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Corticosteroid Pharmacology - University-Level Full Q&A

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Q1. What are corticosteroids? How are they classified?

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Q2. Describe the biosynthesis of corticosteroids.

1. Cholesterol → Pregnenolone (rate-limiting step, regulated by ACTH via StAR protein - steroidogenic acute regulatory protein)
2. Pregnenolone → Progesterone (by 3β-HSD)
3. Progesterone → 17-hydroxyprogesterone (by 17α-hydroxylase / CYP17)
4. 17-hydroxyprogesterone → 11-deoxycortisol (by 21α-hydroxylase / CYP21)
5. 11-deoxycortisol → Cortisol (by 11β-hydroxylase / CYP11B1)

• CYP21 (21-hydroxylase) deficiency: most common cause of congenital adrenal hyperplasia (CAH); shunts precursors to androgen pathway - virilization
• CYP11B1 (11β-hydroxylase) deficiency: second most common CAH; leads to hypertension

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Q3. What is the HPA (Hypothalamic-Pituitary-Adrenal) axis? How does it regulate cortisol?

HYPOTHALAMUS → CRH (corticotropin-releasing hormone)
       ↓
ANTERIOR PITUITARY → ACTH (adrenocorticotropic hormone; from POMC)
       ↓
ADRENAL CORTEX → CORTISOL
       ↓
NEGATIVE FEEDBACK (at both hypothalamus & pituitary)

• The total cortisol secreted daily is approximately 10 mg, equivalent to ~2.5 mg prednisone/day
• Release is circadian: highest in early morning, lowest at night
• Superimposed ultradian pulses occur every 60-120 minutes
• During severe stress (surgery, illness), cortisol may increase sixfold above baseline
• ACTH is derived from pro-opiomelanocortin (POMC), which also gives rise to MSH (explains hyperpigmentation in Addison disease)
• Aldosterone secretion is controlled primarily by angiotensin II and serum K+, not ACTH

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Q4. What is the mechanism of action of glucocorticoids?

1. Glucocorticoid enters cell by passive diffusion (lipophilic molecule)
2. Binds to cytoplasmic GR, displacing heat shock proteins (Hsp90)
3. GR-ligand complex translocates to nucleus
4. Binds to glucocorticoid response elements (GREs) on DNA
5. Activates transcription of anti-inflammatory proteins: lipocortin (annexin-1), IκBα, and others
6. Alternatively, GR interacts with transcription factors AP-1 (c-Fos/c-Jun) and NF-κB, inhibiting pro-inflammatory gene expression (called transrepression)

• Direct interaction with membrane receptors
• Activation of kinase cascades (relevant for pulse/high-dose steroids)

• Stabilize lysosomal membranes
• Inhibit phospholipase A2 (via lipocortin) → reduced arachidonic acid → reduced PGs, LTs, PAF
• Decrease capillary permeability
• Decrease chemotaxis and phagocytosis of neutrophils
• Suppress T-lymphocyte proliferation and cytokine production (IL-1, IL-2, IL-6, TNF-α, IFN-γ)
• Inhibit eosinophil survival

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Q5. What are the physiological and pharmacological effects of glucocorticoids?

Metabolic Effects

Cardiovascular

• Na+ and water retention (via residual mineralocorticoid activity) → hypertension, edema
• Sensitize blood vessels to catecholamines (permissive effect)
• Required for maintenance of normal vascular tone

Anti-inflammatory / Immunosuppressive

• Suppress all phases of inflammation
• Decrease lymphocyte traffic, lymph node and spleen size
• Inhibit antibody production (high doses)

Endocrine

• Suppress HPA axis (adrenal suppression at therapeutic doses)
• Inhibit ADH secretion (mild diuresis with cortisol)
• Block gonadotropin release

CNS

• Euphoria (early), depression, psychosis, insomnia (especially ultradian rhythm disruption)
• Appetite stimulation
• Lower seizure threshold at high doses

Bone/Musculoskeletal

• Decrease bone formation; increase bone resorption → osteoporosis
• Inhibit intestinal Ca2+ absorption; increase renal Ca2+ excretion
• Myopathy (proximal muscle weakness)

Hematologic

• Neutrophilia (demargination + decreased egress)
• Lymphopenia, eosinopenia, monocytopenia
• Erythrocytosis and thrombocytosis (mild)

GI

• Increased gastric acid and pepsin secretion
• Decreased mucus production → peptic ulcer risk (especially with NSAIDs)

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Q6. What are the pharmacokinetic properties of commonly used corticosteroids?

