Elevated blood pressure in the pulmonary vasculature, known as pulmonary arterial hypertension (PAH), stresses the right side of the heart and can increase the risk for functional disability and death. In advanced disease, several drugs can be employed, including calcium-channel blockers, phosphodiesterase-5 inhibitors, prostacyclin analogues, and endothelin (ET)-receptor antagonists. El is an endogenous peptide vasoconstrictor that is present in excessive concentrations in patients with PAH. Sitaxsentan, an ET-receptor antagonist undergoing FDA review, is selective for the [ET.sub.A] receptors. By selectively antagonizing the [ET.sub.A] receptors, sitaxsentan causes pulmonary arterial vasodilation and allows normal functioning of the [ET.sub.B] receptor, thus reducing the effects of ET. Clinical trials have demonstrated that orally administered sitaxsentan improves both 6-minute walking distance and World Health Organization functional class in patients with PAH. Trials have also demonstrated that sitaxsentan is relatively safe, although cases of hepatotoxicity have been reported. Further studies are necessary to better demonstrate the adverse event profile of this agent and to determine how sitaxsentan could be integrated into therapy for patients with PAH.
Pulmonary arterial hypertension (PAH) is a disease characterized by vasoconstriction and overproliferation of the pulmonary arterial endothelium; these factors can stress the right side of the heart and increase the risk for functional disability and death. (1) This disease can be insidious early on because measurement of systemic blood pressure (obtained via a blood pressure cuff on the arm) does not identify those with elevated pulmonary arterial pressures. Only more advanced hemodynamic monitoring, such as echocardiography or the insertion of a pulmonary artery catheter, can be used to determine pulmonary arterial pressure. (2) In a patient without PAH, the pulmonary arterial pressure ranges from 12 to 16 mmHg at rest, whereas a patient with PAH has a pressure >25 mmHg at rest and >30 mmHg during exercise. (2)
Table 1 summarizes the most common types of PAH; 1 of the most common is idiopathic PAH, the etiology of which is not known. (2,3) Another type of PAH is familial disease. Most patients with familial PAH have a defect in the gene encoding Bone Morphogenic Protein Receptor 2 (BMPR2); this defect may be pathogenic, as this receptor is responsible for receiving and transmitting signals related to cellular growth, division, and apoptosis. (2-4)
Patients with PAH have a poor prognosis, with an average survival time of <3 years from diagnosis. Inadequate cardiac output is usually associated with symptoms such as fatigue, dyspnea, atypical chest pain, and presyncope or syncope with exertion. (2) With the onset of right-sided heart failure, patients may exhibit peripheral edema, jugular venous distension, and hepatojugular reflux. (5) Signs of PAH include right ventricular hypertrophy on echocardiography or electrocardiography, and in advanced stages, the development of a third heart sound. (2)
World Health Organization (WHO) functional classes in patients with PAH range from class I, in which there is no limitation with exertion or rest but an elevated pulmonary arterial pressure, to class IV, in which patients cannot exert themselves and have symptoms even at rest. (3) Patients...