How do Endothelin Receptor Antagonists (ERAs) work in Pulmonary Arterial Hypertension (PAH)?

From the Guidelines

Endothelin receptor antagonists (ERAs) are a crucial medication class for treating pulmonary arterial hypertension (PAH) by blocking the effects of endothelin-1, a potent vasoconstrictor that contributes to PAH pathophysiology, as evidenced by studies such as 1. ERAs work by selectively blocking endothelin receptors (either ETA selectively or both ETA and ETB receptors), which prevents vasoconstriction and vascular smooth muscle proliferation in pulmonary arteries. Common ERAs used in PAH include:

• Ambrisentan (5-10 mg once daily)
• Bosentan (62.5-125 mg twice daily)
• Macitentan (10 mg once daily) These medications effectively reduce pulmonary vascular resistance, improve exercise capacity, delay clinical worsening, and may improve survival in PAH patients, as shown in studies like 1 and 1.

Key Benefits of ERAs

• Improve exercise capacity
• Delay clinical worsening
• May improve survival
• Reduce pulmonary vascular resistance

Side Effects and Monitoring

Side effects include:

• Liver function abnormalities (particularly with bosentan, requiring monthly monitoring) 1
• Peripheral edema
• Anemia
• Potential teratogenicity (pregnancy category X) Regular monitoring of liver function, hemoglobin, and pregnancy testing in women of childbearing potential is essential during ERA therapy.

Combination Therapy

Combination therapy, using two or more classes of drugs simultaneously, has been used successfully in the treatment of PAH, as discussed in 1. This approach can address multiple signaling pathways involved in the disease, including the prostacyclin pathway, the endothelin pathway, and the NO pathway.

Recommendations

ERAs are typically used as initial therapy in WHO Functional Class II-III patients, often in combination with phosphodiesterase-5 inhibitors or prostacyclins for more advanced disease, as recommended in 1 and 1. The choice of ERA and combination therapy should be individualized based on patient characteristics, disease severity, and response to treatment.

From the FDA Drug Label

Endothelin-1 (ET-1) is a potent autocrine and paracrine peptide. Two receptor subtypes, ETA and ETB, mediate the effects of ET-1 in the vascular smooth muscle and endothelium. The primary actions of ETA are vasoconstriction and cell proliferation, while the predominant actions of ETB are vasodilation, antiproliferation, and ET-1 clearance In patients with PAH, plasma ET-1 concentrations are increased as much as 10-fold and correlate with increased mean right atrial pressure and disease severity. Ambrisentan is a high-affinity (Ki=0.011 nM) ETA receptor antagonist with a high selectivity for the ETA versus ETB receptor (>4000-fold).

ERA's Mechanism of Action: Endothelin receptor antagonists (ERAs) like ambrisentan work by blocking the endothelin type-A (ETA) receptor, which is responsible for vasoconstriction and cell proliferation. By selectively blocking the ETA receptor, ERAs can help to reduce pulmonary vascular resistance and improve exercise ability in patients with PAH 2.

From the Research

Mechanism of Endothelin Receptor Antagonists (ERAs) in PAH

• ERAs work by blocking the action of endothelin-1 (ET-1), a potent vasoconstrictor that plays a significant role in the development and progression of pulmonary vasculopathy 3.
• By inhibiting the binding of ET-1 to its receptors, ERAs reduce pulmonary vascular resistance and improve exercise capacity, functional status, and clinical outcome in patients with PAH 4, 3, 5, 6.

Efficacy of ERAs in PAH

• ERAs have been shown to improve exercise capacity, as measured by the 6-minute walk distance (6MWD), and reduce symptoms such as dyspnea and fatigue 4, 5, 7.
• ERAs have also been shown to improve cardiopulmonary hemodynamics, including pulmonary artery pressure, pulmonary vascular resistance, and cardiac index 4, 5, 6.
• The efficacy of ERAs has been demonstrated in several randomized controlled trials, with improvements in functional class, exercise capacity, and clinical outcome 4, 3, 5, 6, 7.

Safety and Tolerability of ERAs

• ERAs are generally well-tolerated, with common side effects including headache, nausea, and diarrhea 4, 5, 7.
• However, ERAs can cause hepatic toxicity, and monitoring of liver function is recommended 4, 5, 7.
• The risk of hepatic toxicity is increased with certain ERAs, such as sitaxsentan, which has been withdrawn from the market due to reports of irreversible liver failure 5.

Comparison of ERAs

• Several ERAs are available, including bosentan, ambrisentan, sitaxsentan, and macitentan 3, 5, 7.
• Network meta-analyses have compared the efficacy and acceptability of these ERAs, with ambrisentan being considered the most appropriate therapy among the four ERAs for PAH patients 7.
• However, the choice of ERA should be individualized based on patient characteristics, disease severity, and comorbidities 6, 7.