Drugs Used in Pulmonary Hypertension

PH Unmasked - The Battle Plan

Pulmonary Hypertension (PH): Mean Pulmonary Arterial Pressure (mPAP) $\ge$ 25 mmHg. WHO Classification Summary (Focus: Group 1 PAH):

• Group 1: PAH (Idiopathic, Heritable, Drug-induced, CTD-APAH)
• Other groups: Left heart, Lung disease/hypoxia, CTEPH, Unclear. Key Pathogenic Pathways (📌 Target "PEN"):
• Prostacyclin (↓PGI₂): Vasodilation. Drugs: Epoprostenol, Selexipag.
• Endothelin (↑ET-1): Vasoconstriction. Drugs: Bosentan, Ambrisentan.
• NO-cGMP (↓NO): Vasodilation. Drugs: Sildenafil, Riociguat.

⭐ Most PAH-specific drugs target Group 1 WHO classification of pulmonary hypertension (PAH).

Prostacyclin Parade - Dilators Deluxe

• MOA: PGI₂ analogs & IP receptor agonists → $↑cAMP$ → vasodilation, anti-proliferative, anti-platelet effects.
• Key Class ADRs: Flushing, headache, jaw pain, diarrhea, hypotension. Infusion site pain (Treprostinil SC).

Endothelin Enders - Squeezing Stoppers

ERAs block endothelin pathway: ↓vasoconstriction, ↓proliferation. 📌 BAM: Bosentan, Ambrisentan, Macitentan.

• MOA:

  • Bosentan/Macitentan: Non-selective ET-A & ET-B blockers.
  • Ambrisentan: Selective ET-A blocker.
  • Effect: ↓Pulmonary Vascular Resistance (PVR), ↓smooth muscle proliferation.

• Key ADRs:

  • ⚠️ Hepatotoxicity (Bosentan highest risk; LFTs monitoring).
  • ⚠️ Teratogenicity (All ERAs - REMS program mandatory).
  • Edema, anemia, headache.

• Comparison of ERAs:

  ERA	Receptor Selectivity	Hepatotoxicity Risk	Key DDI
  Bosentan	ET-A & ET-B	High	CYP inducer (e.g. ↓warfarin)
  Ambrisentan	Selective ET-A	Low	Minimal
  Macitentan	ET-A & ET-B	Low	CYP3A4 substrate

⭐ All ERAs are potent teratogens (contraindicated in pregnancy); REMS program mandatory due to severe birth defect risk.

NO-Go Zone - Relaxers United

Drugs enhancing NO-cGMP signaling for pulmonary vasodilation.

• PDE-5 Inhibitors: Sildenafil, Tadalafil
  • MOA: Inhibit PDE-5 → ↓$cGMP$ degradation → ↑$cGMP$ levels → vasodilation.
  • ADRs: Headache, flushing, hypotension. Sildenafil: visual disturbances (cyanopsia). 📌 "Sildena-FILls vision blue".
  • ⚠️ Contraindication: Nitrates (risk of severe hypotension).
• sGC Stimulators: Riociguat
  • MOA: Directly stimulates soluble guanylate cyclase (sGC) → ↑$cGMP$ production → vasodilation.
  • ADRs: Headache, dizziness, hypotension.
  • ⚠️ Contraindication: Nitrates, PDE-5 inhibitors.

⭐ Sildenafil and other PDE-5 inhibitors are absolutely contraindicated with nitrates due to the risk of profound, life-threatening hypotension.

PAH Pals - The Sidekicks

• Calcium Channel Blockers (CCBs):
  • Strictly for acute vasoreactivity test (AVT) responders (approx. 10-15% of IPAH).
  • High doses (e.g., nifedipine, diltiazem) are essential for efficacy.
• Anticoagulants (e.g., Warfarin):
  • Rationale: Counteract prothrombotic state, preventing in-situ thrombosis and thromboembolism.
• Diuretics (e.g., Furosemide):
  • Key for managing fluid overload and symptoms of Right Heart Failure (RHF).
• Oxygen Therapy:
  • Crucial for patients with hypoxemia; aim to maintain $SaO_2$ > 90%.
• General Approach:
  • Supportive therapies are vital adjuncts. Combination with targeted drugs is standard.

⭐ For patients with PAH, particularly idiopathic PAH, anticoagulation with warfarin is often considered to address the presumed hypercoagulable state and risk of thrombosis.

High‑Yield Points - ⚡ Biggest Takeaways

• Prostacyclin analogues (Epoprostenol, Iloprost) are potent vasodilators & anti-proliferative; Epoprostenol has a short half-life.
• Endothelin receptor antagonists (Bosentan, Ambrisentan) block vasoconstrictor ET-1; Bosentan is hepatotoxic.
• PDE-5 inhibitors (Sildenafil, Tadalafil) ↑cGMP for pulmonary vasodilation; avoid with nitrates.
• Riociguat, an sGC stimulator, is used for PAH and CTEPH.
• High-dose CCBs (Nifedipine) are for vasoreactive PAH patients only, post-vasoreactivity testing.
• Selexipag is an oral IP prostacyclin receptor agonist.