Pulmonary arterial hypertension is a debilitating and fatal lung disease. Patients are diagnosed as having pulmonary arterial hypertension if their mean pulmonary arterial pressure exceeds 25 mmHg at rest or 30 mmHg during exercise. Pulmonary arterial hypertension is subdivided into primary and secondary. Primary pulmonary hypertension (PPH) is idiopathic, while secondary pulmonary hypertension is caused by other diseases, e.g., pulmonary fibrosis, thromboembolism, or drugs. Some 6-12% of PPH patients have familial PPH, which is an autosomal dominant disease. In many families with PPH, mutations of the bone morphogenetic protein receptor type II (BMPR2) gene have been identified. Idiopathic pulmonary arterial hypertension has a particularly poor prognosis. Without lung transplantation the average survival time is 3 years after diagnosis.45'46
In the past the therapy of pulmonary arterial hypertension has been disappointing, although CCAs have been tried with some success. Anticoagulants were used routinely to prevent thromboembolic complications that were common in patients with pulmonary arterial hypertension and right heart failure. During the last decade new approaches to the therapy of pulmonary arterial hypertension have been developed. Prostacyclin (PGI2, eproprostenol) was found to have a beneficial hemodynamic effect and to prolong life in patients with pulmonary arterial hypertension. It has to be administered by constant infusion through a central catheter. Treprostinil, a stable prostacyclin derivative, is currently used; it has to be administered by continuous subcutaneous infusion.
More recently, endothelin antagonists have been evaluated in the therapy of pulmonary arterial hypertension. There are at least two types of endothelin receptors: ETA and ETB. Activation of either receptor aggravates pulmonary arterial hypertension, but activation of ETA receptors appears to be more detrimental. A nonselective endothelin antagonist, bosentan (Figure 5), is used in the therapy of pulmonary arterial hypertension. Its use is based on the evidence that endothelin is overexpressed in patients with pulmonary hypertension and that overproduction of endothelin may lead to pulmonary vascular remodeling. Bosentan is active orally and has been shown to produce short-term benefits in patients with pulmonary arterial hypertension: it improves exercise capacity and reduces pulmonary arterial pressure.47 Its side effects include liver toxicity (elevation of hepatic aminotransferase in 7-14% of patients), teratogenicity, and drug interactions, since bosentan is a substrate for and inducer of CYP3A4 and CYP2C9 isoenzymes. Subsequent to the development of bosentan, other nonselective endothelin antagonists, tezosentan and enrasentan, have been developed. Two ETA-selective endothelin antagonists, darusentan and sitaxsentan (Figure 5), are under clinical investigation. Other compounds reported to have beneficial effects in patients with pulmonary arterial hypertension include sildenafil, N-acetylcysteine, and adrenomedullin. Monocrotaline-induced pulmonary arterial hypertension in rats was found to be reversible by dichloroacetate. In spite of these new developments there is still a need for new drugs to treat pulmonary arterial hypertension, particularly if these drugs could reverse or arrest pulmonary fibrosis that may precede pulmonary arterial hypertension.
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Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...