CVS Pharmacology: Drugs for Heart Failure

Introduction/Overview

Heart failure (HF) represents a spectrum of clinical syndromes characterized by the inability of the myocardium to maintain adequate cardiac output. The prevalence of HF continues to rise globally, largely due to aging populations and increasing survival rates following acute cardiovascular events. Pharmacologic therapy remains the cornerstone of management, aiming to reduce morbidity, mortality, and improve quality of life. This chapter delineates the pharmacologic agents commonly employed in HF, emphasizing their mechanisms, pharmacokinetic properties, therapeutic indications, safety profiles, and clinical nuances. The material is tailored for medical and pharmacy students preparing for clinical rotations and board examinations.

Learning objectives

• Identify major drug classes used in heart failure and describe their pharmacologic rationale.
• Explain the mechanisms of action at molecular and systemic levels for each class.
• Summarize key pharmacokinetic parameters influencing dosing strategies.
• Recognize common adverse effects and critical drug–drug interactions.
• Apply special patient considerations, including comorbid conditions and organ dysfunction, to therapeutic decision‑making.

Classification

1. Neurohormonal Modulators

These agents target the renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system (SNS), both of which are upregulated in HF and contribute to maladaptive remodeling.

• Angiotensin‑converting enzyme inhibitors (ACEi)
• Angiotensin receptor blockers (ARB)
• Angiotensin receptor–neprilysin inhibitors (ARNI)
• Beta‑adrenergic blockers (β‑blockers)
• Mineralocorticoid receptor antagonists (MRA)

2. Diuretics

Volume management is critical; loop diuretics are the principal agents, while thiazide‑like diuretics may be added for refractory edema.

• Loop diuretics (e.g., furosemide, torsemide, bumetanide)
• Thiazide‑like diuretics (e.g., chlorthalidone)

3. Inotropes and Positive Inotropic Agents

Used primarily in acute decompensated HF or advanced chronic HF with low output.

• Digoxin
• Isoproterenol (rare, intravenous only)

4. Novel and Adjunctive Agents

These include agents targeting endothelin receptors, sodium–glucose cotransporter‑2 (SGLT2) inhibitors, and selective phosphodiesterase‑5 inhibitors.

• Endothelin receptor antagonists (e.g., bosentan)
• SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin)
• PDE‑5 inhibitors (e.g., sildenafil, tadalafil)

Mechanism of Action

1. ACE Inhibitors

ACEi block the conversion of angiotensin‑I to angiotensin‑II, thereby reducing vasoconstriction, aldosterone secretion, and sympathetic activation. The resultant decrease in afterload and preload, coupled with anti‑remodeling effects, underpins their mortality benefit in HFrEF.

2. Angiotensin Receptor Blockers

ARBs competitively inhibit angiotensin‑II binding to AT1 receptors, attenuating vasoconstriction and aldosterone release. They offer an alternative for patients intolerant to ACEi, particularly those with cough or angioedema.

3. Angiotensin Receptor–Neprilysin Inhibitors

ARNIs combine an ARB with a neprilysin inhibitor, thereby enhancing natriuretic peptide activity while blocking RAAS. The dual effect reduces preload, afterload, and neurohormonal activation, translating into improved clinical outcomes.

4. Beta‑Adrenoceptor Blockers

Selective and non‑selective β‑blockers antagonize β1‑adrenergic receptors, diminishing heart rate, contractility, and myocardial oxygen demand. Chronic β‑blocker therapy mitigates neurohormonal overdrive and counteracts maladaptive remodeling.

5. Mineralocorticoid Receptor Antagonists

MRAs block aldosterone receptors in the distal nephron, promoting sodium excretion and potassium retention while attenuating fibrosis and remodeling via anti‑aldosterone pathways.

6. Loop Diuretics

Inhibitors of the Na⁺‑K⁺‑2Cl⁻ cotransporter in the thick ascending limb increase natriuresis and diuresis, thereby reducing volume overload and symptomatic congestion.

