Learning Objective

By the end of this section, learners should be able to explain the mechanisms of action, pharmacokinetics, therapeutic uses, adverse effects, and drug interactions of positive inotropic agents used in the management of heart failure.

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Positive Inotropic Agents

Positive inotropes are drugs that increase myocardial contractility and are primarily used in patients with heart failure to improve cardiac output.

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Digoxin

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Mechanism of Action

Direct Effects:

• Inhibits cardiac Na⁺/K⁺-ATPase
  • Leads to ↑ intracellular Na⁺
  • Decreases the activity of Na⁺/Ca²⁺ exchanger
  • Results in ↑ intracellular Ca²⁺
  • Enhances Ca²⁺ release from the sarcoplasmic reticulum
  • Increases actin–myosin interaction
  • Produces increased myocardial contractile force (positive inotropic effect)

Indirect Effects:

• Inhibits neuronal Na⁺/K⁺-ATPase
• Leads to ↑ vagal (parasympathetic) tone
• Results in decreased heart rate and slowed AV nodal conduction

Pharmacokinetics

• Primarily eliminated via renal clearance → use caution in renal impairment
• Long half-life → requires a loading dose
• Large volume of distribution due to tissue protein binding
  • Can be displaced by drugs such as:
    • Verapamil
    • Quinidine

Therapeutic Uses

• Chronic heart failure (CHF)
• Supraventricular tachycardias
  • Contraindicated in Wolff–Parkinson–White syndrome

Adverse Effects

Early Signs

• Anorexia
• Nausea
• Electrocardiographic changes

Late Signs

• Confusion or disorientation
• Visual disturbances
  • Yellow-green discoloration
  • Blurred vision

Toxicity:

• Can produce virtually any type of cardiac arrhythmia

Management of Toxicity

• Administration of digoxin-specific Fab antibody fragments
• Supportive therapy:
• Correction of electrolyte abnormalities
• Class IB antiarrhythmic agents, if needed

Drug Interactions

• Diuretics:
  • ↓ Potassium
  • ↓ Magnesium
  • ↑ Calcium
    → Increase risk of digoxin toxicity
• Quinidine
• Verapamil

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Activity

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Phosphodiesterase III Inhibitors

• (e.g., Inamrinone, Milrinone)
• Used in acute heart failure only
• Increase cAMP in cardiac muscle → ↑ myocardial contractility
• Increase cAMP in vascular smooth muscle → ↓ total peripheral resistance

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Activity

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Sympathomimetic Agents

• (e.g., Dobutamine, Dopamine)
• Used in acute heart failure only
• Stimulate β₁-adrenergic receptors
• Increase myocardial contractility and cardiac output

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