Pulmonary arterial hypertension is a syndrome resulting from restricted flow through the pulmonary arterial circulation resulting in increased pulmonary vascular resistance and ultimately leading to right heart failure.
It is a part of the spectrum of pulmonary hypertension, which is hemodynamic and pathophysiological condition defined as an increase in mean pulmonary arterial pressure ≥25 mmHg at rest.
Typical symptoms include progressive dyspnea on exertion, palpitations, fatigue, weakness, angina, syncope and abdominal distention.

Principles of Therapy

General Therapy Principles

  • Choice of therapy will depend on the approval status/availability of the drug, route of administration, side effect profile, patient preference & practitioner’s experience


Management of Patients with Positive Acute Vasoreactivity

Calcium Antagonists

  • Eg Amlodipine, Diltiazem, Nifedipine
    • Choice of agent should be based on the patient’s heart rate (HR) at baseline
    • Nifedipine & Amlodipine are preferred in those with relative bradycardia; Diltiazem is favored in those with relative tachycardia
  • Of the vasodilators studied in pulmonary arterial hypertension (PAH) patients, calcium (Ca) antagonists have been the most successful
    • Has shown hemodynamic & functional status improvements of >1 year
  • Patients with idiopathic pulmonary arterial hypertension (IPAH) & without right heart failure who demonstrate acute response to vasodilator should be considered for a trial of oral calcium (Ca) antagonist
  • If patients with PAH associated with underlying processes such as scleroderma or congenital heart disease have had positive acute vasoreactivity tests, a trial of calcium (Ca) antagonists should be attempted
  • Single agent treatment of calcium (Ca) antagonists should only continue in patients showing clinical & hemodynamic response
  • Patients with positive acute vasoreactivity & are treated with calcium (Ca) antagonists should be reassessed initially after 3-4 months of therapy with RHC then followed closely for drug safety & efficacy

Management of Patients with Negative Acute Vasoreactivity or Non-Responders to Calcium Antagonists

Endothelin Receptor Antagonists

  • Eg Ambrisentan, Bosentan, Macitentan, Sitaxentan
  • Endothelin receptor antagonism is a promising treatment approach due to increased evidence of the pathogenic role of endothelin-1 in pulmonary arterial hypertension (PAH)
    • Endothelin-1 is a potent vasoconstrictor & a smooth muscle mitogen that might contribute to increase in vascular tone & the pulmonary vascular hypertrophy associated with PAH


  • Relatively selective antagonist of the ETA receptor
  • Demonstrated efficacy on symptoms, exercise capacity, hemodynamics, & time to clinical worsening of patients with idiopathic pulmonary arterial hypertension (IPAH) & PAH associated with connective tissue diseases & human immunodeficiency virus (HIV) infection
  • Require monthly liver function test (LFT) assessment

Bosentan (Oral)

  • Should be considered in PAH patients in functional class (FC) II to III who are not candidates for or who have failed calcium (Ca) antagonists
  • Studies in PAH has shown to improve exercise capacity, functional class, hemodynamics, echocardiographic & Doppler variables & time to clinical worsening
  • Oral active dual ETA & ETB receptor antagonist
  • Liver function tests should be checked monthly & hematocrit checked every 3 months
  • Barrier methods of contraception are recommended over hormonal methods because it may reduce efficacy of hormonal agents & is potentially teratogenic


  • Should be considered for treatment of PAH patients, & for long-term therapy of PAH patients with World Health Organization (WHO) FC-II to III to delay disease progression
  • Modified using the same structure of Bosentan, with improvements in the efficacy & with lesser adverse effects
  • Action: Dual ETA & ETB receptor antagonist; prevents endothelin-1 from binding to ETA & ETB
  • Not recommended for female patients planning to get pregnant or is currently pregnant
  • Studies showed decreased hospitalization in PAH patients on Macitentan therapy

Guanylate Cyclase Stimulators


  • A soluble guanylate cyclase stimulator, an enzyme that helps regulate nitric oxide
  • Treatment option used to improve exercise capacity & hemodynamics, & delay clinical worsening in patients with WHO FC II-III

Prostacyclin Analogs

  • Eg Beraprost, Epoprostenol, Iloprost, Treprostinil
  • Prostacyclin is produced mainly by endothelial cells which can induce potent vasodilatation of all vascular beds; it also inhibits platelet aggregation & has cytoprotective & antiproliferative activities
  • Prostacyclin analogs have been included in pharmacotherapy of PAH for more than a decade

Beraprost (Oral)

  • First chemically stable & orally active prostacyclin analogue
  • Increase in exercise capacity has been shown but this effect persists only up to 3-6 months of therapy with no hemodynamic benefits

Epoprostenol Intravenous (IV)