7. Digoxin

Digoxin inhibits Na⁺/K⁺‑ATPase, leading to an increase in intracellular calcium via the Na⁺/Ca²⁺ exchanger. This enhances contractility and, through vagal tone augmentation, slows conduction through the atrioventricular node, providing rate control in atrial fibrillation.

8. SGLT2 Inhibitors

These agents reduce glucose reabsorption in the proximal tubule, producing osmotic diuresis and natriuresis. The resulting hemodynamic shifts, along with metabolic effects, confer cardiovascular benefits, including reduced HF hospitalization.

Pharmacokinetics

1. ACE Inhibitors (e.g., Enalapril)

Absorption is rapid, with peak plasma concentrations occurring 1–2 h post‑dose. Oral bioavailability is approximately 30 % due to first‑pass metabolism. Distribution is extensive, with a volume of distribution of ~4 L/kg. Metabolized primarily by hepatic cytochrome P450 (CYP2C23) to an active metabolite. Excretion is mainly renal (~30 %), with a terminal half‑life of ~11 h. Renal impairment necessitates dose adjustment, particularly at creatinine clearance <30 mL/min.

2. Angiotensin Receptor Blockers (e.g., Losartan)

Losartan exhibits high oral bioavailability (~60 %). Peak plasma levels are reached within 2 h. Extensive hepatic metabolism via CYP2C9 and CYP3A4 generates an active 4-hydroxyl metabolite. Renal excretion accounts for ~30 % of elimination; thus, dose reduction is recommended when creatinine clearance <30 mL/min. The half‑life of the parent compound is ~2 h, but the active metabolite extends the overall effect to ~6–9 h.

3. Angiotensin Receptor–Neprilysin Inhibitors (e.g., Sacubitril/valsartan)

Sacubitril requires metabolic conversion to its active neprilysin inhibitor, LBQ657. Peak concentrations of LBQ657 occur 4–5 h after dosing. Valsartan has similar pharmacokinetics to losartan. Both agents are primarily renally cleared; hence, caution is advised in severe renal dysfunction. The combined half‑life is ~12 h.

4. Beta‑Blockers (e.g., Metoprolol)

Metoprolol is rapidly absorbed, with peak plasma levels at 1–2 h. Oral bioavailability ranges from 50–60 %. Metabolized by CYP2D6; thus, genetic polymorphisms influence clearance. Distribution is moderate, with a volume of distribution of ~3 L/kg. Renal excretion is minimal (<10 %). The half‑life is ~3–4 h, supporting once‑daily dosing for extended‑release formulations.

5. Mineralocorticoid Receptor Antagonists (e.g., Spironolactone)

Spironolactone is well absorbed orally, with peak concentrations at 2–4 h. Metabolized hepatically via CYP3A4 into active metabolites. Distribution is extensive; half‑life is prolonged (~24 h) due to active metabolites. Renal excretion accounts for ~30 % of elimination, necessitating dose adjustment in severe renal impairment.

6. Loop Diuretics (e.g., Furosemide)

Furosemide has variable oral bioavailability (~50 %) that increases with higher doses. Peak plasma levels occur within 30–60 min. The drug is highly protein‑bound (~90 %) and distributed in the intravascular and interstitial spaces. Metabolism is negligible; excretion is predominantly renal. The half‑life is short (~1 h), but diuretic effects persist longer due to tubular reabsorption inhibition.

7. Digoxin

Digoxin is absorbed slowly, with peak plasma concentrations at 4–6 h. Oral bioavailability is ~70 %. Distribution is extensive, with a volume of distribution of ~7 L/kg, reflecting cardiac tissue accumulation. Metabolized hepatically via CYP3A4; excretion is primarily renal (~90 %). The half‑life ranges from 36–48 h, necessitating careful monitoring of serum levels to avoid toxicity.

8. SGLT2 Inhibitors (e.g., Dapagliflozin)

Dapagliflozin demonstrates rapid absorption, with peak levels at ~1 h. Oral bioavailability is high (>90 %). Metabolized by CYP3A4, with renal excretion of unchanged drug and metabolites. The half‑life is ~12 h, permitting once‑daily dosing. Renal function influences efficacy; in patients with eGFR <30 mL/min, the antihyperglycemic effect diminishes, yet cardiovascular benefits may persist.

