Drugs for Pulmonary Hypertension

PH Overview - Hypertension's Lung Squeeze

• PH: Mean PAP > 20 mmHg at rest.
• WHO Classification:
  • Gr 1: PAH (idiopathic, heritable, drug, CTD).
  • Gr 2: Left heart disease (e.g., HFpEF, HFrEF). Most common.
  • Gr 3: Lung diseases/hypoxia (COPD, ILD).
  • Gr 4: CTEPH (chronic clots), other PA obstructions.
  • Gr 5: Unclear/multifactorial.
• PAH (Gr 1) Goals: ↓Symptoms (dyspnea), ↑exercise capacity (6MWT), improve hemodynamics (↓PVR, ↓mPAP, ↑CO), ↑survival.

  ⭐ WHO Group 1 PAH is the main focus for targeted drug therapies (vasodilators, etc.).

Prostacyclin Pathway - Dilation Power-Ups

• MoA: Mimic prostacyclin ($PGI_2$) or activate its $IP_2$ receptor $\rightarrow$ ↑intracellular cAMP in pulmonary arterial smooth muscle cells (PASMCs) $\rightarrow$ potent vasodilation & inhibition of proliferation.
• Key Drugs & Routes:
  • Epoprostenol: Continuous IV.

    ⭐ Epoprostenol: Very short t½ (3-5 min); requires continuous IV infusion, abrupt cessation is life-threatening.

  • Iloprost: Inhaled, IV.
  • Treprostinil: SC (continuous), IV, Inhaled, Oral (extended-release).
  • Beraprost: Oral (not widely available).
  • Selexipag: Oral (non-prostanoid, selective $IP_2$ agonist).
• Major ADRs: Common: Flushing, headache, jaw pain (classic!), diarrhea. Also: hypotension, nausea, musculoskeletal pain. 📌 Prosta-Pain-Flush (Prostacyclin, Jaw Pain, Flushing).

Endothelin Blockers - Vasoconstriction Villains Vanquished

• Mechanism: Competitively block endothelin (ET-1) receptors (ET_A and/or ET_B) on vascular smooth muscle & endothelium, preventing potent vasoconstriction & cellular proliferation.
• Key Drugs (Oral):
  • Bosentan: Dual (ET_A/ET_B) antagonist.
    • ADR: Hepatotoxicity (dose-dependent, monitor LFTs monthly), anemia, edema.
  • Ambrisentan: Selective ET_A antagonist.
    • ADR: Peripheral edema, headache, nasal congestion, flushing. Generally less hepatotoxic than Bosentan.
  • Macitentan: Dual (ET_A/ET_B) antagonist with good tissue penetration & longer duration.
• ⚠️ Absolute Contraindication: Pregnancy (Category X - highly teratogenic).
  • All require REMS (Risk Evaluation and Mitigation Strategy) programs due to teratogenicity.

⭐ Bosentan can cause significant, dose-related hepatotoxicity, requiring monthly liver enzyme monitoring.

PDE-5 Inhibitors & sGC - Smooth Muscle Relaxers

Act via NO-sGC-cGMP pathway → pulmonary vasodilation by ↑cGMP.

• Mechanism & Drugs:
  • PDE-5 Inhibitors: (Sildenafil, Tadalafil)
    • Prevent cGMP breakdown → ↑cGMP.
    • Tadalafil: longer half-life.
  • sGC Stimulators: (Riociguat)
    • Directly stimulate sGC → ↑cGMP.
• Common ADRs:
  • PDE-5 Inhibitors: Headache, flushing, visual issues (Sildenafil - cyanopsia), myalgia (Tadalafil).
  • Riociguat: Hypotension, headache, GI upset, bleeding.
• Critical Interactions: ⚠️
  • PDE-5 Inhibitors: Absolute contraindication with nitrates (severe hypotension).
  • Riociguat: Contraindicated with nitrates & PDE-5 inhibitors.

⭐ Riociguat is the first drug approved for both PAH and inoperable/persistent CTEPH.

Treatment Strategy & Support - PH Battle Plan

• PAH (WHO G1) Approach: Vasoreactivity test (VRT) is key.
  • VRT Positive: High-dose CCBs.
  • VRT Negative: Risk-stratify. Low/intermediate risk: oral mono/dual therapy (ERAs, PDE5i, sGCs). High risk: IV/SC prostanoids ± combination.
  • Goal-oriented therapy: escalate with sequential combinations; consider transplant.

• Supportive Care:
  • Oxygen ($SaO_2 > \textbf{90}%$)
  • Diuretics (for congestion)
  • Anticoagulants (Warfarin INR \textbf{2-3} in IPAH/HPAH)

⭐ Only ~10% of PAH patients are vasoreactive and benefit from long-term CCB therapy.

High‑Yield Points - ⚡ Biggest Takeaways

• Prostacyclin analogues (Epoprostenol, Iloprost): potent pulmonary vasodilators; IV Epoprostenol has very short half-life.
• Endothelin receptor antagonists (Bosentan): hepatotoxic and teratogenic, requiring LFT monitoring.
• PDE-5 inhibitors (Sildenafil, Tadalafil): enhance cGMP-mediated pulmonary vasodilation; avoid with nitrates.
• Riociguat (sGC stimulator): effective for PAH and CTEPH.
• High-dose CCBs: used only in PAH patients demonstrating acute vasoreactivity.
• Selexipag: oral, selective IP prostacyclin receptor agonist, distinct from prostacyclin analogs.