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Drugs for treating heart failure. A. Introduction. Heart failure (HF) is due to the inability of the ventricles to pump sufficient blood thru-out the body. There are a number of causes of heart failure:. diabetes. from:http://www.nhlbi.nih.gov/health/dci/images/heart_coronary_artery.gif.

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a introduction
A. Introduction
  • Heart failure (HF) is due to the inability of the ventricles to pump sufficient blood thru-out the body.
from http www nhlbi nih gov health dci images heart coronary artery gif
  • coronary artery disease
About 20% of patients diagnosed with heart failure die within 1 year of diagnosis, about 50% die within 5 years.
There is NO cure for heart failure. Treatment goals involve treating/removing the underlying causes in order to improve the quality of life and/or extend life expectancy.
b pathophysiology of heart failure
B. Pathophysiology of heart failure
  • Two important factors which affect cardiac output, and therefore affect how heart failure is treated, are preload and afterload
1 preload
1. Preload
  • Immediately before the chambers of the heart contract they are filled to their maximum capacity with blood.
2 afterload
2. Afterload
  • For the left ventricle to pump blood out of the heart, it must overcome a fairly substantial pressure in the aorta.
Afterload is the pressure in the aorta that must be overcome for blood to be ejected from the left side of the heart.
3 left heart failure aka chf
3. Left heart failure aka CHF
  • If heart failure is on the left side (more common), excess blood accumulates in the left ventricle.
This results in classic symptoms: cough, shortness of breath, especially when a patient is prone
4 right heart failure
4. Right heart failure
  • Here, blood “backs up” into peripheral veins.
This results in classic symptoms: swelling of feet, ankles (peripheral edema) and engorgement of organs such as liver
5 cardiac output
5. Cardiac Output
  • Cardiac output (the amount of blood pumped by the heart per minute) is significantly decreased during heart failure.
c drug class mechanisms of action in treating heart failure
C. Drug class mechanisms of action in treating heart failure
  • There are a number of different mechanisms of action when considering how to treat heart failure:
1. Certain drugs increase the force of contraction. This is called a positive inotropic effect and is characteristic of:
  • a. cardiac glycosides
  • b. phosphodiesterase inhibitors
2. Certain drugs decrease the heart rate. This is characteristic of the adrenergic (beta) blockers.
3. Certain drugs relax vascular smooth muscle which dilates blood vessels and lowers blood pressure. This is characteristic of the vasodilators.
5. Certain drugs affect the renin-angiotensin-aldosterone (RAA) system. This is characteristic of the ACE inhibitors
6. Certain drugs reduce both preload and afterload. This is characteristic of the natriuretic peptides.
1a cardiac glycoside therapy of heart failure
1a. Cardiac glycoside therapy of heart failure
  • The cardiac glycosides are derived from the foxglove plants, Digitalis purpurea and

Digitalis lanata

They have been used to treat heart disorders for over 2000 years, and were

the mainstay of heart failure treatment until the discovery of the ACE inhibitors

Cardiac glycosides have 2 primary actions:
  • 1. Increasing the force of contraction allows the heart to eject more blood per beat which increases cardiac output and improves circulation.

Digoxin stimulates the vagus nerve, which slows the activity of the sinoatrial (SA) and atrioventricular (AV) nodes


This reduced heart rate (known as a negative chronotropic effect) is seen as a lengthening of the PR interval on an ECG.

The specific mechanism of action of the cardiac glycosides is inhibition of the

Na1+- K1+-ATPase pump.

The increased concentration of Na1+ stimulates the Na1+-Ca2+ exchange mechanism, leading to an increase in intracellular Ca2+.
The primary cardiac glycoside available in the U.S. is digoxin (Digitek, Lanoxicaps, Lanoxin).
The antidote for digoxin is called digoxin immune fab (Digibind). It binds digoxin and has a rapid onset of action, less than 1 minute after IV infusion.
It is necessary to have an antidote available as nearly 1/3 of patients taking cardiac glycosides develop symptoms of toxicity.
Symptoms of toxicity: pulse rate below 60 beats/min., confusion, nausea, diarrhea, yellow-green halos around lights, hallucinations
Vincent van Gogh’s “The Starry Night” (1889) is believed, by some physicians, to show evidence of digoxin (aka digitalis) toxicity, in the way he created yellow-green halos around the stars.
1b phosphodiesterase inhibitor therapy of heart failure
1b. Phosphodiesterase inhibitor therapy of heart failure
  • Phosphodiesterase inhibitors are used for short-term control of acute/advanced heart failure that is unresponsive to the “more conventional” ( i.e. diuretics and ACE inhibitors) treatments.
These drugs block phosphodiesterase in cardiac and smooth muscle which prevents the hydrolysis of cAMP.
Phosphodiesterase inhibitors have 2 primary actions:
  • 1. Increasing the force of contraction (similar to the cardiac glycosides)
  • 2. vasodilation
They are generally used for only 2-3 days because they may produce potentially serious adverse effects (ventricular arrhythmias, severe hypotension, thrombocytopenia)
Phosphodiesterase inhibitors include:
  • inamrinone (Inocor): IV, peak effect in 10 min.
  • milrinone (Primacor): IV, peak effect in 2 min.
2 beta adrenergic blocker therapy of heart failure
2. Beta adrenergic blocker therapy of heart failure
  • Selective beta blockers target beta1 receptors in the heart and kidneys. They are used in combination with other drugs to slow the progression of heart failure and to prolong patient survival.

