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Adrenal Steroids Pharmacology — Comprehensive Review

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1. Classification of Adrenal Steroids

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2. Biosynthesis

Cholesterol
    ↓
Pregnenolone ──────────────────────────→ 17α-OH Pregnenolone → DHEA
    ↓                                              ↓
Progesterone ──────────→ 17α-OH Progesterone → Androstenedione
    ↓                              ↓
Deoxycorticosterone          11-Deoxycortisol
    ↓                              ↓ (11β-hydroxylase)
Corticosterone                  CORTISOL
    ↓ (aldosterone synthase)
ALDOSTERONE

• CYP11A1 (P450scc): cholesterol → pregnenolone (rate-limiting step in all zones)
• CYP17 (17α-hydroxylase): required for cortisol and sex steroid synthesis (absent in zona glomerulosa → no cortisol/androgens there)
• CYP21 (21-hydroxylase): most commonly deficient in congenital adrenal hyperplasia
• CYP11B1 (11β-hydroxylase): deoxycortisol → cortisol
• CYP11B2 (aldosterone synthase): in zona glomerulosa only

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3. Regulation

• Glucocorticoids (cortisol): regulated by hypothalamic-pituitary-adrenal (HPA) axis
  • Hypothalamus → CRH → Pituitary → ACTH → Adrenal cortex → Cortisol
  • Cortisol exerts negative feedback at both hypothalamus and pituitary
  • Secretion is pulsatile with a diurnal rhythm (peak ~8 AM, nadir ~midnight)
  • Stress overrides the feedback loop
• Mineralocorticoids (aldosterone): primarily regulated by:
  • Renin–angiotensin system (angiotensin II is the dominant stimulus)
  • Plasma [K⁺] (direct stimulation of zona glomerulosa)
  • ACTH has a minor, permissive role

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4. Mechanism of Action

Genomic (Classical) Mechanism

1. Ligand binding causes dissociation of heat shock proteins (hsp90, hsp70) from the GR
2. The ligand-GR complex dimerizes
3. The complex translocates to the nucleus
4. Binds glucocorticoid response elements (GREs) in the promoter regions of target genes
5. Transactivation → upregulates anti-inflammatory genes (lipocortin/annexin-1, IκBα)
6. Transrepression → binds and inhibits transcription factors like AP-1 and NF-κB, reducing pro-inflammatory cytokine synthesis (IL-1, IL-6, TNF-α)

Non-Genomic Mechanism

• Membrane-bound GRs
• Direct effects on membrane ion channels and signaling cascades
• Not blocked by transcription inhibitors

Mineralocorticoid Receptor (MR) Mechanism

Note: Cortisol has equal affinity for MR compared to aldosterone, but in aldosterone-target tissues, the enzyme 11β-HSD2 (11β-hydroxysteroid dehydrogenase type 2) converts cortisol to inactive cortisone, protecting MR selectivity.

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5. Pharmacokinetics

Natural Corticosteroids

Synthetic Corticosteroids

• Oral bioavailability: Most synthetic glucocorticoids are well absorbed orally
• Fluorination at C9 → increases glucocorticoid and mineralocorticoid potency (e.g., fludrocortisone, dexamethasone)
• 16α-methylation or 16β-methylation → virtually eliminates mineralocorticoid activity (e.g., dexamethasone, betamethasone)
• Esterification at C17 or C21 → alters duration and route of administration

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6. Comparative Potency Table

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7. Physiological & Pharmacological Effects

A. Glucocorticoid Effects

Metabolic Effects

• Carbohydrate: ↑ gluconeogenesis, ↑ glycogen synthesis in liver → hyperglycemia; ↓ peripheral glucose uptake (anti-insulin)
• Protein: Catabolic in peripheral tissues (muscle wasting, skin thinning); anabolic in liver
• Fat: Lipolysis in extremities; fat redistribution → central obesity, moon face, buffalo hump (Cushingoid pattern)
• Bone: ↓ osteoblast activity, ↑ osteoclast activity → osteoporosis (major long-term adverse effect)
• Calcium: ↓ intestinal Ca²⁺ absorption, ↑ renal Ca²⁺ excretion

Anti-inflammatory & Immunosuppressive Effects

• Phospholipase A₂ inhibition via induction of lipocortin (annexin-1) → ↓ arachidonic acid release → ↓ prostaglandins, leukotrienes, PAF
• NF-κB inhibition → ↓ TNF-α, IL-1, IL-2, IL-6, IL-8
• ↓ COX-2 expression
• Lymphocytopenia, eosinopenia (redistribution to lymphoid tissue/apoptosis)
• Neutrophilia (demargination from vessel walls + ↓ apoptosis)
• ↓ Macrophage activation and antigen presentation
• ↓ Mast cell degranulation
• ↓ Antibody synthesis at high doses

