Introduction
Milrinone is a phosphodiesterase-3 (PDE3) inhibitor with both inotropic and vasodilatory properties. It is primarily used in the management of acute heart failure and cardiogenic shock. By increasing intracellular cyclic adenosine monophosphate (cAMP), it enhances myocardial contractility and promotes peripheral vasodilation, making it a valuable drug for short-term use in patients with decompensated heart failure who are refractory to other treatments.
Pharmacokinetics
Milrinone is administered intravenously due to its rapid onset of action. After administration, it has a half-life of approximately 2.5 hours. The onset of action occurs within 5 to 15 minutes after starting an IV infusion, with peak effects observed within 10 to 30 minutes.
Milrinone is primarily eliminated through the kidneys, with approximately 83% of the drug excreted unchanged in the urine. As a result, dose adjustments are often necessary in patients with renal impairment. Due to its renal excretion, accumulation of the drug may occur in patients with compromised renal function, potentially increasing the risk of side effects.
Mechanism of Action
Milrinone works by inhibiting phosphodiesterase-3 (PDE3), an enzyme that breaks down cAMP in cardiac and vascular smooth muscle cells. By increasing the intracellular concentration of cAMP, Milrinone enhances myocardial contractility (positive inotropy) and induces vasodilation (reduction in afterload). This dual action makes Milrinone a potent inodilator, improving cardiac output and reducing the workload on the heart in patients with heart failure.
The increase in cAMP also leads to relaxation of vascular smooth muscle, resulting in reduced systemic vascular resistance and pulmonary vascular resistance, which further improves hemodynamics and reduces the symptoms of heart failure.
Pharmacodynamics
Milrinone increases myocardial contractility without significantly raising heart rate, making it particularly useful in heart failure patients with reduced ejection fraction. It reduces both preload and afterload by causing venous and arterial dilation, thus improving cardiac output and reducing congestion.
The hemodynamic effects of Milrinone include improved left ventricular function, increased stroke volume, and enhanced oxygen delivery to tissues. These effects are beneficial in the treatment of cardiogenic shock and acute heart failure, particularly when other inotropes such as Dobutamine are ineffective or contraindicated.
Adverse Effects
Arrhythmias: Milrinone can increase the risk of ventricular arrhythmias, especially in patients with underlying ischemic heart disease or electrolyte disturbances. Close monitoring of cardiac rhythm is required during administration.
Hypotension: Due to its potent vasodilatory effects, Milrinone can cause significant hypotension, particularly in hypovolemic patients or those receiving concomitant vasodilators. Dose adjustments and careful monitoring of blood pressure are essential.
Thrombocytopenia: Prolonged use of Milrinone has been associated with a reduction in platelet count, leading to thrombocytopenia in some patients.
Increased Mortality (Long-term Use): Studies have shown that long-term use of Milrinone in patients with chronic heart failure may increase mortality, which is why it is generally restricted to short-term use in acute decompensated heart failure.
Renal Impairment: Milrinone is primarily excreted by the kidneys, and patients with renal impairment may experience accumulation of the drug, leading to an increased risk of adverse effects. Dose adjustment is necessary in these patients.
Drug Interactions
Vasodilators: The combined use of Milrinone with other vasodilators, such as nitroglycerin or sodium nitroprusside, can lead to excessive hypotension. Close monitoring of blood pressure is required.
Digoxin: The positive inotropic effects of Milrinone may enhance the effects of Digoxin, increasing the risk of arrhythmias. Careful monitoring of electrolyte levels, particularly potassium, is necessary to avoid digoxin toxicity.
Diuretics: Milrinone may enhance the diuretic effects of loop diuretics like furosemide, potentially increasing the risk of electrolyte imbalances, including hypokalemia.
Beta-blockers: Milrinone may counteract the negative inotropic effects of beta-blockers, improving cardiac output in patients who require both drugs. However, this combination should be carefully titrated.
Dosages
Adults (Heart Failure or Cardiogenic Shock): A loading dose of 50 mcg/kg is typically administered over 10 minutes, followed by a continuous IV infusion of 0.375 to 0.75 mcg/kg/min. The infusion rate may be titrated based on the clinical response, with a maximum dose of 0.75 mcg/kg/min.
Children: For pediatric patients, the dose is typically 50 mcg/kg as a loading dose, followed by 0.25 to 0.75 mcg/kg/min as a continuous infusion. Close monitoring of hemodynamics is required.
Renal Impairment: In patients with renal impairment, the clearance of Milrinone is reduced, and dose adjustments are required. The dose should be reduced, and renal function should be monitored closely during therapy.
Hepatic Impairment: Milrinone is not extensively metabolized by the liver, so no dose adjustment is usually required in patients with hepatic impairment. However, liver function should still be monitored during therapy.