• Well-absorbed orally
• Bound in plasma: ~90% bound to cortisol-binding globulin (CBG/transcortin) and albumin; only free fraction is active
• Half-life: ~1.5-2 hours (plasma); biologic half-life ~8-12 hours
• Metabolized in liver (reduction of ring A, conjugation)
• Excreted in urine as 17-hydroxycorticosteroids

• Structural modifications increase potency, prolong half-life, and reduce mineralocorticoid activity
• Fluorination at C9 increases both glucocorticoid and mineralocorticoid activity (e.g., fludrocortisone is a pure mineralocorticoid)
• Addition of 1,2 double bond (prednisolone) increases glucocorticoid:mineralocorticoid ratio
• Methylation at C16 (dexamethasone, betamethasone) virtually eliminates mineralocorticoid activity

Comparative Potencies (Table 39-1, Katzung):

• Prednisone is a prodrug, converted to prednisolone in the liver (avoid in severe hepatic failure)
• Dexamethasone and betamethasone do not cross-react in cortisol immunoassays (useful for suppression tests and antenatal lung maturation)

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Q7. What are the clinical uses (indications) of corticosteroids?

A. Replacement Therapy (Physiological doses)

1. Addison's disease (primary adrenal insufficiency): hydrocortisone 20-30 mg/day + fludrocortisone
2. Congenital adrenal hyperplasia: suppress ACTH and androgenic excess
3. Acute adrenal crisis: IV hydrocortisone 100 mg every 8 hours + fluids
4. Secondary/tertiary adrenal insufficiency: hydrocortisone alone (aldosterone not needed)

B. Anti-inflammatory / Immunosuppressive (Pharmacological doses)

1. Rheumatoid arthritis: prednisone ≤7.5 mg/day (disease-modifying at low doses)
2. SLE: moderate to high-dose prednisone; pulse methylprednisolone in crisis
3. Vasculitis / Giant cell arteritis: prednisone 40-60 mg/day initially
4. Asthma: inhaled corticosteroids (ICS) are first-line; systemic for acute exacerbations
5. Inflammatory bowel disease (Crohn's, UC): systemic or topical (budesonide)
6. Organ transplantation: immunosuppression (with tacrolimus/cyclosporine)
7. Nephrotic syndrome: prednisone 1 mg/kg/day
8. Allergic disorders: urticaria, angioedema, anaphylaxis (adjunct)
9. Dermatologic conditions: topical for eczema, psoriasis (potency classification Class I-VII)
10. Spinal cord injury: high-dose methylprednisolone (within 8h - controversial)
11. Septic shock: low-dose hydrocortisone in refractory vasopressor-dependent shock
12. COVID-19: dexamethasone 6 mg/day reduces mortality in ventilated patients (RECOVERY trial)

C. Diagnostic Use

• Dexamethasone suppression test: screening for Cushing syndrome
  • Overnight: 1 mg dexamethasone at midnight → morning cortisol <1.8 µg/dL = normal
  • Low-dose (2-day): 0.5 mg q6h × 2 days
  • High-dose: 2 mg q6h × 2 days (distinguishes pituitary from ectopic ACTH)

D. Special Obstetric/Neonatal Uses

• Fetal lung maturation: betamethasone/dexamethasone IM to mothers at 24-34 weeks gestation (enhances surfactant production)
• Fetal CAH protection: dexamethasone given to at-risk mothers

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Q8. What are the adverse effects of corticosteroids?

