What are the mechanisms of action of the medications used to treat chronic heart failure?

Mechanisms of Action of Chronic Heart Failure Medications

The medications used to treat chronic heart failure work through five primary mechanisms: blocking harmful neurohormonal activation (ACE inhibitors, ARBs, beta-blockers, aldosterone antagonists), reducing cardiac workload through vasodilation and diuresis (diuretics, nitrates), slowing heart rate to improve diastolic filling (beta-blockers, digoxin), enhancing myocardial contractility (digoxin), and improving glucose metabolism while reducing sodium reabsorption (SGLT2 inhibitors). 1, 2

Neurohormonal Blockade

ACE Inhibitors

• Inhibit angiotensin-converting enzyme, preventing conversion of angiotensin I to angiotensin II, thereby reducing systemic vasoconstriction and decreasing cardiac afterload 1
• Reduce aldosterone secretion, leading to decreased sodium and water retention 1
• Improve cardiac relaxation and distensibility directly, with long-term effects through regression of ventricular hypertrophy 3
• Provide renoprotective effects through renal arteriole vasodilation, improving blood flow and protecting renal perfusion 1
• The beneficial effects break the vicious cycle where low cardiac output triggers RAA system activation, which further increases afterload and worsens heart failure 1

Angiotensin II Receptor Blockers (ARBs)

• Block angiotensin II receptors directly, providing similar hemodynamic benefits to ACE inhibitors without the bradykinin-mediated side effects like cough 1, 3
• Should be used when ACE inhibitors are not tolerated, though evidence for mortality reduction is less robust than with ACE inhibitors 1

Beta-Adrenergic Receptor Blockers

• Inhibit the adverse effects of chronic sympathetic nervous system activation on the failing heart, which far outweigh their negative inotropic effects 1
• Prevent norepinephrine-induced cardiac hypertrophy while restricting coronary blood supply to thickened ventricular walls, thereby reducing myocardial ischemia 1
• Reduce heart rate and increase diastolic filling period, which is particularly critical in diastolic dysfunction where adequate filling time is essential 3, 2
• Decrease automaticity and triggered activity in cardiac cells, reducing arrhythmia risk 1
• Inhibit norepinephrine-triggered apoptosis (programmed cell death) in terminally differentiated cardiac cells through reduced oxidative stress 1
• Downregulate the RAA system through sympathetic inactivation, and reduce endothelin-1 and thromboxane prostaglandins that promote vasoconstriction 1
• Only bisoprolol, sustained-release metoprolol succinate, and carvedilol have proven mortality benefits—this is not a class effect 1

Aldosterone Receptor Antagonists (Spironolactone)

• Block aldosterone receptors, preventing sodium retention and potassium excretion beyond what ACE inhibitors achieve alone 1
• Retard myocardial fibrosis development, providing direct beneficial effects on cardiac remodeling 4
• Recommended in advanced heart failure (NYHA III-IV) to improve survival and reduce morbidity 1

Diuretic Mechanisms

Loop Diuretics

• Inhibit the NKCC transporter in the loop of Henle, blocking sodium reabsorption and causing natriuresis with subsequent water efflux 1
• Reduce intravascular volume and cardiac preload, decreasing pulmonary congestion and peripheral edema 1, 2
• Decrease cardiac wall tension through preload reduction, relieving symptoms of congestion 5
• Critical caveat: excessive diuresis reduces blood pressure and renal perfusion, potentially triggering compensatory vasoconstriction and acute kidney injury 1

Thiazide Diuretics

• Inhibit the sodium-chloride transporter in the distal tubule, providing additional natriuresis 1
• Counter-balance hyperkalemia from ACE inhibitors and aldosterone antagonists through increased potassium excretion 1
• Should not be used when GFR < 30 mL/min except synergistically with loop diuretics 1, 2

Cardiac Glycosides (Digoxin)

• Inhibit sodium-potassium ATPase, increasing intracellular sodium and subsequently intracellular calcium through sodium-calcium exchange 6
• Increase force and velocity of myocardial systolic contraction (positive inotropic effect) through elevated intracellular calcium 6
• Exert vagomimetic effects on sinoatrial and AV nodes, slowing heart rate and decreasing AV conduction velocity 6
• Sensitize baroreceptors, increasing afferent inhibitory activity and reducing sympathetic nervous system and renin-angiotensin system activity 6
• Decrease neurohormonal activation despite being primarily an inotrope 6
• Does not improve mortality but reduces hospitalizations for heart failure 1

Vasodilators

Nitrates

• Induce venous pooling, decreasing cardiac preload and relieving symptoms of pulmonary congestion 1, 5
• Useful for concomitant angina or acute dyspnea relief 1
• Develop tolerance with frequent dosing unless given with 8-12 hour intervals or combined with ACE inhibitors or hydralazine 1

Hydralazine

• Directly dilate arterioles, decreasing afterload and improving cardiac output 5
• When combined with isosorbide dinitrate, provides balanced vasodilation and improves survival, though with higher side effect rates 1, 5

Calcium Channel Blockers (Limited Role)

Verapamil-Type (Non-Dihydropyridine)

• Lower heart rate and increase diastolic filling period, potentially improving functional status in hypertrophic cardiomyopathy 3
• Contraindicated in systolic dysfunction and when combined with beta-blockers 1

Dihydropyridines (Amlodipine, Felodipine)

• Show neutral effect on survival and may be used only for concomitant hypertension or angina, not for heart failure treatment itself 1

SGLT2 Inhibitors (Emerging Therapy)

• Reduce sodium reabsorption in proximal tubules while improving glucose metabolism 7, 2
• Recommended for both HFrEF and HFpEF based on recent evidence 7, 2

Critical Clinical Pitfalls

• Never use diuretics as monotherapy—they must always be combined with ACE inhibitors or ARBs to avoid adverse outcomes 2
• Avoid excessive diuresis in diastolic dysfunction (HFpEF), as these patients are highly preload-dependent and over-diuresis causes hypotension and reduced cardiac output 3, 2
• Avoid potassium-sparing diuretics during ACE inhibitor initiation due to hyperkalemia risk 1, 2
• Avoid NSAIDs, as they antagonize ACE inhibitor effects and worsen renal function 1, 2
• Diltiazem and verapamil are contraindicated in systolic dysfunction due to negative inotropic effects 1
• Oral inotropes (milrinone, enoximone, vesnarinone) increase mortality and should never be used chronically 1