Pharmacologic Treatments for Pulmonary Hypertension: Exploring Pharmacogenomics

Abstract

Pulmonary hypertension (PH) is a disease with multiple etiologies and is categorized into five broad groups. Of these groups, pulmonary arterial hypertension (PAH) is the most studied and, therefore, all of the currently available drug classes (prostacyclin analogs, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors) were developed to treat PAH. Thus, limited treatment data exist for the less-studied non-PAH forms of PH. Pharmacogenomics can be a tool to better understand the pathways involved in PH, as well as to improve personalization of therapy. However, little pharmacogenomic research has been carried out on this disease. New treatments for PH are on the horizon, deriving from both repurposed currently available drugs and novel therapeutics.

Pulmonary hypertension: Molecular aspects of current therapeutic intervention and future direction

“…Phosphodiesterase level was found to increase in the pulmonary vessel and plays a critical role in the progression of PH (Duarte, Hanson, & Machado, 2013). Phosphodiesterase-1 (PDE-1) has three isoforms which are regulated by calcium-calmodulin and can hydrolyze both cAMP and cGMP ( Figure 2).…”

El endotelio vascular

“…Although the powerful vasodilator and antiplatelet effect of prostacyclin suggested early on its potential use in clinical conditions associated with thrombosis and vasoconstriction (74) , its main clinical use at present is in the management of primary pulmonary hypertension (75,76) , where it has been shown to improve symptoms, induce remodeling of the pulmonary vasculature and reduce mortality. The difficulties related to its intravenous usage as an unstable compound, requiring continuous administration, led to the development of different formulations of prostacyclin or its analogs for intravenous, subcutaneous and inhaled administration (75,76) .…”

“…The difficulties related to its intravenous usage as an unstable compound, requiring continuous administration, led to the development of different formulations of prostacyclin or its analogs for intravenous, subcutaneous and inhaled administration (75,76) . In addition to the use of these compounds, two different approaches have also proven to be useful in the management of primary pulmonary hypertension.…”

“…These are the use of endothelin receptor antagonists and inhibitors of the enzyme 5-phosphodiesterase to boost the effect of endogenous NO on its receptor, the soluble guanylyl cyclase. These compounds, used alone or in different combinations and schedules, have revolutionized the treatment of this complex and fatal disease to the point that the long-term management with orally-active compounds is now being investigated and prostacyclin and nitric oxide receptor agonists are at present the subject of long-term clinical trials (76)(77)(78)(79)(80) . Furthermore, the proliferative nature of the disease, at least in part associated with the release of platelet-derived growth factor, has led to the development and use of different kinase inhibitors (79) .…”

Riociguat, a guanylate cyclase stimulator for the treatment of pulmonary hypertension

“…The 1 year mortality rate of PH is around 10-15%. 3 The WHO classifi cation of PH includes fi ve major categories, including pulmonary treatment available PH remains incurable. The unmet need of the disease, adverse effects of the currently used drugs, and poor response increases the need for the development of new drugs.…”