Glucocorticoid therapy: minimizing side effects - SciELO

1 0021-7557/07/83-05-Suppl /S163 Jornal de PediatriaCopyright 2007 by Sociedade Brasileira de PediatriaREVIEWARTICLEG lucocorticoid therapy : minimizing side effectsCarlos Alberto Longui*AbstractObjective:To describe the main undesirable side effects of Glucocorticoid therapy , mechanisms of action and thenecessary measures to minimize side :Author s experience, supplemented with papers published in :Theprinciplesforminimizingundesirablesi deeffectsofglucocorticoidtherapyinclude: a) only use glucocorticoids if they are essential; b) avoid the use of long-acting glucocorticoids, using short- andintermediate-acting glucocorticoids instead; c) keep treatment as short as possible, since treatment lasting 5 to 7 daysshows fewer side effects and quick recovery of the hypothalamic-pituitary axis; d) use glucocorticoids with local activ-ity preferentially, such as inhaled glucocorticoids; e) use in association with other drugs, especially with other morespecific anti-inflammatory or immune suppressive drugs, promoting a synergistic effect in order to avoid the use ofglucocorticoids or to reduce dosage and duration of Glucocorticoid therapy ; f) indicate the minimum effective dose,respecting individual sensitivity to :In order to choose the best Glucocorticoid schedule it is essential to understand the pharmacologicalcharacteristics and the biological action of glucocorticoids, allowing the most adequate indication, Glucocorticoid dose,mode of administration and the duration of Glucocorticoid Pediatr (Rio J).

2 2007;83(5 Suppl):S163-171:Glucocorticoids, side effects , sensitivity, the 1930s and 1940s, several studies showed theeffects of adrenocorticoid hormones on the balance of elec-trolytes (mineralocorticoids), as well as on the metabolism ofcarbohydrates (glucocorticoids).1,2 Cortisol was synthesizedin 1946, and in 1948 it was first used by Hench in the treat-ment of rheumatoid arthritis. Unfavorable side effects arosesubsequently, limiting the therapeutic use of the 1950s, changes in the structure of cortisol resulted inthe manufacture of new drugs, such as prednisone and pred-nisolone. Subsequent structural modifications of syntheticsteroids (Figure 1) enhanced Glucocorticoid potency andextended the duration of effect (Table 1), and also provideddrugs with different affinities and binding time-courses to theglucocorticoid receptor (GR).

3 Thesenewcharacteristicsresultedinadditio nalcomplica-tions related to longer plasmatic half-life (necessary time-course to reduce initial plasma levels of the drug by 50%) andlonger biologic half-life (residence time of the drug within thetissue, reflecting the duration of action or therapeutic effect ).These compounds also present variations in hepatic metabo-lization (hydroxilation, glucoronidation, sulphatation) and inrenal excretion of inactive metabolites (20% in the free non-conjugate form). Glucocorticoids are lipophilic steroids withbioavailability between 60 and 100% when ,whoseconver-sion to the active form occurs between 5 and 30 min afterintravenous injection. Plasmatic concentration dependsmostly on the capacity to bind to serum proteins, such astranscortin e must also be alert to possible drug interac-tions(Table2)forglucocorticoids, whichcanaggravateintrin-sic diseases or bring on potentially preventable side and conceptsSome definitions and concepts3are essential for under-standing therapeutic effects and possible undesirable sideeffects of glucocorticoids:* Professor Chefe de Cl nica adjunto, Unidade de Endocrinologia Pedi trica, Depto.

4 Pediatria e Puericultura, Irmandade Santa Casa de Miseric rdiade S oPaulo, S o Paulo, SP, Brazil. Professor adjunto, Laborat rio de Medicina Molecular, Depto. Ci ncias Fisiol gicas, Faculdade de Ci ncias M dicas,Santa Casade S o Paulo, S o Paulo, SP, citation:Longui CA. Glucocorticoid therapy : minimizing side effects . J Pediatr (Rio J). 2007;83(5 Suppl) Duration of action: short (up to 12 h); intermediate (12-36h); long (> 36 h);- Duration of treatment: short term (< 10 days); intermedi-ate term (10-30 days); long term (> 30 days);- Therapeutic schedule: single dose (morning or evening);fractionated dose (2-4 times per day); alternate daily dose(every other day); mini-pulse therapy ( mg/kgmethylprednisolone); pulse therapy (10-20 mg/kgmethylprednisolone);- Therapeutic dose: replacement (7-10 mg/m2/dayhydrocortisone);low(<5mgprednisone/m2/day;satura-tionof<50%ofreceptors);medium(5-20mgprednisone/m2/day; saturation between 50-100% of receptors); high(> 20 mg prednisone/m2/day; saturation of 100% ofreceptors).

5 Very high doses (> 50 mg prednisone/m2/day) and pulse therapy (> 150 mg prednisolone/m2)present additional nongenomic effects ;- Stress dose: mild and moderate stress (2 x replacementdose, via an oral, intramuscular or intravascular route);Figure 1- Chemical structure of cortisol and of main synthetic glucocorticoids, such asprednisone, methylprednisolone and dexamethasoneTable 1- Characteristics of half-life and affinity to receptorGlucocorticoidsPlasma life (h)Biologic life (h)Bindingto CBGA ffinityto receptorGlucocorticoid potencyEquivalentdose(mg)Apoptoticpotenc y(EC50) x 10-7 Prednisone* ,190541 x x 10-8 CBG = cortisol binding globulin; = not evaluated.* prednisone (inactive) must be metabolized (liver) to prednisolone (active) by 11 HSD type I enzyme. Glucocorticoid potency was established for its capacity to elevate glycemia.

