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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