Corticosteroids - Complete Pharmacology Notes (KDT / Katzung Style)

Q1 - Classification of Corticosteroids + Pharmacology of Glucocorticoids

A. Classification of Corticosteroids

I. Glucocorticoids (act on carbohydrate, protein, fat metabolism + anti-inflammatory)

• Hydrocortisone (cortisol) - 20 mg equivalent; 1:1 glucocorticoid:mineralocorticoid

• Prednisolone - 5 mg equivalent; 4x glucocorticoid potency
• Prednisone - prodrug, converted to prednisolone
• Methylprednisolone - 4 mg equivalent; 5x glucocorticoid potency; negligible mineralocorticoid activity
• Triamcinolone - 4 mg equivalent; 5x potency; no mineralocorticoid activity

• Dexamethasone - 0.75 mg equivalent; 25-30x glucocorticoid potency; no mineralocorticoid activity
• Betamethasone - 0.6 mg equivalent; 25-30x glucocorticoid potency

• Beclomethasone, budesonide, fluticasone, mometasone, flunisolide, ciclesonide

II. Mineralocorticoids (act on sodium/potassium balance)

• Aldosterone (endogenous, not used therapeutically)
• Fludrocortisone (synthetic; used in Addison disease, postural hypotension)
• Deoxycorticosterone acetate (DOCA)

III. Sex Corticoids (androgens/estrogens - minor classification)

• DHEA, androstenedione (adrenal androgens - weak activity)

B. Pharmacological Actions of Glucocorticoids

1. Metabolic Effects

• Stimulate gluconeogenesis in the liver (increased glucose output)
• Decrease peripheral glucose utilization (anti-insulin effect)
• Activate glycogen synthase - increase hepatic glycogen storage
• Net result: hyperglycemia ("steroid diabetes")

• Catabolic effect on peripheral tissues (muscle, skin, bone, lymphoid tissue)
• Increased amino acid mobilization from muscle - provides substrate for gluconeogenesis
• Decreased protein synthesis peripherally; increased synthesis in liver

• Promote lipolysis - free fatty acids released from adipose tissue
• Redistribution of fat - central/truncal obesity (buffalo hump, moon face, supraclavicular pads)
• Peripheral fat decreased (thin limbs)

2. Anti-inflammatory and Immunosuppressive Effects (Most Clinically Important)

• Inhibit phospholipase A2 (via induction of lipocortin/annexin-1) - blocks arachidonic acid release, thus inhibiting both COX and lipoxygenase pathways - reduces prostaglandins, thromboxanes, and leukotrienes
• Decrease capillary permeability (stabilize capillary endothelium via vasocortin)
• Inhibit vasodilation and reduce edema
• Reduce migration of leukocytes to sites of inflammation
• Decrease phagocyte activity
• Reduce lymphocyte production and promote lympholysis
• Inhibit T-cell proliferation and cytokine production (IL-1, IL-2, IL-6, TNF-alpha, IFN-gamma)
• Stabilize lysosomal membranes (reduce release of lysosomal enzymes)

3. Cardiovascular Effects

• Maintain cardiac output and vascular tone
• Permissive effect: maintain sensitivity of vessels to catecholamines
• Deficiency causes hypotension; excess causes hypertension

4. Renal / Salt and Water Effects

• Cortisol has mild mineralocorticoid activity: promotes Na+ retention, K+ and H+ excretion
• Increases glomerular filtration rate

5. Effect on Blood Cells

• Increase: Erythrocytes, platelets, neutrophils (demargination)
• Decrease: Lymphocytes, eosinophils, monocytes, basophils
• Classic finding: neutrophilia + lymphopenia + eosinopenia (stress leukogram)

6. Musculoskeletal

• Catabolic effect on bone: reduce osteoblast activity, increase osteoclast activity
• Decrease calcium absorption from gut, increase renal calcium excretion
• Long-term: osteoporosis
• High doses/prolonged use: myopathy (proximal muscle weakness)

7. CNS Effects

• Euphoria, mood elevation at low doses
• Insomnia, anxiety, psychosis, depression at high doses
• Lowers seizure threshold

