1.7.1 Pharmacology of Steroids. Most of the known effects of the glucocorticoids are mediated by widely distributed glucocorticoid receptors. Glucocorticoid enters a target cell as a free molecule. In the absence of the hormonal ligand, intracellular glucocorticoid receptors bound to stabilizing proteins are incapable of activating transcription. When a molecule of glucocorticoid binds to the receptor, the complex undergoes conformational changes that allow it to dissociate from the stabilizing protein. The ligand-bound receptor complex, as a homodimer, then is actively transported into the nucleus, where it binds to the glucocorticoid response element (GRE) in the promoter and other non-GRE-containing promoters of the responsive gene and regulates transcription by RNA polymerase II and associated transcription factors. The resulting mRNA is exported to the cytoplasm for the production of protein that brings about the final hormone response.89
The anti-inflammatory and immunosuppressive effect of glucocorticoids has been used widely in medical management. The dramatic reduction of the manifestation of inflammation by glucocorticoids is due to their profound effects in the concentration, distribution, and function of peripheral leukocytes and to their suppressive effects on the inflammatory cytokines and chemokines and on other lipid and glu-colipid mediators of inflammation. Inflammation is characterized by the extravasation and infiltration of leukocytes into the affected tissue mediated by a complex series of interactions of white cell adhesion molecules with those on endothelial cells. Glucocorticoids inhibit these interactions. Glucocorticoids also inhibit the functions of tissue macrophages and other antigen-presenting cells. The ability of macrophages to phagocytose and kill microorganisms and to produce tumor necrosis factor-a, interleukin-1, metalloproteinases, and plasminogen activator is limited by glucocorticoids. Glucocorticoids can influence the inflammatory response by reducing the prostaglandin, leukotriene, and platelet-activating factor synthesis that results from activation of phospholipase A2. Glucocorticoids also reduce expression of cyclooxygenase II in inflammatory cells, reducing the amount of enzyme to produce prostaglandins.89
Glucocorticoids have important dose-related effects on carbohydrate, protein, and fat metabolism. Glucocorticoids increase serum glucose levels and thus stimulate insulin release and inhibit the uptake of glucose by muscle cells, while they stimulate hormone-sensitive lipase and thus lipolysis. The increased insulin secretion stimulates lipogenesis and, to a lesser degree, inhibits lipolysis, leading to a net increase in fat deposition combined with increased release of fatty acids and glycerol into the circulation. Glucocorticoids promote fat redistribution in the body.
Glucocorticoids have catabolic and antianabolic effects in lymphoid and connective tissue, muscle, fat, and skin. Supraphysiologic amounts of glucocorticoids lead to decreased muscle mass and weakness, thinning of the skin, osteoporosis, and reduce growth in children. They appear to antagonize the effect of vitamin D on calcium absorption.
Glucocorticoids have important effects on the nervous system, including behavior and intracranial pressure. Large doses of glucocorticoids have been associated with the development of peptic ulcer, possibly by suppressing the local immune response against Helicobactor pylori. Glucocorticoids given chronically suppress the pituitary release of adrenocorticotropic hormone, growth hormone, thyroid-stimulating hormone, and leutinizing hormone.
1.7.2 Steroids in Ocular Use. The actions of the synthetic steroids used therapeutically are similar to those of cortisol. They bind to the specific intracellular receptor proteins and produce the same effects but have different ratios of glucocorticoid to mineralocorticoid potency. The anti-inflammatory and immunosuppressive effects of glucocorticoids are used for a variety of ocular conditions, such as postoperative inflammation, uveitis, macular edema, hyphema, and ocular trauma. The most common route of administration is topical as solution, suspension, or ointment. Other routes of administration include subconjunctival, subtenon, intraocular, or intravitreal injection. Occasionally, glucocorticoids are administered systemically in ocular-related diseases such as optic neuritis and giant cell arteritis.
1.7.3 IOP Response With Steroid Use. A rise of IOP may occur as an adverse effect of corticosteroid therapy, including all routes of administration, such as topical, inhaled, and systemic administration. The type and potency of the agent, the means and frequency of its administration, and the susceptibility of the patient all affect the duration of time before the IOP rises and the extent of this rise. The higher steroid potency is associated with greater and earlier ocular hypertensive effect.90,91 Approximately one-third of all patients demonstrate some responsiveness to cortico-steroid. Although only a small percentage will have a clinically significant elevation in IOP, patients with primary open-angle glaucoma are more likely to demonstrate this response. Topical steroids have been shown to produce a steroid response over a period of weeks in both normal and glaucomatous eyes.91-93 However, a more acute onset of IOP rise can occur with intensive topical dexamethasone or systemic steroid therapy.90,94 Corticosteroid-induced IOP elevation may develop at any time during long-term corticosteroid administration, and regular IOP monitoring is warranted. Although some corticosteroid preparations such as fluorometholone, rimexolone (Vexol), medrysone (HMS), or loteprednol (Lotemax), which are less potent than prednisolone or dexamethasone, may be less likely to raise IOP, it cannot be overemphasized that even weaker corticosteroids or lower concentrations of stronger drugs can raise IOP in susceptible individuals.
Recently, intraocular injection of depot steroid is shown to be effective in management of a number of retina pathologies with associated improvement of visual outcome. It should be remembered that since the depot steroid cannot be removed, it may result in a prolonged exposure of the ocular tissue to the effect of steroid, and an extended IOP monitoring for several months is required. Studies have reported a high rate of up to 40% of steroid response associated with intraocular injection of triamcinolone.95 Special attention should be paid to patients who are known steroid responders or who already have a glaucomatous optic neuropathy. Furthermore, topical corticosteroid treatment may not be useful as a screening method to exclude any subsequent pressure response with depot steroid injections.96
Although most corticosteroid response of increase in IOP resolved after stopping corticosteroid, the ocular hypertensive response has been shown to be irreversible in about 3% of cases, and particularly when there is a family history of glaucoma or chronic use of steroid.90,94,97
A number of risk factors for developing corticosteroid-induced increase of IOP have been identified. Greater risk of corticosteroid response is noted in patients who have glaucoma or have been diagnosed as glaucoma suspects, patients who are older, and patients with certain types of connective tissue diseases, type I diabetes mellitus, high myopia, and a first-degree relative with primary open-angle glaucoma.98
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