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How Do Pulmonary Arterial Hypertension Medicines Work?

Posted on January 28, 2022
Medically reviewed by
Steven C. Pugliese, M.D.
Article written by
Andrew J. Funk, DC, DACNB

  • Pulmonary arterial hypertension (PAH) is high blood pressure of the arteries that run blood from the heart to the lungs.
  • PAH medications are vasodilators, which help relax and open the blood vessels between the heart and lungs.
  • A doctor may prescribe one medication or a combination, depending on the class of PAH you have

Pulmonary arterial hypertension is high blood pressure of the arteries that take blood from the right side of the heart to the lungs. PAH can make someone feel tired, or it can cause chest pain or difficulty breathing. Symptoms do vary. People with the mildest PAH may not have any symptoms, whereas people with the most severe PAH feel constant symptoms.

The U.S. Food and Drug Administration (FDA) has approved several medications to treat the symptoms of PAH. PAH is a rare but serious disease that can quickly worsen. Currently, there is no cure for PAH, but medication can slow the disease and also decrease symptoms.

PAH medications increase blood flow and reduce stress placed on the heart. (Adobe Stock)


Medications for PAH work as vasodilators, which means they help relax and open the blood vessels that run from the heart to the lungs. This helps to increase blood flow and take away stress placed on the heart — specifically the right ventricle.

The 3 Pathways of PAH Medications

PAH medications work through three main pathways in the body, involving one of the following chemicals: prostacyclin, endothelin, or nitric oxide. Treatment differs based on individual circumstances, so each person needs to work closely with their doctor to find out which medication suits them best.

Prostacyclin Pathway

The inner layer of all blood vessels in the body is made up of cells called vascular endothelial cells. These produce a chemical called prostacyclin, which connects to a receptor on the smooth muscle of all blood vessels.

Prostacyclin connects to this receptor much like how a key fits into the lock of a door. Once this connection is made, multiple chemicals interact, leading to a relaxation of the smooth muscle. This relaxation of smooth muscle causes the opening of blood vessels to become larger, thereby increasing blood flow to the entire body.

People with PAH do not make enough prostacyclin, so drugs that work on this pathway help to balance this deficiency.

Drugs that mimic prostacyclin cause blood vessels in the body to enlarge (systemic vasodilation). Health care professionals consider this group of medications to work well for the high blood pressure that accompanies PAH, but these drugs can have side effects. Drugs that work on this pathway are often the first option chosen by doctors to treat the most severe forms of PAH.

Medications That Work via the Prostacyclin Pathway

In the U.S., there are four primary medications for PAH which mimic prostacyclin. All four need careful dose monitoring by a doctor:

  • Flolan or Veletri (epoprostenol) is administered intravenously.
  • Tyvaso (treprostinil) can be inhaled, taken intravenously, or taken as a pill.
  • Uptravi (selexipag) is swallowed as a tablet.
  • Ventavis (iloprost) is inhaled.

Nitric Oxide Pathway

The inner layer of vascular cells in all blood vessels of the body make nitric oxide. Nitric oxide relaxes and opens blood vessels, which is important for controlling blood pressure in the body. When the inner layer of a blood vessel makes nitric oxide, it travels to the smooth muscle and relaxes it. This allows blood vessels to open up and increase blood flow.

People with PAH have nitric oxide levels in their lungs that are too low. This nitric oxide deficiency adds to the tightening of the arteries leading to the lungs — creating the high blood pressure seen in PAH.

In addition, there is an enzyme called phosphodiesterase-5 (PDE-5) that lives in the walls of all blood vessels. The job of PDE-5 is to block the effect of nitric oxide.

When PDE-5 blocks the effect of nitric oxide in people with PAH — who already have too little nitric oxide in the blood vessels of their lungs — it is even harder for the body to relax the blood vessels that run from the heart to the lungs.

Medications that work on this pathway to block PDE-5 are known as PDE-5 inhibitors. A PDE-5 inhibitor allows the body’s nitric oxide to work more effectively to relax the blood vessels.

Nitric oxide also turns on another enzyme called soluble guanylate cyclase (sGC). This enzyme helps to increase blood flow in the entire body by causing vasodilation of all blood vessels. Medications that serve as sGC stimulators help the body to make more nitric oxide, thus decreasing PAH symptoms.

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Medications That Work via the Nitric Oxide Pathway

There are three main PDE-5 inhibitors that help the body benefit from nitric oxide:

  • Revatio (sildenafil) is available in either a tablet or powder for adults only.
  • Adcirca (tadalafil) comes in a tablet for adults.
  • Vardenafil is not approved to treat PAH. However, some studies show it may improve the symptoms of PAH.

There is only one sGC stimulator approved for PAH: Adempas (riociguat) in tablet form.

Endothelin Pathway

Endothelin is a molecule made in the inner layer of all vascular cells in the body. From there, endothelin travels to the deeper smooth muscle cells, leading to the narrowing of the blood vessels. People with PAH have too much endothelin, causing too much narrowing of the blood vessels of their lungs.

Medications that counteract the effect of endothelin are called endothelin receptor antagonists (ERAs). Since ERAs block endothelin, this group of medications helps to promote relaxation of the blood vessels for people with PAH.

Medications That Work via the Endothelin Pathway

Currently, there are three medications approved for PAH that work on the endothelin pathway. All three are available as tablets:

Why Take One Kind of PAH Medication Over Another?

