Often revered and reviled, corticosteroidsperhaps more than any other class of ophthalmic drugspresent the conundrum of balancing tremendous therapeutic benefits with unwanted side effects.

Developed in the 1940s, these drugs remain the most potent agents against the ravages of inflammation. While many truths and myths abound about the dangers of steroids, far more harm has come from withholding steroids than has occurred from their potential side effects.1

With knowledge of the process of inflammation and the fundamentals of steroids, these agents can be used safely and effectively in the optometric setting.

Inflammation is the bodys protective response to a stimulus it perceives as offensive. While it is protective for the body as a whole, the inflammatory processes can cause scarring and damage to surrounding healthy tissue.

The signs and symptoms of inflammation are well known. They are classically taught in Latin: redness (rubor), heat (calor), pain (dolor) and swelling (tumor).2

The bodys chemical response to inflammation follows the same pathway regardless of the offending agent. Bacteria, viruses, allergens, chemical irritants, cancer cells, foreign bodies, trauma and others produce inflammation that follows a common chemical cascade.

The Inflammatory Cascade
The acute phase of inflammation begins with the degranulation of mast cells. Histamine and phospholipids are released. Histamine causes the immediate symptoms of redness and itching. The enzyme phospholipase A2 converts phospholipids into arachidonic acid. Arachidonic acid may then follow two chemical pathways:

Cyclo-oxygenase. Arachidonic acid may be converted to prostaglandins by cyclo-oxygenase. Prostaglandins mediate the pain response and cause increased vasopermeability. As blood leaks into surrounding tissues from the increased permeability, the symptoms of redness, swelling, heat and pain are produced.

Lipoxygenase. Arachidonic acid may also follow another pathway and be converted to leukotrienes by lipoxygenase. Leukotrienes are responsible for recruiting other blood cells, such as polymorphonucleocytes and eosinophils, to the site of irritation. Polymorphonucleocytes are white blood cells, which play a key role in infection and inflammation. They release enzymes to kill the offending organism. Eosinophils play a role in the late stages of allergy. Both of these cells perform a needed function, but can be damaging to normal surrounding tissue.3

While the chemical cascade may not be visible, its end results are commonly seen clinically. Papillae on the lids are aggregations of eosinophils. Subepithelial infiltrates in the cornea are accumulations of polymorphonucleocytes. Anterior chamber cells in iritis are the result of polymorphonucleocytes spilling into the aqueous due to increased vasopermeability.

Steroids vs. NSAIDs
Steroids work by inhibiting phospholipase A2, thereby blocking both arms of the inflammatory cascade. By blocking the cyclo-oxygenase arm, steroids decrease vasopermeability as well as redness, edema, pain and uveoscleral outflow. Steroids also block the lipoxygenase arm, keeping polymorphonucleocytes and other blood cells sequestered from the site of inflammation.

Nonsteroidal anti-inflammatory drugs (NSAIDs) block only cyclo-oxygenase, not lipoxygenase. Thus NSAIDs are effective mediators against pain and edema. But unlike steroids, they do not possess the effectiveness of sequestering blood cells. NSAIDs are useful in controlling pain and limiting inflammation, but they have not been shown to be clearly effective in treating uveitis, and they play no role in corneal graft rejection.

Treatment with NSAIDs can be an advantage if youre trying to reduce pain without reducing the bodys immune system (i.e., reducing the symptoms of epidemic keratoconjunctivitis). However, if youre trying to prevent tissue damage (i.e., stromal scarring from interstitial herpes simplex keratitis), steroids are the only option.
Potency and Penetration
Corticosteroids differ in their inherent anti-inflammatory ability. Their potency hinges on their penetration. To get to the anterior chamber of the eye, topical ocular preparations must pass through the lipid-rich epithelium of the cornea, then the water-laden stroma, and finally through the mainly lipid endothelium. For a steroid to effectively penetrate the cornea, it must be both lipophilic and hydrophilic. Such preparations are termed biphasic.

