Drugs for Pulmonary Hypertension

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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.). Pulmonary Hypertension Therapeutic Targets

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). Pathways and drugs for pulmonary arterial hypertension

Endothelin Blockers - Vasoconstriction Villains Vanquished

  • Mechanism: Competitively block endothelin (ET-1) receptors (ETA and/or ETB) on vascular smooth muscle & endothelium, preventing potent vasoconstriction & cellular proliferation.
  • Key Drugs (Oral):
    • Bosentan: Dual (ETA/ETB) antagonist.
      • ADR: Hepatotoxicity (dose-dependent, monitor LFTs monthly), anemia, edema.
    • Ambrisentan: Selective ETA antagonist.
      • ADR: Peripheral edema, headache, nasal congestion, flushing. Generally less hepatotoxic than Bosentan.
    • Macitentan: Dual (ETA/ETB) 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.

PAH Treatment Algorithm: PDE5i, SGC, and ERA Drugs

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. PDE5 Inhibitors vs sGC Stimulators for Pulmonary HTN
  • 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.

Practice Questions: Drugs for Pulmonary Hypertension

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Drug not used in pulmonary hypertension is:

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Flashcards: Drugs for Pulmonary Hypertension

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Nicotine causes _____ of the terminal bronchioles of the lungs

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Nicotine causes _____ of the terminal bronchioles of the lungs

constriction (dilation/constriction)

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