Pulmonary arterial hypertension (PAH) is high blood pressure of the arteries that take blood from the right side of the heart to the lungs. PAH is a progressive disease that worsens over time, but treatment can slow its progression and improve both life expectancy and quality of life.

Treatment varies based on the type of PAH, symptoms, severity of symptoms, and other diseases or health conditions a person may have. Researchers have observed that factors like age, sex, race, and ethnicity play a role in which PAH medications people are prescribed and how effective treatments are.

Read on to learn six facts about PAH treatment and help educate yourself if you or a loved one has PAH.

1. Current Treatment Options Can Reduce Symptoms but Not Cure PAH

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

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 increase blood flow and reduce stress placed on the heart — specifically, the right ventricle.

The Three Pathways of PAH Medications

PAH medications work through three main pathways in the body and involve one of the following chemicals: prostacyclin, endothelin, and 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.

2. Some PAH Treatments Target the 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 the smooth muscle to relax. This relaxation of smooth muscle enlarges the opening of blood vessels, increasing blood flow to the entire body.

People with PAH do not make enough prostacyclin, so drugs that work on this pathway help 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 doctors’ first choice for treating the most severe forms of PAH.

Medications That Work via the Prostacyclin Pathway

In the United States, four primary medications for PAH mimic prostacyclin. All four need careful dose monitoring by a doctor:

• Epoprostenol (Flolan or Veletri) is administered intravenously.
• Treprostinil (Tyvaso) can be inhaled, given intravenously, or taken as a pill.
• Selexipag (Uptravi) is swallowed as a tablet.
• Iloprost (Ventavis) is inhaled.

3. Other PAH Treatments Work on the Nitric Oxide Pathway

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

People with PAH have low levels of nitric oxide in their lungs. This deficiency adds to the tightening of the arteries leading to the lungs, creating the high blood pressure and increased risk of blood clots seen in PAH.

In addition, an enzyme called phosphodiesterase-5 (PDE-5) 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 a person with PAH — who already have too little nitric oxide in the blood vessels of their lungs — it becomes even harder for their 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. Researchers have noted that doctors’ prescribing patterns for PDE-5 inhibitors may differ based on a person’s type of PAH, ethnicity, and race.

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

Medications That Work via the Nitric Oxide Pathway

Three main PDE-5 inhibitors help the body benefit from nitric oxide:

• Sildenafil (Revatio) is available as either a tablet or an oral suspension for adults.
• Tadalafil (Adcirca) comes in a tablet for adults.
• Vardenafil is not approved to treat PAH, but some studies show that it may improve the symptoms of PAH.

There is only one sGC stimulator approved by the FDA for PAH: Adempas, a formulation of riociguat, which is taken in tablet form.

4. The Final Group of PAH Drugs Affects the 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 the blood vessels of their lungs to narrow too much.

Medications that counteract the effect of endothelin are called endothelin receptor antagonists (ERAs). Because ERAs block endothelin, this group of medications helps promote relaxation of the blood vessels for people with PAH. Researchers have found some differences in ERA treatment effectiveness based on a person’s sex and race.

Medications That Work via the Endothelin Pathway

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

• Ambrisentan (Letairis or Volibris)
• Bosentan (Tracleer)
• Macitentan (Opsumit)

5. PAH Severity Determines the Choice of Medication

Doctors prescribe different PAH medications based on 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 a slight restriction to physical activity
• Class 3 — People with PAH who experience moderate limits on 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 on someone with PAH. This test allows a doctor to check if the 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 2, doctors do not usually recommend prostacyclin, endothelin, or nitric oxide pathway drugs.

If a CCB is not effective or vasodilator testing does not work, 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. The treatment may be prescribed as 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.

6. Most People Take a Combination of Medications for PAH

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

One clinical trial examined using ambrisentan and tadalafil together in 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 using either 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 decrease the risk of heart failure.

Be sure to talk to your doctor when starting, switching, or combining medications for PAH. Based on the severity and symptoms of your PAH, they can help determine the best treatment plan for you.

Talk With Others Who Understand

On myPHteam, the social network for people with pulmonary hypertension and their loved ones, more than 48,000 members come together to ask questions, give advice, and share their stories.

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