ICD-10 Specific code I27.0: Primary pulmonary hypertension

Ambrisentan is an orally active, propanoic acid-class, ERA selective for the endothelin A (ETA) receptor. Endothelin plays a significant role in the pathophysiology of PAH.

Macitentan is an orally active potent endothelin receptor antagonist, active on both ET_A and ET_B receptors. Endothelin (ET)-1 and its receptors (ET_A and ET_B) mediate a variety of effects such as vasoconstriction, fibrosis, proliferation, hypertrophy, and inflammation. In disease conditions such as PAH, the local ET system is upregulated and is involved in vascular hypertrophy and in organ damage.

Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). Riociguat restores the NO-sGC-cGMP pathway and leads to increased generation of cGMP.

Sildenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5), the enzyme that is responsible for degradation of cGMP. Apart from the presence of this enzyme in the corpus cavernosum of the penis, PDE5 is also present in the pulmonary vasculature. Sildenafil, therefore, increases cGMP within pulmonary vascular smooth muscle cells resulting in relaxation.

Sitaxentan is a potent (Ki 0.43 nM) and highly selective ETA antagonist (approximately 6,500-fold more selective for ETA as compared to ETB). Endothelin-1 (ET-1) is a potent vascular paracrine and autocrine peptide in the lung, and can also promote fibrosis, cell proliferation, cardiac hypertrophy, and remodelling and is pro-inflammatory. ET-1 actions are mediated through endothelin A (ETA) and endothelin B receptors (ETB). ET-1 concentrations are elevated in plasma and lung tissue of patients with pulmonary arterial hypertension (PAH), as well as other cardiovascular disorders and connective tissue diseases.

Tadalafil is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5). When sexual stimulation causes the local release of nitric oxide, inhibition of PDE5 by tadalafil produces increased levels of cGMP in the corpus cavernosum. This results in smooth muscle relaxation and inflow of blood into the penile tissues, thereby producing an erection. The effect of PDE5 inhibition on cGMP concentration in the corpus cavernosum is also observed in the smooth muscle of the prostate, the bladder and their vascular supply. The resulting vascular relaxation increases blood perfusion which may be the mechanism by which symptoms of benign prostatic hyperplasia are reduced.