Oral Glucocortiosteroids in Adrenal Insufficiency

• Adrenal insufficiency results from inadequate adrenocortical function, which may be due to destruction of the adrenal cortex (primary adrenal insufficiency; Addison's disease), deficient pituitary ACTH secretion (secondary adrenal insufficiency), or deficient hypothalamic secretion of CRH or other ACTH secretagogues (tertiary adrenal insufficiency).
• Primary and secondary adrenal insufficiency related to natural causes is uncommon, whereas iatrogenic, tertiary adrenal insufficiency caused by suppression of Hypothalamic-Pituitary-Adrenal (HPA) function by glucocorticoid administration is common
• The treatment of adrenal insufficiency includes replacement of the deficient hormones.
• The goal of treatment is to relieve the symptoms of hormone deficiency without developing signs of hormone excess and usually requires lifelong hormone replacement.
• Correct use of these hormone medications is essential to minimize symptoms and the chance of adrenal crisis

Glucocorticoids

• Several options are available for replacing glucocorticoids; a clinician will work with the patient to determine the regimen that is most effective, convenient, and that causes minimal side effects

First line treatment

• Based on ‘Adrenal Insufficiency a Guide for Pharmacists and Teams’ guideline, hydrocortisone is considered as the first-line drug because:
• It is the closest imitation of what the body produces 
• It is absorbed into the body quicker than other corticosteroids — after taking on an empty stomach it is almost all absorbed by the stomach and in the bloodstream after 30 minute
• It can be easily measured in the bloodstream — monitoring of dosage is easier

• Based on ‘Uptodate’, a longer-acting glucocorticoid like prednisone is sometimes preferred because it can be taken once per day. Occasionally, a small additional dose is needed in the afternoon. However, it can be more difficult to adjust the dose of these longer-acting medications to avoid overtreatment.

Rationale of Glucocorticoids Administration Time

• Glucocorticoids typically are administered in doses that mimic physiologic patterns. 
• Normally, there is a diurnal variation in cortisol secretions, with the highest peak occurring between 6 and 8 ^AM and a decline throughout the day. 
• A second smaller peak occurs in the late evening or early morning. Therefore, in order to mimic endogenous secretions, the glucocorticoids are given twice daily

Monitoring and stopping steroids

• Monitoring during treatment – The development of weight gain or a puffy face is usually a sign of overtreatment, and the glucocorticoid dose is decreased as a result. 
• Higher doses of glucocorticoids are of no benefit and may increase the risk of bone thinning (osteoporosis). A clinician will monitor closely for these complications
• In patients whose disease is unlikely to relapse, steroids should be reduced gradually when they have: 

• Received more than 40 mg prednisolone (or equivalent) daily for more than one week.
• Been given repeat doses in the evening.
• Received more than three weeks' treatment.
• Recently received repeated courses (particularly if taken for longer than three weeks).
• Taken a short course within one year of stopping long-term therapy.
• Other possible causes of adrenal suppression.

• In general, patients taking any steroid dose for less than 2 weeks are not likely to develop HPA axis suppression and can stop therapy suddenly without tapering
• Where there has been chronic therapy, the objective is to rapidly reduce the therapeutic dose to a physiological level (equivalent to 7.5mg/d prednisolone) e.g. by reducing 2.5mg every 3-4 days over a few weeks, and then proceed with slower withdrawal in order to permit the HPA axis to recover.
• After the initial reduction to physiological levels, doses should be reduced by 1mg/d of prednisolone or equivalent every 2-4 weeks depending upon patient's general condition, until the medication is discontinued.
• Alternatively, after the initial reduction to 5-7.5mg of prednisolone, the clinician can switch the patient to HC 20mg/d and reduce by 2.5mg/d every week until the dose of 10mg/d is achieved.
• After 2-3 months on the same dose, the HPA axis function should be assessed through a Corticotropin (ACTH-Synachten) test or through an Insulin Tolerance test (ITT). A pass response to these tests indicates adequate function of the axis and GCs can be safely withdrawn. If the axis has not fully recovered, treatment should be continued and the axis function should be reassessed

References

• Treatment of adrenal insufficiency in adults. https://www.uptodate.com/contents/treatment-of-adrenal-insufficiency-in-adults
• Patient education: Adrenal insufficiency (Addison's disease) (Beyond the Basics). https://www.uptodate.com/contents/adrenal-insufficiency-addisons-disease-beyond-the-basics
• Glucocorticoid Therapy and Adrenal Suppression https://www.ncbi.nlm.nih.gov/books/NBK279156/
• Adrenal Insufficiency: What Pharmacists Should Know. http://www.pharmacytimes.com/publications/issue/2006/2006-12/2006-12-6101
• A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765115/
• Adrenal Insufficiency: Review of Clinical Outcomes With Current Glucocorticoid Replacement Therapy. http://www.medscape.com/viewarticle/837371_5