PH and PAH: Mechanisms of Action of Common Treatment Pathway

Brief review of the endothelin, prostacyclin, and nitric oxide pathways and how they are targeted in patients with PH or PAH.


Charles D. Burger, MD: The FDA-approved therapies for pulmonary arterial hypertension [PAH] target 1 of 3 pathways. Endothelin, more specifically endothelin-1, is produced by the body and causes the blood vessels to constrict or narrow by acting on the vascular smooth muscle cells in the wall of the blood vessel, causing it to tighten up. The idea is to block the effect of endothelin on the blood vessels, on the vascular smooth muscle cells specifically, allowing them to be more open so more blood flow can go through the lung and the heart doesn’t have to generate as high a pressure against that resistance. The heart can function more normally, and the patient has fewer symptoms. There are 3 medications that are FDA approved in that pathway that block the receptor to endothelin on the vascular smooth muscle cells. They’re called endothelin receptor antagonists: bosentan, macitentan, and ambrisentan.

A second pathway—and one that we probably understand the best, because historically it’s been the area of focus in which we’ve had medication for the longest period—is the prostaglandin pathway, or the prostanoid pathway. These agents are also produced by the body, but they open up blood vessels and help keep them healthy. You want to try to reproduce that effect in the body by giving a medication that acts as a prostaglandin, or is a prostaglandin, or acts on receptors and produces the same effect as the prostaglandin.

The third and final pathway is nitric oxide. Some folks get this confused with nitrous oxide, which is laughing gas. It’s not the same thing. Nitric oxide does open up blood vessels, and there are a variety of medications that are approved in this pathway. One of the 2 ways to impact nitric oxide is to increase production. Riociguat is being approved for Group 4 chronic thromboembolic disease and stimulates a pathway that increases the production of nitric oxide, the soluble guanylate cyclase pathway. The other medications block the breakdown of nitric oxide. They’re called PDE5 [phosphodiesterase-5] inhibitors, and they include sildenafil and tadalafil. They keep the nitric oxide the body has produced around longer, opening up blood vessels.

I will say that the long-term benefit of all 3 of these targeted pathways is what we call antiproliferation effect. It helps to heal the blood vessels, which have been scarred or changed morphologically to a certain extent. In the disease state, it helps the vessels go back toward a more normal anatomy, a more normal physiology, and a more normal functional state. It isn’t just the immediate effect of vasodilation, opening up blood vessels, it’s this antiproliferative benefit that’s very important and why the patients are generally on medication indefinitely.

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