What medications can cause primary adrenal insufficiency?

Medications That Can Cause Primary Adrenal Insufficiency

Several medications can cause primary adrenal insufficiency, with antifungal drugs like ketoconazole being the most significant culprits due to their direct inhibition of adrenal steroidogenesis. 1

Medications Directly Associated with Primary Adrenal Insufficiency

Antifungal Medications

• Ketoconazole: Most potent adrenal suppressant among medications

  • Causes adrenal insufficiency by blocking testosterone synthesis and adrenal response to corticotropin 2
  • High doses (800-1200 mg/day) cause prolonged blockade of adrenal function 2
  • FDA warning: "Ketoconazole tablets decrease adrenal corticosteroid secretion at doses of 400 mg and higher" 3
  • Can lead to symptoms such as tiredness, weakness, dizziness, nausea, and vomiting 3

• Fluconazole: At high doses

  • Case reports suggest high-dose fluconazole may cause reversible adrenal insufficiency in critically ill patients 4
  • Less potent than ketoconazole but still a concern at higher doses

Steroidogenesis Inhibitors

• Etomidate: Anesthetic agent that inhibits 11β-hydroxylase

  • Causes adrenal insufficiency even with short-term use 5
  • Associated with increased mortality in critically ill patients with severe illness 5
  • May require glucocorticoid supplementation after administration in severely ill patients 5

• Mitotane: Used for adrenocortical carcinoma

  • Directly toxic to adrenal cortical cells 1

• Metyrapone: Inhibits 11β-hydroxylase enzyme

  • Used diagnostically but can cause adrenal insufficiency as side effect 1

Medications That Affect Cortisol Metabolism

These medications may not directly cause primary adrenal insufficiency but can affect hydrocortisone metabolism in patients already receiving replacement therapy:

• Anti-epileptics/barbiturates: May increase hydrocortisone metabolism, requiring higher doses 1
• Antituberculosis drugs: May increase hydrocortisone metabolism 1
• Topiramate: May increase hydrocortisone metabolism 1

Medications That Interact with Mineralocorticoid Replacement

In patients with primary adrenal insufficiency on fludrocortisone, these medications should be avoided:

• Diuretics 6
• Acetazolamide 6
• Carbenoxolone 6
• NSAIDs 6
• Drospirenone-containing contraceptives: May require higher fludrocortisone doses 6

Clinical Presentation and Diagnosis

Patients with medication-induced adrenal insufficiency typically present with:

• Fatigue (50-95%)
• Nausea and vomiting (20-62%)
• Anorexia and weight loss (43-73%) 7
• Hypotension
• Hyponatremia (common)
• Hyperkalemia (not consistently present) 8
• Hyperpigmentation (in primary adrenal insufficiency)

Monitoring and Management

For patients on medications that can cause adrenal insufficiency:

1. Regular monitoring:

   • Morning serum cortisol and ACTH levels
   • Electrolytes (sodium, potassium)
   • Blood pressure (both supine and standing)

2. Prevention:

   • Use lowest effective dose of high-risk medications
   • Consider alternative medications when possible
   • For patients on ketoconazole, monitor adrenal function, especially at doses ≥400 mg 3

3. Treatment (if adrenal insufficiency develops):

   • Discontinue offending medication if possible
   • Initiate glucocorticoid replacement (hydrocortisone 15-25 mg daily)
   • Add mineralocorticoid replacement (fludrocortisone 0.05-0.2 mg daily) for primary adrenal insufficiency 7
   • Educate patient about stress dosing and emergency management

Important Caveats

• Adrenal function typically recovers after discontinuation of the offending medication, but recovery time varies
• Patients receiving high-dose ketoconazole should be considered potentially unable to mount an adrenal stress response 2
• Patients with critical illness are at higher risk for medication-induced adrenal insufficiency
• Always provide patients with emergency instructions and medication for adrenal crisis prevention

Remember that primary adrenal insufficiency requires both glucocorticoid and mineralocorticoid replacement, unlike secondary adrenal insufficiency which typically only requires glucocorticoid replacement.