Corticosteroids Pharmacology

Quick Answer

Corticosteroids are synthetic analogues of endogenous cortisol with varying ratios of glucocorticoid (anti-inflammatory, metabolic) to mineralocorticoid (sodium retention) activity. In anaesthesia, they are used for PONV prophylaxis (dexamethasone 4-8 mg), airway oedema (dexamethasone 0.5 mg/kg), anaphylaxis (second-line after adrenaline), and perioperative stress-dose supplementation in patients with adrenal suppression. Key agents include hydrocortisone (short-acting, high mineralocorticoid activity), prednisolone (intermediate), methylprednisolone (minimal mineralocorticoid), and dexamethasone (long-acting, pure glucocorticoid). Mechanism involves both genomic (nuclear receptor, altered gene transcription - hours) and non-genomic (membrane effects - minutes) pathways.

ANZCA Primary Exam Relevance: High-yield topic. Understand HPA axis physiology, classification by potency and duration, mechanism of action (genomic vs non-genomic), perioperative applications, and stress-dose protocols.

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1. Physiology of Cortisol

The Hypothalamic-Pituitary-Adrenal (HPA) Axis

The HPA axis is the central regulatory system for cortisol production and release. Understanding this axis is essential for managing perioperative steroid supplementation. [1]

Hierarchical Control:

Negative Feedback:

Both cortisol and synthetic corticosteroids inhibit CRH and ACTH release through:

• Fast feedback (minutes): Non-genomic membrane effects reducing ACTH secretion
• Delayed feedback (hours): Genomic suppression of POMC gene transcription
• Slow feedback (days-weeks): Structural changes in corticotrophs with prolonged exposure [2]

Clinical Pearl: HPA Suppression Threshold

Clinically significant HPA axis suppression occurs with:

• Prednisolone ≥7.5 mg/day for ≥3 weeks
• Any dose of corticosteroid for ≥3 weeks
• Repeated short courses (e.g., asthma exacerbations)
• High-dose inhaled corticosteroids (especially with CYP3A4 inhibitors) [3]

Circadian Rhythm of Cortisol

Cortisol secretion follows a distinct diurnal pattern, essential for normal physiological function:

Clinical Implications:

• Morning cortisol <100 nmol/L suggests adrenal insufficiency
• Baseline cortisol samples should be taken at 08:00-09:00
• The circadian rhythm is lost in critical illness and with exogenous steroid administration [4]

The Stress Response

Surgical stress and critical illness trigger a coordinated neuroendocrine response with cortisol playing a central role:

Magnitude of Cortisol Response by Surgery Type: [5]

Physiological Functions of Stress Cortisol:

1. Cardiovascular: Maintains vascular tone and catecholamine responsiveness
2. Metabolic: Mobilises glucose via gluconeogenesis and glycogenolysis
3. Immune: Modulates inflammatory response (prevents excessive inflammation)
4. Permissive effects: Enables full action of catecholamines on vasculature [6]

Warning: Adrenal Crisis

Patients with HPA axis suppression who cannot mount a stress response may develop adrenal crisis perioperatively, characterised by:

• Refractory hypotension despite fluid and vasopressors
• Cardiovascular collapse
• Hypoglycaemia
• Hyponatraemia, hyperkalaemia
• Altered consciousness

Treatment: IV hydrocortisone 100 mg stat, then 50 mg 6-hourly

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2. Classification of Corticosteroids

Comparison Table: Commonly Used Corticosteroids

[7,8]

Classification by Duration of Action

Short-Acting (8-12 hours biological half-life):

• Hydrocortisone
• Cortisone
• Use: Physiological replacement, acute adrenal insufficiency

Intermediate-Acting (12-36 hours):

• Prednisolone, prednisone
• Methylprednisolone
• Triamcinolone
• Use: Inflammatory conditions, immunosuppression

Long-Acting (36-72 hours):

• Dexamethasone
• Betamethasone
• Use: PONV prophylaxis, cerebral oedema, airway oedema, fetal lung maturation [9]

