Pharmacotherapy of Congestive Heart Failure

Dr Sukanta Sen
Congestive heart failure is the pathophysiologic state in

which the heart is unable to pump blood at a rate

commensurate with the requirements of metabolizing

tissues, or can do so only from an elevated filling pressure.

Heart failure is a complex of symptoms—
• fatigue,
• shortness of breath, and
• Congestion
—that are related to the inadequate perfusion of tissue
during exertion and often to the retention of fluid.
•Its primary cause is an impairment of the heart’s ability to
fill or empty the left ventricle properly.
This chest radiograph shows an enlarged cardiac silhouette and edema at
the lung bases, signs of acute heart failure.
 Signs and symptoms of heart failure include the following:

•Exertional dyspnea and/or dyspnea at rest

•Orthopnea
•Acute pulmonary edema
•Chest pain/pressure and palpitations
•Tachycardia
•Fatigue and weakness
•Nocturia and oliguria
•Anorexia, weight loss, nausea
•Exophthalmos and/or visible pulsation of eyes
•Distention of neck veins
•Weak, rapid, and thready pulse
•Rales, wheezing
•S 3 gallop and/or pulsus alternans
•Increased intensity of P 2 heart sound
•Hepatojugular reflux
•Ascites, hepatomegaly, and/or anasarca
•Central or peripheral cyanosis, pallor
 Diagnosis

Heart failure criteria, classification, and staging

The Framingham criteria for the diagnosis of heart failure consists of the
concurrent presence of either 2 major criteria or 1 major and 2 minor
criteria.

Major criteria include the following:

•Paroxysmal nocturnal dyspnea
•Weight loss of 4.5 kg in 5 days in response to treatment
•Neck vein distention
•Rales
•Acute pulmonary edema
•Hepatojugular reflux
•S 3 gallop
•Central venous pressure greater than 16 cm water
•Circulation time of 25 seconds
•Radiographic cardiomegaly
•Pulmonary edema, visceral congestion, or cardiomegaly at autopsy
Minor criteria are as follows:
•Nocturnal cough
•Dyspnea on ordinary exertion
•A decrease in vital capacity by one third the maximal value recorded
•Pleural effusion
•Tachycardia (rate of 120 bpm)
•Bilateral ankle edema

The New York Heart Association (NYHA) classification system

categorizes heart failure on a scale of I to IV, as follows:
•Class I: No limitation of physical activity
•Class II: Slight limitation of physical activity
•Class III: Marked limitation of physical activity
•Class IV: Symptoms occur even at rest; discomfort with any physical
activity
The American College of Cardiology/American Heart
Association (ACC/AHA) staging system is defined by the
following 4 stages:
•Stage A: High risk of heart failure but no structural heart disease
or symptoms of heart failure
•Stage B: Structural heart disease but no symptoms of heart
failure
•Stage C: Structural heart disease and symptoms of heart failure
•Stage D: Refractory heart failure requiring specialized
interventions
 Testing
The following tests may be useful in the initial evaluation for suspected heart failure:
•Complete blood count (CBC)
•Urinalysis
•Electrolyte levels
•Renal and liver function studies
•Fasting blood glucose levels
•Lipid profile
•Thyroid stimulating hormone (TSH) levels
•B-type natriuretic peptide levels
•N-terminal pro-B-type natriuretic peptide
•Electrocardiography
•Chest radiography
•2-dimensional (2-D) echocardiography
•Nuclear imaging
•Maximal exercise testing
•Pulse oximetry or arterial blood gas
 Management
Treatment includes the following:
•Non-pharmacologic therapy: Oxygen and noninvasive positive pressure ventilation,
dietary sodium and fluid restriction, physical activity as appropriate, and attention to weight
gain
•Pharmacotherapy: Diuretics, vasodilators, inotropic agents, anticoagulants, beta
blockers, and digoxin
Surgical options
Surgical treatment options include the following:
•Electrophysiologic intervention
•Revascularization procedures
•Valve replacement/repair
•Ventricular restoration
•Extracorporeal membrane oxygenation
•Ventricular assist devices
•Heart transplantation
•Total artificial heart
 Pathophysiology- Adaptations
Most important among the adaptations are the following:
•The Frank-Starling mechanism, in which an increased preload helps to sustain
cardiac performance
•Alterations in myocyte regeneration and death
•Myocardial hypertrophy with or without cardiac chamber dilatation, in which
the mass of contractile tissue is augmented
•Activation of neuro-humoral systems
The release of norepinephrine by adrenergic cardiac nerves augments
myocardial contractility and includes activation of the renin-angiotensin-
aldosterone system [RAAS], the sympathetic nervous system [SNS], and
other neurohumoral adjustments that act to maintain arterial pressure and
perfusion of vital organs.
Figure-1 Pathophysiologic mechanisms of heart failure and major sites of
drug action.
Congestive heart failure is accompanied by compensatory neurohormonal
responses, including activation of the sympathetic nervous and renin–
angiotensin–aldosterone axis. Increased ventricular afterload, due to
systemic vasoconstriction and chamber dilation, causes depression in systolic
function.
In addition, increased afterload and the direct effects of angiotensin and
norepinephrine on the ventricular myocardium cause pathologic remodeling
characterized by progressive chamber dilation and loss of contractile function.
Key congestive heart failure medications and their targets of action are
presented.
ACE, angiotensin-converting enzyme; AT1 receptor, type 1 angiotensin receptor.
 DIURETICS
•Diuretics reduce extracellular fluid volume and ventricular filling pressure (or
“preload”).
•Sustained natriuresis and/or a rapid decline in intravascular volume, however,
may “push” one’s profile leftward on the Frank-Starling curve, resulting in an
unwanted decrease in cardiac output.
•In this way, excessive diuresis is counterproductive secondary to reciprocal neuro-
hormonal over-activation from volume depletion. Thus, it is preferable to avoid
diuretics in patients with asymptomatic LV dysfunction and to only administer
the minimal dose required to maintain euvolemia in those patients symptomatic
from hypervolemia.
•Despite the efficacy of loop or thiazide diuretics in controlling congestive
symptoms and improving exercise capacity, their use is not associated with a
reduction in CHF mortality.
 Dietary Na+ Restriction:
• All patients with clinically significant LV dysfunction, regardless of symptom
status, should be advised to limit dietary sodium intake to 2-3 g/day.

Loop Diuretics:
• Furosemide, bumetanide, and torsemide are widely used in the treatment of
CHF.
Q. Due to the increased risk of ototoxicity, ethacrynic acid is recommended
only for patients with sulfonamides allergies.
•Loop diuretics inhibit a specific ion transport protein, the Na+-K+-2Cl–
symporter on the apical membrane of renal epithelial cells in the ascending
limb of the loop of Henle to increase Na+ and fluid delivery to distal nephron
segments. These drugs also enhance K+ secretion, particularly in the presence
of elevated aldosterone levels, as is typical in CHF.
 Thiazide Diuretics:
• Monotherapy with thiazide diuretics has a limited role in CHF. However,
combination therapy with loop diuretics is often effective in those refractory to
loop diuretics alone.
•Thiazide diuretics act on the Na+ Cl– co-transporter in the distal convoluted
tubule and are associated with a greater degree K+ wasting per fluid volume
reduction when compared to loop diuretics.
K+-Sparing Diuretics:
• K+-sparing diuretics inhibit apical membrane Na+-conductance channels in
renal epithelial cells (e.g., amiloride, triamterene) or are mineralocorticoid
(e.g., aldosterone) receptor antagonists (e.g., canrenone, spironolactone, and
eplerenone).
•Collectively, these agents are weak diuretics, but have been used to achieve
volume reduction with limited K+ and Mg2+ wasting.
 Diuretics in Clinical Practice:
•The majority of CHF patients will require chronic administration of
a loop diuretic to maintain euvolemia. In patients with clinically
evident fluid retention, furosemide typically is started at a dose of 40
mg once or twice daily, and the dosage is increased until an adequate
diuresis is achieved.
•A larger initial dose may be necessary in patients with advanced CHF
and azotemia.
•Serum electrolytes and renal function are monitored frequently.
•If present, hypokalemia from therapy may be corrected by oral or
intravenous K+ supplementation or by the addition of a K+-sparing
diuretic.
 Diuretics in the Decompensated Patient:
• In patients with decompensated CHF warranting hospital admission,
repetitive intravenously administered boluses or a constant infusion
titrated to achieve a desired response may be needed to provide
expeditious diuresis.
•A typical continuous furosemide infusion is initiated with a 40-mg
bolus injection followed by a constant rate of 10 mg/h, with
uptitration as necessary.
•If renal perfusion is reduced, drug efficacy may be enhanced by co-
administration of drugs that increase cardiac output (e.g.,
dobutamine).
 ALDOSTERONE ANTAGONISTS
•LV systolic dysfunction decreases renal blood flow and results in
over-activation of the renin–angiotensin–aldosterone axis and may
increase circulating plasma aldosterone levels in CHF to 20-fold
above normal.
•The pathophysiologic effects of hyperaldosteronemia are diverse
and extend beyond Na+ and fluid retention; however, the precise
mechanism by which aldosterone receptor blockade improves
outcome in CHF remains unresolved.
•Aldosterone-receptor antagonists in combination with ACE inhibitor therapy have
provided beneficial effects in clinical trials. In CHF patients with low LV ejection fraction,
spironolactone (25 mg/day) decreased mortality by ~30% (from progressive heart failure or
sudden cardiac death), and patients had fewer CHF-related hospitalizations compared with the
placebo group.
•Treatment was well tolerated; however, 10% of men reported gynecomastia and 2% of all
patients developed severe hyperkalemia (>6.0 mEq/L).
Vasodilator Drugs Used to Treat Heart Failure
 NITROVASODILATORS:

Nitrovasodilators are nitric oxide (NO) donors that activate

soluble guanylate cyclase in vascular smooth muscle cells,
leading to vasodilation.

