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Systemic effects of ototopical dexamethasone.

Endogenous glucocorticoids regulate the metabolism of carbohydrates, proteins, lipids, and other substances throughout the body. Their effect is global, as almost every cellular structure has steroid receptors. They also have an effect on fluid and electrolyte balance, the body's environmental and natural stress, and the function of the kidneys, muscles, and the cardiovascular, immune, and endocrine systems.

The body secretes approximately 10 mg of cortisol per day. The peak plasma concentration of approximately 16 [micro]g/100 ml occurs at approximately 8 a.m. each day, and a trough of approximately 4 [micro]g/100 ml occurs at about 4 p.m. The administration of exogenous steroids reduces the body's production of cortisol in the process known as hypothalamic-pituitary-adrenal (HPA) axis suppression.

Exogenous steroids, regardless of their route of administration, are easily absorbed by the body. They are transported primarily in the serum by globulin and albumin. Steroids are metabolized by the liver, and they are excreted by the kidney and to a considerable extent by the liver.

Synthetic steroids have various degrees of potency relative to that of cortisol. When the anti-inflammatory activity of steroids was assessed, it was found that prednisone is 4 times more active than cortisol and dexamethasone is 25 times more active. (1)

The pharmacokinetic profile of systemically administered dexamethasone was assessed in a study of 10 female volunteers who on separate occasions received 0.5 mg orally, 1.5 mg orally, and 3 mg intramuscularly. (2) Their plasma concentrations were then measured. The authors noted that the maximum serum concentration occurred at 1.6 to 2 hours after administration; maximum levels were 8 ng/ml with the 0.5-mg dose, 14 ng/ml with the 1.5-mg dose, and 36 ng/ml with the 3-mg dose. The half-life of dexamethasone was biphasic, with an alpha phase at 0.8 to 1.1 hours and a beta phase at 4.2 to 6.6 hours; the drug was completely eliminated within 24 hours. There was a sharp drop in endogenous cortisol production in the first 10 hours, but cortisol levels returned to baseline within 48 hours of dexamethasone administration.

Dexamethasone is the only steroid that has been approved by the U.S. Food and Drug Administration for topical application in the middle ear. This article reviews the current information on its systemic effects after ototopical application.

Ototopical dexamethasone

Little information exists on the systemic effects of ototopical steroids. Two studies have provided us with basic knowledge on this subject:

* Abraham et al conducted a single-blind, placebo-controlled experiment in 10 beagles. (3) The dogs were administered two daily doses of a dexamethasone gel applied to the outer auditory canal in one ear (60 [micro]g/kg) for 21 days. The authors noted several systemic effects. Polydipsia and polyuria occurred during treatment, but it resolved 7 days after treatment was stopped. Statistically significant plasma cortisol suppression was noted on days 11 through 19 of therapy, but cortisol concentrations returned to normal 1 week after the cessation of treatment. Additionally, cortisol response to adrenocorticotrophic hormone (ACTH) stimulation was blocked during the experiment. Liver enzyme levels rose by day 11, but there was no change in electrolyte and leukocyte counts. No clinical abnormalities of the external auditory canal, the skin, or the cutaneous pigment were observed. One unfortunate aspect of this study is that the authors did not measure plasma dexamethasone concentrations.

* In a study designed to assess the pharmacokinetics of the ototopical ciprofloxacin/dexamethasone combination, we measured plasma dexamethasone concentrations in 25 children who were undergoing tympanostomy tube insertion. (4) Each child received a single dose (4 drops) of the ototopical combination ciprofloxacin/dexamethasone (840/280 [micro]g) in a sterile suspension. We then measured the plasma concentrations of both drugs at 15 and 30 minutes and at 1, 2, 4, and 6 hours by high-performance liquid chromatography/tandem mass spectrometry. Plasma dexamethasone levels were detectable in 14 of these children. The peak concentration level (mean: 0.90 [+ or -] 1.04 ng/ml; range: <0.05 to 5.10) was reached fairly quickly--within 2 hours (figure). The half-life was 3.9 hours ([+ or -] 2.9). These findings indicate that the degree of systemic exposure to dexamethasone following ototopical administration in pediatric patients is low. We did not investigate ACTH levels, but it is unlikely that dexamethasone triggered any significant suppression of the HPA axis at the plasma levels recorded in this study.

