Milrinone

Usage

• Milrinone is prescribed for the short-term management of acute decompensated heart failure, particularly in patients who are unresponsive to conventional therapies like diuretics, digoxin, or vasodilators. It is also used for short-term treatment of severe cardiac failure, low cardiac output syndrome post-cardiac surgery, cardiogenic shock secondary to acute decompensated systolic heart failure, and occasionally in patients with pulmonary hypertension.
• Pharmacological Classification: Inotropic agent, vasodilator.
• Mechanism of Action: Milrinone is a selective phosphodiesterase 3 inhibitor. By inhibiting this enzyme, it increases intracellular cyclic adenosine monophosphate (cAMP), leading to increased intracellular calcium levels in cardiac myocytes. This results in increased myocardial contractility (positive inotropic effect) and vasodilation, reducing both preload and afterload.

Alternate Names

• International Nonproprietary Name (INN): Milrinone
• Brand Names: Primacor

How It Works

• Pharmacodynamics: Milrinone increases myocardial contractility (positive inotropic effect) and causes vasodilation of both arteries and veins. This leads to improved cardiac output, reduced pulmonary capillary wedge pressure (PCWP), and decreased systemic vascular resistance.
• Pharmacokinetics:
  • Absorption: Administered intravenously, thus 100% bioavailability.
  • Metabolism: Minimally metabolized in the liver, primarily to o-glucuronide conjugate, which possesses some phosphodiesterase inhibitory activity.
  • Elimination: Primarily renal excretion (80-90%), with a half-life of approximately 2-3 hours in patients with normal renal function. The half-life can be significantly prolonged in patients with renal impairment.
• Mode of Action: Milrinone selectively inhibits phosphodiesterase 3, an enzyme that breaks down cAMP. Increased cAMP levels increase intracellular calcium in cardiac myocytes, leading to enhanced contractility. In smooth muscle cells, increased cAMP promotes relaxation, causing vasodilation.
• Receptor Binding/Enzyme Inhibition: Milrinone acts by inhibiting phosphodiesterase 3.
• Elimination Pathways: Primarily renal excretion (80-90% as unchanged drug and metabolites), with minor hepatic metabolism.

Dosage

Standard Dosage

Adults:

• Loading Dose: 50 mcg/kg intravenous (IV) bolus over 10 minutes. This can be omitted or adjusted to a slower rate (e.g., 50 mcg/kg over 1 hour) in hemodynamically unstable patients.
• Maintenance Infusion: 0.375-0.75 mcg/kg/min IV infusion. Titrate according to hemodynamic and clinical response. Maximum dose: 1.13 mg/kg/day.
• Right Heart Failure (Orphan Drug Designation): The dosing is similar to the standard adult dose.

Children:

• Not FDA-approved for use in children. However, off-label use is common, especially in pediatric intensive care units.
• Loading Dose: 50-75 mcg/kg IV over 30-60 minutes.
• Maintenance Infusion: 0.25-0.75 mcg/kg/min IV infusion. Titrate based on hemodynamic response and clinical status.
• Pediatric Safety Considerations: Closely monitor vital signs and cardiac rhythm due to increased risk of arrhythmias and hypotension in children.

Special Cases:

• Elderly Patients: Initiate therapy with a lower maintenance infusion rate due to potential age-related decline in renal function.
• Patients with Renal Impairment: Reduce the maintenance infusion dose based on creatinine clearance.
• Patients with Hepatic Dysfunction: No specific dose adjustment is typically required, but close monitoring is recommended.
• Patients with Comorbid Conditions: Exercise caution in patients with atrial fibrillation/flutter, hypertrophic subaortic stenosis, recent myocardial infarction, and electrolyte abnormalities.

Clinical Use Cases

• Intubation/Surgical Procedures/Mechanical Ventilation/ICU Use/Emergency Situations: The dosing regimen is similar to the standard adult dose. The loading dose may be omitted or administered more slowly in unstable patients. The maintenance infusion rate is titrated based on hemodynamic response and clinical parameters. Continuous ECG monitoring is essential.

Dosage Adjustments

• Renal impairment requires dose reduction based on creatinine clearance.
• In cases of hypotension, reduce or temporarily discontinue milrinone until the patient stabilizes.

Side Effects

Common Side Effects

• Headache
• Hypotension
• Ventricular arrhythmias (e.g., premature ventricular contractions, ventricular tachycardia)

Rare but Serious Side Effects

• Sustained ventricular tachycardia or ventricular fibrillation
• Severe hypotension
• Thrombocytopenia
• Angina/chest pain

Long-Term Effects

• Data limited beyond 48 hours of use. Studies have suggested an increased risk of mortality with prolonged oral use.

