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Treatment

What are common medications for pulmonary hypertension and how do they work?

Doctors have tried to treat pulmonary hypertension with a number of different medications since the disorder was first recognized many years ago. Fortunately, today we have several medical therapies that are targeted specifically at this disease and which are more effective than medicines used in the past. In spite of such progress, many of the medicines used today mainly alleviate symptoms (such as shortness of breath) of pulmonary hypertension rather than targeting the underlying disease. While helping you feel better is very important, it is also a crucial goal to find ways to slow down or reverse the disease itself. Doctors and scientists are actively pursuing clinical trials and experimental research to determine the underlying mechanisms so that better therapies directly aimed at the pulmonary hypertension can be created.


While you may be on a variety of medications, such as diuretics, blood thinners or oxygen, that help with the problems associated with pulmonary hypertension, there are several medicines targeted specifically at the pulmonary vessels and we will discuss these in more detail here. These medicines, called "selective pulmonary vasodilators," are directed at the constricted pulmonary arteries and the elevated resistance in the pulmonary circulation, with the main goal of dilating or opening up the pulmonary vessels without affecting normal blood vessels elsewhere in the body. The most effective medicines are "selective," that is, they work maximally on the blood vessels of the lung but have very little effect on other blood vessels around the body (the systemic circulation).


Today there are four main classes of selective pulmonary vasodilators available for patients. The first class of medications that became available was the prostacyclins, a set of molecules that are found naturally in the body and which have various functions. As related to pulmonary arterial hypertension (PAH), their most important function is to dilate vessels, thereby decreasing the pressures in those vessels. Ideally, we would like to deliver prostacyclins directly to the pulmonary arteries in order to decrease pulmonary artery pressures. This family of medications works by increasing the production of another molecule (called cyclic AMP) that causes muscle cells around the small pulmonary arteries to relax. Other prostacyclin effects that are potentially beneficial in PAH include keeping platelets from clumping together (thereby possibly decreasing the tendency to form clots in the pulmonary arteries) and reducing smooth muscle growth in the walls of the pulmonary arteries (thereby reducing the abnormal thickening of the walls of the blood vessels).


Prostacyclins are very potent, but are limited by their "half-life" or the time that they stay active as medications before being metabolized by the body. The first prostacyclin that became available was epoprostenol (Flolan®), a medication with a half-life so short that it must be given continuously by intravenous infusion. Subsequently other prostacyclins, such as treprostinil (Remodulin®, Tyvaso®, and Orenitram®), iloprost (Ventavis®), and a room temperature stable version of epoprostenol (Veletri®) have been produced with longer half-lives and a variety of delivery methods, including under the skin (subcutaneous infusion), through the lungs as an inhaled mist (nebulizer), or as an oral, extended release tablet (Orenitram®).


The next class of selective pulmonary vasodilators that became available for patients was the endothelin receptor antagonists (ERAs). Endothelin is a very potent vasoconstrictor found in the blood and tissues of the body in both healthy states and in diseases like pulmonary hypertension. ERAs work against, or antagonize, the action of endothelins, hence the name. There are two types of endothelin receptors in the body -- type A receptors and type B receptors. Activation of type A receptors primarily causes vasoconstriction, and activation of type B receptors primarily results in vasodilation. In addition, activation of the type B receptors also results in the clearing of endothelin from the circulating blood. There are currently three oral medications (called Bosentan (Tracleer®), Ambrisentan (Letairis®), and Macitentan (Opsumit®)) in the ERA class. These medications block the endothelin receptors, thereby reducing the vasoconstricting effects of endothelin. Bosentan was the first ERA that became available, and it blocks both type A and type B receptors. It is a pill that is typically taken twice a day. Ambrisentan is another oral ERA that preferentially blocks the A receptor, and is a pill that is taken once daily. Macitentan is the most recently approved once daily pill that blocks both the type A and the type B receptors.


The third class of selective pulmonary vasodilators for patients with pulmonary hypertension is the phosphodiesterase type 5 inhibitors, abbreviated as PDE5i's. Currently, the approved medications in this class are sildenafil (Revatio®) and tadalafil (Adcirca®). These are both oral medications that are taken either three times daily (sildenafil) or once daily (tadalafil). PDE5 is an enzyme that is found in the blood vessels of the lungs; when present, it helps break down a molecule called cyclic GMP that is a potent vasodilator. By inhibiting PDE5, these drugs result in increased cyclic GMP levels in the blood vessels of the lungs and therefore a greater degree of vasodilation.


The newest class of selective pulmonary vasodilators for patients with pulmonary hypertension is the soluble guanylate cyclase stimulators. This class of medications is related to the PDE5i's as discussed above. The guanylate cyclase stimulators increase vasodilation through an increase in the amount of cyclic GMP due to increased production. This is in contrast to the way the PD5Ei's do this (decreased destruction). Currently, there is only one medication in this class approved for patients and it is a pill called riociguat (Adempas®) which is taken three times daily.