Calcium Channel Blockers These agents inhibit the influx of calcium into vascular smooth muscle cells and accomplish pulmonary vasodilation A number of uncontrolled studies have suggested that long-term treatment with such agents given in high doses improves hemodynamics, relieves symptoms, and prolongs survival in children and adults with pulmonary hypertension.77,78 However, only approximately 40% of children show an acute response during vasodilatory testing in the cardiac catheterization laboratory and thus would qualify for chronic therapy Side effects of treatment include systemic hypotension, tachycardia, shortness of breath, and pulmonary edema This therapeutic option is currently less used subsequent to the introduction of more targeted drugs Prostanoids Prostacyclin and its analogues play a pivotal role in the treatment of pulmonary arterial hypertension, the approach being supported by the known imbalance of thromboxane A2 to prostacyclin metabolites in patients with pulmonary hypertension.79,80 Treatment options include continuous intravenous or subcutaneous infusion, oral medications, or inhaled therapy Intravenous Prostaclycin Analogues These agents, when given chronically, improve exercise capacity, hemodynamics, and survival in children with pulmonary arterial hypertension.81–83 This therapy usually requires a placement of a permanent central line and continuous infusion using a small ambulatory pump The two intravenous options that exist are epoprostenol and treprostinil The half-time of epoprostenol is less than 6 minutes Major side effects include flushing, hypotension, headache, and jaw and musculoskeletal pain Intravenous prostacyclin continues to be the fastest, most effective prostacyclin, but with the advent of other administration routes and the logistical problems of central venous access, some clinicians are choosing to initiate intravenous therapy and then transition to oral, inhaled, or subcutaneous therapy However, this requires close monitoring because reports of clinical deterioration have been reported with this transition.84 Subcutaneous Prostacyclin Analogues Treprostinil is a stable prostacyclin analogue, with a similar pharmacologic spectrum to epoprostenol but with a significantly longer half-time of 3 to 4 hours It has been shown to be effective in adults85 and children.86 The drug is usually delivered subcutaneously through the abdominal wall using a portable infusion pump This limits the use to older children with enough subcutaneous fat because the development of dermal irritation or pain at the site of infusion is frequent Other side effects are similar to those for epoprostenol Inhaled Prostacyclin Analogues Iloprost is an inhaled prostacyclin analogue approved in 2004 for treatment of pulmonary hypertension in adults It requires inhalation at least six times a day due to a short half-life, with each inhalation lasting 10 to 15 minutes.87 The inhalation administration route has advantages because there is less systemic absorption and thus reduced systemic side effects such as hypotension However, cooperation with inhalation technique can be difficult in young children and efficacy studies in young children are lacking.88 Oral Prostacyclin Analogues Beraprost is the first orally active analogue, albeit only approved for treatment of the idiopathic form of the disease in Japan After oral administration, peak concentrations are reached after 30 minutes There are two randomized controlled trials using beraprost.89,90 In the first trial, patients were randomized to receive the maximal tolerated dose of beraprost or placebo for 12 weeks The agent improved exercise capacity, particularly in patients with idiopathic arterial pulmonary hypertension, whereas those with associated conditions showed no significant changes However, there were no relevant beneficial effects in cardiopulmonary hemodynamics or functional class The second trial studied the long-term effects of beraprost up to 1 year During the earlier phases of treatment, the data suggested less progression of the disease, with the effect persisting up to 6 months but then attenuating with time After 1 year, there were no longer any differences between the patients receiving beraprost and those having the placebo Recently, oral treprostinil has been approved for use in adults, and trials are currently underway to evaluate its efficacy in children Oral treprostinil has been found to be effective in adults as monotherapy compared with placebo but has yet to demonstrate efficacy in combination therapy.91–93 The role of oral prostacyclins has yet to be fully evaluated but shows promise Endothelin Receptor Antagonists The endothelin system has long been implicated in the pathogenesis of pulmonary arterial hypertension.94–96 It has been shown that antagonism of endothelin receptors improves exercise tolerance, pulmonary hemodynamics, right ventricular hypertrophy, and survival Other favorable effects are the reduction of pulmonary fibrosis and the remodeling of pulmonary arteries.97–101 Side effects include flushing and peripheral edema, both experienced in less than 10% of patients, and elevations in hepatic function tests, observed in approximately 3% of children.102,103 Currently there are three different oral antagonists available for treatment, namely bosentan, which has an almost equal affinity for both A and B endothelin receptors, macitentan, which also is a dual endothelin antagonist, and ambrisentan, a selective antagonist of the A receptor Several reports have demonstrated the benefits of therapy in children.104–107 Most of the current knowledge is based on experience with bosentan, with information related to macitentan and ambrisentan mostly gained from experience with adults.99,108–110 Phosphodiesterase Inhibitors This class of drugs inhibits the degradation of cyclic guanosine monophosphate, the second messenger of nitric oxide, by interacting with different subclasses of phosphodiesterases, thus prolonging the effect of endogenous nitric oxide The currently used sildenafil was developed from its precursor zaprinast and has a 20-fold higher specificity for phosphodiesterase type 5, which is the subtype acting mainly in the lung Sildenafil has been studied most often and may be seen as the prototype of this class of drugs It has immediate effects when given intravenously and reaches a maximum after 30 to 45 minutes when given by the usual oral route It is effective in the short and long term in infants, adolescents, and adults, immediately postoperatively and when used chronically It increases 6-minute walking distance, decreases pulmonary vascular resistance,111,112 and has remodeling effects on the right ventricle and pulmonary vasculature The safety and efficacy of sildenafil was studied in STARTS-1 and STARTS-2 trials,