drugs used in heart failure twardley2011

8/8/2019 Drugs Used in Heart Failure TWArdley2011

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Drugs used in Heart Failure

Drug Groups commonly Used in Heart Failure

1. Diuretics

Mainstay of heart failure managementNo direct effect on cardiac contractility

Reduce venous pressure and ventricular preload

Results in reduction of salt and water retention and edema and its symptomeCOMPOUNDS

Furosemide (generic, Lasix)

Loop DiureticPossesses a free carboxyl group making it a strong acid

Furan ring

Aromatic aminoMOA 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 (Clor CF3 highly active

CH3 diuretics are more lipid-soluble and have a longer duration of action vs Cl

analogsElectron donating groups (-CH3, -OCH3) decreases diuretic activity

Replacement or removal of sulfonamide group in position 7 leads to little or

diminished diuretic activitySaturation 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 coveredMOA - Decreases NaCl reabsorption in the distal convoluted tubule


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2. Aldosterone receptor angagonists

Also diuretics

Additional benefit of decreasing morbidity and mortality in patients with severeheart 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.

COMPOUNDSSpironolactone (generic, Aldactone)

O

SO

O

CH3O

O

O

O

OH

COO-

O

Spironolactone

Canrenone

Canrenoic acid anion

Canrenone is the major active metaboliteCanrenone 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.


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Eplerenone (Inspra)

Similar structure and MOA of spironolactoneMetabolites 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 functionand cardiovascular structure.

COMPOUNDSACE inhibitors can be subclassified into three groups based on their chemical

composition.

A. Sulfhydryl-containing inhibitors

Captopril (generic, Capoten)

Contains the pyrrolidine ring


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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 ring10x more potent than captopril.

Benazepril (generic, Lotensin)

Requires bioactivation to benzaeprilat


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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)


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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


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N

N

R

Acidic group

Acidic groups: A -CO2H

BN

HN

N

N

C HOOC

SAR1. 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 andoral 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)


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Candesartan (Atacand)

Eprosartan (Teveten)

Irbesartan (Avapro)

Olmesartan (Benicar)


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Telmisartan (Micardis)

Valsartan (Diovan)

5. Beta blockers

Competitively blocks B1 receptors

COMPOUNDS

Bisiprolol (generic, Zebeta)


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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 themedically useful cardiac glycosides

All of the cardiac glycosides of which digoxin is the prototype combine a steroidnucleus 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 andincreased Ca2+ stored in sarcoplasmic reticulum.

COMPOUNDSDigoxin (generic, Lanoxicaps, Lanoxin)


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Sugar digitoxose Aglycone digoxigenin

7. Vasodilators

Effective in acute heart failure or

Provides reduction in preload or reduction in afterload or both

COMPOUNDS

VenodilatorsReleases nitric oxide (NO)

Activates guanyl cyclase

Isosorbide dinitrate (generic, Isordil)

Arteriolar dilatorsProbably increases NO synthesis in endothelium

Hydralazine (generic, Apresoline)


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Combination

Releases NO spontaneouslyActivates guanyl cyclase

Nitroprusside (generic, Nitropress)

8. Beta agonists (Positive Inotropic Drugs)

COMPOUNDSCatecholamines

Dobutamine (generic) most widely used B1 agonistProduces an increase in cardiac output with a decrease in ventricular

filling pressure.

Dopamine (generic, Intropin)


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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


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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 ETBIt is a very potent vasoconstrictor.

Endothelin Receptor Antagonists are nonselective inhibitors that producevasodilation and cardiac inhibition

Bosentan (Tracleer)

Has pyrimidines, sulfonamides

drugs used in heart failure twardley2011

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