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(Updated Feb. 4, 2021)
Benefits and Risks
Dexamethasone is recommended for treatment of patients with severe or critical cases of COVID-19 as it can help with inflammation mediated lung injury and reduce progression to respiratory failure and death (1). It can have broad effects on adaptive immunity, which may be integral to covid-19 immunopathology (2). Severe patients include those with O2 sat <90% on room air, respiratory rate >30, signs of severe respiratory distress. Critical patients include those with acute respiratory distress syndrome, sepsis, septic shock, or other conditions that would normally require life-sustaining therapies. (1,3) Subgroup analysis found no benefit among adults >70 years in RECOVERY trial. (4,5) Older age- aged <70 years receiving dexamethasone, 129/1141 died by day 28 (11.3%) compared to 428/2504 patients receiving standard of care (16.5%; [RR 0.64; 0.53-0.78]; ARR 5.2%, NNT 20). For aged 70 <80, mortality rate at day 28 was 155/469 (33.0%) for those randomized to dexamethasone, compared to 271/859 for those receiving standard of care alone (31.5%). RR 1.03 (0.84 1.25) aged 80, mortality rate at day 28 was 198/494 (40.1%) for those receiving dexamethasone compared to 411/958 (42.9%) receiving standard of care alone. RR 0.89 (0.75 – 1.05).
Mechanism of Action
Dexamethasone is a long acting synthetic adrenocortical steroid which decreases inflammation by suppressing neutrophil migration, decreasing production of inflammatory mediators and reversing increased capillary permeability (1). Binds with high affinity to cytoplasmic glucocorticoid receptor (GR). GRs, in the absence of ligand, are primarily in the cell cytoplasm as part of hetero-oligomeric complexes containing heat shock proteins 90, 70 and 50, and other proteins. After binding to its agonist ligand, the GR undergoes conformational changes, dissociates from the heat shock proteins, homodimerizes, and translocates into the nucleus through the nuclear pore via an active process. There, the ligand-activated GR directly interacts with DNA sequences, the glucocorticoid-responsive elements (GREs), in the promoter regions of target genes, or with other transcription factors via protein–protein interactions, indirectly influencing the activity of these factors on their target genes. (6,7)
Dose in Older Adults
No dose adjustment necessary for elderly patients but it is still important to be cautious in the older population, so use the lowest possible dose. Dosage form: tablet – 0.5 mg, 0.75 mg, 2 mg and 4 mg. Dose in renal impairment: no dose adjustment necessary. Dose in hepatic impairment: no dose adjustment necessary. (1) For specific COVID-19 management, the recommended dose is 6 mg once daily for up to 10 days. This is based off of a large randomized control trial done in England which showed decreased 28 day mortality for inpatients receiving respiratory support (35% decrease in ventilated patients and 20% in patients on oxygen supplementation). (3)
Administration Considerations: Take large doses with meals and take antacids between meals to prevent peptic ulcers (8).
Adverse Effects (frequency not defined) (8)
Precautions (1,9) Adrenal suppression- can cause hypercortisolism or suppression of the HPA axis, especially in patients who have been receiving high doses for prolonged periods of time. Suppressed HPA axis could lead to adrenal crisis.
Need to pay special attention to patients who are transferred from systemic corticosteroids to inhaled products due to adrenal insufficiency or withdrawal from steroids. Adrenal insufficiency is particularly worrisome for asthmatic patients and can lead to fatalities.
Immunosuppression- prolonged use of corticosteroids may increase the incidence of secondary infection, cause activation of latent infections, mask acute infection (including fungal infections), prolong or exacerbate viral infections or limit response to killed or inactivated vaccines. Exposure to chickenpox or measles should be avoided. It should not be used to treat ocular herpes simplex. It should not be used to treat cerebral malaria, fungal infections or viral hepatitis. Close observation is required in patients with latent or reactivated TB (restrict use in active TB). Use with extreme caution in patients with Strongyloides infection due to hyperinfection, dissemination and fatalities.
Prolonged treatment with corticosteroids has been associated with Kaposi sarcoma. Acute myopathy has been reported with high dose corticosteroids, usually in patients with neuromuscular transmission disorders.
Perineal burning, tingling, pruritis has been reported with IV administration (usually females and high doses with rapid administration- will resolve in less than 1 minute).
May cause psychiatric disturbances, including depression, euphoria, insomnia, mood swings, personality changes, severe depression and psychotic manifestations. Pre-existing psychiatric conditions may be exacerbated.
Use with caution in people with heart failure, hypertension, myocardial infarction, diabetes, GI disease, head injury, cirrhosis, myasthenia gravis, cataracts, glaucoma, osteoporosis, renal impairment, seizure disorder, systemic sclerosis, thyroid disease. (1,9)
Contraindications: Hypersensitivity to dexamethasone or its components. Allergenic cross reactivity for corticosteroids. Systemic fungal infections. Administration of live virus vaccines in patients receiving immunosuppressive corticosteroid doses. (1,9)
Monitoring Parameters: Hemoglobin, occult blood loss, blood pressure, serum potassium, glucose, BMD, IOP if systemic use >6 weeks, HPA axis suppression (1).
