Pulmonary Arterial Hypertension (PAH)

The treatment of pulmonary arterial hypertension (PAH) relies not only on the targeting of specific signaling pathways, but also on the use of supportive therapy, which includes the administration of oxygen, diuretics, anticoagulants, and cardiac glycosides.¹ 

Cardiac glycosides, such as digoxin, are compounds that can be found in nature, in plants and amphibians.² These drugs block the transmembrane enzyme sodium-potassium adenosine triphosphatase (Na⁺-K⁺ ATPase) in the muscle cells of the heart.^2-4 This enzyme is responsible for the maintenance of an electrochemical ion gradient between the extracellular and intracellular media through the transport of sodium and potassium out of and into the cells, respectively.⁴ The inhibition of Na⁺-K⁺ ATPase leads to a blockage of sodium and potassium ionic transport, increasing the intracellular concentration of calcium and promoting muscular contraction.⁴ Cardiac glycosides, therefore, have the ability to promote an increase in the heart’s contractile strength.³

Digoxin

Digoxin is found in the leaves of Digitalis lanata, and the effects observed following the intake of this drug result from NA⁺-K⁺ ATPase inhibition.⁵ These effects include an increase in the availability of intracellular calcium within the myocardium, leading to increased inotropy and automaticity; a reduction in sympathetic activity; a blockage of the atrioventricular node; a reduction in vasoconstriction; and an increase in renal blood flow.^5,6 Consequently, digoxin promotes an increase in the force and velocity of myocardial contraction and slows the heart rate.⁵ 

Currently, digoxin is commercialized under different brands, such as Lanoxin™ and Cardoxin^®,⁷ and it is indicated for treating mild to moderate heart failure in adults, increasing myocardial contraction in pediatric patients with heart failure, and controlling the resting ventricular rate in patients with chronic atrial fibrillation.⁵ The recommended dose of digoxin must consider several patient characteristics such as age, body weight, and renal function, which may impact the drug’s blood levels.⁵ 

Side effects of digoxin vary according to the dose administered and include cardiac symptoms such as bradycardia and ventricular rate acceleration, gastrointestinal symptoms such as nausea and vomiting, and manifestations of the central nervous system such as headache and disorientation.⁸ Digoxin has a narrow therapeutic index and, therefore, toxicity may occur.⁶ Patients experiencing toxicity may show signs and symptoms that are similar to adverse reactions but are more severe and frequent.⁵ Nausea, vomiting, visual changes, and life-threatening cardiac arrhythmias may be expected, more often with drug levels above 2 ng/mL.^5,6

Get full prescribing information on Digoxin at MPR

Digoxin in Pulmonary Arterial Hypertension

In PAH, digoxin has been shown to improve cardiac output in patients who present with right ventricular dysfunction, even though the role of cardiac glycosides in the treatment of isolated right heart dysfunction is still unclear.^1,9 A previous study evaluated the short-term effects of digoxin on patients with primary pulmonary hypertension, and it reported a favorable hemodynamic effect in right ventricular failure associated with pulmonary hypertension.⁹ Digoxin may also be used to slow the ventricular rate in PAH patients with atrial tachyarrhythmias.^3,10 

A more recent study has reported no benefit in survival following digoxin use in 275 PAH patients with right ventricular dysfunction after a follow up of 37 years.¹¹ The long-term use of digoxin in PAH is still controversial, requiring further data to assess the clinical benefits and chronic effects that may be expected with continued treatment.¹²

References

1. Cicalini S, Petrosillo N. Conventional therapy. In: Smith KA, Fraidenburg DR, Yuan JXJ, eds. Advances in the Management of Pulmonary Arterial Hypertension. London, UK: Future Medicine Ltd; 2013:40-50. doi:10.2217/EBO.12.480

2. Botelho AFM, Pierezan F, Soto-Blanco B, Melo MM. A review of cardiac glycosides: structure, toxicokinetics, clinical signs, diagnosis and antineoplastic potential. Toxicon. 2019;158:63-68. doi:10.1016/j.toxicon.2018.11.429

3. Fallah F. Recent strategies in treatment of pulmonary arterial hypertension, a review. Glob J Health Sci. 2015;7(4):307-322. doi:10.5539/gjhs.v7n4p307

4. Souza E Souza KFC, Moraes BPT, Paixão ICNP, Burth P, Silva AR, Gonçalves-de-Albuquerque CF. Na+/K+-ATPase as a target of cardiac glycosides for the treatment of SARS-CoV-2 infection. Front Pharmacol. 2021;12:624704. doi:10.3389/fphar.2021.624704

5. Lanoxin. Prescribing information. Concordia Pharmaceuticals Inc; 2016. Accessed May 27, 2022.

6. Fine NM. Drugs for heart failure. MSD Manual Professional Version. Updated November 2020. Accessed May 27, 2022.

7. Digoxin. MedlinePlus. Updated June 15, 2017. Accessed May 27, 2022.

8. Patocka J, Nepovimova E, Wu W, Kuca K. Digoxin: pharmacology and toxicology–a review. Environ Toxicol Pharmacol. 2020;79:103400. doi:10.1016/j.etap.2020.103400

9. Rich S, Seidlitz M, Dodin E, et al. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension. Chest. 1998;114(3):787-792. doi:10.1378/chest.114.3.787

10. Galiè N, Humbert M, Vachiery JL, et al; ESC Scientific Document Group. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-119. doi:10.1093/eurheartj/ehv317

11. Saucedo H, Zayas-Hernandez NG, López-Flores JC, Pulido-Zamudio T. Digoxin effect in mortality associated to right ventricular dysfunction in patients with pulmonary hypertension. Eur Respir J. 2019;54(Suppl 63):PA4751. doi:10.1183/13993003.congress-2019.PA4751

12. Lan NSH, Massam BD, Kulkarni SS, Lang CC. Pulmonary arterial hypertension: pathophysiology and treatment. Diseases. 2018;6(2):38. doi:10.3390/diseases6020038

Reviewed by Kyle Habet, MD, on 5/30/2022.

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Kyle Habet, MD

Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.