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.
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.
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.
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.
In the U.S., there are four primary medications for PAH which mimic prostacyclin. All four need careful dose monitoring by a doctor:
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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There are three main PDE-5 inhibitors that help the body benefit from nitric oxide:
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.
Currently, there are three medications approved for PAH that work on the endothelin pathway. All three are available as tablets:
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.
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.
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