8. HPA Axis Suppression

• Exogenous glucocorticoids suppress CRH (hypothalamus) and ACTH (pituitary) via negative feedback
• Leads to adrenal cortical atrophy with prolonged use
• This is the basis of adrenal suppression (see Q2)

9. Anti-allergic Effects

• Inhibit release of histamine from mast cells and basophils
• Reduce IgE-mediated responses

10. Permissive Actions

• Required for normal responses to epinephrine and glucagon (lipolysis, glycogenolysis)
• Deficiency of glucocorticoids reduces the effectiveness of catecholamines

C. Therapeutic Uses of Glucocorticoids

I. As Replacement Therapy (Physiological doses)

• Addison disease (primary adrenal insufficiency): hydrocortisone 20 mg/day + fludrocortisone
• Congenital adrenal hyperplasia (CAH): suppress ACTH overproduction
• Hypopituitarism (secondary adrenal insufficiency)
• Acute adrenal crisis: IV hydrocortisone 100 mg q8h

II. As Anti-inflammatory/Immunosuppressive Agents (Pharmacological/supraphysiological doses)

• Rheumatoid arthritis (short-term, bridging therapy)
• Systemic lupus erythematosus (SLE)
• Polymyalgia rheumatica, vasculitis, polymyositis, dermatomyositis

• Bronchial asthma (inhaled: first-line for persistent asthma; systemic: acute severe asthma)
• COPD exacerbations
• Sarcoidosis, pulmonary fibrosis

• Pemphigus, pemphigoid
• Severe eczema, psoriasis (topical)
• Allergic contact dermatitis

• Inflammatory bowel disease (Crohn disease, ulcerative colitis)

• Cerebral edema (dexamethasone - especially peri-tumoral or post-operative)
• Multiple sclerosis (acute relapse: high-dose IV methylprednisolone)
• Bacterial meningitis (dexamethasone to reduce inflammation)

• Autoimmune hemolytic anemia
• Immune thrombocytopenic purpura (ITP)
• Acute lymphoblastic leukemia (part of chemotherapy protocol)
• Hemolytic disease of newborn

• Prevention and treatment of organ rejection (used with other immunosuppressants)

• Uveitis, optic neuritis, severe allergic conjunctivitis

• Betamethasone/dexamethasone given to mother before preterm birth to accelerate fetal lung maturity (surfactant induction)

• Dexamethasone suppression test for Cushing syndrome

• Nephrotic syndrome (minimal change disease)
• Bell's palsy
• Spinal cord injury
• Cancer-related hypercalcemia
• Nausea with chemotherapy (dexamethasone)

D. Adverse Effects of Glucocorticoids

Metabolic

• Hyperglycemia / steroid diabetes
• Hyperlipidemia
• Cushing syndrome (moon face, central obesity, buffalo hump, striae, skin thinning)
• Negative nitrogen balance

Musculoskeletal

• Osteoporosis (major concern with long-term use) - risk of vertebral and hip fractures
• Avascular necrosis (femoral head, humeral head)
• Myopathy - proximal muscle weakness (especially with fluorinated steroids: triamcinolone, dexamethasone)
• Growth retardation in children

Endocrine / Metabolic

• HPA axis suppression - most important long-term adverse effect
• Adrenal atrophy
• Menstrual irregularities
• Decreased spermatogenesis

Cardiovascular

• Hypertension (Na+ retention, increased renin-angiotensin)
• Increased risk of atherosclerosis
• Edema

Gastrointestinal

• Peptic ulcer disease (especially combined with NSAIDs)
• Gastric hemorrhage
• Pancreatitis (rare)

Immunological

• Immunosuppression - susceptibility to infections (bacterial, fungal, viral, TB reactivation)
• Masks signs of infection (due to anti-inflammatory effect)

Ophthalmic

• Posterior subcapsular cataracts (with prolonged use)
• Raised intraocular pressure / glaucoma

CNS / Psychiatric

• Euphoria, insomnia, psychosis, depression
• Pseudotumor cerebri (on withdrawal)

