Epoprostenol

Action and Spectrum

Actions and spectrum: 

• Vasodilation: epoprostenol dilates blood vessels, particularly in pulmonary circulation. This reduces pulmonary artery pressure and pulmonary vascular resistance, which is beneficial in the treatment of pulmonary arterial hypertension (PAH). 
• Inhibition of platelet aggregation: epoprostenol inhibits the aggregation of platelets, which can help prevent blood clots from forming. This is particularly important in patients with PAH, as they are at increased risk of developing blood clots. 
• Improvement of exercise tolerance: epoprostenol can improve exercise tolerance in patients with PAH, likely due to its vasodilatory effects. 
• Decrease of pulmonary vascular resistance: By reducing pulmonary vascular resistance, epoprostenol can help improve right ventricular function in patients with PAH. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

Nervousness (11%) 

Anxiety (11%) 

Hypotension (16%) 

Flu-like symptoms (25%) 

Rash (25%) 

Eczema (25%) 

Urticaria (25%) 

Vomiting (32%) 

Nausea (32%) 

Diarrhea (37%) 

Myalgia (44%) 

Headache (49%) 

Jaw pain (54%) 

Flushing (58%)  

1-10% 

Tachycardia (1%) 

Hyperesthesia (1%) 

Musculoskeletal pain (2%)  

Frequency not defined 

Thrombocytopenia 

Hemorrhage  

Post marketing Reports 

Endocrine and Metabolic disorders: Hyperthyroidism 

Respiratory, Mediastinal, and Thoracic: Pulmonary embolism 

Blood and lymphatic: hypersplenism, Anemia, pancytopenia, thrombocytopenia, splenomegaly 

Gastrointestinal: Hepatic failure 

Cardiovascular: High cardiac output and failure 

Black Box Warning

Black Box Warning: 

epoprostenol carries a black box warning, which is the strongest warning issued by the US FDA, due to the risk of abrupt discontinuation or interruption of therapy.

This warning highlights the risk of a pulmonary hypertension crisis, which is a potentially life-threatening condition that can occur when epoprostenol therapy is stopped abruptly or interrupted. 

Pulmonary hypertension crisis is characterized by a sudden and severe worsening of PAH symptoms, including shortness of breath, chest pain, dizziness, and fainting. If left untreated, it may lead to various complications, such as right heart failure, shock, and death. 

Contraindication / Caution

Contraindication/Caution: 

Contraindication: 

• Known hypersensitivity to epoprostenol or any of its components. 
• Severe left ventricular dysfunction can be exacerbated by the vasodilatory effects of epoprostenol. 
• Pulmonary edema can also be worsened by the vasodilatory effects of epoprostenol. 
• Uncontrolled systemic hypertension, as epoprostenol, can further reduce blood pressure. 
• Bleeding disorders or a history of bleeding, such as epoprostenol, can increase the risk of bleeding. 
• Any condition that makes intravenous infusion difficult or impossible, such as severe peripheral vascular disease or inadequate venous access. 
• Sepsis or severe infection, as the risk of bleeding and infection, may be increased in these patients.

Caution: 

• Hypotension: epoprostenol can cause a decrease in blood pressure, which may be more pronounced in patients with pre-existing hypotension. Close monitoring of blood pressure is necessary, and adjustments to the dose may be needed to prevent hypotension. 
• Bleeding: epoprostenol can increase the risk of bleeding, particularly in patients with bleeding disorders or those taking anticoagulant medications. Careful monitoring of bleeding time and coagulation tests is recommended. 
• Fluid retention: epoprostenol can cause fluid retention, which can worsen symptoms in patients with congestive heart failure or other conditions associated with fluid overload. Close monitoring of fluid balance and electrolyte levels is necessary. 
• Infection: epoprostenol is administered via intravenous infusion, which can increase the risk of infection. Proper sterile technique and aseptic precautions should be used during administration to reduce the risk of infection. 
• Hepatic or renal impairment: epoprostenol is metabolized by the liver and excreted by the kidneys, and patients with hepatic or renal impairment may be at increased risk of adverse effects. Dose adjustments may be necessary for these patients. 
• Pregnancy and lactation: epoprostenol should be used in pregnant or breastfeeding women with caution, as the safety of the medication in these populations has not been well established.

Comorbidities: 

• Congestive heart failure: Patients with PAH may also have congestive heart failure, which can be exacerbated by the vasodilatory effects of epoprostenol. Close monitoring of fluid balance and electrolyte levels is necessary. 
• Chronic obstructive pulmonary disease (COPD): Patients with PAH may also have COPD, which can make it more difficult to administer epoprostenol via inhalation. In these cases, intravenous administration may be necessary. 
• Thromboembolic disease: Patients with PAH may be at increased risk of thromboembolic disease, and epoprostenol can increase the risk of bleeding. Careful monitoring of bleeding time and coagulation tests is recommended. 
• Hepatic or renal impairment: Patients with PAH may also have hepatic or renal impairment, which can affect the metabolism and elimination of epoprostenol. Dose adjustments may be necessary for these patients. 
• Diabetes: Patients with PAH and diabetes may be at increased risk of hypoglycemia because of epoprostenol on glucose metabolism. 

