The natural history of heart failure is characterized by a slow deterioration of cardiac function, punctuated by episodes of acute cardiac decompensation that are often associated with pulmonary or peripheral edema or both (congestion).
The reduction in cardiac output is best shown by the ventricular function curve (Frank-Starling curve; Figure 13-1). The changes in the ventricular function curve reflect 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 13-1. 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 (see Figure 12-1).
FIGURE 13-1
Ventricular function (Frank-Starling) curves. The abscissa can be any measure of preload: fiber length, filling pressure, pulmonary capillary wedge pressure, etc. The ordinate is a measure of useful external cardiac work: stroke volume, cardiac output, etc. In heart failure, output is reduced at all fiber lengths, and the heart expands because ejection fraction is decreased or filling pressure is increased (or both). As a result, the heart moves from point A to point B. Compensatory sympathetic discharge or effective treatment allows the heart to eject more blood, and the heart moves to point C on the middle curve.
The homeostatic 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 13-2. The major responses include the following: (1) Tachycardia—an early manifestation of increased sympathetic tone. (2) Increased peripheral vascular resistance—another early response, also mediated by increased sympathetic tone. (3) Retention of salt and water by the kidney—an early compensatory response, mediated by the renin-angiotensin-aldosterone system and facilitated by increased sympathetic outflow. Increased blood volume results in edema and pulmonary congestion and contributes to the increased end-diastolic fiber length. (4) Cardiomegaly (enlargement of the heart)—a slower compensatory response, mediated at least in part by sympathetic discharge and angiotensin II. Although these compensatory responses can temporarily improve cardiac output (point C in Figure 13-1), they also increase the load on the heart, and the increased load contributes to further long-term decline in cardiac function. (5) Apoptosis is a later response, and results in a reduction in the number of functioning myocytes and their replacement by connective tissue. Evidence suggests that catecholamines, angiotensin II, and aldosterone play a direct role in these changes.
FIGURE 13-2
Compensatory responses that occur in heart failure. These responses play an important role in the progression of the disease. Dashed arrows indicate interactions between the sympathetic and the renin-angiotensin systems.
Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 13-2.)
Therapeutic Strategies
Pharmacologic therapies for heart failure include the removal of retained salt and water with diuretics; reduction of afterload and salt and water retention by means of angiotensin-converting enzyme (ACE) inhibitors; reduction of excessive sympathetic stimulation by means of 
blockers; reduction of preload or afterload with vasodilators; and in systolic failure, direct augmentation of depressed cardiac contractility with positive inotropic drugs such as digitalis glycosides. Considerable evidence indicates that angiotensin antagonists, some -adrenoceptor blockers, and the aldosterone antagonists spironolactone and eplerenone also have long-term beneficial effects. The use of diuretics is discussed in Chapter 15.
Current clinical evidence suggests that acute heart failure should be treated with a loop diuretic; if very severe, a prompt-acting positive inotropic agent such as a agonist or phosphodiesterase inhibitor and vasodilators should be used as required to optimize filling pressures and blood pressure. Chronic failure is best treated with diuretics (often a loop agent plus spironolactone) plus an ACE inhibitor and, if tolerated, a blocker. Digitalis may be helpful if systolic dysfunction is prominent. Nesiritide, a recombinant form of brain natriuretic peptide, has vasodilating and diuretic properties and has been heavily promoted for use in acute failure.
Cardiac Glycosides
Digitalis glycosides are no longer considered first-line drugs in the treatment of heart failure. However, because they are not discussed elsewhere in this book, we begin our discussion with this group.
Prototypes and Pharmacokinetics
All cardiac glycosides include a steroid nucleus and a lactone ring; most also have one or more sugar residues. The cardiac glycosides are often called "digitalis" because several come from the digitalis (foxglove) plant. Digoxin is the prototype 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. Digoxin has an oral bioavailability of 60-75%, and a half-life of 36-40 h. Elimination is by renal excretion (about 60%) and hepatic metabolism (40%).
Mechanism of Action
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 (Figure 13-3). Inhibition of Na+/K+ ATPase results in a small increase in intracellular sodium. The increased sodium alters the driving force for sodium-calcium exchange by the exchanger, NCX, so that less calcium is removed from the cell. The increased intracellular calcium is stored in the sarcoplasmic reticulum and upon release increases contractile force. Other mechanisms of action for digitalis have been proposed, but they 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 modifies autonomic outflow, and this action has effects on the electrical properties of the heart.
