Adverse effects

Glucocorticoids may cause several adverse effects in the eye and elsewhere in the body.

Complications in the eye include

• glaucoma

• posterior subcapsular cataracts

• exacerbation of bacterial and viral (especially herpetic) infections through suppression of protective immune mechanisms

• fungal infection

• ptosis

• mydriasis

• scleral melting

• eyelid skin atrophy

• pseudohypopyon from intraocular injection

• central serous chorioretinopathy

In the body, oral doses can cause

• suppression of the pituitary–adrenal axis

• gluconeogenesis resulting in hyperglycemia, muscle wasting, and osteoporosis

• redistribution of fat from the periphery to the trunk

• CNS effects, such as euphoria

• insomnia

• aseptic necrosis of the hip

• peptic ulcer

• diabetes mellitus

• occasionally psychosis

Elderly patients have particular difficulty taking long-term systemic steroids. For example, the adverse effect of proximal muscle wasting may make it difficult for these patients to climb stairs. Osteoporosis, another adverse effect of glucocorticoids, exacerbates the risk of falls and fractures for these patients, who are generally at an increased risk of both. Elderly patients with inflammatory diseases may require a steroid-sparing regimen.

Steroid-induced elevation in IOP may occur with topical, intraocular, periocular, nasal, and systemic glucocorticoid therapies. The exact mechanism by which steroids diminish aqueous outflow through the TM remains unknown but may be related to deposition of glycosaminoglycans in the TM.

Individual response to steroids is dependent on the duration, potency, and frequency of therapy and the route of administration of the drug used. Steroid-induced IOP elevation almost never occurs in less than 5 days and is infrequent in less than 2 weeks of use. However, failure of IOP to rise after 6 weeks of therapy does not ensure that a patient will maintain normal IOP after several months of therapy. For this reason, monitoring of IOP at periodic intervals is required throughout the course of long-term steroid therapy to prevent iatrogenic glaucomatous nerve damage. Steroid-induced elevations in IOP are usually reversible by discontinuing therapy if the drug has not been used longer than 1 year; however, if therapy has continued for 18 months or more, permanent elevations of pressure are common.

Table 16-15 lists the anti-inflammatory and IOP-elevating potencies of 6 steroids used in ophthalmic therapy. The anti-inflammatory potencies were determined by an in vitro assay of inhibition of lymphocyte transformation, and the IOP effects were determined by tests in individuals already known to be highly responsive to topical dexamethasone. However, until all these drugs are compared in a model of ocular inflammation relevant to human disease, no conclusion can be reached about the observed dissociation of effects. The lower-than-expected effect on pressure with some of these drugs may be explained by more rapid metabolism of fluorometholone in the eye compared with dexamethasone and by the relatively poor penetration of medrysone. The efficacy of these drugs for intraocular inflammation may be similarly reduced.

When a steroid-induced pressure rise is suspected but continued steroid therapy is warranted, the physician faces the following choices:

• continue the same treatment and closely monitor the status of the optic nerve

• attempt to offset the pressure rise with other drugs or treatments

• reduce the potency, concentration, or frequency of the steroid used while monitoring both pressure and inflammation

• consider a steroid-sparing alternative

Table 16-15 Comparison of Anti-inflammatory^a and IOP-Elevating^b Potencies

Immunomodulatory therapy (IMT) is an important component in the management of ocular inflammation, avoiding the toxicity associated with long-term corticosteroid therapy. IMT drugs are classified as antimetabolites, inhibitors of T-cell signaling, alkylating agents, and biologic response modifiers. Biologic response modifiers inhibit various cytokines, which are active in inflammation. See Table 16-16 for a summary of this class of medications and also BCSC Section 9, Uveitis and Ocular Inflammation.

• Jabs DA. Immunosuppression for the uveitides. Ophthalmology. 2018;125(2):193–202.

