Corticosteroids Study Notes

Corticosteroids Overview

- Instructor: Dr. Bipin

Introduction to Corticosteroids

  • The adrenal cortex secretes steroidal hormones with the following activities:

    1. Glucocorticoid

    2. Mineralocorticoid

    3. Weakly androgenic activities

- The term ‘corticosteroid’ or ‘corticoid’ refers to both natural glucocorticoids and mineralocorticoids as well as their synthetic analogues.

Mineralocorticoids and Hormone Pathways

Biosynthesis Pathway

  • Overview of steroid hormone biosynthesis showcasing:

    1. Cholesterol

    2. Pregnenolone

    3. Progesterone

    4. 17α-Hydroxyprogesterone

    5. Dehydroepiandrosterone (DHEA)

    6. Corticosterone

    7. Aldosterone

    8. Cortisol (Hydrocortisone)

- Diagram (Fig. 20.1) illustrates the simplified pathways of adrenal steroid hormone biosynthesis.

Regulation of Corticosteroid Secretion

Hypothalamo-Pituitary-Adrenal (HPA) Axis

  • ACTH (Adrenocorticotropic Hormone) is released from the anterior pituitary.

  • CRH (Corticotropin-Releasing Hormone) is produced from the hypothalamus.

  • Provides negative feedback regulation of the HPA axis.

Normal Secretion Rates

  1. Hydrocortisone: 10–20 mg daily (around 50% secreted in the morning).

  2. Aldosterone: ~0.125 mg daily.

3. Hydrocortisone is equivalent to cortisol, a glucocorticoid produced by the zona fasciculata of the adrenal cortex.

Detailed Analysis of Cortisol

Cortisol (Hydrocortisone)

  1. Secreted by the adrenal cortex.

  2. Major glucocorticoid in humans.

Corticosterone

  1. Produced in smaller amounts by the adrenal cortex.

  2. Functions mainly as an intermediate in aldosterone synthesis and has slight glucocorticoid effects.

Cortisone

  1. Primarily released in the form of cortisol, not cortisone.

2. Formed from cortisol in peripheral tissues (liver/kidney) via the enzyme 11β-hydroxysteroid dehydrogenase.

Stress Response and Hormonal Regulation

Stress Response Mechanism

  • Higher centers stimulate the hypothalamus to release CRF which acts through the anterior pituitary to stimulate ACTH.

- ACTH's action on the adrenal glands leads to corticosteroid release in response to stress.

Actions of Mineralocorticoid

Mechanisms and Effects

  1. Aldosterone primarily enhances Na+ reabsorption in the distal convoluted tubule of the kidney.

  2. Increases K+ and H+ excretion from the body.

  3. Deficiency leads to:

  4. .Absorption of water without concomitant Na+, causing dilutional hyponatremia.

    • Cellular hydration issues and decreased blood volume, leading to raised hematocrit.

4. Accompanying conditions include hyperkalemia and acidosis as imbalances progress leading to circulatory collapse.

Gene-Mediated Actions of Glucocorticoids

Mechanism of Action

  1. Translocation of glucose transporters and induction of enzymes in the liver:

    • Stimulates gluconeogenesis and glycogenesis.

    • Alters glucose uptake in peripheral tissues and body fat distribution.

  2. Anti-inflammatory Effects:

    • Induction of annexins and inhibition of key inflammatory mediators.

    • Suppression of cytokine production from macrophages and lymphocytes.

- Decreased production of acute phase reactants and adhesion molecules in inflammation.

Major Pharmacological Actions of Corticosteroids

Metabolic Actions

  1. Catabolic Effects:

    • Increases gluconeogenesis and blood sugar levels (diabetogenic).

    • Augments protein breakdown across various tissues.

    • Leads to redistribution of body fat (e.g., moon face, truncal obesity).

  2. Electrolyte Disturbance:

- Effects involve sodium/water retention and potassium loss particularly prevalent with hydrocortisone.

Anti-Inflammatory and Immunosuppressive Actions

Immunosuppressive Effects

  1. Causes lymphocytopenia, especially affecting T-cells.

2. Inhibits cell-mediated immunity notably seen in delayed hypersensitivity reactions.

Clinical Indications for Corticosteroids

Replacement Therapy

  • For conditions like Adrenal insufficiency, Congenital Adrenal Hyperplasia.

Inflammatory/Autoimmune Conditions

  • Examples include Rheumatoid arthritis, IBD, Asthma, Allergic reactions.

Immunosuppression

  • For Transplant rejection, Autoimmune hemolytic anemia.

Miscellaneous Applications

- Managing Cerebral edema, as an antiemetic in high doses (e.g., dexamethasone), treating septic shock.

Adverse Effects of Corticosteroids

Iatrogenic Cushing's Syndrome

  1. Clinical features include:

    • Moon face, Buffalo hump, central obesity.

    • Other symptoms like purple striae, hypertension, osteoporosis, etc.

Specific Side Effects

  1. Metabolic

    • Significant hyperglycemia and risk for steroid diabetes.

  2. Gastrointestinal

    • Peptic ulcers, masking of symptoms like pain typically observed.

  3. Cardiovascular

    • Raised blood pressure (Na+ retention).

  4. CNS effects such as mood swings and psychosis.

  5. Increased risk of infections due to immunosuppressive effects.

6. HPA axis suppression: Abrupt withdrawal can precipitate adrenal crisis.

Diagnosis of Cushing's Syndrome

Clinical Presentation and Testing

  1. Diagnosis may be supported by blood tests showing elevated cortisol and based on the clinical picture associated with excess glucocorticoid effects.

Screening Tests

  • Initial biochemical evaluations include:

    1. 24-hour urine free cortisol collection.

2. Low-dose overnight dexamethasone suppression test.

Diagnostic and Tapering Strategies

ACTH Stimulation Test

  1. Used to determine adrenal cortex secretory capacity.

Tapering Requirement

  • Tapering is crucial to prevent:

    1. HPA Axis Suppression leading to adrenal crisis.

2. Disease flare upon withdrawal of corticosteroids.

Types of Corticosteroids and Comparison

Classification

  • Short-Acting: Hydrocortisone, Cortisone

  • Intermediate-Acting: Prednisolone, Methylprednisolone

  • Long-Acting: Dexamethasone

Relative Potency

- Each corticosteroid has a defined relative glucocorticoid and mineralocorticoid potency which determines clinical application and dosage equivalencies.

Drug Interactions and Contraindications

Interactions

  1. Important interactions include NSAIDs (risk of ulcer), diuretics (risk of hypokalemia), and enzyme inducers (reduce steroid efficacy).

Contraindications

1. Include hypersensitivity, systemic fungal infections, peptic ulcer disease, and active infections amongst others that necessitate caution.

Special Considerations in Treatment

- Tapering necessary after prolonged corticosteroid therapy to allow recovery of the body's normal cortisol production mechanisms.

Summary and Conclusion

  • Corticosteroids play pivotal roles in physiologic regulation and therapeutic management of various disorders across endocrine, inflammatory, and autoimmune conditions. Clinical implications call for an understanding of both their pharmacodynamics and the importance of careful monitoring and management of adverse effects.