Drugs Utilized in Heart Failure

Introduction

• Understanding the pathophysiology of heart failure helps in treatment and understanding drug mechanisms
• Two determinants: ejection fraction (EF)
  • Reduced EF (HFrEF)
  • Preserved EF (HFpEF)
• Common theme: Decreased Cardiac Output

Pathophysiology

• Cardiac Output and Blood Pressure: BP = CO x SVR (Systemic Vascular Resistance)
  • Low CO leads to reduced BP, triggering baroreceptor response
• Baroreceptor Activation: Located in carotid and aortic sinuses
  • Activates Sympathetic Nervous System (SNS)
  • SNS increases norepinephrine and epinephrine release
  • Heart effects: increases heart rate (HR) and contractility via Beta-1 receptors
  • Blood vessels: causes vasoconstriction via Alpha-1 receptors on arteries (↑ SVR) and veins (↑ preload)
• SNS Activation Issues: Increases O2 demand, decreases coronary perfusion, left ventricular hypertrophy, and dilation
• RAAS Activation: SNS also activates kidney JG cells to release renin, leading to Angiotensin II production with various effects:
  • Increases SVR and preload
  • Increases ADH and aldosterone (sodium and water retention)
  • Causes efferent arteriole vasoconstriction (increases GFR but risks CKD)

Drug Mechanisms

General Goals:

1. Increase cardiac output
2. Reduce preload and afterload
3. Manage fluid retention
4. Prevent adverse remodeling

Beta Blockers

• Types: Metoprolol (succinate), bisoprolol, Carvedilol
• Mechanism:
  • Decrease HR and contractility
  • Modulate renin release
  • Carvedilol: additional Alpha-blocking (↓SVR and preload)
• Indications: HFrEF, post-MI, CAD
• Adverse Effects: bradycardia, worsening HF, bronchospasm, hypoglycemia awareness

RAAS Inhibitors

• Types:
  • ACE inhibitors: Lisinopril, Enalapril
  • ARBs: Losartan, Valsartan
  • Aldosterone blockers: Spironolactone, Eplerenone
• Mechanism:
  • ACEi: block conversion of Ang I to Ang II
  • ARBs: block Ang II receptors
  • Aldosterone blockers: block sodium/water retention and potassium excretion
• Indications: HFrEF, HTN
• Adverse Effects: hyperkalemia, renal effects (↑creatinine), ACEi specific - cough and angioedema

ARNi (Angiotensin Receptor-Neprilysin Inhibitor)

• Drug: Sacubitril/Valsartan (Entresto)
• Mechanism:
  • Inhibit neprilysin (↑ BNP)
  • ARB action blocks Ang II
• Indications: Maximal ACEi/ARB with still symptomatic and low EF
• Adverse Effects: similar to ARBs + hypotension, bradykinin effects

Direct-acting Vasodilators

• Types: Hydralazine (arteries), Isosorbide Dinitrate (veins)
• Mechanism:
  • Hydralazine: vasodilates arteries (↓afterload)
  • Isosorbide: venodilates (↓preload)
• Indications: African-American patients, AKI risk (avoid ACEi/ARB)

Diuretics

• Types: Loop diuretics (Furosemide), Thiazides (Metolazone)
• Mechanism: Increase sodium/water excretion (↓ BV & preload)
• Indications: Manage symptoms like pulmonary edema, peripheral edema
• Adverse Effects: Electrolyte imbalances, metabolic alkalosis, hyperuricemia

Ivabradine

• Mechanism: Blocks funny sodium channels in SA node (↓HR, ↑ diastolic filling)
• Indications: HFrEF, HR >70 BPM, maxed out on beta-blocker
• Adverse Effects: Bradycardia, visual disturbances

Positive Inotropic Agents

• Types: Digoxin, Dobutamine, Milrinone
• Mechanism:
  • Digoxin: Blocks Na+/K+ ATPase (↑ Ca²⁺, contractility), reduces HR (vagal stimulation)
  • Dobutamine: Beta-1 agonist (↑ contractility), beta-2 (vasodilation)
  • Milrinone: PDE3 inhibitor (↑ cAMP, contractility, vasodilation)
• Indications: Refractory HF, acute HF with cardiogenic shock
• Adverse Effects: Arrhythmias, specific to drug (e.g., digoxin toxicity, tachycardia for dobutamine)

Patient Management

Chronic Heart Failure

• NYHA Classification (A, B, C, D) guides treatment progression
  • ACEi/ARB, beta blocker, add aldosterone antagonists, ARNi, hydralazine/isosorbide combination (for African-American patients), diuretics for symptom control

Acute Heart Failure

• Classification (Forester Classification)
  • Based on perfusion and congestion: warm/dry, warm/wet, cold/dry, cold/wet
  • Treatments vary by type (diuretics, inotropes, vasodilators, pressors)