Pulmonary Pharmacology · Module 5 of 7

Pulmonary Hypertension Pharmacology

Three deficient vasoactive pathways · Prostacyclin analogs and IP agonists · Endothelin receptor antagonists · PDE-5 inhibitors and sGC stimulators · Combination therapy strategy

PAH is hemodynamically defined as mean pulmonary arterial pressure >20 mmHg at rest by right heart catheterization, with PAWP ≤15 mmHg and PVR >2 Wood units (2022 ESC/ERS thresholds). Group 1 PAH involves three simultaneous pathological processes in small pulmonary arteries: endothelial dysfunction producing an imbalance favoring vasoconstriction (prostacyclin/NO deficient; ET-1 excess); vascular remodeling (smooth muscle and endothelial cell proliferation, intimal thickening, medial hypertrophy, fibrosis); and in situ microthrombosis. Progressive right ventricular failure from sustained pressure overload is the mechanism of death. PAH-specific therapies target the endothelial imbalance — not the structural remodeling, which is largely irreversible. Do not apply Group 1 therapies across other WHO groups without careful evaluation.
Prostacyclin pathway (deficient in PAH): PGI2 acts at IP receptors → Gs → cyclic AMP → PKA → vasodilation + antiproliferation + antiplatelet. Epoprostenol (synthetic PGI2): t½ 2–3 min, IV continuous infusion via permanent central catheter; only PAH drug with RCT mortality benefit (1996 Barst trial); abrupt discontinuation causes fatal rebound pulmonary hypertension; catheter infections and pump failure are major safety concerns. Treprostinil: t½ ~4 h; routes SC/IV/inhaled/oral — SC avoids catheter but causes significant injection site pain. Iloprost: inhaled (6–9×/day) or IV — frequent dosing barrier. Selexipag: oral non-prostanoid IP receptor agonist (37-fold IP selectivity of active metabolite); GRIPHON trial reduced morbidity/mortality composite on background therapy.
Endothelin pathway (overactive in PAH): ET-1 excess produced by dysfunctional endothelium → ETA on smooth muscle → vasoconstriction + proliferation; ETB on endothelium → vasodilation (via NO/PGI2) + ET-1 clearance. Bosentan: dual ETA/ETB antagonist; hepatotoxicity in ~10% — monthly LFTs required; CYP3A4/2C9 inducer (↓warfarin, statins, cyclosporine); teratogenic — two contraceptive methods required for women of childbearing potential (ALL endothelin receptor antagonists). Ambrisentan: selective ETA antagonist; lower hepatotoxicity risk; once-daily. Macitentan: dual ETA/ETB with high tissue penetrance and sustained binding; SERAPHIN trial demonstrated reduced morbidity/mortality composite. Class AEs (all ERAs): teratogenicity, peripheral edema, anemia (hemodilution).
NO–cGMP pathway (deficient in PAH): NO from endothelium → sGC → cyclic GMP → PKG → vasodilation. PDE-5 inhibitors (sildenafil TID, tadalafil QD): block cGMP degradation → sustain vasodilation; SUPER-1 (sildenafil) and PHIRST (tadalafil) trials. Riociguat: direct sGC stimulator — acts by two mechanisms: sensitizes sGC to low NO concentrations present in diseased pulmonary vasculature AND directly stimulates sGC independent of NO; only approved oral therapy for CTEPH (inoperable or post-surgical residual) in addition to PAH. Critical absolute contraindication: PDE-5 inhibitors + nitrates (any form) = fatal hypotension (additive cGMP). Riociguat + PDE-5 inhibitors = prohibited (excessive cGMP and profound hypotension). Riociguat + nitrates also absolutely contraindicated.
Combination therapy — AMBITION trial: upfront dual therapy (ambrisentan + tadalafil) reduced clinical failure composite by 50% versus pooled monotherapy in treatment-naive PAH; established dual ERA + PDE-5 inhibitor as standard initial approach. Triple therapy (add prostacyclin pathway agent) for patients remaining at intermediate/high risk on dual therapy — GRIPHON trial provides evidence base for selexipag as third agent. Risk stratification: three strata (low/intermediate/high) using WHO functional class, 6-minute walk distance, BNP, right atrial pressure, cardiac index, SvO2. Treat-to-target: goal is low-risk status; any follow-up assessment at intermediate/high risk requires treatment escalation. Stability is not success in a progressive obliterative disease.

