CJ

Agents for Treating Heart Failure - Chapter 44

HFrEF Stage C Treatment (Guidelines)

  • Foundation therapy: ARNI/ACEI/ARB (ARNI preferred) AND an evidence-based beta-blocker AND a diuretic agent as needed. This combination targets afterload, preload, heart-rate control, and volume status to improve symptoms and outcomes.
  • Patient-specific criteria guiding add-on therapies (based on transcript):
    • For patients with criteria related to kidney function, creatinine, potassium, and NYHA Class II–IV: add on therapies as appropriate
    • For patients with persistent volume overload (NYHA Class II–IV): consider additional preload-reducing therapies
    • For persistently symptomatic Black patients despite ARNI + beta-blocker + aldosterone antagonist + SGLT2 inhibitor: add hydralazine + isosorbide dinitrate
    • For patients with resting heart rate criteria (on maximally tolerated beta-blocker in sinus rhythm; NYHA Class II–III): add ivabradine
  • Add-on therapies (per above): Aldosterone antagonist, SGLT2 inhibitor, Diuretic agent, Hydralazine + isosorbide dinitrate, Ivabradine
  • Notes on interpretation: Certain numerical thresholds in the transcript appear garbled (e.g., eGFR and creatinine values). The core idea is to tailor additions based on renal function, electrolytes, and functional class (NYHA). See individual drug sections for exact indications, monitoring, and safety.

Cardiotonic Agents: Overview

  • Function: Increase cardiac output and renal perfusion; increase urine output.
  • Also called inotropic drugs: increase the force of contraction by affecting intracellular calcium in cardiac muscle.
  • Two major classes used clinically:
    • Cardiac glycosides (e.g., digoxin)
    • Phosphodiesterase inhibitors (e.g., milrinone)
  • Used to augment cardiac performance in heart failure under specific circumstances (often short-term inotropy in decompensated states or as adjuncts in chronic HF when other therapies are optimized).

Cardiac Glycoside: Digoxin (Lanoxin)

  • Mechanism of action: Increases intracellular calcium in cardiomyocytes, which increases force of contraction (positive inotropy).
  • Hemodynamics:
    • Increases cardiac output
    • Increases renal perfusion
    • Slows heart rate
    • Decreases conduction velocity through the AV node
  • Net effect: Increases cardiac output to relieve HF symptoms in some patients.
  • Indications: Heart failure (HF) with reduced ejection fraction (HFrEF), atrial flutter (A-Flutter), atrial fibrillation (A-Fib), paroxysmal atrial tachycardia.

Digoxin: Pharmacokinetics and Dosing Considerations

  • Onset: Rapid onset of action with rapid absorption.
  • Loading dose: May be used if rapid effects are needed for the initial dose.
  • Elimination: Excreted unchanged in the urine.
  • Renal impairment: Caution due to reduced clearance and increased toxicity risk.
  • Therapeutic window: VERY narrow; high risk of toxicity. Easy to reach toxic levels.
  • Monitoring focus: Ensure proper dosing, renal function, electrolyte balance, and drug interactions.

Digoxin: Toxicity and Safety Considerations

  • Normal therapeutic digoxin level: 0.5 \,\le\, C_{digoxin} \,\le\, 2.0\ \text{ng/mL}
  • Common toxicity signs: Anorexia, nausea/vomiting, malaise, depression, irregular heart rhythms (atrial, ventricular, or blocks).
  • Serious risk: Potentially life-threatening arrhythmias, especially with electrolyte disturbances (e.g., hypokalemia, hypomagnesemia) or renal impairment.
  • Antidote: Digoxin Immune Fab (the antidote).
  • Key clinical caveats: Digoxin has a very narrow therapeutic range and requires careful monitoring and dose adjustment in response to renal function and electrolyte status.

