Endothelins (ETs) are potent vasoactive peptides critical in the human body's various physiological and pathological processes. One of the most promising therapeutic strategies for treating pulmonary arterial hypertension (PAH) involves counteracting the effects of these endothelins using a class of drugs known as endothelin receptor antagonists.

ETs are synthesized through a complex sequence of enzymatic steps, primarily involving an enzyme referred to as endothelin-converting enzyme (ECE). Of particular interest is ECE-1, which acts as the rate-limiting step in synthesizing ET-1, the predominant form of endothelin within the body.

Upon synthesis, ET-1 interacts with two types of receptors — ET_A and ET_B. These interactions trigger biological responses within the body, including vasoconstriction and vasodilation, which can significantly impact blood pressure levels and contribute to conditions like PAH.

Currently, three main endothelin receptor antagonists are available for treating PAH: bosentan (Tracleer), macitentan (Opsumit), and ambrisentan (Letairis). All three drugs are administered orally and work by blocking the actions of ET-1 on its receptors. Bosentan and macitentan are non-selective antagonists, blocking both ET_A and ET_B receptors. This dual action helps alleviate PAH symptoms and slow disease progression. On the other hand, ambrisentan selectively inhibits the ET_A receptor alone, providing a more targeted approach to treatment.

Like all medications, endothelin receptor antagonists come with potential side effects. Common ones include headaches, pulmonary edema (fluid accumulation in the lungs), and nasal congestion or pharyngitis. Additionally, these drugs can lead to elevated liver transaminases, an indicator of liver damage. As such, they should be avoided in patients with moderate-to-severe liver disease.

Pregnancy is another crucial consideration when prescribing these drugs. Due to their potential to cause harm to fetuses, endothelin antagonists should not be used during pregnancy. Women of childbearing age who are prescribed these medications should be advised to use effective contraception during treatment and afterward.