Withdrawal from glucocorticosteroid therapy: …

1 0021-7557/08/84-03/192 Jornal de PediatriaCopyright 2008 by Sociedade Brasileira de PediatriaREVIEWARTICLEW ithdrawal from glucocorticosteroid therapy: clinicalpractice recommendationsCr sio Alves,1 Teresa Cristina Vicente Robazzi,2 Milena Mendon a3 AbstractObjective:To present an up-to-date and practical review of how to safely withdraw glucocorticosteroid :A review of the published literature identified by searching the MEDLINE and LILACS databases(1997-2007), selecting the most representative articles on the of the findings:Three clinical situations may occur during glucocorticoid Withdrawal : adrenalinsufficiency secondary to negative feedback on the hypothalamic-pituitary adrenal (HPA) axis, steroid withdrawalsyndrome and relapse of the disease for which the glucocorticoids were prescribed.

2 Although there is no consensus onhowtobestdiscontinueprolongedglucocort icosteroidtherapy, article updates pediatricians on how to recognize these problems and provides recommendations on how to safelysuspend glucocorticosteroid therapy. A brief review of the pharmacology of glucocorticoids is also :There is no good predictive test for predicting the risk of adrenal insufficiency in patients who havebeen on corticosteroid therapy chronically. There is a need for prospective studies to assess the true incidence of thisproblem and to propose rational strategies for preventing it. The current recommendation is that patients who havebeenonchronicand/orhighdoseglucocort icoidsshouldbeadministeredglucocorticoid sduringstresssituationsunlessthe integrity of the HPA axis has been established by dynamic (RioJ).

3 2008;84(3):192-202:Adrenalinsufficiency, Cushing ssyndrome,steroidwithdrawaltherapy, their introduction to clinical practice, 60 years ago,corticosteroids have been widely used for the treatment of agreat variety of diseases and they are the most powerful of allknown anti-inflammatory ,2 Their use has consider-ablyreducedmorbidityandmortalit yamongpeoplewithseri-ous conditions, such as autoimmune diseases, allergicprocesses, organ transplantation, adrenal insufficiency, con-genital adrenal hyperplasia, and ,when treatment is prolonged and/or corticosteroid doses arehigh,inadditiontothesignificantside-e ffectsassociatedwithtreatment (Cushing's syndrome), suspension or withdrawalin an inappropriate manner can cause three complications.

4 Secondary adrenal insufficiency due to suppression of thehypothalamus-pituitary-adrenal axis (HPA), steroid with-drawalordeprivationsyndromeandreact ivationoftheunder-lying ,6In view of the large number of pediatric patients who areprescribedtreatmentwithcorticosteroid s,theobjectiveofthisarticle is to provide an up-to-date and practical review of howto safely suspend corticosteroid therapy when patients this the physiology and pharmacology of corticosteroidswill be briefly reviewed, describing the principal syndromesassociated with their Withdrawal . The literature review wasbased on searches of the MEDLINE and LILACS databases,1.

5 Doutor. Professor e Coordenador, Resid ncia em Endocrinologia Pedi trica, Departamento de Pediatria, Faculdade de Medicina, Universidade Federal daBahia (UFBA), Salvador, BA, Mestre. Professora, Departamento de Pediatria, Faculdade de Medicina, UFBA, Salvador, BA, Brazil. Membro, Departamento Cient fico de Reumatologia,Sociedade Brasileira de Acad mica de Medicina, UFBA, Salvador, BA, conflicts of interest declared concerning the publication of this C, Robazzi TC, Mendon a M. Withdrawal from glucocorticosteroid therapy: clinical practice recommendations. J Pediatr (Rio J). 2008;84(3) received Nov 13 2007, accepted for publication Jan 08 the most current and most representative articleson the subject published between 1997 and 2007, and alsotext books on the physiology of corticosteroidsThe adrenal gland is made up of two functional units: are produced in the medulla.

