Riociguat

Riociguat, sold under the brand name Adempas, is a medication by Bayer that is a stimulator of soluble guanylyl cyclase (sGC). It is used to treat two forms of pulmonary hypertension (PH): chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). Riociguat constitutes the first drug of the class of sGC stimulators. The drug has a half-life of 12 hours and will decrease dyspnea associated with pulmonary arterial hypertension.

It is available as a generic medication.

Riociguat can cause fetal harm and is therefore contraindicated in pregnant women.

The substance is also contraindicated in pulmonary hypertension in combination with idiopathic interstitial pneumonia (PH-IIP). A clinical trial testing riociguat for this purpose was prematurely terminated because it increased severe adverse effects and mortality in patients with pulmonary hypertension caused by idiopathic interstitial pneumonia when compared to placebo.

Serious adverse effects in clinical trials included bleeding. Hypotension (low blood pressure), headache, and gastrointestinal disorders also occurred.

Nitrates and phosphodiesterase inhibitors (including PDE5 inhibitors) increase the hypotensive (blood pressure lowering) effect of riociguat. Combining such drugs is therefore contraindicated. Riociguat levels in the blood are reduced by tobacco smoking and strong inducers of the liver enzyme CYP3A4, and increased by strong cytochrome inhibitors.

In healthy individuals, nitric oxide (NO) acts as a signaling molecule on vascular smooth muscle cells to induce vasodilation. NO binds to soluble guanylate cyclase (sGC) and mediates the synthesis of the secondary messenger cyclic guanosine monophosphate (cGMP). sGC forms heterodimers consisting of a larger alpha-subunit and a smaller haem-binding beta-subunit. The synthesised cGMP acts as a secondary messenger and activates cGMP-dependent protein kinase (protein kinase G) to regulate cytosolic calcium ion concentration. This changes the actin–myosin contractility, which results in vasodilation. NO is produced by the enzyme endothelial nitric oxide synthetase (eNOS). In patients with pulmonary arterial hypertension eNOS levels are reduced. This results in overall lower levels of endothelial cell-derived NO and reduced vasodilation of smooth muscle cells. NO also reduces pulmonary smooth muscle cell growth and antagonises platelet inhibition, factors which play a key role in the pathogenesis of PAH. In contrast to NO- and haem-independent sGC activators like cinaciguat, the sGC stimulator riociguat directly stimulates sGC activity independent of NO and also acts in synergy with NO to produce anti-aggregatory, anti-proliferative, and vasodilatory effects.

Riociguat at concentration between 0.1 and 100 μM stimulates in a dose-dependent manner sGC activity up to 73-fold. In addition, it acts synergistically with diethylamine/NO, the donor of NO, to increase sGC activity in vitro up to 112-fold. A phase I study showed that riociguat is rapidly absorbed, and maximum plasma concentration is reached between 0.5 and 1.5 h. The mean elimination half-life appears to be 5–10 hours. Riociguat plasma concentrations have been also shown to be quite variable between patients, indicating that for clinical use it is probably necessary to titrate the drug specifically for each individual.