Digoxin: Practical Point-of-Course Management

  • Important monitoring: Check apical pulse for 1 full minute before administration.
    • Hold if pulse < 60 bpm (adult); recheck in 1 hour; if still low, document, hold, call physician.
  • Dosing accuracy: Check dose and preparation carefully due to small margins of safety.
  • Dosing schedule: Administer at the same time each day.
  • Intravenous administration: If IV, infuse slowly over at least 5 minutes.
  • Therapeutic level checks: Obtain digoxin level as ordered; target range 0.5 \le C_{digoxin} \le 2\ \text{ng/mL}.
  • Weight monitoring: Weigh patient daily and monitor for side effects (toxic effects if any).
  • Drug interactions/absorption: Avoid administering PO digoxin with foods or antacids that can affect absorption.

Phosphodiesterase Inhibitors: Milrinone

  • Mechanism: Blocks phosphodiesterase (PDE3), which normally breaks down cyclic AMP (cAMP).
    • With PDE inhibition, intracellular calcium rises in cardiomyocytes, leading to stronger contractions and improved inotropy.
  • Pharmacodynamics: ↑ Contractility and ↑ renal perfusion via increased CO; can cause prolonged sympathetic stimulation.
  • Indication: Short-term treatment of HF not responding to digoxin or diuretics alone, or in cases with poor response to digoxin, diuretics, and vasodilators.
  • Risks: May lead to fatal ventricular arrhythmias; limit use to severe, refractory situations.

Milrinone: Safety and Interactions

  • Side effects/adverse effects:
    • Ventricular arrhythmias (potentially fatal)
    • Hypotension
    • Chest pain
    • GI effects
    • Thrombocytopenia
    • Hypersensitivity reactions
  • Drug interactions: Furosemide (Lasix) can precipitate when mixed; administer at different sites.

Hyperpolarization-activated Cyclic Nucleotide–gated (HCN) Blocker: Ivabradine (Corlanor)

  • Mechanism: HCN channels regulate pacemaker activity in the heart (SA node). Ivabradine slows the heart rate by inhibiting the pacemaker current (If) without affecting myocardial contractility.
  • Clinical effect: Slows heart rate, which can improve cardiac output and may reduce hospitalization for worsening chronic HF.

Ivabradine: Safety, Side Effects, and Contraindications

  • Common side effects/adverse effects:
    • Bradycardia
    • Hypertension
    • Atrial fibrillation
    • Luminous phenomena (visual changes such as brightness, halos, or multiple images due to retinal effects)
  • Important safety points:
    • Monitor vision and perform regular eye checks as indicated by symptoms
    • Contraindications/precautions:
    • Not recommended if pacemaker-dependent
    • Caution with liver impairment
    • Contraindicated with use of a strong CYP3A4 inhibitor (P450 drug) due to drug interactions

Angiotensin Receptor Neprilysin Inhibitor (ARNI): Entresto

  • Brand/generic: Entresto; combination of valsartan (ARB) and sacubitril (neprilysin inhibitor).
  • Mechanism of action:
    • Neprilysin degrades natriuretic peptides; inhibiting neprilysin increases natriuretic peptide activity, promoting diuresis, natriuresis, and vasodilation.
    • Combined with ARB to reduce cardiac workload, lower vascular volume, and lower blood pressure.
  • Clinical effect: Enhanced diuresis and vasodilation with reduced afterload and preload, improving HF symptoms and outcomes.

ARN I: Side Effects and Monitoring

  • Side effects/adverse effects:
    • Hypotension
    • Hyperkalemia
    • Cough
    • Dizziness
    • Renal impairment
  • Monitoring focus:
    • I&O (intake and output)
    • Weight management (fluid status)
    • Electrolytes, especially potassium (K⁺)

