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Note: KD Tripathi's Essentials of Medical Pharmacology is not available in the library. The notes below are compiled from Lippincott Illustrated Reviews: Pharmacology and Goodman & Gilman's, which cover corticosteroids in the same structured, exam-oriented format as KDT. The content is equivalent for pharmacology exam preparation.

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Corticosteroids - Pharmacology Notes

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1. Adrenal Cortex - Zones and Products

• Zones fasciculata and reticularis (and to a lesser extent glomerulosa) are controlled by ACTH from the anterior pituitary
• ACTH is itself released in response to hypothalamic CRH
• Glucocorticoids provide negative feedback on both ACTH (pituitary) and CRH (hypothalamus)
• Cortisol secretion is diurnal - peak in early morning, smaller secondary peak in late afternoon

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2. Mechanism of Action

• Glucocorticoid Receptors (GR / NR3C1) - widely distributed throughout the body
• Mineralocorticoid Receptors (MR / NR3C2) - mainly excretory organs: kidney, colon, salivary glands, sweat glands. Both types also found in brain.

1. Steroid crosses cell membrane (lipid soluble)
2. Binds cytoplasmic receptor (receptor resides in cytoplasm complexed with chaperone proteins - heat shock proteins)
3. Receptor-hormone complex dimerizes
4. Recruits coactivator or corepressor proteins
5. Translocates into nucleus
6. Attaches to glucocorticoid response elements (GREs) on gene promoters
7. Acts as transcription factor - turns genes ON (with coactivators) or OFF (with corepressors)

Because this mechanism involves gene transcription and protein synthesis, many effects take hours to days to manifest.

• Cortisol and aldosterone bind MR with equally high affinity; cortisol has more modest GR affinity
• In mineralocorticoid target tissues, cortisol is converted to inactive cortisone by 11β-HSD2, preventing inappropriate MR activation
• In other tissues, cortisone is converted back to active cortisol by 11β-HSD1

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3. Physiologic and Pharmacologic Effects of Glucocorticoids

A. Metabolism

B. Fluid and Electrolytes

• Glucocorticoids have mild mineralocorticoid-like effects (Na+ retention, K+ loss, hypertension) at high doses
• Decrease Ca²⁺ absorption from gut, increase Ca²⁺ mobilization from bone, increase renal Ca²⁺ excretion → ↓ total body calcium
• Permissive role in free water excretion via the kidney (GC-deficient patients cannot excrete free water normally → hyponatremia)

C. Blood Cell Effects

Mnemonic: "BELM↓, NEPR↑" - Basophils, Eosinophils, Lymphocytes, Monocytes decrease; Neutrophils, Erythrocytes, Platelets, (RBC) Rise

D. Anti-inflammatory and Immunosuppressive Actions (Most Important Therapeutic Property)

1. ↑ Lipocortin (annexin A1) - inhibits phospholipase A2 → blocks arachidonic acid release → ↓ prostaglandins and leukotrienes
2. ↓ Cytokine production - IL-1, IL-2, IL-6, TNF-α, IFN-γ
3. Inhibit NF-κB - key transcription factor for inflammatory genes
4. Stabilize mast cell and basophil membranes → ↓ histamine release
5. Inhibit leukocyte and macrophage responses to mitogens and antigens
6. ↓ Capillary permeability (decrease tissue edema)
7. Inhibit fibroblast proliferation → impaired wound healing

E. Cardiovascular System

• Mineralocorticoid effects (mainly aldosterone): Na⁺ retention → hypertension, cardiac fibrosis
• Glucocorticoids: permissive for catecholamine-mediated vascular tone; maintain normal cardiac output

F. CNS / Behavioral Effects

• Euphoria, anxiety, insomnia at high doses
• Overt psychosis with long-term use
• Affect mood and cognitive function

G. HPA Axis Suppression

• Exogenous glucocorticoids suppress ACTH and CRH via negative feedback
• Prolonged use leads to adrenal cortical atrophy
• Abrupt withdrawal risks adrenal insufficiency (Addisonian crisis)

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4. Specific Corticosteroid Drugs - Comparison Table

• Dexamethasone and betamethasone - no mineralocorticoid activity; longest acting; used for fetal lung maturation (antenatal) and cerebral edema
• Fludrocortisone - highest mineralocorticoid activity; used in Addison's disease and orthostatic hypotension
• Triamcinolone - no mineralocorticoid activity; used in intra-articular injections and topical preparations
• Prednisone is a prodrug, converted to active prednisolone in the liver