Structure-Activity Relationships

The basic steroid nucleus (cyclopentanoperhydrophenanthrene) modifications determine potency:

Clinical Pearl: Choosing a Corticosteroid

• Need mineralocorticoid effect (adrenal insufficiency): Hydrocortisone or fludrocortisone
• Avoid fluid retention (cerebral oedema, PONV): Dexamethasone or methylprednisolone
• Long duration needed (PONV): Dexamethasone (36-72 hour effect)
• Rapid onset needed (anaphylaxis): IV hydrocortisone (most physiological)

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3. Mechanism of Action

Genomic Mechanisms (Classic Pathway)

The primary mechanism of corticosteroid action involves nuclear receptor activation and altered gene transcription. This pathway is responsible for most therapeutic effects but requires hours for full effect. [10]

Step-by-Step Mechanism:

1. Passive Diffusion: Lipophilic corticosteroids cross cell membranes freely

2. Cytoplasmic Receptor Binding: Bind to glucocorticoid receptor (GR), a member of the nuclear receptor superfamily

   • GR exists as an inactive complex with heat shock proteins (HSP90, HSP70, HSP56)
   • Binding causes conformational change and HSP dissociation

3. Nuclear Translocation: Activated GR-steroid complex translocates to nucleus

4. Gene Regulation (two mechanisms):

   a) Transactivation (GRE binding):

   • GR binds as homodimer to glucocorticoid response elements (GREs) in promoter regions
   • Increases transcription of anti-inflammatory genes:
     • Lipocortin-1 (inhibits phospholipase A2)
     • IκB (inhibits NF-κB)
     • IL-10 (anti-inflammatory cytokine)
     • β2-adrenergic receptors

   b) Transrepression (protein-protein interaction):

   • GR interacts with transcription factors without DNA binding
   • Inhibits NF-κB and AP-1 (key pro-inflammatory transcription factors)
   • Reduces transcription of:
     • Cyclooxygenase-2 (COX-2)
     • Inducible nitric oxide synthase (iNOS)
     • Pro-inflammatory cytokines (IL-1, IL-6, TNF-α)
     • Adhesion molecules

5. Protein Synthesis: Altered mRNA → changed protein expression (hours to days)

Exam Detail: Transrepression vs Transactivation

Transrepression (GR inhibiting NF-κB/AP-1) is considered the primary mechanism of anti-inflammatory effects. Transactivation (GRE-mediated gene activation) is responsible for many metabolic side effects.

This distinction has driven development of "dissociated" glucocorticoids that preferentially cause transrepression - though none have yet reached clinical use. [11]

Non-Genomic Mechanisms (Rapid Effects)

Some corticosteroid effects occur within seconds to minutes, too rapid for gene transcription. These non-genomic effects are particularly relevant to anaesthesia. [12]

Time Course of Effects:

• Non-genomic: Seconds to minutes
• Genomic (early): 30 minutes to hours (mRNA changes)
• Genomic (full): Hours to days (protein synthesis and turnover)

Clinical Pearl: PONV Timing

Dexamethasone for PONV prophylaxis should be given at induction (not end of surgery) because:

• Non-genomic effects begin immediately
• Genomic effects (main mechanism) require 2-4 hours
• Peak antiemetic effect occurs 4-6 hours after administration [13]

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4. Pharmacokinetics

Absorption

Oral Bioavailability:

• Prednisolone: 80-90%
• Dexamethasone: 80-90%
• Hydrocortisone: 90%
• Prednisone: requires hepatic conversion to prednisolone (avoid in liver failure) [14]

Distribution

Protein Binding Specifics:

Exam Detail: Transcortin (Corticosteroid-Binding Globulin)

• Transcortin binds cortisol with high affinity but low capacity
• Saturates at ~25 μg/dL cortisol
• Above saturation, free (active) cortisol increases disproportionately
• Synthetic corticosteroids have lower transcortin affinity
• Transcortin levels decreased in: critical illness, nephrotic syndrome, liver failure
• Transcortin levels increased in: pregnancy, oestrogen therapy [15]

Metabolism

Corticosteroids are extensively metabolised in the liver:

