Inotropic agents

1. Definition

• Inotropic agents are drugs that alter the force or energy of myocardial contraction.

• Positive inotropes – increase contractility, used in heart failure, cardiogenic shock, or certain arrhythmias.

• Negative inotropes – decrease contractility, used in conditions like hypertrophic cardiomyopathy or to reduce myocardial oxygen demand.

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2. Classification

A. Positive Inotropic Agents

• Cardiac glycosides – e.g., digoxin, digitoxin.

• Sympathomimetic amines – e.g., dobutamine, dopamine, norepinephrine, epinephrine, isoproterenol.

• Phosphodiesterase III (PDE3) inhibitors – e.g., milrinone, inamrinone.

• Calcium sensitizers – e.g., levosimendan.

• Glucagon – in β-blocker overdose.

B. Negative Inotropic Agents

• Beta-adrenergic blockers – e.g., propranolol, metoprolol.

• Calcium channel blockers (non-dihydropyridines) – e.g., verapamil, diltiazem.

• Antiarrhythmics with negative inotropy – e.g., disopyramide.

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3. Mechanisms of Action

Positive Inotropes

• Increase intracellular calcium availability → stronger myocardial contraction.

• Mechanisms include:

  • β1-receptor stimulation → increased cAMP → increased Ca²⁺ influx.

  • PDE3 inhibition → reduced cAMP breakdown → increased Ca²⁺.

  • Na⁺/K⁺-ATPase inhibition (cardiac glycosides) → increased intracellular Na⁺ → decreased Ca²⁺ extrusion via Na⁺/Ca²⁺ exchanger.

  • Calcium sensitization – increases myofilament responsiveness to Ca²⁺ without increasing intracellular calcium.

Negative Inotropes

• Reduce intracellular calcium availability or myofilament responsiveness.

• Examples: β-blockers (decrease cAMP), non-dihydropyridine calcium channel blockers (reduce Ca²⁺ influx).

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4. Pharmacokinetics (varies by agent)

Cardiac Glycosides (e.g., digoxin)

• Oral and IV forms; narrow therapeutic index; primarily renal excretion.

Sympathomimetic Amines

• IV infusion only; rapid onset; short half-life; metabolized by COMT and MAO.

PDE3 Inhibitors

• IV infusion; onset within minutes; renal elimination.

Calcium Sensitizers

• IV infusion; active metabolites with prolonged effect.

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5. Clinical Indications

Positive Inotropes

• Acute decompensated heart failure with low output.

• Cardiogenic shock.

• Low cardiac output states post-cardiac surgery.

• Certain arrhythmias (e.g., digoxin for rate control in atrial fibrillation with HF).

Negative Inotropes

• Hypertrophic obstructive cardiomyopathy.

• Angina pectoris.

• Certain tachyarrhythmias (rate control).

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6. Contraindications

Positive Inotropes

• Obstructive hypertrophic cardiomyopathy (may worsen obstruction).

• Uncontrolled arrhythmias (can exacerbate).

Negative Inotropes

• Severe systolic heart failure (may worsen contractility).

• Significant bradycardia or AV block.

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7. Adverse Effects

Positive Inotropes

• Arrhythmias (ventricular and supraventricular).

• Myocardial ischemia (due to increased oxygen demand).

• Hypotension (especially with PDE3 inhibitors).

• Digoxin-specific: nausea, vomiting, visual disturbances, confusion, toxicity risk.

Negative Inotropes

• Bradycardia.

• Hypotension.

• Worsening of heart failure in reduced ejection fraction.

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8. Drug Interactions

Positive Inotropes

• Digoxin:

  • Increased toxicity risk with hypokalemia (e.g., diuretics).

  • P-glycoprotein inhibitors (e.g., amiodarone, verapamil) increase serum levels.

• β-agonists: enhanced effects with other sympathomimetics.

• PDE3 inhibitors: avoid with other agents that prolong QT interval.

Negative Inotropes

• β-blockers + calcium channel blockers: additive negative chronotropic/inotropic effects → bradycardia, heart block.

• CYP3A4 interactions (verapamil, diltiazem).

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9. Monitoring

• Cardiac rhythm (ECG).

• Blood pressure and heart rate.

• Electrolytes (especially potassium and magnesium).

• Renal function (digoxin, milrinone).

• Signs of drug toxicity.

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10. Advantages and Limitations

Positive Inotropes

• Rapid improvement in cardiac output in acute settings.

• Useful in patients unresponsive to standard therapy.

Limitations

• Not for long-term use in chronic HF due to increased mortality risk with some agents.

• Arrhythmia risk and myocardial oxygen demand increase.

Negative Inotropes

• Reduce myocardial workload and oxygen demand.

• Control heart rate in arrhythmias.

Limitations

• May worsen symptoms in patients with systolic dysfunction.