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5. Pharmacokinetics

• Absorption: Well absorbed orally; topical, inhaled, intra-articular, and IV routes available
• Binding: >90% bound to plasma proteins - mainly corticosteroid-binding globulin (CBG/transcortin) and albumin
• Metabolism: Liver microsomal oxidizing enzymes (CYP3A4); inactive conjugates excreted in urine
• Prodrugs: Cortisone → cortisol (active); Prednisone → prednisolone (active)
• Half-life vs biological duration: plasma t½ is short for most, but biological (tissue) duration is much longer

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6. Therapeutic Uses

Replacement Therapy (Physiologic)

• Addison's disease (primary adrenal insufficiency): hydrocortisone + fludrocortisone
• Congenital adrenal hyperplasia (CAH): hydrocortisone to suppress androgen overproduction
• Hypopituitarism/secondary adrenal insufficiency: hydrocortisone

Inflammatory and Autoimmune Diseases

• Rheumatoid arthritis, SLE, vasculitis - prednisone 1 mg/kg/day initially
• Inflammatory bowel disease (Crohn's, UC)
• Dermatomyositis, polymyositis, polymyalgia rheumatica
• Minimal change nephrotic syndrome (prednisone 1-2 mg/kg for 6 weeks - >95% remission in 3 months)

Allergic Diseases

• Anaphylaxis (adjunct - primary is epinephrine)
• Allergic rhinitis (intranasal steroids)
• Contact dermatitis, urticaria, drug reactions, angioedema
• Severe asthma - IV methylprednisolone

Respiratory

• Asthma - inhaled corticosteroids (ICS) are mainstay of preventive therapy
• COPD exacerbations
• Antenatal lung maturation (fetal surfactant induction): betamethasone 12 mg IM q24h × 2 doses, OR dexamethasone 6 mg IM q12h × 4 doses (at 26-34 weeks gestation)

Neurological

• Cerebral edema (tumors, abscesses): dexamethasone (no sodium retention)
• Bacterial meningitis (Haemophilus influenzae type b in children) - reduces neurological sequelae
• Spinal cord injury (controversial)

Oncology/Hematology

• Leukemias, lymphomas (cytotoxic immunosuppression)
• Multiple myeloma
• Thrombocytopenia, hemolytic anemia

Infectious Diseases (selected)

• COVID-19 requiring mechanical ventilation: dexamethasone (significant survival benefit - RECOVERY trial)
• HIV + Pneumocystis jirovecii pneumonia (PCP): adjunct steroids reduce respiratory failure and mortality
• Bacterial meningitis in children: dexamethasone reduces sensorineural hearing loss

Organ Transplantation

• Immunosuppression to prevent rejection (usually combined with tacrolimus/cyclosporine + azathioprine)

Ophthalmic

• Uveitis, iritis, keratitis, post-surgical inflammation
• NOT in herpes simplex keratitis (can worsen by suppressing immune response and promoting viral replication)

Dermatology

• Topical: eczema, psoriasis, contact dermatitis
• Intralesional: keloids, lichen planus

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7. Adverse Effects (Long-term / Supraphysiologic Use)

Mnemonic: "STOP Making Bony Cuts For Good"

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8. Contraindications and Precautions

Absolute caution in:

• Peptic ulcer disease (especially with NSAIDs)
• Active systemic infections (TB, fungal, herpes)
• Psychosis
• Uncontrolled diabetes mellitus
• Severe osteoporosis
• Uncontrolled hypertension
• Heart failure

Pre-treatment screening:

• Screen for latent TB (Mantoux/IGRA) before prolonged therapy
• Vaccinate (pneumococcal, influenza, varicella) before starting if possible - efficacy of some vaccines is reduced once on steroids

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9. Dosing Principles

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10. Inhibitors of Corticosteroid Synthesis

Glucocorticoid Receptor Antagonist

• Mifepristone (RU-486) - competitive GR and progesterone receptor antagonist; used in Cushing's syndrome with hyperglycemia; also used for pregnancy termination

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11. Special Scenarios

Topical Steroids (Potency Classes)

• Class 1 (superpotent): Clobetasol propionate
• Class 2-3 (potent): Betamethasone dipropionate, fluocinonide
• Class 4-5 (mid-potency): Triamcinolone acetonide, fluocinolone acetonide
• Class 6-7 (low potency): Hydrocortisone, desonide
• Avoid prolonged use on face, flexures, in infants - systemic absorption risk

Inhaled Corticosteroids (ICS)

• Beclomethasone, budesonide, fluticasone, mometasone, ciclesonide
• Minimize systemic adverse effects by local action
• Main local side effects: oral candidiasis (thrush), dysphonia - prevented by rinsing mouth after use

Antenatal Steroids

• Betamethasone or dexamethasone (both cross placenta; lack 11β-HSD2 inactivation)
• Used at 26-34 weeks gestation for fetal lung maturation
• Reduce: respiratory distress syndrome, intraventricular hemorrhage, neonatal mortality

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