Ординатура / Офтальмология / Английские материалы / Clinical Ocular Pharmacology 5th edition_Bartlett, Jaanus_2008

Since the recognition of the anti-inflammatory activity of adrenocortical extracts in the early 1940s, hydrocortisone (cortisol), the main glucocorticoid secreted by the human adrenal cortex, and various synthetic derivatives have proven useful in ocular inflammatory and autoimmune disease states.The human glucocorticoid receptor gene is one locus on chromosome 5q31-32.There is a variation in both the structure and expression of the gene that generates diversity in glucocorticoid signaling. Although corticosteroids can bring about dramatic clinical results, chronic high-dose therapy is often accompanied by undesirable side effects. Attempts have therefore been made to develop both steroidal and nonsteroidal compounds with effective anti-inflammatory activity but reduced tendency for toxicity. In addition to corticosteroids, two other classes of pharmacologic agents, the nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclosporine A medications, can modulate ocular inflammatory processes.

CORTICOSTEROIDS

Since their introduction into ocular therapy, corticosteroids are still the commonly used agents for control of both posterior and severe anterior segment inflammatory disease. They can be effective in protecting the ocular structures from many of the deleterious effects accompanying the inflammatory response, particularly scarring and neovascularization.They are generally more effective in acute than in chronic inflammatory states, and degenerative diseases usually are completely refractory to steroid therapy. The anti-inflammatory effects of steroids appear to be nonspecific, occurring whether the etiology is allergic, traumatic, or infectious. In most clinical applications steroids do not act directly to correct a specific disorder but appear to modify a preexisting or ongoing response to a foreign or endogenous substance.

PHARMACOLOGIC PRINCIPLES

Present evidence indicates that specific receptor proteins mediate the effects of steroids.The glucocorticoid receptor

inhibits inflammation via three distinct mechanisms. These mechanisms work through both direct and indirect genomic and nongenomic actions. Virtually every tissue has receptors for steroids, a condition that most likely contributes to the many physiologic and pharmacologic effects that occur after steroid administration.This fact has made it difficult to determine which of the many cellular events that occur after steroid administration relate directly to the observed clinical effects. Experimental observations indicate that at least some of the effects at the cellular level result from altered protein production in immunologically competent cells.

Steroids appear to have an effect on nearly every aspect of the immune system.They inhibit both migration of neutrophils into the extracellular space and their adherence to the vascular endothelium at the site of tissue injury. In therapeutic dosages steroids also inhibit macrophage access to the site of inflammation, interfere with lymphocyte activity, and decrease the number of B and T lymphocytes.

Evidence indicates that steroids affect other cells and substances that modulate inflammation. Exposure of human basophils to steroid in culture inhibits histamine release induced by an IgE-dependent stimulus. Steroids inhibit phospholipase A2, which prevents biosynthesis of arachidonic acid and subsequent formation of prostacyclin, thromboxane A, prostaglandins, and leukotrienes. Steroids also decrease capillary permeability and fibroblast proliferation and the quantity of collagen deposition, thereby influencing tissue regeneration and repair.

BIOAVAILABILITY OF TOPICAL

OPHTHALMIC STEROIDS

Ophthalmic steroids vary in their ability to penetrate the cornea and in their subsequent distribution and metabolism in structures. This variability has been attributed to properties of the cornea and physicochemical differences among the individual steroidal compounds. To penetrate the cornea, which consists of both hydrophobic and

222 CHAPTER 12 Anti-Inflammatory Drugs

hydrophilic layers, the ideal steroid should be biphasic in its polarity.This property allows for solubility in both the lipid (hydrophobic) layers of the epithelium and endothelium and the aqueous (hydrophilic) media of the stroma. Deepithelialization of the cornea by removal or inflammation alters the hydrophobic properties of the corneal surface and allows water-soluble preparations to penetrate to a greater extent.

Although each steroid has an inherent water or lipid solubility, this characteristic can be altered by chemical modification of the steroid base into various derivatives. Acetate and alcohol derivatives of the base compound render the steroid molecule more lipophilic or fat soluble. Salts, such as sodium phosphate and hydrochloride, are relatively more hydrophilic or water soluble.The alcohol derivative has intermediate lipophilicity between acetates and salts such as the phosphates.

