What is the mechanism of action of epoprostenol (prostacyclin) in a patient with pulmonary arterial hypertension (PAH)?

Mechanism of Action of Epoprostenol in Pulmonary Arterial Hypertension

Epoprostenol exerts its therapeutic effects through two major pharmacological actions: direct vasodilation of pulmonary and systemic arterial vascular beds, and inhibition of platelet aggregation. 1

Primary Mechanisms

Vasodilatory Effects

• Epoprostenol directly dilates both pulmonary and systemic arterial vascular beds, reducing right- and left-ventricular afterload while increasing cardiac output and stroke volume 1
• The vasodilatory effects are mediated through the IP prostacyclin receptor on vascular smooth muscle cells, leading to relaxation and reduced pulmonary vascular resistance 2
• In acute administration, epoprostenol produces dose-related increases in cardiac index and stroke volume, with dose-related decreases in pulmonary vascular resistance and total pulmonary resistance 1

Antiplatelet and Antiproliferative Actions

• Epoprostenol is the most potent endogenous inhibitor of platelet aggregation, preventing microscopic in situ thromboses that contribute to PAH pathology 3
• Recent evidence demonstrates that prostacyclin analogues significantly decrease platelet reactivity in response to multiple agonists (arachidonic acid and ADP), reduce extracellular vesicle release from platelets and leukocytes, and impair thrombus formation 4
• The drug exhibits cytoprotective and antiproliferative activities on vascular smooth muscle cells, inhibiting cell migration and proliferation 3, 5

Pathophysiological Rationale

Prostacyclin Deficiency in PAH

• A dysregulation of prostacyclin metabolic pathways has been demonstrated in PAH patients, with reduced prostacyclin synthase expression in pulmonary arteries and decreased urinary prostacyclin metabolites 3, 5
• This relative prostacyclin deficiency provides the therapeutic rationale for exogenous prostacyclin replacement 3, 6
• While it remains unclear whether prostacyclin dysregulation is causative or consequential, the deficiency represents a clear therapeutic target 3

Pharmacodynamic Effects

Hemodynamic Changes

• The vasodilatory effects produce variable effects on heart rate: at low doses, vagally-mediated bradycardia occurs, while higher doses cause reflex tachycardia in response to direct vasodilation and hypotension 1
• No major effects on cardiac conduction have been observed 1
• Chronic administration leads to sustained increases in cardiac index, stroke volume, and arterial oxygen saturation, with decreases in mean pulmonary arterial pressure, mean right atrial pressure, total pulmonary resistance, and systemic vascular resistance 1

Additional Pharmacologic Effects

• Beyond cardiovascular effects, epoprostenol produces bronchodilation, inhibits gastric acid secretion, and decreases gastric emptying 1
• High-dose epoprostenol therapy may induce reverse remodeling of pulmonary arteries in some patients, contributing to marked hemodynamic improvements 7

Pharmacokinetic Considerations

• Epoprostenol has an extremely short half-life (approximately 6 minutes in human blood at 37°C and pH 7.4), necessitating continuous intravenous infusion 1
• The drug is rapidly hydrolyzed at neutral pH in blood and undergoes enzymatic degradation 1
• Steady-state plasma concentrations are reached within 15 minutes of infusion and are proportional to infusion rates 1
• Epoprostenol is extensively metabolized to two primary metabolites (6-keto-PGF1α and 6,15-diketo-13,14-dihydro-PGF1α), both with pharmacological activity orders of magnitude less than the parent compound 1

Clinical Implications of Mechanism

The dual mechanism of vasodilation and platelet inhibition explains why epoprostenol is the only PAH therapy proven to reduce mortality in randomized controlled trials. 8 The combination of reduced pulmonary vascular resistance, improved cardiac output, prevention of in situ thrombosis, and potential vascular remodeling effects creates a comprehensive therapeutic approach that addresses multiple pathophysiological mechanisms underlying PAH 3, 1.