Medications for Pulmonary Arterial Hypertension
Medically reviewed by Femi Aremu, PharmD
Pulmonary hypertension (PH) can be challenging for healthcare professionals to diagnose because of its vague symptoms, such as fatigue and shortness of breath.
These symptoms, which may be mild initially, can sometimes lead to a misdiagnosis, such as asthma or heart failure.
In fact, a recent study suggests that board-certified physicians specializing in heart and lung conditions may correctly suspect PH less than 50% of the time.
Related to PH, healthcare providers may also deal with the diagnosis and treatment of pulmonary arterial hypertension (PAH), a specific type of PH characterized by hypertension (high blood pressure) in the pulmonary arteries.
Because PAH can be severe and often challenging to treat, it can lead to severe short- and long-term health challenges.
Read on to learn more about the medications available to treat PAH, including the drug classes and specific drugs that make up these categories.
Dobrila Vignjevic / Getty Images
PAH: Prevalence, Symptoms, and Health Risks
PH is defined as high lung blood pressure with various underlying causes.
In comparison, PAH is a rare and gradually worsening condition in which the blood pressure in the pulmonary arteries becomes too high.
These arteries carry blood from the right side of the heart through the lungs. When this pressure gets too high, the arteries in the lungs become more narrow. This limits blood flow, thus resulting in less oxygen in the blood.
If left untreated, PAH makes the right side of the heart work much harder, which can eventually weaken or damage the heart, leading to right heart failure and even death.
Right heart failure occurs when the heart is too weak to pump adequate blood supply to the lungs.
At-Risk Population(s)
PAH is rare, affecting 1 to 2 out of every 1 million people in the United States.
PAH most commonly affects females between ages 30 and 60, occurring three out of five times more frequently in females than males.
Roughly 1,000 new cases are diagnosed in the United States yearly, with a five-year survival rate of 61%.
Symptoms
The most common symptoms of PAH are shortness of breath and chest pain, especially when walking or engaging in other physical activity.
Other symptoms of PAH include:
Shortness of breath
Chest pain
Swelling of the feet, legs, abdomen, or neck
Causes
Experts don't know precisely what causes PAH. It may be genetic or caused by certain toxins or drugs.
There’s no cure for this condition, but many treatments are available to manage the symptoms and help maintain quality of life.
Pharmaceutical Treatment Options
The number of treatment options for PAH has grown over the past few decades.
The main classes of drugs prescribed to manage this condition include:
Prostacyclin analogs
Endothelin receptor antagonists (ERAs)
Soluble guanylate cyclase (sGC) stimulators
The following subsections will discuss different categories of PAH medications and the specific drugs that make up these categories.
Prostacyclin Analogs
Prostacyclin analogs were the first class of drugs approved for treating PAH. They work by mimicking the effects of a natural hormone called prostacyclin.
Their mechanism of action includes stopping platelets from forming clots in your blood vessels and causing vasodilation of the pulmonary arteries.
When these blood vessels relax and widen, blood flows more efficiently, reducing the pressure.
Prostacyclin analogs are a standard long-term treatment for severe PAH.
Flolan (epoprostenol) was the first drug in this class. It is used in severe cases if other treatments aren’t working well enough.
Prostacyclin analogs come in several forms. They may be given as intravenous (IV, within a vein) infusions, subcutaneous (under the skin) injections, or inhalation. An oral tablet option is also available as Orenitram (treprostinil).
Potentially serious side effects include hypotension (low blood pressure) and an increased risk of bleeding. It’s important not to stop or reduce the dosage of prostacyclin analogs abruptly. Doing so may cause sudden worsening of PAH symptoms.
A similar and newer drug, Uptravi (selexipag), has a comparable mechanism of action as a prostacyclin receptor agonist. It also mimics the effects of the natural hormone prostacyclin.
While not a complete list, the table below compares key details of three prostacyclin analog drugs, including when they were approved by the Food and Drug Administration (FDA):
Drug name: | Flolan (epoprostenol) | Remodulin (treprostinil) | Ventavis (iloprost) |
FDA approval year: | • 1995 | • 2002 | • 2004 |
How it’s given: | • Continuous infusion, intravenous | • Continuous infusion, intravenous or subcutaneous | • Inhalation via special nebulizer system |
FDA-approved for use in adults or children?: | • Adults | • Adults | • Adults |
Typical dosage: | • 2 nanograms per kilogram of body weight per minute (ng/kg/min) | • 1.25 ng/kg/min | • 2.5–5 micrograms (mcg) inhaled via nebulizer six to nine times per day (no more than once every two hours during waking hours) |
Most common side effects: | · Dizziness · Headache · Muscle pain | · Headache · Nausea | · Flushing |
Endothelin Receptor Antagonists (ERAs)
Endothelin receptor antagonists (ERAs) work by binding to a substance called endothelin and blocking its effects. Endothelin is a small protein that causes blood vessels to constrict or narrow, thus raising blood pressure.