Modification of a steroid base influences not only ocular penetration and metabolism but also the formulation of the particular steroid product. The water-soluble salts generally are formulated as solutions, and the more lipid-soluble derivatives are available as suspensions and ointments. Because the acetate and, to a lesser extent, the alcohol preparations are more lipophilic, in theory they should be able to penetrate the intact cornea better than the water-soluble phosphates. Experimental data in both animal models and human subjects appear to support this hypothesis.Topical administration of an acetate or alcohol derivative to an uninflamed eye with an intact epithelium produces significantly higher corneal and aqueous steroid levels than does administration of a phosphate derivative of the same steroid base. In the absence of the corneal epithelium in an uninflamed eye, comparison of bioavailability of topically applied acetate and phosphate derivatives shows that the drug level of the phosphate derivative is several times higher than that of the acetate (Table 12-1). In the presence of intraocular inflammation in an eye with an intact epithelium, the acetate derivative again produces the highest corneal concentration. However, some decrease in the hydrophobic epithelial barrier occurs, as the phosphate derivative attains somewhat higher levels in the anterior chamber of the inflamed eye with an intact epithelium as compared with the uninflamed eye with an intact epithelium.

In addition to variables in clinical signs and symptoms and the ability to penetrate the ocular structures, the derivative of a steroid base also seems to influence its anti-inflammatory efficacy. Using a rabbit corneal model, it was demonstrated that acetate and alcohol derivatives are more effective than the phosphate derivative in suppressing corneal inflammation both in the presence and absence of corneal epithelium (see Table 12-1). The mechanism by which a derivative affects the anti-inflamma- tory activity of a steroid base applied topically to the eye is not known, but some data seem to indicate that receptor binding or metabolism plays a role in the observed antiinflammatory and ocular hypertensive effects.

Table 12-1

Relationship of the Derivative of an Ophthalmic Corticosteroid Base to Its Corneal Concentration

Adapted from Leibowitz HM, Kupferman A. Use of corticosteroids in the treatment of corneal inflammation. In: Leibowitz HM, ed. Corneal disorders: clinical diagnosis and management. Philadelphia: Saunders, 1984.

THERAPEUTIC PRINCIPLES

After five decades of clinical experience with ocular corticosteroid therapy, the use of these drugs remains largely empirical. However, some general therapeutic principles have been suggested:

•The specific type and location of the inflammation determine whether topical, systemic, periocular, or multiple routes of administration are appropriate.

•Treatment should be instituted as soon as possible when indicated, and the dose should be high enough and administration frequent enough to suppress the inflammatory activity.

•The appropriate dose for a specific condition is largely determined by clinical experience and must be reevaluated at frequent intervals during the course of treatment.

•Long-term high-dosage therapy should not be discontinued abruptly.The dose should be tapered over time.

•Short-term low-dosage topical ocular therapy generally does not produce significant side effects.

Ideally, the effective dose should be used for the short-

est time necessary to secure the desired clinical response. The dosage should be individualized as much as possible to the patient and the severity of the condition. The patient’s general health must be considered and close supervision maintained to assess the effects of steroid therapy on the course of the disease and possible adverse effects. With ocular disease the route of steroid administration is an important determinant of the pharmacologic and therapeutic effects observed. Topical ocular therapy is usually satisfactory for inflammatory disorders of the eyelids, conjunctiva, cornea, iris, and ciliary body. In severe forms of anterior uveitis, topical therapy may require supplementation with systemic or periocular (local injection) steroids. Chorioretinitis and optic neuritis are most often treated with systemic steroids.

Topical Ocular Administration

Shortly after the introduction of corticosteroids to ocular therapeutics, clinical use indicated that local treatment was equal to or superior to systemic administration, provided that the diseased tissue could be brought in contact with sufficient concentration of steroid. In general, when possible topical administration is indicated for anterior segment disease. Ease of application, comparatively low cost, and relative absence of systemic complications make it the preferred route of steroid therapy. Selection of a particular topical steroid and the dosage

administered varies with the location and severity of the inflammation.

