What is the half-life of prednisolone (corticosteroid) before considering adrenal insufficiency screening in a patient on long-term therapy?

Half-Life of Prednisolone and Timing for Adrenal Insufficiency Screening

Prednisolone has a plasma half-life of 2-4 hours, and you should wait at least 48 hours after the last dose before performing adrenal insufficiency screening with a cosyntropin stimulation test. 1, 2, 3

Pharmacokinetic Rationale

• Prednisolone is eliminated from plasma with a half-life of 2-4 hours and is metabolized mainly in the liver, excreted in urine as sulfate and glucuronide conjugates 1
• Despite this short plasma half-life, the biological effects on HPA axis suppression persist much longer than the drug's presence in circulation 4
• The 48-hour washout period is the minimum standard used in clinical research to allow prednisolone levels to clear sufficiently for accurate cortisol measurement 2, 3

Evidence-Based Testing Protocol

• Wait 48 hours after stopping prednisolone before performing the cosyntropin (Synacthen) stimulation test 2, 3
• During this 48-hour pause, patients on chronic prednisolone ≥5 mg daily are at risk for adrenal crisis and should be monitored closely 2, 3
• The standard test uses 0.25 mg (250 mcg) cosyntropin IV or IM, with cortisol measured at baseline and 30 minutes post-administration 4, 5
• A peak cortisol <500 nmol/L (<18 μg/dL) at 30 minutes is diagnostic of adrenal insufficiency 4, 5, 6

Critical Clinical Context

• Approximately 39-48% of patients on chronic low-dose prednisolone (5 mg daily) have adrenal insufficiency when tested after 48-hour washout 2
• In PMR/GCA patients on prednisolone 2.5-10 mg daily, 15% had confirmed adrenal insufficiency 3
• HPA axis suppression should be anticipated in any patient receiving >7.5 mg prednisolone equivalent daily for >3 weeks 4
• Even doses as low as 5 mg prednisolone daily for >1 month can cause adrenal suppression in a significant proportion of adults 4

Important Caveats and Pitfalls

• Never attempt diagnostic testing while the patient is actively taking prednisolone—morning cortisol will be falsely low due to iatrogenic secondary adrenal insufficiency, not true adrenal failure 5
• The 48-hour washout is only safe for stable outpatients; if the patient is acutely ill or unstable, immediately treat with IV hydrocortisone 100 mg without waiting for testing 4, 7, 6
• Prednisolone and other exogenous steroids (except dexamethasone) cross-react with cortisol assays, confounding results 5
• If you must treat suspected adrenal crisis but still want diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays 5, 8

Alternative Approach for Long-Term Steroid Users

• For patients on chronic prednisolone who cannot safely stop for 48 hours, consider empiric glucocorticoid replacement and defer definitive testing for 3 months after switching to physiologic hydrocortisone replacement 5
• After 3 months on stable hydrocortisone maintenance therapy, perform ACTH stimulation testing to assess HPA axis recovery 5, 9
• This approach prioritizes patient safety over immediate diagnostic certainty 5

Mortality Considerations

• In primary adrenal insufficiency, mortality is significantly higher with prednisolone compared to hydrocortisone (adjusted HR 2.92 vs 1.90, p=0.0020) 10
• This mortality difference persists even after adjusting for confounders, suggesting prednisolone may not be optimal for long-term replacement therapy 10
• Switching from prednisolone to hydrocortisone for chronic replacement reduces cumulative glucocorticoid exposure and associated complications like avascular necrosis 9