Breaking Down Medication And New Therapies For Pulmonary Hypertension

Pulmonary hypertension is an uncommon ailment. Although there is no cure for pulmonary hypertension, there are therapy alternatives, and more are on the way. Traditional medical remedies, as well as inhaled, oral, subcutaneous (into the skin), and intravenous (into the vein) choices, are among the options available. Depending on the severity of the condition, a lung or heart transplant may be possible.

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What is pulmonary hypertension?

Pulmonary hypertension is a type of high blood pressure that impacts lung arteries and the heart's right side. The lung arteries are constricted, obstructed, or damaged when you suffer from pulmonary hypertension. The deterioration slows down blood flow through the lungs, elevating blood pressure. Consequently, the heart has to work even harder to push blood around the lungs. The increased effort gradually weakens the heart muscle, which ultimately can malfunction.

In some cases, pulmonary hypertension develops slowly without notice and can still be life-threatening. While pulmonary hypertension has no cure, treatment can help manage symptoms and improve quality of life. People with pulmonary hypertension used to live up to 5 years after diagnosis, but with recent developments, they can now live up to 20 years

Causes

Pulmonary hypertension can occur in the context of a variety of different illnesses, including lung and heart disease. Some common causes of pulmonary hypertension include high blood pressure in the lung arteries due to some inherent heart conditions, coronary artery and connective tissue disorders, liver disease (cirrhosis), and other chronic lung conditions. Genetics is also a factor.  

Symptoms

With pulmonary hypertension, you may not notice any signs at first. It typically begins slowly and worsens with time. The most prominent symptom is shortness of breath with activity. You may start to realize that you can no longer accomplish some of the activities you were accustomed to.

Other signs and symptoms include:

  • Fatigue

  • Chest pain or pressure

  • Passing out

  • Swollen legs, ankles, and eventually the abdomen

  • Heart palpitations

  • Bluish lips and skin

Common treatment options

There are several FDA-approved treatment options for pulmonary hypertension. Your doctor will select the one that works best for you. Most patients receive medical therapy to help them breathe better, making it simpler to be active and do everyday activities.

If you run out of breath or have decreased blood oxygen levels, oxygen treatment can help. This involves breathing pure oxygen via nose-fitted apparatus called a nasal cannula. This can help you live longer with pulmonary hypertension.

Your doctor will prescribe blood thinners if there is potential for blood clotting. Other medications help your heart function better and prevent fluid from accumulating in your body. Calcium channel blockers may be prescribed if you have chronic pulmonary hypertension. These medications reduce blood pressure in your lungs and the entire body.

If calcium channel blockers aren't enough, your doctor may refer you to more specialized treatment options. These may include oral tablets, inhaled medications, or drugs administered through an IV.

If medications aren't working in more extreme situations, your physician may suggest a lung transplant or an atrial septostomy operation. An atrial septostomy is a temporary treatment for a patient with severe pulmonary hypertension that may qualify for a lung transplant and is not a permanent cure.

New treatment options for pulmonary hypertension

New treatments and therapies for pulmonary therapy are emerging. However, clinical trials are an effective way to try out new medication while improving outcomes for all. Some of these options are:

Initial triple and double therapy

Initial triple vs. double therapy is one of the recent developments in pulmonary hypertension medication. According to the TRITON study, initial triple oral medication improves hemodynamics, more commonly known as blood flow, in individuals with recently diagnosed pulmonary hypertension. TRITON is the first randomized controlled clinical study in this patient group to compare the effectiveness and safety of initial triple vs. double oral combination therapy.²

Headache, diarrhea, nausea, general body pain, jaw pain, and vomiting are the most prevalent adverse events reported at a greater rate with the triple vs. double therapy clinical trial. Blood flow and clinical characteristics improved significantly with an initial triple and initial double oral therapy in the TRITON trial of newly diagnosed pulmonary hypertension patients. The study found a link between this treatment model and better long-term outcomes. Further, the reported adverse events were consistent with the recognized safety standards for clinical trial medications.

Inhaled nitric oxide at higher doses

Inhaled nitric oxide is a recognized vasodilator that has recently been found to enhance physical activity in individuals with pulmonary fibrosis when administered at a dosage of 45g/kg ideal body weight per hour for two months.³ In the clinical trial, patients treated with higher doses of inhaled nitric oxide significantly improved in moderate to intense physical exercise. It resulted in a total 7% increase in total activity.

Pump-delivered epoprostenol

Blood widening medication, such as epoprostenol, decreases fluid buildup, pulmonary vascular resistance, and blood clotting and increases cardiac output by actively vasodilating the pulmonary artery. Epoprostenol works spontaneously with a half-life of fewer than 6 minutes, needing constant intravenous administration.

Because of its powerful vasodilating effects and narrow therapeutic threshold, sudden withdrawal or substantial dosage adjustments can induce severe rebound effects or even fatality. Users also run the risk of significant consequences, including sepsis and administration mistakes, because epoprostenol infusion necessitates the insertion of a central venous catheter.

NYU Langone developed an FDA-approved implantable pump to supply blood-vessel widening medication.

Stem cell therapy

The growing interest in cell-based gene treatments has aided in the demonstration of stem cells' positive and therapeutic function in the treatment of pulmonary hypertension. Stem cells can develop into other cell types and multiply to generate more cells through self-renewal.

Adult stem cells serve as the body's healing system, restoring mature tissues when damaged. They may now be isolated from various human sources, including bone marrow, adipose tissue, and umbilical cord blood shortly after delivery. They can develop into muscle, bone, cartilage, and other connective tissues.

