Soluble Guanylate Cyclase Stimulators

Soluble guanylate cyclase stimulators (riociguat and vericiguat) raise cyclic GMP independently of nitric oxide. Riociguat treats chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension. Vericiguat treats chronic heart failure with reduced ejection fraction.

Mechanism. Guanylate cyclase is the receptor for nitric oxide, which is deficient in pulmonary hypertension and heart failure. These drugs sensitise the enzyme to endogenous nitric oxide and stimulate it directly at a separate site. Effects are vasodilation and antiproliferative and antifibrotic action.

Pharmacokinetics. Riociguat has bioavailability of about 94 percent and a half life of about 12 hours in patients, so it is given three times daily. It is cleared by CYP1A1, CYP3A4, CYP2C8 and CYP2J2. Smokers have about half the exposure of non-smokers. Vericiguat has bioavailability of about 93 percent with food, a half life of about 30 hours and once daily dosing.

Riociguat. 1 mg orally three times daily for 2 weeks, increased by 0.5 mg three times daily every 2 weeks if systolic pressure is 95 mmHg or more and there are no hypotension symptoms, to a maximum of 2.5 mg three times daily. Start at 0.5 mg three times daily if systolic pressure is under 95 mmHg or hypotension is a risk. Reduce by 0.5 mg if hypotension occurs.

Vericiguat. 2.5 mg once daily with food, doubled to 5 mg then 10 mg once daily at intervals of about 2 weeks as tolerated. Used after worsening heart failure in patients with ejection fraction under 45 percent.

Differences. Riociguat is for pulmonary vascular disease and vericiguat is for heart failure. They must not be combined. Neither is combined with nitrates or phosphodiesterase 5 inhibitors.

CTEPH. Riociguat is the drug used for inoperable disease or persistent pulmonary hypertension after pulmonary endarterectomy. Lifelong anticoagulation continues, and balloon pulmonary angioplasty is considered in specialist centres.

PAH. Riociguat alone or with an endothelin receptor antagonist, and not with a phosphodiesterase 5 inhibitor. To switch from a phosphodiesterase 5 inhibitor, wait at least 24 hours after sildenafil and 48 hours after tadalafil.

Heart failure. Vericiguat is added to usual heart failure therapy after hospitalisation or intravenous diuretic treatment.

Smokers. Higher riociguat doses may be needed, up to 2.5 mg three times daily. Reduce the dose if smoking stops, and watch for hypotension.

Region. Availability is limited and cost is high. Where riociguat is unavailable, lifelong anticoagulation and referral for surgical assessment are the priorities in CTEPH.

Boxed-warning level risk. Embryo-foetal toxicity. Both drugs are contraindicated in pregnancy, so exclude pregnancy before starting and monthly.

Contraindications. Nitrates, phosphodiesterase 5 inhibitors and other guanylate cyclase stimulators. Riociguat is also contraindicated in pulmonary hypertension with idiopathic interstitial pneumonia (higher mortality), in Child-Pugh C liver impairment and when creatinine clearance is under 15 mL/min.

Adverse effects. Hypotension, dizziness, headache, dyspepsia, nausea, peripheral oedema and anaemia. Haemoptysis, including serious pulmonary haemorrhage, occurs with riociguat.

Interactions. Ketoconazole, itraconazole and ritonavir raise riociguat exposure, so start at 0.5 mg three times daily and monitor blood pressure. Antacids reduce absorption, so take riociguat at least 2 hours before or 1 hour after them. Smoking lowers exposure.

Monitoring. Blood pressure and heart rate at each dose change, haemoptysis, haemoglobin and monthly pregnancy tests.

Special groups. Pregnancy: contraindicated. Breastfeeding: avoid. Children: not established. Older adults: higher hypotension risk, so titrate carefully. Hepatic impairment: Child-Pugh B needs close monitoring for riociguat. Renal impairment: limited data when creatinine clearance is under 30 mL/min.

Referral and escalation. Prescribing needs a specialist centre. Major haemoptysis, syncope or symptomatic hypotension needs urgent review.