Pulmonary Hypertension Agents
Verified · Oct 2026PAH is an endothelial disease: too little nitric oxide and prostacyclin, too much endothelin-1. Each drug family targets one of those three pathways — so the second messenger it raises (cGMP or cAMP) predicts both its benefit and its most dangerous interactions.
Nursing view → administration, monitoring and patient teaching
Drugs
Mechanism
Three mechanisms. Endothelin receptor antagonists block endothelin-1 at ETA receptors (vasoconstriction, proliferation) — bosentan and macitentan at both ETA and ETB, ambrisentan selectively at ETA. PDE-5 inhibitors (sildenafil, tadalafil) block the breakdown of cGMP in pulmonary vascular smooth muscle, relaxing it and dilating the pulmonary vascular bed. Riociguat stimulates soluble guanylate cyclase, both sensitizing it to endogenous nitric oxide and stimulating it independently of nitric oxide, increasing cGMP. Epoprostenol and treprostinil are prostacyclin and a prostacyclin analog that directly dilate the pulmonary and systemic arterial beds and inhibit platelet aggregation.
Endothelin-1 and its two receptors
Endothelins are 21-amino-acid peptides with three isoforms; ET-1 is the most abundant. They act on G protein-coupled receptors: ETA, concentrated in pulmonary vascular and airway smooth muscle, mediates vasoconstriction and cell proliferation, while ETB, mostly on the endothelium, mediates vasodilation, antiproliferation and clearance of ET-1 — so blocking ETB can raise circulating ET-1. In PAH, plasma ET-1 rises as much as 10-fold and correlates with right atrial pressure and disease severity, and lung-tissue ET-1 rises up to 9-fold, mainly in the pulmonary arterial endothelium.
The three ERAs differ in receptor selectivity. Bosentan is a competitive antagonist at both receptors with slightly higher affinity for ETA; macitentan also blocks both, with high affinity and sustained receptor occupancy in pulmonary arterial smooth muscle cells; ambrisentan is more than 4000-fold selective for ETA. The labels note that the clinical impact of dual versus ETA-selective blockade is not known.
Nitric oxide → sGC → cGMP: three ways in
Soluble guanylate cyclase (sGC) is the receptor for nitric oxide; when NO binds, sGC synthesizes cGMP, which regulates vascular tone, proliferation, fibrosis and inflammation. cGMP activates cGMP-dependent protein kinase, whose phosphorylation of smooth-muscle targets lowers intracellular calcium, increases potassium efflux and deactivates myosin light chain kinase — relaxation. Pulmonary hypertension is associated with impaired NO synthesis and insufficient stimulation of this pathway.
PDE-5 — the predominant phosphodiesterase in the pulmonary vasculature — degrades cGMP. Sildenafil’s structure mimics cGMP, so it binds the catalytic site as a competitive inhibitor; tadalafil also selectively inhibits PDE-5. Riociguat acts upstream with a dual mode: it sensitizes sGC to endogenous NO by stabilizing NO–sGC binding and directly stimulates sGC at a different site, independently of NO. Nitrates, as NO donors, feed the same enzyme — which is why all three routes add up.
Prostacyclin → IP receptor → cAMP
Prostacyclin (PGI2) is made from arachidonic acid by COX-2 and prostaglandin I synthase, chiefly in vascular endothelial and smooth muscle cells. It binds the IP receptor, a Gs-coupled receptor on platelets and smooth muscle: adenylyl cyclase makes cAMP, and downstream phosphorylation inhibits platelet aggregation, relaxes smooth muscle and reduces cell proliferation. PGI2 is the most potent known natural inhibitor of platelet aggregation.
Epoprostenol is prostacyclin itself — rapidly hydrolyzed at neutral pH in blood and enzymatically degraded, with an in vivo half-life expected to be no more than 6 minutes, so it needs a continuous IV infusion. Treprostinil is a chemically stable analog with a terminal half-life of about 4 hours and near-complete subcutaneous absorption, which is why it can be given subcutaneously, intravenously, by inhalation or as an extended-release tablet. Both directly dilate pulmonary and systemic arterial beds and inhibit platelet aggregation.
