1. Introduction
Agents for Pulmonary Hypertension is defined as a mean pulmonary artery pressure (mPAP) ≥20 mmHg at rest, confirmed by right heart catheterization. PH can be classified into five WHO groups based on etiology:
- Pulmonary arterial hypertension (PAH)
- PH due to left heart disease
- PH due to lung diseases and/or hypoxia
- Chronic thromboembolic pulmonary hypertension (CTEPH)
- PH with unclear or multifactorial mechanisms
Medical management depends on underlying pathophysiology, but several pharmacologic classes directly target pulmonary vascular remodeling, vasoconstriction, and thrombosis.
2. Pharmacologic Classes and Mechanisms
2.1 Prostacyclin (PGI2) Analogs
- Examples: Epoprostenol, Treprostinil, Iloprost
- Mechanism:
- Bind prostacyclin receptors → ↑ cAMP → vasodilation of pulmonary arteries
- Inhibit platelet aggregation and vascular smooth muscle proliferation
- Clinical Use:
- Severe PAH (WHO functional class III–IV)
- IV, subcutaneous, inhaled, or oral formulations
- Adverse Effects:
- Hypotension, flushing, headache
- Jaw pain, diarrhea, nausea
- Catheter-related infections (IV forms)
2.2 Endothelin Receptor Antagonists (ERAs)
- Examples: Bosentan, Ambrisentan, Macitentan
- Mechanism: Block endothelin-1 (ET-1) receptors → reduce pulmonary vasoconstriction and remodeling
- Clinical Use:
- PAH (WHO FC II–III)
- Often used in combination with PDE5 inhibitors
- Adverse Effects:
- Hepatotoxicity (requires LFT monitoring)
- Peripheral edema
- Teratogenic → contraindicated in pregnancy
2.3 Phosphodiesterase Type 5 Inhibitors (PDE5i)
- Examples: Sildenafil, Tadalafil
- Mechanism: Inhibit PDE5 → ↑ cGMP → pulmonary vasodilation
- Clinical Use:
- PAH (WHO FC II–III)
- Often combined with ERAs or prostacyclin analogs
- Adverse Effects:
- Headache, flushing, dyspepsia
- Hypotension
- Rare visual disturbances
2.4 Soluble Guanylate Cyclase (sGC) Stimulators
- Example: Riociguat
- Mechanism: Directly stimulates sGC → ↑ cGMP → pulmonary vasodilation
- Clinical Use:
- PAH and CTEPH
- Adverse Effects:
- Hypotension, headache, dizziness
- Contraindicated with PDE5 inhibitors (risk of severe hypotension)
2.5 Calcium Channel Blockers (CCBs)
- Examples: Amlodipine, Nifedipine, Diltiazem
- Mechanism: Inhibit L-type calcium channels → vasodilation
- Clinical Use:
- Only in PAH patients who respond to acute vasoreactivity testing
- Adverse Effects:
- Hypotension, peripheral edema, dizziness
- Worsening heart failure in some patients
2.6 Soluble Prostacyclin Receptor Agonists (Selective IP Agonists)
- Example: Selexipag
- Mechanism: Selective activation of IP receptors → vasodilation, anti-proliferative effect
- Clinical Use: PAH (oral, long-term therapy)
- Adverse Effects: Headache, nausea, flushing, jaw pain
3. Supportive Therapy
- Oxygen: Maintain SpO2 >90%
- Diuretics: Manage right heart failure and fluid overload
- Anticoagulants: Especially in idiopathic PAH and CTEPH
- Digoxin: Sometimes used for right ventricular dysfunction
4. Clinical Pearls
- Therapy selection: Based on WHO functional class, hemodynamics, and comorbidities
- Combination therapy: Often used for additive effects (e.g., ERA + PDE5i)
- Acute vasoreactivity testing: Guides use of high-dose CCBs
- Pregnancy: Many PAH drugs are teratogenic; specialized care required
5. Monitoring Parameters
| Parameter | Frequency |
|---|---|
| Liver function tests | Monthly (ERAs) |
| Blood pressure | Regularly (all vasodilators) |
| Signs of right heart failure | Ongoing |
| Renal function | Periodic (especially in combination therapy) |
| Hematologic parameters | As indicated (prostacyclin analogs can cause anemia) |
6. Adverse Effect Summary
- Hypotension: All vasodilators
- Peripheral edema: Common with ERAs and CCBs
- Headache, flushing: PDE5i, prostacyclin analogs, selexipag
- Hepatotoxicity: ERAs
- Jaw pain, GI upset: Prostacyclin analogs
7. Summary
Pulmonary hypertension requires targeted therapy based on etiology and functional class. Key pharmacologic agents include:
- Prostacyclin analogs – potent vasodilators, anti-proliferative
- Endothelin receptor antagonists – reduce vasoconstriction and remodeling
- PDE5 inhibitors – enhance NO-cGMP pathway for vasodilation
- sGC stimulators – direct cGMP pathway activation
- Calcium channel blockers – only in acute vasoreactive patients
- Selective IP agonists – oral prostacyclin pathway modulation
Combination therapy and supportive measures improve survival, exercise capacity, and quality of life.
8. References
- Galiè N, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2016;37:67–119.
- McLaughlin VV, et al. Management of pulmonary arterial hypertension. J Am Coll Cardiol. 2015;65:1976–1997.
- Hoeper MM, et al. Pulmonary hypertension: epidemiology and clinical management. Lancet Respir Med. 2013;1:278–288.
- Simonneau G, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62:D34–D41.
- Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 14th Edition, 2021.
