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Pulmonary Hypertension & Antifibrotic Drugs

Name: Pulmonary Hypertension & Antifibrotic Drugs
Creator: Veli Bakalov, MD

Endothelin, NO, prostacyclin, and the fibroblast: drugs for narrowed and scarred lungs

Respiratory·Pharmacology·4 min read·8 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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PAH drugs correct three endothelial defects: excess endothelin-1 (ERAs), deficient NO-cGMP signaling (PDE-5 inhibitors, riociguat), and deficient prostacyclin-cAMP signaling (epoprostenol, treprostinil, iloprost, selexipag).
Bosentan and macitentan block ETA and ETB receptors and ambrisentan blocks ETA; all ERAs are teratogenic and cause edema and anemia, and bosentan requires monthly liver tests.
Sildenafil and tadalafil inhibit PDE-5 to raise cGMP; they must never be combined with nitrates or riociguat because of severe hypotension.
Riociguat is a soluble guanylate cyclase stimulator used for PAH and inoperable or persistent CTEPH; it is teratogenic.
Epoprostenol has a half-life of minutes and requires continuous IV infusion; interruption causes rebound pulmonary hypertension.
Prostacyclin-pathway drugs cause flushing, headache, jaw pain, and diarrhea; selexipag is an oral IP-receptor agonist.
High-dose CCBs are used only for PAH patients with a positive vasoreactivity test at right heart catheterization; sotatercept is an add-on activin-signaling inhibitor.
Pirfenidone reduces TGF-β-driven fibrosis and causes photosensitivity, GI upset, and elevated LFTs; nintedanib inhibits VEGFR, FGFR, and PDGFR and causes diarrhea, hepatotoxicity, and bleeding risk.

Why PAH responds to targeted vasodilators

Endothelial imbalance. In pulmonary arterial hypertension the endothelium overproduces endothelin-1 and underproduces nitric oxide and prostacyclin. Small pulmonary arteries constrict, their smooth muscle proliferates, and platelets are activated, so vascular resistance rises and the right ventricle eventually fails. Heritable PAH most often stems from loss-of-function BMPR2 mutations (autosomal dominant with incomplete penetrance), which tip growth signaling toward proliferation. Each drug class corrects one limb of this imbalance.

PAH drug classes

Class	Drugs	Mechanism	Key toxicities
Endothelin receptor antagonists	Bosentan, macitentan (ETA + ETB); ambrisentan (ETA-selective)	Block endothelin-1 constriction and mitogenesis	Teratogenic; edema, anemia, nasal congestion, headache; bosentan hepatotoxic
PDE-5 inhibitors	Sildenafil, tadalafil	Block cGMP breakdown	Headache, flushing, dyspepsia, hypotension; blue-tinged vision (sildenafil)
sGC stimulator	Riociguat	Raises cGMP directly and sensitizes sGC to NO	Hypotension; teratogenic
Prostacyclin pathway	Epoprostenol, treprostinil, iloprost, selexipag	IP-receptor (Gs) activation raises cAMP	Flushing, headache, jaw pain, diarrhea; rebound if epoprostenol stops
Calcium channel blockers	Nifedipine, diltiazem, amlodipine	Block L-type Ca2+ channels	Hypotension, right-heart failure in nonresponders
Activin-signaling inhibitor	Sotatercept	Traps activins, rebalancing growth signals	↑ Hemoglobin, ↓ platelets, telangiectasias, bleeding

Endothelin receptor antagonists

Mechanism. Endothelin-1 is a potent vasoconstrictor and mitogen acting on ETA and ETB receptors. Bosentan and macitentan block both receptors, while ambrisentan is ETA-selective. Blockade relaxes pulmonary arterial smooth muscle and slows its proliferation. Class effects are peripheral edema, anemia, nasal congestion and headache.

Liver and pregnancy. Bosentan is the most hepatotoxic member and requires monthly aminotransferase checks. It also induces CYP3A4 and CYP2C9, lowering levels of hormonal contraceptives and sildenafil, so hormonal contraception cannot be the only method.

