Ambrisentan (U.S. trade name Letairis; E.U. trade name Volibris; India trade name Pulmonext by MSN labs) is a drug indicated for use in the treatment of pulmonary hypertension. The peptide

endothelin Endothelins are peptides with receptors and effects in many body organs. Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute ...

constricts muscles in blood vessels, increasing blood pressure. Ambrisentan, which relaxes those muscles, is an

endothelin receptor antagonist An endothelin receptor antagonist (ERA) is a drug that blocks endothelin receptors. Three main kinds of ERAs exist: * selective ETA receptor antagonists ( sitaxentan, ambrisentan, atrasentan, BQ-123, zibotentan, edonentan), which affect e ...

, and is selective for the type A

endothelin receptor There are at least four known endothelin receptors, ETA, ETB1, ETB2 and ETC, all of which are G protein-coupled receptors whose activation result in elevation of intracellular-free calcium, which constricts the smooth muscles of the blood vessels ...

(ET_A). Ambrisentan significantly improved exercise capacity (6-minute walk distance) compared with placebo in two double-blind, multicenter trials (ARIES-1 and ARIES-2). Like all endothelin receptor antagonists, Ambrisentan is contraindicated in pregnant women as well as those who are trying to become pregnant, due to the potential for

teratogenic Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related t ...

effects on the fetus. Patients who are on the Ambrisentan must enroll in the Ambrisentan (Letairis) REMS Program. Ambrisentan was approved by the U.S.

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) and the European Medicines Agency (EMA), and designated an orphan drug, for the treatment of pulmonary hypertension.

Clinical uses

Ambrisentan is indicated for the treatment of pulmonary arterial hypertension (WHO Group 1) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening.

Mechanism of action

Ambrisentan is a drug that blocks endothelin, an endogenous hormone found in higher quantities in patients with pulmonary arterial hypertension. Endothelin binds to two receptors, ET_A and ET_B. ET_A is responsible for cell growth in the vessels as well as

vasoconstriction Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vess ...

, while ET_B plays a role in

vasodilation Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstrictio ...

endothelin 1 Endothelin 1 (ET-1), also known as preproendothelin-1 (PPET1), is a potent vasoconstrictor peptide produced by vascular endothelial cells. The protein encoded by this gene ''EDN1'' is proteolytically processed to release endothelin 1. Endotheli ...

clearance, and anti proliferation of cells.

Birth defects

Endothelin receptor activation mediates strong pulmonary vasoconstriction and positive inotropic effect on the heart. These physiologic effects are vital for the development of the fetal cardiopulmonary system. In addition to this, endothelin receptors are also known to play a role in neural crest cell migration, growth, and differentiation. As such, endothelin receptor antagonists such as Ambrisentan are known to be teratogenic. Ambrisentan has a high risk of liver damage, and of birth defects if a woman becomes pregnant while taking it. In the U.S., doctors who prescribe it, and patients who take it, must enroll in a special program, the LETAIRIS Education and Access Program (LEAP), to learn about those risks. Ambrisentan is available only through specialty pharmacies.

Hepatic impairment

Ambrisentan is not recommended in patients with moderate or severe hepatic impairment. The medication should also be discontinued if the liver aminotransferase enzymes for the patients are increased more than fivefold, or if the elevations are more than twofold and are accompanied by changes in bilirubin.

Publications

References

External links

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