Dexamethasone

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Created On: 14/07/2020

Dexamethasone is a synthetic adrenocortical steroid used for its potent anti-inflammatory and immunosuppressive effects in disorders of many organ systems including cancers.

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Introduction

Dexamethasone is a synthetic adrenocortical steroid used for its potent anti-inflammatory and immunosuppressive effects in disorders of many organ systems including cancers.¹

The initial findings from a recent clinical trial (RECOVERY) found dexamethasone to be a lifesaver for critically ill COVID-19 patients. It has shown to reduce mortality by about 1/3^rd and 1/5^th in patients with COVID-19 requiring ventilator and oxygen support, respectively.²

Pharmacological Class: Glucocorticosteroid

Indications

COVID-19: WHO supports the preliminary results from the recovery trial suggesting dexamethasone to be a promising lifesaving drug in patients with severe respiratory complications of COVID-19.²

Other Indications: Dexamethasone is used to treat many disease conditions like primary or secondary adrenocortical insufficiency, rheumatic disorders, exacerbation or as maintenance therapy in patients with collagen diseases, allergic states, dermatologic diseases, ophthalmic diseases, gastrointestinal diseases, respiratory diseases, neoplastic diseases and hematologic disorders, edematous states, meningitis and Cerebral Edema associated with primary or metastatic brain tumor, craniotomy, or head injury.³

Pharmachologic action

Almost 5% of all COVID-19 patients develop acute respiratory distress syndrome (ARDS). It is assumed that inflammation and cytokine storm is involved in the pathophysiological pathway to ARDS in COVID-19 patients. Dexamethasone readily diffuses through the host cell membranes and binds to the glucocorticoid receptor in the cell cytoplasm, which triggers a cascade of reactions suppressing pro-inflammatory cytokines (IL-1, IL-2, IL-6, IL-8, TNF, and IFN-gamma). Dexamethasone also inhibits the over activation of macrophages which is responsible for cytokine storm. Thus dexamethasone exerts both, immuosuppressive as well as anti-inflammatory effects, thereby providing relief to the COVID-19 patients with severe complications like ARDS. ^{4, 5, 6}

Dosage

Dosage as per clinical study on COVID-19 patients¹

6 mg once per day (either by mouth or by intravenous injection) for ten days⁷

Recommended dosage for other indications³

Adult dose: The initial dosage varies from 0.75 to 9 mg a day depending on the disease being treated. The dosage requirements are variable and must be individualized based on the disease severity and patient’s response.
Pediatric dose: The initial dose range is 0.02 to 0.3 mg/kg/day in three or four divided doses (0.6 to 9 mg/m²bsa/day)

Pharmacokinetics

Absorption via the intramuscular route is slower than via the intravenous route. The oral bioavailability of oral dexamethasone ranges between 70%-80%. It is approximately 77% protein bound in plasma. Dexamethasone is 6-hydroxylated by CYP3A4 to 6α- and 6β-hydroxydexamethasone. It is <10% eliminated in urine. Other pharmacokinetic parameters are mentioned below in the table:

Parameters	6 mg oral dexamethasone	4 mg intravenous dexamethasone
AUC(0.∞) (μg l−1 h)	774	626
t1/2 (h)	6.9	9.0
Volume of distribution (l kg−1)	1.09	0.94
Mean residence time (h)	12.4	10.3
Clearance (l h−1)	7.7	6.4

AUC(0,∞), area under the concentration–time curve to infinity; t1/2, terminal half-life.

Contraindications

Contraindicated in³

patients with systemic fungal infections as dexamethasone aggravates systemic fungal infections
patients with known hypersensitivity to any component of dexamethasone

Drug interaction

Aminoglutethimide: Aminoglutethimide may diminish adrenal suppression by dexamethasone
Amphotericin B injection and potassium-depleting agents: When dexamethasone is administered concomitantly with potassium-depleting agents (e.g., amphotericin B, diuretics), patients should be observed closely for development of hypokalemia
Antibiotics: Macrolide antibiotics have been reported to cause a significant decrease in clearance of dexamethasone
Antidiabetics: As dexamethasone may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required
Anticholinesterases: Concomitant use of anticholinesterase agents and dexamethasone may cause severe weakness in patients with myasthenia gravis. When possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating dexamethasone³