Adverse Drug Reactions (ADR)

• Torsades de pointes (a type of polymorphic ventricular tachycardia)
• Anaphylaxis (severe allergic reaction)

Contraindications

• Hypersensitivity to milrinone or inamrinone
• Severe aortic or pulmonary valvular stenosis
• Hypertrophic subaortic stenosis

Drug Interactions

• Disopyramide: Concurrent use is contraindicated due to increased risk of arrhythmias.
• Drugs that prolong the QT interval: Use with caution due to increased risk of torsades de pointes.
• Antihypertensive agents: May potentiate hypotension.
• Furosemide, Bumetanide, Sodium Bicarbonate IV Solutions: Incompatible in IV admixtures.
• Ozanimod and Ponesimod: Serious interactions, avoid concomitant use.
• Anagrelide, Cilostazol, Riociguat, and other PDE3 Inhibitors: Use with caution due to potential additive effects.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C (animal studies show risk, human studies lacking)
• Fetal Risks: Potential for increased resorption rate (miscarriage) in animals at high doses.
• Breastfeeding: It is unknown if milrinone is excreted in human milk. Exercise caution when administering to breastfeeding women.

Drug Profile Summary

• Mechanism of Action: Phosphodiesterase 3 inhibitor, leading to positive inotropic and vasodilatory effects.
• Side Effects: Headache, hypotension, ventricular arrhythmias, angina. Serious but rare: severe hypotension, sustained ventricular tachycardia/fibrillation, thrombocytopenia.
• Contraindications: Hypersensitivity, severe valvular stenosis, hypertrophic subaortic stenosis.
• Drug Interactions: Disopyramide, QT prolonging drugs, antihypertensives, ozanimod, ponesimod, anagrelide, cilostazol, riociguat.
• Pregnancy & Breastfeeding: Category C; use with caution. Unknown excretion in breast milk.
• Dosage: Adult: 50 mcg/kg loading dose, 0.375-0.75 mcg/kg/min maintenance infusion. Pediatric: 50-75 mcg/kg loading dose, 0.25-0.75 mcg/kg/min maintenance. Adjust for renal impairment.
• Monitoring Parameters: ECG, blood pressure, heart rate, renal function, electrolytes.

Popular Combinations

• Often used with vasopressors (e.g., norepinephrine) to maintain mean arterial pressure while providing inotropic support and vasodilation.

Precautions

• General Precautions: Close monitoring of cardiac rhythm, blood pressure, and renal function. Correct electrolyte abnormalities before starting.
• Specific Populations: Avoid in pregnancy unless absolutely necessary. Exercise caution during breastfeeding. Adjust dosage in elderly and patients with renal impairment.
• Lifestyle Considerations: No specific lifestyle considerations are usually associated with short-term milrinone use.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Milrinone?

A: Adult: 50 mcg/kg loading dose IV over 10 minutes, followed by 0.375-0.75 mcg/kg/min maintenance infusion. Pediatric (off-label): 50-75 mcg/kg loading dose over 30-60 minutes, followed by 0.25-0.75 mcg/kg/min maintenance infusion. Adjust for renal impairment.

Q2: What is the mechanism of action of Milrinone?

A: Milrinone inhibits phosphodiesterase 3, leading to increased cAMP, increased intracellular calcium in cardiomyocytes, and enhanced myocardial contractility and vasodilation.

Q3: What are the common side effects of Milrinone?

A: Headache, hypotension, and ventricular arrhythmias.

Q4: What are the contraindications for using Milrinone?

A: Hypersensitivity, severe aortic or pulmonary valvular stenosis, hypertrophic subaortic stenosis.

Q5: How does renal impairment affect Milrinone dosing?

A: Reduce maintenance infusion dose based on creatinine clearance. The loading dose is usually not affected.

Q6: Can Milrinone be used in pregnant or breastfeeding women?

A: Pregnancy Category C. Use only if potential benefit outweighs risk. Unknown if excreted in breast milk; exercise caution.

Q7: What are the key drug interactions to consider with Milrinone?

A: Disopyramide, QT-prolonging agents, antihypertensives, ozanimod, ponesimod, anagrelide, cilostazol, riociguat.

Q8: How is Milrinone administered?

A: As an intravenous bolus followed by continuous intravenous infusion.

Q9: What is the maximum recommended dose of Milrinone?

A: 1.13 mg/kg/day.

Q10: What are the monitoring parameters for patients on Milrinone?

A: ECG, blood pressure, heart rate, renal function, and electrolytes.