Drugs used in Heart Failure

Drug Groups commonly Used in Heart Failure

1. Diuretics
Mainstay of heart failure management
No direct effect on cardiac contractility
Reduce venous pressure and ventricular preload
Results in reduction of salt and water retention and edema and its symptome
COMPOUNDS
Furosemide (generic, Lasix)

Loop Diuretic
Possesses a free carboxyl group making it a strong acid
Furan ring
Aromatic amino
MOA – Decreases NaCl and KCl reabsorption in thick ascending limb of the loop
of Henle in the nephron

Hydrochlorothiazide (generic, Esidrix, Hydro-DIURIL, combination)

Thiazide Diuretic

Weakly acidic
An electron withdrawing group is necessary at position 6 for diuretic activity (Cl
or CF3 highly active
CH3 diuretics are more lipid-soluble and have a longer duration of action vs Cl
analogs
Electron donating groups (-CH3, -OCH3) decreases diuretic activity
Replacement or removal of sulfonamide group in position 7 leads to little or
diminished diuretic activity
Saturation of the double bond to give a 3,4-dihydro derivative 10x more active
than unsaturated analog
Other SAR will be discussed when diuretics are covered
MOA - Decreases NaCl reabsorption in the distal convoluted tubule
2. Aldosterone receptor angagonists
Also diuretics
Additional benefit of decreasing morbidity and mortality in patients with severe
heart failure who are also receiving ACE inhibitors and other standard therapy.
Aldosterone promotes salt and water retention and potassium and hydrogen ion
excretion. An aldosterone antagonists will promote diuresis.

COMPOUNDS
Spironolactone (generic, Aldactone)
O O

O O

S
O CH3 O Canrenone
O
Spironolactone

COO-

OH

Canrenoic acid anion

Canrenone is the major active metabolite
Canrenone is interconvertible with its canrenoate anion
MOA – binds to the receptor preventing aldosterone binding to the receptor
(mineralcorticoid receptor) prevents reabsorption of sodium, chloride and water,
therefore excretion occurs.
Eplerenone (Inspra)

Similar structure and MOA of spironolactone

Metabolites are inactive
Epoxide functional group
More selective antialdosterone effect

3. Angiotensin-converting enzyme inhibitors (ACE Inhibitors)

Angiotensin converting enzyme converts Angiotensin I to Angiotensin II
Angiotensin II is a potent vasoconstrictor that affects peripheral resistance, renal function
and cardiovascular structure.

COMPOUNDS
ACE inhibitors can be subclassified into three groups based on their chemical
composition.

A. Sulfhydryl-containing inhibitors

Captopril (generic, Capoten)

Contains the pyrrolidine ring

B. Phosphonate-containing inhibitors

Fosinopril (generic, Monopril)

Bioactivation via esterase gives the active compound Fosinoprilat.

C. Dicarboxylate-containing inhibitors

Enalapril (generic, Vasotec, Vasotec I.V.)

Enalapril undergoes bioactivation by esterases to Enalaprilat the active metabolite

Enalapril is a pro-drug
Contains the pyrrolidine ring
10x more potent than captopril.

Benazepril (generic, Lotensin)

Requires bioactivation to benzaeprilat

Lisinopril (generic, Prinivil, Zestril)

Contains the basic amino acid lysine (- CH2CH2CH2CH2NH2)

Does not require bioactivation because none of the carboxylic acid groups are esterified.
Contains the pyrrolidine ring

Moexipril (generic, Univasc)

Perindopril (Aceon)

Quinapril (generic, Accupril)

Ramipril (Altace)

Trandolapril (Mavik)

4. Angiotensin II receptor blockers (ARBs)

Reduce peripheral resistance and thereby reduce afterload
Reduce salt and water retention thereby reducing preload
The Angiotensin II receptor exists in at least two subtypes, type 1 (AT1) and type
2 (AT2).
AT1 receptors are located in the brain, neuronal, vascular, renal, hepatic, adrenal,
and myocardial tissues and mediate the cardiovascular, renal and CNS effects of
angiotensin II.
All currently available ARBs are 10,000 fold selective for AT1 and act as
competitive antagonists
 N
Acidic groups: A -CO2H

HN
N
N B
N
R N

C HOOC
Acidic group

SAR
1. The acidic group amino acids of angiotensin II. Groups capable include (A)
carboxylic acid, (B) phenyl tetrazole, (C) phenyl carboxylate
2. In the biphenyl series, the tetrazole and carboxylate groups must be in the ortho
position for optimal activity (tetrazole is superior in terms of stability, lipophilicity and
oral bioavailability)
3. The n-butyl group of the model compound provides hydrophobic binding (can be
replaced with an ethyl ether or an n-propyl group)
4. The imidiazole ring or an isosteric equivalent is required.
5. Substitution can vary at the “R” position

COMPOUNDS
Losartan (Cozarr)
Candesartan (Atacand)

Eprosartan (Teveten)

Irbesartan (Avapro)

Olmesartan (Benicar)
Telmisartan (Micardis)

Valsartan (Diovan)

5. Beta blockers
Competitively blocks B1 receptors

COMPOUNDS
Bisiprolol (generic, Zebeta)
Carvedilol (Coreg)
Racemic mixture

Metoprolol (Lopressor, Toprol XL)

Racemic mixture

6. Cardiac glycosides
Digitalis is the genus name for the famil of plants that provide most of the
medically useful cardiac glycosides
All of the cardiac glycosides of which digoxin is the prototype combine a steroid
nucleus linked to a lactone ring at the 17 position and a series of sugars at carbon
3 of the nucleus.
MOA – Na+, K+ATPase inhibition results in reduced Ca2+ expulsion and
increased Ca2+ stored in sarcoplasmic reticulum.

COMPOUNDS
Digoxin (generic, Lanoxicaps, Lanoxin)
Sugar – digitoxose Aglycone – digoxigenin

7. Vasodilators
Effective in acute heart failure or
Provides reduction in preload or reduction in afterload or both

COMPOUNDS
Venodilators
Releases nitric oxide (NO)
Activates guanyl cyclase

Isosorbide dinitrate (generic, Isordil)

Arteriolar dilators
Probably increases NO synthesis in endothelium
Hydralazine (generic, Apresoline)
 Combination
Releases NO spontaneously
Activates guanyl cyclase
Nitroprusside (generic, Nitropress)

8. Beta agonists (Positive Inotropic Drugs)

COMPOUNDS
Catecholamines
Dobutamine (generic) – most widely used B1 agonist
Produces an increase in cardiac output with a decrease in ventricular
filling pressure.

Dopamine (generic, Intropin)

9. Bipyridines (Positive Inotropic Drugs)
Inhibit phosphodiesterase isozyme 3 (PDE-3)
Increase myocardial contractility by increasing inward calcium flux in the heart
during the action potential.

COMPOUNDS
Inamrinone (generic)

Milrinone (generic, Primacor)

10. Natriutetic peptide

Synthetic form of the endogenous peptide brain natriuretic peptide (BNP)
approved for use in acute cardiac failure.
Increases cGMP in smooth muscle cells and reduces venous and arteriolar tone
Causes diuresis
Also a vasodilator
COMPOUND
Nesiritide (Natrecor)

11. Endothelin Receptor Antagonists

Endothelin-1 (ET-1) is a 21-aminoacid peptide that is produced by the vascular
endothelium.
Two receptor subtypes ETA and ETB
It is a very potent vasoconstrictor.
Endothelin Receptor Antagonists are nonselective inhibitors that produce
vasodilation and cardiac inhibition

Bosentan (Tracleer)

Has pyrimidines, sulfonamides