Cardiovascular Effects

• Maintain vascular tone and responsiveness to catecholamines
• Permissive effect on pressor responses
• Mineralocorticoid effects: Na⁺ retention → volume expansion → hypertension (with high doses)

Renal Effects

• At physiological doses: mild Na⁺ retention (weak mineralocorticoid effect of cortisol)
• ↑ GFR
• ↑ free water clearance (deficiency → hyponatremia in Addison's)

CNS Effects

• Euphoria, emotional lability, insomnia at pharmacological doses
• Psychosis with very high doses
• ↓ Brain ACTH release (negative feedback)

HPA Axis Suppression

• Exogenous glucocorticoids suppress the HPA axis, which is dose- and duration-dependent
• Abrupt withdrawal after prolonged use → adrenal crisis (Addisonian crisis)

Other Effects

• Growth: Inhibit GH secretion and IGF-1 action → growth retardation in children
• Hematopoiesis: ↑ RBCs, platelets, neutrophils; ↓ lymphocytes, eosinophils, basophils
• Lung maturation: Stimulate surfactant synthesis in fetal lungs

B. Mineralocorticoid Effects (Aldosterone/Fludrocortisone)

• Principal target: renal collecting tubule principal cells
• ↑ ENaC on apical membrane → Na⁺ reabsorption
• ↑ Na⁺/K⁺-ATPase on basolateral membrane → K⁺ excretion
• Net: Na⁺ and water retention, K⁺ and H⁺ excretion → hypokalemic metabolic alkalosis in excess

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8. Clinical Uses

Replacement Therapy

• Primary adrenal insufficiency (Addison's disease): hydrocortisone 15–25 mg/day in split doses + fludrocortisone 0.05–0.2 mg/day
• Secondary adrenal insufficiency: glucocorticoids only (aldosterone secretion is ACTH-independent)
• Congenital adrenal hyperplasia (21-hydroxylase deficiency): hydrocortisone to suppress ACTH + fludrocortisone for mineralocorticoid replacement
• Acute adrenal crisis: IV hydrocortisone 100 mg every 8 hours + fluids + electrolyte correction
• Stress dosing: "Sick day rules" — double/triple maintenance dose during illness; IV hydrocortisone during surgery

Anti-inflammatory / Immunosuppressive Uses

• Rheumatoid arthritis, SLE, vasculitis
• Inflammatory bowel disease (ulcerative colitis, Crohn's)
• Asthma, COPD exacerbations (systemic); inhaled corticosteroids for chronic asthma
• Allergic rhinitis (intranasal)
• Nephrotic syndrome
• Organ transplantation (prevention of rejection)
• Autoimmune hemolytic anemia, immune thrombocytopenia (ITP)
• Multiple sclerosis (acute relapses)

Specific Indications

• Cerebral edema (vasogenic): dexamethasone (does not alter CSF pressure; preferred for tumor-related edema)
• Septic shock: Hydrocortisone IV in vasopressor-refractory septic shock (stress-dose steroids, per surviving sepsis guidelines)
• Fetal lung maturation: Betamethasone or dexamethasone IM to mothers at 24–34 weeks gestation (reduces neonatal RDS)
• Croup (laryngotracheobronchitis): dexamethasone
• Thyroid storm, severe thyroiditis
• Hypercalcemia (sarcoidosis, vitamin D toxicity)
• Diagnostic: Dexamethasone suppression test (overnight: 1 mg; low-dose: 0.5 mg q6h × 2 days; high-dose: 2 mg q6h × 2 days) — for Cushing's syndrome work-up

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9. Routes of Administration

Topical Potency Classes (I = Most Potent → VII = Least Potent)

• Class I (superpotent): Clobetasol propionate 0.05%, halobetasol propionate
• Class II (potent): Fluocinonide 0.05%, betamethasone dipropionate
• Class III–IV (moderate): Triamcinolone acetonide 0.1%, fluocinolone acetonide
• Class V–VI: Betamethasone valerate 0.1%, hydrocortisone butyrate
• Class VII (least potent): Hydrocortisone 1–2.5%

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10. Adverse Effects

Short-term (Days to Weeks)

