Corticosteroids

Corticosteroids are among the most heavily examined pharmacology topics in NEET PG because they straddle endocrinology, immunology, and every clinical subject. This set covers glucocorticoid and mineralocorticoid pharmacology, the molecular anti-inflammatory mechanism, relative potencies, adverse effects, Cushing's features, and the high-yield rules of pulse dosing, tapering, and adrenal crisis prevention.

Definition & classification

Corticosteroids are steroid hormones synthesised by the adrenal cortex (and their synthetic analogues). The natural human glucocorticoid is cortisol (hydrocortisone) and the natural mineralocorticoid is aldosterone. Synthesis follows the steroidogenic pathway from cholesterol; the rate-limiting step is cholesterol → pregnenolone via the side-chain cleavage enzyme (CYP11A1, "desmolase"), stimulated by ACTH acting on the zona fasciculata/reticularis.

The adrenal cortex has three zones — a useful mnemonic is "GFR — Salt, Sugar, Sex":

• Glomerulosa → mineralocorticoids (aldosterone) — "salt"
• Fasciculata → glucocorticoids (cortisol) — "sugar"
• Reticularis → androgens (DHEA) — "sex"

Glucocorticoids are classified pharmacologically by duration of action and by their glucocorticoid vs mineralocorticoid potency ratio.

Class (by duration)	Drug	Anti-inflammatory (GC) potency	Mineralocorticoid potency	Approx. equivalent dose (mg)	Biological t½ (hrs)
Short-acting	Hydrocortisone (cortisol)	1	1	20	8–12
Short-acting	Cortisone	0.8	0.8	25	8–12
Intermediate	Prednisolone	4	0.8	5	12–36
Intermediate	Methylprednisolone	5	0.5	4	12–36
Intermediate	Triamcinolone	5	0	4	12–36
Long-acting	Dexamethasone	25–30	~0	0.75	36–72
Long-acting	Betamethasone	25–30	~0	0.6	36–72

High-yield: The single most-asked equivalence — Hydrocortisone 20 mg = Prednisolone 5 mg = Methylprednisolone 4 mg = Dexamethasone 0.75 mg. Anti-inflammatory potency rises in this same order; mineralocorticoid activity falls in this order (highest in hydrocortisone, essentially nil in dexamethasone/betamethasone).

High-yield: Fludrocortisone is the most potent mineralocorticoid (≈ 125–150× hydrocortisone for salt-retention) and is the agent used as mineralocorticoid replacement in Addison's disease and salt-wasting CAH.

Etiology & pathophysiology — mechanism of action

Glucocorticoids are lipophilic and diffuse across the cell membrane to bind the cytosolic glucocorticoid receptor (GR), which is held inactive by HSP90. On binding, HSP90 dissociates, the receptor-ligand complex dimerises and translocates to the nucleus, where it binds glucocorticoid response elements (GREs) on DNA. This produces both transactivation (increased transcription) and transrepression (decreased transcription) — the genomic effect explains the characteristic delay of hours before clinical benefit.

The two pillars of the anti-inflammatory effect:

1. Induction of lipocortin-1 (annexin A1) → lipocortin inhibits phospholipase A₂ → blocks liberation of arachidonic acid → reduces synthesis of both prostaglandins and leukotrienes (entire eicosanoid cascade, unlike NSAIDs which spare leukotrienes).
2. Inhibition of NF-κB (the master pro-inflammatory transcription factor) → ↓ COX-2, ↓ iNOS, ↓ pro-inflammatory cytokines (IL-1, IL-2, IL-6, TNF-α).

Mechanism flow: GC enters cell → binds cytosolic GR (HSP90 released) → complex enters nucleus → binds GRE → ↑ lipocortin-1 + ↓ NF-κB → ↓ PLA₂ and ↓ COX-2 → ↓ prostaglandins, leukotrienes, cytokines → anti-inflammatory & immunosuppressive effect.

High-yield: Glucocorticoids inhibit phospholipase A₂ (via lipocortin) — the step above cyclooxygenase. This is why steroids reduce leukotrienes while NSAIDs do not. A favourite distractor is "direct inhibition of COX" — that is wrong; the COX-2 reduction is at the transcriptional level via NF-κB suppression.

