Agents for pulmonary hypertension

Introduction

Pulmonary hypertension (PH) is a progressive and potentially life-threatening condition characterized by elevated pulmonary arterial pressure (mPAP ≥ 20 mmHg at rest, per updated 2022 ESC/ERS guidelines) and pulmonary vascular resistance (PVR > 2 Wood units). It leads to right ventricular hypertrophy, right heart failure, and premature mortality.

Management of PH depends on the underlying cause and classification. The World Health Organization (WHO) categorizes PH into five groups:

1. Group 1: Pulmonary arterial hypertension (PAH) – idiopathic, heritable, drug-induced, or associated with connective tissue disease, HIV, congenital heart disease.

2. Group 2: PH due to left heart disease.

3. Group 3: PH due to lung diseases and/or hypoxia.

4. Group 4: Chronic thromboembolic pulmonary hypertension (CTEPH).

5. Group 5: PH with unclear or multifactorial mechanisms.

Pharmacological therapy is best established for Group 1 (PAH) and Group 4 (CTEPH). Agents target the three main pathophysiological pathways involved in PAH:

• Endothelin pathway – vasoconstriction and proliferation.

• Nitric oxide–cGMP pathway – vasodilation, antiproliferative effects.

• Prostacyclin pathway – vasodilation, anti-proliferation, anti-thrombosis.

In this review, we cover all major drug classes, mechanisms, generic drugs, and clinical applications.

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Pathophysiological Targets and Drug Classes

1. Endothelin Receptor Antagonists (ERAs)

• Mechanism: Block endothelin-1, a potent vasoconstrictor and smooth muscle mitogen, from binding to ETA and ETB receptors.

• Drugs: Bosentan, Ambrisentan, Macitentan.

2. Phosphodiesterase-5 (PDE-5) Inhibitors

• Mechanism: Prevent degradation of cGMP, enhancing nitric oxide–mediated vasodilation.

• Drugs: Sildenafil, Tadalafil, Vardenafil (off-label).

3. Soluble Guanylate Cyclase (sGC) Stimulators

• Mechanism: Directly stimulate sGC and increase sensitivity to nitric oxide, raising cGMP levels.

• Drug: Riociguat.

4. Prostacyclin Analogues and Prostacyclin Receptor Agonists

• Mechanism: Mimic prostacyclin (PGI₂), causing vasodilation, inhibition of platelet aggregation, and antiproliferative effects.

• Drugs:

  • Intravenous/inhaled: Epoprostenol, Iloprost, Treprostinil.

  • Oral selective receptor agonist: Selexipag.

5. Calcium Channel Blockers (CCBs)

• Mechanism: Vasodilation via inhibition of calcium influx in vascular smooth muscle.

• Drugs: Amlodipine, Diltiazem, Nifedipine (effective only in vasoreactive patients).

6. Anticoagulants, Diuretics, Oxygen, and Supportive Therapy

• Used in selected patients for symptom control and to address complications.

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Detailed Drug Classes and Agents

1. Endothelin Receptor Antagonists (ERAs)

Bosentan

• Receptor activity: Dual ETA/ETB antagonist.

• Indications: WHO Group 1 PAH, functional class II–IV.

• Dose: 62.5 mg orally twice daily for 4 weeks, then 125 mg twice daily.

• Adverse effects: Hepatotoxicity (requires monthly LFTs), anemia, teratogenicity, edema.

Ambrisentan

• Receptor activity: Selective ETA antagonist.

• Dose: 5–10 mg orally once daily.

• Advantages: Lower risk of hepatotoxicity compared to bosentan.

• Adverse effects: Peripheral edema, nasal congestion, anemia.

Macitentan

• Receptor activity: Dual ERA with higher tissue penetration.

• Dose: 10 mg orally once daily.

• Clinical data: SERAPHIN trial showed significant reduction in morbidity and mortality.

• Adverse effects: Headache, anemia, liver dysfunction.

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2. Phosphodiesterase-5 Inhibitors (PDE-5 inhibitors)

Sildenafil

• Mechanism: Inhibits PDE-5, preventing breakdown of cGMP.

• Dose: 20 mg orally three times daily.

• Indications: PAH, WHO functional class II–III.

• Adverse effects: Headache, flushing, nasal congestion, visual disturbances.

Tadalafil

• Dose: 40 mg orally once daily.

• Advantages: Once-daily dosing, improved exercise capacity.

• Adverse effects: Myalgia, dyspepsia, flushing.

