Bosentan – Endothelin Receptor Antagonist for Pulmonary Hypertension
Bosentan is an endothelin receptor antagonist with high affinity for endothelin type A (ETA) and type B (ETB) receptors. Endothelin-1 is a potent endogenous vasoconstrictor peptide that promotes vascular smooth muscle cell proliferation and tissue fibrosis. In pulmonary arterial hypertension (PAH), plasma and lung tissue levels of endothelin-1 are significantly elevated, leading to vasoconstriction and pathological remodeling of the pulmonary vascular bed. Bosentan blocks the action of endothelin-1 on both receptor types, thereby reducing pulmonary vascular resistance, improving hemodynamic parameters, and slowing the progression of heart failure associated with this condition.
The pharmacokinetic profile of bosentan is characterized by good absorption following oral administration, with an absolute bioavailability of approximately 50%. Peak plasma concentrations are reached within 3 to 5 hours. The drug binds extensively to plasma proteins (over 98%). Metabolism occurs in the liver via cytochrome P450 isoenzymes (CYP2C9 and CYP3A4). The drug acts as an inducer of these enzymes, which may lead to reduced plasma concentrations of co-administered medications. The terminal elimination half-life is approximately 5 hours. Elimination occurs primarily via the feces through biliary excretion. Due to the risk of hepatotoxicity and teratogenicity, bosentan therapy requires strict medical monitoring.
The drug is administered orally. Mandatory requirements for therapy include regular monitoring of liver function (ALT/AST transaminase activity) prior to treatment initiation and monthly during the treatment course.
Indications
Bosentan is indicated for the long-term management of patients with the following pathological states:
- Pulmonary Arterial Hypertension (PAH): treatment of patients with PAH (idiopathic, heritable, or associated with connective tissue disease) to improve exercise capacity and reduce symptoms (WHO functional classes II–IV).
- Prevention of Digital Ulcers: reduction in the frequency of new digital ulcers in patients with systemic sclerosis.
Dosage and administration
The dosing regimen of bosentan is customized individually, with mandatory dose titration at the beginning of therapy.
- Standard Adult Dose: the initial dose is 62.5 mg twice daily for the first 4 weeks of therapy. Upon good tolerability, the dose is increased to the maintenance dose of 125 mg twice daily.
- Administration Method: tablets must be swallowed with water, irrespective of meal times. Tablets must not be chewed.
- Dose Modification for Hepatotoxicity: if liver transaminase (ALT/AST) levels rise above 3 times the upper limit of normal (ULN), dose adjustment or temporary treatment cessation is required until indicators normalize.
- Treatment Discontinuation: when deciding to stop therapy, a gradual reduction of the dose is recommended to avoid "rebound" effects (abrupt clinical deterioration).
