Prostacyclin Pathway Drugs

Prostacyclin drugs replace or mimic prostacyclin, a potent pulmonary vasodilator that also inhibits platelets and smooth muscle proliferation. They are the most effective drugs for severe pulmonary arterial hypertension, and epoprostenol has the strongest survival evidence in advanced disease. The group includes epoprostenol, treprostinil, iloprost, beraprost and the oral IP receptor agonist selexipag.

Mechanism. Binding to the IP receptor raises cyclic AMP, causing vasodilation and inhibiting platelet aggregation and proliferation. Treprostinil also acts at DP1 and EP2 receptors. Selexipag is a non-prostanoid IP agonist whose active metabolite has a half life of 9 to 14 hours.

Pharmacokinetics. Epoprostenol has a half life of 3 to 5 minutes and needs a continuous central line infusion. Treprostinil has a half life of about 4 hours, and oral extended release absorption is better with food. Iloprost acts for 60 to 90 minutes after inhalation. Selexipag is a prodrug converted to its active metabolite.

Differences. Continuous parenteral delivery is for high risk disease. Inhaled and oral drugs are for lower risk disease or as add-on treatment. Subcutaneous treprostinil avoids a central line but causes painful infusion sites. Selexipag is oral and the least potent.

High risk PAH. Intravenous epoprostenol, or intravenous or subcutaneous treprostinil, with an endothelin receptor antagonist and a phosphodiesterase 5 inhibitor.

Add-on treatment. Selexipag, oral or inhaled treprostinil, or inhaled iloprost added to an endothelin receptor antagonist and phosphodiesterase 5 inhibitor when response is inadequate.

Interstitial lung disease with pulmonary hypertension. Inhaled treprostinil improves 6 minute walk distance.

Changing agent or route. Done by specialists with gradual overlap, never by abrupt stopping.

Hepatic impairment. Treprostinil: start at 0.625 ng/kg/min in mild to moderate impairment and avoid in severe impairment. Selexipag: in Child-Pugh B start 200 mcg once daily and increase once daily, and avoid in Child-Pugh C. Renal impairment: no adjustment.

Region. Parenteral and inhaled prostacyclins are costly and uncommon in East Africa. Early referral to a specialist centre is needed for high risk disease. Where they are unavailable, the usual limit is an endothelin receptor antagonist with a phosphodiesterase 5 inhibitor.

Rebound. Abrupt interruption or pump failure causes rebound pulmonary hypertension, syncope and death within minutes to hours. This is a boxed-warning level risk. Provide a backup pump, spare cassettes and tubing, and train the patient. If infusion stops, restart at once through any intravenous line at the same rate and call the specialist centre.

Line infection. Central catheter bloodstream infection, including gram negative organisms with intravenous treprostinil. Fever needs urgent blood cultures and antibiotics.

Common adverse effects. Headache, flushing, jaw pain, diarrhoea, nausea, leg pain and hypotension. Epoprostenol also causes thrombocytopenia and high output heart failure. Inhaled drugs cause cough and bronchospasm. Selexipag can lower TSH and cause anaemia.

Contraindications. Epoprostenol in left ventricular systolic dysfunction with heart failure and in pulmonary veno-occlusive disease. Selexipag with strong CYP2C8 inhibitors such as gemfibrozil.

Interactions. Vasodilators and antihypertensives add hypotension. Anticoagulants and antiplatelets add bleeding risk. Clopidogrel with selexipag: reduce selexipag to once daily. Rifampicin lowers selexipag exposure.

Monitoring. Functional class, 6 minute walk distance, NT-proBNP, line site, pump function, platelets with epoprostenol, blood pressure and thyroid function with selexipag.

Special groups. Pregnancy: limited data, used under specialist care in life-threatening disease. Breastfeeding: avoid. Children: epoprostenol start 0.5 to 2 ng/kg/min under specialist care. Older adults: start low.

Referral and escalation. Specialist centre only. Syncope, fever with a central line, pump failure or infusion interruption needs emergency care.