What medications are used to treat pulmonary hypertension?

Medications for Pulmonary Hypertension

The primary medications for pulmonary hypertension include endothelin receptor antagonists (ERAs), phosphodiesterase type-5 inhibitors (PDE-5i), prostanoids, and soluble guanylate cyclase stimulators, with treatment selection based on risk stratification and WHO functional class. 1

Risk Stratification Approach

Treatment decisions should be guided by risk stratification into low, intermediate, or high-risk categories based on:

• Clinical signs of right ventricular failure
• WHO functional class (I-IV)
• 6-minute walk distance
• BNP/NT-proBNP levels

Parameter	Low Risk	Intermediate Risk	High Risk
Clinical signs of RV failure	Absent	Absent	Present
WHO functional class	I-II	III	IV
6MWD	>440m	165-440m	<165m
BNP	<50 ng/L	50-300 ng/L	>300 ng/L
NT-proBNP	<300 ng/L	300-1400 ng/L	>1400 ng/L

Medication Classes and Selection Algorithm

1. Phosphodiesterase Type-5 Inhibitors (PDE-5i)

• Mechanism: Enhance vasodilation through the NO/cGMP pathway
• Options:
  • Sildenafil: 20mg three times daily (approved dose), though higher doses up to 80mg TID may be used in clinical practice 2
  • Tadalafil: Once-daily dosing 3
• Benefits: Improve exercise capacity, hemodynamics, and WHO functional class 2, 4
• Side effects: Headache, flushing, epistaxis, hypotension 2, 5
• Contraindications: Concurrent use of nitrates or nicorandil due to risk of profound hypotension 5, 3

2. Endothelin Receptor Antagonists (ERAs)

• Mechanism: Block endothelin receptors that cause vasoconstriction and smooth muscle proliferation
• Options:
  • Bosentan: Non-selective ERA (blocks both ETA and ETB receptors)
  • Ambrisentan: Selective for ETA receptors
  • Macitentan: Dual ERA with sustained receptor binding
• Benefits: Improve exercise capacity, hemodynamics, and delay clinical worsening 2
• Side effects:
  • Bosentan: Liver function abnormalities (3-5%), requires monthly monitoring 2
  • Ambrisentan: Peripheral edema, lower incidence of liver abnormalities (0.8-3%) 2
• Contraindications: Pregnancy (teratogenic) 1

3. Prostanoids

• Mechanism: Vasodilation and inhibition of platelet aggregation
• Options:
  • Epoprostenol: Intravenous administration
  • Treprostinil: Available in intravenous, subcutaneous, and inhaled forms 2
• Benefits: Improve exercise capacity, hemodynamics, and survival (epoprostenol) 1
• Side effects: Headache, flushing, jaw pain, diarrhea, nausea, infusion site pain (subcutaneous) 1

4. Soluble Guanylate Cyclase Stimulators

• Mechanism: Stimulate soluble guanylate cyclase directly
• Options: Riociguat
• Benefits: Effective as both monotherapy and combination therapy 2
• Side effects: Hypotension, headache, dizziness 2
• Contraindications: Concurrent use with PDE-5 inhibitors 3

Treatment Algorithm Based on WHO Functional Class

WHO Functional Class I

• Generally not included in clinical trials
• Consider treating if not candidates for calcium channel blockers 2

WHO Functional Class II-III (Low to Intermediate Risk)

• First-line: Initial oral combination therapy with an ERA plus a PDE-5 inhibitor 1
  • Ambrisentan plus tadalafil combination has shown superiority over monotherapy 1
• Alternative: Monotherapy with either:
  • ERA (bosentan, ambrisentan, or macitentan)
  • PDE-5 inhibitor (sildenafil or tadalafil)
  • Riociguat 2, 1

WHO Functional Class IV (High Risk)

• First-line: Intravenous epoprostenol (only therapy proven to improve survival) 1
• Alternative: Consider initial combination therapy including a prostanoid 1

Special Considerations

Vasoreactive Patients

• Calcium channel blockers are only indicated for patients who demonstrate positive acute vasoreactivity testing during right heart catheterization 1
• Not recommended for patients with Eisenmenger's syndrome 1

Eisenmenger's Syndrome

• Bosentan is specifically indicated for WHO FC III patients with Eisenmenger's syndrome (Class I recommendation) 2
• Other ERAs, PDE-5 inhibitors, and prostanoids should be considered 2

PAH Associated with Connective Tissue Disease

• Sildenafil has shown efficacy in improving exercise capacity, hemodynamics, and functional class in patients with PAH-CTD 6
• Mean increases in 6-minute walk distance of 42m with 20mg TID dosing 6

Monitoring and Follow-up

• Regular assessment every 3-6 months for stable patients 1
• Monitor for:
  • Clinical status and exercise capacity
  • Liver function tests (monthly for bosentan, at least every 3 months for other ERAs) 2
  • Drug interactions (particularly with warfarin, HIV medications, and statins) 2

Treatment Escalation

If inadequate response to initial therapy:

1. Add a second or third class of medication
2. Consider referral for lung transplantation evaluation if maximum medical therapy fails 1

Remember that early diagnosis and prompt initiation of appropriate therapy are critical for improving outcomes in pulmonary hypertension patients.