Topical therapy usually should continue at a reduced dosage for several days to several weeks after inflammatory signs and symptoms have disappeared, because prematurely discontinuing treatment can lead to relapse, particularly with high-dosage therapy. Corticosteroids reduce the leukocyte elements of the blood. Consequently, white cells proliferate when therapy stops. The immature cells can produce large quantities of antibodies to residual antigen in the ocular tissue. A massive polymorphonuclear leukocytic reaction follows the resultant antigen-antibody reaction.This sequence of events,unless interrupted immediately, can lead to a recurring, serious, necrotizing inflammatory reaction. Thus, depending on the response obtained and the dosage used, topical therapy should generally be tapered over several days to weeks.

Systemic Treatment

Inflammations of the posterior segment, optic nerve, or orbit usually require systemic administration of steroids. Selection of the particular steroid preparation and the dosage remains largely an individual choice, but the tendency is to use compounds with minimal mineralocorticoid activity. Table 12-2 compares various systemic steroids to hydrocortisone in terms of equivalent dose (20 mg) and relative anti-inflammatory and sodium-retaining activities when giving a value of 1.0 for hydrocortisone. Prednisone is a popular agent of choice for oral administration. For intravenous administration, methylprednisolone sodium succinate has proven useful.

Because adverse effects are more likely to occur with systemic therapy (Box 12-1), dosage should be individualized as much as possible for each patient.With long-term therapy the lowest possible dose to control the disease is advocated.

224 CHAPTER 12 Anti-Inflammatory Drugs

Box 12-1 Systemic Effects of Corticosteroid

Therapy

Adrenal insufficiency

Cushing’s syndrome

Peptic ulceration

Osteoporosis

Hypertension

Muscle weakness or atrophy

Inhibition of growth

Diabetes

Activation of infection

Mood changes

Delay in wound healing

Some general therapeutic guidelines for systemic steroids have been suggested. For most mild to moderate ocular inflammatory disorders, an initial daily dose of 20 to 40 mg of prednisone or its equivalent is recommended. For patients with severe inflammation, initial daily doses of 40 to 60 mg of prednisone or its equivalent should be used. If no improvement occurs within 48 to 72 hours, an increase of 80 to 100 mg or more may be necessary. As soon as the clinical response occurs the dose should be decreased over days or weeks, depending on the length of treatment. Reduction should be in graduated decrements, guided strictly by the clinical course of the disease, usually reducing the daily dosage by 10 mg for larger doses and 2 to 5 mg for smaller doses at intervals of 3 to 4 days. Once a dose level of 15 to 20 mg is reached, the patient should remain at that level for 1 to 2 weeks to prevent recurrent flare-up of inflammation. If exacerbation of the inflammation follows a given dose reduction, the dose of steroid must be immediately raised to the prereduction level. As long as evidence of active disease persists, therapy must continue at a level that permits control of signs or symptoms.

The available steroids vary in their ability to suppress the inflammatory response.Table 12-2 shows the approximate equivalent doses of systemic steroids in current use. Methylprednisolone is commercially available in a package for programmed delivery of oral steroid tapered over 6 days of therapy.This formulation (Medrol DosePak) is highly convenient for short-term treatment and helps to ensure patient compliance in the tapering schedule.

Local Injection

Periocular steroids can be administered by subconjunctival, sub-Tenon’s capsule, or retrobulbar injection. A topical anesthetic often is instilled before the steroid is injected. This route of administration can be effective during surgical procedures, as a supplement to topical and systemic steroids in cases of severe inflammation,and in patients not compliant with the prescribed regimen.

One study compared vitreous and serum concentrations after 7.5-mg oral doses of dexamethasone with peribulbar injections of 5 mg dexamethasone phosphate. Peribulbar administration of the agent resulted in 3.9% higher intravitreal than vitreous concentrations, but serum dexamethasone levels were approximately equal with both routes of administration.

Experiments using labeled methylprednisolone acetate (Depo-Medrol) indicate that retrobulbar injection can deliver high concentrations of medication to sclera, choroid,retina,and vitreous for a week or longer. Long-term repository vehicles containing triamcinolone acetonide injected beneath Tenon’s capsule have proven valuable in several chronic inflammatory conditions,including anterior uveitis. Locally injected methylprednisolone acetate and triamcinolone acetate have been shown to be effective in the treatment of chalazia. Combined excision and drainage with intralesional steroid injection is another option associated with a high success rate.

