++
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
++
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.
++
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.
++
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.
++
++
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.
++
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, 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.
++
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.