However, there is increased activation of the sympathetic nervous system in patients with heart failure that causes tachycardia and increases stress on the heart.


Beta blockers slow the heart rate, which allows the heart to both fill and function more effectively.

Beta blockers used in the treatment of heart failure include:
  • acebutolol: (Sectral)
  • atenolol (Tenormin)
  • bisoprolol (Zebeta)
  • esmolol (Brevibloc)

The “preferred” beta blockers for the treatment of heart failure are:

  • carvedilol (Coreg)
  • metoprolol (Lopressor)
3 vasodilator therapy of heart failure
3. Vasodilator therapy of heart failure
  • Vasodilators generally play a minor role in the drug therapy of heart failure.
They reduce the symptoms of heart failure by decreasingcardiac oxygen demand.
Vasodilators indicated for the treatment of heart failure include:
  • hydralazine (Apresoline): acts on smooth muscle of arterioles, increases heart rate and cardiac output
isosorbide dinitrate (Isordil, Sorbitrate): causes venodilation, particularly in the larger veins and vena cava

This reduces both venous return to the heart and preload, allowing the heart to pump more forcefully.

4 diuretic therapy of heart failure
4. Diuretic therapy of heart failure
  • Diuretics are one of the “more conventional” treatments for heart failure.

Diuretic therapy, as well as sodium restriction is recommended for patients with mild heart failure

They reduce fluid overload and lower blood pressure which reduces the workload on the heart and increases cardiac output.
To control mild heart failure in patients with normal kidney function:
  • chlorothiazide (Diuril) or hydrochlorothiazide (Hydrodiuril)
  • methylclothiazide (Enduron, Aquatensen)
For patients with more advanced heart failure, low kidney function, and/or more severe edema:
  • furosemide (Lasix)
  • bumetanide (Bumex)
  • torsemide (Demadex)

Some studies have shown that treatment of heart failure with a potassium sparing diuretic reduces mortality.


These diuretics are more effective when the aldosterone level is elevated as they are either:


competitive inhibitors of the aldosterone receptor, or

  • decrease aldosterone activity by blocking Na1+ channels in the collecting ducts

Potassium sparing diuretics used in the treatment of heart failure include:

  • spironolactone (Aldactone)
  • eplerenone (Indira)
  • amiloride (Midamor)
  • triamterene (Dyrenium)
5 ace inhibitor acei therapy of hf
5. ACE inhibitor (ACEI) therapy of HF
  • ACE inhibitors have become the preferred drugs for the treatment of heart failure.

They inhibit angiotensin II. Angiotensin II causes vasoconstriction, and release of aldosterone and ADH.

ACE inhibitors which have been approved by the FDA in the treatment of heart failure include:
  • captopril (capoten)
  • enalapril maleate (Vasotec)
  • fosinopril (Monopril)
  • lisinopril (Prinivil, Zestril)
  • quinapril (Accupril)
  • ramipril (Altace)
6 natriuretic peptide therapy of hf
6. Natriuretic peptide therapy of HF
  • Natriuretic peptide was approved in 2001 for the treatment of heart failure.
It is a small peptide hormone structurally identical to a hormone secreted by the heart, beta-type natriuretic peptide (hBNP)
When heart failure occurs, the ventricles secrete hBNP in response to the increased stretching of the ventricular walls.
hBNP acts on the kidney, increasing excretion of Na1+ and water, thus lowering blood pressure.
The natriuretic peptide which has been approved for the treatment of heart failure is nesiritide (Natrecor).
It is approved only for severe heart failure because of the potentially serious side effects: apnea, hypotension, arrhythmias.