ERAs block endothelin-related effects on the smooth muscle cells lining your blood vessels.
This causes your blood vessels to relax and widen, which lowers pressure, reduces strain on the heart, eases PAH symptoms, and improves tolerance of physical activity.
ERAs are prescribed to help slow the progression of PAH.
ERAs carry serious risks, including a black box warning, the most severe type of warning from the FDA, due to the risk of congenital disabilities.
Due to this risk, females with reproductive potential are required to enroll in a particular program, take regular pregnancy tests, and use acceptable forms of birth control.
ERAs also pose risks of severe liver injury or liver failure, such as in the case of Opsumit (macitentan), Tracleer (bosentan), and Letairis (ambrisentan).
The table below summarizes critical details about three ERAs:
Drug name: | Tracleer (bosentan) | Letairis (ambrisentan) | Opsumit (macitentan) |
FDA approval year: | • 2001 | • 2007 | • 2013 |
How it’s given: | • Oral tablet, oral suspension | • Oral tablet | • Oral tablet |
Approved for use in adults or children?: | • Adults and children 3 and older | • Adults | • Adults |
Typical dosage: | • Ages 13+: 62.5 milligrams (mg) twice daily for four weeks then increase to 125 mg twice daily • Ages 12 and under: Given twice daily; specific dosage is based on child’s body weight | • 5 mg daily; Dose may be increased to 10 mg daily after a minimum of four weeks | • 10 mg once daily |
Most common side effects: | · Respiratory tract infection | · Swelling in the arms, legs, or feet · Stuffy nose · Flushing | · Anemia |
Phosphodiesterase-5 (PDE-5) Inhibitors
Phosphodiesterase-5 (PDE-5) inhibitors enhance the effects of nitric oxide in the body.
In other words, PDE-5 inhibitors cause blood vessels to open wider, improving blood flow and decreasing pressure. These medications are also used for erectile dysfunction.
Your body produces nitric oxide to relax blood vessels. Nitric oxide attaches to receptors on blood vessel walls, triggering the production of cyclic GMP (cGMP). cGMP signals your blood vessel muscles to relax, widening the vessels.
These drugs work by blocking an enzyme that would ordinarily break down cGMP. Taking the drug causes cGMP to build up, amplifying its relaxing effects on the blood vessels.
PDE-5 inhibitors should not be taken with nitrates or riociguat due to the risk of dangerously low blood pressure. PDE-5 inhibitors may also cause severe side effects such as vision changes and hearing loss.
The table below highlights some of the crucial details about a few drugs in this class that are approved for treating PAH:
Drug name: | Revatio (sildenafil) | Adcirca (tadalafil) | Tadliq (tadalafil) |
FDA approval year: | • 2005 (originally approved in 1995 as Viagra) | • 2009 (originally approved in 2003 as Cialis) | • 2022 (originally approved in 2003 as Cialis) |
How it’s given: | • Oral tablet, oral liquid suspension, or intravenous infusion | • Oral tablet | • Oral suspension |
Approved for use in adults or children?: | • Adults and children 1 year and older | • Adult | • Adult |
Typical dosage: | • Adults: 20 mg taken by mouth three times a day or 10 mg given IV three times a day | • 40 mg once daily | • 40 mg once daily |
Most common side effects: | · Headache | · Headache | · Headache |
Soluble Guanylate Cyclase (sGC) Stimulators
SGC is a substance produced in the body that causes the blood vessels in the lungs to dilate (become wider). This process is similar to the PDE5 inhibitors, so these two medicine classes aren't taken together.
Adempas (riociguat) is the only drug in its class of soluble guanylate cyclase (sGC) stimulators.
The drug is FDA-approved to treat PAH, more specifically, to improve tolerance for activity, reduce symptom severity, and delay clinical worsening.
Note that sGC stimulators carry a black box warning due to toxic effects on a developing fetus and are therefore unsafe to take during pregnancy.
Like PDE-5 inhibitors, riociguat stimulates increased cGMP production, leading to relaxation and widening blood vessels, thus lowering pressure.
Additionally, riociguat also offers protection against fibrosis (scar tissue) in the lungs.
Irritation in the lungs can lead to fibrosis and inflammation. However, riociguat can combat this and aid in diminishing pulmonary fibrosis.