Why cGMP drugs never mix
Nitrates increase cGMP formation while PDE-5 inhibitors block its degradation, so together they produce severe, potentially life-threatening hypotension; the tadalafil labels attribute the potentiation to their combined effect on the NO–cGMP pathway. Riociguat potentiated the blood-pressure fall from sublingual nitroglycerin taken 4 and 8 hours after a dose, with syncope in some patients.
Riociguat plus sildenafil showed additive hemodynamic effects; among PAH patients on both, there was one death possibly related to the combination and a high rate of discontinuation for hypotension. Riociguat is therefore contraindicated with any PDE-5 inhibitor — and with nonspecific PDE inhibitors such as dipyridamole and theophylline.
Comparing the drugs
Endothelin receptor antagonists
| Drug | Receptor selectivity | Liver | Metabolism and half-life | Signature interaction |
|---|---|---|---|---|
| Bosentan | Dual ETA/ETB (competitive; slightly higher ETA affinity) | Boxed hepatotoxicity: ALT/AST ≥ 3× ULN in ~11%; REMS with monthly tests | Hepatic, biliary excretion (< 3% in urine); induces CYP2C9 and CYP3A, auto-inducing to 50–65% of single-dose levels; t½ ~5 h | Contraindicated with cyclosporine A and glyburide; lowers hormonal-contraceptive levels |
| Ambrisentan | ETA-selective (> 4000-fold) | No hepatotoxicity warning; ALT/AST > 3× ULN 0% vs 2.3% on placebo (12-week trials) | CYP3A, CYP2C19 and UGTs; neither inhibits nor induces drug-metabolizing enzymes; terminal t½ 15 h (effective ~9 h) | Cyclosporine raises exposure — ambrisentan dose capped |
| Macitentan | Dual ETA/ETB; high affinity, sustained receptor occupancy | ERA hepatotoxicity warning; liver enzymes at baseline, then as indicated | CYP3A4 → active metabolite (3× the parent exposure, ~40% of activity); t½ ~16 h (metabolite ~48 h) | Avoid strong CYP3A4 inducers (rifampin) and inhibitors (ketoconazole, ritonavir) |
All three carry the embryo-fetal toxicity boxed warning; bosentan is the only one with a REMS in the current labels.
cGMP-pathway drugs
| Drug | Target | Half-life | Clearance | Nitrate and cross-use rule |
|---|---|---|---|---|
| Sildenafil | PDE-5 (only ~10× selective over retinal PDE-6; ~4000× over cardiac PDE-3) | ~4 h (parent and active N-desmethyl metabolite) | CYP3A (major), CYP2C9 (minor); metabolite gives ~20% of the effect; ~80% in feces | Nitrates in any form, regularly or intermittently, contraindicated; riociguat contraindicated |
| Tadalafil | PDE-5 (700× over PDE-6, > 10,000× over PDE-3; also inhibits PDE-11) | 15 h in healthy subjects; 35 h in pulmonary hypertension (not on bosentan) | CYP3A → catechol metabolites, not expected to be active; 61% feces, 36% urine | No nitrate within 48 h of the last dose; GC stimulators contraindicated |
| Riociguat | sGC — NO-sensitizing and NO-independent stimulation | ~12 h in patients (7 h in healthy subjects) | CYP1A1 (→ active M1; inducible by cigarette smoke), CYP3A4/3A5, CYP2J2; P-gp/BCRP substrate | Contraindicated with nitrates or NO donors, PDE-5 inhibitors, dipyridamole/theophylline and other sGC stimulators |
Prostacyclin-pathway drugs
| Drug | What it is | Half-life | Routes | Clearance |
|---|---|---|---|---|
| Epoprostenol | Prostacyclin itself (PGI2) | In vivo ≤ 6 min | Continuous IV infusion via a central venous catheter | Hydrolyzed at neutral pH and enzymatically degraded to much weaker metabolites (e.g., 6-keto-PGF1α) |
| Treprostinil | Chemically stable prostacyclin analog | ~4 h (subcutaneous) | SC (preferred) or IV infusion; inhaled; oral | Hepatic CYP2C8 (gemfibrozil ↑, rifampin ↓ exposure); not cleared by dialysis |
Pharmacokinetics
- Auto-induction — bosentan
- Bosentan induces CYP2C9 and CYP3A (possibly CYP2C19); with repeated dosing its plasma levels fall to 50–65% of single-dose levels, reaching steady state in 3–5 days. Oral bioavailability is about 50% and unaffected by food; it is > 98% albumin-bound and eliminated by biliary excretion after hepatic metabolism.
