Prostacyclin Receptor Agonists

General Pharmacology

Prostacyclin (PGI₂) is a product of arachidonic acid metabolism within vascular endothelium and is a potent vasodilator. PGI₂ released by the endothelium binds to prostacyclin (IP) receptors on vascular smooth muscle, leading to activation of the Gs-protein pathway, formation of cAMP, inhibition of myosin light chain kinase, and reduced myosin light chain phosphorylation. PGI₂ is also an important inhibitor of platelet adhesion to the vascular endothelium and is an inhibitor of vascular smooth muscle proliferation that occurs in disease states. These actions are similar to those of nitric oxide, which is also produced by the vascular endothelium, although nitric oxide acts through cGMP-dependent mechanisms. Endothelial dysfunction or damage, which occurs in atherosclerosis, for example, makes blood vessels more susceptible to vasospasm and thrombosis. 

Therapeutic Indications and Specific Drugs

The discovery of vasodilatory and antiplatelet actions of PGI₂ led to studies investigating the use of PGI₂ and specific analogues to treat vasoconstrictive and occlusive disorders.

One condition for which PGI₂ and its analogues are approved is pulmonary arterial hypertension (PAH). The rationale for using PGI₂ as a treatment is that idiopathic PAH is associated with reduced vascular production of PGI₂; therefore, drugs that bind to the IP receptor may help to restore the loss of an important vasodilator influence on the vasculature. 

Epoprostenol is a synthetic PGI₂ with a short half-life (3-5 min), which requires the use of continuous intravenous infusions. Iloprost was the first PGI₂ analog developed, and is formulated for administration by inhalation, which helps to reduce the systemic vasodilation. Treprostinil is a PGI₂ analogue that is distinguished by its much longer half-life. Formulations are available for this drug to be administered intravenously and subcutaneously by continuous infusion, orally, or by inhalation. Selexipag is an orally active IP receptor agonist that is structurally unrelated to the other IP agonists. Its active metabolite has a half-life of ~12 hr and therefore can be administered twice-daily.

Side Effects and Contraindications

Common side effects of IP receptor agonists include flushing, headaches, gastrointestinal (diarrhea/nausea/vomiting), musculoskeletal pain, and systemic hypotension. Epoprostenol is contraindicated in patients with severe systolic heart failure. The antiplatelet action of these drugs increases the risk of bleeding. Pulmonary edema can occur because of precapillary vasodilation.

Revised 11/30/2023