Pregnancy / Lactation

Pregnancy consideration: US FDA pregnancy category: Not assigned 

Lactation: It is not known whether epoprostenol is excreted in human milk  

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 
• Category B: There is no evidence of risk to the fetus found in animal reproduction studies and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women. 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh risks over benefits These category drugs should be prohibited for pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

epoprostenol is a synthetic prostacyclin analog that acts as a vasodilator and inhibitor of platelet aggregation. It is structurally similar to prostaglandin I2 (PGI2), which is a potent vasodilator and inhibitor of platelet aggregation produced by endothelial cells.

epoprostenol works by binding to the prostacyclin receptor on smooth muscle cells and platelets, leading to the activation of adenylate cyclase and subsequent production of cyclic adenosine monophosphate (cAMP).

The increase in cAMP levels may lead to the relaxation of vascular smooth muscle and inhibition of platelet aggregation, ultimately resulting in increased blood flow and reduced blood clotting.  

Pharmacodynamics: 

The pharmacodynamics of epoprostenol is related to its mechanism of action as a potent vasodilator and inhibitor of platelet aggregation. 

Vasodilation: epoprostenol acts as a vasodilator by binding to prostacyclin receptors on smooth muscle cells and platelets, which leads to an increase in cyclic adenosine monophosphate (cAMP) levels. The increase in cAMP levels leads to the relaxation of vascular smooth muscle cells, resulting in the dilation of blood vessels and increased blood flow. In the pulmonary arteries, epoprostenol causes selective vasodilation, which leads to a reduction in pulmonary arterial pressure and resistance. 

Platelet aggregation inhibition: epoprostenol inhibits platelet aggregation by binding to the prostacyclin receptor on platelets and inducing an increase in cAMP levels. The increase in cAMP levels inhibits platelet activation and aggregation, which reduces the risk of thrombus formation in the pulmonary vasculature. 

Other effects: epoprostenol also has anti-inflammatory effects, which may contribute to its therapeutic effects in pulmonary arterial hypertension.  

Pharmacokinetics: 

Absorption 

epoprostenol is administered intravenously, resulting in immediate and complete absorption of the drug into the bloodstream. 

Distribution 

epoprostenol has a low volume of distribution, indicating that it is primarily distributed in the plasma rather than the tissues. The protein binding of epoprostenol is low, and it is rapidly cleared from the plasma. 

Metabolism 

epoprostenol is rapidly metabolized in the body by the enzyme prostacyclin synthase, which converts it to the biologically inactive metabolite 6-keto-PGF1α. The short half-life of epoprostenol, which is only a few minutes, is attributed to its rapid metabolism and clearance from the body. 

Elimination and excretion 

epoprostenol is primarily eliminated through renal excretion. Studies have shown that approximately 60% to 80% of a given dose of epoprostenol is excreted unchanged in the urine. The remainder of the drug is likely cleared through hepatic metabolism or other routes. 

Adminstartion

Administration: 

epoprostenol is administered via continuous intravenous infusion using an ambulatory infusion pump. The recommended starting dose is 2 ng/kg/min, which can be increased gradually as needed to achieve the desired therapeutic effect. The maximum recommended dose is 40 ng/kg/min. 

epoprostenol should be administered by a healthcare professional experienced in the management of pulmonary arterial hypertension, as adjustments to the dose may be necessary based on individual patient response and adverse effects. 

The infusion site should be monitored regularly for signs of infection or other complications, and the drug should be administered through a central venous catheter to minimize the risk of tissue damage and extravasation. It is important to ensure that the infusion pump is functioning properly and that the drug is being administered at the correct rate and dose. 

epoprostenol should not be administered by bolus injection or through an arterial catheter, as this can lead to serious adverse effects such as systemic hypotension, thrombosis, and tissue necrosis. The drug should also be discontinued gradually to avoid the risk of rebound pulmonary hypertension. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: epoprostenol 

Pronounced: [ EE-poe-PROST-en-ol ]  

Why do we use epoprostenol? 

epoprostenol is used to treat pulmonary arterial hypertension (PAH). It is a potent vasodilator and inhibits platelet aggregation, leading to improved blood flow and decreased pulmonary vascular resistance. 

epoprostenol has been shown to improve exercise capacity, hemodynamics, and symptoms in patients with PAH, and it is approved by the US FDA for the treatment of idiopathic PAH, familial PAH, and PAH associated with connective tissue diseases. 

In addition, epoprostenol has also been used in acute respiratory distress syndrome (ARDS) and as a potential treatment for sickle cell disease and ischemia-reperfusion injury. However, these uses are still investigational and have not been approved by regulatory agencies.