- Hepatic impairment — bosentan
- In moderate hepatic impairment (Child-Pugh B) with portopulmonary hypertension, bosentan steady-state AUC was 4.7 times and its active metabolite 12.4 times higher; severe impairment has not been studied.
- Active metabolite — macitentan
- Oxidative depropylation, mainly by CYP3A4, forms an active metabolite whose exposure is 3 times that of macitentan and contributes about 40% of the activity; half-lives are about 16 h (parent) and 48 h (metabolite). A moderate dual CYP3A4/CYP2C9 inhibitor such as fluconazole is predicted to raise macitentan exposure about 4-fold.
- Effective half-life — ambrisentan
- Terminal half-life is 15 h, but the trough is about 15% of the peak with an accumulation factor of 1.2, giving an effective half-life of about 9 h. It is 99% protein-bound, eliminated mainly by non-renal routes, and a P-gp and OATP substrate.
- Absorption and elimination — sildenafil, tadalafil
- Sildenafil’s oral bioavailability averages 41%; a high-fat meal delays its peak by about 60 minutes and lowers the peak 29%. Tadalafil absorption is unaffected by food and it is 94% protein-bound; its half-life lengthens from 15 h in healthy subjects to 35 h in pulmonary hypertension (without concomitant bosentan). Both are excreted as metabolites, mainly in feces.
- Smoking — riociguat
- CYP1A1 forms the active metabolite M1 and is inducible by polycyclic aromatic hydrocarbons in cigarette smoke, so plasma concentrations are 50–60% lower in smokers. Riociguat is about 95% protein-bound and is not expected to be dialyzable.
- Short half-life — epoprostenol
- Rapid hydrolysis at neutral pH plus enzymatic degradation give an in vivo half-life of no more than about 6 minutes — the pharmacokinetic reason it must be infused continuously and why interruptions are dangerous.
- Absorption and metabolism — treprostinil
- Subcutaneous bioavailability approximates 100%; elimination is biphasic with a terminal half-life of about 4 h. It is metabolized in the liver by CYP2C8 to inactive metabolites, so CYP2C8 inhibitors (gemfibrozil) raise and inducers (rifampin) lower exposure.
Uses & drug choice
- Pulmonary arterial hypertension (PAH, WHO Group 1) — every drug on this page
- Bosentan (idiopathic or congenital PAH, age 3 and older) and sildenafil (ages 1 to 17) for PAH in children
- Riociguat for chronic thromboembolic pulmonary hypertension (CTEPH, WHO Group 4) that persists or recurs after surgery or is inoperable
- Inhaled treprostinil (Tyvaso, Tyvaso DPI) for pulmonary hypertension associated with interstitial lung disease (PH-ILD, WHO Group 3)
- Treprostinil infusion (Remodulin) for patients with PAH who need to transition from epoprostenol
Adverse effects
- Embryo-fetal toxicity (ERAs)
- Endothelin signaling is needed for development: bosentan caused malformations of the head, mouth, face and large blood vessels in rats, similar to those in endothelin-1 knockout mice, which marks embryo-fetal toxicity as a class effect; ambrisentan caused lower-jaw, palate, heart and great-vessel malformations and failure of thymus and thyroid formation.
- Hepatotoxicity (bosentan)
- Aminotransferase elevations are dose-dependent, occur early or late, usually progress slowly, are typically asymptomatic and usually reverse after interruption — hence monthly monitoring; glyburide increases the risk (contraindicated).
- Hemoglobin decrease (ERAs)
- Falls early and then stabilizes; the cause is unknown but it does not appear to result from hemorrhage or hemolysis.
- Headache, flushing, hypotension
- Extensions of vasodilation, the main pharmacologic effect — with epoprostenol these were also the effects that limited dose increases.
- Blue/green color-vision change (PDE-5 inhibitors)
- Inhibition of PDE-6, the retinal phototransduction enzyme; sildenafil is only about 10 times as potent for PDE-5 as for PDE-6, tadalafil about 700 times.