The use of periocular steroids has several limitations and complications. The injections are usually somewhat uncomfortable, and thus patients prefer to avoid them. Adverse ocular effects have included retinal detachment, optic nerve atrophy, and preretinal membrane formation. Intraocular pressure (IOP) can rise, particularly because the drug may remain in the eye for several days to weeks. Some of the observed effects may result from the vehicle rather than from the steroid itself.

Periocular injection of steroids should be reserved for those situations requiring an anti-inflammatory effect greater than that obtainable with topical or systemic administration. Concurrent administration of steroid by both topical and subconjunctival routes does appear to produce an additive therapeutic effect in severe inflammations, but periocular injection alone does not necessarily result in greater anti-inflammatory effects.These facts suggest that topical administration should be the primary route of steroid therapy for anterior segment inflammations. Table 12-3 compares the advantages and disadvantages of the three routes of steroid administration.

Intravitreal Corticosteroid Use

Corticosteroids administered intravitreally bypass the blood–ocular barrier to achieve therapeutic levels in the eye while minimizing systemic side effects. Initial studies of intravitreal corticosteroids combined dexamethasone and gentamicin in the treatment of inflammation associated with experimentally reduced endophthalmitis.As of late, interest has shifted to triamcinolone acetonide because of the longer half-life in the vitreous and its use in treatment of proliferative vitreoretinopathies.

The use of intravitreal corticosteroids is presently being explored in the treatment options of exudative macular degeneration and proliferative diabetic retinopathy. The rational for their use stems from the fact that corticosteroids as a drug class represent one of the most

potent antiangiogenic agents known. In fact, the ability of corticosteroids to reduce vascular permeability has resulted in a wide array of intravitreal treatments for macular edema associated with many ocular diseases.

One of the most common adverse events associated with the type of treatment is ocular hypertension. In one study intravitreal injections of 25 mg triamcinolone acetonide resulted in ocular hypertension in approximately 50% of treated eyes, commencing 1 to 2 months after the injection. IOP was responsive to topical therapy and normalized after approximately 6 months after the injection. Other studies reported that patients who failed medical therapy required surgical intervention to reduce iatrogenic pressure elevations.

Inflammation is another serious side effect of intravitreal injections of corticosteroids. Pseudoendophthalmitis, sterile endophthalmitis, and infectious endophthalmitis have all been reported after injection. True infectious endophthalmitis tends to present later than pseudoendophthalmitis, usually occurring 1 to 2 weeks after injection. This might be caused by the masking effect of the presence of corticosteroid injected into the eye. Steroid endophthalmitis tends to be self-limiting, and some

investigators believe the use of topical steroids may actually hasten the recovery.

Novel Delivery Devices for

Intraocular Steroids

The success of intravitreal implants, such as achieved with ganciclovir, has renewed interest in developing an intravitreal corticosteroid implant to further enhance the intravitreal route of administration, thus reducing the need for multiple injections. Bausch and Lomb and Control Delivery Systems have developed an intravitreal implant that can deliver the corticosteroid fluocinolone acetonide (Retrisert) to posterior eye tissue for up to 3 years. The implant, which was approved in 2005 by the U.S. Food and Drug Administration (FDA), delivers 0.59 or 2.1 mg of fluocinolone acetonide. The long-term ocular side effects of this device are unknown at this time.

A biodegradable implant is being developed that consists of a steroid combined with a degradable polymer that gradually releases the corticosteroid as a polymer that undergoes hydrolysis. The breakdown byproducts of this implant are glycolic acid and lactic acid,which are then

226 CHAPTER 12 Anti-Inflammatory Drugs

further metabolized to water and carbon dioxide.With this delivery system no permanent devices remain in the eye after treatment. At this writing, the Posurdex (Allergan Inc., Irvine, CA) implant, which contains dexamethasone, was under phase II clinical trials for posterior segment use.

Finally, conjugate drugs that are covalently linked with corticosteroids decrease drug solubility and consequently increase its half-life.This allows a limited amount of active drug to be present at any given time. Studies covalently linked 5-fluorouracil with dexamethasone and covalently linked 5-fluorouracil with triamcinolone administered by intravitreal injection. More recently, a fluocinolone with 5-fluorouracil conjugate has been investigated for possible use against proliferative vitreoretinopathies.