Compared with oral administration, ototopical administration of dexamethasone results in significantly lower plasma concentrations. While an oral dose of 500 [micro]g of dexamethasone will result in a serum concentration of 0.008 [micro]g/ml, an ototopical dose of 280 [micro]g will yield a plasma concentration of only 0.001 to 0.002 [micro]g/ml.

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The systemic effects of ototopical dexamethasone are dependent on its absorption via the middle ear structures. Absorption is dependent on the clinical state of the tympanum--that is, absorption is decreased when the mucosa is edematous and fluid is present. Absorption is also dependent on the limited total dosage applied to the middle ear; compared with parenteral administration, topical administration delivers only minimal amounts of dexamethasone to the middle ear in each application.

Several animal and human studies have involved various methods of delivering dexamethasone transtympanically. (5,6) These studies demonstrated round window permeability, with measurable levels of drug in the perilymph. Plasma concentrations of dexamethasone are significantly lower after transtympanic application than after oral or intravenous administration. Regrettably, these studies did not include any objective measurements of systemic effects or pharmacokinetic properties; however, no evidence of adverse systemic reactions was observed. Moreover, many studies have demonstrated the effectiveness of ototopical dexamethasone for the treatment of sudden hearing loss, Meniere's disease, tinnitus, and otitis media, and none of these studies demonstrated any evidence of ototoxicity.

Conclusion

Ototopical administration of dexamethasone produces beneficial therapeutic effects in a number of otologic conditions. Plasma levels of ototopically administered dexamethasone are detectable only when measured by sophisticated and highly sensitive techniques. Administration of transtympanic dexamethasone in high concentrations and over a prolonged period of time temporarily sup presses cortisol production in dogs without any evidence of systemic effects. Systemic absorption of dexamethasone is much greater after parenteral administration than after transtympanic application. No significant systemic effects have been recorded in humans treated with therapeutic doses of dexamethasone-containing drops.

References

(1.) Schimmer BP, Parker KL. Adrenocorticotrophic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones. In: Hardman JG, Limbird LE, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill; 2001: chap 60.

(2.) Loew D, Schuster O, Graul EH. Dose-dependent pharmacokinetics of dexamethasone. Eur J Clin Pharmacol 1986;30(2):225-30.

(3.) Abraham G, Gottschalk J, Ungemach FR. Evidence for ototopical glucocorticoid-induced decrease in hypothal amic-pituitary-adrenal axis response and liver function. Endocrinology 2005;146(7): 3163-71.

(4.) Spektor Z, Jasek MC, Jasheway D, et al. Pharmacokinetics of topical Ciprodex otic suspension in pediatric and adolescent patients after tympanostomy tube surgery. Presented at the annual meeting of the American Society of Pediatric Otolaryngology; May 2-3, 2004; Phoenix.

(5.) Chandrasekhar SS, Rubinstein RY, Kwartler JA, et al. Dexamethasone pharmacokinetics in the inner ear: Comparison of route of administration and use of facilitating agents. Otolaryngol Head Neck Surg 2000; 122(4):521-8.

(6.) Parnes LS, Sun AH, Freeman DJ. Corticosteroid pharmacokinetics in the inner ear fluids: An animal study followed by clinical application. Laryngoscope 1999;109(7 Pt 2): 1-17.

Zorik Spektor, MD, FAAP
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Author:Spektor, Zorik
Publication:Ear, Nose and Throat Journal
Date:Nov 1, 2007
Words:1250
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