{"id":355,"date":"2020-02-16T11:02:29","date_gmt":"2020-02-16T05:32:29","guid":{"rendered":"https:\/\/medicineplexus.com\/?p=355"},"modified":"2020-02-16T11:02:29","modified_gmt":"2020-02-16T05:32:29","slug":"endothelin-and-endothelin-receptor-antagonists","status":"publish","type":"post","link":"https:\/\/medicineplexus.com\/endothelin-and-endothelin-receptor-antagonists\/","title":{"rendered":"Endothelin and Endothelin Receptor Antagonists"},"content":{"rendered":"\n<p><strong>Endothelin and Endothelin Receptor Antagonists<\/strong><\/p>\n\n\n\n<p>Endothelin is a very potent vasoconstrictor peptide derived from the endothelial cells of vasculature.<\/p>\n\n\n\n<figure class=\"wp-block-image size-large\"><img loading=\"lazy\" decoding=\"async\" width=\"399\" height=\"543\" src=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-30.png?w=399\" alt=\"\" class=\"wp-image-356\" srcset=\"https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-30.png 399w, https:\/\/medicineplexus.com\/wp-content\/uploads\/2020\/02\/image-30-220x300.png 220w\" sizes=\"(max-width: 399px) 100vw, 399px\" \/><\/figure>\n\n\n\n<p><strong><em>Biosynthesis.<\/em><\/strong><\/p>\n\n\n\n<ul><li>ECE-1 is the rate-limiting step in ET-1 synthesis.<\/li><li>ETs interact with two GPCRs, the ETA and ETB receptors<\/li><\/ul>\n\n\n\n<p><strong><em>Endothelin Signaling.<\/em><\/strong><\/p>\n\n\n\n<ul><li>Endothelin 1 \u00e0 potent, endothelium-derived, constricting factor \u00e0 mediated by the ETA receptor<img loading=\"lazy\" decoding=\"async\" width=\"400\" height=\"544\" src=\"\"><\/li><\/ul>\n\n\n\n<p><strong><em>\u25cfNonselective dual action receptor antagonists \u2013 <\/em><\/strong><em>bosentan and macitentan<\/em><\/p>\n\n\n\n<p><strong><em>\u25cfSelective receptor antagonists of endothelin receptor A \u2013 <\/em><\/strong><em>ambrisentan and sitaxsentan<\/em><\/p>\n\n\n\n<p><strong><em>Sitaxsentan was withdrawn <\/em><\/strong><strong><em>\u00e0<\/em><\/strong><strong><em> several fatal cases of hepatoxicity<\/em><\/strong><\/p>\n\n\n\n<p><em>Ambrisentan is the least hepatotoxic of the ERAs<\/em><\/p>\n\n\n\n<p><strong><em>Commonalities.<\/em><\/strong><\/p>\n\n\n\n<ul><li>Common side effects of the class\u00e0 headache, pulmonary edema, and nasal congestion\/pharyngitis, with a <strong>risk of testicular atrophy and infertility.<\/strong><\/li><li>Bosentan and ambrisentan may <strong>increase liver transaminases, <\/strong>which should be monitored closely, and the drugs are <strong>contraindicated in patients with moderate-to-severe liver disease<\/strong><\/li><li>the elevation of liver enzymes generally resolves after discontinuation of treatment.<\/li><\/ul>\n\n\n\n<ul><li>metabolized by CYP3A4 and to some extent by CYPs 2C9 and 2C19.<\/li><li>Inhibitors of these CYPs (e.g., ketoconazole and ritonoavir) can increase bosentan and macitentan exposure<\/li><\/ul>\n\n\n\n<ul><li>The ERAs are <strong>potent teratogens<\/strong> and should be used with caution in women of childbearing age.<\/li><\/ul>\n\n\n\n<ul><li>must not be used in pregnant patients.<\/li><li>Documentation of a negative pregnancy test prior to initiation of therapy and a clear contraceptive plan are recommended, and fertile women must use two acceptable methods of birth control while taking ET antagonists.<\/li><\/ul>\n\n\n\n<p><strong><em>Bosentan.<\/em><\/strong><\/p>\n\n\n\n<ul><li>orally effective, competitive <strong>antagonist of ETA and ETB receptors<\/strong>.<\/li><li>In patients with <strong>PAH with mild to-severe functional impairment (functional classes II\u2013IV<\/strong>)<\/li><li>improves symptoms, functional capacity, and pulmonary hemodynamic parameters<\/li><li>usually started at 62.5 mg twice daily, increasing to 125 mg twice daily after 4 weeks.<\/li><\/ul>\n\n\n\n<p><strong><em>Macitentan.<\/em><\/strong><\/p>\n\n\n\n<ul><li>an orally active, <strong>competitive ETA and ETB receptor antagonist.