Usage
Levosimendan is prescribed for the short-term treatment of acutely decompensated severe chronic heart failure in adults, specifically when conventional therapy is insufficient and inotropic support is deemed necessary. It is also used in cardiogenic shock post-cardiac surgery in patients with a left ventricular ejection fraction less than 40%. Its pharmacological classification is as an inodilator and calcium sensitizer. Levosimendan increases myocardial contractility by sensitizing the heart muscle to calcium, allowing for stronger contractions without increasing intracellular calcium levels. It also acts as a vasodilator, opening ATP-sensitive potassium channels in blood vessels, leading to decreased preload and afterload.
Alternate Names
Levosimendan is also known by its research name, ODM-109. A popular brand name for levosimendan is Simdax.
How It Works
Pharmacodynamics: Levosimendan exerts its inotropic effects by binding to cardiac troponin C (cTnC) during systole, increasing calcium sensitivity and enhancing myocardial contractility without raising intracellular calcium concentrations. Its vasodilatory effects stem from the opening of ATP-sensitive potassium channels in vascular smooth muscle, decreasing systemic and pulmonary vascular resistance. This combined inodilator effect leads to increased cardiac output, stroke volume, and ejection fraction, while reducing preload and afterload pressures. Diastolic function is typically not negatively impacted.
Pharmacokinetics: Administered intravenously, levosimendan is rapidly metabolized by the liver. It has a short half-life of approximately 1 hour. However, its major metabolites, OR-1855 and OR-1896, are also pharmacologically active, with OR-1896 being the main active metabolite responsible for the prolonged hemodynamic effects. OR-1896 reaches peak plasma concentration 48-78 hours after administration and has a much longer half-life of about 70-80 hours. This results in haemodynamic effects that can persist for 7-10 days after a 24-hour infusion. Levosimendan and its metabolites are primarily eliminated through the kidneys.
Mode of Action: Levosimendan binds to cardiac troponin C during systole, sensitizing the myofilaments to calcium. It does not affect intracellular calcium concentrations. It also opens vascular ATP-sensitive potassium channels.
Elimination Pathways: Levosimendan and its metabolites are primarily excreted renally, with some hepatic metabolism.
Dosage
Standard Dosage
Adults:
The recommended dose is a continuous intravenous infusion of 0.05–0.2 mcg/kg/min, ideally administered through a central line. A loading dose of 6-12 mcg/kg over 10 minutes is sometimes used, particularly if a rapid haemodynamic effect is needed and the patient’s blood pressure is stable. However, loading doses are frequently omitted due to the risk of hypotension. The infusion is usually continued for 24 hours.
Children:
Levosimendan is contraindicated in children and adolescents under 18 years of age.
Special Cases:
- Elderly Patients: No specific dose adjustment is typically required.
- Patients with Renal Impairment: Levosimendan is contraindicated in severe renal impairment (creatinine clearance < 30 mL/min). Caution is advised in mild to moderate renal impairment, with closer monitoring recommended for at least 5 days.
- Patients with Hepatic Dysfunction: Levosimendan is contraindicated in severe hepatic impairment. Caution is advised in mild to moderate hepatic impairment, with closer monitoring also recommended for at least 5 days.
- Patients with Comorbid Conditions: Careful dose adjustment and monitoring are necessary in patients with hypotension, hypovolemia, tachycardia, or electrolyte imbalances, particularly hypokalemia. Use with caution in patients with long QT syndrome or receiving other QT-prolonging drugs.
Clinical Use Cases
- Intubation/Surgical Procedures/Mechanical Ventilation/ICU Use/Emergency Situations: The dosage guidelines are generally the same as the standard dosage described above, tailored to individual patient needs and hemodynamic response. In emergency situations requiring rapid hemodynamic support, a loading dose may be considered if blood pressure is adequate, followed by continuous infusion.
Dosage Adjustments
Dose adjustments may be necessary in patients with mild to moderate renal or hepatic impairment, and for those experiencing side effects like hypotension or tachycardia. Monitor ECG, blood pressure, heart rate, and serum potassium regularly, continuing for at least 3 days (or 5 days in patients with mild to moderate renal/hepatic impairment) after stopping the infusion, or until the patient is clinically stable.
Side Effects
Common Side Effects:
Headache, hypotension, and nausea are the most frequently reported. Hypokalaemia, decreased haemoglobin and haematocrit, ventricular tachycardia, atrial fibrillation, ventricular extrasystoles, myocardial ischemia, cardiac failure, diarrhea, constipation, dizziness, and insomnia can also occur.
Rare but Serious Side Effects:
Severe hypotension, ventricular tachycardia, and other life-threatening arrhythmias are possible.