Alternate-Day Therapy

In 1963, it was reported that single-dose, alternate-day, systemic administration of corticosteroid can be as effective as divided-dose daily treatment. With the alternate-day regimen, a patient receives the entire total dose that would be given over a 2-day period as a single dose every other morning.This regimen permits metabolic recovery and prevents toxic effects from accumulating. The concept of alternate-day systemic therapy applies only to shorter acting systemic steroids, such as prednisone. Compounds with longer half-lives, such as triamcinolone and dexamethasone, continue their activity on the off-treatment day. Because the normal physiologic release of adrenocorticotropic hormone and cortisol is characterized by episodic secretion, with highest levels occurring at 8:00 AM, administration of single-dose therapy or the first dose of the day in divided-dose therapy should occur in the early morning.

Alternate-day therapy can prove useful for such conditions as chronic uveitis that require long-term systemic administration. This approach has also been advocated for treatment of chronic conditions in children because it minimizes growth suppression.The alternate-day regimen has not been widely accepted, and modifications have been suggested. Clinical experience also indicates that this treatment method is not as effective as divided daily doses, particularly in severe ocular inflammatory conditions. Adrenal gland suppression and other side effects associated with systemic therapy can still occur with the alternate-day regimen.

CLINICAL USES

Box 12-2 lists the primary ocular inflammatory disorders in which steroids may provide a therapeutic benefit. Steroids are generally contraindicated in most ocular infections because they are not bactericidal and because they reduce resistance to many types of invading microorganisms, including bacteria, viruses, and fungi. In particular, because of the difficulty in controlling replication of fungi in ocular infection,steroid use can enhance microbial replication in this and other types of infections

Box 12-2 Indications for Use of Corticosteroids in Ocular Disease

Eyelids

Allergic blepharitis

Contact dermatitis

Herpes zoster dermatoblepharitis

Chemical burns

Neonatal hemangioma

Conjunctiva

Allergic conjunctivitis

Vernal conjunctivitis

Herpes zoster conjunctivitis

Chemical burns

Mucocutaneous conjunctival lesions

Cornea

Immune reaction after keratoplasty

Herpes zoster keratitis

Disciform keratitis

Marginal corneal infiltrates

Superficial punctate keratitis

Chemical burns

Acne rosacea keratitis

Interstitial keratitis

Uvea

Anterior uveitis

Posterior uveitis

Sympathetic ophthalmia

Sclera

Scleritis

Episcleritis

Retina

Retinal vasculitis

Optic nerve

Optic neuritis

Temporal arteritis

Globe

Endophthalmitis

Hemorrhagic glaucoma

Orbit

Pseudotumor

Graves’ ophthalmopathy

Extraocular muscles

Ocular myasthenia gravis

and also can mask evidence of progression of an infection. In severe infections marked by considerable ocular involvement and a threat to vision, steroids may be used within 48 hours of starting the appropriate anti-infective therapy.

OPHTHALMIC CORTICOSTEROIDS

Prednisolone

A synthetic analogue of the major glucocorticoid hydrocortisone (cortisol), prednisolone has proven an effective

anti-inflammatory agent in patients with external and intraocular inflammations. It is commercially formulated as an acetate and a phosphate (Table 12-4). Experimental models using inflamed rabbit corneas indicate that the mean decrease in corneal inflammation is greater for the prednisolone acetate derivative than for the phosphate, regardless of whether the corneal epithelium is intact or absent (see Table 12-1). The acetate substitution in the 21 position of the steroid molecule may increase the affinity of the steroid for its receptor, possibly explaining part of the enhanced effect. This increased affinity could enhance its pharmacologic response and also, in some way, alter its metabolism in ocular tissue.

Prednisolone acetate is available in 0.125% and 1.0% concentrations. Kinetic studies have shown that raising the concentration of prednisolone acetate from 1.0% to 1.5% or 3.0% does not enhance its anti-inflammatory effects. In severe inflammatory reactions, topical dosing of prednisolone acetate 1% at 1-minute intervals for 5 minutes each hour may provide the best clinical suppression of inflammation (Table 12-5). As compared with other topical ocular steroids,1% prednisolone acetate is generally considered the most effective anti-inflammatory agent for anterior segment ocular inflammation.

Dexamethasone

solution. It is also formulated as dexamethasone sodium phosphate ointment, 0.05% (see Table 12-4). Experimental studies indicate that dexamethasone alcohol is superior in anti-inflammatory activity to dexamethasone sodium phosphate, whether in the presence or absence of the corneal epithelium (see Table 12-1).

