Written by Kellie Ball, PharmD, MPH, BCACP and Danielle Dennis, PharmD, BCPS
What is Pulmonary Hypertension (PH)?
PH is a complex, often fatal condition characterized by abnormally high pressures in the pulmonary arteries caused in large part by smooth muscle and endothelial cell proliferation.(1) If left untreated, these complex and multifactorial processes may lead to right ventricle dysfunction, heart failure, and death.(2) PH describes a group of disorders that fall into one of five different groups depending on cause although some overlap between groups exist.(1) World Health Organization (WHO) Classifications and common causes are shown in Table 1. PH symptoms are often nondescript such as dizziness, fatigue, and shortness of breath, which may lead to delays in diagnosis and treatment.(2) Diagnosis typically involves many tests and labs followed by a right heart catheterization (RHC), the gold standard for PH diagnosis.(3)
Group 1 pulmonary arterial hypertension (PAH) represents a rare, severe group of PH with a growing number of studies and targeted medication treatments. The cause of PAH is often unknown. PAH affects about 15-60 people per 1 million, predominantly women at 70-80%, and individuals 50-65 years of age.(4,5)
Table 1: WHO Classifications and Common Causes of PH (2)
CHD: congenital heart disease; LVEF: left ventricular ejection fraction; COPD: chronic obstructive pulmonary disease; OSA: obstructive sleep apnea; ILD-PH: interstitial lung disease pulmonary hypertension
How is PAH Treated?
Generally, PAH treatment focuses on the WHO PAH subgroup, WHO functional class (WHO-FC), risk status, and individual patient factors such as rate of progression, disease- or drug-drug interactions, and medication tolerability.(3) After diagnosis, a comprehensive prognostic evaluation, risk assessments, and treatment goals are established to aid in choosing pharmacotherapy. Risk stratification calculators such as REVEAL and three-strata model can estimate one-year survival and one-year mortality, respectfully.(3) These scores can include many different factors like WHO PAH subgroup cause, WHO-FC, blood pressure, 6-minute walk test (6MWD), ECHO findings, initial RHC hemodynamics, and NT-proBNP.(3) WHO-FC refers to functional classification of PH modified after the New York Heart Association functional classification according to the WHO 1998.(6)
Treatment is divided into managing systemic fluid retention with loop diuretics alone or in combination with thiazides and/or mineralocorticoid receptor antagonists as well as managing underlying vasocontraction and cell proliferation with targeted therapies.(3) Pharmacotherapy can include specific calcium channel blockers (CCBs), including nifedipine, diltiazem, and amlodipine, though favorable responses occur in less than 10% of specific PAH (IPAH, HPAH, DPAH) patients.(3) Responders are those who have a significant, immediate, hemodynamic response to pulmonary vasodilators during RHC.(3) At one year, these patients had less severe disease noted by a greater proportion of patients in WHO-FC II, improved 6MWD, and less severe hemodynamics in RHC.(7) CCB daily doses for PAH are relatively high compared to typical daily dosing (Table 2).
Historically, three major pathways are targeted in PAH: nitric oxide (NO), endothelin-1 (ET-1), and prostacyclin.(2) Medications target these pathways and treat PAH by controlling pulmonary vascular tone and cell proliferation resulting in vasodilation, reducing right ventricular afterload, and improving cardiopulmonary hemodynamics.(3,8) One medication from each pathway may be used in treatment along with diuretics.(3) Within the NO pathway, a phosphodiesterase-5 inhibitor (PDE-5i) or soluble guanylate (sGC) stimulator is used to stimulate vasodilation and inhibits proliferation within vascular smooth cells.(2) Within the ET-1 pathway, endothelin receptor antagonist ERAs are used to block potent vasoconstriction and the driver of pulmonary vascular remodeling that is upregulated in patients with PAH.(2) Within the prostacyclin pathway, prostacyclin analogs or receptor agonists promote vasodilation, inhibit platelet aggregation, and lead to antiproliferation.(2) As of March 2024, sotatercept, a fourth pathway, has been approved for use in PAH that modulates the transforming growth factor beta (TGF-B) receptor by acting as a ligand trap for activin.(9) Ultimately, it is proposed to rebalance pulmonary vascular homeostasis toward growth inhibition and proapoptotic signaling, potentially leading to reverse remodeling.(9) Medications used in PAH treatment are listed in Table 2.
