Administering Corticosteroids in Neurologic Diseases

CE Send comments/questions via email compendium@medimedia.com, fax 800-556-3288, or web CompendiumVet.com The main pharmacologic effects of glucocorticosteroids pertain to their antiinflammatory properties, immunosuppressive effects, and potential tumoricidal role. Central nervous system (CNS) trauma involves multiple and complex pathophysiologic processes that may benefit from corticosteroid administration. Unfortunately, clinical trials of these drugs have not proven that they have a definitive or superior role in treating CNS trauma. CNS inflammation may be infectious, but in many cases a specific pathogen is not confirmed as the cause; in either case, patients may benefit from the actions of steroids in the initial period. Other neurologic diseases, such as cerebrovascular disease, may not benefit from corticosteroid therapy, whereas for some types of neurologic neoplasia, it may be the only beneficial treatment available. tions of glucocorticosteroids in veterinary neurology based on experimental and clinical research evidence. PHYSIOLOGY AND MECHANISM OF ACTION Corticosteroids are primarily produced by the zona glomerulosa (which produces aldosterone) and zona fasciculata (which produces cortisol and corticosterone) of the adrenal gland and have a plethora of functions. Corticosteroids are constantly synthesized under the control of the hypothalamus (via the effect of corticotropin-releasing hormone on the pituitary) and pituitary (via adrenocorticotropic hormone [ACTH]). Cortisol and corticosterone concentrations in plasma influence ACTH secretion in such a way that increased concentrations inhibit release of ACTH and reduced concentrations COMPENDIUM 210 March 2005 Administering Corticosteroids in Neurologic Diseases Simon R. Platt, BVM&S, DACVIM (Neurology), DECVN, MRCVS Carley J. Abramson, DVM, DACVIM (Neurology), MRCVS Laurent S. Garosi, DVM, DECVN, MRCVS aThe Animal Health Trust, Centre for Small Animal Studies Newmarket, Suffolk, England bThe Ohio State University stimulate release of ACTH. Exogenous corticosteroid administration can also suppress ACTH secretion, with the degree of suppression depending on the particular drug administered. At least three steroid receptors have been identified and associated with different physiologic effects. Every cell type has glucocorticosteroid receptors, with the type and concentration of the particular receptor varying between species and tissue. Glucocorticoid receptors are located in the cytoplasm of the target cell and are inactivated until bound to a steroid ligand. Steroids are thought to enter the cell by passive diffusion; after they have bound to the receptor, the glucocorticosteroid– receptor complex translocates to the nucleus, where it binds to regulatory proteins of target genes. Transcription of the gene and subsequent formation of the targeted protein is either induced or inhibited. The proteins encoded by these genes are responsible for physiologic and hence pharmacologic effects of the glucocorticosteroids. The natural function of glucocorticosteroids is to protect glucose-dependent cerebral functions by stimulating formation of glucose by the liver, decreasing its peripheral use, and promoting its storage as glycogen. Gluconeogenesis is the result of increased precursors and induction of hepatic enzymes that catalyze reactions, which are both necessary for glucose synthesis. Increased breakdown of proteins, particularly skeletal muscle and collagen, provides gluconeogenic precursors. This effect can be exhibited clinically as muscle wasting and delayed wound healing. The metabolism of lipids is also affected by glucocorticosteroids, which promote lipolysis and inhibit long-chain fatty acid synthesis. Glucocorticoids influence water and electrolyte balance through mineralocorticoid actions. Synthetic glucocorticoids possess varying degrees of mineralocorticoid activity, but all have less than 1% of the mineralocorticoid activity of aldosterone. Glucocorticoids also impart a permissive effect on tubular mechanisms that maintain the glomerular filtration rate; they have an inhibitory effect on antidiuretic hormone and may decrease the permeability of the distal renal tubules to water via a direct action. Glucocorticoids are most frequently used in clinical medicine for their antiinflammatory and immunosuppressive actions. Their action is on leukocyte numbers as well as function, ultimately impacting both humoral and cell-mediated arms of the immune response. Specifically, glucocorticosteroids inhibit the enzyme phospholipase A2 via lipocortin, which converts arachidonic acid to prostaglandin and leukotriene metabolites. Glucocorticoids also inhibit release of tumor necrosis factor and interleukin-2 from activated macrophages. Tumor necrosis factor induces cytotoxicity and can enhance neutrophil and eosinophil function. The immunosuppressive effects of glucocorticosteroids are more pronounced on the cellular arm than on the humoral arm of the immune system. Glucocorticoids have minimal effects on plasma immunoglobulin concentrations but can modulate immunoglobulin function, inhibiting such processes as bacterial opsonization. The immunosuppressive actions of glucocorticosteroids, like their antiinflammatory actions, involve disruption of the intercellular communication of leukocytes via interference with lymphokine production, biologic action, or both. The effects of glucocorticosteroids on the central nervous system (CNS) are well documented. Indirectly, glucocorticosteroids maintain adequate plasma concentrations of glucose for cerebral functions, maintain cerebral blood flow, and influence electrolyte balance in the CNS. In humans, glucocorticosteroids are believed to influence mood (including euphoria), behavior, and brain excitability. The euphoric effect commonly recognized in dogs is likely to reflect differences in glucocorticosteroid receptors. TRAUMA Head Trauma Severe head trauma is associated with a high level of mortality in human and veterinary patients. The appropriate therapy for head trauma patients remains controMarch 2005 COMPENDIUM Administering Corticosteroids in Neurologic Diseases 211 CE A definitive diagnosis of neurologic disease is often required before glucocorticosteroid administration can be advised in an appropriate regimen.