Phase I Reactions:

• Reduction: 11β-hydroxysteroid dehydrogenase (11β-HSD) interconverts active/inactive forms
  • 11β-HSD1 (liver, adipose): Converts cortisone → cortisol (activating)
  • 11β-HSD2 (kidney): Converts cortisol → cortisone (inactivating, protects MR)
• Hydroxylation: CYP3A4 is the primary enzyme for oxidative metabolism

Phase II Reactions:

• Glucuronidation and sulfation
• Water-soluble conjugates excreted in urine and bile

Drug-Specific Metabolism:

Warning: CYP3A4 Interactions

CYP3A4 Inhibitors (increase corticosteroid effect):

• Ketoconazole, itraconazole, fluconazole
• Ritonavir, HIV protease inhibitors
• Macrolides (erythromycin, clarithromycin)
• Grapefruit juice

CYP3A4 Inducers (decrease corticosteroid effect):

• Rifampicin (can cause adrenal crisis in replacement patients)
• Phenytoin, carbamazepine, phenobarbital
• St John's wort [16]

Elimination

Note: Biological half-life (duration of pharmacological effect) is much longer than plasma half-life due to genomic mechanisms.

Individual Drug Profiles

Hydrocortisone:

• Most similar to endogenous cortisol
• Equal glucocorticoid and mineralocorticoid activity
• Preferred for adrenal replacement (mimics physiology)
• IV form for acute adrenal insufficiency and anaphylaxis
• Dose: 100 mg IV for stress dosing; 20 mg mane/10 mg nocte for replacement [17]

Prednisolone:

• 4× glucocorticoid potency of cortisol
• Reduced but significant mineralocorticoid activity
• Most commonly prescribed oral corticosteroid
• Active drug (unlike prednisone which is a prodrug)
• Dose: 5-60 mg daily depending on indication

Methylprednisolone:

• 5× glucocorticoid potency
• Minimal mineralocorticoid activity
• Available IV (sodium succinate) for acute use
• Preferred for pulse therapy (multiple sclerosis, spinal cord injury)
• Dose: 500-1000 mg IV for pulse therapy

Dexamethasone:

• 25-30× glucocorticoid potency
• Zero mineralocorticoid activity
• Long duration of action (36-72 hours)
• Preferred in anaesthesia for PONV, airway oedema, cerebral oedema
• Crosses placenta (used for fetal lung maturation)
• Dose: 4-8 mg IV for PONV; 8-16 mg for airway oedema [18]

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5. Clinical Applications in Anaesthesia

PONV Prophylaxis (Dexamethasone)

Dexamethasone is one of the most effective single agents for PONV prophylaxis with a number needed to treat (NNT) of approximately 4. [19]

Mechanism of Antiemetic Effect:

• Inhibition of prostaglandin synthesis in CNS
• Reduced serotonin release in GI tract
• Central antiemetic action (mechanism not fully understood)
• Possible direct effect on chemoreceptor trigger zone

Dosing:

• Adults: 4-8 mg IV at induction
• Paediatrics: 0.15-0.5 mg/kg (max 8 mg)
• Evidence suggests 4 mg is as effective as 8 mg for PONV (DREAMS trial) [20]

Timing:

• Administer at induction (not end of surgery)
• Allows 2-4 hours for genomic effects
• Duration of antiemetic effect: 24-72 hours

Efficacy:

• Reduces PONV by approximately 25% as single agent
• Synergistic with ondansetron, droperidol
• Part of multimodal PONV prophylaxis (SAMBA guidelines)

Concerns:

• Perineal burning/itching with rapid IV injection (administer over 1-2 minutes)
• Hyperglycaemia - clinically significant in diabetics
• Theoretical wound infection risk (conflicting evidence)
• Tumour lysis syndrome concern in undiagnosed haematological malignancy

Clinical Pearl: PONV Risk Factors (Apfel Score)

Risk Factor	Points
Female	1
Non-smoker	1
History of PONV/motion sickness	1
Postoperative opioids	1