The concept of cell repair underpins stem cell-based therapeutics. There are three types of stem cell therapies, namely:

  • Endothelial progenitor cell therapy

  • Mesenchymal stem cell therapy

  • Induced pluripotent stem cell therapy

These stem cell therapies improve blood flow by remodeling the vasculature of the pulmonary arteries. They also inhibit lung inflammation.

Gene therapy

Defective genes caused by mutations or gene expression errors may contribute to illness by boosting proliferation, harming endothelial cells, and disrupting the balance. As a result, developing safe and effective gene delivery methods is a viable strategy in treating pulmonary hypertension.

Gene therapy is an experimental technology that permits the transfer of nucleic acid into the cells of patients to cure a variety of ailments. A vast amount of data suggests that therapeutic delivery of specific genes to restore or regulate gene expression treats pulmonary hypertension and inhibits disease progression.

Many gene delivery techniques such as intranasal or oral administration using inhalation devices and intratracheal infusion can be employed. Furthermore, direct airway administration reduces systemic adverse effects and bypasses preliminary metabolism and absorption in the liver.

Riociguat

Riociguat is the sole medication presently licensed for WHO group 4 pulmonary hypertension. It helps patients with pulmonary hypertension increase their exercise tolerance blood flow and limit disease progression. Riociguat is typically well-tolerated, with headache, dizziness, stomach discomfort, swollen legs and hands, and hypotension being the most prevalent adverse effects.

Using riociguat during pregnancy is not safe as it carries the risk of causing defects. Pregnancy testing and counseling on contraceptive methods are required for women of reproductive age.

Smoking status should also be evaluated while on medication since it decreases riociguat concentrations by 50% to 60%, requiring greater dosages.⁴ 

Selexipag

The FDA has recently approved selexipag. It is an oral drug that increases pulmonary vasodilation, inhibits blood clotting, and improves artery structure. Selexipag has been shown to delay disease advancement and lower hospitalization risk. Selexipag offers the convenience of oral administration twice a day and may have lesser digestive tract side effects. The dose is started at 200μg twice a day and gradually increases weekly until the maximum tolerated dose (should not exceed 1600μg) is reached.

Iloprost

Iloprost is an inhalation formulation for pulmonary hypertension. Iloprost has been demonstrated in trials to increase exercise capacity. As iloprost remains active for only 25 minutes, it is delivered at a beginning dose of 2.5g administered six to nine times a day to achieve a therapeutic effect.

Because of the frequency of dosage, taking about 10 minutes every time, its usage is restricted in practice and is preferred for patients with chronic disease. It is widely tolerated, with the most common side effects being flushing and jaw pain. Due to the method of administration, additional adverse effects include cough and throat discomfort.

Treprostinil

Treprostinil is recommended for patients with rapid disease development. Treprostinil remains active for around 4 hours, which gives it greater flexibility and reduces the danger of rebound hypertension as opposed to epoprostenol. It is inhaled in a nebulizer and is prescribed for patients with exercise intolerance symptoms and those who need to transition off epoprostenol. Treprostinil is started at lower doses and adjusted according to effectiveness and tolerability.

Treprostinil infusion systems

The FDA-approved remunity pump delivery system offers three days of continuous subcutaneous treatment for people aged 22 and above. This system has a water-resistant minimalistic design, prefilled cassette convenience, and is programmable via wireless control. The delivery system was given marketing authorization in February 2021 and is available for purchase.

The cassettes for the pump are preloaded and given to the patient by a specialty pharmacy. Remodulin (ISR) is also being developed as an implantable device that will allow patients to receive IV medication without using an external pump, reducing infection risk, IV malfunctions, and discomfort.⁵

The Trevyent PatchPump system, designated as an orphan drug in 2016, is made to provide treprostinil for two days (48 hours) with less discomfort at administration. The pump comes pre-filled and ready to use.

Sotatercept

Sotatercept is a first-in-class medicine that can help restore vascular homeostasis.⁶ Every three weeks, it is given as a subcutaneous injection. Sotatercept in conjunction with background therapy successfully improves the condition of pulmonary hypertension patients. Some side effects are headache, diarrhea, swollen hands and feet, dizziness, fatigue, low potassium levels, and nausea.

The FDA has designated sotatercept as a breakthrough treatment, and the current phase 3 randomized trial is evaluating a higher sotatercept dose every three weeks, with results expected in December 2022. 

The lowdown

As a result of advances in pharmacology and recent results from pivotal studies assessing the efficacy of various therapies, the therapeutic paradigm for pulmonary hypertension has shifted. New treatment options and better delivery formulations have been added to the arsenal for treating pulmonary hypertension. These medicines promise more convenience and the possibility of fewer adverse effects, and improved therapeutic outcomes.

Combined use of these medications has also improved efficacy and lowered the risk of mortality and disease progression. Early commencement of combination medicines and a personalized treatment plan is likely to improve survival.

  1. Assessment of survival in patients with primary pulmonary hypertension (2002)

  2. ​​Efficacy and safety of initial triple oral versus initial double oral combination therapy in patients with newly diagnosed pulmonary arterial hypertension (PAH): Results of the randomized controlled TRITON study (2020)

  3. A randomized, double-blind, placebo-controlled study to assess the safety and efficacy of pulsed, inhaled nitric oxide (iNO) in subjects at risk of pulmonary hypertension (PH) associated with fibrotic interstitial lung disease (fILD) on long term oxygen therapy (2020)

  4. Clinical pharmacokinetic and pharmacodynamic profile of riociguat (2018)

  5. Implantable system for remodulin post-approval study | ClinicalTrials.gov

  6. A study of sotatercept for the treatment of pulmonary arterial hypertension (PAH) | ClinicalTrials.gov

Other Sources:

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