Aprocitentan: Dual endothelin eta/etb receptor antagonist treatment of resistant hypertension

Hypertension is a major contributor to cardiovascular, cerebrovascular and kidney disease that is present in nearly half of Americans, with high rates worldwide. Despite the availability of 11 classes of antihypertensive medications developed over the last 70 years, successful management of hypertension is challenging for many patients and their healthcare providers. The frequent need for polypharmacy can be associated with troubling side effects that interfere with sustainable treatment. A novel class of medications used for treatment of pulmonary hypertension, endothelin receptor antagonists (ERAs), have potential for treatment of systemic hypertension, but many have unwanted side effects. Aprocitentan, a dual endothelin ETA/ETB receptor antagonist, demonstrates potent blood pressure reduction with effects similar to or more potent than those of an established antihypertensive, lisinopril. Aprocitentan is also well tolerated with mild and transient side effects, primarily consisting of headache, nausea, uncontrolled hypertension and nasopharyngitis. The drug appears to avert many of the serious side effects displayed by other ERA drugs but patient education and monitoring for teratogenicity, fluid retention and peripheral edema, and anemia is required. Aprocitentan has potential for treatment of the subset of 12-18% of hypertensive patients who have resistant hypertension. In this review, we cover endothelin receptor biology, the class of ERA drugs, and preclinical and phase I to III clinical data for aprocitentan.