Mineralocorticoid action: aldosterone binds the mineralocorticoid receptor (MR) in renal collecting-duct principal cells → ↑ ENaC and Na⁺/K⁺-ATPase → Na⁺/water retention, K⁺ and H⁺ excretion. The enzyme 11β-HSD2 normally converts cortisol → cortisone in the kidney to protect MR from cortisol; its deficiency or inhibition (e.g. liquorice, carbenoxolone) lets cortisol activate MR → apparent mineralocorticoid excess (hypertension, hypokalaemia).

Physiological & pharmacological effects

• Carbohydrate/protein/fat: ↑ gluconeogenesis and insulin resistance (hyperglycaemia, "steroid diabetes"); protein catabolism (muscle wasting, thin skin, poor healing); redistribution of fat to face/trunk (moon face, buffalo hump, central obesity) with limb wasting.
• Permissive effect: required for catecholamines/glucagon to act on vasculature and lipolysis — basis of vasopressor support in adrenal crisis.
• Bone: ↓ osteoblast activity, ↑ osteoclast activity, ↓ intestinal Ca²⁺ absorption, ↑ renal Ca²⁺ loss → osteoporosis.
• Immune/blood: lym, eosino-, basopenia but neutrophilia (demargination) and monocytopenia.
• CNS: mood elevation, insomnia, psychosis; CRH/ACTH suppression (negative feedback).
• GI: peptic ulcer risk (esp. with NSAIDs).

High-yield: Steroids cause a neutrophilic leukocytosis (margination release + reduced extravasation) but a lymphopenia and eosinopenia. A raised total WBC on steroids is often just demargination, not infection.

Clinical features of glucocorticoid excess — Cushing's syndrome

Chronic glucocorticoid excess (exogenous steroids are the commonest cause overall; endogenous Cushing's disease = pituitary ACTH adenoma is the commonest endogenous cause) produces:

• Central obesity, moon facies, buffalo hump, supraclavicular fat pads
• Purple/violaceous striae (>1 cm), easy bruising, thin skin
• Proximal myopathy (difficulty rising from chair)
• Hypertension, hyperglycaemia/diabetes, hypokalaemic metabolic alkalosis
• Osteoporosis, avascular necrosis (femoral head)
• Hirsutism, acne, menstrual irregularity, immunosuppression
• Psychiatric disturbance

Feature	Exogenous (iatrogenic) Cushing's	Endogenous Cushing's
Cause	Therapeutic steroids	ACTH adenoma / adrenal tumour / ectopic ACTH
Adrenal androgens	Low (acne/hirsutism rare)	Often high (acne, hirsutism)
Skin pigmentation	Absent	Present if ACTH-dependent (POMC)
Plasma ACTH & cortisol	Both suppressed	Variable; cortisol high
Bilateral adrenals	Atrophic	Hyperplastic/mass

High-yield: Iatrogenic Cushing's is best discriminated from endogenous by low/absent adrenal androgen and ACTH-driven pigmentation features, plus a suppressed morning cortisol and ACTH.

Diagnosis & investigations (Cushing's screening)

Screening tests for hypercortisolism (any one positive → confirm with a second):

1. Overnight 1 mg dexamethasone suppression test — failure to suppress 8 a.m. cortisol below 1.8 µg/dL is abnormal.
2. Late-night salivary cortisol (loss of diurnal rhythm).
3. 24-hour urinary free cortisol (≥ 3× upper limit is diagnostic).

Localisation flow: confirm hypercortisolism → measure plasma ACTH → if suppressed = ACTH-independent (adrenal) → CT adrenals; if normal/high = ACTH-dependent → high-dose dexamethasone suppression (8 mg) + pituitary MRI + inferior petrosal sinus sampling to separate pituitary (suppresses) from ectopic ACTH (does not suppress).