The human aqueous humor contains detectable levels of both dexamethasone alcohol and dexamethasone phosphate within 30 minutes of topical application.

Table 12-5

Anti-Inflammatory Effect of Different Dosage Schedules for Topical Administration of Prednisolone Acetate 1%

Dexamethasone is available as an alcohol or phosphate derivative in the form of a 0.1% ophthalmic suspension or

Reprinted with permission from Leibowitz HM, Kupferman A. Anti-inflammatory medications. Int Ophthalmol Clin 1980;20: 117–134.

228 CHAPTER 12 Anti-Inflammatory Drugs

Peak levels occur between 90 and 120 minutes. Thereafter drug levels diminish, but detectable amounts remain 12 hours after administration. Observations such as this suggest that dexamethasone is resistant to metabolism after penetration into the aqueous humor.

Fluorometholone

Unlike prednisolone and dexamethasone, which are structurally related to cortisol, fluorometholone is a fluorinated structural analogue of progesterone. Formulated both as an alcohol and acetate derivative, fluorometholone has proven to be an effective agent in external ocular inflammations, with relatively low potential for elevating IOP.

After topical application to the eye, fluorometholone alcohol penetrates and is rapidly metabolized within the aqueous humor. Comparative anti-inflammatory studies indicate that the efficacy of fluorometholone alcohol is somewhat less than dexamethasone alcohol and prednisolone acetate (see Table 12-1). Increasing the concentration of fluorometholone alcohol from 0.1% to 0.25% does not significantly increase its anti-inflammatory activity but does enhance its tendency to raise IOP. The 17-acetate derivative of fluorometholone has demonstrated greater anti-inflammatory activity in the experimental rabbit keratitis model than has fluorometholone alcohol. However, studies with fluorometholone acetate show that it is metabolized slowly as compared with the alcohol derivative (Figure 12-1). Thus it is possible that the 17-acetate substitution to the fluorometholone base not only enhances its anti-inflammatory effects, but also impedes its metabolism.

Clinical evaluation of patients with conjunctivitis, episcleritis, and scleritis indicates that fluorometholone acetate improves clinical signs and symptoms of inflammation significantly more than fluorometholone alcohol. Furthermore, when fluorometholone acetate 0.1% was compared with prednisolone acetate 1.0% in patients

TIME AFTER INSTILLATION (hr)

Figure 12-1 Aqueous humor steroid activity using the glucocorticoid receptor assay after administration of topical unlabeled fluorometholone 0.1% and fluorometholone acetate 0.1% in rabbits. (Adapted from Polansky JR. Basic pharmacology of corticosteroids. Curr Top Ocul Inflam 1993;1:19.)

with moderate inflammation, no difference in the antiinflammatory effects of the two steroids was observed.

Medrysone

Like fluorometholone, medrysone is a synthetic derivative of progesterone. As compared with prednisolone, dexamethasone, and fluorometholone, medrysone exhibits limited corneal penetration and a lower affinity for glucocorticoid receptors. In clinical use it appears to be the weakest of the available ophthalmic steroids. Medrysone can be useful for superficial ocular inflammations, including allergic and atopic conjunctivitis, but intraocular inflammatory conditions generally do not respond. Clinical experience with medrysone has also indicated that it is less likely to cause a significant rise in IOP. However, caution needs to be exercised in patients known to respond to steroids with a rise in IOP (so-called steroid responders), because pressure increases can lead to ocular damage.

Loteprednol Etabonate

Loteprednol etabonate (LE) was designed as an analogue of prednisolone according to the “soft drug” concept. Synthesis of a soft drug is achieved by starting with a known inactive and nontoxic metabolite of an active drug.The inactive metabolite then is structurally modified to an active but metabolically unstable compound that undergoes, in vivo, a predictable one-step transformation to the inactive metabolite after its pharmacologic effects have been expressed at or near the site of application. LE and its metabolites are present in the cornea, aqueous humor, iris, and ciliary body after ocular administration.