Risk: 0 points = 10%, 1 = 21%, 2 = 39%, 3 = 61%, 4 = 79% Dexamethasone recommended for score ≥2

Airway Oedema

Corticosteroids reduce airway oedema through anti-inflammatory effects, decreased capillary permeability, and reduced mucus production. [21]

Indications:

• Post-extubation stridor/laryngeal oedema
• Croup (laryngotracheobronchitis)
• Anticipated difficult airway with oedema
• Angioedema (adjunct to adrenaline)
• Smoke inhalation
• Anaphylaxis (adjunct)

Dosing for Airway Oedema:

• Dexamethasone: 0.5-1 mg/kg IV (max 16 mg)
• Or methylprednisolone: 1-2 mg/kg IV
• Repeat dosing may be required

Prevention of Post-Extubation Stridor:

• Dexamethasone 0.5 mg/kg IV 6-12 hours pre-extubation
• Multiple doses more effective than single dose
• Most benefit in high-risk patients (prolonged intubation, traumatic intubation, self-extubation history) [22]

Anaphylaxis (Second-Line Agent)

Warning: Steroids are NOT First-Line

Adrenaline is ALWAYS the first-line treatment for anaphylaxis. Corticosteroids have NO role in acute management of cardiovascular collapse or bronchospasm. They are given to potentially prevent biphasic reactions (occurring in 1-20% of cases).

Role in Anaphylaxis:

• May prevent or attenuate biphasic reactions (second phase 1-72 hours later)
• Evidence for benefit is weak/moderate quality
• Should not delay adrenaline or resuscitation

Dosing:

• Hydrocortisone 200 mg IV (most commonly used)
• Or dexamethasone 8-16 mg IV
• Or methylprednisolone 125 mg IV

Timing: After adrenaline and fluid resuscitation initiated [23]

Adrenal Suppression Management

Patients on chronic corticosteroids or with HPA axis suppression require perioperative steroid supplementation.

Who is at Risk?

• Prednisolone ≥5 mg/day (or equivalent) for ≥3 weeks
• Any corticosteroid for ≥3 weeks in past year
• Cushing's syndrome or adrenal disease
• High-dose inhaled steroids (especially with CYP3A4 inhibitors)
• Bilateral adrenalectomy
• Hypopituitarism

Assessment:

• History of steroid use (dose, duration, timing)
• Clinical features of adrenal insufficiency
• If uncertain: short Synacthen test (but don't delay surgery)

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6. Perioperative Steroid Supplementation

When Steroid Cover is Required

Traditional "stress dose" steroid protocols have been revised. Current evidence suggests lower doses are often adequate. [24,25]

Modern Approach (Endocrine Society Guidelines):

Key Principles:

1. Continue usual steroid dose (most important step)
2. Supplementation only if unable to take oral medications or surgery >moderate stress
3. Taper back to usual dose over 1-3 days postoperatively
4. Watch for signs of adrenal insufficiency

Sick Day Rules for Patients on Steroids

For Patients on Long-Term Steroids:

• Minor illness (cold, minor infection): Double usual dose
• Vomiting/unable to take oral: IM hydrocortisone 100 mg, seek medical attention
• Surgery: As per supplementation guidelines above
• Severe illness/accident: IM hydrocortisone 100 mg, emergency department

Evidence for Stress-Dose Steroids

Historical Context: Traditional "stress-dose" protocols (hydrocortisone 100 mg 8-hourly) were based on theoretical calculations and case reports from the 1950s, not controlled trials.

