DRUGS USED IN

HEART FAILURE
 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
PATHOPHYSIOLOGY
HEART FAILURE

• 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.
• It is frequently associated with chronic hypertension, valvular disease, coronary
artery disease, and a variety of cardiomyopathies.
• About one third of cases are due to a reduction of cardiac contractile force and
ejection fraction (systolic failure). Another third is caused by stiffening or other
changes of the ventricles that prevent adequate filling during diastole; ejection
fraction may be normal (diastolic failure).
HEART FAILURE

• . 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
(congestive heart failure).
• The homeostatic responses to depressed cardiac
output are extremely important and are mediated
mainly by the sympathetic nervous system and the
renin-angiotensin-aldosterone system.
• Increased blood volume results in edema and
pulmonary congestion and contributes to the
increased end-diastolic fiber length. Cardiomegaly
(enlargement and remodeling of the heart)—a slower
compensatory response, mediated at least in part by
sympathetic discharge and angiotensin II, is common.
Therapeutic strategies
Pharmacologic therapies for heart failure
includes:

• 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 β 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.
CARDIAC GLYCOSIDES
A. Prototypes and Pharmacokinetics

• All cardiac glycosides are cardenolides (they include a steroid nucleus and a
lactone ring); most also have one or more sugar residues, justifying the
glycoside designation. 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. Digitoxin
is a very similar but longer-acting molecule; it also comes from the foxglove
plant but 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%).
B. Mechanism of
Action
• Inhibition of Na+ /K+ ATPase (the “sodium
pump”) of the cell membrane by digitalis is
well documented and is considered to be the
primary biochemical mechanism of action.
 C. Cardiac Effects

1. 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.
2. Electrical effects—Electrical effects include early cardiac parasympathomimetic responses
and later arrhythmogenic actions.
a. 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.
b. Toxic responses—Increased automaticity, caused by intracellular calcium overload, is the most
important manifestation of digitalis toxicity.
D. Clinical Uses

1. Congestive heart failure—Digitalis is the traditional positive inotropic agent

used in the treatment of chronic heart failure.
2. 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.
E. 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
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.
Digitalisinduced vomiting may deplete serum magnesium and similarly facilitate
toxicity. These ion interactions are important when treating digitalis toxicity.
F. Digitalis Toxicity

• The major signs of digitalis toxicity are arrhythmias, nausea, vomiting, and
diarrhea. Rarely, confusion or hallucinations and visual or endocrine
aberrations may occur. Arrhythmias are 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,
Treatment of digitalis toxicity includes several
steps, as follows.

1. Correction of potassium or magnesium deficiency

2. Antiarrhythmic drugs
3. Digoxin antibodies
OTHER DRUGS USED IN
CONGESTIVE HEART
FAILURE
A. 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, unlike other diuretics,
spironolactone and eplerenone (aldosterone antagonist diuretics) have
significant long-term benefits and can reduce mortality in chronic failure.
B. 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.
C. Beta1-Adrenoceptor Agonists

• Dobutamine 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.
D. Beta-Adrenoceptor Antagonists

• Several β blockers (carvedilol, labetalol, metoprolol, Chapter 10) have been

shown in long-term studies to slow progression of chronic heart failure. This
benefit of β blockers had long been recognized in patients with hypertrophic
cardiomyopathy but has also been shown to occur in patients without
cardiomyopathy. Nebivolol, a β blocker with vasodilator effects approved for
the treatment of hypertension, is investigational in heart failure. Beta blockers
are of no value in acute failure and may be detrimental if systolic dysfunction
is marked
E. Phosphodiesterase Inhibitors

• Milrinone is the major representative 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 β-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, but they also cause arrhythmias. These agents
should not be used in chronic failure because they have been shown to increase morbidity
and mortality.
F. 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 achieved with
proper adjustment of venous return (preload) and reduction of impedance 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).
F. Vasodilators

• 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 this
combination has been shown to reduce mortality due to heart failure in African
Americans. Calcium channel blockers (eg, verapamil) are of no value in heart
failure.
G. 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.