Endothelin Receptor Antagonists

Endothelin receptor antagonists (bosentan, ambrisentan and macitentan) block the action of endothelin-1 and are oral first-line drugs for pulmonary arterial hypertension. Bosentan is also used to prevent digital ulcers in systemic sclerosis, and macitentan is used in inoperable CTEPH in some regions.

Mechanism. Endothelin-1 acts at ETA receptors on smooth muscle to cause vasoconstriction, proliferation and fibrosis. ETB receptors on smooth muscle also constrict, and ETB receptors on endothelium clear endothelin and release nitric oxide and prostacyclin. Bosentan and macitentan block both receptors, and ambrisentan is selective for ETA.

Pharmacokinetics. Bosentan has bioavailability of about 50 percent, a half life of about 5 hours, is cleared by CYP2C9 and CYP3A4, and induces both enzymes. Ambrisentan has a half life of about 15 hours and is cleared by glucuronidation and CYP3A4. Macitentan has an active metabolite with a half life of about 48 hours, cleared by CYP3A4.

Children. Bosentan 2 mg/kg twice daily is used in children by specialists, and dosing of other agents in children differs by region.

Differences. Hepatotoxicity is highest with bosentan, and about 10 percent of patients have transaminases over 3 times the upper limit of normal. Peripheral oedema is most frequent with ambrisentan. Bosentan has the most drug interactions because it induces enzymes.

PAH. In functional class II to III, ambrisentan or macitentan with tadalafil is the usual initial combination. Monotherapy is used when combination is not possible. Add to an existing phosphodiesterase 5 inhibitor if response is inadequate. Bosentan is used where other agents are unavailable or too costly.

CTEPH. Macitentan 10 mg once daily for inoperable or persistent disease, in regions where licensed.

Systemic sclerosis digital ulcers. Bosentan 62.5 mg twice daily for 4 weeks, then 125 mg twice daily, to reduce new ulcers.

Avoid. Idiopathic pulmonary fibrosis (ambrisentan increased progression and hospitalisation), group 2 heart failure (fluid retention and worsening) and group 3 disease.

Switching. Change bosentan to ambrisentan or macitentan if liver enzymes rise or interactions are troublesome.

Boxed-warning level risks. Embryo-foetal toxicity for the whole class, and hepatotoxicity with bosentan. Exclude pregnancy before starting and monthly during treatment. Advise a highly effective method (intrauterine device or implant) or two methods together, and note that hormonal contraceptives alone are unreliable with bosentan.

Hepatotoxicity with bosentan. Check ALT and AST before starting and every month. If either is over 3 times the upper limit of normal, reduce the dose or interrupt and recheck every 2 weeks. If over 8 times the upper limit, or with symptoms, or with bilirubin over 2 times the upper limit, stop permanently.

Fluid retention and anaemia. Peripheral oedema and worsening right heart failure can occur. Check haemoglobin at baseline, at 1 month and every 3 months. Suspect pulmonary veno-occlusive disease if pulmonary oedema follows the first doses.

Other adverse effects. Headache, nasal congestion, flushing, and reduced sperm count in men.

Interactions. Bosentan lowers hormonal contraceptive, sildenafil, simvastatin and warfarin levels. Ciclosporin and glibenclamide are contraindicated with bosentan. Ritonavir and lopinavir raise bosentan levels, so start at 62.5 mg once daily or on alternate days. Avoid strong CYP3A4 inhibitors and inducers with macitentan, and limit ambrisentan to 5 mg daily with ciclosporin.

Special groups. Pregnancy: contraindicated. Breastfeeding: avoid. Hepatic impairment: bosentan is contraindicated in Child-Pugh B or C, and ambrisentan and macitentan are avoided in severe impairment. Renal impairment: no adjustment. Older adults: watch for oedema and anaemia.

Referral and escalation. Prescribing needs a specialist centre. Jaundice, rising transaminases, worsening oedema, a positive pregnancy test or marked fall in haemoglobin needs urgent review.