Readers Write: Itraconazole and adrenal function
Itraconazole and adrenal function
By David A. Stevens, MD, Chief, Division Infectious Disease, Santa Clara Valley Medical Center, San Jose, CA, Professor of Medicine,Stanford University
In a recent discussion of a clinical case in the New England Journal of Medicine1, the authors correctly indicate itraconazole is recommended for all but the most severe cases of disseminated histoplasmosis (when amphotericin B is used). Fluconazole, though recognized as inferior, was selected for the patient's therapy, owing to concerns about itraconazole-mediated adrenal suppression (the patient had fungal adrenal involvement).
There may be unwarranted concern about adrenal suppression by itraconazole. Although another related triazole, ketoconazole, was indeed shown by us to block steroid synthesis and suppress adrenal function (the key references and the history are given in ref. 2), sufficient to actually be useful to treat Cushing's syndrome, there is, in contrast, negligible evidence of any adrenal suppression by itraconazole.2-5.
In chronic dosing up to 200 mg itraconazole daily in volunteers and patients, plasma cortisol levels and response to ACTH were normal.3 In doses up to 400 mg/day, the usual dose for systemic infections, responses to ACTH in patients were shown to be normal.4 At high (>400 mg/day) doses, only one of 8 patients, receiving 600 mg/day, had a blunted response to ACTH, after a month of therapy.5 After 6 weeks of therapy, that patient had symptoms and laboratory values consistent with depressed adrenal function. When the daily dose was then dropped to 400 mg, these findings reversed.
The superior drug for histoplasmosis therapy could have been used, with monitoring of adrenal function and hormone supplementation if necessary, in the case presented.1
References
- Lee AI, et al. A bird's-eye view of fever. New Eng J Med 2011;365:1727-32.
- Stevens, DA. Ketoconazole metamorphosis: an antimicrobial becomes an endocrine drug. Arch Intern Med 1985;145:813-5.
- De Coster R, et al. Effects of itraconazole on the pituitary-testicular-adrenal axis: an overview of preclinical and clinical studies. In, Recent Trends in the Discovery , Development and Evaluation of Antifungal Agents. RA Fromtling (ed.) 1987, JR Prous Science Publishers, Barcelona. p.251-61.
- Phillips P, et al. Adrenal responses to corticotropin during therapy with itraconazole. Antimicrob Agents Chemother 1987;31:647-9.
- Sharkey PK, et al. High dose itraconazole in the therapy of severe mycoses. Antimicrob Agents Chemother 1991;707-13.
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