Congestive heart failure positive inotropics

Positive inotropes are agents that increase myocardial contractility, and are used to support cardiac function in conditions such as decompensated congestive heart failure, cardiogenic shock, septic shock, myocardial infarction, cardiomyopathy, etc. Examples of positive inotropes include digoxin, dobutamine, dopamine and phosphodiesterase-III inhibitors like amrinone and milrinone.

1. Agents that increase intracellular cAMP
   • Alpha-adrenergic agonists
   • Phosphodiesterase inhibitors
2. Agents that affect sarcolemmal ion pumps/channels
   • Digoxin
3. Agents that modulate intracellular calcium mechanisms by either:
   • Release of sarcoplasmic reticulum calcium (IP3)
   • Increased sensitization of the contractile proteins to calcium
4. Drugs having multiple mechanisms of action
   • Pimobendan
   • Vesnarinone

• Inhibits Na,K+-ATPase resulting in an increase in intracellular Na+, extracellular Ca2+ exchange increasing the velocity and extent of sarcomere shortening.
• ACC/AHA recommend digoxin for symptomatic patients with left ventricular systolic dysfunction.
• Commonly used in patients with heart failure and atrial fibrillation to reduce the ventricular response rate.
• Mortality has not been shown to be improved with use of digoxin^[1], but the use of digoxin has been associated with a reduction in hospitalization in the RALES study.
• There is no need to load a CHF patient with digoxin. For the majority of patients with normal renal function, a daily dose of 0.25 mg of digoxin is usually adequate. In the older patient or in those patients with renal impairment, a dose of 0.125 mg per day may be adequate.
• Drugs that increase the concentration of digoxin include antibiotics and anticholinergic agents as well as amiodarone, quinidine and verapamil.
• In the RALES study, a level of < 1 ng/ml was associated with efficacy. Levels above 1 ng/ml were not associated with greater efficacy and were associated with higher mortality.

• Activates beta-1 receptors resulting in enhanced cardiac contractility.
• Long-term dobutamine infusions are arrhythmogenic and increase mortality.
• Dobutamine also slightly reduces afterload

Dopamine is associated with a dose dependent mechanism of action:

• At low doses: (≤2 µg/kg/min), selectively dilate splanchnic and renal arterial beds and increase renal perfusion.
• At intermediate doses: (2 to 10 µg/kg/min), increase norepinephrine secretion and result in increased cardiac contractility, heart rate and systemic vascular resistance.
• At higher doses: (5 to 20 µg/kg/min), result in direct alpha-adrenergic receptor stimulation and increases systemic vascular resistance.

• Phosphodiesterase-III inhibitor that enhances cardiac contractility by increasing intracellular cyclic adenosine monophosphate (cAMP).
• Potent pulmonary vasodilator that may benefit some patients with pulmonary hypertension.
• Unlike dobutamine, milrinone is beneficial in decompensated heart failure patients who are on beta-blocker therapy.
• Long term milrinone infusions are arrhythmogenic, and increase mortality.

• 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines^[4]

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