Modern Evidence:

• Multiple RCTs show patients on chronic steroids undergoing moderate surgery do NOT need stress doses beyond their usual replacement
• Marik and Varon (2008) systematic review: no difference in outcomes with supraphysiological stress doses vs usual doses [26]
• However, for major surgery and critical illness, some supplementation is prudent

Current Consensus:

• Avoid supraphysiological doses
• "Hydrocortisone 25-75 mg/day is adequate for most surgical stress"
• Reserve higher doses (100-200 mg/day) for major surgery, septic shock, true adrenal crisis

Clinical Pearl: Practical Approach

1. Patient takes steroids: Continue usual dose, add hydrocortisone 25-50 mg IV if moderate surgery
2. Patient stopped steroids <3 months ago: Treat as if still on steroids
3. Unknown steroid history with unexplained hypotension: Give hydrocortisone 100 mg IV empirically
4. Confirmed adrenal insufficiency: Follow endocrinology guidelines

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7. Adverse Effects

Perioperative Concerns

Hyperglycaemia: [27]

• Occurs in 40-60% of patients receiving dexamethasone 8 mg
• Peak effect 4-8 hours post-administration
• More pronounced in diabetics and pre-diabetics
• Usually mild (increase of 1-2 mmol/L) and self-limiting
• Management: Monitor BSL, short-acting insulin if >10-12 mmol/L

Immunosuppression:

• Single doses unlikely to cause clinically significant immunosuppression
• Theoretical concern about increased surgical site infection (conflicting evidence)
• Large meta-analyses show no increased infection risk with single-dose dexamethasone for PONV [28]

Wound Healing:

• Glucocorticoids inhibit collagen synthesis and fibroblast function
• Single perioperative doses unlikely to significantly impair healing
• Chronic use definitely impairs wound healing
• May be relevant for plastic surgery, anastomoses in high-risk patients

Adrenal Suppression:

• Single doses: No clinically significant HPA suppression
• Short courses (<1 week): Minimal suppression, no taper needed
• Courses >3 weeks: Gradual taper required to allow HPA axis recovery

Systemic Adverse Effects (Chronic Use)

Exam Detail: Steroid-Induced Osteoporosis

• Occurs in 30-50% of patients on long-term steroids
• Risk begins within first 3-6 months
• Vertebral fractures most common
• Prevention: Calcium, vitamin D, bisphosphonates for high-risk patients
• Equivalent to >5 mg prednisolone/day for >3 months requires bone protection [29]

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8. Drug Interactions

Pharmacokinetic Interactions

Pharmacodynamic Interactions

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9. Indigenous Health Considerations

Indigenous Health

Aboriginal, Torres Strait Islander, and Maori Patient Considerations

When administering corticosteroids to Aboriginal, Torres Strait Islander, or Maori patients, several important factors warrant specific consideration:

Higher Prevalence of Corticosteroid-Sensitive Conditions: Indigenous Australians have significantly higher rates of conditions requiring corticosteroid use, including asthma (1.5-2× higher prevalence), COPD, rheumatic heart disease (8-10× higher), and autoimmune conditions. This means higher baseline exposure to corticosteroids and greater risk of complications. [30]

Diabetes and Metabolic Complications: Type 2 diabetes prevalence is 3-4 times higher in Aboriginal and Torres Strait Islander peoples. Corticosteroid-induced hyperglycaemia is therefore more common and more severe in this population. Blood glucose monitoring should be more frequent, and lower thresholds for insulin therapy may be appropriate. Pre-existing diabetes should be optimised before elective surgery where steroids will be used.

Infection Risk: Higher rates of chronic infections (including tuberculosis, strongyloidiasis, and chronic hepatitis B) mean that corticosteroid immunosuppression carries additional risks. Prior to planned immunosuppressive steroid therapy, screening for latent infections should be considered. Strongyloides hyperinfection syndrome is a particular concern in endemic areas, and empirical ivermectin treatment may be warranted before high-dose corticosteroids.

Renal and Hepatic Disease: Chronic kidney disease is 3-5 times more prevalent in Indigenous Australians. While corticosteroids themselves do not require renal dose adjustment, the complications of steroid use (hypertension, diabetes, fluid retention) are particularly problematic in patients with existing renal disease. Higher rates of alcohol-related liver disease may affect prednisone activation (hepatic conversion to prednisolone).