Patients with PAH may be on 1-4 medications depending on the severity of their disease.(4) More recent research suggests treatment should be initiated with at least dual therapy with a PDE-5i and ERA.(10) Depending on the combination of medications and risk calculations, these treatments have been shown to benefit patients through improvements in exercise capacity, quality of life, and time to clinical worsening.(2) Patients are evaluated frequently in the months following diagnosis to establish and maximize medication therapy.(4)
Table 2: Medications used in PAH Treatment (3,11)
*Only recommended for patients with a positive acute pulmonary vasoreactivity test during right heart catheterization
PDE-5i: phosphodiesterase-5 enzyme inhibitor; sGC: soluble guanylate cyclase stimulator; ERA: endothelin receptor antagonist; CCB: calcium channel blocker; TID: three times daily; QID: four times daily; PO: by mouth; BID: twice daily; IV: intravenous; DPI: dry powder inhaler; ng/kg/min: nanogram per kilogram per minute; SQ: subcutaneous
Where do Pharmacists Fit in PH Treatment?
PH is a complicated disease state that includes a multidisciplinary healthcare team and patient/caregiver support to manage medications with a variety of side effects, monitoring parameters, and medication access issues. As medication experts within clinic or specialty pharmacy settings, pharmacists have the unique opportunity to offer guidance on therapy selection, ensure access to medications, and support patient adherence to medications.
1. Poch D, Mandel J. Pulmonary Hypertension. Ann Intern Med. 2021;174(4):ITC49-ITC64. doi:10.7326/AITC202104200 Bousseau S, Sobrano Fais R, Gu S, et al. Pathophysiology and new advances in pulmonary hypertension. BMJMED 2023;2:e000137. doi:10.1136/ bmjmed-2022-000137.
2. Pulmonary hypertension association. Pulmonary Hypertension Association. 2024.https://phassociation.org/.
3. 2022 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension: Developed by the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Eur Heart J 2022;Aug 26.
4. Hoeper MM, Simon R Gibbs J. The changing landscape of pulmonary arterial hypertension and implications for patient care. Eur Respir Rev. 2014;23(134):450-457. doi:10.1183/09059180.00007814.
5. Westerhof BE, Saouti N, van der Laarse WJ, Westerhof N, Vonk Noordegraaf A. Treatment strategies for the right heart in pulmonary hypertension. Cardiovasc Res. 2017;113(12):1465-1473. doi:10.1093/cvr/cvx148.
6. Barst RJ, McGoon M, Torbicki A, Sitbon O, Krowka MJ, Olschewski H, et al. Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43:40S–47S.
7. Sitbon O, Humbert M, Jais X, Ioos V, Hamid AM, Provencher S, et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005;111:3105–3111.
8. Sitbon O, Morrell N. Pathways in pulmonary arterial hypertension: the future is here. Eur Respir Rev. 2012;21(126):321–327.)
9. Hoeper MM, Badesch DB, Ghofrani HA, et al. Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2023;388(16):1478-1490. doi:10.1056/NEJMoa2213558
10. Chin KM, Sitbon O, Doelberg M, et al. Three- Versus Two-Drug Therapy for Patients With Newly Diagnosed Pulmonary Arterial Hypertension. J Am Coll Cardiol. 2021;78(14):1393-1403. doi:10.1016/j.jacc.2021.07.057
Lexi-Drugs. Hudson, OH: Lexicomp, 2024. http://online.lexi.com/. Accessed August 3, 2024.
Kellie Ball, PharmD, MPH, BCACP
Ambulatory Pharmacist Specialist
PGY2 Ambulatory Care Residency Program Coordinator
University of Tennessee Medical Center
Knoxville, TN
Danielle Dennis, PharmD, BCPS
Internal Medicine/Pulmonary Pharmacist Specialist
University of Tennessee Medical Center
Knoxville, TN
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