Dexamethasone

Philip Showalter Hench created dexamethasone for the first time in 1957, and it was authorized for use in medicine in 1958. As a steroid hormone belonging to the glucocorticoid class, dexamethasone shares many similarities with the naturally occurring hormone cortisol, which is generated by the adrenal glands.  Fluorinated, 3-oxa-Delta-(1), Delta-(4), glucocorticoid, 20-oxo, 11beta-hydroxy, and 17alpha-hydroxy steroids are all analogous to dexamethasone [Figure 1]. It originates from hydride of a pregnant woman. It is an artificial component of the glucocorticoid class and is utilized worldwide as an Adrenergic, xenobiotic, antiemetic, antineoplastic, and both an immunosuppressive medication and an analgesic.

Figure 1: The molecular structure of  Dexamethasone

Dexamethasone is used to treat several disorders, including some that closely resemble cortisol, the hormone that humans' adrenal glands normally make, rheumatic issues, several skin conditions, serious asthma, allergies, and long-term obstructive lung disease. It is is a well-known and often used anti-inflammatory medication to address ailments where the immune system of the body fails to operate correctly, causing inflammation and injury to tissue. Dexamethasone inhibits the synthesis of the chemicals that promote inflammation, prostaglandins and cytokines. It is also used to treat cancer patients' nausea and vomiting that is brought on by a side effect of the delivery of chemotherapeutic medications .

Depending on the dosage, dexamethasone's mode of action can be either non-genomic (when taken at high dosages) or genomic (when used at low doses). Dexamethasone acts primarily through the genomic mechanism, which takes longer to act, but it also acts through the non-genomic method, which acts faster and carries a higher risk of side effects. Dextamethasone is a tiny, lipophilic molecule that may diffuse through cell membranes with ease. Once within the target cell's cytoplasm, it binds to glucocorticoid receptors there.

The glucocorticoid receptor (GR) on the cell membrane is bound by dexamethasone (Figure 2). This complex formation causes the corticosteroid to translocate into the cell and go to the nucleus. Here, it binds selectively to several DNA locations in a reversible manner, stimulating (transactivating) and suppressing (trans-repressing) a wide range of gene transcription . Pro-inflammatory cytokines, including interleukin IL-1, IL-2, IL-6, IL-8 , TNF, IFN-gamma, VEGF, and prostaglandins, can be inhibited by it. Notably, five of these correlate with the severity of SARS-CoV-2. Moreover, it has the ability to trigger the manufacture of the glucocorticoid response element, which in turn activates the production of anti-inflammatory cytokines, including IL-10and lipocortin-1 .

Figure 2: The A schematic illustration illustrating the mechanism governing the effects of corticosteroids (generally) on the genomic (continuous arrows) and non-genomic (dashed arrows) aspects of mammalian skeletal muscle fibers

When dexamethasone is taken in large quantities, it binds to the membrane-associated GR on certain cells, including T lymphocytes, which inhibits receptor signaling and the T lymphocyte-mediated immunological response. Focal adhesion kinase (FAK) is activated when the glucocorticoid receptor binds to integrins (Figure 3). Furthermore, a large dosage of dexamethasone also affects how Ca⁺² and Na⁺¹ flow across the cell membrane, which quickly reduces inflammation .

Dextamethasone has been on the World Health Organization's (WHO) Model List of Essential Medicines since 1977. The body's immune system is triggered in the battle against corona infection, resulting in inflammation as the immunological reaction. Nevertheless, every now and then the immune system goes into overdrive (a cytokine storm), causing fetal responses and assaulting the body's cells. The coronavirus exacerbates end-organ illness, coagulopathy, and respiratory failure. The use of Dextamethasone has not been recommended in the early stages of COVID-19 infection since it is associated with immune system suppression . Utilizing them during the initial stages of infection could lead to viral proliferation and undermine the body's natural defenses . According to the results of multiple clinical trials (Figure 3) on CS in people with COVID-19, steroidal therapy is intended to provide the best possible care for SARS-COV-2 persons whose illness worsens.

Figure 3: The A %age-related decrease in the death rate in ARDS linked to COVID-19 with Dexamethasone.

Studies have shown that a major contributing factor to ARDS in COVID-19 patients is the excessive and uncontrollably high production of soluble inflammatory markers termed as "cytokine storm." ARDS, which is characterized by immune cell infiltration in the lungs and hypoxemia, is the main cause of death in COVID-19 cases.In acute respiratory distress syndrome (ARDS), inflammation damages the alveolar-capillary membranes, increasing lung permeability and causing high-protein edematous fluid to leak into the air sacs. Pro-inflammatory cytokines (IL-6, IL-12, interferon-gamma) and chemokines (CXCL10, CCL2) have been linked to the lung inflammation linked to ARDS, according to earlier studies on SARS and MERS . After a cytokine storm, the immune system launches an assault on the body's cells, which in extreme situations of infection can result in multi-organ failure, ARDS, and even death. Because corticosteroids can cause side effects, infections, and other problems when used, it is important to closely evaluate their possible function in suppressing the inflammatory pathway in critical conditions. The generation of pro-inflammatory cytokines by macrophages in lung alveoli is a pathophysiological aspect of COVID-19.  The generation of pro-inflammatory cytokines by macrophages in lung alveoli is a pathogenesis associated with COVID-19. Corticosteroids are used to reduce lung inflammation caused by the host, as this can prevent acute lung damage and ARDS. Patients with COVID-19 who received a brief course of methylprednisolone showed improved clinical results, according to one small randomized controlled trial . Synthetic glucocorticoids like dexamethasone have been used in the past to treat autoimmune illnesses such arthritis, asthma, and allergic responses. It works by obstructing the two inflammatory pathways—vasodilation and immune cell migration. Dexamethasone penetrates the membrane of the host cell and attaches itself to glucocorticoid receptors found in the cytoplasm of the cell. This sets off a chain reaction of immune cell reactions that results in the pro-inflammatory suppression cytokines IL-1, IL-2, IL-6, IL-8, TNF, and IFN-γ by reducing gene transcription. Five of these pro-inflammatory cytokines are linked to the advancement of COVID-19. Additionally, it suppresses neutrophil adherence to endothelial cells, blocking the release of lysosomal enzymes and inhibiting chemotaxis at the site of inflammation. IL-10 is an anti-inflammatory cytokine mediator that is expressed at higher levels in the human genome. Additionally, they prevent the activation of macrophages, which are one of the main causes of the cytokine storm in COVID-19-infected people (Figure 4).

Figure 4: Cytokine storm in COVID-19 related ARDS and action of dexamethasone.

While dexamethasone has shown to be a successful treatment for COVID-19, using dexamethasone is linked to certain serious adverse effects. The adverse effects of dexamethasone that are most frequently associated with anxiety, weight gain, fluid retention, hormonal imbalance, and irregular sleep patterns.  Dexamethasone is a flexible drug with a wide range of therapeutic uses, to sum up. It is an essential tool in the treatment of many illnesses due to its capacity to reduce inflammation and alter the immune system. It should, however, be taken sparingly because excessive or prolonged use can have negative effects. The astonishing effect that dexamethasone has played in lowering mortality during the COVID-19 pandemic highlights the significance of this medication in contemporary medicine. With more research, dexamethasone's potential uses and advantages might increase, providing patients with a range of illnesses with hope.