Doctors prescribe different PAH medications based upon the severity of the disease. The World Health Organization (WHO) has established four functional classes of PAH:

  • Class 1 — People with PAH who have no limits on their physical activity
  • Class 2 — People with PAH that causes slight restriction to their physical activity
  • Class 3 — People with PAH who experience moderate limits on their physical activity
  • Class 4 — People with PAH who experience symptoms whether they are active or at rest

Determining the Best Treatment

Doctors will initially perform acute pulmonary vasodilator testing in someone with PAH. This test allows a doctor to check if someone’s lung arteries quickly relax in response to specific vasodilating medications.

If a person’s lung arteries relax and open up in response to this test, the doctor may prescribe a calcium-channel blocker (CCB) depending on the severity of PAH. If the CCB keeps a person’s PAH at class 1 or class 2, doctors do not usually recommend prostacyclin, endothelin, or nitric oxide pathway drugs.

If a CCB is not effective, or if vasodilator testing does not work, then a physician will prescribe a medication that affects one of the three pathways discussed above.

People with class 2 or 3 PAH who do not improve with vasodilator testing may begin endothelin or nitric oxide pathways drugs. They may be prescribed one drug or a combination.

People with class 4 PAH who do not improve with vasodilator testing may begin either endothelin or nitric oxide pathway drugs, along with a prostacyclin treatment.

Lastly, one study on 61 people with class 3 PAH found that if participants did not respond well to a PDE-5 inhibitor, some responded better to an sGC stimulator drug. However, the study authors noted that more research is needed on this subject.

Why Take a Combination of Medications for PAH?

Taking more than one group of PAH medication can improve quality of life for people with PAH. This strategy can also help people with PAH live longer.

One clinical trial examined using both ambrisentan and tadalafil together for 500 people with class 2 or 3 PAH who had not previously taken medication for the condition. Researchers found that the two drugs were more effective for treating PAH than either drug alone, although the combination therapy also had some side effects. Another study on 18 people with class 3 or 4 PAH showed that taking an endothelin receptor antagonist, a prostacyclin analog, and a PDE-5 inhibitor together helped to decrease the risk of heart failure.

Be sure to talk to your doctor when starting, switching, or combining medications for PAH. They can help you determine the best treatment plan for your PAH.

Talk With Others Who Understand

On myPHteam, the social network for people with pulmonary hypertension and their loved ones, more than 40,000 members come together to ask questions, give advice, and share their stories.

Are you living with pulmonary arterial hypertension? Which treatments have helped you? Share your experience in the comments below, or start a conversation by posting on your Activities page.

References
  1. The Prostacyclin Analogue Treprostinil in the Treatment of Pulmonary Arterial Hypertension — Basic & Clinical Pharmacological & Toxicology
  2. Recent Advances in the Management of Pulmonary Arterial Hypertension — F1000 Research
  3. What Is Pulmonary Hypertension? — American Thoracic Society
  4. Treating and Managing Pulmonary Arterial Hypertension — American Lung Association
  5. The Prostacyclin Pathway in Pulmonary Arterial Hypertension: A Clinical Review — Expert Review of Respiratory Medicine
  6. Pulmonary Hypertension — Medical Clinics of North America
  7. Prostacyclin Analogs — LiverTox
  8. Regulation of Nitric Oxide Production in Health and Disease — Current Opinion in Clinical Nutrition and Metabolic Care
  9. Nitric Oxide Deficiency in Pulmonary Hypertension: Pathobiology and Implications for Therapy — Pulmonary Circulation
  10. Therapies for Pulmonary Arterial Hypertension: Where Are We Today, Where Do We Go Tomorrow? — European Respiratory Review
  11. Nitric Oxide Pathway and Phosphodiesterase Inhibitors in Pulmonary Arterial Hypertension — Journal of the American College of Cardiology
  12. Therapy for Pulmonary Arterial Hypertension: Glance on Nitric Oxide Pathway — Frontiers in Pharmacology
  13. Vardenafil in Pulmonary Arterial Hypertension: A Randomized, Double-Blind, Placebo-Controlled Study — American Journal of Respiratory and Critical Care Medicine
  14. FDA Drug Safety Communication: FDA Clarifies Warning About Pediatric Use of Revatio (Sildenafil) for Pulmonary Arterial Hypertension — U.S. Food & Drug Administration
  15. Highlights of Prescribing Information: Adcirca — U.S. Food & Drug Administration
  16. Riociguat (Oral Route) — Mayo Clinic
  17. Endothelin Receptor Antagonists in Pulmonary Arterial Hypertension — European Respiratory Journal
  18. Endothelin Receptor Antagonists — Pulmonary Hypertension Association UK
  19. The WHO Functional Class — Pulmonary Hypertension Association UK
  20. Treatment Algorithm for PAH — Journal of the American College of Cardiology
  21. Acute Vasodilator Testing — Pulmonary Hypertension Association
  22. RESPITE: Switching to Riociguat in Pulmonary Arterial Hypertension Patients With Inadequate Response to Phosphodiesterase-5 Inhibitors — The European Respiratory Journal
  23. Are Two Drugs Better Than One for PAH? — Pulmonary Hypertension Association
  24. Initial Use of Ambrisentan Plus Tadalafil in Pulmonary Arterial Hypertension — The New England Journal of Medicine
  25. Upfront Triple Combination Therapy in Pulmonary Arterial Hypertension: A Pilot Study — European Respiratory Journal
All updates must be accompanied by text or a picture.
Steven C. Pugliese, M.D. is affiliated with the Hospital of the University of Pennsylvania in Philadelphia, serving as the director of the pulmonary embolism response team, co-director of the comprehensive pulmonary embolism program, and an assistant professor of clinical medicine. Review provided by VeriMed Healthcare Network. Learn more about him here.
Andrew J. Funk, DC, DACNB has held board certification in neurology with the American Chiropractic Neurology Board since 2015. Learn more about him here.

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