Management — therapeutic uses & drug of choice (DOC)

Glucocorticoids are first-line/DOC in a wide range of conditions. High-yield DOCs:

Indication	Preferred corticosteroid / rationale
Acute severe asthma	Systemic prednisolone/hydrocortisone
Antenatal fetal lung maturity	Betamethasone (or dexamethasone) — cross placenta, low MR effect
Cerebral oedema (tumour)	Dexamethasone (least mineralocorticoid → no fluid retention)
Bacterial meningitis (adjunct)	Dexamethasone before/with first antibiotic
Adrenal crisis	IV hydrocortisone 100 mg
Addison's replacement	Hydrocortisone + fludrocortisone
Congenital adrenal hyperplasia	Hydrocortisone (kids) ± fludrocortisone
Septic shock (refractory)	IV hydrocortisone
Autoimmune flares (SLE, vasculitis)	Prednisolone; pulse methylprednisolone for severe
Allergic/anaphylaxis (adjunct)	Hydrocortisone (adrenaline is first-line)
COVID-19 needing O₂	Dexamethasone (RECOVERY trial)

High-yield: Dexamethasone is preferred where fluid retention must be avoided (cerebral oedema, raised ICP) and for antenatal lung maturity because of negligible mineralocorticoid activity. Hydrocortisone is the DOC in acute adrenal crisis because it provides both glucocorticoid and some mineralocorticoid cover and acts fast IV.

Pulse vs maintenance dosing

• Pulse therapy = very high IV dose (e.g. methylprednisolone 0.5–1 g/day IV × 3 days) for life- or organ-threatening autoimmune disease (lupus nephritis, severe vasculitis, transplant rejection, optic neuritis). Rationale: rapid, profound non-genomic + genomic immunosuppression with relatively fewer long-term toxicities than equivalent prolonged oral high-dose therapy, and quicker control of the flare.
• Maintenance therapy = lowest effective daily/alternate-day dose to control disease while limiting cumulative toxicity. Alternate-day dosing of a short/intermediate agent (prednisolone) given as a single morning dose mimics the natural diurnal peak and causes less HPA-axis suppression and growth retardation.

High-yield: Morning single-dose and alternate-day regimens reduce HPA suppression because they respect the natural circadian cortisol rhythm (peak ~8 a.m.).

Tapering & avoidance of adrenal crisis

Exogenous glucocorticoids suppress CRH→ACTH→adrenal axis; abrupt withdrawal after >2–3 weeks of supraphysiological dosing risks acute adrenal insufficiency (Addisonian crisis).

Withdrawal flow: assess duration/dose → if used < 3 weeks or truly low dose, can usually stop abruptly → if prolonged/high dose, taper gradually (reduce ~10–20% every few days–weeks) → "stress dosing" (increase dose) during surgery, sepsis, trauma → monitor for crisis symptoms.

High-yield: Adrenal (Addisonian) crisis = hypotension/shock, hyponatraemia, hyperkalaemia, hypoglycaemia, fever, abdominal pain. Treatment = IV hydrocortisone 100 mg stat + IV normal saline + dextrose; do not wait for confirmatory tests. Sudden steroid cessation, infection, or surgery in a steroid-dependent patient are classic triggers.

Adverse effects (systemic) — high-yield list

A useful mnemonic — "CUSHINGOID MAP":

• Cataracts (posterior subcapsular) & glaucoma
• Ulcers (peptic)
• Striae / skin thinning / bruising
• Hypertension / Hyperglycaemia
• Infections (immunosuppression — TB reactivation, fungal, opportunistic)
• Necrosis — avascular necrosis of femoral head
• Growth retardation (children)
• Osteoporosis
• Immunosuppression
• Diabetes / Depression-psychosis
• Myopathy (proximal)
• Activation of HPA suppression / Adipose redistribution
• Pancreatitis / Psychosis

High-yield: Posterior subcapsular cataract and avascular (aseptic) necrosis of the femoral head are signature long-term steroid toxicities frequently asked. Steroids also cause a hypokalaemic metabolic alkalosis via mineralocorticoid effect (less with dexamethasone).

Special points:

• Osteoporosis prophylaxis: anyone on ≥ 5–7.5 mg prednisolone for ≥ 3 months should get calcium + vitamin D, and bisphosphonates if at risk — most-tested preventive measure.
• Live vaccines are contraindicated on high-dose immunosuppressive steroids.
• Latent TB screening before long-term steroids/biologics.
• Growth suppression in children — minimise with alternate-day dosing.
• Topical/inhaled: skin atrophy, oral candidiasis, dysphonia (rinse mouth after inhaler).

