8: Heart Failure Drugs

Heart Failure Drugs - Lecture 09

• Heart failure drugs aim to improve cardiac function and reduce symptoms, decreasing morbidity and mortality.
• Addressing underlying issues (e.g., valve disease, CAD, arrhythmias) is crucial.
• Reducing clinical symptoms and morbidity (pulmonary congestion, systemic edema, dyspnea).
• Improving cardiovascular function (organ perfusion, cardiovascular functional reserve).
• Reducing mortality.

Learning Objectives

• Understanding major cardiovascular, pulmonary, and renal complications of heart failure.
• Defining therapeutic targets and goals for treating heart failure.
• Describing how different drug classes (vasodilators, RAAS inhibitors, beta-blockers, inotropics, diuretics, SGLT2 inhibitors) are used in heart failure treatment, with examples of specific drugs.
• Differentiating drug treatment strategies for both acute and chronic heart failure, and comparing treatment between HFrEF and HFpEF.

Cardiovascular, Pulmonary, and Renal Signs/Symptoms

• Reduced cardiac output and organ perfusion.
• Reduced exercise tolerance.
• Dyspnea.
• Pulmonary edema.
• Impaired lung gas exchange.
• Fluid retention (increased blood volume).
• Renal sodium retention.
• Elevated systemic vascular resistance.
• Sympathetic activation.
• Cardiac remodeling.
• Arrhythmias.

Drug Treatment - Physiological Targets

• Renin-angiotensin-aldosterone system (RAAS) inhibitors (ACEIs, ARBs, ARNIs) to reduce afterload, preload, blood volume, and remodeling.
• Cardiac sympathetic activation reduction with beta-blockers to reduce remodeling and arrhythmias.
• Volume overload and edema reduction with diuretics to reduce blood volume, venous pressures, and preload.
• SGLT2 inhibitors are included to benefit cardiac metabolic function.

Vasodilators

• RAAS inhibitors, neprilysin inhibitors, and direct-acting arterial and venous dilators.

Vasodilator Effects on Frank-Starling Curves

• Mixed vasodilators reduce afterload and preload, impacting stroke volume and ejection fraction (EF).
• Arterial vasodilators reduce afterload (e.g., hydralazine).
• Venous vasodilators reduce preload (e.g., isosorbide dinitrate).

Reducing Afterload in Systolic Dysfunction

• Reducing afterload with an arterial vasodilator drug leads to decreased end-systolic volume (ESV), end-diastolic volume (EDV), improved stroke volume, and improved ejection fraction.
• Failing hearts are more responsive to afterload changes than normal hearts.

Specific Drugs: ACE Inhibitors

• MOA: Block the formation of angiotensin II.
• Actions: Dilate arteries and veins, reduce sympathetic activity, decrease vasopressin release, and attenuate cardiac remodeling.
• Examples: lisinopril and enalapril.

Specific Drugs: ARBs

• MOA: Block angiotensin II type 1 (AT1) receptors.
• Actions: Similar to ACEIs in reducing afterload, preload, and remodeling.
• Examples: valsartan and losartan.

Specific Drugs: Neprilysin Inhibitors

• MOA: Inhibit neprilysin, increasing circulating natriuretic peptide (ANP), attenuating the RAAS system, and dilating vessels.
• Sacubitril (combined with valsartan) is an ARNI used in acute heart failure.

Specific Drugs: Hydralazine and Isosorbide Dinitrate

• Hydralazine: Direct-acting arterial vasodilator, decreasing afterload.
• Isosorbide dinitrate: Nitrodilator primarily dilating veins, reducing preload.

Beta-blockers

• Traditionally considered contraindicated in heart failure.
• Newer beta-blockers show efficacy in reducing risk of hospitalization and death.
• Benefits are noted after several months, and are commonly used with diuretics and ACE inhibitors.

Beta-blockers in CHF

• Specific drugs: carvedilol, metoprolol, and other beta blockers.
• Rationale: Excessive sympathetic activation in heart failure downregulates beta-1 receptors, reducing inotropic reserve.

Diuretics

• Increase Na+ and H2O excretion by kidneys.
• Actions: Reduce blood volume, CVP, ventricular preload, and pulmonary and systemic edema; and reduce systemic vascular resistance (SVR) with prolonged therapy.
• Potential problems: potassium loss, excessive volume reduction.
• Examples: furosemide (loop diuretic), thiazide diuretics, and potassium-sparing diuretics such as spironolactone and eplerenone.

Cardiostimulatory (Inotropic) Drugs

• Beta-agonists, PDE inhibitors, and digoxin.
• Drugs are used for patients with refractory, late-stage heart failure and acute cardiogenic shock.

Sympathomimetics

• Mimic the effects of sympathetic activation by stimulating beta-adrenoceptors and increasing intracellular calcium.
• Used in acute heart failure except in end-stage.

Dopamine

• Immediate precursor for norepinephrine synthesis in sympathetic nerve terminals.
• Low doses: cause systemic vasodilation and renal vasodilation, positive inotropy and chronotropy.
• High doses: α1-mediated vasoconstriction, increasing systemic resistance and producing hypertension.

Dobutamine (Dopamine Analog)

• Primarily beta-1 adrenoceptors.
• Used in acute heart failure, cardiogenic shock, and refractory heart failure.
• Short half-life, loss of efficacy with beta-1 receptor downregulation, and potential arrhythmogenicity.

Inodilators – phosphodiesterase (PDE3) inhibitors

• MOA: Increase cAMP levels in the heart and vasculature.
• Actions: Systemic vasodilation, mild-to-moderate positive inotropy, but often have increased chronic mortality as well as the potential for arrhythmias.
• Used in acute heart failure.

Cardiac Glycosides (digoxin)

• Inhibits Na+/K+-ATPase, increasing intracellular Ca++.
• Stimulates inotropy, increases ejection fraction, and decreases heart rate.
• Inhibits sympathetic activity. -Low therapeutic index.

Pharmacokinetics

• Digoxin has a half-life of 40 hours and is eliminated by the kidneys.
• Digitalization (reaching steady-state without loading doses) takes 5-7 days.
• Renal function and lean body mass are essential considerations.
• Toxicity increased by decreased potassium, magnesium, and increased calcium.

SGLT2 Inhibitors

• Most recent class used in heart failure, primary use for type 2 diabetes.
• MOA: Inhibit sodium-glucose co-transporter-2 (SGLT2) in the kidneys, increasing glucose excretion and promoting renal sodium and water excretion (natriuresis), lowering arterial blood pressure, and improving diastolic function.

Acute vs. Chronic Therapy in HFrEF

• Acute Systolic Failure: loop diuretics, arterial and mixed vasodilators, sympathomimetics (beta agonists), and PDE inhibitors.
• Chronic Systolic Failure: diuretics (usually a loop diuretic), K+-sparing diuretics, ACEI, ARB, ARNI, newer beta-blockers, digoxin, and SGLT2 inhibitors.

HFpEF: Drug Treatment Guidelines

• No clear guidelines; drugs primarily treat comorbidities (e.g., hypertension, atrial fibrillation, diabetes).
• Beta-blockers and calcium-channel blockers (e.g., verapamil).
• SGLT2 inhibitors.
• Aldosterone receptor antagonists.
• Diuretics for severe edema.