The clinical efficacy of LE has been assessed in randomized placebo-controlled human studies for such conditions as giant papillary conjunctivitis, seasonal allergic conjunctivitis, postoperative inflammation, and acute anterior uveitis.The potential efficacy of LE 0.5% in patients with contact lens–associated giant papillary conjunctivitis has been studied in three double-masked, placebocontrolled, parallel study groups. Patients on LE showed improvement of papillae of at least one grade at the final 6-week visit. LE was also significantly more effective in relieving itching and lens intolerance.The effects of LE on both signs and symptoms was observed by the end of the first week and maintained throughout the 6-week study period.

The efficacy of LE 0.2% and 0.5% has been compared with a placebo vehicle in patients in whom seasonal allergic conjunctivitis has been diagnosed. Patients on either concentration of LE had fewer signs and symptoms, including severity of itching and bulbar conjunctival injection, than did the placebo groups when treated four times daily for 6 weeks.

LE 0.5% has also been compared with a placebo vehicle in controlling chamber cell and flare reaction in patients

undergoing cataract surgery with intraocular lens implantation. Starting 1 day after surgery in patients with at least moderate postoperative inflammation, use of LE four times daily for 14 days led to a clinically meaningful reduction in signs and symptoms of anterior chamber inflammation when compared with placebo. The safety and efficacy of LE 0.5% has been compared with prednisolone acetate 1.0% in acute anterior uveitis. Clinically meaningful reduction in symptoms and signs, such as anterior chamber cell and flare, was achieved in both treatment groups; however, LE was less effective than prednisolone acetate.

LE is commercially available as a 0.5% suspension (Lotemax) and a 0.2% suspension (Alrex) (see Table 12-4). Class labeling for Lotemax includes any eye inflammation responsive to steroids, whereas Alrex is indicated for seasonal allergic conjunctivitis and other mild non–vision-threatening conditions.

Rimexolone

Like fluorometholone, rimexolone lacks a hydroxyl group in the 21 position. Available as a 1% ophthalmic suspension (Vexol) (see Table 12-4), it has FDA approval for treatment of uveitis and postoperative inflammation.

Two multicenter studies have compared rimexolone 1% and prednisolone acetate 1% in patients with acute uveitis, recurrent iridocyclitis, or chronic uveitis. Both controlled studies and clinical experience with rimexolone appear to indicate that its efficacy is comparable with prednisolone acetate only if administered in aggressive pulse doses to patients with moderate inflammatory reactions.

The anti-inflammatory effect of rimexolone has been compared with placebo after cataract extraction. Rimexolone was both clinically and statistically more effective in suppressing cells, flare, keratin precipitates, and photophobia, with no between-group differences in IOP. Rimexolone has not been FDA approved for allergies or giant papillary conjunctivitis.

SIDE EFFECTS OF OPHTHALMIC

CORTICOSTEROIDS

Although the effectiveness of these agents in the treatment of ocular inflammation has stood the test of time,the use of corticosteroids can be associated with side effects. Adverse events can occur with all routes of administration and all preparations currently available. Systemic absorption of corticosteroid occurs with topical use on the eyes, skin, and mucosa of the upper respiratory tract. The incidence of side effects appears to rise significantly with long-term high-dose therapy, although short-term high-dose therapy appears to cause fewer side effects than prolonged courses with lower doses. Ocular complications can develop after either local or systemic steroid administration and range from actual physical damage to

Box 12-3 Ocular Effects of Corticosteroid

Therapy

Posterior subcapsular cataracts

Ocular hypertension or glaucoma

Secondary ocular infection

Retardation of corneal epithelial healing

Keratitis

Corneal thinning or melting

Scleral thinning

Uveitis

Mydriasis

Ptosis

Transient ocular discomfort

the ocular tissue to interference with healing and immune mechanisms (Box 12-3).

Cataracts

Posterior subcapsular cataracts (PSCs) can occur with all routes of administration (Figure 12-2), including systemic, topical, cutaneous, nasal aerosols, and inhalation corticosteroids. In a study of 44 rheumatoid arthritis patients treated with various steroids, including prednisone and dexamethasone, 17 (39%) developed bilateral PSCs. Dosage and duration of therapy appeared to be correlated with the incidence of cataract development. Patients who received prednisone therapy for 1 to 4 years showed an 11% incidence if the dose range was less than 10 mg/day, a 30% incidence if the dose was

Figure 12-2 Posterior subcapsular cataract (arrows) in a 48-year-old man who had taken oral prednisone, 7.5 mg/day, for 13 years for the treatment of rheumatoid arthritis.Visual acuity was 20/30 (6/9).

