Endothelin receptor antagonists are oral medications approved to treat patients with PAH to help them feel better (have fewer symptoms), do more (improved exercise ability), and slow disease progression.
Current ERAs that are FDA-approved in adults include:
Endothelin receptor antagonists (ERA) block the pathway for endothelin, a substance produced by the lining of the pulmonary vessels. Endothelin levels are abnormally elevated in PH, causing narrowing and thickening of the blood vessels of the lungs. This causes the pressure in the pulmonary vessels to increase. Blocking the action of endothelin allows the blood vessels of the lungs to relax and can slow the progression of PH.
Some patients may experience leg swelling. If you experience this side effect, you should inform your PH team for further evaluation. Elevated liver enzymes have been found to occur in patients treated with ERAs. With bosentan (Tracleer), patients are required to complete monthly liver function testing because of this side effect and risk for liver failure if not monitored. Reduced red blood cell counts may also occur in some instances. Some people experience sinus congestion.
Your doctors will regularly monitor your blood work based on your risk and the type of ERA you are receiving. Discuss the risks and benefits of your PAH therapy with your PH team before starting new medications and when you experience changes in symptoms or there is a concern for side effects.
ERAs are known to be teratogens, which means they can cause harm to an unborn baby. Pregnancy must be avoided when taking an ERA. Female patients who could possibly become pregnant are required to use two forms of contraception and complete monthly pregnancy tests to continue this medication safely. If the patient becomes pregnant while taking an ERA, the PH team should be called as soon as possible for guidance and care.
If you are a caregiver who could potentially become pregnant or are planning to be pregnant, you should avoid handling this medication if possible.
Please refer to the following sites:
https://www.tracleer.com/
https://www.janssencarepath.com/patient/opsumit/patient-support
https://www.letairis.com/patients/
https://phassociation.org/patients/treatments/ambrisentan/
https://www.opsynvi.com/
https://www.winrevair.com/?utm_source=bing&utm_medium=cpc&utm_campaign=Sotatercept_Brand%20Name%20Only_BRND_NA_ENGM_EXCT_TEXT_NA&utm_term=winrevair&utm_content=Brand%20Name&utm_kxconfid=ut5vrhsig&utm_brand=sotaterceptconsumer&&msclkid=a509d7ee6ecf16f32698b0ed6bd2566a&gclid=a509d7ee6ecf16f32698b0ed6bd2566a&gclsrc=3p.ds
Phosphodiesterase inhibitors (PDE5Is) are oral medications FDA-approved to treat adults with PAH to help them feel better (fewer symptoms), do more (improved exercise ability), and slow disease progression.
Currently approved PDE5Is include:
PDE5Is work by increasing the effects of nitric oxide in the blood vessels of the lung. Nitric oxide is normally produced by the lining of the blood vessels of the lung and causes the blood vessels to relax and prevents thickening. In PH, nitric oxide levels are reduced, leading to narrowing and thickening of the vessels and increased pressure. PDE5Is help to restore normal levels of nitric oxide, thereby allowing pulmonary vessels to relax and reducing the pressure.
Please note, sildenafil taken for the purposes of PAH is multiple times a day, as opposed to the as-needed use for erectile dysfunction, another indication for this medication. Tadalafil is longer acting and is taken once daily for PAH.
Some of the frequently seen side effects include headache, flushing, muscle pain, nasal congestion, nausea, and an upset stomach. It may also cause lower blood pressures throughout the body.
Certain medications are dangerous to use in combination with PDE5Is. You should not take nitrates, other phosphodiesterase inhibitors (such as sildenafil used for erectile dysfunction), riociguat or Adempas (another medication used for PH) and/or alpha blocking medications (medications for high blood pressure) if using PDE5Is, as this can lead to dangerously low blood pressure.
In rare instances, prolonged erection (called priapism) may occur. If this occurs, please contact your PH team immediately.
Riociguat (Adempas) is another medication that acts on the nitric oxide pathway (similar to PDE5I) to help patients with PAH and CTEPH feel better (fewer symptoms), do more (improved exercise ability) and slow down disease progression.
Riociguat is an oral guanylate cyclase inhibitor that works by increasing the activity of nitric oxide in the blood vessels of the lungs. Nitric oxide is normally produced by the lining of the blood vessels of the lung and causes the blood vessels to relax and prevents thickening. In PH, nitric oxide levels are reduced, leading to narrowing and thickening of the vessels and increased pressure. Riociguat helps to restore the action of nitric oxide, thereby allowing pulmonary vessels to relax and reducing the pressure.
