11.21 Medications for Heart Failure'

Drugs for Heart Failure

• Peter W. Abel, PhD, Professor and ChairDepartment of Pharmacology and NeuroscienceSchool of Medicine

Objectives

• Pathophysiology of Heart Failure

  • Describe basic pathophysiology of heart failure.

  • Discuss adaptive and compensatory mechanisms in heart failure.

• Pharmacological Effects

  • Explain effects of various drugs on cardiac cells and remodeling in heart failure.

• Drug Evaluation

  • Evaluate drugs for heart failure:

    • Angiotensin converting enzyme inhibitors (ACEi)

    • Angiotensin receptor blockers (ARB) ± Neprilysin inhibitor (NI)

    • β-adrenergic receptor blockers

    • Spironolactone

    • Diuretics

    • Digoxin/Digitalis

Heart Failure Overview

• Definition

  • Inability of heart to supply sufficient blood for adequate tissue perfusion.

• Causes

  • Chronic hypertension, myocardial infarction, heart valve issues, coronary artery disease.

• Consequences

  • Ventricular dysfunction leads to remodeling and reduced cardiac output.

  • Results in insufficient tissue perfusion, fluid retention, and volume overload.

Ventricular Remodeling

• Types of Dysfunction

  • Diastolic dysfunction

  • Systolic dysfunction

• Remodeling Impact

  • Leads to decreased cardiac output (CO) and further complications in heart failure.

Signs & Symptoms of Heart Failure

• Symptoms

  • Fatigue, exercise intolerance due to inadequate tissue perfusion.

  • Venous distension, peripheral or pulmonary edema due to volume overload.

Compensatory Mechanisms in Heart Failure

• Neurohormonal Responses

  • Increased sympathetic discharge (Norepinephrine).

  • Activation of renin-angiotensin-aldosterone system (RAAS).

  • Results in increased blood pressure (afterload) and fluid retention.

  • Leads to worsened heart failure.

Primary Drugs for Heart Failure

• Drug Classes

  • Angiotensin converting enzyme (ACE) inhibitors

  • Angiotensin receptor blockers (ARB) ± Neprilysin inhibitor (ARNI)

  • β-Adrenergic receptor blockers

  • Diuretics

  • Spironolactone

  • Digoxin/Digitalis

Renin-Angiotensin System (RAS)

• Pathway

  • Renin converts angiotensinogen to angiotensin I.

  • ACE converts angiotensin I to angiotensin II.

  • Angiotensin II effects:

    • Potent vasoconstrictor, increases blood pressure.

    • Increases aldosterone secretion, leading to Na+ retention.

    • Promotes cardiovascular remodeling.

Angiotensin Converting Enzyme Inhibitors (ACEIs)

• Prototype: Enalapril

  • Inhibits angiotensin II formation and increases bradykinin levels.

  • Outcomes:

    • Decreased vasoconstriction and afterload.

    • Reduced sodium/water retention.

    • Decreased cardiac remodeling and increased survival in heart failure patients.

Angiotensin Receptor Blockers (ARBs)

• Prototype: Losartan

  • Block angiotensin II receptors

  • Effects include improved survival, decreased cell proliferation, and cardiac remodeling.

  • Useful as ACEI alternatives for patients experiencing side effects.

Entresto® (ARNI)

• Components

  • Combination of Valsartan (ARB) and Sacubitril (neprilysin inhibitor).

• Mechanism

  • Inhibits neprilysin, increasing levels of BNP, promoting vasodilation, diuresis, and reduced remodeling.

• Therapeutic Role

  • Used to further reduce morbidity and mortality in heart failure patients.

ACEI and ARB Adverse Effects

• Common Side Effects

  • ACEIs: Cough, Angioedema

  • ARBs: Less bradykinin effects, angioedema

• Additional Concerns

  • Hyperkalemia, dental issues (taste disturbances), fetal harm (pregnancy category D).

β-Adrenergic Receptor Blockers

• Types

  • Non-selective (1st generation), Cardioselective (2nd generation), Vasodilator β blockers (3rd generation).

• Mechanism

  • Decreases cardiac output, renin release, and blood pressure.

• Heart Failure Use

  • Reduces excess sympathetic stimulation, protects against arrhythmias, decreases afterload, prevents remodeling.

• Dental Adverse Effects

  • Limit epinephrine use with non-selective β blockers.

Diuretics

• Functions

  • Promote Na+ and water excretion, reduce fluid volume, and edema.

• Types

  • Thiazide diuretics, Loop diuretics, Potassium-sparing diuretics (spironolactone).

Spironolactone and Eplerenone

• Mechanism

  • Aldosterone receptor blockade.

• Benefits

  • Reduces myocardial fibrosis and necrosis, improves outcomes in heart failure.

• Adverse Effects

  • Spironolactone increases plasma potassium; Eplerenone has fewer hormonal effects.

Digoxin (Digitalis)

• Mechanism

  • Inhibits Na+, K+-ATPase, increasing intracellular Ca2+, improving contractility and CO.

• Hemodynamic Benefits

  • Increases cardiac output, decreases sympathetic tone.

• Adverse Effects

  • Narrow therapeutic window, potential for arrhythmias, nausea, vomiting, visual disturbances.

Dental Adverse Effects of Digoxin

• Drug Interactions

  • Certain antibiotics may enhance digoxin effects.

  • Avoid NSAIDs due to sodium retention and vasoconstriction effects.

Na+-Glucose Co-Transporter 2 (SGLT2) Inhibitors

• Dapagliflozin (Farxiga)

  • Action: Inhibits glucose reabsorption in the renal proximal tubule.

• Adverse Effects

  • Urinary and genital infections, risk of dehydration.

• Therapeutic Use

  • Effective for type II diabetes and heart failure, part of modern treatment strategies.

Cardiovascular Combination Drugs

• Classes

  • Antilipid agents, Calcium Channel Blockers, Diuretics, β-Blockers, ACEIs, ARBs, α-Receptor Blockers, Nitroglycerin, Others (clonidine, digoxin).