Pulmonary Hypertension Pharmacology
Three deficient vasoactive pathways, approved drug classes, and combination therapy strategy
The Three Therapeutic Pathways
Pathway 1 — Deficient
Prostacyclin
- PGI2 → IP receptor → cAMP ↑ → vasodilation
- Epoprostenol: IV continuous; survival benefit
- Treprostinil: SC/IV/inhaled/oral
- Selexipag: oral IP agonist (GRIPHON)
Pathway 2 — Overactive
Endothelin-1
- ET-1 → ET-A receptor → vasoconstriction
- Bosentan: dual ET-A/B; hepatotoxicity; CYP inducer
- Ambrisentan: selective ET-A; lower hepatotox risk
- Macitentan: dual ET-A/B; SERAPHIN trial
- All: teratogenic — contraception required
Pathway 3 — Deficient
Nitric Oxide / cGMP
- NO → sGC → cGMP ↑ → vasodilation
- Sildenafil / Tadalafil: PDE-5 inhibitors
- Riociguat: sGC stimulator; also CTEPH
- All: absolute contraindication with nitrates
Key Drug Properties
|
Drug |
Pathway |
Route |
Key Point |
| Prostacyclin | Epoprostenol | IP agonist | IV continuous | Only PAH drug with RCT survival benefit |
| Prostacyclin | Selexipag | IP agonist | Oral | Non-prostanoid; GRIPHON trial |
| Endothelin | Bosentan | Dual ERA | Oral | CYP3A4/2C9 inducer; monthly LFTs |
| Endothelin | Macitentan | Dual ERA | Oral | SERAPHIN: reduced morbidity/mortality |
| NO/cGMP | Sildenafil | PDE-5 inhibitor | Oral TID | Nitrate combo: fatal hypotension |
| NO/cGMP | Riociguat | sGC stimulator | Oral TID | Only oral therapy for CTEPH |
Combination Therapy Strategy (AMBITION Trial)
Newly diagnosed: upfront dual therapy — ERA + PDE-5 inhibitor (ambrisentan + tadalafil reduced clinical failure by 50% vs monotherapy).
Persistent high risk: add prostacyclin pathway agent (triple therapy).
Goal: achieve and maintain low-risk status — reassess every 3–6 months.
Absolute Contraindication
PDE-5 inhibitors + nitrates = fatal hypotension. Riociguat + PDE-5 inhibitors = prohibited (excessive cGMP). ERA + pregnancy = teratogenic.