BNP = brain natriuretic peptide · cAMP = cyclic adenosine monophosphate · cGMP = cyclic guanosine monophosphate · CTEPH = chronic thromboembolic pulmonary hypertension · ERA = endothelin receptor antagonist · ESC = European Society of Cardiology · ET-1 = endothelin-1 · ERS = European Respiratory Society · ETA = endothelin receptor type A · ETB = endothelin receptor type B · IP = prostacyclin receptor · LFT = liver function test · NO = nitric oxide · PAH = pulmonary arterial hypertension · PAWP = pulmonary arterial wedge pressure · PDE-5 = phosphodiesterase-5 · PGI2 = prostacyclin · PKA = protein kinase A · PKG = protein kinase G · PVR = pulmonary vascular resistance · RCT = randomized controlled trial · sGC = soluble guanylate cyclase · SvO2 = mixed venous oxygen saturation · WHO = World Health Organization

The Three Therapeutic Pathways in PAH

Pathway 1 — Deficient in PAH

Prostacyclin (PGI2)

Endothelial PGI2 → IP receptor → Gs → cyclic AMP ↑ → PKA → vasodilation + antiproliferation + antiplatelet
Deficient in PAH — restoring signaling produces clinical benefit
Epoprostenol: IV continuous; only PAH drug with RCT mortality benefit
Treprostinil: SC/IV/inhaled/oral; t½ ~4 h
Selexipag: oral non-prostanoid IP agonist; GRIPHON trial

Pathway 2 — Overactive in PAH

Endothelin-1

ET-1 excess from dysfunctional endothelium → ETA on smooth muscle → vasoconstriction + proliferation
ETB on endothelium → vasodilation (NO/PGI2) + ET-1 clearance — blocking ETB is counterproductive
Overactive in PAH — blockade reduces both vasoconstriction and remodeling
Bosentan: dual ETA/ETB; hepatotoxicity; CYP3A4/2C9 inducer
Ambrisentan: selective ETA; lower hepatotox
Macitentan: dual ETA/ETB; SERAPHIN trial

Pathway 3 — Deficient in PAH

Nitric Oxide / cGMP

Endothelial NO → sGC → cyclic GMP ↑ → PKG → vasodilation
Deficient in PAH — two approaches to amplify
Sildenafil / Tadalafil: PDE-5 inhibitors — block cGMP degradation
Riociguat: sGC stimulator — directly increases cGMP production; also approved for CTEPH
Absolute CI: PDE-5 inhibitors + nitrates = fatal hypotension; riociguat + PDE-5 inhibitors prohibited

Prostacyclin Pathway Agents

Prostacyclin Analog — IV

Epoprostenol

Only PAH drug with RCT mortality benefit (1996 Barst trial)
t½ 2–3 min — requires continuous IV infusion via permanent central catheter
Abrupt discontinuation: fatal rebound pulmonary hypertension
Major safety concerns: catheter infections, pump failures — require ongoing vigilance
Chemically unstable at room temperature in many formulations

Prostacyclin Analog — Multi-Route

Treprostinil

t½ ~4 h — enables multiple routes
SC: avoids central catheter; most studied route
SC injection site pain — significant tolerability barrier for many patients
IV: alternative if SC not tolerated
Inhaled: targets ventilated lung segments — improved V/Q matching
Oral: extended-release tablet

Non-Prostanoid IP Agonist — Oral

Selexipag

Selective IP receptor agonist — not a prostacyclin analog
Active metabolite (hydrolysis product) has 37-fold IP selectivity over other prostaglandin receptors
Fewer off-target prostaglandin receptor side effects vs prostacyclin analogs
GRIPHON trial: reduced morbidity/mortality composite on background ERA ± PDE-5 inhibitor therapy
Ideal oral third agent in triple therapy regimens

Endothelin Receptor Antagonists

Dual ERA — First-in-Class

Bosentan

Blocks both ETA and ETB receptors
First oral agent approved for PAH (BREATHE-1 trial)
Hepatotoxicity ~10% — monthly LFT monitoring required
CYP3A4/2C9 inducer — reduces warfarin, statins, cyclosporine, and other drug levels
Teratogenic — two reliable contraceptive methods required

Selective ERA

Ambrisentan

Selective ETA antagonist — preserves ETB-mediated vasodilation and ET-1 clearance
Lower hepatotoxicity risk than bosentan
Once-daily oral dosing
AMBITION trial partner: ambrisentan + tadalafil = standard upfront dual therapy
Teratogenic — contraception required