FIGURE 13-3
Schematic diagram of a cardiac sarcomere with the cellular components involved in excitation-contraction coupling and the sites of action of several drugs. Factors involved in excitation-contraction coupling include Na+/K+ATPase; Na+/Ca2+ exchanger, NCX; voltage-gated calcium channel (Cav-L); calcium transporter (SERCA) in the wall of the sarcoplasmic reticulum (SR); calcium release channel in the SR, RyR (ryanodine receptor); and the site of calcium interaction with the troponin-tropomyosin system. CalS, calsequestrin, a calcium-binding protein in the SR.
(Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 13-1.)
Cardiac Effects
Mechanical Effects
The increase in contractility evoked by digitalis results in increased ventricular ejection, decreased end-systolic and end-diastolic size, 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 (point C in Figure 13-1).
Electrical Effects
Electrical effects include early cardiac parasympathomimetic responses and later arrhythmogenic actions. They are summarized in Table 13-1.
TABLE 13-1 Major actions of cardiac glycosides on cardiac electrical function.
Tissue Variable Atrial Muscle AV Node Purkinje System, Ventricles Effective refractory period 
(PANS) 
(PANS) (Direct) Conduction velocity (PANS) (PANS) Negligible Automaticity (Direct) (Direct) (Direct) Electrocardiogram before arrhythmias Negligible PR interval QT interval; T-wave inversion; ST-segment depression Arrhythmias Atrial tachycardia, fibrillation AV nodal tachycardia, AV blockade Premature ventricular beats, bigeminy, ventricular tachycardia, ventricular fibrillation
AV, atrioventricular; PANS, parasympathomimetic actions; direct, direct membrane actions.
Early Responses
Increased PR interval, caused by the decrease in atrioventricular (AV) conduction velocity, and flattening of the T wave are common electrocardiogram (ECG) effects. The effects on the atria and AV node are largely parasympathetic (mediated by the vagus nerve) and can be partially blocked by atropine. 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 ventricular rate. Shortened QT, inversion of the T, and ST depression may occur later.
Toxic Responses
Increased automaticity, caused by intracellular calcium overload, is the most important manifestation of digitalis toxicity. Intracellular calcium overload results in delayed afterdepolarizations, which may evoke extrasystoles, tachycardia, or fibrillation in any part of the heart. In the ventricles, the extrasystoles are recognized as premature ventricular beats (PVBs). When PVBs are coupled to normal beats in a 1:1 fashion, the rhythm is called bigeminy (Figure 13-4).
FIGURE 13-4
Electrocardiographic record showing digitalis-induced bigeminy. The complexes marked NSR are normal sinus rhythm beats; an inverted T wave and depressed ST segment are present. The complexes marked PVB are premature ventricular beats.
Clinical Uses
Congestive Heart Failure
Digitalis is the traditional positive inotropic agent used in the treatment of chronic heart failure. However, careful clinical studies indicate that while digitalis may improve functional status (reducing symptoms), it does not prolong life. Other agents (diuretics, ACE inhibitors, vasodilators) may be equally effective and less toxic, and some of these alternative therapies do prolong life (see later discussion). 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.
Atrial Fibrillation
In atrial flutter and fibrillation, it is desirable to reduce the conduction velocity or increase the refractory period of the AV node so that ventricular rate is controlled within a range 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 blockers and calcium channel blockers, but these drugs have negative inotropic effects.
Interactions
Quinidine causes a well-documented reduction in digoxin clearance and can increase the serum digoxin level if digoxin dosage is not adjusted. Several other drugs have been shown to have the same effect (amiodarone, verapamil, others), but the interactions with these drugs are not clinically significant. Digitalis toxicity, especially arrhythmogenesis, is increased by hypokalemia, hypomagnesemia, and hypercalcemia. Loop diuretics and thiazides, which are always included in the treatment of heart failure, may significantly reduce serum potassium and thus precipitate digitalis toxicity. Digitalis-induced vomiting may deplete serum magnesium and similarly facilitate toxicity. These ion interactions are important in treating digitalis toxicity.
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 arrhythmias is important because this manifestation of digitalis toxicity is common and dangerous. Chronic intoxication is an extension of the therapeutic effect of the drug and is caused by excessive calcium accumulation in cardiac cells (calcium overload). This overload triggers abnormal automaticity and the arrhythmias noted in Table 13-1.
Severe, acute intoxication caused by suicidal or accidental extreme overdose results in cardiac depression leading to cardiac arrest rather than tachycardia or fibrillation.
Treatment of digitalis toxicity includes several steps, as follows.
Correction of Potassium or Magnesium Deficiency
Correction of potassium deficiency (caused, eg, by diuretic use) is useful in chronic digitalis intoxication. Mild toxicity may often be managed by omitting 1 or 2 doses of digitalis and giving oral or parenteral K+ supplements. Potassium should not be raised above the level of 5 mEq/L. Similarly, if hypomagnesemia is present, it should be treated by normalizing serum magnesium. Severe acute intoxication (as in suicidal overdoses) usually causes marked hyperkalemia and should not be treated with supplemental potassium.
