Pharmacology of Dexamethasone

Introduction/Overview

Dexamethasone is a potent synthetic glucocorticoid, a cornerstone agent in the therapeutic arsenal for managing a wide spectrum of inflammatory, autoimmune, allergic, and neoplastic conditions. As a member of the corticosteroid class, its clinical utility stems from its profound anti-inflammatory and immunosuppressive properties, which significantly exceed those of the endogenous hormone cortisol. The introduction of synthetic glucocorticoids like dexamethasone represented a pivotal advancement in medical therapeutics, enabling the modulation of immune and inflammatory pathways with a potency and duration of action not achievable with natural steroids. Its importance is further underscored by its role in critical care, oncology, and neurology, where it can be life-saving.

The clinical relevance of dexamethasone extends from routine outpatient management of allergic reactions to emergent treatment of cerebral edema and septic shock. Its ability to suppress inflammation rapidly makes it indispensable in acute settings, while its utility in chronic conditions, though limited by long-term toxicity, remains significant. A landmark demonstration of its impact was its proven mortality benefit in patients with severe COVID-19 requiring respiratory support, reaffirming its vital role in modern medicine. Understanding its pharmacology is therefore essential for the safe and effective application of this powerful, double-edged therapeutic.

Learning Objectives

• Describe the molecular mechanism of action of dexamethasone, including its genomic and non-genomic pathways, and its interaction with the glucocorticoid receptor.
• Outline the pharmacokinetic profile of dexamethasone, including its absorption, distribution, metabolism, excretion, and the implications of its long half-life on dosing regimens.
• Identify the major therapeutic indications for dexamethasone, distinguishing between FDA-approved uses and common evidence-based off-label applications.
• Analyze the spectrum of adverse effects associated with dexamethasone therapy, categorizing them by frequency and severity, and explain the principles for mitigating these risks.
• Evaluate special population considerations, including use in pregnancy, pediatrics, geriatrics, and patients with organ impairment, to guide individualized therapy.

Classification

Dexamethasone is classified within multiple hierarchical systems based on its chemical structure, pharmacological action, and therapeutic use.

Therapeutic and Pharmacological Classification

Primarily, dexamethasone is classified as a corticosteroid or glucocorticoid. It is not a mineralocorticoid, as it exhibits negligible salt-retaining activity. Within the glucocorticoid class, it is categorized as a long-acting synthetic steroid. This classification is based on its biological half-life, which exceeds 36 hours, in contrast to short-acting agents like hydrocortisone (8-12 hours) or intermediate-acting agents like prednisone (18-36 hours). Therapeutically, it falls under several broad categories: anti-inflammatory agent, immunosuppressant, antiemetic (particularly in chemotherapy-induced nausea and vomiting protocols), and diagnostic agent (in the dexamethasone suppression test for Cushing’s syndrome).

Chemical Classification

Chemically, dexamethasone is a fluorinated synthetic pregnane derivative. Its systematic name is 9-fluoro-11β,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione. The key structural modifications from the endogenous cortisol (hydrocortisone) that confer its enhanced glucocorticoid potency and prolonged duration of action include:

• Fluorination at the 9α position: This significantly increases glucocorticoid receptor binding affinity and anti-inflammatory potency.
• Introduction of a double bond between C-1 and C-2: This enhances glucocorticoid activity relative to mineralocorticoid activity.
• Methylation at the 16α position: This modification further abolishes mineralocorticoid activity, making dexamethasone a “pure” glucocorticoid without significant sodium-retaining effects.

These structural alterations result in a compound with a glucocorticoid receptor binding affinity approximately 7 to 10 times greater than prednisolone and 25 to 30 times greater than cortisol. Its anti-inflammatory potency is similarly magnified, being roughly 25-30 times more potent than hydrocortisone on a milligram-per-milligram basis.

Mechanism of Action

The therapeutic and adverse effects of dexamethasone are mediated primarily through its interaction with the intracellular glucocorticoid receptor (GR), leading to modulation of gene transcription. Effects can be broadly categorized into genomic (slow, occurring over hours) and non-genomic (rapid, occurring within minutes) pathways.