6 Anti-inflammatory potencies are proportional to the glucocorticoidpotency,although the exact proportions have not been established. The suppressive potency of hypothalamic-pituitary-adrenal axis (HPA) is similar to the gluco-corticoid potency in single-dose evaluation, but becomes different when glucocorticoids are used chronically, as it now depends on the duration of de Pediatria - Vol. 83, No. 5(Suppl), 2007 Glucocorticoid therapy - Longui CAS164severe stress (5 x substitutive dose, intramuscular orintravascular); shock (10-15 x substitutive dose, intravas-cular bolus, followed by continuous maintenance).Therapeutic indicationsGlucocorticoids have a broad spectrum of therapeuticindications1-3and may be administered as replacementtherapy in cases of adrenocorticoid insufficiency or in dis-eases such as Cushing s syndrome.

7 They may also be usedin the acute treatment of both hypoglycemia and hypercalce-mia. They can induce cell maturation (type II pneumocyte),cell differentiation (neural crest lineages) or even cell death(apoptosis), thus allowing their use in the treatment oftumors, especially hematopoietic lineage tumors. However,glucocorticoids play central roles in the treatment of diseasesinvolving immune and inflammatory have a hyperglycemic effect as they pro-vide a combined action both reducing peripheral use of glu-cose (as they reduce insulin sensitivity) and increasingglucose production by stimulating both glucogenolysis andgluconeogenesis. These effects are associated with muscularproteolysis and with heterogeneous lipid metabolism abnor-malities, combining areas of lipolysis and lipogenesis (espe-cially visceral). ,theyinducecalcium redistribution from intravascular to intracellularTable 2- Interaction of glucocorticoids with other pharmaceuticals and with diseasesInfluence of other pharmaceuticals on glucocorticoidsMedication[Serum] side effectsAspirin anti-inflammatory effectAmphotericin B clearanceCoumarinics potassemiaCyclophosphamide hepat.

8 Hepat. glycemiaIsoniazid clearanceOral Hypoglycemics glycemiaInfluence of glucocorticoids on other pharmaceuticalsMedication[Serum] side effectsAntiacids clearanceCarbamazepine KCholestyramine intest. absorptionCyclosporine hepat. clearanceErythromycin hepat. eliminationOral contraceptives hepat. eliminationPhenob/Hydantal cytochrome P450 Rifampicin cytochrome P450 Influence of diseases on Glucocorticoid pharmacokineticsDiseaseEffect on glucocorticoidsRenal insufficiency clearanceNephrotic syndrome total concentrationHepatic insufficiency clearanceInflammatory bowel diseasevariable absorptionAcute lymphocytic leukemia clearanceObesity clearanceGlucocorticoid therapy - Longui CAJornal de Pediatria - Vol. 83, No. 5(Suppl), 2007S165S165space. In the medium and long term, they reduce osteoblas-tic activity, intestinal absorption and renal calcium can modulate cell proliferation,4as theyreducetheexpressionsoftheheterodimer jun-fosandc-myc,among other transcription factors that decide on cell overlifeand multiplication, determining the pause between G1 phaseand S phase of the cell cycle.

9 They can also induce apoptoticcell death, culminating in the activation of proteins withnuclear activity involved in the degradation of DNA, RNA andother structural cell response and immunomodulationThey are the main indications for ,6 Glu-cocorticoid action on the immune system takes place at vari-ous points, culminating in deviation toward a Thelper2 (Th2)typeresponse,withanti-inflammatoryc haracteristicsdepen-dent on the increase of cytokines such as interleukins IL, IL4,IL5, IL6, IL10, IL13, and in the granulocyte-macrophagecolony-stimulating factor (GMSF). It also induces transform-ing growth factor (TGF ) secretion, which is able to reducelymphocyte T activation and cell proliferation. Glucocorti-coids are able to inhibit pro-inflammatory cytokines, such asinterleukinsIL2andIL12,interferongamma (INF )andtumornecrosis factor (TNF ), as well as adhesion molecules such aslipocortin-1,vascularadhesionmolecules (VCAM-1)andinter-cellular adhesion molecules (ICAM), and also enzymes, suchas inducible nitric oxide synthase (INOS), cyclooxygenase(COX2) and phospholipase (PLA2).

10 One of the main mecha-nisms of modulating action of glucocorticoids on the inflam-matory process acts on the expression rate of transcriptionfactors,suchasnuclearfactor kappaB(NFkB),inhibitorypro-tein for NFkB (IkB), and IkB protein kinase (IKK). Nonge-nomic Glucocorticoid effects are also present, determininghistamine decrease of action, and reduction in prostaglandinsynthesis (reducing phospholipase A2) and in plasminogenactivation. In appreciating these mechanisms, it is importantto understand the molecular mechanisms of glucocorticoidaction (Figure 2) and its main interactions in cellular trans-duction is the only possible way to under-stand the main implications of Glucocorticoid use in the deathorproliferationofcells(Figure3),asw ellasinthemodulationof inflammatory response (Figure 4).8 Undesirable side effectsThere is a long list of undesirable side effects1,2associ-ated with corticotherapy, usually related to duration of treat-ment and use of longer-acting in fat distributionCentripetalobesity,moonfacie s,buffalohump,supraclav-icular fat systemOsteoporosis,bonefractures,weaknes s,myopathy,proxi-mal muscle atrophy; aseptic necrosis of femoral and dysfunctionMenstrual disorders, decreased libido, impotence,hypothyroidism, growth failure and short stature (children).