What is the recommended treatment regimen for primary adrenal insufficiency (Addison’s disease), including glucocorticoid and mineralocorticoid replacement, dosing schedule, stress dosing, and monitoring?

Treatment of Primary Adrenal Insufficiency

Patients with primary adrenal insufficiency require lifelong replacement with both hydrocortisone (15-25 mg daily in divided doses) and fludrocortisone (0.05-0.2 mg once daily), with immediate access to emergency injectable hydrocortisone 100 mg for adrenal crisis. 1, 2

Glucocorticoid Replacement

First-Line Therapy

• Hydrocortisone (HC) or cortisone acetate (CA) are the preferred glucocorticoids because they most closely mimic physiological cortisol production, unlike synthetic alternatives that carry undesirable long-term metabolic effects. 1, 3
• The total daily dose should be 15-25 mg of hydrocortisone (or 20-30 mg of cortisone acetate), which approximates the 5-10 mg/m² body surface area that normal adrenal glands produce. 1, 4, 3

Dosing Schedule

• Divide the total dose into 2-3 administrations: take the first dose immediately upon awakening, and the last dose 4-6 hours before bedtime to simulate the natural circadian rhythm with morning cortisol peak. 1, 5
• For patients with morning nausea or poor appetite, waking earlier to take the first dose then returning to sleep often relieves these symptoms. 1
• Night-shift workers must adjust timing accordingly (e.g., 10 mg upon awakening before work rather than at 7:00 AM). 1

Monitoring and Dose Adjustment

• Clinical assessment is the primary monitoring tool—plasma ACTH and serum cortisol levels are not useful for dose adjustment. 1
• Signs of over-replacement: weight gain, insomnia, peripheral edema. 1
• Signs of under-replacement: lethargy, nausea, poor appetite, weight loss, increased or uneven skin pigmentation. 1
• Fine-tune dosing by asking about energy levels throughout the day, mental concentration, daytime somnolence, ease of falling asleep, and any "dips" in energy. 1

Mineralocorticoid Replacement

Standard Therapy

• Fludrocortisone 0.05-0.2 mg once daily is required for all patients with primary adrenal insufficiency to replace aldosterone deficiency. 4, 5, 2, 3
• The FDA-approved dose for Addison's disease is 0.1 mg daily, with a range of 0.1 mg three times weekly to 0.2 mg daily depending on response. 2
• Children and young adults often require higher doses within this range. 5

Monitoring

• Target normotension, normokalemia, and plasma renin activity in the upper normal range. 6
• If transient hypertension develops, reduce the dose to 0.05 mg daily. 2
• Many patients may be chronically under-replaced if salt craving and postural dizziness persist despite treatment. 6

Critical Safety Point

• Never discontinue fludrocortisone—hydrocortisone alone does not provide adequate mineralocorticoid activity at physiological replacement doses. 7

Stress Dosing and Adrenal Crisis Management

Minor Illness (Fever, Cold, Gastroenteritis)

• Double the usual hydrocortisone dose during minor illnesses. 4, 7
• Continue doubled doses until recovery. 4

Major Stress (Surgery, Severe Illness, Trauma)

• Increase hydrocortisone to stress doses (typically 50-100 mg every 6-8 hours depending on severity). 4

Adrenal Crisis (Life-Threatening Emergency)

• Immediately administer hydrocortisone 100 mg IV or IM, followed by 100 mg every 6-8 hours until recovery. 4, 5, 7, 8
• Rapidly infuse isotonic (0.9%) sodium chloride solution at 1 L/hour until hemodynamic improvement. 4
• Adrenal crisis occurs at a rate of 6-8 per 100 patient-years and carries a mortality rate 2.19-fold higher for men and 2.86-fold higher for women. 7, 8
• Never reduce or withdraw steroids during fever or acute illness—persistent fever may represent inadequate glucocorticoid coverage rather than infection. 7

Patient Education and Safety Measures

Essential Education

• Train patients in self-administration of intramuscular hydrocortisone 100 mg for emergency use when vomiting prevents oral intake. 1, 4, 7
• Educate on recognizing adrenal crisis symptoms: severe weakness, confusion, abdominal pain, vomiting, hypotension. 8
• Teach when to double doses (minor illness) versus when to seek emergency care (vomiting, severe illness, inability to take oral medication). 4, 5, 7

Safety Identification

• All patients must wear a Medic Alert bracelet or necklace and carry a steroid emergency card stating their diagnosis and need for immediate hydrocortisone. 1, 4, 5, 7
• Delays in emergency hydrocortisone administration can be fatal—many patients report having to argue with emergency department staff for treatment. 1

Drug Interactions

Important CYP3A4 Interactions

• CYP3A4 is the key enzyme metabolizing hydrocortisone—concomitant medications can significantly affect hydrocortisone efficacy. 1
• Enzyme inducers (rifampin, phenytoin, carbamazepine) may require increased hydrocortisone doses. 1
• Enzyme inhibitors (ketoconazole, itraconazole) may necessitate dose reduction. 1

Follow-Up and Monitoring

Annual Assessment

• Evaluate at least annually: general well-being, weight, blood pressure, serum electrolytes (sodium and potassium). 4, 5, 7
• Screen for new autoimmune disorders, particularly hypothyroidism, as approximately 50% of patients with autoimmune primary adrenal insufficiency develop other autoimmune conditions. 4, 5
• Assess for complications of glucocorticoid therapy (osteoporosis, metabolic syndrome if over-replaced). 4

Sodium Supplementation

• Many patients require increased dietary sodium chloride intake to compensate for renal sodium losses. 1

Special Populations

Pregnancy

• Gradually increase hydrocortisone by 2.5-10 mg daily during the third trimester to meet increased physiological demands. 5
• Fludrocortisone requirements typically remain stable. 5

Pediatric Dosing

• Children require 6-10 mg/m² body surface area of hydrocortisone daily. 5
• Higher fludrocortisone doses (within the 0.05-0.2 mg range) are often needed. 5