Half-Life of Hydrocortisone
The elimination half-life of hydrocortisone is approximately 90 minutes (1.5 hours) when administered orally in conventional immediate-release formulations. 1, 2
Pharmacokinetic Properties
The plasma half-life ranges from 76.5 minutes on average, with individual variation spanning 40-225 minutes in patients with adrenal insufficiency, demonstrating significant interpatient variability. 3
This short half-life necessitates multiple daily doses (typically 2-3 times per day) to maintain adequate cortisol levels, as conventional immediate-release tablets produce high peaks and low troughs between doses. 1
Clinical Implications of Short Half-Life
The brief half-life explains why hydrocortisone is preferred over longer-acting corticosteroids like dexamethasone for physiologic replacement therapy, as it better mimics the natural diurnal cortisol rhythm when dosed appropriately (2/3 morning, 1/3 afternoon). 4
Time to plasma cortisol concentration falling below 100 nmol/L averages 289 minutes (range 140-540 minutes) after oral administration, influenced by both absorption rate and elimination half-life. 3
Maximum plasma concentration (Cmax) occurs at approximately 67 minutes (range 20-118 minutes) after oral dosing, with substantial interindividual variation. 3
Comparison with Dexamethasone
Dexamethasone has a "much longer biological half-life" compared to hydrocortisone, which contributes to its higher relative potency and increased risk of adverse neurodevelopmental effects, particularly in neonatal populations. 4
This longer half-life of dexamethasone makes it unsuitable for physiologic cortisol replacement and increases the risk of over-replacement and Cushingoid side effects. 4
Dosing Considerations Based on Half-Life
The short 90-minute half-life requires sustained administration every 4-6 hours when high blood levels are needed during stress situations or adrenal crisis. 5
Continuous intravenous infusion (200 mg over 24 hours) is superior to intermittent bolus dosing for maintaining physiologic cortisol concentrations during major stress, as it compensates for the rapid elimination. 5, 6
Extended-release formulations have been developed to overcome the limitations of the short half-life, enabling once- or twice-daily dosing, though the clinical benefits remain under investigation. 2
Practical Clinical Pitfalls
Do not assume standard dosing intervals work for all patients—the 3-fold variation in half-life (40-225 minutes) means some patients may require more frequent dosing to avoid periods of inadequate cortisol coverage. 3
Patients with both fast absorption (short tmax) and fast elimination (short half-life) reach subtherapeutic levels most quickly (249.5 minutes), while those with slow absorption but fast elimination paradoxically maintain levels longer (380 minutes). 3
The pharmacodynamic effect lags behind pharmacokinetics—maximum suppression of adrenal hormones occurs approximately 3 hours after morning dosing, not at peak plasma concentration. 7