Unlike nitroprusside, which is converted to NO• by cellular

reducing agents such as glutathione, nitroglycerin and other
organic nitrates undergo a more complex enzymatic
biotransformation to NO• or bioactive S-nitrosothiols.
• Intravenous nitroglycerin is a vasoactive NO donor that is
used in the intensive care unit setting.

• Unlike nitroprusside, nitroglycerin is relatively selective for

venous capacitance vessels, particularly at low infusion rates.

• In CHF, intravenous nitroglycerin is most commonly used

in the treatment of LV dysfunction due to an acute
myocardial ischemia.
TARGETING NEUROHORMONAL REGULATION: THE RENIN–
ANGIOTENSIN–ALDOSTERONE AXIS AND VASOPRESSIN
ANTAGONISTS
•ACE inhibitors suppress AngII (and aldosterone) production,
decrease sympathetic nervous system activity, and potentiate the
effects of diuretics in CHF.
•ACE inhibitors are preferential arterial vasodilators.
•ACE-inhibitor–mediated decreases in LV afterload result in
increased stroke volume and cardiac output.
•Heart rate typically is unchanged with treatment.
•ACE-inhibitor therapy typically is initiated at a low dose (e.g., 6.25
mg of captopril, 5 mg of lisinopril) to avoid iatrogenic hypotension.
 ACE Inhibitors and Survival in CHF:
• When compared with other vasodilators, ACE inhibitors appear
superior in reducing mortality in CHF.

• ACE inhibitors improve survival in patients with CHF due to

systolic dysfunction.

• ACE inhibitors also prevent the development of clinically

significant LV dysfunction after acute MI.

• ACE inhibitors appear to confer these benefits by preventing

post-infarction associated adverse ventricular remodeling.

• In asymptomatic patients with LV dysfunction, ACE inhibitors

slow the development of symptomatic CHF.
 DIRECT RENIN INHIBITORS:
• Maximal pharmacologic ACE inhibition alone may be insufficient for optimal
attenuation of AngII-induced cardiovascular dysfunction in patients with CHF.
Several molecular mechanisms may contribute:
• ACE-independent pathways that facilitate AngI → AngII conversion
• Suppression of the negative feedback exerted by AngII on renin secretion in the
kidney
Thus, inhibition of renin to further suppress AngII synthesis in CHF has
gained popularity.
Renin mediated conversion of angiotensinogen to AngI is the first and rate-limiting
step in the biochemical cascade that generates AngII and aldosterone .
• Aliskiren is the first orally administered direct renin inhibitor to obtain
FDA approval for use in clinical practice.
• The pharmacokinetic: bioavailability (2.7%) and a long plasma t1/2 (~23 h)
• Aliskiren is as effective as an ARB for monotherapy of mild-to-moderate
hypertension. It also appears to exert beneficial effects on myocardial
remodeling by decreasing LV mass in hypertensive patients, suggesting that
direct renin inhibition may attenuate hypertension-induced end-organ damage.
 Q. β ADRENERGIC RECEPTOR ANTAGONISTS
Mechanism of Action:
•By preventing myocardial ischemia without significantly
influencing serum electrolytes, β receptor antagonists probably
influence mortality, in part, by decreasing the frequency of
unstable tachyarrhythmias to which CHF patients are particularly
prone.
•In addition, these agents may influence survival by favorably
affecting LV geometry, specifically by decreasing LV chamber size
and increasing LV ejection fraction.
 β ADRENERGIC RECEPTOR ANTAGONISTS

•Through inhibition of sustained sympathetic nervous system

activation, these agents prevent or delay progression of

myocardial contractile dysfunction by inhibiting maladaptive

proliferative cell signaling in the myocardium, reducing

catecholamine-induced cardiomyocyte toxicity, and decreasing

myocyte apoptosis.

•β Receptor antagonists may also induce positive LV remodeling by

decreasing oxidative stress in the myocardium.

