Endothelin receptor Antagonists are oral medications approved to treat patients with pulmonary hypertension to help them feel better (have fewer symptoms), do more (improved exercise ability) and slow down disease progression.
Current ERAs that are FDA-approved in adults include:
Endothelin receptor antagonists (ERA) work by blocking the pathway for endothelin, a mediator that is produced by the lining of the pulmonary vessels. Endothelin levels are abnormally elevated in pulmonary hypertension 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 this agent allows the blood vessels of the lungs to relax and can slow the progression of pulmonary hypertension.
Some patients may experience leg swelling. If you experience this side effect, you should let your doctor know for further evaluation. Elevated liver enzymes have been found to occur in patients treated with ERAs. With bosentan, patients are required to complete monthly liver function testing because of this side effect and risk for liver failure if not monitored.
Your doctor will monitor your blood work at regular intervals based on your risk and the type of ERA you are receiving. Reduced red blood cell counts may also occur in some instances. Discuss 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 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 a ERAs. If a patient is female and in the reproductive age group, you will be required to use two forms of contraception and complete take 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. In pediatrics when these medications are used, parents may have to cut and dissolve in water to make a suspension, and this leads to a risk of breathing in pill particles.
Phosphodiesterase inhibitors (PDE5Is) are oral medications FDA-approved to treat adults with pulmonary hypertension to help them feel better (fewer symptoms), do more (improved exercise ability) and slow down 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 pulmonary hypertension, 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 pulmonary hypertension 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 PH
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.
The use of PDE5Is at the same time you are using nitrates, other phosphodiesterase inhibitors (such as sildenafil used for erectile dysfunction), riociguat (another medication used for PH) and/or alpha blocking medications (medications for high blood pressure) is contra-indicated 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 is another medication that acts on the nitric oxide pathway (similar to PDE5I) to help patients with pulmonary hypertension 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 pulmonary hypertension, nitric oxide levels are reduced, leading to narrowing and thickening of the vessels and increased pressure. Riociguat helps to restore normal effects of nitric oxide, thereby allowing pulmonary vessels to relax and reducing the pressure.
It is currently approved for use in group 1 pulmonary arterial hypertension and group 4 pulmonary hypertension due to chronic thromboembolic disease (due to blood clots).
Headache, nausea, vomiting, low blood pressure, anemia (low red blood cell counts), nasal congestion and heart burn 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 take monthly pregnancy tests to continue this medication safely. If you would 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 pulmonary arterial hypertension. 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 pulmonary arterial hypertension.
Of note, epoprostenol has a short duration of action with a half-life of about 3 to 5 minutes.
Given the short duration of action of epoprostenol, delivery via continuous IV infusion is necessary. Patients will need a long-term intravenous (IV) 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.
Of note, the original formulation of epoprostenol is not stable at room temperature and needs refrigeration while stored and ice packs while being infused. Epoprostenol is available as a generic formulation. Other formulations of epoprostenol such Flolan and Veletri (which is stable at room temperature) are now also available.
Jaw pain, 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 the dose is increased and usually become milder as the body gets used to this medication.
Given the short duration of action of epoprostenol, sudden discontinuation in therapy can be dangerous and lead to 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.
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 update your PH Team if you develop any signs of systemic infection like fever or chills.
Epoprostenol clearance is reduced in patients with liver insufficiency and lower doses may be needed to ensure tolerability. Epoprostenol use has not been studied in patients with kidney failure, and similar issues with tolerability may occur, necessitating a change in the dose of epoprostenol.
https://www.veletri.com/
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.
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). Based on the severity of your disease and your ability to manage this medication, your PH team will decide which one is most suitable for you.
Intravenous and Subcutaneous treprostinil:
Jaw pain, 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 the dose is increased and usually become milder as the body gets used to this medication.
Sudden discontinuation in therapy can be dangerous and lead to rebound pulmonary hypertension which can be life threatening. If your medication is interrupted or suddenly discontinued, please let your doctor know immediately and go to the closest hospital ER to have it restarted. You may need to call EMS for immediate help.
Having an intra-venous catheter may also 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 update your PH Team if you develop any signs of systemic infection like fever or chills.
For patients on subcutaneous treprostinil, the injection site is placed by the patient, will cause some pain at the site for a short period after starting and then the pain will subside. After a period of time that can be several weeks or longer, the site will become painful and the patient will need to put in a new site and take out the old one.
Treprostinil clearance is reduced in patients with liver insufficiency and lower doses may be needed to ensure tolerability. Treprostinil use has not been studied in patients with kidney failure, and similar issues with tolerability may occur, necessitating a change in dose.
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 pulmonary arterial hypertension (PAH) and with group 3 pulmonary hypertension due to lung tissue changes (interstitial lung disease).
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) 4 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, headache, gastrointestinal effects, muscle, jaw or bone pain, dizziness, flushing and low blood pressure.
Please let your doctor know if you experience any of the above side effects.
https://www.tyvaso.com/pdf/TYVASO-PI.pdf
https://www.tyvaso.com/pah/
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 pulmonary arterial hypertension (PAH).
Headache, gastrointestinal effects, muscle, jaw or bone pain, dizziness, flushing and low blood pressure and are similar to other forms of treprostinil.
Sudden discontinuation of oral treprostinil can lead to worsening pulmonary hypertension and therefore medication adherence is important. If a patient misses a dose, they should take the missed dose as soon as possible.
https://www.orenitram.com/
Selexipag is a prostacyclin receptor agonist which acts by directly binding to and activating prostacyclin receptors and helps to treat pulmonary hypertension in a similar manner to other prostacyclins.
It is currently approved for group 1 pulmonary arterial hypertension.
Selexipag can be delivered orally (by mouth) or intravenously (IV).
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.
Medication adherence to selexipag is important and missed doses can lead to worsening pulmonary hypertension.
https://uptravi.com
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 ‘vasoreactive 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 vasoreactive 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.
Calcium channel blockers for long term use are given as an oral medication. IV formulations of calcium channel blockers do exist which can be for patients in the hospital.
Headaches, flushing, leg swelling and light-headedness are some of the commonly seen side effects.