Dermatological

• Skin thinning, striae, easy bruising
• Acne, hirsutism
• Impaired wound healing

Fluid/Electrolyte (more with mineralocorticoid-active steroids)

• Sodium retention, edema
• Hypokalemia
• Metabolic alkalosis

Pediatric

• Growth suppression
• Behavioral changes

E. Contraindications to Glucocorticoids

Absolute Contraindications (relative in life-threatening situations):

• Systemic fungal infections
• Active untreated tuberculosis (can reactivate latent TB)
• Hypersensitivity to corticosteroids

Relative Contraindications:

• Peptic ulcer disease
• Diabetes mellitus (will worsen glycemia)
• Hypertension (will elevate BP further)
• Osteoporosis (will worsen bone loss)
• Psychosis (may precipitate steroid psychosis)
• Congestive heart failure
• Renal insufficiency
• Glaucoma
• Herpes simplex eye infection (can lead to corneal perforation)
• Pregnancy (first trimester - risk of cleft palate; use only if essential)
• Live virus vaccines should not be given to patients on immunosuppressive doses

Q2 - Steroid Withdrawal Syndrome and Adrenal Suppression

A. Adrenal Suppression (HPA Axis Suppression)

Mechanism:

• The hypothalamic-pituitary-adrenal (HPA) axis is regulated by negative feedback.
• Exogenous glucocorticoids suppress the release of CRH from the hypothalamus and ACTH from the pituitary.
• With prolonged suppression, the adrenal cortex undergoes atrophy due to lack of ACTH stimulation.
• The adrenal gland loses its ability to synthesize adequate cortisol in response to physiological stress.

When does suppression occur?

• Suppression is unlikely with:
  • Use for <3 weeks at any dose
  • Alternate-day therapy with short-acting agents
  • Morning single doses (mimics diurnal rhythm)
• Suppression is likely with:
  • Doses equivalent to >7.5 mg prednisone/day for >3 weeks
  • Evening/bedtime dosing
  • Large doses, regardless of duration

Recovery after cessation:

• Pituitary ACTH secretion recovers first (within weeks to months)
• Adrenal cortical recovery follows but may take 6-12 months or longer
• During recovery, the patient is vulnerable to adrenal crisis with physiological stress

Clinical features of adrenal insufficiency (from suppression):

• Weakness, fatigue
• Hypotension (especially orthostatic/postural)
• Nausea, vomiting
• Hyponatremia, hyperkalemia
• Hypoglycemia
• Fever
• Weight loss

B. Steroid Withdrawal Syndrome

Definition:

Mechanism:

• The body has been adapted to supraphysiological glucocorticoid levels.
• Abrupt withdrawal results in a relative deficiency state.
• The physiology becomes dependent on high glucocorticoid levels.
• Even normal cortisol levels feel inadequate after prolonged high-dose exposure.

Clinical features:

• Anorexia, malaise, lethargy
• Nausea, sometimes vomiting
• Weight loss
• Headache, fever
• Myalgia, arthralgia
• Desquamation (skin peeling)
• Psychological symptoms: depression, rebound inflammation

Key distinction from true adrenal insufficiency:

Prevention:

• Slow tapering of doses rather than abrupt cessation
• Standard tapering: reduce by ~10-25% every 1-2 weeks
• Below physiological dose (<5 mg prednisone/day), taper even more slowly
• Stress-dosing during illness, surgery, or trauma
• Patient education: never stop abruptly

Q3 - Clinical Case: Abrupt Steroid Stoppage

a) Probable Diagnosis

b) Why Does This Occur?

• Long-term exogenous glucocorticoid therapy suppresses the HPA axis via negative feedback on the hypothalamus (CRH) and pituitary (ACTH).
• Chronic ACTH deficiency leads to adrenal cortical atrophy - the adrenal glands lose their functional capacity.
• When exogenous steroids are suddenly stopped, the atrophied adrenal cortex cannot produce sufficient cortisol to meet even basal physiological needs.
• The resultant cortisol deficiency causes:
  • Weakness - loss of glucocorticoid-dependent vascular tone and muscle metabolism
  • Hypotension - glucocorticoids are required for vascular smooth muscle sensitivity to catecholamines; without cortisol, severe vasodilation and hypotension result
  • Vomiting/nausea - direct effect of cortisol deficiency on GI motility and electrolyte balance
  • Hyponatremia, hyperkalemia, hypoglycemia may also occur

c) How Can It Be Prevented?

