Heart Failure Pharmacology

🫀 Heart Failure — Pathophysiology

Syndrome of impaired ventricular filling or ejection
Two primary phenotypes:
- Systolic dysfunction (reduced ejection fraction, HFrEF)
- Diastolic dysfunction (preserved ejection fraction, HFpEF)
Most common etiology: left systolic dysfunction secondary to coronary artery disease

Pathophysiological cascade:
↓ Cardiac output → Neurohormonal activation (RAAS, SNS) → ↑ Preload & afterload → Maladaptive remodeling
Remodeling: myocardial fibrosis, chamber dilation, loss of contractile units
RAAS and SNS activation drive progressive dysfunction

HFrEF

HFpEF

Therapeutic goals:
- ↓ Preload → diuretics, ACEIs, ARBs, venodilators
- ↓ Afterload → ACEIs, ARBs, arteriodilators
- ↑ Contractility → digoxin, β-agonists, PDE III inhibitors
- ↓ Remodeling → ACEIs, ARBs, spironolactone, β-blockers

Drug Class	Mechanism	Role in CHF
ACE Inhibitors	↓ Angiotensin II	First-line chronic therapy; ↓ preload, afterload, remodeling
ARBs	Block AT1 receptors	Alternative to ACEIs; same benefits
β-Blockers (metoprolol, bisoprolol, carvedilol)	↓ SNS activity	Antiarrhythmic; ↓ remodeling; improve survival
Loop / Thiazide diuretics	↓ Na⁺ reabsorption	↓ Preload; symptom relief
Spironolactone / Eplerenone	Aldosterone receptor blockade	↓ Remodeling; advanced CHF
Hydralazine + Isosorbide dinitrate	Arterial + venous dilation	Chronic therapy when ACEI/ARB not tolerated

Three major classes of positive inotropes:
- Cardiac glycosides (digoxin)
- β-adrenergic agonists (dobutamine, dopamine)
- Phosphodiesterase III inhibitors (inamrinone, milrinone)

Drug	Mechanism	Use	Key feature
Digoxin	Na⁺/K⁺-ATPase inhibitor → ↑ intracellular Ca²⁺	Chronic CHF; supraventricular tachycardias	Positive inotrope + vagal effect
Dobutamine	β₁ agonist → ↑ cAMP → ↑ Ca²⁺	Acute CHF	Selective β₁; less vasodilation
Dopamine	Dopamine + β₁ + α agonist (dose-dependent)	Acute CHF with hypotension	Pressor at high doses
Inamrinone / Milrinone	PDE III inhibition → ↑ cAMP	Acute CHF	↑ Inotropy + ↓ TPR

PDE III inhibitors:
- ↑ cAMP in cardiac myocytes → ↑ contractility
- ↑ cAMP in vascular smooth muscle → ↓ total peripheral resistance
- Use limited to acute settings due to arrhythmia risk and mortality concerns
Sympathomimetics (dobutamine, dopamine):
- Activate β₁ receptors → ↑ cAMP → ↑ intracellular Ca²⁺
- Dobutamine: relatively β₁-selective; mild vasodilation
- Dopamine: dose-dependent effects (low dose: dopaminergic; moderate: β₁; high: α)
- Both used for acute CHF with hemodynamic compromise

                        Inotropes increase myocardial oxygen demand — use with caution in ischemic heart disease

                    

Direct effect:
Inhibit Na⁺/K⁺-ATPase → ↑ Intracellular Na⁺ → ↓ Na⁺/Ca²⁺ exchange → ↑ Intracellular Ca²⁺ → ↑ SR Ca²⁺ release → ↑ Actin-myosin interaction → ↑ contractility
Indirect effect:
- Inhibits neuronal Na⁺/K⁺-ATPase
- ↑ Vagal tone → ↓ AV conduction, ↓ heart rate

Pharmacokinetics

Clinical uses

Toxicity — early signs:
- Anorexia, nausea, vomiting
- ECG changes (ST-segment depression, T-wave inversion, prolonged PR)
Toxicity — late signs:
- Disorientation, confusion
- Visual disturbances (yellow-green halos, blurring)
- Any cardiac arrhythmia (especially ventricular ectopy, bradyarrhythmias)

Digoxin toxicity management: Fab antibody fragments (digoxin immune Fab) are specific antidote
Supportive therapy: correct electrolytes (K⁺, Mg²⁺); class IB antiarrhythmics for arrhythmias

Drug interactions:
- Diuretics: ↓ K⁺, ↓ Mg²⁺, ↑ Ca²⁺ → ↑ risk of toxicity
- Quinidine and verapamil: displace digoxin from tissue binding → ↑ serum levels

Sacubitril — neprilysin inhibitor
- Neprilysin degrades atrial and brain natriuretic peptides (ANP, BNP)
- Inhibition → ↑ ANP/BNP → ↓ blood volume, ↓ blood pressure
- Also inhibits bradykinin metabolism (contributes to side effects)
- Used in combination with valsartan (ARB) as ARNI
- Indicated for CHF with reduced ejection fraction (HFrEF)
- Side effects: hypotension, cough, angioedema (bradykinin-mediated)

Ivabradine — funny channel (I_f) blocker
- I_f channels regulate SA node automaticity (diastolic depolarization)
- ↓ Slope of diastolic depolarization → ↓ heart rate
- No direct effect on contractility or intracardiac conduction
- Indicated for chronic HFrEF patients with:
  - LVEF ≤ 35%
  - Sinus rhythm
  - Resting heart rate ≥ 70 bpm
  - Despite maximum tolerated β-blocker dose
- Side effects: bradycardia, blurred vision, ↑ risk of atrial fibrillation

                        ARNI (sacubitril/valsartan) has shown superior outcomes compared to ACEI alone in HFrEF

                    

Exam traps

Digoxin is NOT first-line for chronic CHF — ACEIs/ARBs are
Digoxin DOES NOT improve survival (unlike ACEIs, ARBs, β-blockers, spironolactone)
Inotropes (dobutamine, milrinone) are for ACUTE CHF, not chronic
Wolff-Parkinson-White syndrome: avoid digoxin, β-blockers, CCBs, adenosine — block accessory pathway with class IA or III agents

Clinical reasoning

Diastolic dysfunction (HFpEF) responds best to β-blockers + diuretics
Systolic dysfunction (HFrEF) benefits from ACEIs/ARBs, β-blockers, aldosterone antagonists, and ARNI
Hydralazine + isosorbide dinitrate is preferred when ACEI/ARB not tolerated

Remodeling reduction is a key therapeutic goal:
- ACEIs / ARBs
- Spironolactone / eplerenone
- β-blockers (metoprolol, bisoprolol, carvedilol)
Loop diuretics are used for volume overload — monitor electrolytes closely

Ivabradine is only for patients in sinus rhythm with HR ≥ 70 bpm despite β-blocker therapy
Sacubitril is contraindicated with concurrent ACEI use (risk of angioedema) — washout period required