Pulmonary Arterial Hypertension Drugs

## Overview

Pulmonary arterial hypertension (PAH) is characterized by progressive remodeling of pulmonary arterioles, leading to elevated pulmonary vascular resistance and right heart failure. Three molecular pathways are targeted: the endothelin pathway (overactive vasoconstriction), the nitric oxide pathway (deficient vasodilation), and the prostacyclin pathway (deficient vasodilation and anti-proliferative signaling). Modern treatment uses upfront combination therapy.

## Endothelin Receptor Antagonists

Endothelin-1 (ET-1) is massively overexpressed in PAH, driving vasoconstriction and smooth muscle proliferation via ETA and ETB receptors.

- **Bosentan**: Dual ETA/ETB antagonist. Requires monthly liver function monitoring (hepatotoxicity ~10%). CYP inducer reducing sildenafil and contraceptive levels.
- **Ambrisentan**: Selective ETA antagonist. Lower hepatotoxicity risk but more peripheral edema. Contraindicated in idiopathic pulmonary fibrosis.
- **Macitentan**: Dual antagonist with improved tissue penetration. SERAPHIN trial showed reduced morbidity and mortality. Preferred over bosentan.

## Nitric Oxide Pathway

Impaired NO signaling reduces cGMP-mediated vasodilation in PAH.

- **PDE5 inhibitors**: Sildenafil and tadalafil prevent cGMP breakdown, enhancing NO-mediated vasodilation. Sildenafil is dosed 20 mg TID for PAH (much lower than erectile dysfunction dosing). Tadalafil 40 mg daily offers once-daily convenience. Both improve exercise capacity and hemodynamics.
- **Soluble guanylate cyclase stimulator**: Riociguat directly stimulates sGC independently of NO and also sensitizes sGC to available NO. Effective in PAH and chronic thromboembolic PH (CTEPH). Cannot be combined with PDE5 inhibitors (risk of severe hypotension).

## Prostacyclin Pathway

Prostacyclin (PGI2) is a potent vasodilator, antiproliferative, and antiplatelet agent that is deficient in PAH.

- **Epoprostenol**: IV continuous infusion with proven survival benefit in severe PAH. Requires permanent central venous catheter. Half-life ~6 minutes; rebound PH if interrupted.
- **Treprostinil**: Available IV, subcutaneous, inhaled, and oral. Inhaled form (Tyvaso) targets pulmonary vasculature directly.
- **Iloprost**: Inhaled analogue requiring 6-9 daily inhalations. Short duration limits utility.
- **Selexipag**: Oral IP receptor agonist. GRIPHON trial showed reduced disease progression. GI side effects common during uptitration.

## Combination Strategy

Current guidelines recommend initial combination therapy with an endothelin antagonist plus a PDE5 inhibitor for most newly diagnosed PAH patients (AMBITION trial). Parenteral prostacyclins are added for severe or deteriorating disease. Triple therapy targeting all three pathways is used in refractory cases.

## Key Takeaways

- Three pathways are targeted: endothelin, NO/cGMP, and prostacyclin
- Macitentan and tadalafil are preferred initial oral combination agents
- Epoprostenol (continuous IV) remains the strongest therapy for severe PAH
- Upfront combination therapy is superior to sequential monotherapy addition