- Severe hypotension with nitrates or between cGMP drugs
- Nitrates raise cGMP formation, PDE-5 inhibitors block its breakdown and riociguat drives sGC directly; combining them summates cGMP-mediated vasodilation.
- Rebound pulmonary hypertension (prostacyclins)
- Epoprostenol’s half-life is minutes, so an interruption removes the drug almost at once; rebound dyspnea, dizziness and asthenia follow, and one death was attributed to interruption.
- Bleeding (prostacyclins)
- IP-receptor cAMP signaling inhibits platelet aggregation — a second major pharmacologic action of epoprostenol and treprostinil.
Toxicity & antidote
Prostacyclin overdose looks like exaggerated pharmacology — flushing, headache, hypotension, tachycardia, nausea, vomiting and diarrhea — and usually needs only a dose reduction; fatal hypoxemia, hypotension and respiratory arrest have been reported with epoprostenol. Treprostinil overdoses in trials came from accidental boluses, pump-programming errors and prescribing errors, and treprostinil is not cleared by dialysis.
A 10,000 mg bosentan overdose caused nausea, vomiting, hypotension, dizziness, sweating and blurred vision, with recovery within 24 hours on blood-pressure support. Care is supportive, with close blood-pressure monitoring and support for riociguat. Dialysis is not expected to help for riociguat, sildenafil, macitentan or bosentan because they are extensively protein-bound.
Interactions
Contraindications
- Pregnancy (bosentan, ambrisentan, macitentan, riociguat) — Boxed warning — these drugs may cause fetal harm based on animal data.
- Sildenafil or tadalafil with organic nitrates in any form, regularly or intermittently — no nitrate within 48 hours of the last tadalafil dose — PDE-5 inhibitors potentiate the hypotensive effect of nitrates through the combined effect on the nitric oxide–cGMP pathway.
- Riociguat with nitrates or nitric oxide donors (such as amyl nitrite) in any form — The combination causes hypotension.
- Riociguat with a PDE-5 inhibitor (sildenafil, tadalafil, vardenafil) or a nonspecific PDE inhibitor (dipyridamole, theophylline) — Hypotension. Riociguat is not given within 24 hours of sildenafil, or 24 hours before or within 48 hours after tadalafil; riociguat is stopped at least 24 hours before a PDE-5 inhibitor is started.
- Riociguat with another soluble guanylate cyclase stimulator — Labeled contraindication (pharmacodynamic interaction).
- Bosentan with cyclosporine A or with glyburide — Cyclosporine markedly increases bosentan concentrations; glyburide with bosentan increased the risk of liver enzyme elevations.
- Ambrisentan: idiopathic pulmonary fibrosis, including IPF with pulmonary hypertension (WHO Group 3) — In a trial in IPF, ambrisentan showed a greater risk of disease progression or death.
- Riociguat: pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP) — Labeled contraindication.
- Epoprostenol: chronic use in heart failure due to severe left-ventricular systolic dysfunction, or in patients who develop pulmonary edema during dose initiation — A heart-failure survival study was stopped for higher mortality with epoprostenol; pulmonary edema during initiation may signal PVOD.
- Oral treprostinil (Orenitram): severe hepatic impairment (Child-Pugh C) — Systemic exposure increases.
- Hypersensitivity to bosentan, macitentan, sildenafil, tadalafil or epoprostenol — Labeled contraindication — reported reactions include DRESS, anaphylaxis and angioedema (bosentan), anaphylaxis (sildenafil), and Stevens-Johnson syndrome and exfoliative dermatitis (tadalafil).
- Resting hypotension, fluid depletion, left-ventricular outflow obstruction or autonomic dysfunction (PDE-5 inhibitors, riociguat) use caution — Vasodilation may cause symptomatic hypotension or ischemia.
- Pulmonary veno-occlusive disease use caution — Pulmonary vasodilators may significantly worsen it; use is not recommended.
- Bosentan: aminotransferases > 3× ULN before starting; ambrisentan: clinically significant anemia; macitentan: severe anemia use caution — Bosentan should generally be avoided (hepatotoxicity is harder to monitor); starting ambrisentan or macitentan is not recommended because they lower hemoglobin.
