Could spironolactone treat COVID-19-related pneumonia and pulmonary fibrosis?

By Dr. Liji Thomas, MDJan 27 2021

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), there have been over 100 million documented infections and over 2.1 million deaths. The struggle to contain the spread of the virus continues, exacerbated by the uncertainty surrounding its clinical manifestations.

Effective antiviral therapeutics have been hard to come by, and most governments have pinned their faith to vaccines instead. Even for those who survive severe or critical COVID-19, long-term complications may arise, among the more serious ones being pulmonary fibrosis.

Study: COVID-19—The Potential Beneficial Therapeutic Effects of Spironolactone during SARS-CoV-2 Infection. Image Credit: Alexander Khoruzhenko / Shutterstock

A new paper published in the journal Pharmaceuticals describes the potential of the drug spironolactone, a potassium-sparing diuretic and anti-androgen, in preventing or alleviating the severity of COVID-19 pneumonia, and in preventing pulmonary fibrosis.

Spironolactone

Spironolactone is a widely used safe anti-hypertensive and anti-androgenic drug. It antagonizes mineralocorticoid receptors (MRs). It also affects the renin–angiotensin–aldosterone system (RAAS) and angiotensin-converting enzyme 2 (ACE2) expression, while reducing the activity of transmembrane serine protease 2 (TMPRSS2).

RAAS activity

Its activity on the RAAS via its suppression of mineralocorticoid receptor activity reduces collagen synthesis and could help correct the perturbed RAAS signaling in COVID-19-associated pneumonia. Aldosterone, the final step of the RAAS, mediates 90% of all adrenal mineralocorticoid activity, being crucial in its regulation of sodium, potassium and body fluids.

The synthesis of aldosterone is mediated by the CYP11B2 gene, in response to stimulation by angiotensin II and an increase in extracellular potassium ion concentrations. Mineralocorticoid receptors are found in a wide range of tissues, enabling aldosterone to have extensive effects on the body, rather than being simply a mineralocorticoid kidney hormone.

In particular, aldosterone mediates inflammation and modulates energy metabolism, including collagen synthesis, in many tissues.

Anti-androgenic activity

Spironolactone also inhibits the androgen-dependent expression of TMPRSS2, which mediates viral-cell membrane fusion and viral entry. This protease reacts to androgens as well.

Its anti-androgenic action may also be key in its ability to prevent acute lung injury (ALI) in COVID-19. This is all the more since the male sex, obesity, and hypertension are all known to be risk factors for an adverse outcome in COVID-19. While both men and women have an equal risk of SARS-CoV-2 infection, men are at double the risk of mortality from COVID-19 relative to women.

Again, male pattern hair loss among hospitalized COVID-19 patients seems to support the association of severity with androgen levels. Fully two-thirds of COVID-19 patients in one study had androgenetic alopecia. Individuals of African-American origin also have 6-16 times the number of deaths relative to patients of other ethnicities.

Anti-inflammatory activity

Spironolactone has the potential to modulate inflammatory cytokine release, including TNF-α and MCP-1, IL-2, IL-6, IL-15 and granulocyte-macrophage colony-stimulating factor (GM-CSF). This is important in view of the hyperinflammatory state associated with severe COVID-19, which often leads to acute respiratory distress syndrome (ARDS) in this condition.

Such patients show exaggerated inflammatory responses (‘cytokine storms’), with a rise in proinflammatory Th17 T cells and cytotoxic CD8+ T cell activation. Spironolactone could prevent these polarizing changes.

Anti-fibrotic activity

Some earlier studies have suggested that aldosterone is among the “master regulators of extracellular matrix remodeling.” This hormone affects the extracellular matrix and prevents fibrosis via its effects on collagen synthesis. Spironolactone deserves study as a safe potential inhibitor of pulmonary fibrosis in COVID-19.

Antioxidant protection

Finally, spironolactone has antioxidant activity, which could protect the tissues against the oxidative stress triggered by SARS-CoV-2. This could have an important benefit in preventing adverse outcomes in COVID-19 infection.

Spironolactone in heart failure

Spironolactone has been approved by the US Food and Drug Administration (FDA) for the treatment of heart failure due to several causes. It can reduce both the number of deaths and the episodes of hospitalization in such patients. Some studies indicate that it may reduce chronic heart fibrosis, while treating hypertension in heart failure.

Spironolactone could also prevent pulmonary fibrosis; however, only animal studies are available to support this claim.

Spironolactone in COVID-19

It is thought that both the host cell receptor, ACE2, and TMPRSS2, on the cell membrane, are required for viral entry into the cells.  The expression of both these proteins is at its highest level on type 2 pneumocyte cells of the nasal cavity, which could explain the clinical features of COVID-19.

The excessive ACE2 expression in hypertensive and obese patients, and high TMPRSS2 expression in individuals who have high androgen levels, are factors that increase the risk for COVID-19.

Spironolactone, being a mineralocorticoid receptor antagonist and antiandrogen, has multiple helpful actions in COVID-19. Its effects on the RAAS could help correct the perturbed RAAS signaling in COVID-19-associated pneumonia.

In this context, spironolactone and its prodrug, potassium canrenoate, may have important advantages in the treatment of patients with COVID-19 pneumonia via its activity on androgen receptors, its aldosterone inhibition, its suppression of fibrotic activity, and anti-inflammatory actions. Its progestogenic actions are a significant barrier to its widespread acceptance among male patients.

Despite this, “it seems to be an ideal candidate drug not only for combating the severe and long-term complications of severe SARS-CoV-2 infection, but also for the prophylactic and early treatment of COVID-19.”