Receptor Interaction and Genomic Mechanisms

Dexamethasone, being highly lipophilic, passively diffuses across the plasma membrane into the cytoplasm of target cells. In the cytoplasm, it binds with high affinity to the ubiquitously expressed glucocorticoid receptor-α (GRα), which is normally complexed with chaperone proteins including heat shock protein 90 (Hsp90) and immunophilin. Upon ligand binding, a conformational change occurs in the GR, causing dissociation of the chaperone proteins. This exposes nuclear localization signals, allowing the activated dexamethasone-GR complex to translocate into the nucleus.

Within the nucleus, the complex exerts its effects via two principal genomic mechanisms:

1. Transactivation: The dimerized dexamethasone-GR complex binds to specific DNA sequences known as glucocorticoid response elements (GREs) located in the promoter regions of target genes. This binding recruits co-activators and the transcriptional machinery, leading to increased transcription of anti-inflammatory proteins. Key proteins upregulated via transactivation include:
   • Annexin-1 (lipocortin-1): Inhibits phospholipase A₂, reducing the release of arachidonic acid and subsequent synthesis of pro-inflammatory prostaglandins and leukotrienes.
   • IκBα: The inhibitor of nuclear factor kappa B (NF-κB). Increased IκBα sequesters NF-κB in the cytoplasm, preventing its nuclear translocation and the transcription of numerous pro-inflammatory cytokines (e.g., TNF-α, IL-1, IL-2, IL-6).
   • Glucocorticoid-induced leucine zipper (GILZ): Inhibits the actions of transcription factors like AP-1 and NF-κB.
2. Transrepression: This mechanism is considered primarily responsible for the therapeutic anti-inflammatory effects. The dexamethasone-GR complex can interfere with the activity of pro-inflammatory transcription factors such as NF-κB and activator protein-1 (AP-1) through direct protein-protein interactions. This does not require DNA binding by the GR and results in the repression of genes encoding cytokines, chemokines, adhesion molecules, and inflammatory enzymes (e.g., cyclooxygenase-2, inducible nitric oxide synthase).

Cellular and Systemic Effects

The molecular actions translate into broad cellular and systemic pharmacological effects:

• Anti-inflammatory: Suppresses all phases of inflammation (vascular, exudative, proliferative). It stabilizes lysosomal membranes, reduces capillary permeability, inhibits leukocyte migration and phagocytosis, and suppresses the release of histamine and kinins.
• Immunosuppressive: Causes lymphocytopenia (particularly T-cells), inhibits T-cell proliferation and cytokine production, and reduces antibody production by B-cells. It also induces apoptosis in immature and activated lymphocytes.
• Metabolic Effects: Promotes gluconeogenesis, reduces glucose utilization in peripheral tissues, and antagonizes insulin action, leading to hyperglycemia. It stimulates lipolysis and redistributes body fat. It also promotes protein catabolism in muscle, skin, and bone, leading to muscle wasting and thinning of the skin.
• Cardiovascular: Enhances vascular sensitivity to catecholamines (permissive effect), supporting vascular tone and blood pressure.
• Central Nervous System: Can affect mood, behavior, and appetite. It is critical for the feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis.

Non-Genomic Mechanisms

Some effects of dexamethasone, particularly at very high doses, occur too rapidly to be explained by gene transcription. These non-genomic effects may involve:

• Interaction with membrane-associated GRs or other receptors.
• Non-specific interactions with cellular membranes, affecting ion channels and signaling cascades.
• Inhibition of phospholipase A₂ via annexin-1 induction on a faster timescale.

These rapid mechanisms may contribute to the immediate benefits seen in conditions like acute airway obstruction or cerebral edema.

Pharmacokinetics

The pharmacokinetic profile of dexamethasone is characterized by excellent oral bioavailability, a large volume of distribution, a long half-life, and hepatic metabolism, which collectively inform its dosing strategies and duration of action.