Long-Term Effects:
Data on the long-term effects are limited, as the drug is typically used for short-term treatment. The prolonged half-life of the active metabolite means that hemodynamic effects can persist for 7-10 days.
Contraindications
Absolute contraindications include hypersensitivity to levosimendan, severe hypotension, severe tachycardia, significant mechanical obstruction to ventricular filling or outflow, severe renal impairment, severe hepatic impairment, and history of Torsades de Pointes.
Drug Interactions
Concomitant use of other vasodilators or inotropes can potentiate the hypotensive effects of levosimendan. Co-administration of isosorbide mononitrate can significantly increase the orthostatic hypotensive response. Levosimendan may inhibit CYP2C8, potentially increasing the exposure of drugs metabolized by this enzyme. Avoid co-administration with sensitive CYP2C8 substrates.
Pregnancy and Breastfeeding
Levosimendan should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. Animal studies have shown some toxic effects on reproduction. It is not recommended during breastfeeding as levosimendan and its metabolites can be excreted in breast milk.
Drug Profile Summary
- Mechanism of Action: Calcium sensitizer and vasodilator, enhancing myocardial contractility and reducing preload/afterload without increasing intracellular calcium.
- Side Effects: Headache, hypotension, nausea, hypokalaemia, and arrhythmias. Rarely, severe hypotension and life-threatening arrhythmias.
- Contraindications: Hypersensitivity, severe hypotension/tachycardia, ventricular outflow obstruction, severe renal/hepatic impairment, Torsades de Pointes history.
- Drug Interactions: Other vasodilators/inotropes (increased hypotension risk), isosorbide mononitrate (potentiated orthostatic hypotension), CYP2C8 substrates (increased exposure).
- Pregnancy & Breastfeeding: Use with caution in pregnancy only if benefit outweighs risk. Not recommended during breastfeeding.
- Dosage: 0.05-0.2 mcg/kg/min continuous IV infusion for 24 hrs. Loading dose (6-12 mcg/kg over 10 min) may be considered if hemodynamically stable and rapid effect needed.
- Monitoring Parameters: ECG, blood pressure, heart rate, serum potassium, urine output, and other hemodynamic parameters. Continue monitoring for at least 3-5 days post-infusion.
Popular Combinations
Levosimendan can be combined with other vasoactive agents like norepinephrine or dobutamine in cases of cardiogenic shock or severe heart failure. However, careful monitoring is crucial due to the increased risk of hypotension.
Precautions
Correct hypovolemia and hypokalemia before starting levosimendan. Closely monitor patients with renal or hepatic impairment. Continuous ECG monitoring is essential. Exercise caution in patients with a history of arrhythmias or those receiving QT-prolonging drugs. Avoid or reduce loading dose in patients with hypotension. Advise patients against consuming alcohol during treatment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Levosimendan?
A: 0.05-0.2 mcg/kg/min continuous IV infusion for 24 hours. Loading dose of 6-12 mcg/kg over 10 min may be considered in select cases but is often omitted due to the risk of hypotension.
Q2: What are the most common side effects?
A: Headache, hypotension, and nausea.
Q3: What are the contraindications for Levosimendan?
A: Hypersensitivity, severe hypotension, severe tachycardia, significant mechanical obstruction of ventricular filling or outflow, severe renal/hepatic impairment, and a history of Torsades de Pointes.
Q4: How does Levosimendan differ from other inotropes like dobutamine?
A: Levosimendan is a calcium sensitizer, enhancing contractility without increasing intracellular calcium. It also has vasodilatory effects. Dobutamine is a beta-adrenergic agonist, which increases intracellular calcium and can have more pronounced effects on heart rate and oxygen consumption.
Q5: Can Levosimendan be used in patients with renal impairment?
A: It is contraindicated in severe renal impairment. Use with caution in mild to moderate renal impairment with careful monitoring.
Q6: Is Levosimendan safe to use in pregnancy?
A: Only if the potential benefit outweighs the potential risk to the fetus.
Q7: How should Levosimendan be administered?
A: As a continuous IV infusion, preferably through a central line.
Q8: What monitoring is required during Levosimendan therapy?
A: Continuous ECG, blood pressure, and heart rate monitoring. Also monitor serum potassium, urine output and other relevant hemodynamic parameters. Monitoring should continue for 3-5 days post-infusion.
Q9: Can Levosimendan be used with other vasodilators?
A: Use with caution, as it can potentiate hypotensive effects.
Q10: What is the duration of Levosimendan’s hemodynamic effects?
A: Although the drug itself has a short half-life, its active metabolites have prolonged half-lives, resulting in hemodynamic effects that can persist for 7-10 days after a 24-hour infusion.