It is currently approved for use in group 1 PAH and group 4 pulmonary hypertension due to chronic thromboembolic disease(CTEPH).
Headache, nausea, vomiting, low blood pressure, anemia (low red blood cell counts), nasal congestion and heartburn are some common side effects that may be seen.
In rare instances, serious bleeding may occur.
Riociguat is known to be teratogenic which means this medication can cause harm to an unborn baby. Pregnancy must be avoided when taking riociguat. If you are a female in the reproductive age group, you will be required to use two forms of contraception and complete monthly pregnancy tests. If you become pregnant while taking riociguat, you should call your PH team as soon as possible for guidance and care.
Epoprostenol was the first prostacyclin to be approved for use in PAH. It acts through the prostacyclin pathway causing the blood vessels of the lungs to relax and prevents thickening. It is usually produced by the lining of the blood vessels of the lungs; however, these levels are reduced in PAH.
Given the short duration of action of epoprostenol, delivery via continuous IV infusion is necessary. Patients require a long-term intravenous (IV) catheter connected to a battery powered medication pump which ensures a continuous flow of medication. Patients need to be comfortable with self-administration and have a reliable home support environment.
Of note, the original formulation of epoprostenol is not stable at room temperature and requires refrigeration while stored and ice packs while being infused. Epoprostenol is available as a generic formulation. Other formulations of epoprostenol such as Flolan and Veletri (which is stable at room temperature and does not require ice packs) are now also available.
Jaw pain/discomfort, headache, nausea, vomiting, diarrhea, and flushing are some of the commonly seen side effects. These are usually most pronounced when it is first started or as the dose is increased. Typically, these side-effects become more mild as the body gets used to this medication.
Of note, epoprostenol has a short duration of action with a half-life of about 3 to 5 minutes. Given this short duration of action of epoprostenol, sudden discontinuation in therapy can be dangerous and quickly lead to a condition called rebound pulmonary hypertension which can be life threatening. If your medication is interrupted or suddenly discontinued, please let your PH team know immediately and go to the closest hospital ER to have it restarted. Often you will need to call EMS for immediate help. Patients on epoprostenol therapy should always have access to a back up pump in case of pump failure.
Having an intravenous catheter can be associated with certain complications like clots in the catheter (catheter thrombosis) or infection of the catheter site. It is important to keep your catheter site clean and immediately notify your PH team if you develop any signs of infection such as fever, chills, or redness and or drainage around the catheter site
Epoprostenol dosing may need to be altered in patients who have liver disease or kidney failure. This is something that your PH specialist will take into account.
Treprostinil acts through the prostacyclin pathway causing the blood vessels of the lungs to relax and prevents thickening. It is usually produced by the lining of the blood vessels of the lungs; however, these levels are reduced in PAH.
Of note, treprostinil has a longer duration of action compared to epoprostenol, with a half-life of 3-4 hours.
Treprostinil can be administered via continuous intravenous infusion, subcutaneously (underneath the skin), inhaled and orally. Patients with IV infusions will need a long-term intravenous catheter connected to a battery powered medication pump which ensures a continuous flow of medication. Patients will need to be comfortable with self-administration and have a reliable home support environment.
Since treprostinil can be administered subcutaneously, this avoids some of the side effects of having an intravenous catheter (such as clots in catheter and infection). The decision of which delivery method is optimal is based on the severity of your disease, your ability to manage this medication, and conversations regarding risks and benefits between you and your PH team.
Intravenous and Subcutaneous treprostinil:
Treprostinil can be administered via continuous intravenous infusion, subcutaneously (underneath the skin), inhaled and orally. Patients with IV infusions will need a long-term intravenous catheter connected to a battery powered medication pump which ensures a continuous flow of medication. Patients will need to be comfortable with self-administration and have a reliable home support environment.
Since treprostinil can be administered subcutaneously, this avoids some of the side effects of having an intravenous catheter (such as clots in catheter and infection). The decision of which delivery method is optimal is based on the severity of your disease, your ability to manage this medication, and conversations regarding risks and benefits between you and your PH team.
Treprostinil acts through the prostacyclin pathway causing the blood vessels of the lungs to relax and prevents thickening. It is usually produced by the lining of the blood vessels of the lungs; however, these levels are reduced in pulmonary arterial hypertension.
