How Medications Work to Help Improve Your PAH

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by United Therapeutics |

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Finding the right medications as part of your treatment plan for pulmonary arterial hypertension (PAH) may help improve your PAH symptoms while doing everyday activities. There are multiple classes of PAH medications, however, and knowing the difference between them can be difficult.

What’s Happening in My Body That’s Causing PAH Symptoms?

To understand how PAH medications work, knowing how PAH affects your body is the first step. PAH occurs when the blood vessels in the lungs narrow.

This narrowing slows blood flow and increases blood pressure in these vessels. The right side of the heart must then work harder to pump blood through these vessels. This increased workload weakens the right heart muscle over time, eventually leading it to fail.

PAH treatment centers around three substances produced by the inner layer of the smaller blood vessels in the lungs. These three important substances that help blood vessels stay healthy are:

  • Nitric oxide: Helps blood vessels stay open
  • Endothelin: Causes blood vessels to narrow
  • Prostacyclin: Helps blood vessels stay open, assists in preventing blood clots, and slows down rapid cell growth, which can prevent blood vessels from thickening

Proper levels of these substances help ensure that blood vessels stay open and blood flows normally. There is typically an imbalance in one or more of these substances, however, for those diagnosed with PAH.

Why is Treating More Than One Pathway Important For Most PAH Patients?

Each PAH medication is designed to work on one of the three substances, and treating a substance imbalance is also known as a “pathway”. In PAH, the treatment pathways are the nitric oxide pathway, the endothelin pathway, and the prostacyclin pathway.

Currently, there is no test available that determines which substances in your body are out of balance. This makes it difficult to know which pathways to treat. Clinical studies have shown that PAH patients generally respond better when more than one pathway is treated, leading researchers to conclude that many PAH patients have more than one imbalanced pathway.1

What Type of PAH Medications Are Used to Treat Each Pathway?

There are specific classes of medicine that treat each pathway. Each class of medicines works in a unique way to help improve the potential substance imbalance of the substance associated with a treatment pathway.

Pathways Chart

Nitric Oxide Pathway Medications

People with PAH often do not have enough nitric oxide in their bodies. There are two PAH medication classes – known as sGCS and PDE-5i class medications – that work on the nitric oxide pathway in two different ways.

The first way involves encouraging the binding of nitric oxide and soluble guanylate cyclase (sGC), which is a special enzyme in the body. This binding produces cyclic guanosine monophosphate (cGMP). cGMP is an important molecule that helps keep blood vessels from narrowing. A soluble guanylate cyclase stimulator (sGCS) class medication helps stimulate the body to produce more sGC, leading to more cGMP production. More cGMP supports healthier, less narrow blood vessels.

In comparison, the second way involves protecting cGMP by interfering with a process that leads to its breakdown. Phosphodiesterase type 5 (PDE-5) is a molecule in the body that naturally breaks down cGMP. When left unchecked, this breakdown of cGMP leads to less healthy and more narrow blood vessels. A phosphodiesterase type 5 inhibitor (PDE-5i) class medication works by preventing PDE-5 from breaking down cGMP.

Both sGCS and PDE-5i medication classes work on the nitric oxide pathway in different ways, but ultimately help cGMP to do its important work in keeping blood vessels open.2

Endothelin Pathway Medications

Endothelin is a substance in the body that causes blood vessels to narrow, and people with PAH often produce too much of it. Endothelin works to narrow blood vessels when it binds to certain receptors in blood vessel cells. An endothelin receptor antagonist (ERA) class medication interferes with that binding process, limiting the narrowing that endothelin causes in blood vessels.3

Prostacyclin Pathway Medications

People with PAH often have a lack of prostacyclin in their bodies. Prostacyclin binds to specific prostacyclin receptors. This binding leads to an increase of an essential molecule (cyclic adenosine monophosphate, or cAMP) that acts as a messenger in the body and helps trigger many biological functions. One of those functions is activating a protein known as protein kinase A.4 Protein kinase A works to help blood vessels stay open and prevent blood clots from forming. Protein kinase A also helps stop blood vessels from thickening by slowing rapid cell growth.5-7

Prostacyclin-class (PCY) medications work by inducing synthetic prostacyclin in the body. These medications act like natural prostacyclin and trigger the binding process that increases the messenger molecules that activate protein kinase A.4

Talk to a PAH Specialist About PAH Medications and Your Treatment Plan

Discussing all the medication classes available with a PAH specialist can help you find the right treatment plan. Not all cardiologists or pulmonologists have experience using each class of medication. A PAH specialist will consider all PAH medication classes and devise a treatment plan based on your risk status and PAH treatment guidelines.

If you are currently on a treatment plan and still experiencing symptoms, there may be more that you can do. Different classes of PAH medicines work in unique ways to improve your condition.

Talk with your doctor about each treatment pathway and all the classes of medications that are available. Doing so may help you and your doctor find the right medications and may allow you to do more daily activities with fewer symptoms getting in the way.

To learn more about PAH and treatment pathways, visit

This article was sponsored by the PAH Initiative, where knowledge meets inspiration. The PAH Initiative, sponsored by United Therapeutics, is dedicated to advancing patient care in pulmonary arterial hypertension.


  1. Galiè N, Channick RN, Frantz RP, et al. Risk stratification and medical therapy of pulmonary arterial hypertension. European Respiratory Journal. 2019; 53: 1801889. doi: 10.1183/13993003.01889-2018
  2. Parikh V, Bhardwaj A, Nair A. Pharmacotherapy for pulmonary arterial hypertension. J Thorac Dis. 2019; 11(Suppl 14): S1767-S1781. doi:10.21037/jtd.2019.09.14
  3. Dupuis J, Hoeper MM. Endothelin receptor antagonists in pulmonary arterial hypertension. European Respiratory Journal. 2008; 31(2): 407-415. doi: 10.1183/09031936.00078207
  4. Ruan CH, Dixon RA, Willerson JT, Ruan KH. Prostacyclin therapy for pulmonary arterial hypertension. Tex Heart Inst J. 2010; 37(4): 391-399.
  5. Yusuf MZ, Raslan Z, Atkinson L, et al. Prostacyclin reverses platelet stress fibre formation causing platelet aggregate instability. Scientific Reports. 2017; 7(1). doi:10.1038/s41598-017-05817-9
  6. Robinson-White A. Protein kinase-A activity in PRKAR1A-mutant cells, and regulation of mitogen-activated protein kinases ERK1/2. Human Molecular Genetics. 2003; 12(13): 1475-1484. doi:10.1093/hmg/ddg160
  7. Hopkins N, McLoughlin P. The structural basis of pulmonary hypertension in chronic lung disease: remodelling, rarefaction or angiogenesis?. J Anat. 2002; 201(4): 335-348. doi:10.1046/j.1469-7580.2002.00096.x

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