What medications are used to treat pulmonary hypertension?

Medications for Pulmonary Arterial Hypertension

For treatment-naive patients with WHO functional class II-III pulmonary arterial hypertension, start with initial combination therapy using ambrisentan (10 mg daily) plus tadalafil (40 mg daily), which significantly delays clinical failure and improves exercise capacity compared to monotherapy. 1

Drug Classes and Specific Agents

Endothelin Receptor Antagonists (ERAs)

• Bosentan: Dual endothelin receptor antagonist, dosed at 62.5 mg twice daily for 4 weeks, then 125 mg twice daily maintenance 2, 3

  • Improved 6-minute walk distance by 44 meters compared to placebo (p<0.001) 3
  • Monitor liver function: 11% incidence of elevated transaminases (>3x upper limit normal) 2
  • Contraindicated with cyclosporine and glibenclamide due to marked drug interactions 2

• Ambrisentan: Endothelin type A receptor-selective antagonist, dosed 1-10 mg once daily 2

  • Increased 6-minute walk distance by 36.1 meters (p=0.0001) across all dose groups 2
  • Lower hepatic toxicity: only 3.1% incidence of elevated transaminases 2
  • Contraindicated in idiopathic pulmonary fibrosis (increased mortality in ARTEMIS-IPF trial) 1

• Macitentan: Can be added to stable PDE5 inhibitor or inhaled prostanoid therapy 4

Phosphodiesterase-5 Inhibitors

• Sildenafil: FDA-approved at 20 mg three times daily 2, 5

  • All doses (20,40,80 mg tid) improved 6-minute walk distance by 45-50 meters (p<0.001 for all) 2
  • Long-term data available only for 80 mg tid dosing, though FDA approved 20 mg tid 2
  • Absolute contraindication with nitrates or nicorandil: causes profound, potentially fatal systemic hypotension 1, 5

• Tadalafil: Dosed 40 mg once daily 1

  • In combination with ambrisentan, improved 6-minute walk distance by 49 meters vs 24 meters with monotherapy (p<0.001) 1
  • Contraindicated with nitrates and guanylate cyclase stimulators (riociguat) 6

Prostacyclin Analogues

• Epoprostenol (IV): For WHO functional class III-IV patients 2

  • Reserved for high-risk patients or those failing oral therapy 4

• Treprostinil: Available as IV, subcutaneous, or inhaled formulations 2

  • Inhaled treprostinil: initial dose 3 inhalations (18 mcg) every 6 hours, titrate up to 9 inhalations (54 mcg) every 6 hours 2
  • Recommended as add-on to stable ETRA or PDE5 inhibitor therapy 2

• Iloprost (inhaled): Can be added to stable ETRA or PDE5 inhibitor therapy 2

Soluble Guanylate Cyclase Stimulator

• Riociguat: Alternative pathway targeting agent 2
  • Cannot be combined with PDE5 inhibitors (contraindicated) 6

Prostacyclin Receptor Agonist

• Selexipag: Oral selective prostacyclin receptor agonist 2

Calcium Channel Blockers

• Only for vasoreactive patients: Must demonstrate acute vasoreactivity during right heart catheterization (fall in mean PAP ≥10 mmHg to ≤40 mmHg with unchanged/increased cardiac output) 2, 4
• Options: amlodipine, diltiazem, or nifedipine 2, 4
• Not recommended for Eisenmenger's syndrome 2

Treatment Algorithm by Risk Stratification

Low-to-Intermediate Risk (WHO FC II-III)

1. First-line: Initial combination therapy with ambrisentan plus tadalafil 1
2. Alternative: Monotherapy with ERA or PDE5 inhibitor if combination not feasible 2

High Risk (WHO FC IV)

• Intravenous prostacyclins required (epoprostenol preferred) 1, 4
• More aggressive initial therapy mandatory 1

Sequential Add-On Therapy

• For inadequate response on monotherapy: add second agent from different class 2, 4
• Adding tadalafil to existing ambrisentan improved 6-minute walk distance by 54.4 meters (p<0.05) 1

Critical Drug Interactions

Absolute Contraindications

• PDE5 inhibitors + nitrates/nicorandil: profound systemic hypotension 1, 5, 6
• Bosentan + cyclosporine: markedly increases bosentan levels 2
• Bosentan + glibenclamide: increased aminotransferase elevations 2
• Tadalafil + riociguat: contraindicated 6

Significant Interactions Requiring Monitoring

• Bosentan + sildenafil: sildenafil levels decrease 50%, bosentan levels increase 50% 2
  • May not require dose adjustment but monitor response 2
• Bosentan + warfarin: decreases warfarin exposure up to 50% via CYP2C9 induction 7
• Bosentan + simvastatin/atorvastatin: decreases statin levels up to 50% 2
• Sildenafil + HIV protease inhibitors: ritonavir/saquinovir markedly increase sildenafil levels, requiring dose adjustment 2

Supportive Therapies

Anticoagulation

• Consider for idiopathic PAH patients and those with indwelling IV catheters 2, 4
• Contraindicated if significant hemoptysis present 2

Adjunctive Measures

• Diuretics: for fluid retention management 4
• Supplemental oxygen: maintain saturations >91%, especially during air travel 4
• Immunizations: influenza and pneumococcal vaccines recommended 2, 4

Monitoring for Treatment Failure

Definition of Inadequate Response

• No improvement or worsening of WHO functional class 2, 1
• Decline in 6-minute walk distance from baseline 1
• Clinical worsening events: hospitalization, need for additional therapy, death 1

Action for Treatment Failure

• Add second or third agent from different drug class 2, 4
• Consider lung transplant evaluation after inadequate response to initial therapy 1
• Refer for transplant listing after failure of maximal combination therapy 1

Special Population Considerations

Pregnancy

• Avoid pregnancy in all PAH patients 2
• ERAs (bosentan, ambrisentan, macitentan) and riociguat are pregnancy category X 2
• If pregnancy occurs, manage at specialized pulmonary hypertension center 2, 4

Group 2 PH (Left Heart Disease)

• PAH-specific therapies not recommended - optimize heart failure treatment instead 1

Group 3 PH (Lung Disease)

• Consider PAH-specific therapy only if severe PH (mean PAP >35-40 mmHg) disproportionate to lung disease 1