RECENT ADVANCE
DRUGS USED IN
HEART FAILURE
PRESENTED BY :AKANSHA DOBHAL
(M.PHARM 1ST SEM)
SUBMITTED TO : DR.PREETI SHARMA
CONTENT
INTRODUCTION
Traditional pharmacological approaches to HF management.
Novel pharmacological approaches to HF management.
HEART FAILURE
When the heart is unable to provide adequate blood supply to
meet the body’s oxygen demand. The pumping ability of the heart
is reduced and the cardiac output decreases. Thus ventricles are
not completely emptied resulting in increased venous pressure in
the pulmonary and systemic circulation. It might be because:
• The heart is too weak to squeeze properly (systolic heart failure).
• The heart is too stiff and doesn't fill with blood properly (diastolic
heart failure).
Types of Heart Failure
Heart failure can be classified based on the ejection fraction (EF), which
is the percentage of blood the left ventricle pumps out during each
contraction. The two main types are:
1. Heart Failure with Reduced Ejection Fraction (HFrEF)
• Definition:
• HFrEF occurs when the heart muscle is weakened and cannot contract
effectively to pump blood forward.
• Ejection Fraction (EF): Less than 40%.
• Mechanism (Systolic Dysfunction):
• The heart loses its ability to contract properly during systole (the phase when
the heart pumps blood).
• Results in reduced stroke volume (amount of blood pumped out per beat),
causing a decrease in cardiac output (CO).
• Blood backs up into the lungs and systemic circulation, leading to symptoms
of congestion.
2. Heart Failure with Preserved Ejection Fraction (HFpEF)
• Definition:
• HFpEF occurs when the heart maintains normal contraction strength but
cannot relax properly to fill with blood during diastole.
• Ejection Fraction (EF): Greater than or equal to 50%.
• Mechanism (Diastolic Dysfunction):
• The heart muscle becomes stiff or less compliant.
• This stiffness impairs ventricular relaxation and reduces filling during
diastole.
• Reduced filling means less blood is available to pump out, even though
the heart pumps a "normal percentage" of what it receives.
Traditional pharmacological approaches to HF
management.
1. ACE Inhibitors and ARBs
Mechanism of Action:
• ACE Inhibitors (e.g., Enalapril, Lisinopril):
• Block the angiotensin-converting enzyme (ACE), preventing the conversion of
angiotensin I to angiotensin II.
• Angiotensin II is a potent vasoconstrictor that also stimulates aldosterone secretion and
promotes cardiac remodeling.
• By inhibiting angiotensin II:
• Vasodilation occurs, reducing afterload (pressure the heart must pump against).
• Reduced aldosterone secretion lowers sodium and water retention, reducing preload
(volume entering the heart).
• Decreased myocardial remodeling and fibrosis improve long-term cardiac function.
ARBs (e.g., Losartan, Valsartan):
• Block the angiotensin II receptor (AT1 receptor), directly preventing its
harmful effects without affecting ACE.
• Similar benefits to ACE inhibitors but used in patients who cannot
tolerate ACE inhibitors (e.g., due to cough or angioedema).
2. Beta-Blockers
Mechanism of Action:
• Examples: Bisoprolol, Metoprolol (beta-1 selective), Carvedilol (non-
selective + alpha-blocking).
• Block beta-adrenergic receptors in the heart, kidneys, and vascular
system to counteract the overactivation of the sympathetic nervous
system (SNS) in HF.
• Cardiac Effects:
• Reduce heart rate (negative chronotropy): Allows more time for ventricular filling
during diastole.
• Reduce contractility (negative inotropy): Decreases myocardial oxygen demand
and limits stress on the heart.
• Renal Effects:
• Inhibit renin release from juxtaglomerular cells in the kidney, suppressing RAAS
activation.
• Long-term Effects : Reduce harmful effects of such as myocardial
hypertrophy, ischemia, and arrhythmias.
• Improve survival and reduce hospitalizations in HFrEF.
3. Mineralocorticoid Receptor Antagonists (MRAs)
Mechanism of Action:
• Examples: Spironolactone, Eplerenone.
• Block the mineralocorticoid receptor in the distal tubule of the nephron,
antagonizing aldosterone's effects:
• Renal Effects:
• Inhibit sodium reabsorption and potassium excretion, leading to mild diuresis and
potassium conservation.
• Cardiac and Vascular Effects:
• Reduce myocardial and vascular fibrosis, which aldosterone promotes during
chronic HF.
• Decrease left ventricular hypertrophy and stiffness, improving heart function over
time.
• Additional Benefits:
• Spironolactone has anti-androgenic properties, whereas Eplerenone is more
selective for mineralocorticoid receptors, reducing side effects.
4. Diuretics
Mechanism of Action:
• Loop Diuretics (e.g., Furosemide, Torsemide):
• Inhibit the Na+/K+/2Cl− cotransporter in the thick ascending limb of the loop
of Henle.
• This reduces sodium, potassium, and chloride reabsorption, leading to:
• Increased diuresis (fluid loss).
• Reduced blood volume and venous pressure, lowering preload and improving
symptoms of congestion (e.g., pulmonary edema, leg swelling).