This medication is approved for use in patients with group 1 PAH and with group 3 PH due to lung scarring (interstitial lung disease, also known as PH-ILD).
Inhaled treprostinil is administered through a specialized inhaler device that delivers the treprostinil to the lungs by the patient breathing in the medication. Your PH Team and specialty pharmacy nurses will show you how to use this device. Inhaled treprostinil needs to be taken up to 9 to 12 puffs (or the maximum tolerated dose) four times a day, and adherence is very important.
There is also a dry powder inhaler formulation delivered through a special hand-held inhaler device that is taken as one breath four times per day. Your PH Team and specialty pharmacy nurses will also show you how to use this device.
Some of the commonly reported side effects are cough and throat irritation. The side effects of headache, gastrointestinal effects, muscle, jaw or bone pain, dizziness, flushing and low blood pressure may be present as well, but are often less in patients who take this medication by inhalation instead of other routes.
Please let your PH team know if you experience any of the above side effects.
Treprostinil acts through the prostacyclin pathway causing the blood vessels of the lungs to relax and prevents thickening. It is usually produced by the lining of the blood vessels of the lungs; however, these levels are reduced in PAH.
This medication is approved for use in patients with group 1 PAH.
Orenitram comes in 5 tablet strengths and is taken with food to help absorb the medication, usually 3 times daily (every 8 hours).
Headache, gastrointestinal effects (nausea, diarrhea), muscle, jaw or bone pain, dizziness, flushing and low blood pressure can be seen.
Sudden discontinuation of oral treprostinil can lead to worsening PH and therefore medication adherence is important. If a patient misses a dose, they should take the missed dose as soon as possible.
Selexipag is a prostacyclin receptor agonist which acts by directly binding to and activating prostacyclin receptors and helps to treat PAH in a similar manner to other prostacyclins.
It is currently approved for group 1 PAH.
Selexipag is delivered orally (by mouth). Selexipeg comes in 8 tablet strengths and is taken twice daily. For people hospitalized and unable to take the oral pill, there is an intravenous form of selexipag available in some hospitals.
Side effects reported from selexipag are similar to other prostacylins and include headache, gastrointestinal effects, muscle, jaw or bone pain, dizziness, flushing and low blood pressure.
It is important to take selexipag regularly without interruption as missed doses can lead to worsening PAH.
Calcium channel blockers are medications that act by blocking the entry of calcium into the cells, thereby causing them to relax. Some commonly used calcium blockers are verapamil and diltiazem.
Calcium channel blockers may be indicated in a very select group of patients with PAH (Group 1 pulmonary arterial hypertension) who display a positive ‘vasoreactivity test’ during right heart catheterization. This test involves delivering a medication that causes the pulmonary arteries to relax during the right heart catheterization and subsequently measuring pressure changes. Only a small percentage of patients with PAH have a positive vasoreactivity test and will be started on calcium channel blockers. About half of the patients started on calcium channel blockers will respond well, indicating improved long term survival. Without a positive vasodilator test, using these medications may be detrimental.
Calcium channel blockers for long term use are given as an oral medication.
Headaches, flushing, leg swelling, low blood pressures and light-headedness are some of the commonly seen side effects.
Sotatercept was approved for use in the US in April 2024. It is a new class of medication that has been shown to help PAH patients already treated with vasodilator therapies. It is the first treatment that does not work mainly as a vasodilator - rather, it helps to address the blood vessel changes that cause PH directly. It has been shown to help patients feel better (fewer symptoms), do more (improved exercise ability) and prevent disease progression.
Sotatercept is taken as a self- or caregiver-administered subcutaneous (under the skin) injection every three weeks.
Sotatercept’s development stems from years of work to understand the BMPR2 pathway - the gene most common hereditary cause of pulmonary hypertension. The BMPR2 pathway is imbalanced in many patients with PH (not just those with a genetic form), and this is one of the root causes of the overactive growth within the lung blood vessels that leads to the development of PH. Sotatercept binds one of the key signaling molecules that causes the BMPR2 pathway dysfunction, helping to restore it to a more normal state. In animal studies of PH, it was shown to reverse some of the vessel changes that drive PH.
Sotatercept appears to cause a mild increased risk of bleeding - particularly nose bleeds. In some subjects it caused an increase in red blood cell count and/or a decrease in platelet count. Your PH team will monitor your blood counts with your first 5 doses, and intermittently thereafter. In addition, it has been noted that some patients may develop ‘telangiectasias’ - small red blood vessels (‘spider veins’) on the skin.
