KEY FEATURES

Steroids have been extensively used to treat macular edema due to diabetic retinopathy, venous occlusive disease, ocular inflammation, and also in cases of choroidal neovascularization (CNV). The various intraocular steroids that have been used include dexamethasone, triamcinolone, and fluocinolone. This chapter provides an extensive description of the pathophysiology of macular edema as well as the pharmacology, efficacy, and adverse effects associated with the use of steroids in various retinal diseases.At the end of the chapter, a section is devoted to ongoing clinical trials for the treatment of macular edema secondary to retinal vascular diseases, and also to the development of new and exciting drug delivery systems for long-term delivery of steroids.

INTRODUCTION

Macular edema occurs when a variety of disease states induce changes to retinal capillaries, resulting in a breakdown of the tight junctions that form the blood–retinal barrier, and subsequent increased retinal vascular permeability.1 Chronic, low-grade inflammation of the retinal microvasculature appears to be a significant contributor to this process. As such, the goals of therapy for macular edema should be to reduce inflammation, restore blood–retinal barrier patency, and interfere with the production or action of vascular endothelial growth factor (VEGF) and other proinflammatory cytokines. Several agents have the potential to achieve one or more of these goals. However, corticosteroids are unique in that they are the one class of agents that acts upon most of the multiple processes in the pathophysiology of macular edema (Figure 30.1). For example, corticosteroids are capable of inhibiting prostaglandin and leukotriene synthesis as well as interfering with intercellular adhesion molecule-1 (ICAM-1), interleukin-6, VEGF-α, and stromal cell derived factor-1 pathways2–5 Corticosteroids also have been shown to decrease paracellular permeability and increase tight junction integrity both by directly restoring tight junctional proteins to their proper location at the cell border and by increasing the gene expression of those proteins.6–9

Corticosteroid usage in ophthalmology dates back to the early 1950s. Periocular and intraocular usage of corticosteroids, after a period of disrepute due to its side-effects, is in a phase of renaissance with the advent of long-acting steroids such as triamcinolone acetonide. Over the last two decades there has been an extensive increase in usage of steroids to treat macular edema due to diabetic retinopathy,10,11 venous occlusive disease,11 ocular inflammation,12,13 and also in cases of CNV.14,15 Triamcinolone acetonide is especially being used for conditions requiring long-term administration such as uveitis, macular edema secondary to retinal vascular disease, diabetic macular edema, and CNV. Dexamethasone is also used clinically to reduce intraocular inflammation, but since it is only available in a soluble form, its duration of action is much less than that of triamcinolone acetonide. Fluocinolone acetonide is currently utilized in a drug delivery implant placed in the vitreous cavity (Retisert, Bausch & Lomb), and additional intravitreal drug delivery implants are being developed using dexamethasone (Ozurdex, Allergan), triamcinolone acetonide (I-vation, Surmodics), and fluocinolone acetonide (Medidur/Iluvien, Alimera). The ongoing clinical trials on the use of various steroids in retinal diseases will be discussed briefly at the end of this chapter.

PHARMACOLOGY

STRUCTURE

Triamcinolone acetonide is designated chemically as 9-fluoro- 11b,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17acetal with acetone. The empirical formula is C24H31FO6 and the molecular weight is 434.50 Da (Figure 30.2).

Macular edema

Figure 30.1  Targets of corticosteriod-based therapies. CRVO, central retinal vein occlusion; IL-1, interleukin-1; TNF-α, tumor necrosis factor-α.

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Figure 30.2  Triamcinolone acetonide is designated chemically as 9-fluoro-11b,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone. The empirical formula is C24H31FO6 and the molecular weight is 434.50 Da.