What is the physiologic replacement dose of hydrocortisone for an adult with primary adrenal insufficiency (Addison disease)?

Physiological Replacement Dose of Hydrocortisone for Addison's Disease

The physiological replacement dose of hydrocortisone for adults with primary adrenal insufficiency (Addison's disease) is 15–25 mg daily, divided into 2–3 doses, with the first dose taken immediately upon awakening. 1

Standard Dosing Regimens

Three-Dose Schedule (Preferred for Most Patients)

• 10 mg at 07:00,5 mg at 12:00, and 2.5–5 mg at 16:00 is the most common regimen, mimicking the physiological diurnal cortisol rhythm 1
• Alternative three-dose schedules include 15 mg + 5 mg + 5 mg, 10 mg + 5 mg + 5 mg, or 7.5 mg + 5 mg + 2.5 mg 1
• The final dose should be taken at least 6 hours before bedtime to avoid insomnia 1

Two-Dose Schedule (For Adherence Issues)

• 15 mg at 07:00 + 5 mg at 12:00, or 10 mg + 10 mg, or 10 mg + 5 mg may be used when adherence to a three-dose schedule is problematic or for patients with long work shifts 1

Physiological Rationale

• Normal adrenal function produces 5–10 mg cortisol per m² body surface area per day, which is equivalent to 15–25 mg oral hydrocortisone 1
• Hydrocortisone is preferred because it allows recreation of the diurnal cortisol rhythm, with approximately 2/3 of the dose given in the morning and 1/3 in the early afternoon 2

Critical Dosing Principles

Maximum Daily Dose

• Titrate hydrocortisone to a maximum of 30 mg daily total dose for residual symptoms of adrenal insufficiency 2
• Daily doses above 25–30 mg enter the supraphysiologic range and increase the risk of iatrogenic Cushing's syndrome 3

Signs of Incorrect Dosing

• Over-replacement: weight gain, insomnia, peripheral edema, bruising, thin skin, hypertension, and hyperglycemia 2, 1
• Under-replacement: lethargy, nausea, poor appetite, weight loss, and increased or uneven pigmentation 1

Alternative Glucocorticoid Regimens

Second-Line Options

• Cortisone acetate 25–37.5 mg daily in divided doses may be used when hydrocortisone is unavailable; it requires hepatic conversion to active hydrocortisone 1
• Prednisolone 4–5 mg daily (single morning dose or 3 mg + 1–2 mg later) is reserved for patients intolerant of hydrocortisone or with adherence problems 1
• Hydrocortisone 20 mg is equivalent to prednisone 5 mg 2

Avoid Dexamethasone

• Dexamethasone should be avoided for maintenance therapy because of prolonged glucocorticoid activity and increased risk of iatrogenic Cushing's syndrome 1, 3

Essential Mineralocorticoid Replacement

All patients with primary adrenal insufficiency require fludrocortisone 50–200 µg once daily in the morning in addition to glucocorticoid replacement 1

Dosing Adjustments

• Dose may be increased up to 500 µg daily in children, younger adults, or during the third trimester of pregnancy when progesterone antagonizes mineralocorticoid action 1
• Target plasma renin activity to the upper half of the reference range 1

Monitoring Adequacy

• Clinical signs of under-replacement: orthostatic hypotension, salt cravings, light-headedness 1
• Clinical signs of over-replacement: peripheral edema, hypertension 1
• Laboratory monitoring includes serum sodium, potassium, and plasma renin activity 1

Common Pitfall

• Under-replacement of fludrocortisone is common and may lead clinicians to over-replace glucocorticoids, increasing the risk of adrenal crises and glucocorticoid-related complications 1
• If essential hypertension develops, fludrocortisone dose should be reduced (never stopped) and a vasodilator added 1

Drug and Food Interactions

Medications That Increase Hydrocortisone Requirements

• Anti-epileptic drugs/barbiturates, rifampin, etomidate, and topiramate increase hydrocortisone clearance and require higher doses 1

Substances That Decrease Hydrocortisone Requirements

• Grapefruit juice and liquorice decrease hydrocortisone clearance and may require dose reduction 1

Medications Affecting Fludrocortisone

• Diuretics, acetazolamide, NSAIDs, carbenoxolone, and liquorice may blunt fludrocortisone effect and should be used cautiously 1
• Drospirenone-containing contraceptives may necessitate an increased fludrocortisone dose 1

Stress-Dosing Protocol

Minor Illness or Physical Stress

• Double or triple the usual hydrocortisone dose during fever, gastroenteritis, or minor procedures 1

Severe Illness or Adrenal Crisis

• Give 100 mg hydrocortisone intramuscularly immediately, then 100 mg every 6–8 hours until recovery 1
• Concurrently infuse 0.9% sodium chloride at 1 L/h initially until hemodynamic stability is achieved 1
• All patients must carry emergency injectable hydrocortisone and be instructed in self-administration 1

Monitoring and Follow-Up

Clinical Assessment Is Primary

• Plasma ACTH and serum cortisol levels are not useful for dose titration; clinical assessment remains the primary tool 1
• Fine-tuning involves systematic questioning about energy throughout the day, mental concentration, daytime somnolence, and ease of falling asleep 1

Annual Review

• Measurement of weight, blood pressure (supine and standing), and serum electrolytes 1
• Bone mineral density assessment every 3–5 years to detect chronic glucocorticoid excess 3

Special Situations

Morning Nausea

• Awaken earlier to take the first hydrocortisone dose, then return to sleep 1

Night-Shift Workers

• Align dosing with individual sleep-wake cycles (e.g., 10 mg upon awakening before work) 1

Pregnancy

• May require modest adjustments to both hydrocortisone and fludrocortisone, especially in the third trimester 1
• Administer parenteral hydrocortisone during delivery 1

Patient Education Essentials

• Wear Medic-Alert identification jewelry 1
• Carry a steroid emergency card and have access to injectable hydrocortisone 1
• Sodium intake should be unrestricted; potassium-containing salt substitutes should be avoided 1
• Education on stress dosing for sick days and use of emergency injections is mandatory 2