Discontinuation/withdrawal considerations: Rapid reduction in dose can lead to adrenal insufficiency and therefore, gradual tapering is recommended. Can also get increased intracranial pressure with withdrawal of therapy. (9)
Pharmacodynamics: Genomic effects: After binding and activation by dexamethasone, the glucocorticoid receptor (GR) binds glucocorticoid response elements in the promoter region of target genes, and activates transcription (transactivation) or inhibits the transactivating function of transcription factors (transrepression), such as activator protein 1 and nuclear factor kappa B (NF-B) [10,11]. Transrepression appears to be due to the interaction between the activated GC receptor and transcription factors resulting in reduced expression of pro-inflammatory genes . Transactivation is responsible for some anti-inflammatory effects through activation of anti-inflammatory genes, such as interleukin (IL)-10, annexin 1 and inhibitor of NF-B , as well as for GC side effects due to enhanced expression of genes involved in metabolic processes [14,15] Beneficial anti-inflammatory effects are mediated to a major extent via transrepression, while many side effects are due to transactivation. 
Nongenomic effects: Thought to be mediated by affecting the physicochemical property of cell membranes, or through binding intracellular or membrane-bound GRs . Nongenomic GC activities have been observed in cellular systems, such as early GC effects on inflammatory signal transduction cascades (including mitogen-activated protein kinases (MAPK)), calcium influx, neutrophil degranulation, phagocytosis by macrophages, cellular adhesion and actin cytoskeleton).(17-20) In addition, glucocorticoids may interfere with T-cell receptor (TCR) signalling through selective targeting of membrane-bound glucocorticoid receptors. (21)
Pharmacokinetic considerations in older adults: no differences in bioavailability or excretion in older adults (65 years of age) and younger adults. No dose adjustments necessary based on age.
Absorption: Bioavailability 61% to 81%.(22-24) T is 1.2 to 2.7 hours (22,24,25) .
Effects of food: No effect on AUC; C decreased by 23%. (26)
Distribution: 75% protein binding (27); Vd: 0.59 to 1.15 L/kg (22-24)
Metabolism: 6-hydroxylation is the major metabolic pathway of dexamethasone, and hydroxylation both at the 6 and at the 6 position have shown to be CYP3A4-mediated in human liver microsomes in vitro (28,29).
Elimination half-life: 3.1 to 6.9 hours (22-25)
Excretion: ~ 9% excreted unchanged in urine, with glucuronides present in small amounts (28,30)
Pharmacokinetics in renal impairment: In a study of six patients with normal renal function and six patients with chronic kidney disease, there was no significant difference between the groups with respect to clearance, volume of distribution or half-life of dexamethasone (31).
Pharmacokinetics in hepatic impairment: No available evidence
Clinically Significant Drug Interactions
CYP3A4 inducers: dexamethasone concentrations. Phenobarbital increased the clearance of dexamethasone by 88% and decreased its half-life by 44% in 11 patients with asthma (32). Phenytoin increased the clearance of dexamethasone 3-fold in a study of 16 patients (33)
CYP3A4 inhibitors: dexamethasone concentrations: Itraconazole increased the AUC of oral and intravenous dexamethasone 3.7-fold and 3.3-fold, respectively. (34)
Dexamethasone induces CYP3A4 in vitro, but clinical relevance uncertain. In a study of 12 healthy volunteers, dexamethasone 8 mg twice a day for days increased CYP3A4 activity by an average of 25.7% using the erythromycin breath test. (35) CYP3A4 induction was inversely correlated with the baseline erythromycin breath test, suggesting that induction could be most important in subjects with low baseline activity of CYP3A4. (35)
In a study of 10 healthy volunteers, dexamethasone 1.5mg/kg for 4 days did not have significant effects on triazolam pharmacokinetics. (36). In a study of 61 patients with relapsed or refractory multiple myeloma or non-Hodgkin’s lymphoma enrolled and randomized to receive 3 cycles of bortezomib, dexamethasone 40mg daily on day 1-4 and 9-12 during bortezomib cycle 3 had no effect on the AUC of bortezomib. In contrast, rifampin reduced the AUC of bortezomib by ~ 45%. (37)
May increase risk of gastrointestinal bleeding and ulcers with NSAIDS or warfarin (1).
Dexamathasone [Internet]. [cited 2020 Oct 22]. Available from: https://www.micromedexsolutions.com/micromedex2/librarian/CS/8E7EF3/ND_PR/evidencexpert/ND_P/evidencexpert/DUPLICATIONSHIELDSYNC/5EC0B6/ND_PG/evidencexpert/ND_B/evidencexpert/ND_AppProduct/evidencexpert/ND_T/evidencexpert/PFActionId/evidencexpert.DoIntegratedSearchSearchTerm=Dexamethasone&fromInterSaltBase=true&false=null&false=null&=null#