Specific drugs and regimens

Appropriate selection from the available corticosteroid drugs, formulations, and dosage regimens are contingent on the clinical situation. Steroids can be administered topically, periocularly, intravenously, or intravitreally (Table 16-17). All corticosteroids may exacerbate infections and lead to ocular adverse effects. Recent research in corticosteroids has focused on medications that can be used intraocularly and periocularly as well as developing drugs with decreased effect on IOP. As a general rule, however, the more potent the steroid, the more prevalent and severe are the adverse events.

Rimexolone, 1%, is a synthetic topical steroid designed to minimize IOP elevations, similar to fluorinated steroids. Elevated IOP has been reported with this medication, but it is rare. Ocular adverse effects still include secondary glaucoma and posterior subcapsular cataracts. Systemic adverse effects, including headache, hypotension, rhinitis, pharyngitis, and taste perversion, occur in fewer than 2% of patients.

Loteprednol etabonate, 0.5%, is structurally similar to other steroids but lacks a ketone group at position 20. Loteprednol etabonate, 0.2%, is marketed for the temporary treatment of allergic conjunctivitis. The combination drug loteprednol etabonate (0.5%)/tobramycin (0.3%) is approved for superficial bacterial infections of the eye with inflammation. Studies have shown that in corticosteroid responders treated with loteprednol, the incidence of clinically significant IOP elevation is low.

Difluprednate is a difluorinated derivative of prednisolone. Its glucocorticoid receptorbinding affinity and corneal penetration are greatly enhanced by modification of the glucocorticoid molecule with the addition of fluorine atoms and ester groups at several carbon positions. Difluprednate is formulated as a stable oil-in-water emulsion to achieve consistent dose uniformity compared with suspensions, regardless of bottle storage position or shaking before use. Although the strong therapeutic potency of difluprednate emulsion is desirable, IOP increase has been reported anecdotally and clinically to be greater than that of other moderate to strong topical steroids.

Fluocinolone acetonide is available in 2 intraocular devices. A nonbiodegradable implant with 0.59 mg of fluocinolone acetonide surgically placed in the pars plana region was approved by the FDA for the treatment of chronic noninfectious posterior uveitis. It is designed to release fluocinolone acetonide at a nominal initial rate of 0.6 µg/d, decreasing over the first month to a steady state between 0.3 and 0.4 µg/d over approximately 30 months. Another 0.19-mg nonbiodegradable implant, delivered by intravitreal injection, was FDA approved for the treatment of diabetic macular edema in patients who are not steroid responders. It releases fluocinolone acetonide at an average rate of 0.2 µg/d for 36 months.

Table 16-16 Immunomodulatory Medications in the Treatment of Uveitis

Table 16-17 Usual Route of Corticosteroid Administration in Ocular Inflammation

A 0.7-mg dexamethasone biodegradable polymer matrix for injection into the vitreous cavity was approved for the treatment of macular edema secondary to retinal vein occlusion, noninfectious posterior uveitis, and diabetic macular edema. The polymer dissolves, and dexamethasone is slowly released for up to 6 months, with clinical efficacy lasting at least 3 months.

A 40-mg/mL preservative-free triamcinolone acetonide injectable suspension was FDA approved for intraocular use. Its indications include visualization during vitrectomy and treatment of sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammatory conditions that do not respond to topical corticosteroids.

• Armaly MF. Effect of corticosteroids on intraocular pressure and fluid dynamics, I: the effect of dexamethasone in the normal eye. Arch Ophthalmol. 1963;70(4):482–491.

• Armaly MF. Effect of corticosteroids on intraocular pressure and fluid dynamics, II: the effect of dexamethasone in the glaucomatous eye. Arch Ophthalmol. 1963;70(4):492–499.

• Donnenfeld ED. Difluprednate for the prevention of ocular inflammation postsurgery: an update. Clin Ophthalmol. 2011;5:811–816.

• Mulki L, Foster CS. Difluprednate for inflammatory eye disorders. Drugs Today (Barcelona). 2011;47(5):327–333.

Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.