Dual ERA — High Tissue Penetrance

Macitentan

Dual ETA/ETB antagonist with high tissue penetrance and sustained receptor binding
SERAPHIN trial: reduced morbidity/mortality composite endpoint vs placebo
Strongest morbidity/mortality evidence among ERAs
Once-daily oral dosing
Teratogenic — contraception required; anemia; nasopharyngitis

Nitric Oxide–cGMP Pathway Agents

PDE-5 Inhibitors

Sildenafil / Tadalafil

Inhibit PDE-5 → block cyclic GMP degradation in pulmonary arterial smooth muscle → sustained vasodilation
Sildenafil: three times daily; SUPER-1 trial — improved exercise capacity and hemodynamics
Tadalafil: once daily (PHIRST trial) — preferred for adherence
Well-tolerated: headache, flushing, nasal congestion from systemic vasodilation
Absolute CI with nitrates of any form — additive cyclic GMP → fatal systemic hypotension
Do not combine with riociguat — excessive cyclic GMP

sGC Stimulator

Riociguat

Directly stimulates sGC via two complementary mechanisms:
1. Sensitizes sGC to low NO concentrations present in diseased pulmonary vasculature
2. Directly stimulates sGC independent of NO — effective even when endothelial NO production is severely impaired
Only approved oral therapy for CTEPH — for inoperable or post-surgical residual disease
Also approved for Group 1 PAH; three times daily dosing
Absolute CI with nitrates AND with PDE-5 inhibitors — prohibited combination

Combination Therapy and Risk Stratification

Risk at Presentation	Initial Strategy	Evidence Base	Escalation Trigger
Low–Intermediate risk, newly diagnosed	Upfront dual therapy: ERA + PDE-5 inhibitor (ambrisentan + tadalafil preferred)	AMBITION trial: 50% reduction in clinical failure vs pooled monotherapy	Any follow-up assessment at intermediate/high risk = escalate immediately
High risk or deteriorating on dual therapy	Triple therapy: add prostacyclin pathway agent (selexipag oral; treprostinil inhaled/SC/IV; epoprostenol IV)	GRIPHON trial: selexipag on background ERA ± PDE-5 inhibitor reduced morbidity/mortality	Persistent high risk despite triple therapy: consider lung transplant evaluation

Risk Stratification and Treat-to-Target

Three-strata risk assessment (low / intermediate / high) using: WHO functional class, 6-minute walk distance, BNP/NT-proBNP, right atrial pressure, cardiac index, and mixed venous oxygen saturation (SvO2). Reassess every 3–6 months.

Goal: low-risk status. Stability at intermediate risk is not an acceptable outcome in a progressively obliterative disease. Any follow-up assessment at intermediate or high risk is a treatment failure requiring escalation — the same treat-to-target principle applied in oncology and rheumatology. Do not accept stable but suboptimal disease.

Absolute Contraindications — PAH Pharmacology

PDE-5 inhibitors (sildenafil, tadalafil) + nitrates of any form (nitroglycerin, isosorbide mononitrate/dinitrate, amyl nitrite): additive cyclic GMP elevation → profound, potentially fatal systemic hypotension. Absolutely contraindicated regardless of indication.

Riociguat + nitrates: same mechanism — absolutely contraindicated. Riociguat + PDE-5 inhibitors: prohibited — excessive cyclic GMP accumulation and severe hypotension.

ERA + pregnancy: all endothelin receptor antagonists are teratogenic. Two reliable contraceptive methods required for all women of childbearing potential throughout ERA treatment. Immediately discontinue if pregnancy occurs and seek specialist guidance.

Epoprostenol: never abruptly discontinue — fatal rebound pulmonary hypertension.

Suggested References

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Katzung BG (ed)	Basic and Clinical Pharmacology, 15th ed.	McGraw-Hill, 2021
Brunton LL, Knollmann BC (eds)	Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th ed.	McGraw-Hill, 2023
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Sitbon O, Channick R, Chin KM, et al	Selexipag for the treatment of pulmonary arterial hypertension	N Engl J Med. 2015;373(26):2522–2533
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Ghofrani HA, Galie N, Grimminger F, et al	Riociguat for the treatment of pulmonary arterial hypertension	N Engl J Med. 2013;369(4):330–340
Galie N, Barberà JA, Frost AE, et al	Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension (AMBITION)	N Engl J Med. 2015;373(9):834–844
Dupuis J, Hoeper MM	Endothelin receptor antagonists in pulmonary arterial hypertension	Eur Respir J. 2008;31(2):407–415