<\/strong><\/li><li>At a dose of 10 mg daily, macitentan improves the time to disease progression or death in PAH and improves symptoms, functional capacity, and pulmonary hemodynamic measurements<\/li><li>relatively well tolerated and has thus far not been associated with elevation of liver-associated enzymes, but caution is recommended.<\/li><\/ul>\n\n\n\n<p><strong><em>Ambrisentan.<\/em><\/strong><\/p>\n\n\n\n<ul><li>Unlike bosentan and macitentan, ambrisentan is a relatively <strong>selective ETA antagonist<\/strong> (approximately 4000 times greater affinity for ETA than ETB).<\/li><li>initiated at a dose of 5 mg daily and increased to a maximum of 10 mg daily.<\/li><li><strong>Liver-associated enzyme abnormalities are much less common than with bosentan<\/strong>, yet monitoring of liver function tests is still recommended.<\/li><\/ul>\n\n\n\n<p><strong>Congestive heart failure (CHF)<\/strong><\/p>\n\n\n\n<p>CHF is a disease process characterised by impaired left ventricular function, increased peripheral and pulmonary vascular resistance, and sodium and water retention.<\/p>\n\n\n\n<p>In patients with CHF, circulating ET-1 is elevated and correlates with symptoms20 and haemodynamic severity<\/p>\n\n\n\n<p>Infusion of the mixed ETA\/B antagonist, bosentan, has been shown to improve systemic and pulmonary haemodynamics in patients with CHF<\/p>\n\n\n\n<p><strong>Role of endothelin receptor antagonists in pulmonary arterial hypertension<\/strong><\/p>\n\n\n\n<p><strong><em>Rationale for Antagonizing ET\u2019s Effects in PAH.<\/em><\/strong><\/p>\n\n\n\n<ul><li>Endothelin 1 is implicated as a contributory factor in idiopathic PAH<\/li><li>Plasma ET-1 levels are <strong>increased up to 10-fold<\/strong> in patients with PAH and<\/li><li>correlate well with <strong>severity of disease and the elevation of right atrial pressure.<\/strong><\/li><li>There are no clinically available specific inhibitors of ECE-1, the rate-limiting step in ET-1 synthesis, but a number of orally effective small molecule antagonists of ET receptors have been developed.<\/li><li>Despite the opposing effects of ETA and ETB receptor activation, pharmacological targeting of specific ETA receptors has not led to significantly altered clinical responses compared to dual antagonism (e.g.,&nbsp; antagonism of ET-1 binding to both ETA and ETB receptors) in treating PAH.<\/li><\/ul>\n\n\n\n<p>High concentrations of ET-1 have been recorded in the lungs of patients with PAH<\/p>\n\n\n\n<p>Bosentan, an orally active non-selective endothelin receptor antagonist, has been proved to be effective in the treatment of pulmonary arterial hypertension (PAH)<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Endothelin and Endothelin Receptor Antagonists Endothelin is a very potent vasoconstrictor peptide derived from the endothelial cells of vasculature. Biosynthesis. ECE-1 is the rate-limiting step in ET-1 synthesis. ETs interact with two GPCRs, the ETA and ETB receptors Endothelin Signaling. Endothelin 1 \u00e0 potent, endothelium-derived, constricting factor \u00e0 mediated by the ETA receptor \u25cfNonselective dual[&#8230;]\n","protected":false},"author":3,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_seopress_robots_primary_cat":"","_seopress_titles_title":"","_seopress_titles_desc":"","_seopress_robots_index":"","footnotes":""},"categories":[3],"tags":[],"_links":{"self":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/355"}],"collection":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/comments?post=355"}],"version-history":[{"count":0,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/posts\/355\/revisions"}],"wp:attachment":[{"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/media?parent=355"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/categories?post=355"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/medicineplexus.com\/wp-json\/wp\/v2\/tags?post=355"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}