Therapeutic Uses/Clinical Applications

1. Heart Failure with Reduced Ejection Fraction (HFrEF)

First‑line therapy includes ACEi or ARB, β‑blocker, MRA, and loop diuretic for symptom control. ARNIs have replaced ACEi/ARB in patients who tolerate them. SGLT2 inhibitors are adjunctive, reducing hospitalizations and mortality regardless of glycemic status. Digoxin may be employed for rate control in atrial fibrillation or as a modest inotropic agent in advanced HF.

2. Heart Failure with Preserved Ejection Fraction (HFpEF)

Evidence supports the use of SGLT2 inhibitors and ARNI to improve symptoms and reduce hospitalization. Other agents, such as MRAs and diuretics, remain mainstays for volume management. Beta‑blockers are considered in patients with concomitant arrhythmias or ischemic disease.

3. Acute Decompensated Heart Failure (ADHF)

Loop diuretics are first-line for congestion relief. Inotropes (digoxin, dobutamine) may be reserved for low output states. Vasodilators (nitroglycerin, nesiritide) can be added for refractory hypertension or pulmonary edema. ARNI initiation is generally deferred until stabilization.

4. Atrial Fibrillation in Heart Failure

Rate control strategies include β‑blockers and digoxin. Rhythm control may involve antiarrhythmic agents, though efficacy is limited in advanced HF. Catheter ablation is increasingly considered in selected patients.

5. Chronic Kidney Disease (CKD) and HF

ACEi/ARB/ARNI initiation is beneficial in CKD patients with HF, but dose titration must consider eGFR and potassium levels. MRAs are particularly effective but carry hyperkalemia risk. Diuretics are tailored to fluid status and renal function.

6. Comorbid Diabetes Mellitus

SGLT2 inhibitors confer both glycemic control and HF benefits, making them attractive in diabetic HF patients. Dapagliflozin and empagliflozin are commonly prescribed.

Adverse Effects

1. ACE Inhibitors

Common: cough, hyperkalemia, hypotension, angioedema (rare). Renal dysfunction may precipitate acute kidney injury.

2. Angiotensin Receptor Blockers

Common: dizziness, hyperkalemia, hypotension. Angioedema is less frequent than with ACEi.

3. Angiotensin Receptor–Neprilysin Inhibitors

Elevated risk of hypotension, syncope, hyperkalemia, and renal impairment. Angioedema risk is comparable to ARB alone, but monitoring is essential.

4. Beta‑Blockers

Hypotension, bradycardia, fatigue, dyspnea, and potential exacerbation of COPD. New‑onset or worsening depression has been reported.

5. Mineralocorticoid Receptor Antagonists

Hyperkalemia, gynecomastia (spironolactone), menstrual irregularities, and renal dysfunction.

6. Loop Diuretics

Electrolyte disturbances (hypokalemia, hyponatremia), dehydration, ototoxicity (high doses), and potential for hypotension.

7. Digoxin

Arrhythmias, GI upset, visual disturbances (yellow‑tinted vision), and neurotoxicity at high levels. Concomitant use of drugs that prolong the QT interval increases risk.

8. SGLT2 Inhibitors

Genital mycotic infections, genital pruritus, volume depletion, and rare ketoacidosis. Lower incidence of hypoglycemia.

9. Endothelin Receptor Antagonists

Fluid retention, liver enzyme elevations, and hypotension.

10. PDE‑5 Inhibitors

Headache, flushing, dyspepsia, visual disturbances, and rare priapism. Concomitant use with nitrates is contraindicated.

Drug Interactions

1. ACE Inhibitors, ARBs, ARNIs

Concurrent use with potassium‑sparing diuretics, NSAIDs, or high‑dose potassium supplements can precipitate hyperkalemia. NSAIDs may reduce renal perfusion and attenuate antihypertensive effects.