  • Synthetic prostacyclin that has shown symptomatic & hemodynamic improvements as well as survival in patients with idiopathic pulmonary arterial hypertension (IPAH) in functional class III-IV
  • Multicenter trials of long-term IV Epoprostenol showed improvement in exercise capacity & hemodyna­mics in patients with PAH associated with scleroderma
  • Treatment of choice in PAH in functional class IV who are not candidates for or who have failed Ca antagonist therapy
  • Epoprostenol is preferred by most experts in class IV patients in unstable condition because of its proven survival improvement, worldwide experience & the rapidity of action
  • Exact mechanism of action is still unknown but has shown pulmonary vasodilator properties
  • Disadvantage of therapy is the need to administer by continuous IV infusion

Iloprost [Inhaled & Intravenous (IV)]

  • A chemically stable prostacyclin analog for IV & aerosol administration
  • Studies have shown increase in exercise capacity & improvement of symptoms, peripheral vascular resistance (PVR) & clinical events with inhaled therapy
  • Continuous IV administration appears to be as effective as Epoprostenol in a small series of patients with PAH & chronic thromboembolic pulmonary hypertension (CTEPH)
    • It is a more potent pulmonary vasodilator than acute inhaled NO
  • Approved for use in functional class III & IV PAH
  • Disadvantages of inhaled therapy is the short duration of action & therefore 6-9 inhalations/day are needed

Treprostinil [Inhaled, Intravenous (IV) or Subcutaneous (SC)]

  • A stable tricyclic benzidine analogue of Epoprostenol with a half-life of about 4.5 hours
  • Administered via micro-infusion pumps & small subcutaneous catheters similar to those used for administration of insulin
  • Recently approved as an inhaled prostacyclin analogue
  • Has been shown to improve exercise capacity, hemodynamics & clinical events
    • Those who benefited the most are those who were more compromised at baseline & in subjects who could tolerate the higher dose 
  • Disadvantage of therapy is pain & erythema occurring at the infusion site

Prostacyclin Receptor Agonist

Selexipag (Oral)

  • Studies have shown that Selexipag may decrease pulmonary vascular resistance & morbidity/mortality events (eg death, disease progression, need for hospitalization & surgery)
  • Mechanism of action: selective prostacyclin IP receptor agonist that in turn triggers smooth muscle vasodilation & inhibits platelet aggregation
  • Recommended for use in PAH patients with WHO-FC II & III

Phosphodiesterase Inhibitors

Sildenafil (Oral)

  • Has shown favorable effects in IPAH, PAH associated with connective tissue diseases, congenital heart disease (CHD) & CTEPH on exercise capacity, symptoms & hemodynamics in clinical studies
  • Long-term data (available only at a dose of 80 mg TID) in patients completing 1 year of treatment with Sildenafil monotherapy showed sustained improvement at 1 year in the 6-minute walk test (6MWT) 
  • Action: Orally active, potent & selective inhibitor of cGMP phosphodiesterase type-5 that exerts its pharmacological effect by increasing intracellular concentration of cGMP, inducing relaxation & antiproliferative effects on vascular smooth muscle cells


  • A longer-acting selective phosphodiesterase type-5 inhibitor currently undergoing clinical studies
  • Has shown favorable results on exercise capacity, symptoms, hemodynamic & time to clinical worsening at the largest dose in the study while demonstrating durability of these effects
  • Side effect profile is similar to Sildenafil


  • Currently under study for its use in the treatment of PAH
  • Previous studies conducted showed an increase in the 6MWT
  • Mechanism of action: a selective phosphodiesterase type 5 inhibitor which may stimulate vascular relaxation by increasing cGMP concentrations in smooth muscles

Combination Therapy

  • Recommended for non-vasoreactive patients not responding adequately to monotherapy, but should be instituted by expert centers only
  • Safety & efficacy of combination therapy in PAH is a subject of active investigation

Initial Combination Therapy

  • Eg Ambrisentan + Tadalafil, Bosentan + Sildenafil + Epoprostenol IV, Bosentan + Epoprostenol IV
  • Used for WHO-FC II-III after initial monotherapy has been deemed ineffective
  • IV treatments may be used in WHO-FC IV PAH patients who are unresponsive to oral formulations

Sequential Combination Therapy

  • Eg Macitentan added to Sildenafil, Riociguat added to Bosentan, inhaled Treprostinil added to Sildenafil or Bosentan, Sildenafil added to Epoprostenol or Bosentan, Ambrisentan added to Sildenafil
  • Used for WHO-FC II-IV PAH patients unresponsive to initial combination oral & IV therapies
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Stephen Padilla, 21 Nov 2018
Use of triple therapy consisting of a long acting muscarinic antagonist (LAMA), long acting β agonist (LABA) and inhaled corticosteroid (ICS) leads to a reduced rate of moderate or severe exacerbations of chronic obstructive pulmonary disease (COPD) and better lung function and health-related quality of life compared with dual therapy (ICS and LABA or LAMA and LABA) or LAMA monotherapy, according to the results of a meta-analysis.