Systemic glucocorticoids

Mechanism of action of glucocorticoids

The effects of glucocorticoids are mediated via genomic and nongenomic mechanisms. In general, with the use of oral therapeutic glucocorticoids, the effect of glucocorticoids is mediated via genomic mechanism. The human GR gene is one of the loci on chromosome 5 _q 31-32, and the human GR messenger RNA has alternative splice variants that produce the target proteins. The GR binds to cortisone and initiates the dissociation of molecular chaperones, such as heat-shock proteins, from the receptor. Within the cell, glucocorticoids act in the cell through genomic and nongenomic paths in three ways. First, the glucocorticoid-GR complex penetrates the nucleus and binds to the DNA sequences called glucocorticoid-responsive elements, which initiates the transcription process mediated by RNA polymerase II. In the second way, interactions between the cortisol-glucocorticoid-receptor complex and other transcription factors [such as nuclear factor-kB (NF-kB)] are involved in the regulation of other glucocorticoid-responsive genes. Most antiinflammatory effects are thought to occur due to inhibited gene transcription via NF-kB and the adverse effects of glucocorticoids are mediated via activation of transcription of certain genes (transactivation). The third way involves nongenomic mechanisms and consists of glucocorticoids signaling through membrane-associated receptors and secondary messengers. At dosages more than 100 mg/day of prednisolone, GRs become saturated and this involves the emergence of nongenomic mechanisms. When acting through genomic mechanisms, glucocorticoids take at least 30 minutes to several hours to show an effect and glucocorticoids can have also a rapid onset (seconds to minutes). In pulse therapy, glucocorticoids act faster (within minutes) via nongenomic mechanisms. The response to pulse therapy might be biphasic involving an early rapid nongenomic effect and a delayed and more sustained genomic effect.

Antiinflammatory and immunosuppressive effects of glucocorticoids

Glucocorticoids exert their antiinflammatory and immunosuppressive effects by acting on different cellular pathways, which are considered complex. Glucocorticoids acts first via their antiinflammatory effects and promote immunosuppressive effects at a later stage through the inhibition of antibody synthesis as effects on humoral immune response. Antiinflammatory effects of glucocorticoids are mediated by their ability to: (1) increase the blood count of neutrophils and decrease their trafficking; (2) decrease the blood count of macrophages and monocytes, trafficking and their phagocytosis and bactericidal effects, and inhibit antigen presentation, which may increase susceptibility to infection; (3) decrease lymphocyte blood count, trafficking, and cytokine production; (4) decrease the blood count of eosinophils and to increase apoptosis; and (5) decrease the blood count of basophils and the release of mediators of inflammation. Glucocorticoids also suppress fibroblast proliferation IL-1 and tumor necrosis factor induced metalloproteinase synthesis. Glucocorticoids inhibit the activity of several T helper type 1 cytokines including IL-1β, IL-2, IL-3, and IL-6. Glucocorticoids also have the ability to inhibit the production of cylcoxygenase-2 and the formation of arachidonic acid metabolites through the induction of expression of lipocortin-1 (an inhibitor of phospholipase A2).

Glucocorticoids have the ability to block antibody production via different mechanisms: (1) Lymphopenia (T cells are affected more than B cells), which is secondary to lymphocytes redistribution, mainly to the bone marrow and spleen, or apoptosis ; (2) inhibition of IL2 synthesis and signaling; (3) inhibition of signal transduction events critical for T-cell activation; (4) inhibition of antigen-presenting cell function; and (5) B-cell suppression via inhibition of BLys (by high dose dexamethasone). ¹⁸

Forms of synthetic steroids

Synthetic steroids are more potent than natural steroid hormones. Glucocorticoids with an 11-keto such as cortisone and prednisone are biologically inactive. Cortisone and prednisone activation is processed in the liver via the hepatic enzymes where 11-keto is reduced to 11-hydroxy configuration to become active. This phenomenon results in the conversion of cortisone to cortisol and prednisone to prednisolone. The use of prednisolone might be more efficacious in patient with liver disease. Tissue concentration of biologically active glucocorticoids is controlled by two intracellular enzymes; 11 β-hydroxysteroid dehydrogenase type 1 which promotes the activation of inactive forms of glucocorticoids, whereas 11 β-hydroxysteroid dehydrogenase type 2 which promotes the conversion of active glucocorticoids to inactive forms. The potency of glucocorticoids is related to the structural differences in the steroid configuration where the introduction of a double bond between the 1 and 2 positions of cortisol results in prednisolone and the addition of six-methyl group to the last produces methylprednisolone. It is known that prednisolone is 4 times more potent than cortisol and methylprednisolone is 5 times more potent than cortisol. Glucocorticoids biologic half-lives (8–48 hour) is longer than their plasma half-lives (0.5–4 hour) ( Table 63.1 ). The metabolism of synthetic steroids is in the liver and inactive metabolites are eliminated by the kidneys. Synthetic steroids bound to transport protein cannot pass the placenta. The placenta contains 11 β-hydroxysteroid dehydrogenase type 2, which catalyzes the active glucocorticoids received from the blood of the mother to inactive forms. Dexamethasone and betamethasone have almost no affinity for transport proteins and are usually not metabolized by 11 β-hydroxysteroid dehydrogenase type 2 in the placenta, thus they reach the fetal blood without alteration. Prednisone is the most frequently prescribed synthetic steroid in lupus and other rheumatic diseases due to its short plasma half-life and the availability of tablets in different doses. Both prednisone and prednisolone are excreted in breast milk but in small quantities, and it is recommended to avoid breastfeeding for 4 hours after the intake of prednisone and prednisolone.