The chemical base to which a topical steroid is attached will determine its ability to penetrate the anterior chamber. In the normal eye, an acetate base penetrates the best, followed by alcohols, and then phosphates. Removal of the lipid-rich epithelium (such as a corneal abrasion or corneal ulcer) will allow a phosphate base to reach a much higher concentration. Also, inflammation can break down the lipid barriers, allowing for more penetration of phosphate.5

Solution vs. Suspension vs. Ointment
The base of the corticosteroid also helps determine if the drug can be produced as a solution or suspension. Phosphate bases, which are water-soluble, are marketed as solutions. Acetates are prepared as suspensions.

The advantage of a solution: It doesnt require shaking prior to instillation to deliver a uniform dose of active ingredient to the eye.

The advantage of suspension: Small particles of the drug persist in the cul-de-sac, resulting in prolonged contact time and higher penetration.

Given this comparison, one would think ointments would be the ultimate delivery system. However, petrolatum fails to release the drug rapidly to the precorneal tear film, so despite a prolonged contact time, less drug is available than a suspension for penetration.5

Pearls for Using Steroids

Use the right tool. Fortunately, we have many topical steroids to pick from, so pick the right tool for the job. For surface inflammation (episcleritis, allergic conjunctivitis, etc.), pick the less-penetrating varieties (FML, Alrex). These steroids have ample anti-inflammatory action at the ocular surface with less propensity to increase IOP.

For moderate inflammation, Lotemax, Vexol and Flarex are good choices. They have good anti-inflammatory activity with less steroid-induced IOP response compared with other agents.

For severe or deeper inflammation, use your biggest gun: prednisolone acetate 1% (Pred Forte, Econopred Plus). If the patient has a history of steroid response, pre-existing glaucoma or other risk factors, consider Vexol or Lotemax. Remember, treatment for severe posterior uveitis can be supplemented with oral steroids or periocular steroid injections if topicals are not controlling the inflammation.

Hit it hard, hit it fast. Unlike many drugs, topical steroids do not have a therapeutic effect that tops out beyond a certain dose. In one study, increasing the instillation of prednisolone acetate 1% from every four hours to every two hours to every one houreven to every 15 minutesresulted in further decreases in corneal inflammation at every level.5 So, dont be afraid to prescribe a topical steroid beyond q.i.d. dosing, especially for initial treatment. One drop every hour while awake is initially appropriate for moderate to severe inflammation.1 Hitting inflammation hard and gaining control right away is better than gradually increasing the dose over days to weeks to achieve the desired effect.

The only exception to this rule is for treating severe bacterial or viral infections. To decrease the inflammation associated with a corneal ulcer or stromal herpes keratitis, use only enough of the drug to achieve the intended effect, and always use the appropriate antibiotic or antiviral concurrently.

Taper appropriately. Just as important as the initial dose is the taper. Prolonged use of corticosteroids reduces the more mature circulating leukocytic elements. If the steroid is stopped abruptly, proliferation of immature cells produces great quantities of antibodies to the minimal residual antigen still remaining in the tissue, which can result in a rebound inflammation.5 This is more common for systemic steroids than topical application, but prolonged topical therapy (usually longer than a month) can also cause this.

Once inflammation is controlled, a typical taper for topical steroids is to halve the dose for each given time interval. For example, if you were giving a steroid q.i.d. for five days, taper the drug to b.i.d. for five days, then q.d. for five days before discontinuing. The longer the treatment period, the longer the taper.

Treat the cells, not the flare. Inflammatory cells seen in the anterior chamber or vitreous represent polymorphonucleocytes responding to inflammation. Aqueous flare results from vascular incompetence in the iris or ciliary body and often persists long after active inflammation is quelled.4 Therefore, base your treatment decisions in uveitis on whats happening with the cells, not the flare.

Handle the pressure. Remember, you have a two-week window before you have to worry about an IOP increase from topical steroids. Also remember, should IOP increase, it will usually normalize two to four weeks after stopping the steroids. In the interim, a number of treatment strategies can help:

If inflammation has resolved, simply taper and stop the steroid. Healthy optic nerves can tolerate IOP in the high 20s or low 30s for a few weeks without any measurable damage to structure or function.

