Overview
Riociguat (brand name Adempas) is a small-molecule soluble guanylate cyclase (sGC) stimulator developed by Bayer and FDA-approved in 2013. It is indicated for adults with WHO Group 1 pulmonary arterial hypertension (PAH) to improve exercise capacity, WHO functional class, and delay clinical worsening, and for WHO Group 4 chronic thromboembolic pulmonary hypertension (CTEPH) that is persistent/recurrent after surgical treatment or inoperable. It is the only FDA-approved pharmacotherapy for CTEPH.
Riociguat has a dual mode of action: it sensitizes sGC to endogenous nitric oxide and directly stimulates sGC independent of NO, increasing intracellular cGMP. The result is potent pulmonary vasodilation, anti-proliferative and anti-fibrotic effects in pulmonary vasculature, and improvement in right ventricular afterload.
Pivotal trials CHEST-1 (CTEPH) and PATENT-1 (PAH) demonstrated significant improvements in 6-minute walk distance and clinical outcomes. Riociguat is contraindicated with PDE5 inhibitors (sildenafil, tadalafil) due to synergistic hypotension and with nitrates of any form.
Quick facts
- Mechanism
- Soluble guanylate cyclase (sGC) stimulator that increases cGMP independent of and synergistic with NO
- Primary use
- Pulmonary arterial hypertension (PAH); inoperable or persistent CTEPH
- Evidence
- strong
- FDA
- Approved
- Route
- Oral tablet (titrated to 2.5 mg three times daily)
- Typical results
- Improves 6-minute walk distance, WHO functional class, and pulmonary hemodynamics in PAH and CTEPH
Chemical information
Riociguat (C₂₀H₁₉FN₈O₂) is a longevity compound with a molecular weight of 422.42 g/mol. Its structural characteristics underpin its biological activity in longevity and anti-aging research.
How Riociguat works
Riociguat binds an allosteric site on sGC, sensitizing the enzyme to endogenous nitric oxide and directly stimulating cGMP production even when NO is reduced. Elevated cGMP in pulmonary vascular smooth muscle activates PKG, leading to vasodilation, reduced cellular proliferation, and reduced fibrosis. This is particularly relevant in PAH and CTEPH, where endogenous NO bioavailability is impaired.
The NO-sGC-cGMP pathway is central to pulmonary vascular homeostasis. In pulmonary hypertension, endothelial dysfunction reduces NO production, impairing this pathway. PDE5 inhibitors prolong cGMP availability but require some NO substrate; riociguat is unique in stimulating sGC directly even in NO-deficient states.
Beyond vasodilation, sustained sGC stimulation has anti-proliferative effects on pulmonary artery smooth muscle cells, reduces fibroblast activation, and may attenuate maladaptive vascular remodeling that drives PAH and CTEPH progression.
Riociguat is dosed by individualized titration starting at 1 mg three times daily, increasing every 2 weeks based on systolic blood pressure tolerance to a maximum of 2.5 mg three times daily.
- sGC stimulation: Allosteric enhancer that sensitizes sGC to NO and stimulates it directly
- cGMP elevation: Drives PKG-mediated pulmonary vasodilation
- Anti-proliferative: Reduces pulmonary vascular smooth-muscle proliferation
- Anti-fibrotic: Attenuates pulmonary vascular remodeling
- Only approved CTEPH drug: Unique role in inoperable/persistent CTEPH
Pharmacokinetics
| Parameter | Value | Significance |
|---|---|---|
| Oral bioavailability | ~94% | Reliable oral absorption |
| Tmax | 1–1.5 hours | Rapid onset |
| Half-life | ~7 hours (healthy); ~12 hours (PAH patients) | Supports three-times-daily dosing |
| Metabolism | CYP1A1, CYP3A4, CYP2C8, CYP2J2; UGT1A1/1A9 | Multiple interaction routes |
| Elimination | Renal (40%) and biliary/fecal (53%) | Dose adjustments may be needed in organ impairment |
Dosing & administration
Riociguat dosing varies by indication and individual factors. Refer to the official prescribing information for approved indications.
Any use should be conducted under qualified medical supervision with appropriate monitoring of safety markers.
Side effects & safety
Safety data for Riociguat is established for approved indications via clinical trials. Long-term effects in humans remain incompletely characterized.
Common
- • Headache
- • Dizziness
- • Hypotension
- • Dyspepsia and nausea
- • Peripheral edema
- • Nasal congestion
Serious / potential risks
- • Symptomatic hypotension and syncope
- • Hemoptysis and pulmonary hemorrhage (boxed warning in some labels)
- • Embryo-fetal toxicity (boxed warning; REMS program in US)
- • Severe hepatic impairment cautions
- • Anemia
Drug interactions
| Medication | Interaction | Recommendation |
|---|---|---|
| PDE5 inhibitors (sildenafil, tadalafil, vardenafil) | Synergistic cGMP elevation with profound hypotension | CONTRAINDICATED combination |
| Nitrates and NO donors | Profound hypotension | CONTRAINDICATED in any form (including amyl nitrite) |
| Strong CYP3A4 and P-gp inhibitors (azoles, HIV protease inhibitors) | Increased riociguat exposure and hypotension | Avoid or reduce dose with close monitoring |
| Smoking (CYP1A1 induction) | Decreased riociguat plasma concentrations | Smokers may require higher doses; counsel on cessation |
| Antacids | Reduced riociguat absorption | Separate doses by at least 1 hour |
Storage & handling
Lyophilized (powder)
- • Store at -20°C to 4°C (freezer or refrigerator)
- • Protect from light and moisture
- • Stable for 12–24 months when stored properly
- • Keep in original sealed container until reconstitution
Reconstituted solution
- • Refrigerate at 2–8°C after reconstitution
- • Use bacteriostatic water for multi-dose reconstitution
- • Typical stability: 14–28 days refrigerated
- • Do not freeze reconstituted solution
Cost & availability
| Source | Cost | Notes |
|---|---|---|
| Research suppliers | Varies widely | Quality and purity vary significantly between sources |
| Compounding pharmacies | Prescription required | Higher quality assurance and purity testing |
The bottom line
Riociguat is a longevity compound with research interest in pulmonary hypertension, sgc stimulator, vasodilation. While preclinical evidence is encouraging, it has received FDA approval for specific indications. Any use should be under qualified medical supervision.
Best for
- • Researchers studying longevity and anti-aging research
- • Individuals interested in pulmonary hypertension under medical guidance
Not for
- • Self-administration without medical supervision
- • Pregnant or breastfeeding individuals
- • Individuals with contraindicated conditions
Related compounds
Frequently asked questions
References
- [1] Ghofrani HA, Galiè N, Grimminger F, et al.. Riociguat for the treatment of pulmonary arterial hypertension (PATENT-1). N Engl J Med (2013). doi: 10.1056/NEJMoa1209655 PMID: 23883378
- [2] Ghofrani HA, D'Armini AM, Grimminger F, et al.. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension (CHEST-1). N Engl J Med (2013). doi: 10.1056/NEJMoa1209657 PMID: 23883377
- [3] Stasch JP, Pacher P, Evgenov OV.. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation (2011). doi: 10.1161/CIRCULATIONAHA.110.981738 PMID: 21788598