Inotropes

• Principle: Positive inotropes are drugs that increase myocardial contractility (inotropy). The primary mechanism is by increasing intracellular calcium (Ca²⁺) concentration or increasing the myofilaments’ sensitivity to Ca²⁺. They are used in acute settings like cardiogenic shock and decompensated heart failure to improve cardiac output.

Catecholamines & Sympathomimetics

These agents act on adrenergic receptors. The main goal in shock is to improve cardiac output and maintain mean arterial pressure (MAP) for organ perfusion.

• Dobutamine
  • MoA: Primarily a β₁ agonist > β₂, α₁. This increases contractility and heart rate. β₂ agonism leads to mild vasodilation, decreasing afterload.
  • Clinical Use: Cardiogenic shock and acute decompensated heart failure where increased contractility is needed without significant vasoconstriction. Used in pharmacologic stress tests.
  • Key Side Effects: Tachyarrhythmias, can worsen hypotension in some cases, increases myocardial O₂ demand which may induce ischemia.
• Dopamine
  • MoA: Effects are dose-dependent:
    • Low dose (1-3 mcg/kg/min): Acts on D₁ receptors in the kidney, causing renal vasodilation.
    • Medium dose (3-10 mcg/kg/min): Acts on β₁ receptors in the heart, increasing contractility and HR (inotropic effect).
    • High dose (>10 mcg/kg/min): Acts on α₁ receptors, causing systemic vasoconstriction and increasing blood pressure.
  • Clinical Use: Used in cardiogenic or septic shock, particularly when both inotropic support and vasoconstriction are required. Often used for symptomatic bradycardia.
  • Key Side Effects: Tachyarrhythmias are common. High doses can cause excessive vasoconstriction, leading to ischemia.
• Epinephrine & Norepinephrine
  • Epinephrine: Potent β₁, β₂, and α₁ agonist. Increases contractility, HR, and causes vasoconstriction. Used in anaphylactic shock and cardiac arrest.
  • Norepinephrine: Primarily an α₁ > β₁ agonist. It is mainly a vasopressor but has modest inotropic effects. First-line agent for most types of shock, especially septic shock.

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Phosphodiesterase-3 (PDE-3) Inhibitors

• Milrinone
  • MoA: Selectively inhibits PDE-3, preventing the breakdown of cAMP in cardiac and smooth muscle cells.
  • Effect: Increased intracellular cAMP leads to ↑ Ca²⁺ influx in the heart (↑ inotropy) and smooth muscle relaxation (vasodilation). Often called an “inodilator”.
  • Clinical Use: Acute decompensated heart failure, especially for patients on chronic β-blocker therapy (as its mechanism bypasses the β-receptor). Use is limited in hypotensive patients due to its vasodilatory effects.
  • Key Side Effects: Hypotension, tachyarrhythmias, and potential for increased mortality with long-term use.

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Cardiac Glycosides

• Digoxin
  • MoA: Has two primary mechanisms:
    1. Inotropy: Directly inhibits the Na⁺/K⁺-ATPase pump in cardiomyocytes. This leads to ↑ intracellular Na⁺, which reduces the activity of the Na⁺/Ca²⁺ exchanger, ultimately causing ↑ intracellular Ca²⁺ and increased contractility.
    2. Chronotropy: Increases vagal (parasympathetic) tone, which slows conduction at the AV node and decreases the heart rate.
  • Clinical Use:
    • Heart Failure with Reduced EF (HFrEF): Used for symptomatic improvement but does not improve mortality.
    • Atrial Fibrillation: For rate control, due to its effect on the AV node.
  • Toxicity (High-Yield):
    • Narrow therapeutic window.
    • Triggers: Hypokalemia is a major risk factor as K⁺ and digoxin compete for the same binding site on the Na⁺/K⁺ pump. Renal failure also increases risk.
    • Symptoms: GI distress (nausea, vomiting), neurologic symptoms (confusion), and classic blurry yellow vision (xanthopsia).
    • ECG: “Scooped” ST segments (digitalis effect), AV block, and various arrhythmias (especially atrial tachycardia with block).
    • Labs: Toxicity can cause hyperkalemia; the degree of elevation correlates with mortality.
    • Antidote: Anti-digoxin Fab fragments (DigiFab).

Feature	Dobutamine / Milrinone	Digoxin
Mechanism	↑ cAMP → ↑ Contractility & Vasodilation (Milrinone)	Na+/K+-ATPase inhibitor → ↑ Contractility; ↑ Vagal tone
Heart Rate	↑ (Dobutamine) or Neutral	↓
Afterload	↓	No significant effect
Primary Use	Acute Decompensated HF; Cardiogenic Shock (IV)	Chronic Systolic HF (symptoms); A-Fib Rate Control (PO)
Key Adverse Effects	Arrhythmias, Hypotension (esp. Milrinone)	GI distress, Yellow vision, AV block, Arrhythmia
Toxicity Antidote	Supportive care (short half-life)	Digoxin-specific Ab fragments (DigiFab)

Comparison of IV Inotropes

Agent	Contractility (β1)	Heart Rate (β1)	SVR (α1/β2)	Primary Use Case
Dobutamine	+++	+	↓	Cardiogenic shock (“cold & wet” HF)
Dopamine	++ (med dose)	++ (med dose)	↑↑ (high dose)	Shock with bradycardia/hypotension
Milrinone	++	+	↓↓	ADHF on β-blockers, RV failure