6 The adrenal cortexaccounts for 90% of the gland, surrounding thecentrally-located medulla. Histologically, the adrenal cortexis subdivided into the zona glomerulosa, the zona fasciculataand the zona reticularis, which produce three classes ofhormones: mineralocorticoids, glucocorticoids and zona fasciculata is responsible for the synthesis ofglucocorticoids,ofwhichgroupcortisol(h ydrocortisone) or adrenocorticotrophic hormone (ACTH), whichis secreted by the anterior pituitary, which in turn is regulatedby a hypothalamic hormone, corticotrophin-releasing hor-mone (CRH).8 Both ACTH and CRH are controlled by cortisolthrough a feedback mechanism, , the greater the plasmacortisol concentration, the less ACTH and CRH are released,and the lower the serum cortisol levels, the greater a circadian or nyctohemeral rhythm.

7 In individuals with anormal sleep/wake rhythm, the highest concentrations ofACTH and cortisol occur during the early morning, at 6 and 8amrespectively,decreasingduringtheafter noon(50%ofthemorning level by 4 pm) and reaching their lowest levels ,cor-tisol secretion is also regulated by neural stimuli originatingin the central nervous system and triggered by stressful situ-ations, which explains the elevated serum cortisol levelsobserved in these in circulation, 75-80% of the cortisol binds with atransport protein, an alpha-globulin called transcortin or cor-tisol binding globulin (CBG). Only a small fraction (6%) existsas a free hormone, and passes through cell membranes bind-ing to specific plasma hormone-receptorcomplex enters the nucleus where it will stimulate, suppressorinfluencetheprocessofproteinsy nthesisbymeansofinter-action with DNA (genomic action) or with proteins involved inthe transcription process (non-genomic action).

8 8,11A thirdmechanism which was not dependent on intra-nuclear actioncould explain the rapid action of some corticosteroids, whichsupports their use for pulse is metabolizedby the hepatic cells and its products, more polar andwater-soluble, ,innormaladultswhoarenotunder stress, the adrenal gland secretes an average of 20mg/day of , recent studies have indicatedthatthelevelofproductionislower still,ataround5-7mg/m2/day,orapproximate ly8-15 ,13,14 Thislevelofsecre-tion is the equivalent to approximately 10-12 mg/m2/day ofhydrocortisone administered orally, compensating for theincomplete bioavailability resulting from intestinal absorp-tion and hepatic pharmacology of corticosteroidsSyntheticcorticosteroidan aloguesareproducedbymeansof structural modifications to their basic molecule that areintended to emphasize specific pharmacological preparations vary in terms of their glucocorticoidmineralocorticoid and anti-inflammatory power.

9 However,their tendency to cause adrenal depression is correlated withtheir glucocorticoid is considered the basis of reference for analyzingglucocorticoidactivity,andisgiv enavalueof1,whiledexam-ethasone,themostp owerful,isratedat25,basedontheclas-sic, or genomic, mechanism of action. Therefore, if cortisol(hydrocortisone) is being given at 20 mg/day, then the dex-amethasone dose needed to achieve similar effects will be 25times smaller or mineralocorticoid action isrelatedtothemaintenanceofelectrolyticb alanceintheextra-cellular fluid, primarily determining water and sodium reten-tion, potassium depletion and metabolic alkalosis.

10 Theseeffectsoccuraftercorticosteroidshav eboundtotype1recep-tors in renal cells, which, in turn, bind to is the only glucocorticoid that has been shownnot to have mineralocorticoid are divided into three groups dependingon the duration of ACTH suppression caused by a standarddose(equivalentto50mgofprednison e):shortaction(hydro-cortisone, cortisone, deflazacort), which suppress ACTH forlessthan36hours;intermediateaction(tr iamcinolone,pred-nisone, prednisolone, methylprednisolone), which suppressACTH foraround48hours;andprolongedaction(dexa metha-sone, betamethasone), which suppress ACTH for more than48 hours.