Endocrine/Metabolic

• Cushing syndrome (iatrogenic): moon face, central obesity, buffalo hump, striae, hyperglycemia
• Adrenal suppression: HPA axis suppression → secondary adrenal insufficiency; most dangerous if drug stopped abruptly
  • Risk after as little as 2 weeks of supraphysiologic doses
• Dyslipidemia

Musculoskeletal

• Osteoporosis: decreased osteoblast activity + increased osteoclast activity; greatest bone loss in first 3-6 months
• Osteonecrosis (avascular necrosis): especially femoral head; related to dose
• Myopathy: proximal muscle weakness (type II fiber atrophy); worse with fluorinated steroids (triamcinolone)

Cardiovascular

• Hypertension (Na+ and water retention)
• Edema
• Atherosclerosis acceleration

Metabolic

• Hyperglycemia / "steroid diabetes"
• Hypokalemia
• Metabolic alkalosis
• Hyperlipidemia
• Weight gain

Immunologic

• Increased susceptibility to infections (bacterial, fungal, viral - especially Pneumocystis, TB, herpes)
• Reactivation of latent TB (screen before starting)
• Impaired wound healing

GI

• Peptic ulcer disease (risk multiplied with NSAIDs)
• Gastritis, GI hemorrhage

Ophthalmologic

• Posterior subcapsular cataracts (characteristic of steroid use)
• Glaucoma (especially with topical steroids; IOP ↑)

Dermatologic (topical and systemic)

• Skin thinning and atrophy
• Striae (stretch marks)
• Acne, hirsutism
• Impaired wound healing

CNS

• Insomnia, mood swings, euphoria
• Depression, psychosis (especially high doses)
• Pseudotumor cerebri (benign intracranial hypertension, especially on withdrawal)

Growth

• Growth suppression in children (even with inhaled corticosteroids at high doses)

Dose-effect thresholds (prednisone equivalent):

• 5 mg/day: weight gain, epistaxis

• 7.5 mg/day: glaucoma, depression, hypertension

• Prolonged use even at <7.5 mg/day: osteoporosis, myopathy, infections

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Q9. What is adrenal suppression and how should corticosteroids be withdrawn?

• Patients on >7.5 mg prednisone/day for >3 weeks are at risk
• Cannot mount an adequate stress response to surgery, trauma, illness
• May develop acute adrenal crisis (circulatory collapse, shock)

• Gradual tapering is mandatory after prolonged therapy
• Physiologic dose (~5-7.5 mg prednisone/day) must be maintained for weeks to months before complete discontinuation
• Adrenal function generally recovers with slow taper
• Symptoms of withdrawal may occur even at doses as low as 1 mg/day prednisone (fatigue, arthralgia, malaise - independent of true adrenal insufficiency)

• Patients on chronic steroids receive supplemental hydrocortisone before major surgery (hydrocortisone 50-100 mg IV before induction, then q8h for 24-48h)

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Q10. What are the mineralocorticoids? What is the mechanism of action of aldosterone?

1. Enters renal tubular cell (principal cell of collecting duct)
2. Binds to mineralocorticoid receptor (MR)
3. MR-ligand complex enters nucleus → activates gene transcription
4. Increases synthesis of:
   • Epithelial Na+ channels (ENaC) on luminal membrane
   • Na+/K+ ATPase on basolateral membrane
   • Mitochondrial proteins to generate energy
5. Net effect: Na+ reabsorption + K+ excretion + H+ excretion → volume expansion, hypokalemia, metabolic alkalosis

• Addison's disease (primary adrenal insufficiency): 0.05-0.2 mg/day
• Congenital adrenal hyperplasia (salt-wasting form)
• Orthostatic hypotension (autonomic neuropathy)

• Hypertension, hypokalemia, metabolic alkalosis
• Low renin, high aldosterone

• Spironolactone and eplerenone: competitive MR antagonists; used in heart failure, hyperaldosteronism, hypertension
• Spironolactone also blocks androgen receptors (causes gynecomastia)

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Q11. What are the adrenocortical antagonists (synthesis inhibitors)?