Side effects

Common

Infection
Mood fluctuations
Weight gain
Difficulty in sleeping
Nervousness
Acid hypersecretion

Uncommon

Dry skin
Cushing’s syndrome
Periods irregularity
Diabetes
Gastrointestinal bleeding
Puffy face owing to water retention

Very rare

Broken bone
Myopathy
Liver enlargement
Angiodema
Anemia
Chronic heart faliure
Hallucinations
Kaposi's Sarcoma

Precautions

Treatment with dexamethasone should be initiated with the lowest possible dose. When dose reduction in dosage is possible, it should be gradual.
Should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis as they may increase the risk of a perforation
Should be used with caution patients with congestive heart failure, hypertension, or renal insufficiency
Dexamethasone decrease bone formation and increase bone resorption both through their effect on calcium regulation and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age.
Intraocular pressure should be monitored in patients receiving treatment with dexamethasone for >6 weeks as it may elevate the pressure in some individuals

Clinical evidence

Dexamethasone reduces mortality rate by up to 1/3^rd in COVID-19 hospitalized patients with severe respiratory complications: A recent randomized clinical trial tested a range of potential treatments for COVID-19, including low-dose dexamethasone. In this study, 2104 patients were randomized to receive dexamethasone 6 mg once a day (orally or IV) for 10 days. These patients were compared with 4321 patients who were randomized to usual care alone. Among the patients who received usual care alone, 28-day mortality was found to be highest in those who required ventilation (41%), intermediate in those patients who required oxygen only (25%), and lowest among those who did not require any respiratory intervention (13%). Dexamethasone was found to reduce deaths by one-third in ventilated patients (rate ratio 0.65 [95% confidence interval 0.48 to 0.88]; p=0.0003) and by one fifth in other patients receiving oxygen only (0.80 [0.67 to 0.96]; p=0.0021). There was no benefit among those patients who did not require respiratory support (1.22 [0.86 to 1.75]; p=0.14).⁸

Early dexamethasone use may reduce duration of mechanical ventilation and overall mortality in patients with established moderate-to-severe acute respiratory distress syndrome (ARDS): A multicentre, randomized controlled trial in a network of 17 ICUs in teaching hospitals across Spain was performed to evaluate the effects of dexamethasone in ARDS. A total of 277 patients with established ARDS were included in the study and were randomized to 139 patients in the dexamethasone group and 138 in the control group. The primary outcome of the study was the number of ventilator-free days at 28 days while the secondary outcome was all-cause mortality 60 days post-randomization. The mean number of ventilator-free days was higher in the dexamethasone group than in the control group (between-group difference 4·8 days [95% CI 2·57 to 7·03]; p<0·0001). At 60 days, 29 (21%) patients in the dexamethasone group and 50 (36%) patients in the control group had died (between-group difference -15·3% [-25·9 to -4·9]; p=0·0047). There was no significant difference in the proportion of adverse events between the dexamethasone group and control group.¹⁰

References

Pubchem compound id: 5743
WHO welcomes preliminary results about dexamethasone use in treating critically ill COVID-19 patients available through link: https://www.who.int/news-room/detail/16-06-2020-who-welcomes-preliminary-results-about-dexamethasone-use-in-treating-critically-ill-covid-19-patients Last accessed on 01/07/2020
FDA reference id: 45955E
Coronavirus breakthrough: dexamethasone is first drug shown to save lives available through link: https://www.nature.com/articles/d41586-020-01824-5 Last accessed on 01/07/2020
ClinicalTrials.gov Identifier: NCT04327401available through link: https://clinicaltrials.gov/ct2/show/NCT04327401 Last accessed on 01/07/2020
https://medium.com/@shinjieyong/biology-of-dexamethasone-the-first-lifesaving-drug-for-covid-19-357ed9daaf7a Last accessed on 01/07/2020
Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19 available through link: https://www.recoverytrial.net/files/recovery_dexamethasone_statement_160620_v2final.pdf Last accessed on 01/07/2020
Br J Clin Pharmacol. 2014 Jul; 78(1): 78–83.
https://www.drugbank.ca/drugs/DB01234#reference-A188721 Last accessed on 01/07/2020
Lancet Respir Med. 2020 Mar;8(3):267-276. doi: 10.1016/S2213-2600(19)30417-5. Epub 2020 Feb 7.