Several vasodilating or vasomodulating drugs are available. However, much of the information about them comes from studies in patients with idiopathic pulmonary artery hypertension or pulmonary hypertension due to connective tissue disease, and no randomized controlled trials in portopulmonary hypertension have been performed.
Prostanoids have been used successfully to lower pulmonary pressures in portopulmonary hypertension.
Epoprostenol (Flolan) is a pulmonary and systemic vasodilator as well as an inhibitor of platelet aggregation. It is given as a continuous intravenous infusion via an indwelling central venous catheter and a portable infusion pump. It has a very short half-life, requires mixing, and must be kept cold with ice packs, making it somewhat cumbersome to administer.
This medication has been shown to improve cardiopulmonary hemodynamics and exercise capacity in portopulmonary hypertension, although a survival advantage has not been documented to date.27 In several case series, some patients with portopulmonary hypertension treated with intravenous epoprostenol responded with a reduction in pulmonary pressures and successfully underwent liver transplantation.28–31
Complications of intravenous epoprostenol therapy include central venous catheter thrombosis, infection, and infusion pump failure; a backup pump must be available at all times. Patients with portopulmonary hypertension may also develop progressive splenomegaly and thrombocytopenia that may be due to increased blood flow in the splanchnic circulation.32
Treprostinil (Remodulin) has a longer half-life and does not have to be kept cold. It is given as a 24-hour intravenous or subcutaneous infusion, using an infusion pump that is smaller than that used with epoprostenol.
Although treprostinil is easier for patients to use, larger doses are necessary to achieve the same effect as with epoprostenol. With subcutaneous administration, the biggest drawback is site pain. Prostacyclin-related side effects include flushing, diarrhea, jaw discomfort, and lower extremity pain.
Iloprost (Ventavis) has the advantage of being given by inhalation. It is very short-acting, however, and requires six to nine inhalations per day.
Endothelin receptor blockers
Bosentan (Tracleer) is an oral agent that has been approved by the US Food and Drug Administration (FDA) for the treatment of pulmonary hypertension, including in patients with portopulmonary hypertension who have mild hepatic derangement. This medication is a dual endothelin receptor antagonist, nonselectively blocking the endothelin A and B receptors on the endothelial and vascular smooth muscle cells so that ET-1 cannot bind and cause vasoconstriction.
In approximately 10% of patients, bosentan can cause elevations in aminotransferase, alkaline phosphatase, and bilirubin levels, which therefore must be checked monthly.33 Irreversible hepatic toxicity is uncommon; in most cases, liver function abnormalities return to baseline levels when the medication is stopped. The presumed mechanism is impairment of bile-salt transporters, leading to bile-salt accumulation in the liver.34 Bosentan’s use in patients with liver disease has not been well studied, although several case reports have described its use in patients with portopulmonary hypertension.35–38
Ambrisentan (Letairis) is a selective endothelin receptor-A blocker that has just received FDA approval for the treatment of pulmonary artery hypertension. It has not yet been studied in portopulmonary hypertension. Elevations in liver enzymes and bilirubin may also occur, and monthly monitoring is indicated.
Another oral agent that might be effective in portopulmonary hypertension is sildenafil (Revatio). A phosphodiesterase-5 inhibitor, it selectively inhibits the cyclic guanosine monophosphatase-specific phosphodiesterase type 5 enzyme that is found in large concentrations in pulmonary artery smooth muscle cells.
In other forms of pulmonary hypertension, sildenafil has been shown to increase cardiac output and decrease pulmonary artery pressures and pulmonary vascular resistance without serious adverse events.39–41
In one reported case, treatment with sildenafil in a patient with portopulmonary hypertension decreased the mean pulmonary artery pressure from 56 mm Hg to 28 to 31 mm Hg, and the patient underwent successful liver transplantation.42 A recent case series of 14 patients with portopulmonary hypertension treated with sildenafil documents some improvement in 6-minute walking distance, suggesting that sildenafil as monotherapy or in combination therapy might be effective in portopulmonary hypertension.43 However, in 3 of these patients, the cardiac index decreased and pulmonary vascular resistance increased.44
We must emphasize that controlled studies in portopulmonary hypertension need to be done to find the optimal therapy.