What is the role of sildenafil (phosphodiesterase type 5 inhibitor) and bosentan (endothelin receptor antagonist) in treating a child with persistent pulmonary hypertension (PPH)?

Sildenafil and Bosentan in Persistent Pulmonary Hypertension: Mechanism and Role

Combination therapy with sildenafil (a phosphodiesterase-5 inhibitor) and bosentan (an endothelin receptor antagonist) targets two distinct pathophysiologic pathways in persistent pulmonary hypertension, providing synergistic pulmonary vasodilation and improved survival outcomes in children with severe disease. 1

Mechanism of Action

Sildenafil (PDE5 Inhibitor)

• Increases cyclic GMP levels in pulmonary vascular smooth muscle cells by inhibiting phosphodiesterase-5, which is upregulated in pulmonary hypertension 1
• Promotes pulmonary vasodilation and vascular remodeling through the nitric oxide-cGMP pathway 1
• Improves oxygenation index in PPHN patients, whether used with or without inhaled nitric oxide 1

Bosentan (Endothelin Receptor Antagonist)

• Blocks both ETA and ETB receptors (dual antagonist), preventing endothelin-1-mediated vasoconstriction 1
• Reduces pulmonary artery pressure and pulmonary vascular resistance by antagonizing the effects of endothelin-1, which is overexpressed in pulmonary hypertension 1
• Addresses the endothelin pathway independently from the nitric oxide pathway, providing complementary mechanism to sildenafil 1

Clinical Efficacy in Pediatric Pulmonary Hypertension

Sildenafil Outcomes

• Improves exercise capacity significantly: 6-minute walk distance increased from 278±114 to 443±107 meters at 6 months (P=0.02) in children with PAH 1
• Reduces mean pulmonary artery pressure and pulmonary vascular resistance at 12 months with sustained benefit 1
• Demonstrates efficacy in PPHN, IPAH, and PH associated with congenital heart disease 1

Bosentan Outcomes

• Provides sustained clinical and hemodynamic improvement with 2-year survival estimates of 91% in children 1
• Improves or maintains WHO functional class in 90% of pediatric patients (46% improved, 44% unchanged) 2
• Reduces mean pulmonary artery pressure from 64±3 to 57±3 mm Hg (p=0.005) and pulmonary vascular resistance from 20±2 to 15±2 U·m² (p=0.01) 2

Combination Therapy Rationale

• Addresses multiple pathophysiologic pathways simultaneously (nitric oxide-cGMP and endothelin pathways), potentially providing synergistic benefits 1
• More effective in reducing pulmonary artery pressures in high-risk PPHN patients compared to sildenafil monotherapy 3
• May improve survival and reduce need for lung transplantation in severe PAH when combined with prostacyclin analogs 1
• Bosentan pharmacokinetics are not altered by concurrent sildenafil therapy, making combination safe 1

Dosing Guidelines

Sildenafil Dosing

• Infants <1 year: 0.5-1 mg/kg orally three times daily 4
• Children <20 kg: 10 mg orally three times daily 4
• Children >20 kg: 20 mg orally three times daily 4
• Critical warning: Avoid high-dose sildenafil (hazard ratio 3.5 for mortality, p=0.015) in children aged 1-17 years 4

Bosentan Dosing

• Well tolerated in children with lower rates of elevated transaminases (2.7%) compared to patients ≥12 years (7.8%) 1
• Requires long-term liver function monitoring due to risk of hepatotoxicity 1

Critical Safety Considerations

Sildenafil Warnings

• Can increase intrapulmonary shunting and worsen hypoxemia in postoperative congenital heart disease patients 1, 4
• Delay use in extremely preterm infants until retinal vascularization is established to avoid vision complications 4
• FDA warning against high-dose therapy in children 1-17 years due to increased mortality risk 4

Bosentan Warnings

• Monitor liver function tests regularly: Elevated hepatic aminotransferases occur in approximately 3% of children 1
• Teratogenic effects: Contraindicated in pregnancy 1
• Additional side effects: Anemia, peripheral edema (possibly from negative inotropic effects on right ventricle), decreased oral contraceptive effectiveness 1

Treatment Strategy for This Patient

Initial Assessment

• This child is on combination therapy, suggesting either inadequate response to monotherapy or high-risk disease requiring upfront dual therapy 5
• American Heart Association guidelines recommend oral monotherapy (either PDE5 inhibitor or ERA) for lower-risk PAH, with escalation to combination therapy for persistent symptoms 5

Monitoring Parameters

• Serial echocardiograms to assess right ventricular function and pulmonary artery pressures 5
• NT-proBNP or BNP levels as biomarkers of disease severity 5
• Six-minute walk distance if child is >8 years old 5
• Liver function tests for bosentan monitoring 1
• Oxygen saturation monitoring: Maintain >92% with supplemental oxygen if needed 5

Common Pitfall

The beneficial response to bosentan progressively declines after 1 year, with more rapid decline in children who have more severe disease at baseline 1. This necessitates close monitoring and potential escalation to prostacyclin therapy if deterioration occurs despite combination oral therapy.