If IOP is increased and inflammation is still present, consider switching to Lotemax or Vexol.

If IOP remains unacceptable, add a glaucoma drug until the steroid is discontinued. The increased IOP is due to decreased aqueous outflow, so glaucoma agents that reduce aqueous production (beta blockers, alpha adrenergic agonists and carbonic anhydrase inhibitors) work well. Prostaglandin analogues are contraindicated in an inflamed eye.

Remember, as long as the patient uses the steroid, the steroid response can occur anytime after two weeks, even years later. Any patient on long-term steroid therapy requires an IOP check every three months, even if using just one drop of topical steroid a day. 

Prescribe name brands. While generics are cheaper, some researchers have questioned their ability to treat ocular inflammation.16-18 Generics must have the same active ingredient as the equivalent brand name, but generics are not required to sustain identical therapeutic outcomes as name brands.16 Solubility, penetration, pH, and bottle-tip design may help determine the topical steroids overall effectiveness, not just the active ingredient.17,18 In light of the serious outcomes of uncontrolled ocular inflammation, prescribing name brands makes sense. C.J.K.

Whats Most Effective?
Studies have shown that the overall anti-inflammatory effect in the eye for topical agents is highest for prednisolone acetate 1.0% ophthalmic suspension.5 This is followed in effectiveness by dexamethasone alcohol 0.1% suspension and then fluorometholone alcohol 0.1% suspension. (Fluorometholone acetate was not tested in this comparison, but one would expect higher effectiveness than fluorometholone alcohol, given its better penetration). Least effective are prednisolone phosphate 1.0% ophthalmic solution and dexamethasone phosphate 0.1% solution, respectively.

Topical Steroid Side Effects
The side effects of these drugs have sometimes been exaggerated and misunderstood. For the treatment of many ocular conditions, short-term use of steroids has minimal risks and significant therapeutic benefits. Side effects from long-term use, however, can potentially outweigh the benefits.

Although much safer than their systemic counterparts, topical steroids can produce many side effects, notably:

Elevated intraocular pressure. Perhaps the most worrisome and misunderstood complication of topical steroids is elevated IOP. This side effect is more common with topical therapy than with oral or parenteral.6 Although increased IOP from steroids is a legitimate concern, the fear of this potential event should not be a reason to withhold these drugs. With proper knowledge of the steroid response, we can anticipate elevated IOP and effectively control it.

Steroid-induced elevated IOP rarely occurs within the first two weeks of treatment.5 After this, IOP increase can occur anytime from weeks to years. Withdrawal of the steroid usually results in IOP returning to baseline in two to four weeks.7 In the interim, elevated IOP can be managed with conventional glaucoma medications, if needed.

Steroid-induced elevated IOP occurs in 18% to 36% of the general population. It is more common in patients more than 40 years of age, diabetics, high myopes and previously diagnosed open-angle glaucoma patients.7

Many mechanisms have been suggested as the cause of steroid-induced glaucoma. Accumulations of glycosaminogylcans in the trabecular meshwork, inhibition of prostaglandins that reduce IOP, and heredity have all been implicated.7,8 Whatever the cause, resistance to aqueous outflow is generally accepted as the main cause of increased IOP.

The incidence of IOP response varies with the drug being administered. Among the traditional topical steroids, IOP increases occur most frequently with dexamethasone-based agents and least frequently with the fluorometholones.1,7

Cataracts. Perhaps less serious than steroid-induced glaucoma is steroid-induced cataract. This is because untreated ocular inflammation also induces cataract formation which, unlike elevated IOP or glaucoma, can be wholly eliminated by surgery.9

The classic steroid-induced opacity is a posterior subcapsular cataract (PSC). Other than its location, there are no other clinical characteristics to differentiate a steroid-induced cataract from other PSCs.5

In contrast to steroid-induced glaucoma, steroid-induced cataracts are much more common with systemic steroid administration versus topical.6 The critical dose appears to be the equivalent of at least 10 to 15mg of prednisone per day for at least one year, although individual responses vary considerably.10 The incidence of corticosteroid-induced cataracts in randomized controlled trials ranges from 6.4% to 38.7% with oral steroid use.8,10,11 The incidence of cataract formation from topical administration is much less. The exact incidence varies widely in studies and is difficult to ascertain, given that intraocular inflammation itself can cause cataracts.