Cultural Considerations:

• Ensure culturally appropriate consent processes, involving family and Aboriginal Health Workers where available
• Communication about "steroids" may require clarification (distinguish from anabolic steroids)
• Medication adherence may be affected by remoteness and socioeconomic factors
• Discharge planning should consider access to follow-up care and monitoring in remote communities

Maori Health Considerations: Similar considerations apply to Maori patients in Aotearoa New Zealand, with higher prevalence of rheumatic heart disease, gout, and type 2 diabetes. Whanau-centred care and involvement of Maori Health Workers can improve outcomes and adherence to steroid regimens.

Practical Recommendations:

1. Screen for diabetes (HbA1c) before elective steroid use
2. Screen for latent TB and strongyloidiasis before immunosuppressive doses
3. More frequent blood glucose monitoring perioperatively
4. Involve Aboriginal Health Workers/Maori Health Workers in discharge planning
5. Ensure clear communication about sick day rules for patients on chronic steroids

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10. SAQ Practice Question

SAQ: Corticosteroids in Anaesthesia (15 marks)

A 58-year-old woman presents for elective total knee replacement. She has rheumatoid arthritis and has been taking prednisolone 10 mg daily for the past 2 years. Her other medications include methotrexate, folic acid, and pantoprazole.

(a) Describe the physiological role of cortisol in the stress response and why this patient may be at risk perioperatively. (4 marks)

(b) Outline the mechanism of action of corticosteroids, including both genomic and non-genomic pathways. (4 marks)

(c) What perioperative steroid supplementation would you recommend for this patient? Justify your answer. (4 marks)

(d) She is also at high risk of PONV. Discuss the use of dexamethasone for PONV prophylaxis in this patient. (3 marks)

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Model Answer

(a) Physiological Role of Cortisol and Perioperative Risk (4 marks)

Cortisol in Stress Response:

• Cortisol is released from the adrenal cortex in response to surgical stress via HPA axis activation (0.5 marks)
• Maintains vascular tone and catecholamine responsiveness (essential for blood pressure maintenance) (0.5 marks)
• Provides metabolic support through gluconeogenesis and glycogenolysis (0.5 marks)
• Modulates inflammatory response to prevent excessive inflammation (0.5 marks)

Why This Patient is at Risk:

• Prednisolone 10 mg daily for 2 years has caused HPA axis suppression (0.5 marks)
• The adrenal glands have atrophied and cannot mount an adequate cortisol response to surgical stress (0.5 marks)
• Without supplementation, she may develop perioperative adrenal crisis: refractory hypotension, cardiovascular collapse, hypoglycaemia (0.5 marks)
• Risk is proportional to surgical stress - total knee replacement is moderate stress surgery (0.5 marks)

(b) Mechanism of Action (4 marks)

Genomic Mechanisms (Primary pathway - hours for effect):

• Corticosteroids cross cell membranes and bind to cytoplasmic glucocorticoid receptor (GR) (0.5 marks)
• Activated GR-steroid complex translocates to the nucleus (0.5 marks)
• Transactivation: GR binds to glucocorticoid response elements (GREs), increasing transcription of anti-inflammatory genes (lipocortin-1, IκB, IL-10) (0.5 marks)
• Transrepression: GR inhibits pro-inflammatory transcription factors (NF-κB, AP-1), reducing COX-2, iNOS, TNF-α, IL-1, IL-6 (0.5 marks)

Non-Genomic Mechanisms (Rapid - seconds to minutes):

• Membrane stabilisation: Reduced membrane fluidity and permeability (0.5 marks)
• Membrane receptor effects: Rapid signalling cascades via putative membrane GR (0.5 marks)
• Ion channel modulation: Effects on Ca²⁺ and K⁺ channels (0.5 marks)
• Inhibition of phospholipase A2: Reduced arachidonic acid release (0.5 marks)

(c) Perioperative Steroid Supplementation (4 marks)

Recommendation:

• Continue usual prednisolone 10 mg on morning of surgery (oral or IV equivalent if NBM) (1 mark)
• Hydrocortisone 50 mg IV at induction (1 mark)
• Continue usual prednisolone dose postoperatively once tolerating oral (0.5 marks)

Justification:

• Total knee replacement is moderate stress surgery (cortisol demand ~50-75 mg/day equivalent) (0.5 marks)
• Patient's usual 10 mg prednisolone = 40 mg hydrocortisone equivalent, plus 50 mg IV supplementation = adequate coverage (0.5 marks)
• Modern evidence shows physiological supplementation is adequate; supraphysiological "stress doses" (100 mg 6-hourly) are not required for moderate surgery (0.5 marks)

(d) Dexamethasone for PONV (3 marks)

Use in This Patient:

• Dexamethasone 4-8 mg IV at induction is appropriate for PONV prophylaxis (0.5 marks)
• Already receiving corticosteroid supplementation, so additional antiemetic benefit without significant added risk (0.5 marks)

Considerations:

• Patient on immunosuppression (prednisolone, methotrexate) - single dose dexamethasone unlikely to significantly increase infection risk (0.5 marks)
• Monitor blood glucose - not diabetic, but RA patients have increased metabolic risk (0.5 marks)
• Administer slowly (over 1-2 minutes) to avoid perineal discomfort (0.5 marks)
• NNT ~4 for preventing PONV; synergistic with ondansetron (0.5 marks)

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11. Viva Scenario

Viva Scenario: Perioperative Corticosteroid Management (20 marks)

Clinical Scenario: A 45-year-old man with Addison's disease (primary adrenal insufficiency) is scheduled for emergency laparoscopic appendicectomy. He normally takes hydrocortisone 20 mg in the morning and 10 mg in the evening, plus fludrocortisone 100 mcg daily. He last took his medications yesterday morning and has been vomiting for 12 hours.

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Examiner Questions and Model Answers:

Q1: What is Addison's disease and why is this patient at high risk perioperatively? (4 marks)

Addison's disease is primary adrenal insufficiency - destruction or dysfunction of the adrenal cortex resulting in deficiency of both glucocorticoids (cortisol) and mineralocorticoids (aldosterone). Common causes include autoimmune adrenalitis (most common in developed countries), tuberculosis, and bilateral adrenal haemorrhage. (1 mark)

This patient is at high risk because:

• He has no endogenous cortisol production and cannot mount a stress response (1 mark)
• He has missed doses (last taken 36+ hours ago) and may already be in early adrenal crisis (0.5 marks)
• Vomiting prevents oral replacement and accelerates fluid/electrolyte losses (0.5 marks)
• Emergency surgery represents significant physiological stress requiring increased cortisol (0.5 marks)
• Combined glucocorticoid and mineralocorticoid deficiency puts him at risk of hypotension, hypoglycaemia, hyperkalaemia, and hyponatraemia (0.5 marks)

Q2: What clinical features would suggest impending or established adrenal crisis? (3 marks)

Cardiovascular:

• Hypotension, often refractory to fluids and vasopressors (0.5 marks)
• Tachycardia, cardiovascular collapse (0.5 marks)

Metabolic/Biochemical:

• Hypoglycaemia (0.5 marks)
• Hyponatraemia (mineralocorticoid deficiency) (0.5 marks)
• Hyperkalaemia (mineralocorticoid deficiency) (0.5 marks)

Other:

• Altered consciousness, confusion, lethargy (0.25 marks)
• Nausea, vomiting, abdominal pain (may mimic acute abdomen) (0.25 marks)

Q3: Outline your immediate preoperative management. (4 marks)

Immediate Resuscitation:

• IV access and blood tests (glucose, electrolytes, cortisol level if time permits) (0.5 marks)
• IV fluid resuscitation: 0.9% saline bolus (address hypovolaemia and hyponatraemia) (0.5 marks)
• IV dextrose if hypoglycaemic (0.5 marks)

Steroid Replacement:

• Hydrocortisone 100 mg IV stat immediately (1 mark)
• This provides both glucocorticoid and mineralocorticoid activity at this dose (0.5 marks)
• Continue hydrocortisone 50 mg IV 6-hourly or 200 mg/24hr as continuous infusion (0.5 marks)
• Fludrocortisone not acutely necessary as high-dose hydrocortisone provides mineralocorticoid effect (0.5 marks)

Q4: Describe the mechanism of action of hydrocortisone. (3 marks)

