Medicinal Chemistry II CVS: Congestive Heart Failure

CHAPTER 3:
DRUGS OF CONGESTIVE HEART FAILURE (CHF)
Sam Dawbaa, Pharm. Chem. Ph.D.

Cardiac failure can be described as the inability of the heart to pump blood effectively at a rate
that meets the needs of metabolizing tissues. This is the direct result of reduced contractility of the
cardiac muscles, especially those of the ventricles, which causes a decrease in cardiac output,
increasing the blood volume of the heart (hence the term “congested”). As a result, systemic blood
pressure and renal blood flow are both reduced, which often leads to the development of edema in the
lower extremities and the lung (pulmonary edema) as well as renal failure.

1.1 Symptoms:
The main symptoms of heart failure are: 1) dyspnea, 2) fatigue, 3) fluid retention
(edema).

1.2 Causes:
1. Atherosclerosis. 4. Valvular heart disease.
2. Myocardial infarction. 5. Dilated cardiomyopathy.
3. Hypertension. 6. Congenital heart disease.
1.3 Progression of the disease:
Activation of the sympathetic nervous system, the renin-angiotensin-aldosterone system,
& cardiac remodeling (loss of myoctyes, hypertrophy, & fibrosis) to compensate failure of
the heart may contribute to the progression of the disease.

1.4 Classification of Drugs Used in the Treatment of Heart Failure

1. Positive inotropic agents: Cardiac glycosides.
2. Direct vasodilators.
3. Diuretics
4. Renin-Angiotensin system blockers: Angiotensin-Converting Enzyme (ACE) inhibitors
and Angiotensin receptor blockers.
5. Phosphodiesterase III inhibitors.

2.1 CHEMISTRY .
Cardiac glycosides are composed of a sugar and an aglycone (non-sugar part).

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Medicinal Chemistry II CVS: Congestive Heart Failure

A. Aglycone
• It is a steroid nucleus.
• Rings A-B and C-D are cis fused. Rings B-C
are trans fused → U-shaped aglycone.
• Methyl groups: C-10 and C-13.
• OH groups: C-3 (site of sugar binding), and
C-14. Other OH groups can be found at C-12
& C-16 in some cardiac glycosides →
differences in the genins e.g., digitoxigenin,
digoxigenin, & gitoxigenin. The addition of OH groups also
affect the pharmacokinetics.
• Ring at C-17: cardenolides (glycosides of plant origin) have
five-membered, α,β-unsaturated lactone ring.
Bufadienolides (glycosides of animal origin) have six-
membered lactone ring with two conjugated double bonds
(usually referred to as a-pyrone).

B. Sugar
• Monosaccharides or polysaccharides
with β-1,4-glucosidic linkage can attach
C-3 of the aglycone.
• The most common sugars are: d-glucose, d-digitoxose, l-rhamnose, and
d-cymarose.

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Medicinal Chemistry II CVS: Congestive Heart Failure

2.2 SARs .

2.3 CLINICALLY USED CARDIAC GLYCOSIDES .

• DIGOXIN & DIGITOXIN
• MOA: Cardiac muscle contraction/relaxation occurs as
follows:
o Contraction: Ca2+ enters the muscle cells →↑
cytoplasmic levels of calcium → Ca2+-calmodulin
complex → muscular contraction.
o Relaxation: Na+/Ca2+-exchanger has the function to
diffuse the Ca2+ out & the Na+ into the cardiac cell
→↑ intracellular Na+ & ↓intracellular Ca2+ →
prevention of Ca2+-calmodulin complex formation →
muscular relaxation.
o Note: The Na+ balance inside & out the cell is restored by the action of Na+/K+ ATPase
which diffuse the Na+ out the cell and replace it with K+.
o DIGOXIN & DIGITOXIN inhibit Na+/K+ ATPase → inhibition of the Na+/Ca2+-
exchanger →↑ cytoplasmic levels of Ca2+ which enhances the contractility of the
cardiac muscle.

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Medicinal Chemistry II CVS: Congestive Heart Failure

• The administration of cardiac glycosides to a patient with

CHF increases cardiac muscle contraction, reduces heart
rate, and decreases both edema and the heart size.
• TU: primarily CHF. Cardiac glycosides can also be used
in cases of atrial flutter or fibrillation and paroxysmal
atrial tachycardia.
• Toxicity:
o Digoxin & digitoxin have narrow therapeutic
index → toxic dose is only 2- to 3-fold the
therapeutic dose → common intoxication.
o Toxicity is a result of Na+/K+ ATPase inhibition
→↑ intracellular Ca2+ levels → characteristic cardia arrhythmias observed in toxicity.
o Coadministration of thiazide diuretics or glucocorticoids → hypokalemia (↓ potassium
levels) → Na+/K+ ATPase inhibition.
o Mild to moderate toxicity: anorexia, nausea, vomiting, muscular weakness, bradycardia,
& ventricular premature contractions.
o Severe toxicity: blurred vision, disorientation, diarrhea, ventricular tachycardia, & AV
block.
o Treatment of intoxication: stop taking cardiac glycoside + potassium salts +
antiarrhythmic (phenytoix, lidocaine, or propranolol) + digoxin antibody e.g., Dig-Bind.

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Medicinal Chemistry II CVS: Congestive Heart Failure

• MOA: Phosphodiesterase enzymes hydrolyzes cAMP. PDE 3 inhibitors →↑ intracellular

cAMP →↑ intracellular Ca2+ → cardiac muscle contraction.
• SE: life-threatening cardiac arrhythmias (PDE 3 inhibitors are not used for long term
treatment of CHF). Other SE include headache & hypotension (due to their vasodilatory
effects).

3.1 PRODUCTS .
1. INAMRINONE & MILRINONE
• They are bipyridine derivatives.
• TU: short-term intravenous treatment of CHF patients who does not
respond to digitalis, diuretics, or vasodilators.
• Milrinone is the drug of choice for short-term therapy of CHF
because its greater PDE3 selectivity, shorter t1/2 (30 – 60 minutes)
and fewer side effects
• Milrinone is 10-fold more potent than inamrinone. It is better tolerated (no
thrombocytopenia and GI disturbances)
• Inamrinone can cause thrombocytopenia, GI disturbances, impaired hepatic functions.
• Inamrinone oral & IV dosage forms are available. IV (inamrinone lactate) form is diluted
in NaCl solution and preserved in sodium metabisulfite (need protection from light).
• Inamrinone lactate should not be diluted with dextrose solutions because chemical
reactions occurs in 24 hours.
• Inamrinone + furosemide → precipitate formation.
• Milrinone and inamrinone are renal excreted → dose adjustment should be made in
patients with renal function impairment.

4.1 PRODUCTS: DOBUTAMINE .

• Dobutamine is a potent β1-agonist on the myocardium which is
derived from dopamine.
• It has fewer side effects than dopamine.
• It is given only by IV route because of extensive first-pass
metabolism by COMT.
• It can cause myocardial β-receptor desensitization →↓ responsiveness →↓ efficacy of the
drug.

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