2. Beta‑Blockers

Co‑administration with calcium channel blockers (especially verapamil, diltiazem) can amplify bradycardia or hypotension. CYP2D6 inhibitors (e.g., fluoxetine) increase β‑blocker plasma concentrations, raising toxicity risk.

3. Mineralocorticoid Receptor Antagonists

Combination with ACEi/ARB/ARNI amplifies hyperkalemia risk. Concomitant use of potassium‑sparing diuretics further elevates this risk.

4. Loop Diuretics

High‑dose furosemide may potentiate the hypotensive effect of ACEi/ARB. Interaction with digoxin can increase digoxin serum levels by reducing renal clearance.

5. Digoxin

Drugs that inhibit P-glycoprotein (e.g., ketoconazole) or CYP3A4 (e.g., clarithromycin) increase digoxin levels. NSAIDs may reduce renal clearance, raising toxicity risk.

6. SGLT2 Inhibitors

Volume‑depleting agents (diuretics) may augment hypotension. Renally excreted drugs may have altered clearance due to enhanced diuresis.

7. Endothelin Receptor Antagonists

Co‑administration with drugs metabolized via CYP3A4 may cause increased plasma concentrations and toxicity.

8. PDE‑5 Inhibitors

Interaction with nitrates produces severe hypotension; thus, concurrent use is contraindicated.

Special Considerations

1. Pregnancy and Lactation

ACEi, ARBs, ARNIs, and MRAs are contraindicated in pregnancy due to teratogenicity (renal dysgenesis, oligohydramnios). β‑blockers are category C; low‑dose therapy may be considered when benefits outweigh risks. Loop diuretics are category C but can be used for volume overload. Digoxin is category B but monitoring is advised. SGLT2 inhibitors are not recommended during pregnancy or lactation due to insufficient data.

2. Pediatric Considerations

Evidence for many HF agents in children remains limited. ACEi and β‑blockers are used cautiously, with dosing based on weight and age. Loop diuretics are common for symptom relief. SGLT2 inhibitors lack sufficient pediatric data; thus, use is not recommended.

3. Geriatric Patients

Polypharmacy increases interaction risk. Dose adjustments for renal impairment and careful monitoring of blood pressure and potassium are essential. Cognitive function may impact adherence; simplified regimens are advantageous.

4. Renal Impairment

ACEi/ARB/ARNI initiation should be cautious, with dose titration and monitoring of serum creatinine and potassium. MRAs carry higher hyperkalemia risk; thus, conservative dosing is mandated. Loop diuretics remain effective but may necessitate higher doses to overcome diuretic resistance. SGLT2 inhibitors retain cardiovascular benefits even at eGFR 30–45 mL/min, yet efficacy decreases below 30 mL/min.

5. Hepatic Impairment

ACEi and β‑blocker metabolism may be altered in hepatic disease; monitoring for hypotension and bradycardia is advised. MRAs are hepatically metabolized; caution is needed in cirrhosis. SGLT2 inhibitors are minimally hepatically metabolized; thus, they are generally well tolerated.

Summary/Key Points

• Neurohormonal modulation with ACEi/ARB/ARNI, β‑blockers, and MRAs remains foundational for HFrEF, reducing mortality and remodeling.
• Loop diuretics effectively alleviate congestion but do not impact survival; dose adjustments must account for renal function and electrolyte balance.
• Digoxin provides modest inotropy and rate control; careful monitoring of serum levels mitigates toxicity.
• SGLT2 inhibitors have emerged as first‑line adjuncts for both HFrEF and HFpEF, offering reductions in hospitalization independent of glycemic control.
• Drug interactions are frequent; awareness of renal and hepatic metabolism, as well as pharmacodynamic overlaps, is essential to prevent adverse events.
• Special populations—pregnancy, pediatrics, geriatrics—require tailored dosing, vigilant monitoring, and sometimes alternative therapies.
• Ongoing clinical trials continue to refine the pharmacologic armamentarium; emerging agents such as endothelin receptor antagonists and novel neprilysin inhibitors may further expand therapeutic options.

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