- Retinitis pigmentosa or other hereditary degenerative retinal disorders (sildenafil, tadalafil) use caution — Use is not recommended — no safety data, and some patients have genetic disorders of retinal phosphodiesterases.
- Pulmonary hypertension from sickle cell disease (sildenafil) use caution — Vaso-occlusive crises requiring hospitalization were more common with sildenafil.
- Penile deformity or conditions predisposing to priapism — sickle cell anemia, multiple myeloma, leukemia (PDE-5 inhibitors) use caution — Use with caution — risk of priapism.
- Asthma, COPD or other bronchial hyperreactivity (inhaled treprostinil) use caution — Increased risk of acute bronchospasm.
- Oral treprostinil: diverticulosis, or moderate hepatic impairment use caution — The tablet shell does not dissolve and can lodge in a diverticulum; use is avoided in moderate hepatic impairment.
High-yield
- Endothelin → block it:
-entan(bosentan, ambrisentan, macitentan) - Nitric oxide–cGMP → boost it:
-afil(sildenafil, tadalafil) and-ciguat(riociguat) - Prostacyclin → replace it:
prost(epoprostenol, treprostinil)
PAH has too little NO and prostacyclin and too much endothelin-1.
- No nitrates or NO donors
- No PDE-5 inhibitors (or dipyridamole, theophylline)
- No other sGC stimulator
- No pregnancy (boxed warning)
- No PH from idiopathic interstitial pneumonias
Practice questions
Q1A 29-year-old woman with idiopathic pulmonary arterial hypertension, WHO functional class II, is to start a drug that is more than 4000-fold selective for the ETA receptor. She takes a combined oral contraceptive.
Which test must be done before the first dose?
- A.Electrocardiogram
- B.Serum creatinine
- C.Monthly aminotransferases for 3 months before starting
- D.Thyroid-stimulating hormone
- E.Pregnancy test
Show answer
E. Pregnancy test — Ambrisentan, like all ERAs and riociguat, carries a boxed warning for embryo-fetal toxicity: pregnancy is excluded before starting, contraception is used before, during and for one month after treatment, and the drug is stopped when pregnancy is detected. Monthly aminotransferase monitoring belongs to bosentan’s hepatotoxicity box; ambrisentan has no hepatotoxicity warning (ALT/AST > 3× ULN in 0% vs 2.3% on placebo). At usual doses, without metabolic inhibitors, ambrisentan is not expected to prolong the QT interval significantly, and mild or moderate renal impairment needs no dose adjustment — so neither an ECG nor a serum creatinine is a prerequisite.
Q2A 62-year-old man with PAH who takes tadalafil once daily comes to the emergency department with crushing chest pain 20 hours after his last dose. Sublingual nitroglycerin is being considered.
What is the main concern with giving nitroglycerin?
- A.Tadalafil inhibits the CYP3A metabolism of nitroglycerin
- B.Nitroglycerin inhibits PDE-5 and doubles tadalafil’s effect
- C.Nitroglycerin increases cGMP formation while tadalafil blocks its breakdown, causing profound hypotension
- D.Tadalafil causes methemoglobinemia with nitrates
- E.Both drugs block soluble guanylate cyclase
Show answer
C. Nitroglycerin increases cGMP formation while tadalafil blocks its breakdown, causing profound hypotension — Nitrates increase cGMP formation and PDE-5 inhibitors block cGMP degradation, so together they cause severe hypotension; the tadalafil labels say not to use nitrates within 48 hours of the last dose, and tadalafil’s half-life is about 35 hours in pulmonary hypertension. Tadalafil is itself a CYP3A substrate — the danger is pharmacodynamic, through the shared NO–cGMP pathway — and neither drug blocks sGC.
Q3A 45-year-old woman with PAH receives continuous IV epoprostenol through a tunneled central catheter. Her pump’s battery fails at home and the infusion stops for about an hour. She arrives short of breath, dizzy and weak, without fever or flushing.
What is the most likely explanation?