• Hyperglycemia / precipitation of steroid diabetes
• Fluid retention, hypertension
• Hypokalemia
• Psychiatric: insomnia, euphoria, mood swings, psychosis
• Increased susceptibility to infection (masking signs)
• Peptic ulceration (especially with NSAIDs)

Long-term (Weeks to Months)

• Osteoporosis — most serious; give prophylactic calcium, vitamin D, bisphosphonates
• Cushing syndrome: central obesity, moon face, buffalo hump, striae, easy bruising
• HPA axis suppression → risk of adrenal crisis on withdrawal
• Cataract (posterior subcapsular)
• Glaucoma
• Avascular necrosis of bone (femoral head most common)
• Growth retardation in children
• Myopathy (proximal muscle weakness)
• Impaired wound healing
• Skin atrophy, striae, hirsutism

Management of Adverse Effects

• Use the lowest effective dose for the shortest duration
• Alternate-day dosing reduces HPA suppression and some metabolic effects
• Tapering required after >2–3 weeks of pharmacological doses to allow HPA axis recovery
• Monitor bone density (DEXA scan); supplement calcium + vitamin D; consider bisphosphonates

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11. Mineralocorticoid Antagonists

Spironolactone

• Competitive antagonist at the MR
• Additional anti-androgenic effects (blocks androgen receptor)
• Uses: primary hyperaldosteronism, heart failure, resistant hypertension, ascites (cirrhosis)
• Adverse effects: gynecomastia, menstrual irregularities, hyperkalemia

Eplerenone

• Selective MR antagonist (no anti-androgenic effects)
• Uses: heart failure post-MI, hypertension
• Fewer endocrine adverse effects than spironolactone

Finerenone

• Non-steroidal selective MR antagonist (newer)
• Approved for CKD with T2DM (cardiovascular and renal protection)

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12. Glucocorticoid Synthesis Inhibitors & Antagonists

Metyrapone

• Inhibits 11β-hydroxylase (CYP11B1) → blocks cortisol synthesis
• Used: Cushing's syndrome (off-surgery), metyrapone stimulation test (tests pituitary reserve)
• Effect: ↑ 11-deoxycortisol, ↓ cortisol

Ketoconazole

• Fungal CYP inhibitor that also inhibits adrenal CYP17 and CYP11B1
• Used: Cushing's syndrome (medical management)
• Hepatotoxicity is a concern

Aminoglutethimide

• Inhibits CYP11A1 (cholesterol → pregnenolone) — blocks all steroid synthesis
• Historical use: adrenal tumors, Cushing's; largely replaced by newer agents

Mitotane (o,p'-DDD)

• Adrenolytic agent — selectively destroys zona fasciculata and zona reticularis
• First-line medical therapy for adrenocortical carcinoma
• Requires glucocorticoid replacement during use

Etomidate

• IV anesthetic that also inhibits 11β-hydroxylase — used for rapid cortisol reduction in severe Cushing's (ICU setting)

Mifepristone (RU-486)

• Potent glucocorticoid receptor antagonist (also progesterone antagonist)
• Approved for Cushing's syndrome in patients with glucose intolerance/diabetes who cannot have surgery
• Does not lower plasma cortisol levels (levels may rise due to loss of feedback); monitor clinically

Osilodrostat & Levoketoconazole

• Newer agents for Cushing's syndrome:
  • Osilodrostat: inhibits 11β-hydroxylase (CYP11B1) and aldosterone synthase
  • Levoketoconazole: more potent/selective version of ketoconazole for steroidogenesis inhibition

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13. ACTH vs. Adrenocortical Steroids

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14. Key Clinical Scenarios

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Summary: Key Pharmacology Points

1. Cortisol is the prototype glucocorticoid; aldosterone is the prototype mineralocorticoid
2. Mechanism is primarily genomic via intracellular nuclear receptors (GR, MR)
3. 11β-HSD2 protects MR specificity by inactivating cortisol to cortisone in kidney
4. Synthetic modifications (fluorination, methylation) alter potency and receptor selectivity
5. Dexamethasone = high glucocorticoid potency, no mineralocorticoid effect, long half-life → ideal for cerebral edema, fetal lung maturation, suppression testing
6. Fludrocortisone = the only clinically useful oral mineralocorticoid for replacement
7. HPA suppression is inevitable with prolonged pharmacological use; taper gradually
8. Anti-inflammatory mechanism: Lipocortin induction → ↓ phospholipase A₂ + NF-κB inhibition → ↓ cytokine/eicosanoid synthesis
9. Spironolactone/eplerenone block MR; metyrapone/ketoconazole block synthesis; mifepristone blocks GR

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