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3. Soluble Guanylate Cyclase (sGC) Stimulator

Riociguat

• Mechanism: Stimulates sGC independently and synergistically with NO.

• Indications: PAH (Group 1) and CTEPH (Group 4).

• Dose: Start 1 mg orally three times daily, titrated to 2.5 mg three times daily.

• Adverse effects: Hypotension, dizziness, headache, GI upset.

• Contraindication: Pregnancy (teratogenic) and concomitant use with PDE-5 inhibitors (severe hypotension).

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4. Prostacyclin Analogues and Prostacyclin Receptor Agonists

Epoprostenol (Flolan, Veletri)

• Administration: Continuous IV infusion via central line (short half-life).

• Dose: Start 2 ng/kg/min, titrate upward (typical 25–40 ng/kg/min).

• Adverse effects: Jaw pain, flushing, diarrhea, hypotension, catheter infections.

• Clinical impact: Improves survival in PAH.

Treprostinil

• Forms: Subcutaneous, intravenous, inhaled, or oral.

• Dose:

  • SC/IV: Start at 1.25 ng/kg/min, increase weekly.

  • Inhaled: 3 breaths (18 mcg) 4 times daily, titrated.

  • Oral: 0.25–0.5 mg twice daily, titrated upward.

• Advantages: Longer half-life than epoprostenol.

Iloprost

• Form: Inhaled prostacyclin analogue.

• Dose: 2.5–5 mcg inhaled 6–9 times daily.

• Advantages: Non-invasive, but requires frequent inhalations.

Selexipag (oral selective IP receptor agonist)

• Dose: Start 200 mcg twice daily, titrate weekly to maximum tolerated (up to 1600 mcg twice daily).

• Adverse effects: Headache, diarrhea, flushing, jaw pain.

• Clinical trial: GRIPHON study demonstrated reduced disease progression.

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5. Calcium Channel Blockers (CCBs)

• Only for vasoreactive patients confirmed by acute vasodilator testing (positive test: drop in mPAP ≥ 10 mmHg to ≤ 40 mmHg with maintained cardiac output).

• Amlodipine: 20–30 mg/day orally.

• Nifedipine (long-acting): 120–240 mg/day orally.

• Diltiazem: 240–720 mg/day orally.

• Limitations: Only 5–10% of patients are responders.

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6. Supportive Therapy

• Diuretics: Furosemide, spironolactone to manage right heart failure and edema.

• Oxygen therapy: For hypoxemia.

• Anticoagulation: Warfarin (INR 1.5–2.5) historically used in idiopathic PAH; still considered in CTEPH.

• Digoxin: May be used for atrial arrhythmias and RV dysfunction.

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Contraindications

• ERAs: Pregnancy (Category X), liver dysfunction (bosentan).

• PDE-5 inhibitors: Concomitant nitrate or riociguat use (severe hypotension).

• Riociguat: Pregnancy, PDE-5 inhibitors.

• Prostacyclin analogues: Uncontrolled bleeding, severe hypotension.

• CCBs: Non-vasoreactive patients (risk of worsening heart failure).

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Adverse Effects

• ERAs: Hepatotoxicity, edema, anemia, teratogenicity.

• PDE-5 inhibitors: Headache, flushing, visual disturbance, systemic hypotension.

• Riociguat: Hypotension, dyspepsia, dizziness.

• Prostacyclins: Flushing, jaw pain, diarrhea, hypotension, sepsis risk with IV infusion.

• CCBs: Peripheral edema, bradycardia (diltiazem), hypotension.

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Drug Interactions

1. Bosentan: Induces CYP3A4 → reduces sildenafil and oral contraceptive efficacy.

2. Eplerenone/Spironolactone: Caution in patients on MRAs (hyperkalemia).

3. PDE-5 inhibitors and nitrates: Contraindicated (severe hypotension).

4. Riociguat with PDE-5 inhibitors: Contraindicated (additive hypotension).

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Clinical Considerations

• Initial Evaluation: Acute vasoreactivity testing determines suitability for CCB therapy.

• Treatment Goals: Improve exercise capacity, WHO functional class, hemodynamics, and survival.

• Combination Therapy: Increasingly used (e.g., ERA + PDE-5 inhibitor, or ERA + prostacyclin).

• Advanced PAH: Prostacyclin therapy (IV/SC treprostinil or epoprostenol) considered gold standard for severe disease.

• CTEPH: Riociguat is the drug of choice if surgery (pulmonary endarterectomy) is not possible.