Antiarrhythmic Drugs
Antiarrhythmic drugs may be useful if increased automaticity is prominent and does not respond to normalization of serum potassium. Agents that do not severely impair cardiac contractility (eg, lidocaine or phenytoin) are favored, but drugs such as propranolol have also been used successfully. Severe acute digitalis overdose usually causes marked inhibition of all cardiac pacemakers, and an electronic pacemaker may be required. Antiarrhythmic drugs are dangerous in such patients.
Digoxin Antibodies
Digoxin antibodies (Fab fragments; Digibind) are extremely effective and should always be used if other therapies appear to be failing. They are effective for poisoning with many cardiac glycosides in addition to digoxin and may save patients who would otherwise die.
Skill Keeper: Maintenance Dose Calculations
(See Chapter 3)
Digoxin has a narrow therapeutic window, and its dosing must be carefully managed. The drug's minimum effective concentration is about 1 ng/mL. About 60% is excreted in the urine; the rest is metabolized in the liver. The normal clearance of digoxin is 7 L/h/70 kg; volume of distribution is 500 L/70 kg; and bioavailability is 70%. If your 70-kg patient's renal function is only 30% of normal, what daily oral maintenance dosage should be used to achieve a safe plasma concentration of 1 ng/mL? The Skill Keeper Answer appears at the end of the chapter.
Other Drugs Used in Congestive Heart Failure
The other major agents used in heart failure include diuretics, ACE inhibitors, 1-selective sympathomimetics, blockers, phosphodiesterase inhibitors, and vasodilators.
Diuretics
Diuretics are the first-line therapy for both systolic and diastolic failure and are used in heart failure before digitalis and other drugs are considered. Furosemide is a very useful agent for immediate reduction of the pulmonary congestion and severe edema associated with acute heart failure and for moderate or severe chronic failure. Thiazides such as hydrochlorothiazide are sometimes sufficient for mild chronic failure. Clinical studies suggest that spironolactone and eplerenone (aldosterone antagonist diuretics) have significant long-term benefits and can reduce mortality in chronic failure. The pharmacology of the diuretics is discussed in Chapter 15.
Angiotensin Antagonists
These agents have been shown to reduce morbidity and mortality in chronic heart failure. Although they have no direct positive inotropic action, angiotensin antagonists reduce aldosterone secretion, salt and water retention, and vascular resistance. They are now considered, along with diuretics, to be first-line drugs for chronic heart failure. The angiotensin receptor blockers (ARBs, eg, losartan ) appear to have the same benefits as ACE inhibitors (eg, captopril ), although experience with ARBs is not as extensive as with ACE inhibitors.
Beta1-Adrenoceptor Agonists
Dobutamine (1-selective) and dopamine are often useful in acute failure in which systolic function is markedly depressed. However, they are not appropriate for chronic failure because of tolerance, lack of oral efficacy, and significant arrhythmogenic effects.
Beta-Adrenoceptor Antagonists
Several blockers ( carvedilol, labetalol, metoprolol , Chapter 10) have been shown in long-term studies to reduce progression of chronic heart failure. This benefit of blockers had long been recognized in patients with hypertrophic cardiomyopathy but has now been shown to occur also in patients without cardiomyopathy. Nebivolol, a newer blocker with vasodilator effects, is investigational in heart failure. Beta blockers are not of value in acute failure and may be detrimental if systolic dysfunction is marked.
Phosphodiesterase Inhibitors
Inamrinone and milrinone are the major representatives of this infrequently used group. Theophylline (in the form of its salt, aminophylline ) was commonly used for acute failure in the past. 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 -adrenoceptor agonists. Phosphodiesterase inhibitors also cause vasodilation, which may be responsible for a major part of their beneficial effect. At sufficiently high concentrations, these agents may increase the sensitivity of the contractile protein system to calcium. These agents should not be used in chronic failure because they have been shown to increase morbidity and mortality.
Vasodilators
Vasodilator therapy with nitroprusside or nitroglycerin is often used for acute severe 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 (preload) and reduction of resistance to ventricular ejection (afterload). Vasodilator therapy can be dramatically effective, especially in cases in which increased afterload is a major factor in causing the failure (eg, continuing hypertension in an individual who has just had an infarct). The natriuretic peptide nesiritide acts chiefly by causing vasodilation, although it does have natriuretic effects as well. It is given by IV infusion for acute failure only. Nesiritide has significant renal toxicity and renal function must be monitored. Chronic heart failure sometimes responds favorably to oral vasodilators such as hydralazine or isosorbide dinitrate (or both), and the combination has been shown to reduce mortality in African Americans. Calcium channel blockers (eg, verapamil) are of no value in heart failure.
