Epoprostenol for Pulmonary Arterial Hypertension
Epoprostenol is a synthetic prostacyclin that serves as a potent vasodilator and platelet aggregation inhibitor, primarily used for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity, hemodynamics, and survival. 1
Pharmacology and Mechanism of Action
Epoprostenol (PGI2, prostacyclin) is a naturally occurring prostaglandin derived from arachidonic acid with two major pharmacological actions:
- Direct vasodilation of pulmonary and systemic arterial vascular beds
- Inhibition of platelet aggregation 1
Patients with PAH show decreased expression of prostacyclin synthase in lung tissue, making prostacyclin replacement a pathophysiologically targeted therapy 2.
Formulation and Administration
Epoprostenol has several important pharmaceutical characteristics:
- Available as a sterile lyophilized powder for intravenous administration
- Very short half-life (3-5 minutes) in circulation
- Unstable at room temperature (stable for only 8 hours)
- Rapidly converted to stable metabolites 2
Due to these properties, epoprostenol must be administered via:
- Continuous intravenous infusion
- Permanent tunnelized catheters (Hickman)
- Infusion pumps (e.g., CADD pump)
- Cold packs to maintain stability 2
Subcutaneous catheters with reservoirs and transcutaneous needles are discouraged for administration 2.
Dosing
The dosing protocol for epoprostenol follows a careful titration schedule:
- Initial dose: 2-4 ng/kg/min
- Target dose for first 2-4 weeks: 10-15 ng/kg/min
- Maintenance dose: typically 20-40 ng/kg/min (individualized)
- Dose adjustments based on side effects (flushing, headache, diarrhea, leg pain) 2
Clinical Efficacy
Epoprostenol has demonstrated significant benefits in PAH:
- Survival benefit: The only prostacyclin shown in randomized controlled trials to improve survival in idiopathic PAH 2
- Exercise capacity: Improves 6-minute walk distance significantly compared to conventional therapy 2
- Hemodynamics: Reduces mean pulmonary artery pressure and pulmonary vascular resistance 2
- Symptoms: Improves NYHA functional class, Borg dyspnea scores, and quality of life 2
In a landmark 12-week trial, patients receiving epoprostenol showed a median distance walked in 6 minutes of 362 m (from 315 m at baseline) versus a decrease to 204 m (from 270 m) in the conventional therapy group 2.
Indications
Epoprostenol is FDA-approved for:
- Treatment of PAH (WHO Group 1) to improve exercise capacity
- Primarily effective in patients with NYHA Functional Class III-IV symptoms
- Idiopathic or heritable PAH
- PAH associated with connective tissue diseases 1
Adverse Effects
Common side effects include:
- Flushing, jaw pain, diarrhea, headache, backache
- Foot and leg pain, abdominal cramping, nausea
- Rarely hypotension 2
More serious complications related to the delivery system:
- Pump malfunction
- Local site infection
- Catheter obstruction
- Sepsis (reported in 0.14-0.19 episodes per patient) 2
Important Precautions
Several critical precautions must be observed:
- Avoid abrupt discontinuation: Can lead to rebound pulmonary hypertension, clinical deterioration, and potentially death
- Patients should always carry spare medication and infusion pumps
- Careful monitoring during dose adjustments is essential 2
- Long-term overdosage can lead to high-output cardiac failure 2
Clinical Outcomes and Prognosis
Long-term survival with epoprostenol therapy:
- 1-year survival: approximately 85%
- 3-year survival: approximately 65%
- 5-year survival: approximately 55% 2
Factors associated with poor outcomes include:
- History of right-sided heart failure
- NYHA functional class IV at baseline
- 6-minute walk test <250 m
- Right atrial pressure >12 mm Hg
- Mean pulmonary artery pressure >65 mm Hg
- Failure to improve to NYHA class I-II after 3 months of therapy
- Absence of a fall in total pulmonary resistance of >30% 2
Lung transplantation should be considered for patients who remain in NYHA class III-IV or fail to achieve significant hemodynamic improvement after 3 months of epoprostenol therapy 2.