A Review on Drug of Pediatric Pulmonary Arterial Hypertension (PAH), their Chemistry and Pharmaceutical Dosage Forms
Hypertension, specifically pulmonary hypertension, is a syndromethat can affect pediatric patients as well as adults. Pulmonary arterial hypertension (PAH) in pediatric patients, while rare, can be a lifethreateningcondition. There is no cure for PAH, only treatment options forchildren that are largely based on the results of adult studies. These therapies, however, can improve quality of life and survival. Treatment can be challenging because of the less approved medications and tolerable dosage forms for pediatric patients. Pediatric pulmonary arterial hypertension (PAH) shares common features of adult disease, but is associated with several additional disorders and challenges that require unique approaches. Current classes of medications primarily used to treat pediatric hypertension include phosphodiesterase inhibitors, endothelin receptor antagonists, and prostacyclins. Additional agents that may be utilized in selected pediatric patients include calcium channel blockers, anticoagulants, and inhalednitric oxide. Updates are provided on issues related to utility of the previous classification system to reflect pediatric-specific aetiologies and approaches to medical and interventional management of PAH. Also updates are provided about currently available drug substance and their details, pharmaceutical dosage forms and their details along with the mechanism of action, pharmacokinetics of the drug. These emerging data are improving the identification of appropriate targets for goal-oriented therapy inchildren. Such data will likely improve future advanced pharmaceutical dosage development and product design to enhance outcomes in pediatric PAH.
Keywords: Pulmonary arterial hypertension, pediatric hypertension, PAH
2. Georg Hansmann,ChristianApitz. Treatment of children with pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary Hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.Heart. 2016; 102: 67–85
3. Dr. Andreas Rieth. What can be expected from current treatments for pulmonary hypertension?. European Society of Cardiology. 2017 Jan; 14(34)
4. Shahzad G. Raja and Shahbaz M. Raja. Treating pulmonary arterial hypertension: current treatments and future prospects. Therapeutic Advances in Chronic Disease. 2011; 2(6): 359-370
5. Michael D. McGoon. Upfront triple therapy for pulmonary arterial hypertension: is three a crowd or critical mass?. EurRespir J 2014; 43:1556–1559
6. Ghio S, Gavazzi A, Campana C, Inserra C, Klersy C, Sebastiani R, Arbustini E, Recusani F, Tavazzi L. Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure. J Am Coll Cardiol. 2001 Jan; 37(1):183-8.
7. McGoon MD, Benza RL, Escribano-Subias P, Jiang X, Miller DP, Peacock AJ, Pepke- Zaba J, Pulido T, Rich S, Rosenkranz S, Suissa S, Humbert M. Pulmonary arterial hypertension: epidemiology and registries. J Am CollCardiol. 2013 Dec 24;62.
8. Kanwar MK, Thenappan T, Vachiery JL. Update in treatment options in pulmonary hypertension. J Heart Lung Transplant. 2016 Jun; 35(6):695-703.
9. D'Alto M, Scognamiglio G, Dimopoulos K, Bossone E, Vizza D, Romeo E, Vonk- Noordergraaf A, Gaine S, Peacock A, Naeije R. Right heart and pulmonary vessels structure and function. Echocardiography. 2015 Jan; 32Suppl 1:S3-10.
10. Cogswell R, McGlothlin D, Kobashigawa E, Shaw R, De Marco T. Performance of the REVEAL model in WHO Group 2 to 5 pulmonary hypertension: application beyond pulmonary arterial hypertension. J Heart Lung Transplant. 2013 Mar; 32(3):293-8.
Haddad F, Doyle R, Murphy DJ, Hunt SA. Right ventricular function in cardiovascular disease, part II: pathophysiology, clinical importance, and management of right ventricular failure. Circulation. 2008 Apr 1;117 (13):1717-31.
11. Vonk-Noordegraaf A, Haddad F, Chin KM, Forfia PR, Kawut SM, Lumens J, Naeije R, Newman J, Oudiz RJ, Provencher S, Torbicki A, Voelkel NF, Hassoun PM. Right heart adaptation to pulmonary arterial hypertension: physiology and pathobiology. J Am Coll Cardiol. 2013 Dec 24; 62(25 Suppl):D22-33.
12. Benza RL, Gomberg-Maitland M, Miller DP, Frost A, Frantz RP, Foreman AJ, Badesch DB, McGoon MD. The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest. 2012 Feb;141(2):354-62.