• Thiazide Diuretics (e.g., Hydrochlorothiazide):
• Inhibit the Na+/Cl− cotransporter in the distal tubule.
• Less potent than loop diuretics but helpful in combination for refractory fluid
retention.
• Potassium-Sparing Diuretics (e.g., Amiloride, Spironolactone):
• Reduce potassium loss by inhibiting aldosterone or directly affecting sodium
channels.
Novel pharmacological approaches to HF
management
1.Finerenone:
Mechanism of Action:
Aldosterone's Role: Aldosterone is a hormone that binds to
mineralocorticoid receptors (MR) in the kidneys, heart, and blood
vessels. It promotes sodium retention, water retention, and potassium
loss, leading to high blood pressure and damage to the heart and
kidneys over time.
Finerenone’s Action:
1. Finerenone blocks these mineralocorticoid receptors.
2. By doing so, it prevents the harmful effects of aldosterone, like
inflammation and scarring (fibrosis) in heart and kidney tissues.
3. Unlike older steroidal MRA drugs, finerenone is non-steroidal, meaning it
binds more selectively and tightly to MR. This reduces side effects like
excessive potassium levels (hyperkalemia).
2.Sotagliflozin (Inpefa) Detailed Mechanism and Usage
Mechanism of Action
1. Dual Inhibition:
1. SGLT1 (Sodium-Glucose Transporter 1):
1. Found mainly in the intestines.
2. It helps absorb glucose from food.
3. By blocking SGLT1, Sotagliflozin reduces how much glucose enters the
bloodstream after meals.
2. SGLT2 (Sodium-Glucose Transporter 2):
1. Found mainly in the kidneys.
2. It reabsorbs glucose back into the blood from urine.
3. By blocking SGLT2, Sotagliflozin increases the amount of glucose excreted in urine,
lowering blood sugar levels.
2. Heart Failure Benefits:
1. Improves heart function: Reduces fluid overload by increasing the excretion
of salt and water through urine.
2. Decreases workload on the heart: Relaxes blood vessels and improves
energy use in heart tissues.
3.Omecamtiv Mecarbil:
Mechanism of Action
• Omecamtiv Mecarbil is a cardiac myosin activator.
• What it does:
• Targets Cardiac Myosin: Myosin is a protein in heart muscle cells
that helps the heart contract.
• Improves Contraction: The drug binds to myosin and makes it
work more efficiently.
• It increases the duration of contraction without increasing
oxygen demand (unlike traditional drugs like inotropes).
• Enhances Systolic Function: Boosts the heart's ability to pump
blood during the contraction phase.
Cardiopoietic cell therapy
Cardiopoietic cell therapy uses mesenchymal stem cells (MSCs), which
are a type of adult stem cell capable of differentiating into various cell
types, including those in the heart. Here's how it works in detail:
Mesenchymal Stem Cell (MSC) Harvesting:
1. MSCs are typically isolated from sources like bone marrow, adipose
tissue, or umbilical cord.
2. These cells are multipotent, meaning they can transform into different
types of cells, including those of the heart (cardiomyocytes).
Cardiopoietic Conditioning:
1. Before being injected into the heart, the MSCs are exposed to specific
cardiopoietic factors (growth factors or signaling molecules). These
factors encourage the MSCs to develop into heart muscle cells
(cardiomyocytes) or support cells like vascular cells (for blood vessel
formation).
Improvement of Heart Function:
1. By regenerating the heart muscle and improving tissue repair, cardiopoietic cell therapy helps to
restore the heart's structure and function.
2.This can lead to reduced scar tissue formation, improved heart pumping ability, and
better blood flow in the heart.
Benefits:
• Structural Reversal: The therapy aims to reverse the damage caused by heart attacks or
• chronic heart disease.
• Functional Improvement: It can help improve the heart's ability to pump blood and
reduce heart failure symptoms.
In ongoing clinical trials, cardiopoietic cell therapy shows promise in improving the function
and structure of the heart, With potential benefits in patients with conditions like heart failure or
those recovering from myocardial infarctions (heart attacks).
Acoramidis (also known as AG10) is a novel oral drug being developed
for the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM).
It works by stabilizing the transthyretin (TTR) protein, preventing it from
misfolding and forming amyloid deposits that damage the heart and
other organs. This mechanism helps reduce the progression of the
disease, improve cardiac function, and lower the risk of cardiovascular
events such as heart failure and hospitalizations.
As of 2024, acoramidis has shown promising results in Phase 3 trials
REFERENCE
•McMurray JJV et al. PARADIGM-HF Trial. NEJM, 2014.
•Packer M et al. EMPEROR-Reduced Trial. NEJM, 2020.
•2023 AHA/ACC Guidelines for Heart Failure Management.
•Faricimab Clinical Trial, 2023.
•Finerenone Approval Report, 2024
•Gillmore JD, Judge DP, Cappelli F, et al; ATTRibute-CM Investigators. Efficacy and Safety of
Acoramidis in Transthyretin Amyloid Cardiomyopathy.N Engl J Med. 2024 Jan 11;390(2):132-142.
doi: 10.1056/NEJMoa2305434. PMID: 38197816.