The table below summarizes other vital details about Adempas:
Drug name: | Adempas (riociguat) |
FDA approval year: | • 2013 |
How it’s given: | • Oral tablet |
Approved for use in adults or children?: | • Adults |
Typical dosage: | • 1 mg taken three times a day to start; dose may be increased by 0.5 mg every two weeks up to a maximum of 2.5 mg taken three times daily (total dose of 7.5 mg per day) |
Most common side effects: | · Headache |
Calcium Channel Blockers (CCBs)
CCBs are a group of medications that treat conditions affecting the heart and blood vessels, including hypertension.
Norvasc (amlodipine), a popular CCB, works by blocking calcium from entering cells, which helps relax smooth muscles in blood vessels, making them more comprehensive and reducing pressure.
Other PAH CCBs include Procardia XL (nifedipine) and Cardizem CD (diltiazem).
Common side effects of CCBs include dizziness, constipation, flushing, headache, and swelling in the ankles or feet. Some individuals may also experience heart palpitations.
However, these drugs aren’t specifically FDA-approved for this purpose.
Unfortunately, CCBs only seem helpful for a small percentage of people with PAH.
Combination Therapies for PAH
As explained above, the current drug therapies for PAH work by targeting one of the following three main pathways:
Nitric oxide/cGMP, targeted by PDE5 inhibitors and riociguat
Endothelin, targeted by ERAs
Prostacyclin, targeted by prostacyclin analogs
In some cases, healthcare providers might recommend combining more than one type of medication for PAH.
The goal of combination therapy is to target multiple pathways involved in PAH at the same time. Typically, combination therapy is prescribed for people with severe PAH.
Combination therapies for PAH often include:
Combination of Opsumit (macitentan) + PDE-5 Inhibitor: Combining macitentan, an ERA, with a PDE-5 inhibitor, such as tadalafil, will target both the endothelin and nitric oxide/cGMP pathways at the same time, resulting in improved dilation (widening) of the pulmonary blood vessels. The combination may substantially reduce pulmonary artery pressure than a single drug alone, potentially leading to better symptom management and improved walking or other physical activity tolerance.
Uptravi (selexipag) + ERA: Combining Uptravi (selexipag) and an ERA drug, such as Opsumit (macitentan), targets the endothelin pathway from two different angles. Selexipag is a prostacyclin receptor agonist that widens blood vessels, and the ERA blocks endothelin’s constricting effect on blood vessels. So, this drug combination works synergistically to reduce pulmonary artery constriction and inflammation, improving blood flow through the lungs and reducing workload on the right side of the heart.
The choice between these two combination regimens depends on the patient’s needs.
Your healthcare team will determine the proper treatment approach based on your PAH severity and how well you’ve tolerated previous treatments.
Summary
Various treatment options are available for pulmonary arterial hypertension (PAH).
Medications like prostacyclin analogs and endothelin receptor antagonists help relax blood vessels in the lungs, making it easier for the heart to pump blood and improve your tolerance of physical activity.
PDE-5 inhibitors, soluble guanylate cyclase (sGC) stimulators, and calcium channel blockers are commonly used to manage symptoms.
Oxygen therapy can also be used to increase oxygen levels in the blood. In some cases, surgeries might be an option.
Treatment choices depend on the severity of your PAH (based on the WHO classification system). A healthcare provider can discuss the best treatment plan for you.
Regular checkups and monitoring are vital for people living with PAH to ensure optimal management and a better quality of life.
Research is ongoing to develop new treatments for PAH. A new drug called elafin is being investigated for treating PAH and seems to prevent inflammation and blood vessel damage.
Likewise, the Pediatric Pulmonary Hypertension Network continues investigating PAH treatment options for children.
Frequently Asked Questions
What is the role of oxygen supplementation in managing PAH?
When you breathe, your lungs take in oxygen, which gets carried throughout your body in your blood. However, trouble breathing is a common symptom of PAH.
Oxygen therapy boosts the amount of oxygen in your blood, making it easier to breathe, and helps your body deliver oxygen-rich blood throughout your tissues and organs.
What is the role of anticoagulants in managing PAH?
PAH increases the risk of lung blood clots, which can be life-threatening. Anticoagulants, such as Jantoven (warfarin), can reduce this risk in people with PAH.
Also known as blood thinners, these drugs help prevent blood clots from forming in the blood vessels.
What are some non-drug strategies for managing PAH?
Besides medications, some people may have surgeries to manage PAH. Receiving a lung transplant is an option for severe PAH.
In addition, supportive lifestyle habits include following a healthy diet, watching your salt intake, and remaining as physically active as possible.
Read the original article on Verywell Health.