13. McLaughlin VV, Gaine SP, Howard LS, Leuchte HH, Mathier MA, Mehta S, Palazzini M, Park MH, Tapson VF, Sitbon O. Treatment goals of pulmonary hypertension. J Am CollCardiol. 2013 Dec 24;62
14. TRACLEER® (bosentan) tablets, for oral use, TRACLEER® (bosentan) tablets for oral suspension Initial; U.S. Approval: 2001. Available at:
15. Letairis (ambrisentan) tablets, for oral use; Initial U.S. Approval: 2007. Available at:
16. OPSUMIT(macitentan) tablets, for oral use; Initial U.S. Approval: 2013. Available at:
17. REVATIO (sildenafil) tablets, for oral use; REVATIO (sildenafil) for oral suspension; REVATIO (sildenafil) injection, for intravenous use; Initial U.S. Approval: 1998. Available at:
18. ADCIRCA (tadalafil) tablets for oral administration; Initial U.S. Approval: 2003. Available at:
19. Adempas (riociguat) tablets, for oral use; Initial U.S. Approval: 2013. Available at:
20. Markus Follmann,Jens Ackerstaff, Gorden Redlich, Frank Wunder, Dieter Lang, Armin Kern, Peter Fey, Nils Griebenow, Walter Kroh, Eva-Maria Becker-Pelster, Axel Kretschmer, Volker Geiss, Volkhart Li, Alexander Straub, Joachim Mittendorf, Rolf Jautelat, HartmutSchirok, Karl-Heinz Schlemmer, KlemensLustig, Michael Gerisch, Andreas Knorr, Hanna Tinel, Thomas Mondritzki, Hubert Trübel, Peter Sandner, and Johannes-Peter Stasch. Discovery of the Soluble Guanylate Cyclase Stimulator Vericiguat(BAY 1021189) for the Treatment of Chronic Heart Failure. Journal of Medicinal Chemistry. 2017 May; 60:5146−5161
21. Vericiguat Reduced the Risk of Heart Failure Hospitalization or Cardiovascular Death in Patients with Worsening Chronic Heart Failure with Reduced Ejection Fraction, Compared to Placebo When Added to Available Heart Failure Therapies. Merck and Bayer’s Investigational Drug Vericiguat Meets Primary Endpoint in Phase 3 Study of Patients with Worsening Chronic Heart Failure. Published on Merck Newsroom Home. 2019 Nov; Source URL :https://www.mrknewsroom.com/news-release/research-and-development-news/merck-and-bayers-investigationaldrug-vericiguat-meets-pr
22. VELETRI (epoprostenol) for Injection Initial U.S. Approval: 1995. Available at:
23. REMODULIN® (treprostinil) Injection, for subcutaneous or intravenous use Initial U.S. Approval: May 2002. Available at:
24. Ventavis (iloprost) Inhalation Solution. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021779s019lbl.pdf
25. Beraprost (sodium salt). Item No.18230. Product Information. Cayman Chemical. www.caymanchem.com
26. Li Wang, MDa,b, Xinyi Zhu, MDa, Liang-Ping Zhao, MDa, Maosong Wang, MDa, Xiang Liu, MDa, Yuqi Chen, MDa, JianChang Chen, PhDa, WeiTing Xu, MDa. Effect of beraprost on pulmonary hypertension due to left ventricular systolic dysfunction.Medicine.2019 March;98(16):1-6
27. UPTRAVI® (selexipag) tablets, for oral use: Initial U.S. Approval: 2015. Available at:
28. Assessment report for Volibris. Procedure No. EMEA/H/C/000839.EuropeanMedicines Agency Evaluation of Medicines for Human Use.Doc.Ref.:EMEA/123999/2008
29. Assessment report for Opsumit. Procedure No. EMEA/H/C/002697/0000. European Medicines Agency Evaluation of Medicines for Human Use. Doc.Ref.: EMA/CHMP/457699/2013
30. Schubert S, Peters B, Berger F. Interventional re-opening of a PDA for reverse Potts shunt circulation after ADOI implantation in a child. Catheter CardiovascInterv 2017;89: 133–136.
31. Esch JJ, Shah PB, Cockrill BA, etal.Transcatheter Potts shunt creation in patients with severe pulmonary arterial hypertension: initial clinical experience. J Heart Lung Transplant 2013;32: 381–387.
32. Salna M, VanBoxtel B, Rosenzweig EB, et al. Modified Potts shunt in an adult with idiopathic pulmonary arterial hypertension. Ann Am ThoracSoc 2017; 14: 607–609.
33. Adatia I, Haworth SG, Wegner M, et al. Clinical trials in neonates and children: report of the pulmonary hypertension academic research consortium pediatric advisory committee. PulmCirc 2013; 3: 252–266.
