[Pharmacology of glucocorticoids and ENT pathology]

Abstract

1. NATURAL AND SYNTHETIC HORMONES: Glucocorticoids are indispensable circulating hormones implicated in carbohydrate and protein metabolism. They also have strong antiinflammatory effects used in therapy. This antiinflammatory activity has led to the development of synthetic compounds with an antiinflammatory action that is much greater than that of the natural hormones (cortisol, cortisone) with reduced mineralocorticoid activity. 2. ANTIINFLAMMATORY EFFICACY OF GLUCOCORTICOIDS: The action of glucocorticoids on the majority of the cells involved in inflammatory reactions, particularly in allergy, and their induction of synthesis of new inflammation mediators explains their antiinflammatory effect. 3.

Mechanisms of action: The antiinflammatory properties of glucocorticoids result basically from their inhibitory effect on synthesis of proinflammatory proteins, in particular many cytokines. Corticoids reduce the production of prostanoids by inhibiting the expression of COX-2, but are much less effective on the production of leukotrienes. Corticoids inhibit the degranulation of human basophils (histamine release) but have no effect on mast cells. 4. ACTIVATION OF A CYTOPLASMIC RECEPTOR: The antiinflammatory effect of glucocorticoids is mediated by binding to a cytoplasmic receptor which, when activated, migrates to the nucleus. The activated receptor can interact with transcription factors (NF-kappa B, AP-1) inhibiting the synthesis of proinflammatory proteins (cytokines, COX-2...). This "transrepressive" activity explains most of the antiinflammatory effects of glucocorticoids. 5. ACTION OF THE ACTIVATED RECEPTOR: The activated receptor can bind to specific sites present on the regulator region of target genes, inducing their transcription (or transactivation). This induction effect on protein synthesis concerns the renin-angiotensin system, neoglucogenesis, and bone metabolism. Increased production of these proteins explain the metabolic and endocrine effects of glucocorticoids which, when exaggerated, particularly with general administration, can lead to undesirable effects. At the present time, our knowledge suggests it would be best to have molecules with a predominant transrepressive activity (antiinflammatory activity) since the transactivator effects appeared to be associated with the undesirable metabolic effects of glucocorticoids. 6. OTHER PHARMACEUTICAL PROPERTIES: Glucocorticoids also have properties that do not require gene expression. These "non-genomic" effects could occur at high dosage "pulse" therapy. We will have to wait for more pertinent clinical information on these effects to use the power of these non-genomic effects to guide our choice of the appropriate glucocorticoid in given clinical situations. 7. LOCAL TREATMENT FOR ALLERGIC RHINITIS: Given locally glucocorticoids reduce the concentration of many inflammatory mediators and the number of inflammatory cells in secretions and nasal biopsies. The efficacy of glucocorticoids is perfectly established in this indication as well as in nasal polyposis. 8. LOCAL TOLERANCE: During the first days of treatment, local application of corticoids on the inflammatory mucosal surface can cause irritation and/or sneezing. These manifestations generally subside in a few days and are more frequent with solutions containing glycol. The dry nose sensation, sometimes associated with minimal epistaxis, is classically reported, though at a low frequency. A few rare cases of ulceration of perforation of the septum have been report and it would be difficult to exclude a mechanical cause related to administration route. It is clear that the risk of mucosal atrophy has been eliminated with the use of nasal corticosteroids. 9. EVALUATION OF THE SYSTEMIC EFFECT OF NASAL CORTICOSTEROIDS: Most of the studies have examined the hypothalamo-pituitary-adrenal axis. These studies have rarely demonstrated, an then in isolated cases, any significant modification at recommended doses. Likewise for other markers of passage into the systemic circulation such as osteocalcine or the number of circulating eosinophils. There is also very little risk of growth impairment in children or cataracts in adults. 10. SHORT-COURSE GENERAL CORTICOSTEROID THERAPY: Short periods are sometimes recommended for rhinitis, sinusitis, polyposis or laryngitis. Use of a short duration treatment (about one week) at doses in the 1 mg/kg/d range, induce a transient inhibition of the corticoadrenal axis in about half the patients; this inhibition disappears in most all cases in two weeks. The clinical risk associated with this alteration in patients under stress (infection, trauma...) remains hypothetical. In any case, it would be advisable to avoid repeating short-course general corticosteroid therapy at close intervals.