Inhibitors of steroid synthesis/action (commonly paired)

Drug	Action	Use
Ketoconazole	Inhibits multiple CYP steroidogenic enzymes	Cushing's
Metyrapone	Inhibits 11β-hydroxylase	Cushing's / test of HPA
Mitotane	Adrenocortical cytotoxic	Adrenal carcinoma
Aminoglutethimide	Inhibits desmolase (CYP11A1)	Steroid excess
Mifepristone	GR (and PR) antagonist	Cushing's with diabetes
Spironolactone/eplerenone	MR antagonist	Hyperaldosteronism
Osilodrostat	11β-hydroxylase inhibitor (newer)	Cushing's disease

Complications & monitoring

Long-term therapy demands monitoring of blood pressure, blood glucose, weight, bone mineral density (DEXA), serum potassium, eye examination, and growth in children. Watch for masked infection (steroids blunt fever and inflammatory signs), delayed wound healing, and steroid-induced psychosis.

Key differentials & contrast points

• Glucocorticoid vs NSAID anti-inflammatory: steroids block PLA₂ (both PG + LT); NSAIDs block only COX (PG only).
• Cushing's syndrome vs disease: syndrome = any cause of cortisol excess; disease = pituitary ACTH-secreting adenoma specifically.
• Primary (Addison's) vs secondary adrenal insufficiency: primary has hyperpigmentation (high ACTH/POMC) and hyperkalaemia (aldosterone lost); secondary (pituitary or steroid-induced) has no hyperpigmentation and normal/near-normal potassium (RAAS intact).
• Dexamethasone vs hydrocortisone: dexamethasone — long-acting, no salt retention, used for oedema/antenatal; hydrocortisone — short-acting, salt-retaining, used for replacement/crisis.

Recently asked / exam angle

• Equivalent anti-inflammatory doses (the 20/5/4/0.75 mg set) and ranking of mineralocorticoid potency — perennial favourite.
• "Which steroid for cerebral oedema / antenatal lung maturity?" → Dexamethasone/Betamethasone (low MR activity).
• Mechanism: lipocortin-1 induction → PLA₂ inhibition; NF-κB suppression. Distinguishing from COX inhibition.
• Fludrocortisone as the strongest mineralocorticoid and DOC for mineralocorticoid replacement.
• Adrenal crisis management — IV hydrocortisone + saline, and the need to taper after prolonged use.
• Signature toxicities: posterior subcapsular cataract, avascular necrosis, osteoporosis prophylaxis with bisphosphonates + Ca/Vit D.
• 1 mg overnight dexamethasone suppression cut-off (1.8 µg/dL) and the ACTH-based localisation algorithm.
• RECOVERY trial: dexamethasone reduces mortality in COVID-19 patients needing oxygen/ventilation.
• 11β-HSD2 / liquorice → apparent mineralocorticoid excess.

Rapid revision

1. Cortex zones GFR: Glomerulosa→aldosterone, Fasciculata→cortisol, Reticularis→androgens; ACTH drives the inner two.
2. Equivalence: Hydrocortisone 20 = Prednisolone 5 = Methylprednisolone 4 = Dexamethasone 0.75 mg.
3. Anti-inflammatory potency ↑ and mineralocorticoid potency ↓ from hydrocortisone → dexamethasone.
4. Fludrocortisone = most potent mineralocorticoid; DOC for mineralocorticoid replacement.
5. Mechanism: GR binding → lipocortin-1 ↑ (PLA₂ ↓) + NF-κB ↓ → blocks PGs and leukotrienes.
6. Dexamethasone/betamethasone for cerebral oedema and antenatal lung maturity (no salt retention).
7. Hydrocortisone IV 100 mg = DOC for adrenal crisis; give with saline + dextrose.
8. Steroids cause neutrophilia but lymphopenia + eosinopenia.
9. Taper after > 2–3 weeks of therapy; stress-dose during surgery/sepsis to prevent crisis.
10. Signature toxicities: posterior subcapsular cataract, avascular necrosis of femur, osteoporosis (give Ca + Vit D ± bisphosphonate).
11. Overnight 1 mg dexamethasone suppression: cortisol fails to fall < 1.8 µg/dL = abnormal.
12. Iatrogenic Cushing's = suppressed ACTH, atrophic adrenals, low androgens; primary insufficiency = hyperpigmentation + hyperkalaemia.