Absorption

Dexamethasone is well absorbed from the gastrointestinal tract after oral administration, with a bioavailability ranging from 60% to 85%. Absorption is rapid, with peak plasma concentrations (C_max) typically achieved within 1 to 2 hours post-ingestion. The presence of food does not significantly impair its absorption, though it may slightly delay the time to C_max. When administered intramuscularly or intravenously, absorption is complete and rapid, with intravenous administration providing immediate systemic availability. Topical, ophthalmic, and intra-articular formulations provide local effects with variable systemic absorption depending on the site, surface area, and integrity of the barrier.

Distribution

Dexamethasone is widely distributed throughout body tissues due to its high lipophilicity. Its volume of distribution is approximately 0.8 to 1.2 L/kg, indicating extensive tissue penetration. It readily crosses the blood-brain barrier, a property crucial for its use in treating cerebral edema and central nervous system malignancies. It also crosses the placenta and is excreted in breast milk. In plasma, approximately 70-77% of dexamethasone is bound to proteins, primarily albumin. The binding is relatively weak and non-specific compared to cortisol’s binding to corticosteroid-binding globulin (transcortin), meaning a larger proportion of dexamethasone exists in the free, pharmacologically active form.

Metabolism

Dexamethasone undergoes extensive hepatic metabolism, primarily via the cytochrome P450 (CYP) enzyme system, with CYP3A4 being the major isoform involved. The primary metabolic pathways include hydroxylation at the 6β-position and reduction of the 3-keto and 20-keto groups, followed by conjugation with sulfate or glucuronic acid. These processes render the metabolites water-soluble and pharmacologically inactive. The metabolism of dexamethasone is saturable at high doses, which can lead to non-linear pharmacokinetics. Hepatic enzyme inducers (e.g., phenobarbital, phenytoin, rifampin) can significantly increase its clearance, potentially leading to therapeutic failure, while inhibitors may increase exposure and toxicity.

Excretion

The metabolites of dexamethasone are eliminated predominantly by renal excretion. Less than 10% of an administered dose is excreted unchanged in the urine. The total body clearance is relatively low, ranging from 0.11 to 0.21 L/h/kg. In patients with renal impairment, the elimination of inactive metabolites may be delayed, but this does not typically necessitate dose adjustment for dexamethasone itself, as the parent drug clearance is primarily hepatic. Biliary excretion and fecal elimination account for a minor portion of total elimination.

Half-life and Dosing Considerations

The plasma elimination half-life (t_1/2) of dexamethasone is long, ranging from 36 to 54 hours. This is a reflection of its low clearance and extensive tissue distribution. The biological half-life, which reflects the duration of its pharmacological effect, is even longer, often exceeding 72 hours. This prolonged action has critical implications for dosing:

• Once-daily dosing is often sufficient for many chronic conditions due to sustained receptor occupancy.
• The long t_1/2 allows dexamethasone to produce sustained suppression of the HPA axis, even with once-daily morning dosing intended to mimic the diurnal rhythm.
• When used for antiemetic prophylaxis in chemotherapy, a single dose or a short course can provide coverage for delayed nausea and vomiting.
• The prolonged effect necessitates careful tapering when discontinuing therapy after more than 2-3 weeks of use to avoid adrenal insufficiency.

The relationship between dose, concentration, and effect is complex. While many anti-inflammatory and immunosuppressive effects follow a graded dose-response, some effects (like HPA axis suppression) occur even at low doses. The therapeutic index is narrow for chronic use, as many adverse effects are extensions of its pharmacological actions.

Therapeutic Uses/Clinical Applications

Dexamethasone’s potent glucocorticoid activity lends itself to a diverse array of clinical applications, spanning nearly every medical specialty. Its uses can be categorized by the primary pharmacological effect being exploited.

Approved Indications

The FDA-approved indications for dexamethasone are extensive and include:

• Endocrine Disorders: Primary or secondary adrenal insufficiency (in conjunction with a mineralocorticoid), congenital adrenal hyperplasia, non-suppurative thyroiditis, and hypercalcemia associated with cancer.
• Rheumatic Disorders: As adjunctive therapy for short-term administration in acute gouty arthritis, acute rheumatic carditis, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, and systemic lupus erythematosus during acute exacerbations.
• Collagen Vascular Diseases: During exacerbations or as maintenance therapy in systemic dermatomyositis and systemic lupus erythematosus.
• Dermatological Diseases: Pemphigus, severe erythema multiforme (Stevens-Johnson syndrome), exfoliative dermatitis, severe psoriasis, and contact dermatitis.
• Allergic States: Control of severe or incapacitating allergic conditions refractory to conventional treatment, such as seasonal or perennial allergic rhinitis, bronchial asthma, serum sickness, and drug hypersensitivity reactions.
• Ophthalmic Diseases: Severe acute and chronic allergic and inflammatory processes involving the eye and its adnexa, such as allergic conjunctivitis, keratitis, optic neuritis, and sympathetic ophthalmia.
• Respiratory Diseases: Symptomatic sarcoidosis, berylliosis, fulminating or disseminated pulmonary tuberculosis (with appropriate antituberculous chemotherapy), and aspiration pneumonitis.
• Hematologic Disorders: Idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, and as part of combination chemotherapy for acute lymphoblastic leukemia and lymphomas.
• Neoplastic Diseases: For palliative management of leukemias and lymphomas in adults and acute leukemia in children. It is also a critical component of regimens for chemotherapy-induced nausea and vomiting (CINV) and for managing complications like cerebral edema from metastatic brain tumors.
• Edematous States: To induce diuresis or remission of proteinuria in nephrotic syndrome (without uremia) of the idiopathic type or due to lupus erythematosus.
• Gastrointestinal Diseases: To tide patients over critical periods of ulcerative colitis and Crohn’s disease.
• Neurological Conditions: Cerebral edema associated with primary or metastatic brain tumors, craniotomy, or head injury.
• Miscellaneous: Tuberculous meningitis with subarachnoid block or impending block (with antituberculous drugs), diagnostic testing of adrenal cortical hyperfunction (dexamethasone suppression test).

Common Off-Label Uses

Beyond its official labeling, dexamethasone is widely used based on strong clinical evidence for several conditions:

• Antiemetic in Chemotherapy: It is a cornerstone of antiemetic regimens for both highly emetogenic and moderately emetogenic chemotherapy, often combined with a 5-HT₃ receptor antagonist and a neurokinin-1 (NK1) receptor antagonist. A single dose of 8-20 mg IV is standard.
• Septic Shock: Based on the ADRENAL and APROCCHSS trials, low-dose dexamethasone (e.g., 6 mg IV daily for up to 10 days) may be considered in adults with septic shock who require ongoing vasopressor support, as it may reduce time to shock reversal and mortality.
• COVID-19: The RECOVERY trial demonstrated that dexamethasone 6 mg orally or IV once daily for up to 10 days reduced mortality in hospitalized patients with COVID-19 who required supplemental oxygen or mechanical ventilation.
• Perioperative Nausea and Vomiting (PONV) Prophylaxis: A single dose (4-5 mg IV) is effective for preventing PONV, particularly in high-risk patients.
• Acute Mountain Sickness (AMS) and High-Altitude Cerebral Edema (HACE): Dexamethasone (4 mg every 6 hours) is used for prevention and treatment of AMS and as a primary treatment for HACE.
• Spinal Cord Compression from Metastatic Cancer: High-dose dexamethasone (e.g., a 10 mg IV bolus followed by 4-6 mg every 6 hours) is a standard initial therapy to reduce edema and preserve neurological function while definitive treatment (surgery or radiation) is arranged.
• Croup (Laryngotracheobronchitis): A single dose (0.15-0.6 mg/kg, typically 0.6 mg/kg) is highly effective in reducing symptoms and avoiding hospital admission.
• Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): Short courses may be used as an alternative to prednisone, though evidence specifically for dexamethasone is less robust.
• Antenatal Corticosteroid Therapy: While betamethasone is the preferred agent, dexamethasone is used in some protocols to promote fetal lung maturation in threatened preterm birth.

Adverse Effects

The adverse effect profile of dexamethasone is a direct consequence of its extensive glucocorticoid receptor-mediated actions and is generally dose- and duration-dependent. Effects range from common, mild, and reversible to severe, life-threatening, and permanent.

Common Side Effects

These effects are frequently observed even with short-term or moderate-dose therapy:

• Endocrine/Metabolic: Hyperglycemia (steroid-induced diabetes), insulin resistance, weight gain with central obesity, and fluid retention (though less than with mineralocorticoids).
• Neuropsychiatric: Insomnia, mood changes (euphoria, irritability, anxiety), cognitive impairment, and increased appetite.
• Gastrointestinal: Dyspepsia, nausea, and increased risk of peptic ulcer disease, particularly when combined with NSAIDs.
• Musculoskeletal: Proximal muscle weakness (steroid myopathy), muscle wasting.
• Dermatological: Skin thinning, easy bruising (purpura), impaired wound healing, striae, and facial flushing.
• Ophthalmic: Posterior subcapsular cataracts and increased intraocular pressure (glaucoma) with prolonged use.

Serious and Rare Adverse Reactions

Long-term or high-dose therapy significantly increases the risk of these more severe complications:

• Infections: Profound immunosuppression increases susceptibility to bacterial, viral (e.g., herpes simplex, varicella-zoster), fungal, and opportunistic infections (e.g., Pneumocystis jirovecii pneumonia). It can also mask typical signs of infection like fever and inflammation.
• Cardiovascular: Hypertension, accelerated atherosclerosis, dyslipidemia, and increased risk of thromboembolic events.
• Musculoskeletal: Osteoporosis and atraumatic fractures (vertebral and femoral neck), osteonecrosis (avascular necrosis) of the femoral or humeral heads, and growth suppression in children.
• Endocrine: Suppression of the hypothalamic-pituitary-adrenal (HPA) axis, leading to adrenal insufficiency upon withdrawal. Cushingoid habitus (moon face, buffalo hump, truncal obesity).
• Gastrointestinal: Pancreatitis, intestinal perforation (particularly in patients with inflammatory bowel disease), and fatty liver.
• Neuropsychiatric: Severe psychiatric disturbances including psychosis, delirium, and major depression. Pseudotumor cerebri (benign intracranial hypertension), especially upon withdrawal in children.
• Ophthalmic: Exophthalmos in susceptible individuals.
• Withdrawal Syndrome: Upon abrupt cessation after prolonged therapy, symptoms may include fatigue, weakness, arthralgias, myalgias, fever, nausea, orthostatic hypotension, and hypoglycemia. An acute adrenal crisis can be fatal.

Black Box Warnings and Contraindications

Dexamethasone carries several black box warnings, the strongest FDA-mandated safety alerts:

1. Corticosteroids may cause serious and fatal infections. Administration of live or live-attenuated vaccines is contraindicated. Close observation is required in patients with latent tuberculosis or tuberculin reactivity.
2. Prolonged use may cause hypercortisolism (Cushing’s syndrome) and HPA axis suppression. Withdrawal must be gradual to allow for recovery of adrenal function.
3. Corticosteroids may mask signs of infection and new infections may appear.
4. Decreased bone density may occur with prolonged use.
5. Rare instances of anaphylactoid reactions have occurred.

There are no absolute contraindications in life-threatening situations. Relative contraindications include systemic fungal infection, known hypersensitivity to dexamethasone or its components, and administration of live virus vaccines. Intrathecal administration is contraindicated due to the risk of severe adverse events, including death.

Drug Interactions

Dexamethasone participates in numerous pharmacokinetic and pharmacodynamic drug interactions, which can alter its efficacy or toxicity, or the effects of concomitant medications.

Major Pharmacokinetic Interactions

• Enzyme Inducers: Drugs that induce CYP3A4, such as phenobarbital, phenytoin, carbamazepine, rifampin, and St. John’s wort, can significantly increase the hepatic metabolism and clearance of dexamethasone. This can lead to subtherapeutic glucocorticoid levels and potential therapeutic failure, necessitating a dose increase. Conversely, upon discontinuation of the inducer, dexamethasone levels may rise, increasing toxicity risk.
• Enzyme Inhibitors: Potent CYP3A4 inhibitors like clarithromycin, itraconazole, ketoconazole, ritonavir, and nefazodone can decrease dexamethasone metabolism, leading to increased plasma concentrations and an elevated risk of corticosteroid-related adverse effects. Dose reduction may be required.
• Other Interactions: Dexamethasone itself is a weak to moderate inducer of CYP3A4 and possibly other enzymes (e.g., CYP2C9). It can therefore increase the metabolism and reduce the efficacy of drugs metabolized by these pathways, such as warfarin (requiring more frequent INR monitoring), cyclosporine, tacrolimus, phenytoin, and some oral contraceptives.

Major Pharmacodynamic Interactions

• Anticoagulants/Antiplatelets: Dexamethasone may increase the risk of gastrointestinal ulceration and bleeding when combined with NSAIDs (e.g., ibuprofen, naproxen), aspirin, or warfarin. It may also alter the response to warfarin, as noted above.
• Antidiabetic Agents: By inducing insulin resistance and gluconeogenesis, dexamethasone antagonizes the effects of insulin and oral hypoglycemics (e.g., metformin, sulfonylureas), leading to hyperglycemia. Increased monitoring of blood glucose and dose adjustments of antidiabetic therapy are typically required.
• Diuretics (especially potassium-depleting): Concomitant use with thiazide or loop diuretics (e.g., furosemide) can exacerbate potassium loss, increasing the risk of severe hypokalemia. Although dexamethasone has minimal mineralocorticoid activity, this interaction can still be clinically significant.
• Cardiac Glycosides: Hypokalemia induced by dexamethasone (often in combination with diuretics) can potentiate the toxic effects of digoxin, increasing the risk of digitalis-induced arrhythmias.
• Vaccines: The immunosuppressive effects of dexamethasone can diminish the antibody response to inactivated vaccines and increase the risk of disseminated infection with live vaccines (e.g., MMR, varicella, yellow fever). Administration of live vaccines is contraindicated in patients receiving immunosuppressive doses.
• Neuromuscular Blocking Agents: Dexamethasone may potentiate or antagonize the effects of these agents; careful monitoring of neuromuscular function is advised during anesthesia.
• Other Immunosuppressants: Additive immunosuppression and increased infection risk occur with concurrent use of other agents like cyclosporine, tacrolimus, and biologics (e.g., TNF-α inhibitors).

Special Considerations

The use of dexamethasone requires careful tailoring to specific patient populations due to altered pharmacokinetics, pharmacodynamics, or unique risks.

Pregnancy and Lactation

Pregnancy (FDA Category C/D): Dexamethasone crosses the placenta. Animal studies have shown teratogenic effects (cleft palate) at high doses. Human data are observational; while a clear increased risk of oral clefts is associated with first-trimester use, the absolute risk remains low. The benefit of treating serious maternal disease often outweighs the potential fetal risk. When used for fetal lung maturation in preterm labor, the benefit is clearly established for the fetus, though betamethasone is the preferred agent due to more extensive safety data. Chronic use in pregnancy may lead to fetal adrenal suppression. Lactation: Dexamethasone is excreted in breast milk in low concentrations. While considered compatible with breastfeeding by the American Academy of Pediatrics, especially at low doses, monitoring the infant for signs of glucocorticoid effects (e.g., poor weight gain) is prudent. Dosing immediately after breastfeeding can minimize infant exposure.

Pediatric Considerations

Children are particularly susceptible to certain adverse effects of dexamethasone. Growth suppression is a major concern with chronic therapy, mediated through inhibition of growth hormone secretion and direct effects on epiphyseal cartilage. Growth should be monitored meticulously, and the use of alternate-day dosing may mitigate this effect. The risk of infections, including varicella, is heightened. Behavioral changes and pseudotumor cerebri are more common in children. Dosing is typically weight-based (mg/kg), but due to the drug’s long half-life and potency, careful calculation and consideration of the indication are required. For croup, a single high dose (0.6 mg/kg) is standard.