The cause of steroid-induced cataracts may involve many mechanisms. The suggested etiologies: binding of the steroid molecule to lens protein; inhibition of the lens pump; and elevated glucose in the aqueous.8

Other side effects. Mydriasis, ptosis, inhibition of corneal epithelial or stromal healing, punctate staining, and corneal-scleral melting are all less common side effects of steroids. Reactivation of herpes simplex keratitis in previously infected patients has also been attributed to topical steroids.
The Drugs
Prednisolones. Prednisolone acetate 1% (Pred Forte, Allergan, and Econopred Plus, Alcon) has the greatest anti-inflammatory efficiency of all topical steroids.1 It remains the best choice for severe ocular inflammation. As with all suspensions, prednisolone acetate requires shaking before use to equally distribute the particles, which tend to settle to the bottom of the bottle. Prednisolone acetate is also available in a much weaker 0.125% formulation (Pred Mild, Allergan, and Econopred, Alcon).

Prednisolone sodium phosphate 1% (Inflamase Forte, Novartis) and 0.125% (Inflamase Mild, Novartis) are other options of prednisolone. The phosphate base will not provide as much penetration as prednisolone acetate; however, it is formulated as a solution and does not require shaking. Prednisolone sodium phosphate is most appropriate for moderate inflammation.

Dexamethasone. Topical dexamethasone preparations are potent agents for surface inflammation, but they do not penetrate well for intraocular inflammation. They also have the highest propensity to increase IOP.1 Various suppliers provide a 0.1% formulation. TobraDex suspension and ointment (Alcon) are popular combinations of dexamethasone and tobramycin (an aminoglycoside antibiotic) in a single preparation.

Fluorometholone. Fluorometholone has traditionally been considered the best of class for avoiding the steroid-induced IOP response, most likely because of its poor corneal penetration. Fluorometholone alcohol 0.1% (FML, Allergan, and Fluor-Op, Novartis) is effective for mild surface inflammation. Its low propensity for side effects also makes it a good choice for long-term therapy. Fluorometholone is one of the few steroids available in an ophthalmic ointment.

Fluorometholone is also available combined with an acetate base (Flarex, Alcon, and eFlone, Novartis) for better penetration.12 This formulation is effective for moderate inflammation.

Newer Drugs
A recent trend in anti-inflammatory therapy is the development of soft steroids. A soft drug is a biologically active compound with a predictable inactivation to a nontoxic substance after achieving its therapeutic role.13 The aim of this type of drug is to lower toxicity and increase more specific actions at a target organ.14

Rimexolone 1% (Vexol, Alcon) is a soft steroid with an anti-inflammatory activity approaching that of prednisolone acetate 1%, but with a steroid response rate similar to fluorometholone.15 Rimexolone has a high steroid receptor-binding affinity and is rapidly degraded to inactive metabolites.4 It was originally approved for anterior uveitis and postoperative inflammation following cataract surgery.12

Loteprednol etabonate 0.5% (Lotemax, Bausch & Lomb) is another soft steroid. Its anti-inflammatory efficacy may be a little less than prednisolone acetate 1%, but it is less likely to increase IOP.9 Loteprednol is structurally similar to prednisolone, but rapidly undergoes hydrolysis in the anterior chamber to become an inactive derivative.4 It has shown clinical efficacy for various ocular inflammatory conditions, including postoperative inflammation and giant papillary conjunctivitis. A weaker version of loteprednol in a 0.2% formulation (Alrex, Bausch & Lomb) is available for seasonal allergic conjunctivitis.15

With knowledge of the concepts of inflammation and the fundamentals of corticosteroid therapy, these agents can be used safely and effectively for treating a number of ocular conditions in the optometric office. 

Dr. Cakanac is in private practice in Pittsburgh and is a clinical instructor in the Department of Ophthalmology at the University of Pittsburgh School of Medicine.

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Vol. No: 142:4Issue: 4/15/05