Research Corner: The role of the prostacyclin pathway in PAH and the drugs targeting this pathway

Research Corner: New PH therapies, pathways and clinical trials


Contributed by Mohamad Taha, PH Researcher

In this issue, we will address some questions regarding PH therapy, more specifically, the role of the prostacyclin pathway in PAH and the drugs targeting this pathway.    

­—What is the prostacyclin pathway composed of?

This pathway is one of the crucial pathways controlling blood vessel relaxation/ tightening (vasodilation/vasoconstriction) in the lungs. A crucial molecule called prostaglandin H2 is produced within our cells. This molecule can either be converted into prostacyclin, one of the crucial molecules leading to blood vessel relaxation (vasodilation), or thromboxane, one of the crucial molecules leading to blood vessel tightening (vasoconstriction). Prostacyclin is usually produced in endothelial cells—the cells lining the inside of blood vessels—but then is taken up by smooth muscle cells—the cells constituting the second layer of a blood vessel and that is important for vessel contraction. To function, prostacyclin has to bind to its receptor on the cell surface, leading to relaxation (vasodilation) of the blood vessels. Thromboxane has an opposing effect to prostacyclin on blood vessels and can lead to increased formation of blood clots.

—How does this pathway work?

High levels of prostacyclin/low levels of thromboxane lead to blood vessel relaxation.  

Low levels of prostacyclin /high levels of thromboxane lead to blood vessel tightening, formation of blood clots.

—Why is this pathway important in PAH?

In PAH, there is a dramatic decrease in prostacyclin levels and higher levels of thromboxane production. This results in low blood vessel relaxation, and constant constriction, leading to narrowing of the blood vessels in the lungs. The effect of this is increased pressure in the lungs and pulmonary arteries. Furthermore, thromboxane can lead to formation of blood clots in blood vessels, which can contribute to Chronic Thrombo Embolic Pulmonary Hypertension (CTEPH, WHO class IV).

—What treatments target this pathway in PAH and how do they work?

Therapies attempt to enhance prostacyclin pathway in order to increase blood vessel relaxation. The first class of drugs is pure prostacyclin (Epoprostenol, Beraprost). The other class of drugs are prostacyclin analogs which act to stimulate blood vessel relaxation (Iloprost, Treprostinil). Recently, prostacyclin receptor activators were also developed and currently are being tested (Selexipag). These therapies all attempt to increase blood vessel relaxation and reduce chances of blood clot formation.

—Currently, which therapies targeting this pathway are approved for PAH in Canada?

The use of intravenous Epoprostenol (Flolan®, Caripul®, Veletri®) is approved in Canada. Treprostinil (Remodulin®) is also approved for both intravenous and subcutaneous delivery. For the full list, please click here.

—What does research show about these drugs? Which one is better?       

Unlike other PAH treatments, prostacyclin pathway targeted treatments are complex therapies with some adverse side effects (including headache, nausea, rash, diarrhea). Furthermore, many of those drugs are unstable at room temperature and degrade rapidly. Thus, treatments require administration by a center with expertise in the delivery systems (intravenous, subcutaneous or inhalation) and management of side effects. One cannot say that one drug is definitely better than another since each patient is affected differently by the disease and will have a different response to each drug. Thus, it is very important to discuss with a PH specialist which drug is most appropriate for each patient.


1) Irene M. Lang and Sean P. Gaine. “Recent Advances in Targeting the Prostacyclin Pathway in Pulmonary Arterial Hypertension.” European Respiratory Review Journal.

Please always keep in mind that while I can provide you with a small insight into PH research, you should always be able to get answers from your Pulmonary Hypertension Specialist, who is more familiar with your specific case and your treatment history.

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