Pulmonary hypertension therapies

PAH Pathophysiology - Pressure Cooker Lungs

• Core Imbalance: ↓Vasodilators (Nitric Oxide, Prostacyclin) & ↑Vasoconstrictors (Endothelin-1, TXA2).
• Vascular Remodeling: Smooth muscle & endothelial cell proliferation leads to thickened arterial walls, fibrosis, and in-situ thrombosis.
• Hemodynamic Result: ↑Pulmonary Vascular Resistance (PVR) → ↑Mean Pulmonary Artery Pressure (mPAP) > 20 mmHg.

⭐ Heritable PAH is often due to a mutation in the Bone Morphogenetic Protein Receptor Type 2 (BMPR2) gene, which normally inhibits vascular smooth muscle proliferation.

Endothelin Receptor Antagonists - Don't Squeeze Me!

• Mechanism: Competitively antagonize endothelin-1 (ET-1) receptors (ET-A & ET-B) on pulmonary artery smooth muscle. This blocks potent vasoconstriction and smooth muscle proliferation, leading to vasodilation and ↓ pulmonary vascular resistance.
• Drugs: Bosentan, Ambrisentan, Macitentan (oral).
• Use: Pulmonary Arterial Hypertension (PAH).
• Adverse Effects:
  • Hepatotoxicity (monitor LFTs, esp. Bosentan).
  • Peripheral edema, flushing, headache.

⭐ ⚠️ Teratogenic: All are contraindicated in pregnancy. A negative pregnancy test and two forms of contraception are required for females of childbearing potential.

📌 Mnemonic: The "-sentan" drugs are sent to block endothelin.

Prostacyclin Pathway Agonists - Potent Pipe Openers

• Mechanism: Prostacyclin (PGI₂) analogs (Epoprostenol, Iloprost, Treprostinil) and IP receptor agonists (Selexipag).
  • ↑ cAMP in pulmonary vascular smooth muscle → potent vasodilation.
  • Also inhibit platelet aggregation.
• Use: Pulmonary Arterial Hypertension (PAH).
• Adverse Effects: Flushing, headache, jaw pain, diarrhea, hypotension.
  • 📌 Think "Potent Pipe Openers" causing a rush: flushing, headaches.
• Kinetics: Vary by drug; Epoprostenol is IV, Iloprost is inhaled, Treprostinil can be given via multiple routes (SC, IV, inhaled, oral).

⭐ Epoprostenol has a very short half-life (~6 minutes), requiring continuous IV infusion. Abrupt cessation can cause rebound pulmonary hypertension and is potentially fatal.

NO-cGMP Pathway Enhancers - Relax & Dilate

• Mechanism: Increase levels of cyclic guanosine monophosphate ($cGMP$) to promote pulmonary artery smooth muscle relaxation and vasodilation.

• Phosphodiesterase-5 (PDE-5) Inhibitors: -afil

  • Sildenafil, Tadalafil
  • Inhibit the breakdown of cGMP.
  • Side Effects: Headache, flushing, dyspepsia, cyanopsia (blue-tinted vision with sildenafil).

• Soluble Guanylate Cyclase (sGC) Stimulators:

  • Riociguat
  • Directly stimulates sGC, increasing cGMP production.

⭐ Contraindication: Co-administration of PDE-5 inhibitors or riociguat with any form of nitrates (e.g., nitroglycerin) is contraindicated due to risk of profound, life-threatening hypotension.

• Endothelin receptor antagonists (e.g., Bosentan, Ambrisentan) block vasoconstriction but require monitoring for hepatotoxicity.
• PDE-5 inhibitors (e.g., Sildenafil, Tadalafil) increase cGMP, leading to smooth muscle relaxation and vasodilation.
• Prostacyclin analogs (e.g., Epoprostenol, Iloprost) are potent vasodilators; side effects include flushing and jaw pain.
• Riociguat, a soluble guanylate cyclase stimulator, is teratogenic.
• Use of PDE-5 inhibitors with nitrates is contraindicated due to severe hypotension.