HARD QUIZ HF DRUGS

Heart Failure Drugs - Lecture 09

• Heart failure drugs aim to improve cardiac function and reduce symptoms, thereby decreasing morbidity and mortality.
• If possible, address underlying conditions like valve disease, coronary artery disease, and arrhythmias.
• Reduce clinical symptoms and morbidity, including pulmonary congestion, systemic edema, and dyspnea.
• Improve cardiovascular function, including organ perfusion and increase cardiovascular functional reserve.
• Reduce mortality.

Learning Objectives

• Describe major cardiovascular, pulmonary, and renal complications of heart failure.
• Describe the therapeutic targets and goals for treating heart failure.
• Detail how different drug classes (vasodilators, RAAS inhibitors, beta-blockers, inotropic drugs, diuretics, SGLT2 inhibitors) treat heart failure, providing specific examples.
• Explain drug treatment differences in acute versus chronic heart failure (HFrEF vs HFpEF).

Cardiovascular, Pulmonary, and Renal Signs and Symptoms of Heart Failure

• Reduced cardiac output and organ perfusion, leading to reduced exercise tolerance.
• Dyspnea, even at rest.
• Pulmonary edema.
• Impaired lung gas exchange.
• Fluid retention due to increased blood volume.
• Renal sodium retention.
• RAAS activation and increased vasopressin.
• Elevated systemic vascular resistance.
• Sympathetic activation.
• Cardiac remodeling.
• Arrhythmias.

Therapeutic Goals

• Correct any underlying problems like valve disease, coronary artery disease, and arrhythmias.
• Reduce clinical symptoms and morbidity.
• Improve cardiovascular function, including organ perfusion and functional reserve.
• Reduce mortality.

Drug Treatment - Physiological Targets

• Renin-angiotensin-aldosterone system (RAAS): ACE inhibitors, ARBs, and ARNIs reduce afterload, preload, blood volume, and cardiac remodeling.
• Cardiac sympathetic activation: Beta-blockers reduce cardiac remodeling and arrhythmias.
• Volume overload and edema: Diuretics decrease blood volume, venous pressures, and preload.
• Improving cardiac metabolic function: SGLT2 inhibitors.

Vasodilators

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

Vasodilator Effects on Frank-Starling Curves

• Mixed vasodilators (reduce afterload and preload) include ACE inhibitors, ARBs, and sodium nitroprusside.
• Arterial vasodilators (reduce afterload) include hydralazine.
• Venous vasodilators (reduce preload) include isosorbide dinitrate.

Reducing Afterload in Patients with Systolic Dysfunction (HFrEF)

• Reducing afterload with an arterial vasodilator drug leads to decreased ESV, EDV, and increased SV and EF.
• Failing hearts are more responsive to afterload changes than normal hearts.

Specific Drugs

• ACE Inhibitors: Block angiotensin II formation, dilate arteries and veins, reduce vasopressin release, and attenuate cardiac remodeling. Examples: lisinopril, enalapril.
• ARBs: Block angiotensin II receptors, similar actions to ACEIs. Examples: valsartan, losartan.
• Neprilysin Inhibitors: Inhibit neprilysin, increase circulating ANP, reduce RAAS system activity, and dilate vessels. Combined with ARBs (valsartan) in ARNI drugs to treat heart failure.
• Hydralazine: Direct-acting arterial vasodilator, reduces afterload primarily.
• Isosorbide Dinitrate: Nitrodilator, primarily dilates veins, reduces preload.

Beta-blockers in Chronic Heart Failure (CHF)

• Newer beta-blockers are efficacious (reduce hospitalizations and death).
• Beta-blockers reverse heart remodeling, decrease chamber size, and increase ejection fraction.
• Typically used with diuretics, ACE inhibitors, or ARBs.

Beta-blockers in CHF (cont.)

• Excessive beta-adrenergic stimulation in CHF downregulates beta receptors, thereby reducing inotropic reserve.
• Excessive sympathetic activation contributes to hypertrophy and dysfunctional changes in signal transduction mechanisms.
• Positive antiarrhythmic benefits are observed.

Diuretics

• Increase sodium and water excretion by the kidneys.
• Reduce blood volume and CVP.
• Reduce ventricular preload and pulmonary/systemic edema.
• Reduce SVR (chronic therapy).
• Minimal effect on ventricular stroke volume and cardiac output except in cases of overdose.
• Types of diuretics include loop diuretics, thiazide diuretics, and K+-sparing diuretics.
• Furosemide is the primary loop diuretic for CHF.
• Less potent thiazide diuretics are used in mild CHF.
• Potential problems include K+ loss and excessive volume reduction (monitor for arrhythmias).
• Spironolactone and eplerenone are aldosterone antagonists for K+-sparing, improving mortality when used with ACE inhibitors or loop diuretics, especially post-MI CHF.

Cardiostimulatory/Inotropic Drugs

• Beta-agonists, PDE inhibitors, and digoxin are used in these cases.

Sympathomimetics

• Mimic sympathetic effects by stimulating beta-adrenoceptors.
• Used only for acute, not chronic, heart failure. Types include Dopamine/Dobutamine.
• Dopamine is used in low doses to cause systemic vasodilation and in high doses for α₁-mediated vasoconstriction.
• Dobutamine primarily acts on β₁-adrenoceptors, increasing cardiac output and reducing preload, but can be arrhythmogenic and has a short half-life.

Inodilators – Phosphodiesterase (PDE3) Inhibitors

• Increase cAMP in the heart and vasculature.
• Cause systemic vasodilation, mild-to-moderate positive inotropy, and tachycardia.
• Used only for acute heart failure and increase mortality and arrhythmogenic potential in chronic failure. Drugs including Milrinone and Inamrinone are examples.

Cardiac Glycosides (Digoxin)

• Inhibit Na+/K+-ATPase, leading to intracellular Ca++ increase, enhancing inotropy, and increasing ejection fraction.
• Decrease heart rate (parasympathomimetic effect).
• Inhibit sympathetic activity.
• Low therapeutic index; easily toxic.

Pharmacokinetics

• Digoxin has a half-life of 40 hours and requires renal elimination.
• Digitalization (reaching steady state without loading doses) takes 5-7 days.
• Renal function and lean body mass are crucial considerations.
• Digoxin toxicity is increased by low potassium, low magnesium, and high calcium.

SGLT2 Inhibitors

• Lower blood glucose by inhibiting SGLT2.
• Increase urinary glucose excretion.
• Cause natriuresis, diuresis, and lower arterial pressure, without increasing heart rate.
• Clinical trials show benefits for HFpEF (with or without diabetes) and in patients with mildly reduced ejection fractions (HFmrEF). These generally improve diastolic stiffness and diastolic function.

Acute vs. Chronic Therapy in HFrEF

• Acute systolic failure: Loop diuretics, arterial and mixed vasodilators, PDE inhibitors, and sympathomimetics (beta agonists).
• Chronic systolic failure: Diuretics, ACEIs, ARBs, ARNI, newer beta-blockers, and SGLT2 inhibitors.

HFpEF: Drug Treatment Guidelines

• No clearly defined guidelines; treatment focuses on comorbidities. Common drugs include: beta-blockers, calcium-channel blockers (e.g., verapamil), SGLT2 inhibitors, aldosterone receptor antagonists, and diuretics if necessary for severe edema. Also, K+-sparing diuretics are key.