1. Never stop abruptly - always taper corticosteroids gradually:
   • Reduce dose by 10-25% every 1-2 weeks
   • When approaching physiological levels (5 mg prednisone/day equivalent), taper even more slowly
2. Alternate-day therapy: Use short-acting agents (prednisolone) on alternate mornings to minimize HPA suppression while maintaining therapeutic effect
3. Morning dosing: A single morning dose mimics the natural diurnal cortisol peak and causes less HPA suppression
4. Stress dosing: Patients on long-term corticosteroids must receive increased doses during physiological stress (surgery, serious illness, major trauma) - this is called the "sick day rule" or steroid cover
5. Patient education: Patients must be explicitly told NOT to stop steroids abruptly and to carry a steroid card/medical alert bracelet
6. Assessment of HPA recovery: Measure morning cortisol and ACTH stimulation test to determine when the adrenal axis has recovered before complete withdrawal
7. Treatment of acute adrenal crisis (if it occurs):
   • IV hydrocortisone 100 mg immediately, then 50-100 mg q6-8h
   • IV 0.9% normal saline to correct hypotension
   • IV dextrose for hypoglycemia
   • Treat the precipitating cause

Q4 - Short Note: Inhaled Corticosteroids (ICS) in Bronchial Asthma

Definition

Available ICS Agents

Mechanism of Action

• Bind to glucocorticoid receptors in airway epithelial cells
• Suppress production of pro-inflammatory cytokines (IL-1, IL-2, IL-4, IL-5, TNF-alpha)
• Inhibit phospholipase A2 (via lipocortin induction) - reduce prostaglandins and leukotrienes
• Reduce mucosal edema, decrease airway secretions
• Reduce eosinophilic infiltration in airway mucosa
• Decrease airway hyperresponsiveness (AHR) - the hallmark of asthma
• Reduce smooth muscle hypertrophy and subepithelial fibrosis with long-term use (reduce remodeling)

Role / Therapeutic Place

• First-line controller therapy for all grades of persistent asthma (mild, moderate, severe) per GINA (Global Initiative for Asthma) guidelines
• Reduce frequency and severity of exacerbations
• Decrease need for rescue bronchodilators
• Improve peak expiratory flow and FEV1
• Reduce asthma-related hospitalization and mortality

Doses (Adult Approximate Equivalents)

Advantages Over Systemic Corticosteroids

• Act locally with high topical potency
• Very low systemic bioavailability (beclomethasone ~20%, budesonide ~11%, fluticasone <1%)
• First-pass hepatic metabolism reduces systemic effects
• Significantly reduced systemic adverse effects
• Can be used long-term safely (in appropriate doses)

Adverse Effects of ICS

• Oropharyngeal candidiasis (thrush) - most common local side effect
• Dysphonia (hoarseness) - due to vocal cord myopathy
• Cough and throat irritation

• Adrenal suppression (minimal at standard doses; becomes significant >800 mcg/day budesonide equivalent)
• Growth retardation in children (at high doses - remains controversial)
• Osteoporosis (with very high doses over many years)
• Posterior subcapsular cataract (rare, high doses)
• Skin thinning, bruising (at high doses)

Important Points (Exam Tips - MBBS)

1. ICS do NOT have bronchodilator activity - they are preventers, not relievers
2. Patients must be educated to use ICS regularly even when asymptomatic
3. Short-acting beta-2 agonist (SABA, e.g., salbutamol) is used as a rescue (reliever) drug
4. Spacer devices improve drug delivery and reduce oropharyngeal side effects
5. Ciclesonide is a prodrug - activated by airway esterases to active metabolite (des-ciclesonide), minimizing oropharyngeal effects
6. Budesonide nebulizer is used in acute asthma in children and for home nebulization