Endothelin Receptor Antagonist

Endothelin receptor antagonist are pharmacological agents that block endothelin receptors. They are used to treat pulmonary arterial hypertension (PAH).
They were discovered in late 1980s.
Pulmonary arterial hypertension is a pathological condition characterized by progressive increase in pulmonary vascular resistance which may lead to right ventricular failure and death.

Endothelin and Endothelin Receptors

Figure 1- Vasoconstriction caused by endothelin

Endothelin is a polypeptide isolated from vascular endothelium and is found in several tissues including brain, kidney, intestine and adrenal glands. Endothelin is potent vasoconstrictor and enhance secretion of many hormones. Among 3 types of endothelin- ET-1, ET-2 and ET-3, ET-1 is most potent and long acting vasoconstrictor. It plays important role in peripheral vascular resistance and possess hypertrophic and proinflammatory properties.
There are two types of endothelin receptors- ET-A and ET-B. ET-A is present on vascular smooth muscles, heart, lung and kidney. ET-B is present mainly on brain and in minimal quantity in heart, vessels, lung and kidney.
ET-1 mainly activate ET-A receptor and causes vasoconstriction, bronchoconstriction, aldosterone release and smooth muscle proliferation. ET-B present on smooth muscle also causes vasoconstriction.
In patients with PAH, plasma and lung level of ET-1 is elevated.

There are 2 main types of endothelin receptor antagonist in clinical use.

Dual antagonist– which blocks both ET-A and ET-B receptors. Example includes bosentan, macitentan.
Selective ET-A receptor antagonist– which blocks only ET-A receptors. Example includes sitaxsentan, atrasentan etc.

Endothelin receptor antagonist block endothelin receptor and inhibit binding of endothelin to endothelin receptors. Hence, they antagonize the effect of powerful vasoconstrictor and smooth muscle mitogen hormone endothelin 1.

Bosentan is a non-selective ET-1 receptor antagonist which blocks both ET-A and ET-B receptors. It is administered orally and achieves peak concentration after 3 hours of oral administration. Metabolism takes place mainly in liver and is excreted in bile. It should be avoided in patients with moderate or severe hepatic impairment and elevated liver amino transferases.
Macitentan is derivative of bosentan, has similar characteristic with less risk of liver toxicity.
Sitaxsentan is around 6500 times more selective for ET-A than for ET-B receptors. Its oral bioavailability is high around 90%. It has long duration of action. Around 50-60 % is excreted via urine and remaining is excreted via feces.
Ambrisentan is rapidly absorbed into systemic circulation after oral administration. Its half-life is more than 6 hours and has oral bioavailability of about 90%. It is excreted mostly unchanged in bile.

They can cause hepatic toxicity.
They are potent teratogens and hence contraindicated in pregnancy.
Some side effects are due to vasodilation like headache, cutaneous flushing and edema formation.

Bosentan and sitaxsentan induce cytochrome P450 enzymes and may alter metabolism of drugs which are metabolized by same pathway. They alter metabolism of warfarin and oral contraceptives.
Ketoconazole and Fluvastatin increases the plasma level of bosentan. Bosentan decreases exposure to cyclosporine A, glibenclamide and simvastatin.

Raja SG. Endothelin Receptor Antagonists for Pulmonary Hypertesnion: An Overview. Cardiovascular Therapeutics. 2010; 28: e65-e71.
A Comprehensive Guide to Toxicology in Nonclinical Drug Development (Second Edition). 2017, 7-38.
Pocket Companion to Brenner and Rector’s the Kidney (Eighth Edition). 2011, 511-545.
Pharmacology and Pharmacotherapeutics. 24th edition.
https://www.ncbi.nlm.nih.gov/books/NBK542293/