34. Ploegstra MJ, Ivy DD, Wheeler JG, et al. Growth in children with pulmonary arterial hypertension: a longitudinal retrospective multiregistry study. Lancet Respir Med 2016; 4: 281–290.
35. Tissot C, Beghetti M. Review of inhaled iloprost for the control of pulmonary artery hypertension in children. Vasc Health Risk Manag 2009; 5: 325–331.
36. Krishnan U, Takatsuki S, Ivy DD, et al. Effectiveness and safety of inhaled treprostinil for the treatment of pulmonary arterial hypertension in children. Am J Cardiol 2012; 110: 1704–1709.
37. Lammers AE, Hislop AA, Flynn Y, et al. Epoprostenol treatment in children with severe pulmonary hypertension. Heart 2007; 93: 739–743.
38. Rosenzweig EB, Kerstein D, Barst RJ. Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects. Circulation 1999; 99: 1858–1865.
39. Siehr SL, Ivy DD, Miller-Reed K, et al. Children with pulmonary arterial hypertension and prostanoid therapy: long-term hemodynamics. J Heart Lung Transplant 2013; 32: 546–552.
40. Levy M, Del Cerro MJ, Nadaud S, et al. Safety, efficacy and management of subcutaneous treprostinil infusions in the treatment of severe pediatric pulmonary hypertension. Int J Cardiol 2018; 264: 153–157.
41. Levy M, Celermajer DS, Bourges-Petit E, et al. Add-on therapy with subcutaneous treprostinil for refractory pediatric pulmonary hypertension. J Pediatr 2011; 158: 584–588.
42. Rosenzweig EB. Tadalafil for the treatment of pulmonary arterial hypertension. Expert OpinPharmacother 2010; 11: 127–132.
43. Takatsuki S, Calderbank M, Ivy DD. Initial experience with tadalafil in pediatric pulmonary arterial hypertension. PediatrCardiol 2012; 33: 683–688.
44. Limsuwan A, Wanitkul S, Khosithset A, et al. Aerosolized iloprost for postoperative pulmonary hypertensive crisis in children with congenital heart disease. Int J Cardiol 2008; 129: 333–338.
45. Ivy DD, Doran AK, Smith KJ, et al. Short- and long-term effects of inhaled iloprost therapy in children with pulmonary arterial hypertension. J Am CollCardiol 2008; 51: 161–169.
46. Melnick L, Barst RJ, Rowan CA, et al. Effectiveness of transition from intravenous epoprostenol to oral/ inhaled targeted pulmonary arterial hypertension therapy in pediatric idiopathic and familial pulmonary arterial hypertension. Am J Cardiol 2010; 105: 1485–1489.
47. Barst RJ, Beghetti M, Pulido T, et al; STARTS-2 Investigators.STARTS-2: long-term survival with oral sildenafi l monotherapy in treatment-naive pediatric pulmonary arterial hypertension. Circulation. 2014;129(19):1914–1923
48. Uslu S, Kumtepe S, Bulbul A, Comert S, Bolat F, Nuhoglu A. A comparison of magnesium sulphate and sildenafi l in the treatment of the newborns with persistent pulmonary hypertension: a randomized controlled trial. J Trop Pediatr. 2011;57(4):245–250
49. Vargas-Origel A, Gomez-Rodriguez G, Aldana-Valenzuela C, Vela-Huerta MM, Alarcon-Santos SB, AmadoR–Licona N. The use of sildenafil inpersistent pulmonary hypertension of the newborn. Am J Perinatol. 2010;27(3):225–230
50. Peiravian F, Amirghofran AA, Borzouee M, Ajami GH, Sabri MR, Kolaee S. Oral sildenafil to control pulmonary hypertension after congenital heart surgery. Asian CardiovascThorac Ann.2007;15(2):113–117
51. Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persistent pulmonary hypertension of the newborn. Pediatrics. 2006;117(4):1077–1083
52. Kahveci H, Yilmaz O, Avsar UZ, et al. Oral sildenafil and inhaled iloprost in the treatment of pulmonary hypertension of the newborn. Pediatr Pulmonol. 2014;49(12):1205–1213
53. Chinwe Unegbu, Corina Noje, John D. Coulson, Jodi B. Segal, MPH, Lewis Romer. Pulmonary Hypertension Therapy and a Systematic Review of Efficacy and Safety of PDE-5 Inhibitors. Journal of the American Academy of Pediatrics. 2017 March; 139(3): 1-21
54. Mark R. Prausnitz and Robert Langer. Transdermal drug delivery. Nat Biotechnol. 2008 Nov; 26(11): 1261–1268.
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).