Synthesis Inhibitors

Receptor Antagonists

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Q12. What are the principles of topical corticosteroid use?

• Class I (superpotent): Clobetasol propionate 0.05%, halobetasol
• Class IV-V (moderate): Triamcinolone acetonide 0.1%, mometasone
• Class VI-VII (low): Hydrocortisone 0.5-1%, desonide

1. Use the least potent agent effective for the condition
2. Vehicle matters: ointments > creams > lotions in potency (occlusion increases absorption)
3. Avoid superpotent steroids on face, groin, axillae, and in children
4. Limit use to 2-4 weeks for high-potency agents
5. Tachyphylaxis occurs with prolonged use - requires drug holidays

• Skin atrophy, striae, telangiectasias
• Perioral dermatitis, steroid acne
• HPA axis suppression (significant with Class I over large area)
• Glaucoma (periocular application)
• Rebound dermatitis on withdrawal (especially potent agents on face)

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Q13. What are the precautions and contraindications for systemic corticosteroids?

Absolute Contraindications (relative in life-threatening situations)

• Systemic fungal infections (without antifungal cover)
• Active peptic ulcer (use with PPI cover if unavoidable)
• Untreated tuberculosis

Precautions / Monitoring Required

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Q14. What is alternate-day therapy and when is it used?

• "Off" days allow partial recovery of HPA axis
• Reduces: growth suppression, myopathy, hypertension, opportunistic infections, electrolyte imbalances
• Does not reduce risk of osteoporosis or cataracts substantially
• Glucose fluctuations may be problematic in diabetics

• Long-term maintenance therapy in chronic inflammatory diseases (e.g., asthma, nephrotic syndrome in children)
• To taper off systemic steroids

• Rheumatoid arthritis (disease activity not controlled on "off" days)

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Q15. What is Congenital Adrenal Hyperplasia (CAH)? How does pharmacology relate?

• Reduced cortisol → elevated ACTH → adrenal hyperplasia
• Excess precursors shunted to androgen pathway → virilization
• Salt-wasting form: aldosterone also deficient
• Classic diagnostic marker: elevated 17-hydroxyprogesterone; confirmed by ACTH stimulation test

• Glucocorticoid replacement: hydrocortisone 10-20 mg/m²/day (children) to suppress ACTH and excess androgens
• Mineralocorticoid: fludrocortisone + salt supplementation in salt-wasting form
• Monitoring: 17-hydroxyprogesterone, androstenedione, growth velocity, bone age
• Prenatal therapy: dexamethasone to mother in at-risk pregnancies (to prevent virilization of female fetus)

• Excess 11-deoxycortisol and DOC → hypertension + virilization
• Treatment: glucocorticoids to suppress ACTH

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Summary Table: Key Corticosteroids at a Glance

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High-Yield Points for University Exams

1. Cortisol = major endogenous glucocorticoid; aldosterone = major mineralocorticoid
2. Mechanism: nuclear receptor (GR) → transactivation (anti-inflammatory genes) + transrepression (NF-κB, AP-1 inhibition)
3. Lipocortin-1 (annexin-1) inhibits phospholipase A2 - key anti-inflammatory mediator
4. Dexamethasone has zero mineralocorticoid activity; preferred for suppression testing and cerebral edema
5. Prednisone is a prodrug → converted to prednisolone in the liver
6. Adrenal suppression - taper slowly; provide stress dosing perioperatively
7. Cushing syndrome features: moon face, central obesity, purple striae, buffalo hump, proximal myopathy, osteoporosis, hyperglycemia
8. CAH: 21-hydroxylase deficiency = most common; marker = 17-hydroxyprogesterone
9. Topical steroids: Class I (clobetasol) most potent; avoid on face/flexures
10. Alternate-day therapy reduces HPA suppression and some side effects

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