CARDIAC GLYCOSIDES

The benefits of cardiac glycosides in CHF are generally attributed

to:

 Inhibition of the plasma membrane Na+, K+-ATPase in

myocytes

 A positive inotropic effect on the failing myocardium

 Suppression of rapid ventricular rate response in CHF-

associated atrial fibrillation

 Regulation of downstream deleterious effects of sympathetic

nervous system overactivation
 Mechanism of the Positive Inotropic Effect:
• With cardiac myocyte depolarization, Ca2+ enters the cell via the L-
type Ca2+ channel and triggers the release of stored Ca2+ from the
sarcoplasmic reticulum via the ryanodine receptor (RyR).

• This Ca2+-induced Ca2+ release increases the level of cytosolic

Ca2+ available for interaction with myocyte contractile proteins,
ultimately increasing myocardial contraction force.

• During myocyte repolarization and relaxation, cellular Ca2+ is

resequestered by the sarcoplasmic reticular Ca2+-ATPase and is
removed from the cell by the Na+ Ca2+ exchanger and by the
sarcolemmal Ca2+-ATPase.
• Cardiac glycosides bind and inhibit the phosphorylated α subunit of the
sarcolemmal Na+, K+-ATPase and thereby decreasing Na+ extrusion and
increasing cytosolic [Na+]. This decreases the transmembrane Na+
gradient that drives Na+–Ca2+ exchange during myocyte repolarization. As
a consequence, less Ca2+ is removed from the cell and more Ca2+ is
accumulated in the sarcoplasmic reticulum (SR) by SERCA2.

• This increase in releasable Ca2+ (from the SR) is the mechanism by which
cardiac glycosides enhance myocardial contractility.

• Elevated extracellular K+ levels (i.e., hyperkalemia) cause

dephosphorylation of the ATPase α subunit, altering the site of action of the
most commonly used cardiac glycoside, digoxin, and thereby reducing the
drug’s effect.
Electrophysiologic Actions:
• At therapeutic plasma concentrations (i.e., 1-2 ng/mL), digoxin decreases
automaticity and increases the maximal diastolic resting membrane
potential in atrial and atrioventricular (AV) nodal tissues. This occurs via
increases in vagal tone and sympathetic nervous system activity inhibition.
• In addition, digoxin prolongs the effective refractory period and decreases
conduction velocity in AV nodal tissue. Collectively, these may contribute to
sinus bradycardia, sinus arrest, prolongation of AV conduction, or high-
grade AV block.
• At higher concentrations, cardiac glycosides may increase sympathetic nervous
system activity that influences cardiac tissue automaticity, change associated
with atrial and ventricular arrhythmias. Increased intracellular Ca2+ loading
and sympathetic tone increases the spontaneous (phase 4) rate of diastolic
depolarization as well as promoting delayed after depolarization; together,
these decrease the threshold for generation of a propagated action potential
and predisposes to malignant ventricular arrhythmias.
 Clinical Use of Digoxin in Heart Failure:

• Overall, digoxin use usually is limited to CHF patients with

LV systolic dysfunction in atrial fibrillation or to patients in
sinus rhythm who remain symptomatic despite maximal
therapy with ACE inhibitors and β adrenergic receptor
antagonists.

• The latter agents are viewed as first-line therapies because

of their proven mortality benefit.
 Digoxin Toxicity:

• Common electrophysiologic manifestations of digoxin toxicity are ectopic beats

originating from the AV junction or ventricle, first-degree AV block, abnormally
slow ventricular rate response to atrial fibrillation, or an accelerated AV
junctional pacemaker.

• Lidocaine or phenytoin, which have minimal effects on AV conduction, may be

used for the treatment of digoxin-induced ventricular arrhythmias that
threaten hemodynamic compromise.
• Inhibition of the Na+, K+- ATPase activity of skeletal muscle can cause
hyperkalemia.

• An effective antidote for digoxin toxicity is anti-digoxin immunotherapy.

Purified Fab fragments from ovine anti-digoxin antisera (DIGIBIND) are
usually dosed by the estimated total dose of digoxin ingested in order to achieve
a fully neutralizing effect.
VASOPRESSIN RECEPTOR ANTAGONISTS:
• Neurohumoral dysregulation in CHF includes abnormal arginine vasopressin
(AVP) secretion, resulting in the perturbation of fluid balance.
•AVP is secreted into the systemic circulation in response to: (1) serum
hypertonicity-induced activation of anterior pituitary osmoreceptors, and (2) a
perceived drop in blood pressure detected by baroreceptors in the carotid artery,
aortic arch, and left Atrium.
•Tolvaptan, which preferentially binds the V2 receptor over the V1a receptor
(receptor selectivity ~29:1), is perhaps the most widely tested vasopressin receptor
antagonist in patients with CHF and also is approved for hyponatremia.
•Due to the risk of overly rapid correction of hyponatremia causing osmotic
demyelination, tolvaptan should be started only in a hospital setting where
Na+ levels can be monitored closely.