Medical Treatment of Pulmonary Arterial Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease leading to right ventricular failure and death if left untreated. Over the past two decades, progress in the understanding of pathophysiological mechanisms of the disease has led to the development of medications targeting the three major pathways of endothelial dysfunction: prostanoids, endothelin-receptor antagonists, and phosphodiesterase type-5 inhibitors. Efficacy of PAH-targeted medications has been demonstrated in monotherapy through randomized clinical trials leading to their regulatory approval. However, despite the growing numbers of available PAH-targeted medications, many patients with PAH continue to deteriorate and the disease ultimately remains fatal. The availability of multiple classes of drugs targeting different pathophysiological pathways provides strong biological rationale for the use of combination therapy in PAH. Evidence to support this strategy is growing, and many studies have demonstrated that combination therapy, administered as either a sequential or an initial regimen, can improve long-term outcomes in PAH. Treatment strategy for PAH has thereby changed significantly over the past decade, combination therapy becoming progressively the gold standard of care in patients with PAH. This is underscored by the current European Society of Cardiology/European Respiratory Society guidelines, in which combination therapy now plays a central part in the treatment algorithm.

Management of Pulmonary Arterial Hypertension

“…By binding to ET A and ET B receptors located in smooth muscle cells, ET-1 stimulates cellular proliferation, fibrosis, inflammation, and vasoconstriction [4,58]. The effects of ET-1 via ET B on endothelial cells result in increased production of prostacyclin and NO and subsequent vasodilation [3,59]. Both ET A and ET B receptors are found in high concentrations within the pulmonary vasculature, and as such, serve as an important focus for targeted drug therapy [59].…”

“…The effects of ET-1 via ET B on endothelial cells result in increased production of prostacyclin and NO and subsequent vasodilation [3,59]. Both ET A and ET B receptors are found in high concentrations within the pulmonary vasculature, and as such, serve as an important focus for targeted drug therapy [59]. There are currently three FDAapproved endothelin-receptor antagonists (ERA) with varying degrees of affinity for ET A and ET B receptors: ambrisentan, bosentan, and macitentan.…”

Oxygen-Sensitivity and Pulmonary Selectivity of Vasodilators as Potential Drugs for Pulmonary Hypertension

“…This imbalance includes a decrease in the production of vasodilators/growth inhibitors such as NO and prostacyclin, while there is an increase in the production of vasoconstrictor/pro-mitogens such as endothelin-1 (ET-1), thromboxane A 2 (TXA 2 ) and serotonin (5-HT) [5][6][7]. Current PAH treatments, based on drugs mimicking or inhibiting these endogenous vasoactive factors, are categorized into three classes: (1) prostacyclin and IP receptor agonists, (2) phosphodiesterase type 5 (PDE5) inhibitors and soluble guanylate cyclase (sGC) stimulators and (3) ET-1 receptor antagonists [8,9]. These therapies are limited by several factors.…”

Management of hospitalized patients with pulmonary arterial hypertension and COVID‐19 infection

“…Pulmonary arterial hypertension (PAH), a chronic, progressively fatal condition, requires complicated medical management. 3 Patients with PAH are very sensitive to the changes in their cardiopulmonary status and any disruption in treatment or development of additional cardiac or pulmonary pathology can trigger a rapid course of decline leading to death. Furthermore, all-cause hospitalization itself is a risk factor for disease progression in PAH.…”