- A.Rebound pulmonary hypertension after interruption of a drug with a half-life of minutes
- B.Catheter-related bloodstream infection
- C.Epoprostenol overdose
- D.Anaphylaxis to the diluent
- E.Bleeding from platelet inhibition
Show answer
A. Rebound pulmonary hypertension after interruption of a drug with a half-life of minutes — Epoprostenol’s in vivo half-life is no more than about 6 minutes, so an interruption removes it almost at once; abrupt withdrawal causes rebound pulmonary hypertension with dyspnea, dizziness and asthenia, and a death has been attributed to an interruption — hence the backup pump. Overdose would instead look like excess vasodilation — flushing, headache, hypotension, tachycardia.
Q4A 58-year-old man has chronic thromboembolic pulmonary hypertension that is inoperable. He is started on an oral drug labelled for this indication and is told that his dose may need adjusting if he stops smoking.
Which mechanism best describes this drug?
- A.Inhibits PDE-5 so cGMP is not degraded
- B.Blocks ETA and ETB receptors
- C.Activates the IP receptor to raise cAMP
- D.Sensitizes soluble guanylate cyclase to nitric oxide and stimulates it directly, independent of nitric oxide
- E.Inhibits the late sodium current
Show answer
D. Sensitizes soluble guanylate cyclase to nitric oxide and stimulates it directly, independent of nitric oxide — Riociguat is the sGC stimulator labelled for persistent or recurrent CTEPH after surgery or inoperable CTEPH. It stabilizes NO–sGC binding and also stimulates sGC at a separate site without NO. Its active metabolite is formed by CYP1A1, which cigarette smoke induces, so levels are 50–60% lower in smokers and a dose decrease may be needed after quitting. PDE-5 inhibitors only slow cGMP breakdown, and riociguat is contraindicated with them.
Sources
- TRACLEER (bosentan) — FDA label: boxed warnings (hepatotoxicity, embryo-fetal toxicity), REMS, contraindications, interactions — FDA / DailyMed
- LETAIRIS (ambrisentan) — FDA label: boxed warning, ETA selectivity, IPF contraindication, hemoglobin — FDA / DailyMed
- OPSUMIT (macitentan) — FDA label: boxed warning, hepatotoxicity, hemoglobin, CYP3A4 interactions — FDA / DailyMed
- REVATIO (sildenafil) — FDA label: mechanism, nitrate and riociguat contraindications, vision, hearing, epistaxis — FDA / DailyMed
- ADCIRCA (tadalafil) — FDA label: mechanism, nitrate 48-hour rule, warnings, interactions — FDA / DailyMed
- ALYQ (tadalafil) tablets — FDA label — FDA / DailyMed
- TADLIQ (tadalafil) oral suspension — FDA label: administration — FDA / DailyMed
- ADEMPAS (riociguat) — FDA label: boxed warning, sGC mechanism, contraindications, hypotension, bleeding, smoking — FDA / DailyMed
- VELETRI (epoprostenol) — FDA label: contraindications, central-line infusion, withdrawal, half-life — FDA / DailyMed
- REMODULIN (treprostinil) injection — FDA label: subcutaneous vs IV infusion, bloodstream infection, withdrawal, CYP2C8 — FDA / DailyMed
- TYVASO (treprostinil) inhalation solution — FDA label: PH-ILD indication, bronchospasm, administration — FDA / DailyMed
- TYVASO DPI (treprostinil) inhalation powder — FDA label: inhaler use and care — FDA / DailyMed
- ORENITRAM (treprostinil) extended-release tablets — FDA label: hepatic contraindication, administration, diverticulosis — FDA / DailyMed
- Bosentan — mechanism (ETA/ETB), REMS, monitoring — StatPearls (NCBI)
- Treprostinil — WHO groups, routes, adverse effects — StatPearls (NCBI)
- Physiology, Prostaglandin I2 — IP receptor and cAMP signaling — StatPearls (NCBI)
- Pulmonary Arterial Hypertension (Group 1) — pathophysiology — StatPearls (NCBI)
- The use of stems in the selection of INN (stems -entan, -afil, -ciguat, prost) — World Health Organization
- Sildenafil — cGMP mimicry and protein kinase G signaling; nitrate synergy — StatPearls (NCBI)
By LearnDrugs
Educational summary for medical students. Always verify against current prescribing information and guidelines. Not medical advice.