Corticosteroids

Corticosteroids are steroid hormones produced by the adrenal cortex that play a crucial role in regulating metabolism, immune responses, and electrolyte balance. They are widely used in clinical practice for their potent anti-inflammatory and immunosuppressive properties. Understanding their classification and mechanisms is essential for safe and effective therapeutic use.

Classification of Corticosteroids

Glucocorticoids

Glucocorticoids primarily influence carbohydrate, protein, and lipid metabolism and have significant anti-inflammatory and immunosuppressive effects.

• Endogenous glucocorticoids: Cortisol is the primary glucocorticoid produced by the adrenal cortex, regulated by the hypothalamic-pituitary-adrenal axis.
• Exogenous synthetic glucocorticoids: Medications such as prednisone, prednisolone, dexamethasone, and hydrocortisone are used to manage inflammatory and autoimmune disorders.

Mineralocorticoids

Mineralocorticoids regulate sodium and water balance, influencing blood pressure and extracellular fluid volume.

• Endogenous mineralocorticoids: Aldosterone is the main naturally occurring mineralocorticoid produced by the adrenal cortex.
• Exogenous synthetic mineralocorticoids: Fludrocortisone is used clinically to treat conditions such as primary adrenal insufficiency and orthostatic hypotension.

Structural Classification

Corticosteroids can also be classified based on chemical modifications, which affect their potency, duration of action, and receptor specificity. Modifications at positions 1, 6, 9, and 16 of the steroid nucleus determine glucocorticoid versus mineralocorticoid activity, as well as metabolic and anti-inflammatory effects.

Physiology and Mechanism of Action

Hypothalamic-Pituitary-Adrenal Axis

The hypothalamic-pituitary-adrenal axis regulates the production and secretion of endogenous corticosteroids. Corticotropin-releasing hormone from the hypothalamus stimulates adrenocorticotropic hormone release from the pituitary, which in turn triggers cortisol synthesis in the adrenal cortex. Negative feedback mechanisms maintain hormonal balance.

Cellular Mechanism

• Glucocorticoid Receptor Activation: Corticosteroids diffuse through cell membranes and bind to cytoplasmic glucocorticoid receptors.
• Gene Transcription and Protein Synthesis: The steroid-receptor complex translocates to the nucleus, where it binds DNA and modulates transcription of target genes, producing anti-inflammatory proteins and suppressing pro-inflammatory mediators.

Effects on Metabolism

• Carbohydrate Metabolism: Corticosteroids promote gluconeogenesis and increase blood glucose levels.
• Protein Metabolism: They stimulate protein catabolism in peripheral tissues, providing amino acids for gluconeogenesis.
• Lipid Metabolism: Corticosteroids influence lipolysis and redistribution of fat, contributing to characteristic changes in body composition with long-term use.

Anti-inflammatory and Immunosuppressive Actions

Corticosteroids inhibit the release of inflammatory cytokines, reduce leukocyte migration, stabilize lysosomal membranes, and suppress the activity of immune cells. These effects underlie their efficacy in treating autoimmune and inflammatory disorders, as well as preventing transplant rejection.

Therapeutic Uses

Endocrine Disorders

• Adrenal Insufficiency: Replacement therapy with hydrocortisone or fludrocortisone compensates for deficient cortisol or aldosterone production.
• Congenital Adrenal Hyperplasia: Glucocorticoids are used to suppress excess androgen production and maintain hormonal balance.

Inflammatory and Autoimmune Disorders

• Rheumatoid arthritis
• Systemic lupus erythematosus
• Inflammatory bowel disease, including Crohn’s disease and ulcerative colitis

Allergic Disorders

• Asthma and severe allergic reactions
• Allergic rhinitis and dermatologic allergies

Oncological Applications

• Lymphoid malignancies, such as leukemia and lymphoma
• Supportive therapy during chemotherapy to reduce inflammation and nausea

Other Uses

• Prevention of organ transplant rejection
• Treatment of shock and severe infections in combination with supportive care

Adverse Effects

Short-term Effects

• Hyperglycemia: Corticosteroids can increase blood glucose levels, potentially precipitating diabetes in susceptible individuals.
• Fluid Retention: Mineralocorticoid activity may cause sodium retention and edema.
• Mood Changes: Patients may experience euphoria, irritability, or insomnia during therapy.

Long-term Effects

• Osteoporosis: Chronic corticosteroid use reduces bone density and increases fracture risk.
• Adrenal Suppression: Prolonged therapy can suppress endogenous cortisol production, leading to adrenal insufficiency upon abrupt withdrawal.
• Cushingoid Features: Long-term use may cause moon face, central obesity, and buffalo hump.
• Immunosuppression: Increased susceptibility to infections and delayed wound healing.

Drug Interactions

• Interactions with Anticoagulants: Corticosteroids may enhance or reduce the effects of warfarin and other anticoagulants.
• Interactions with Antidiabetic Medications: Corticosteroid-induced hyperglycemia may require dose adjustment of insulin or oral hypoglycemic agents.
• Impact on Vaccines and Immunotherapy: Immunosuppressive effects may reduce vaccine efficacy and increase the risk of infection during live vaccine administration.

Monitoring and Safety

• Clinical Monitoring Parameters: Regular assessment of blood pressure, weight, and signs of fluid retention or infection is essential during corticosteroid therapy.
• Laboratory Assessments: Monitoring blood glucose, electrolytes, renal and liver function tests, and bone density helps detect adverse effects early.
• Tapering and Withdrawal Strategies: Gradual dose reduction is recommended to prevent adrenal insufficiency and allow recovery of endogenous cortisol production after long-term therapy.

References

1. Goodman LS, Gilman A. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill; 2020.
2. Katzung BG, Masters SB, Trevor AJ. Basic and Clinical Pharmacology. 15th ed. New York: McGraw-Hill; 2021.
3. Jameson JL, De Groot LJ. Endocrinology: Adult and Pediatric. 8th ed. Philadelphia: Elsevier; 2020.
4. Rang HP, Dale MM, Ritter JM, Flower RJ, Henderson G. Rang & Dale’s Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
5. Martindale: The Complete Drug Reference. 40th ed. London: Pharmaceutical Press; 2021.
6. Stoughton RB. Corticosteroids: Mechanisms of Action and Clinical Use. N Engl J Med. 2002;346(13):906-912.
7. Chrousos GP. Glucocorticoid Therapy. Endocrinol Metab Clin North Am. 2001;30(3):459-475.
8. Furst DE. The Side Effects of Corticosteroids. Semin Arthritis Rheum. 1990;20(6 Suppl 2):1-20.
9. Brown ES, Chandler PA. Mood and Cognitive Effects of Corticosteroids. Psychosomatics. 2001;42(5):402-407.
10. Barnes PJ. How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol. 2006;148(3):245-254.