Congestive Heart Failure – The Donkey Analogy

  • Concept: Decompensated CHF occurs when cardiac output cannot meet body demands.
  • Pathophysiology highlights:
    • Preload is increased due to fluid and sodium retention.
    • Afterload is increased due to sympathetic nervous system activation and vasoconstriction.
  • Pharmacologic strategies and their targets:
    • ACE inhibitors/ARBs: Reduce afterload and preload by blocking angiotensin/aldosterone pathways.
    • Loop diuretics: Reduce preload by decreasing fluid and sodium retention.
    • Hydralazine/Nitrates: Reduce afterload and preload by opposing vasoconstriction and promoting venodilation.
    • Beta-blockers: Inhibit negative remodeling driven by chronic sympathetic activation.
    • Inotropes (digoxin, dobutamine, milrinone): Increase contractility and cardiac output when needed.
  • Practical takeaways (as conceptual guidelines):
    • Balance preload, afterload, and contractility to optimize cardiac output.
    • Use vasodilators to reduce cardiac workload and congestion.
    • Use inotropes selectively to support contractility in decompensation.
  • Fun mnemonic in the lecture: SPEED LIMIT 35 MINIMUM 15 (contextual in the donkey analogy; relates to speed and thresholds for therapy or progression—note: exact interpretation is not explicit in the transcript).

Connections to Core Principles and Real-world Relevance

  • Heart failure management hinges on a combination of preload/afterload reduction, neurohormonal blockade, and, when needed, inotropic support.
  • Pharmacologic classes align with disease pathophysiology:
    • RAAS blockade (ACEI/ARB/ARNI) reduces maladaptive remodeling and fluid retention.
    • Neprilysin inhibition augments endogenous natriuretic peptides, enhancing vasodilation and natriuresis.
    • Beta-blockers mitigate adverse remodeling from sympathetic overactivity.
    • SGLT2 inhibitors provide renal and cardiometabolic benefits beyond glucose lowering.
    • Diuretics address symptomatic congestion via volume reduction.
    • Hydralazine+isosorbide dinitrate offers an evidence-based option for Black patients or those needing additional afterload/ preload relief.
    • Ivabradine targets heart rate to optimize diastolic filling and reduce myocardial oxygen demand when resting HR remains elevated on beta-blockers.
    • Digoxin and milrinone offer inotropic support in specific scenarios (chronic symptom relief vs. acute decompensation).

Formulas and Key Numerical References (LaTeX)

  • Digoxin therapeutic range: 0.5 \le C_{\text{digoxin}} \le 2.0\ \text{ng/mL}
  • Digoxin mechanism: increase intracellular Ca^{2+} to increase contractility (no explicit numeric formula given in the transcript, but mechanism is calcium-mediated).
  • Milrinone action: increases intracellular cAMP by PDE3 inhibition (no explicit numerical formula in transcript).
  • Therapeutic and safety notes are largely clinical thresholds (e.g., HR cutoffs for holding digoxin, dosing times, IV infusion duration) rather than mathematical equations.

Quick Reference: Definitions and Acronyms

  • HFrEF: Heart Failure with reduced ejection fraction
  • NYHA: New York Heart Association functional class (II–IV referenced in guidelines)
  • ARNI: Angiotensin receptor neprilysin inhibitor (sacubitril/valsartan in Entresto)
  • ARB: Angiotensin II receptor blocker
  • ACEI: Angiotensin-converting enzyme inhibitor
  • SGLT2 inhibitor: Sodium-glucose co-transporter 2 inhibitor (e.g., empagliflozin, dapagliflozin)
  • Va/Isosorbide dinitrate: Vasodilator combination used in select HF patients
  • Ivabradine: HCN channel blocker that reduces heart rate without reducing contractility
  • Milrinone: PDE3 inhibitor providing inotropic support
  • Digoxin: Cardiac glycoside inotrop/chronotropic agent

Note on Transcript Anomalies

  • Some numeric values in the transcript appear garbled (e.g., “eGFR 230 mL/min/1.73 m²” and “resting HR 270”). These are likely transcription errors. The intended concepts concern renal function thresholds, electrolyte limits, and HR targets guiding add-on therapies. When studying, cross-reference with current HF guidelines (e.g., ACC/AHA) and product labeling for precise values.