Nonpharmacologic Therapy
A variety of surgical procedures to remove nonfunctional regions of damaged myocardium have been attempted with mixed results. Resynchronization of right and left ventricular contraction by means of a pacemaker has been beneficial in patients with long QRS (indicating conduction abnormalities). Patients with coronary artery disease and heart failure may have improved systolic function after coronary revascularization.
Skill Keeper Answer: Maintenance Dose Calculations
(See Chapter 3)
Maintenance dosage is equal to CL x Cp ÷ F, so
Maintenance dosage for a patient with normal renal function
= 7 L/h x 1 ng/mL ÷ 0.7 = 7 L/h x 1 mcg/L ÷ 0.7
= 10 mcg/h x 24 h/d = 240 mcg/d = 0.24 mg/d
But this patient has only 30% of normal renal function, so
CL (total) = 0.3 x CL (renal [60% of total]) + CL (liver [40% of total])
CL (total) = 0.3 x 0.6 x 7 L/h + 0.4 x 7 L/h, and
CL (total) = 1.26 L/h + 2.8 L/h = 4.06 L/h, and
Maintenance dosage = 4.06 L/h x 1 mcg/L ÷ 0.7 = 5.8 mcg/h = 139 mcg/d = 0.14 mg/d
Checklist
When you complete this chapter, you should be able to:
Describe the strategies and list the major drug groups used in the treatment of acute heart failure and chronic failure.
Describe the mechanism of action of digitalis and its major effects. Indicate why digitalis is no longer considered a first-line therapy for chronic heart failure.
Describe the nature and mechanism of digitalis's toxic effects on the heart.
List some positive inotropic drugs other than digitalis that have been used in heart failure.
Describe the beneficial effects of diuretics, vasodilators, ACE inhibitors, and other drugs that lack positive inotropic effects in heart failure.
Drug Summary Table: Drugs Used in Heart Failure
Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions Diuretics Furosemide Reduces preload, edema by powerful diuretic action on thick ascending limb in nephron; vasodilating effect on pulmonary vessels Acute and chronic heart failure, especially acute pulmonary edema; other edematous conditions, hypercalcemia (see Chapter 15) Oral, parenteral Duration: 2-4 h Ototoxicity; hypovolemia, hypokalemia Hydrochlorothiazide Reduces preload, edema by modest diuretic action on the distal convoluted tubule in nephron Mild chronic heart failure, chronic renal stone, nephrogenic diabetes insipidus Oral Duration: 8-12 h Hypokalemia, hyperglycemia, hyperuricemia, hyperlipidemia Spironolactone Antagonist of aldosterone in kidney plus poorly understood reduction in mortality Chronic heart failure, aldosteronism Oral Duration: 24-48 h Hyperkalemia; gynecomastia Angiotensin-converting enzyme (ACE) inhibitors Captopril Blocks angiotensin-converting enzyme, reduces all levels, decreases vascular tone and aldosterone secretion Heart failure, hypertension, diabetes Oral; short half-life but large doses used Duration: 12-24 h Cough, renal damage, hyperkalemia Benazepril, enalapril, others: Like captopril Losartan, candesartan, others: Angiotensin receptor blockers (see Chapter 11) Positive inotropic drugs Cardiac glycosides: digoxin Inhibits Na+/K+ ATPase sodium pump and increases intracellular Na+, decreasing Ca2+ expulsion and increasing cardiac contractility
Heart failure, nodal arrhythmias Oral, parenteral Duration: 40 h Arrhythmogenic! Nausea, vomiting, diarrhea, visual changes (rare) Sympathomimetics: dobutamine 1-Selective sympathomimetic, increases cAMP and force of contraction
Acute heart failure Parenteral Duration: minutes Arrhythmias Beta blockers Carvedilol, metoprolol, bisoprolol Poorly understood reduction of mortality, possibly by decreasing remodeling Chronic heart failure Oral Duration varies (see Chapter 10) Cardiac depression (see Chapter 10) Vasodilators Nitroprusside Rapid, powerful vasodilation reduces preload and afterload Acute severe decompensated failure IV only Duration: minutes Excessive hypotension; thiocyanate and cyanide toxicity Hydralazine + isosorbide dinitrate Poorly understood reduction in mortality Chronic failure in African Americans Oral Headache, tachycardia Nesiritide Atrial peptide vasodilator, diuretic Acute severe decompensated failure Parenteral Duration: minutes Renal damage, hypotension
cAMP, cyclic adenosine monophosphate.