230 CHAPTER 12 Anti-Inflammatory Drugs

10 to 15 mg/day, and an 80% incidence if the dose was greater than 15 mg/day.

Additional evidence became available when several investigators observed an increased incidence of PSCs in children receiving systemic steroid therapy for rheumatoid arthritis, systemic lupus erythematosus, and the nephrotic syndrome. Although steroid-related PSCs do not usually occur in adults within the first year of therapy, regardless of dose, children can manifest lens changes at lower doses and within shorter periods.

Topical ocular steroid administration also may cause the development of cataracts in both children and adults. Use of topical steroids for several years to eliminate redness associated with contact lens wear resulted in PSC formation as well as glaucoma and visual field loss. The opacities associated with steroid administration resemble those produced by ionizing radiation and ocular disease such as uveitis, retinitis pigmentosa, and retinal detachment. They differ from opacities associated with diabetes and trauma but are indistinguishable from lens changes associated with posterior subcapsular agerelated cataract.

In most patients lens changes accompanying steroid therapy do not significantly impair visual acuity. In fewer than 10% of patients receiving long-term therapy is vision reduced to less than 20/60 (6/18). Patients seldom complain of visual problems unless the practitioner makes a direct inquiry. Photophobia and glare may be complaints. Once vision is affected, reduction or cessation of steroid therapy seldom resolves the opacity, but it does halt its progression;in some cases the area of opacity decreases.

Dexamethasone phosphate

WEEK

Figure 12-3 Weekly intraocular pressure responses of eyes treated with medrysone 1%, fluorometholone 0.1%, and dexamethasone phosphate 0.1%. Each point represents a mean value (mm Hg) of 12 eyes. (Reprinted with permission from Mindel JS, Tovitian HO, Smith H, et al. Comparative ocular pressure elevations of topical corticosteroids. Arch Ophthalmol 1980;98:1578. Copyright 1980, American Medical Association.)

Although it now is generally accepted that corticosteroids are cataractogenic, the mechanisms for development of the lens opacities have still not been fully elucidated. The relationship among total dose, dosage schedule, patient age, associated disease, and the steroid administered requires further study. Possibly, glucocorticoids cause cataract formation by gaining entry to the lens fiber cells.After reacting with specific amino groups of lens crystallins, a conformational change occurs within the cells, exposing sulfhydryl groups. These then form disulfide bonds, which subsequently lead to protein aggregation and, finally, to complexes that refract light. Significant causative factors might include the relationship of the lens changes to total dose, duration of therapy, and individual susceptibility. Several studies have suggested that the most important factor in steroidinduced PSC formation may be individual susceptibility to the effects of corticosteroids. An ethnic susceptibility may also exist. Reportedly, Hispanics are more predisposed to PSC development than are whites or blacks. Diabetic patients also appear to be more susceptible with topical steroid administration.

Ocular Hypertension or Glaucoma

After the introduction of corticosteroids for treating ocular inflammatory disease, reports began to appear in the literature that implicated topical steroid therapy as a cause of elevated IOP. In 1962 after reported observations with topical steroid therapy it became generally accepted that these agents can produce the clinical picture of open-angle glaucoma.

More conclusive evidence of the ability of steroids to raise IOP comes from controlled studies in which patients showed reversible elevations of pressure with repeated use of topical steroids. The hypertensive response can occur in both normal and glaucomatous eyes and usually develops 2 to 8 weeks after initiation of therapy. The effect on pressure and the associated reduction in outflow facility generally are reversible and return to their original levels within 1 to 3 weeks after steroid administration terminates. Pressure elevations are usually greater in eyes with open-angle glaucoma and tend to be higher than normal in children of glaucoma patients.

Topically administered steroids tend to produce ocular hypertension in certain susceptible individuals. Statistical analysis of volunteers given topical dexamethasone 0.1% three times daily indicated three separate groups of responders in the general population.The largest group in the volunteer population responded with an average pressure elevation of 1.6 mm Hg after 4 weeks of topical dexamethasone administration. A second group responded with an average elevation of 10 mm Hg. Pressure elevations of 16 mm Hg or greater occurred in the third group. The groups also differed in the timing of their pressure elevation:The second and third groups showed a continued and steady pressure elevation during the 4 weeks of