Genomic Mechanism (Primary):

• Binds to intracellular glucocorticoid receptor (GR) in cytoplasm (0.5 marks)
• GR-steroid complex translocates to nucleus (0.25 marks)
• Transactivation: Binds GREs, increases anti-inflammatory gene transcription (0.5 marks)
• Transrepression: Inhibits NF-κB and AP-1, reducing pro-inflammatory mediators (0.5 marks)
• Effect requires hours (protein synthesis) (0.25 marks)

Non-Genomic Mechanism:

• Rapid effects via membrane stabilisation and receptor effects (0.5 marks)
• Onset in minutes (0.25 marks)
• Maintains vascular tone and catecholamine responsiveness (0.25 marks)

Q5: Compare hydrocortisone with dexamethasone. Why would hydrocortisone be preferred in this situation? (3 marks)

Property	Hydrocortisone	Dexamethasone
Glucocorticoid potency	1	25-30
Mineralocorticoid potency	1	0
Duration	Short (8-12 h)	Long (36-54 h)
Equivalent dose	20 mg	0.75 mg
(1 mark for comparison)

Why hydrocortisone is preferred:

• Patient with Addison's disease needs mineralocorticoid replacement - dexamethasone has zero mineralocorticoid activity (1 mark)
• Hydrocortisone is physiologically identical to endogenous cortisol (0.5 marks)
• Short duration allows flexible titration in rapidly changing clinical situation (0.5 marks)

Q6: What postoperative steroid regimen would you recommend? (3 marks)

Immediate Postoperative:

• Continue hydrocortisone 50 mg IV 6-hourly for 24-48 hours (or 200 mg/day as infusion) (1 mark)
• Monitor for signs of over- or under-replacement (0.5 marks)

Step-Down:

• Once stable and eating: reduce to hydrocortisone 50 mg 8-hourly, then 25 mg 8-hourly (0.5 marks)
• Resume usual oral regimen (hydrocortisone 20 mg mane, 10 mg nocte) when tolerating diet (0.5 marks)

Mineralocorticoid:

• Resume fludrocortisone 100 mcg daily when taking oral medications (0.5 marks)
• Not needed while on high-dose IV hydrocortisone (provides mineralocorticoid cover)

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12. Key Points Summary

Summary

Essential Facts for ANZCA Primary Examination

Category	Key Point
HPA Axis	CRH → ACTH → Cortisol; negative feedback at hypothalamus and pituitary
Circadian rhythm	Peak 06:00-09:00, nadir 00:00-03:00
Stress response	Minor surgery 1.5-2×, moderate 2-3×, major 3-5× baseline cortisol
Suppression risk	Prednisolone ≥7.5 mg/day or any steroid ≥3 weeks
Classification	Short (hydrocortisone), intermediate (prednisolone), long (dexamethasone)
Dexamethasone	25-30× glucocorticoid potency, zero mineralocorticoid, t½ 36-54 hours
Genomic mechanism	GR activation → nucleus → transactivation (GRE) + transrepression (NF-κB/AP-1)
Non-genomic	Membrane effects, seconds-minutes onset
PONV dosing	Dexamethasone 4-8 mg IV at induction
Airway oedema	Dexamethasone 0.5 mg/kg IV
Anaphylaxis	Second-line only; hydrocortisone 200 mg IV after adrenaline
Stress dosing	Modern approach: continue usual dose + hydrocortisone 50-100 mg IV for moderate-major surgery
Adrenal crisis	Refractory hypotension, hypoglycaemia, hyponatraemia, hyperkalaemia
CYP3A4	Primary metabolic enzyme; inhibitors increase effect, inducers decrease
Hyperglycaemia	40-60% incidence with dexamethasone 8 mg; monitor in diabetics

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13. References

1. Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Engl J Med. 1995;332(20):1351-1362. PMID: 7715646

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Content Version: 1.0
Created: February 2025
Last Reviewed: February 2025
Next Review: February 2026
Authors: MedVellum Content Team
Quality Score: 54/56 (Gold Standard)
Citation Count: 32
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