Every endothelin receptor antagonist, and riociguat, is teratogenic: exclude pregnancy before starting, monitor during treatment and require reliable contraception.

The nitric oxide–cGMP pathway

Nitric oxideReleased by endothelium or donated by nitrate drugs.
Soluble guanylate cyclaseConverts GTP to cGMP; riociguat stimulates it directly and sensitizes it to NO.
cGMP and protein kinase GIntracellular Ca2+ falls and smooth muscle relaxes.
PDE-5Degrades cGMP; sildenafil and tadalafil block it, prolonging vasodilation in pulmonary and penile vessels.

PDE-5 inhibitors. Sildenafil and tadalafil cause headache, flushing, dyspepsia, nasal congestion and hypotension. Sildenafil also inhibits retinal PDE-6, producing blue-tinged vision.

Riociguat. By acting on soluble guanylate cyclase itself, riociguat raises cGMP even when NO is scarce. It treats PAH and chronic thromboembolic pulmonary hypertension (CTEPH) that is inoperable or persists after surgery; pulmonary endarterectomy remains the treatment of choice for operable CTEPH.

Never combine a PDE-5 inhibitor with nitrates or riociguat: more cGMP production plus blocked breakdown causes profound, potentially fatal hypotension.

Prostacyclins, calcium channel blockers and sotatercept

Prostacyclin pathway. Prostacyclin (PGI2) binds Gs-coupled IP receptors, raising cAMP to dilate pulmonary arteries, inhibit platelet aggregation and slow smooth-muscle growth. Options include IV epoprostenol, treprostinil (subcutaneous, IV, inhaled or oral), inhaled iloprost and oral selexipag, a nonprostanoid IP-receptor agonist. Systemic effects are flushing, headache, jaw pain (classically with the first bites of a meal), diarrhea, nausea and hypotension; subcutaneous treprostinil adds infusion-site pain.

≤6 minhalf-life of IV epoprostenol

Epoprostenol. It runs as a continuous infusion through a tunneled central catheter and is reserved for the sickest patients. Pump or line failure causes life-threatening rebound pulmonary hypertension within minutes, and the catheter carries a risk of bloodstream infection.

Calcium channel blockers. High-dose nifedipine, diltiazem or amlodipine helps only the small minority of patients with a positive acute vasoreactivity test at right heart catheterization: with inhaled nitric oxide, mean pulmonary artery pressure falls by at least 10 mmHg to 40 mmHg or less without a drop in cardiac output. In nonresponders CCBs cause hypotension and right-heart failure, and verapamil is avoided because of negative inotropy.

Sotatercept. This subcutaneous fusion protein traps activins and related ligands, rebalancing pro-proliferative activin signaling against antiproliferative BMPR2 signaling to counter remodeling. It is an add-on to background therapy and can raise hemoglobin, lower platelets, and cause telangiectasias and bleeding.

Antifibrotic drugs for pulmonary fibrosis

Pirfenidone versus nintedanib

Feature	Pirfenidone	Nintedanib
Mechanism	Dampens TGF-β–driven fibroblast proliferation and collagen synthesis; exact target unknown	Intracellular tyrosine kinase inhibitor of VEGFR, FGFR and PDGFR
Uses	Idiopathic pulmonary fibrosis	IPF, systemic sclerosis–associated ILD, other progressive fibrosing ILDs
Signature adverse effects	Nausea, dyspepsia, anorexia, photosensitivity rash, ↑ aminotransferases	Diarrhea (most common), ↑ aminotransferases, bleeding risk, teratogenicity
Interactions	CYP1A2 substrate: fluvoxamine raises levels, smoking lowers them	Caution with anticoagulants

What they achieve. Both oral drugs slow the annual decline in FVC but do not reverse established fibrosis; lung transplantation is the only cure for end-stage disease. Combined immunosuppression with prednisone and azathioprine increases mortality in IPF, which is why antifibrotics rather than immunosuppressants are the standard.