What are the treatment options for patients with pulmonary arterial hypertension (PAH) using ETa receptor antagonists, such as ambrisentan (Endothelin A receptor antagonist), bosentan (Endothelin receptor antagonist), or sitaxentan (Endothelin receptor antagonist)?

Endothelin Receptor Antagonists for Pulmonary Arterial Hypertension Treatment

For patients with pulmonary arterial hypertension (PAH), endothelin receptor antagonists (ERAs) including bosentan, ambrisentan, and sitaxsentan are effective treatment options, with bosentan recommended as first-line therapy for functional class III patients and ambrisentan offering a favorable hepatic safety profile. 1

Mechanism of Action and Classification

• Endothelin-1 is a potent vasoconstrictor and smooth muscle mitogen that contributes to increased vascular tone and pulmonary vascular hypertrophy in PAH 1
• Two distinct endothelin receptor isoforms exist:
  • ETA receptors - facilitate vasoconstriction and proliferation of vascular smooth muscle cells 1
  • ETB receptors - involved in clearance of endothelin and can cause vasodilation and NO release 1
• ERAs are classified based on receptor selectivity:
  • Selective ETA antagonists: ambrisentan, sitaxsentan 1
  • Dual ETA/ETB antagonists: bosentan 1

Treatment Options by Functional Class

Functional Class II

• Limited data available for specific ERA recommendations
• Patients who failed or are not candidates for calcium channel blocker (CCB) therapy may benefit from ERAs 1
• Clinical trials enrollment encouraged 1

Functional Class III

• Bosentan is recommended with grade A recommendation (good evidence, substantial benefit) 1
• Ambrisentan is FDA-approved for functional class II-III patients 2
• Treatment algorithm prioritizes ERAs as first-line therapy along with prostanoids 1

Functional Class IV

• IV epoprostenol is the treatment of choice (grade A recommendation) 1
• Bosentan is recommended with grade B recommendation (fair evidence, intermediate benefit) 1

Specific Endothelin Receptor Antagonists

Bosentan

• Dual ETA/ETB receptor antagonist 1
• Dosing: 62.5 mg twice daily for 4 weeks, then increase to 125 mg twice daily 1
• Efficacy:
  • Improves exercise capacity (6-minute walk distance) 1
  • Improves functional class 1
  • Improves hemodynamics 1
• Safety concerns:
  • Hepatotoxicity - requires monthly liver function monitoring 1
  • Incidence of elevated aminotransferases (>3× normal): 10% at higher doses 1
  • Potential teratogenic effects - contraception required 1
  • Mild anemia may occur 1

Ambrisentan

• Selective ETA receptor antagonist 1
• FDA approved for PAH functional class II-III 2
• Dosing: 5 mg once daily, may increase to 10 mg 2
• Efficacy:
  • Improves exercise capacity - placebo-corrected treatment effects of 31-51 m in 6-minute walk distance 3
  • Improves WHO functional class 3
  • Improves time to clinical worsening 3
• Safety profile:
  • Lower risk of hepatotoxicity compared to other ERAs 3, 4
  • Most common adverse events: peripheral edema, nasal congestion, sinusitis, and flushing 2
  • Embryo-fetal toxicity - contraception required 2

Sitaxsentan

• Highly selective ETA receptor antagonist (6,000-fold more selective for ETA vs ETB) 1
• Not FDA approved in the United States (available in Europe, Canada, Australia) 1
• Efficacy:
  • Improves exercise capacity - 31.4 m improvement in 6-minute walk distance at 100 mg dose 5
  • Improves WHO functional class 5
• Safety concerns:
  • Associated with fatal hepatitis at higher doses 1
  • Increases INR/prothrombin time due to CYP2C9 inhibition (warfarin interaction) 1
  • Incidence of elevated hepatic transaminases: 3% at 100 mg dose 5

Important Monitoring and Safety Considerations

• Liver function tests:
  • Required monthly for bosentan 1
  • Less frequent monitoring needed for ambrisentan due to lower hepatotoxicity risk 3
• Pregnancy testing:
  • All ERAs are teratogenic 2
  • Monthly pregnancy tests required 2
  • Effective contraception mandatory during treatment and for one month after discontinuation 2
• Hemoglobin/hematocrit:
  • Monitor regularly, especially with bosentan which may cause mild anemia 1
• Drug interactions:
  • Sitaxsentan affects warfarin metabolism - requires dose adjustment 1
  • Cyclosporine increases ambrisentan exposure - limit dose to 5 mg daily 2

Transitioning Between ERAs

• Patients can safely transition from ambrisentan to bosentan without hemodynamic or hematologic deterioration 6
• Consider transitioning when:
  • Inadequate response to initial ERA
  • Development of side effects specific to one agent
  • Need for different dosing schedule

Comparative Effectiveness

• Bosentan and ambrisentan have comparable efficacy in improving exercise capacity 4
• Ambrisentan exhibits fewer hepatic side effects compared to bosentan 4
• Macitentan (newer ERA) has longer duration of action than both bosentan and ambrisentan 4

Common Pitfalls to Avoid

• Initiating ERAs without baseline liver function tests 1
• Failing to monitor for pregnancy in women of childbearing potential 2
• Using ERAs in patients with idiopathic pulmonary fibrosis (contraindicated) 2
• Not reducing warfarin dose when initiating sitaxsentan 1
• Empirical use of ERAs without assessing vasoreactivity first 1