An overview of the three major therapeutic pathways in pulmonary arterial hypertension

Therapeutic pathwaysNitric oxide (NO)Prostacyclin (PGI2)Endothelin 1 (ET1)
Levels in PAHReducedReducedIncreased
Aim of therapyTo increase NOTo increase PGI2To reduce ET1
Current available drugsSildenafilEpoprostenolMacitentan
Routes of administrationOralOral, parenteral, inhaledOral
Method of actionTo increase cGMP via the inhibition of PD5 or by direct stimulation of sGCTo increase the conversion of ATP to cAMPTo inhibit ETA receptors ± ETB receptors
 Common side-effectsSystemic vasodilation resulting in hypotension, flushing, light-headedness, gastrointestinal side-effects (e.g. nausea, diarrhoea)
 Specific drug side-effectsSildenafil and tadalafil: ocular side-effectsParenteral prostacyclin: thrombocytopenia, bone marrow suppressionMacitentan: anaemia Bosentan: deranged transaminases

The aim of therapy is to promote vasodilation in the pulmonary circulation. Within the nitric oxide pathway, sildenafil and tadalafil are phosphodiesterase type-5 (PD5) inhibitors and riociguat is a soluble guanylate cyclase (sGC) stimulator. In the endothelin (ET) pathway, bosentan and macitentan are dual ET receptor antagonists (i.e. they block both ETA and ETB receptors) and ambrisentan is a selective ETA receptor antagonist. Modern therapy typically consists of double or triple combination therapy, using one drug from each therapeutic pathway. Monotherapy is uncommon and should only be considered in patients with low-risk profiles. cGMP: cyclic guanosine monophosphate.