RIOCI 1

Indications

• Chronic thromboembolic pulmonary hypertension (CTEPH)
• Pulmonary arterial hypertension (PAH) associated with connective tissue disease

Mechanism of action

Riociguat acts as a stimulator of soluble guanylate cyclase (sGC), an enzyme that plays a crucial role in the cardiopulmonary system and serves as a receptor for nitric oxide (NO). By binding to sGC, riociguat catalyzes the synthesis of cyclic guanosine monophosphate (cGMP), a signaling molecule that regulates vascular tone, proliferation, fibrosis, and inflammation. Riociguat has a dual action: it sensitizes sGC to endogenous NO by stabilizing the NO-sGC interaction and directly stimulates sGC independently of NO. This stimulation increases cGMP generation, leading to vasodilation and improved cardiovascular function.

Pharmacodynamics

The pharmacodynamic effects of riociguat primarily involve vasodilation, which decreases pulmonary artery pressure and improves blood flow. By increasing intracellular cGMP levels, riociguat leads to relaxation of vascular smooth muscle and reduction in vascular resistance. This mechanism is particularly beneficial in patients with pulmonary hypertension, where endothelial dysfunction and insufficient nitric oxide signaling are prevalent. The drug's efficacy is associated with improved exercise capacity and quality of life for patients suffering from conditions like CTEPH and PAH.

Pharmacokinetics

Riociguat is administered orally and undergoes extensive metabolism, primarily in the liver, with a half-life of approximately 12 hours. Its absorption is affected by food intake; therefore, it should be taken consistently with or without food. The drug is highly bound to plasma proteins, and its clearance can be influenced by hepatic function. Dosage adjustments may be necessary in patients with moderate hepatic impairment, and it is contraindicated in severe impairment. Renal function also impacts its pharmacokinetics, with caution advised in patients with creatinine clearance below 30 mL/min.

Contra-indications

• History of serious haemoptysis
• Pulmonary hypertension associated with idiopathic interstitial pneumonia
• Pulmonary veno-occlusive disease
• Severe hepatic impairment

Adverse effects

• Anaemia
• Constipation
• Diarrhoea
• Dizziness
• Dysphagia
• Gastrointestinal discomfort
• Gastrointestinal disorders
• Headache
• Hypotension
• Nasal congestion
• Nausea
• Palpitations
• Peripheral oedema
• Vomiting

Interactions

• Ritonavir (increases exposure)
• Abacavir (increases exposure)
• NRTIs (increases exposure)
• Ketoconazole (unknown effect, increases exposure)
• Ciclosporin (unknown effect, increases exposure)
• Macitentan (increased risk of hypotension)

Precautions

• Caution in patients with autonomic dysfunction and elderly patients due to the risk of hypotension
• Monitor haemoglobin concentration before treatment and as indicated
• Smoking cessation is advised as it may reduce response to treatment
• Patient card should be provided to patients for recognition of liver disorder symptoms

Pregnancy

Avoid use due to toxicity observed in animal studies.

Breast-feeding

Manufacturer advises to avoid use as it is present in milk in animal studies.

Storage

Store at room temperature, away from moisture and light.

Formulations

• Riociguat 10 mg tablets
• Riociguat 1 mg tablets

Mechanism of action

Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). When NO binds to sGC, the enzyme catalyzes synthesis of the signaling molecule cyclic guanosine monophosphate (cGMP). Intracellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis and inflammation. Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide and insufficient stimulation of the NO-sGC-cGMP pathway. Riociguat has a dual mode of action. It sensitizes sGC to endogenous NO by stabilizing the NO-sGC binding. Riociguat also directly stimulates sGC via a different binding site, independently of NO. Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation.