MOA of dexamethasone

Mechanism of Action of Dexamethasone

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Introduction

Dexamethasone is a long-acting, highly potent synthetic glucocorticoid with negligible mineralocorticoid activity. It is extensively used for its anti-inflammatory, immunosuppressive, anti-edema, and antiemetic properties across multiple specialties, including internal medicine, oncology, neurology, pulmonology, and critical care. Because of its strong genomic effects and long duration of action, dexamethasone is a high-yield corticosteroid in pharmacology and clinical entrance examinations.

Mechanism of action of dexamethasone
MOA of dexamethasone
MOA of dexamethasone Flowchart
Dexamethasone Mechanism of Action Flowchart

Mechanism of Action (Step-wise)

Dexamethasone acts primarily through intracellular glucocorticoid receptor–mediated genomic mechanisms, leading to broad suppression of inflammatory and immune pathways.

Step-wise mechanism:

  1. Cell Membrane Diffusion
    Dexamethasone is lipophilic and freely diffuses across the cell membrane into the cytoplasm.
  2. Binding to Glucocorticoid Receptor (GR)
    In the cytoplasm, it binds to inactive glucocorticoid receptors associated with heat-shock proteins (HSPs).
  3. Receptor Activation and Nuclear Translocation
    Binding causes dissociation of HSPs, allowing the steroid–receptor complex to translocate into the nucleus.
  4. Interaction with Glucocorticoid Response Elements (GREs)
    The complex binds to GREs on DNA, modulating transcription of specific genes.
  5. Upregulation of Anti-inflammatory Proteins
    Increased synthesis of:
    • Lipocortin-1 (annexin A1), which inhibits phospholipase A₂
    • Anti-inflammatory cytokines (e.g., IL-10)
  6. Downregulation of Pro-inflammatory Genes
    Suppression of transcription of:
    • Pro-inflammatory cytokines (IL-1, IL-2, IL-6, TNF-α)
    • COX-2
    • Inducible nitric oxide synthase (iNOS)
  7. Inhibition of Arachidonic Acid Cascade
    Reduced formation of prostaglandins and leukotrienes leads to powerful anti-inflammatory effects.
  8. Immunosuppression and Anti-edema Effects
    Decreased leukocyte migration, capillary permeability, and lymphocyte proliferation result in immunosuppression and reduction of cerebral and tumor-related edema.

Pharmacokinetics

  • Absorption: Well absorbed orally; effective IV and IM
  • Distribution: Widely distributed; crosses blood–brain barrier and placenta
  • Protein binding: Moderate
  • Metabolism: Hepatic metabolism
  • Elimination: Renal excretion of metabolites
  • Plasma half-life: ~4–5 hours
  • Biological half-life: 36–72 hours (long-acting)
  • Mineralocorticoid activity: Negligible

Clinical Uses

Dexamethasone is used in a wide variety of inflammatory, immune, and oncologic conditions:

  • Cerebral edema (brain tumors, head injury)
  • Severe allergic and inflammatory disorders
  • Autoimmune diseases
  • Acute respiratory distress and severe COVID-19
  • Antiemetic in chemotherapy-induced nausea and vomiting
  • Adjuvant therapy in malignancies (leukemia, lymphoma)
  • Diagnostic suppression test for Cushing syndrome
  • Prevention of neonatal respiratory distress syndrome

Adverse Effects

Adverse effects depend on dose and duration of therapy:

  • Endocrine & metabolic:
    • Hyperglycemia
    • Cushingoid features
    • Adrenal suppression
  • Musculoskeletal:
    • Osteoporosis
    • Proximal myopathy
  • Immune:
    • Increased infection risk
    • Reactivation of latent infections
  • Gastrointestinal:
    • Peptic ulcer disease
  • Neuropsychiatric:
    • Mood changes
    • Psychosis

Abrupt discontinuation after prolonged use may precipitate acute adrenal insufficiency.

Comparative Analysis (must include a table + explanation)

Comparison of Common Glucocorticoids

FeatureDexamethasonePrednisoloneHydrocortisone
Anti-inflammatory potencyVery highModerateLow
Duration of actionLongIntermediateShort
Mineralocorticoid activityNegligibleLowHigh
Use in cerebral edemaYesLimitedNo
HPA axis suppressionStrongModerateMild

Explanation:
Dexamethasone is preferred when potent and sustained anti-inflammatory action is required without fluid retention. Hydrocortisone is used mainly for adrenal replacement, while prednisolone is commonly used for chronic inflammatory conditions.

MCQs (10–15)

  1. Dexamethasone exerts its effects primarily by:
    a) Blocking COX enzymes directly
    b) Activating membrane receptors
    c) Modulating gene transcription
    d) Inhibiting histamine release

Answer: c) Modulating gene transcription

  1. Dexamethasone binds to which receptor?
    a) G-protein–coupled receptor
    b) Tyrosine kinase receptor
    c) Nuclear glucocorticoid receptor
    d) Ion channel receptor

Answer: c) Nuclear glucocorticoid receptor

  1. The anti-inflammatory effect of dexamethasone involves inhibition of:
    a) Phospholipase A₂
    b) DNA gyrase
    c) Na⁺/K⁺-ATPase
    d) Acetylcholinesterase

Answer: a) Phospholipase A₂

  1. Dexamethasone has minimal mineralocorticoid activity, so it causes:
    a) Sodium retention
    b) Potassium retention
    c) Minimal fluid retention
    d) Severe hypertension

Answer: c) Minimal fluid retention

  1. Which condition is dexamethasone especially useful for?
    a) Addison disease
    b) Cerebral edema
    c) Hypotension
    d) Heart failure

Answer: b) Cerebral edema

  1. Dexamethasone reduces prostaglandin synthesis by:
    a) Direct COX inhibition
    b) Reducing arachidonic acid availability
    c) Blocking prostaglandin receptors
    d) Increasing lipoxygenase activity

Answer: b) Reducing arachidonic acid availability

  1. Long-term dexamethasone therapy may cause:
    a) Hyperkalemia
    b) Osteoporosis
    c) Hypoglycemia
    d) Bradycardia

Answer: b) Osteoporosis

  1. Dexamethasone suppresses immunity mainly by inhibiting:
    a) Neutrophil migration and T-cell function
    b) Antibody degradation
    c) Complement activation
    d) Mast cell stabilization

Answer: a) Neutrophil migration and T-cell function

  1. Dexamethasone is classified as a:
    a) Mineralocorticoid
    b) Short-acting glucocorticoid
    c) Long-acting glucocorticoid
    d) NSAID

Answer: c) Long-acting glucocorticoid

  1. Abrupt withdrawal of dexamethasone can lead to:
    a) Thyroid storm
    b) Neuroleptic malignant syndrome
    c) Adrenal insufficiency
    d) Serotonin syndrome

Answer: c) Adrenal insufficiency

FAQs (minimum 5)

  1. What is the primary mechanism of dexamethasone?
    Genomic modulation of inflammatory and immune gene transcription via glucocorticoid receptors.
  2. Why is dexamethasone preferred in cerebral edema?
    Due to its strong anti-edema effect and minimal mineralocorticoid activity.
  3. Does dexamethasone act faster than NSAIDs?
    No, its onset is slower because it requires gene transcription.
  4. Why must dexamethasone be tapered?
    To prevent adrenal insufficiency from HPA axis suppression.
  5. Does dexamethasone cause fluid retention?
    Minimal, because it has negligible mineralocorticoid activity.
  6. Is dexamethasone immunosuppressive?
    Yes, it strongly suppresses both innate and adaptive immunity.

References

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