Geriatric Considerations

Elderly patients may be more sensitive to both the therapeutic and adverse effects of dexamethasone. Age-related changes, such as decreased lean body mass, increased fat mass, and potential decline in renal or hepatic function, can alter pharmacokinetics. The risks of hypertension, hyperglycemia, osteoporosis, and psychiatric effects are heightened. The presence of comorbidities and polypharmacy increases the potential for drug interactions. The principle of “start low and go slow” often applies, using the lowest effective dose for the shortest possible duration.

Renal and Hepatic Impairment

Renal Impairment: Dose adjustment is not routinely required for dexamethasone itself, as renal excretion of the parent drug is minimal. However, the accumulation of inactive metabolites is possible in severe renal failure. The clinical significance of this is unclear. More importantly, the fluid retention and electrolyte disturbances (hypokalemia) caused by dexamethasone must be managed cautiously in patients with compromised renal function. Hepatic Impairment: Since dexamethasone is extensively metabolized in the liver, significant hepatic impairment (e.g., cirrhosis) can reduce its clearance, prolong its half-life, and increase systemic exposure. This increases the risk of toxicity. A dose reduction may be necessary, and patients should be closely monitored for signs of corticosteroid excess. In patients with liver disease, the hypoalbuminemia often present may increase the fraction of free, active drug.

Summary/Key Points

• Dexamethasone is a potent, long-acting, synthetic glucocorticoid with minimal mineralocorticoid activity, making it a pure anti-inflammatory and immunosuppressive agent.
• Its mechanism is primarily genomic, involving cytosolic glucocorticoid receptor binding, nuclear translocation, and modulation of gene transcription (transactivation and transrepression), leading to the suppression of key inflammatory mediators like cytokines, prostaglandins, and leukotrienes.
• Pharmacokinetically, it is well-absorbed orally, widely distributed (including across the blood-brain barrier), metabolized hepatically by CYP3A4, and has a long plasma half-life (36-54 hours) that permits once-daily dosing but necessitates gradual withdrawal after prolonged use.
• Its therapeutic applications are vast, spanning endocrine, rheumatic, allergic, dermatologic, hematologic, neoplastic, and neurological disorders. Landmark evidence supports its use in COVID-19 pneumonia, septic shock, chemotherapy-induced nausea, and cerebral edema.
• The adverse effect profile is extensive and dose/duration-dependent, including metabolic (hyperglycemia, weight gain), musculoskeletal (osteoporosis, myopathy), infectious (immunosuppression), neuropsychiatric, gastrointestinal, and ophthalmic complications. HPA axis suppression is a critical concern.
• Significant drug interactions occur with CYP3A4 inducers/inhibitors, anticoagulants, antidiabetics, diuretics, and vaccines. Live vaccines are contraindicated.
• Special population management is crucial: caution in pregnancy/lactation, vigilance for growth suppression in children, increased sensitivity in the elderly, and potential need for dose adjustment in severe hepatic impairment.

Clinical Pearls

• For most chronic inflammatory conditions, the goal is to use the lowest effective dose for the shortest possible duration to minimize toxicity.
• When discontinuing therapy after >2-3 weeks, a gradual taper is mandatory to prevent adrenal insufficiency. The rate of taper depends on the dose and duration of therapy.
• Single-dose or short-course dexamethasone is remarkably safe and effective for conditions like croup, PONV prophylaxis, and chemotherapy-induced nausea, with minimal risk of long-term sequelae.
• Always consider prophylaxis for common complications: gastric protection (e.g., PPI) with concomitant NSAIDs, calcium/vitamin D and possibly bisphosphonates for bone protection with long-term use, and monitoring for hyperglycemia.
• In acutely ill patients (e.g., septic shock, cerebral edema), do not delay therapy for fear of long-term side effects; the immediate life-saving benefit outweighs the risks of short-term use.
• Patient education is key: instruct patients not to stop the medication abruptly, to report signs of infection or hyperglycemia, and to inform all healthcare providers of their steroid use, especially before surgeries or vaccinations.

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