Pulmonary arterial hypertension endothelin

AHF acute heart failure, CHF chronic heart failure, CRF chronic renal failure, NEP neutral endopeptidase, ECE endothelin converting enzyme, PAH pulmonary arterial hypertension. 

Mechanism of Action An antihypertensive that blocks endothelin-l, the neurohormone that constricts pulmonary arteries. Therapeutic Effect Improves exercise ability and slows clinical worsening of pulmonary arterial hypertension (PAH). Pharmacokinetics Highlybound to plasma proteins, mainlyalbumin. Metabolized in the liver. Eliminated by biliary excretion. Half-life Approximately 5 hr. 

Bosentan Nonselective antagonist of endothelin ETA and ETB receptors Vasodilation Pulmonary arterial hypertension... 

Dupuis J, Hoeper MM Endothelin receptor antagonists in pulmonary arterial hypertension. Eur Respir J 2008 31 407. [PMID 18238950]... 

Opitz CF et al Inhibition of endothelin receptors in the treatment of pulmonary arterial hypertension Does selectivity matter Eur Heart J 2008 29 1936. [PMID 18562303]... 

In a double-blind, placebo-controlled study, the Bosentan Randomized trial of Endothelin Antagonist Therapy for Pulmonary Arterial I lypertension (BREATHE-2), 33 patients took epoprostenol (2 ng/kg/ min initially, increasing to a mean dosage of 14 ng/kg/min at week 16) and were then randomized for 16 weeks in a 2 1 ratio to bosentan (62.5 mg bd for 4 weeks then 125 mg bd) or placebo (11). There was a non-significant trend towards hemodynamic and clinical improvement with to the combination. There were several early and late major complications (four withdrawals with bosentan + epoprostenol two deaths due to cardiopulmonary failure, one clinical worsening, and one increase in hepatic transaminases and one withdrawal due to increased hepatic transaminases with placebo + epoprostenol. Power was the major limitation of this study, in which only 33 patients were enrolled, and the results should be interpreted with caution. Additional information is needed to evaluate the benefit to harm balance of combined bosentan + epoprostenol therapy in pulmonary arterial hypertension. 

Endothelin Antagonists for the Treatment of Pulmonary Arterial Hypertension... 

Barst RJ, Rich S, Widlitz A, Horn EM, McLaughlin V, McFarhn J. Clinical efficacy of sitaxsentan, an endothelin-A receptor antagonist, in patients with pulmonary arterial hypertension open-label pilot study. Chest 2002 121(6) 1860-8. 

Badesch DB, Bodin F, Channick RN, Frost A, Rainisio M, Robbins IM, Roux S, Rubin LJ, Simonneau G, Sitbon O, Tapson VF. Complete results of the first randomized, placebo-controlled study of bosentan, a dual endothelin receptor antagonist, in pulmonary arterial hypertension. Curr Ther Res Clin Exp 2002 63 227M6. 

Indications Pulmonary arterial hypertension Category Endothelin receptor antagonist Vasodilator Half-life 15 Hours... 

FIGURE 8.6 Targets for current therapies in pulmonary arterial hypertension (PAH) and their three major pathways endothelin, nitric oxide, and prostacyclin. (From Ref. 83, with permission.)... 

Ahmadi-Simab K, Lamprecht P, Hellmisch B, Gross WL. Treatment of pulmonary arterial hypertension (PAH) with oral endothelin-receptor antagonist bosentan in systemic sclerosis BREATHE-1 trial and clinical experience. Z Rheumatol 2004 63(6) 495-7. [Article in German]... 

Barst RJ, Langleben D, Badesch D, et al STRIDE-2 Study Group. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol 2006 47(10) 2049-56. 

Bosentan is an endothelin receptor antagonist. It antagonized endothelin (ET) receptor by binding to ET and ETg receptors in the endothelium and vascular smooth muscle. Bosentan is indicated in treatment of pulmonary arterial hypertension in patients with WHO class III and IV symptoms, to improve exercise ability, and decrease the rate of clinical worsening. 

Secondary causes of pulmonary arterial hypertension (PAH), including appetite suppressant drugs associated with PAH, have been reviewed [97 j. Newer trends in the treatment of PAH, especially the status of prostacyclin analogues and endothelin-1 receptor antagonists, have been addressed. 

Corris PA, Langleben D. The Achilles heel of endothelin receptor therapy for pulmonary arterial hypertension. Eur Respir J 2010 35(2) 460-1. 

Liver The availability of ambrisentan in patients with pulmonary artery hypertension who have previously discontinued other endothelin receptor antagonists because of liver function abnormalities provides an important option for patients who have had adverse reactions to bosentan or sitaxsentan [76 ]. Ambrisentan is a... 

The endothelins interact with two endothelin receptors, ETa and ETb. Endothelins are highly potent vasoconstrictors and endothelin antagonists have the potential to be used clinically to treat pulmonary arterial hypertension (PAH), congestive heart failure, stroke, kidney failure, asthma, pain, and cancer. The small molecule bosentan (Tracleer) interacts with both ETa and ETb receptors and was the first endothelin antagonist to be used clinically for the treatment of PAH. Additional compounds are in clinical development or have reached the market. ... 

There is increasing evidence that endothelins participate in a variety of cardiovascular diseases, including hypertension, cardiac hypertrophy, heart failure, atherosclerosis, coronary artery disease, and myocardial infarction. Endothelins have also been implicated in pulmonary diseases, including asthma and pulmonary hypertension, as well as in several renal diseases. This evidence includes findings of increased endothelin levels in the blood, increased expression of endothelin mRNA in endothelial or vascular smooth muscle cells, and the responses to administration of endothelin antagonists. 

Trials of the effects of endothelin receptor antagonists in patients with heart failure, coronary artery disease, arterial hjtpertension, and pulmonary hjtpertension have been reviewed (6), as have their uses in treating cancers (7) and cerebral vasospasm (8), and their potential uses in atherosclerosis, re-stenosis, myocarditis, shock, and portal hypertension (9)... 

Endothelin is produced by both endothelial and smooth muscle cells and exerts vasodilator and vasoconstrictor effects via ETA and ETB receptor subtypes, respectively (88). The net effect of endothelin infused to the fetus is dependent upon the vascular bed in question and the proportion of ETA and ETB receptors a sustained pulmonary hypertension and modulation of carotid artery responses to hypoxia via action at ETA receptors (64,89,90) and a renal vasodilatation by ETB-receptor mediated NO release (91). As a result, it is likely that the observed lack of effect of specific antagonism of ETA receptors during late gestation on peripheral vascular resistance or arterial pressure reflects the net effect in a number of vascular beds. 

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