RX PERSPECTIVE
Using Steroids with Confidence
An expert offers pearls and key principles.

Like it or not, it's often impossible to solve the numerous problems of ocular inflammation without steroids. We learn to love their benefits, and fear their mischief. Our therapeutic decisions can be perplexing because we can choose from a wide variety of topical, ointment, injection, implant, and systemic steroids, as well as newer nonsteroidal, anti-inflammatory and anti-metabolite medications. When it comes to topical steroids in a busy clinical practice, the familiar epithet "can't live with them, can't live without them" applies.

Few will dispute the efficacy of topical steroids in controlling postoperative inflammation, severe allergy, or cicatrizing uveitis. In many cases, judicious use of frequent, high-potency steroids early in the course of inflammatory disease will actually reduce the overall requirement for anti-inflammatory medication during a given episode.

FINDING THE LINE BETWEEN INDISCRIMINATE AND OVERLY CONSERVATIVE

The astute clinician is well advised to become intimately familiar with a few favorite topical preparations, which will well serve patients and physician alike. To shy away in ignorance or overly conservative fear of steroid preparations will undoubtedly lead to poorer outcomes and numerous unnecessary patient visits.

On the other hand, indiscriminate use of any steroid preparation will eventually lead to a disastrous outcome simply through the law of averages. These are some of the key principles on which I base my prescribing of steroids:

Hit 'em hard and hit 'em fast. Aggressive initial therapy can be a patient's best friend when anti-inflammatory medications are indicated. By committing to prompt treatment, both physician and patient acknowledge the serious nature of the disease process, be it corneal transplant rejection, severe acute iritis, or debilitating vernal keratoconjunctivitis. Hourly medications for these and other equally devastating conditions, with around-the-clock use in some circumstances, isn't unreasonable.

Most clinicians find that early, aggressive therapy will prevent complications as well as reduce the need for prolonged subsequent therapy or indefinite chronic therapy when permanent breakdown of the blood aqueous barrier has been allowed to occur.

Potent medications, such as prednisolone acetate 1% (Pred Forte), loteprednol etabonate 0.5% (Lotemax), prednisolone phosphate 1% (Inflamase Forte), or dexamethasone 0.1% (Maxidex) drops, are most appropriate in these urgent situations.

Weaker steroids, or weaker concentrations of the stronger steroids, are less appropriate for potentially blinding acute inflammatory disease. Medrysone 1% (HMS) provides at best a placebo effect, and at worst toxicity and a false sense of security.

Use low-dose potent drops, not frequent weak drops. Often we're tempted to use t.i.d. or b.i.d. steroid drops to maintain consistent tissue levels. This is certainly reasonable during the weaning process following successful control of an acute episode. In the maintenance phase, however, it's much more helpful to the patient to use low-dose, high-potency drops to improve compliance, reduce cost, and reduce preservative toxicity whenever possible. Even low-dose benzalkonium chloride can create hypersensitivity reactions in selected individuals.

A contact lens-dependent keratoconus patient with controlled vernal keratoconjunctivitis, for example, is much happier on q.d. prednisolone acetate 1% than q.i.d. fluorometholone 0.1%, although either of these regimens should produce roughly similar control.

Potent suspensions are suspensions. Remind your patients to shake the bottles of suspension topical steroids, the milky white ones, about 30 times vigorously prior to instillation. This will help to prevent medication clumping and the application of mostly vehicle from settled bottles. Most of the commercially available potent topical preparations are suspensions, which allow a higher concentration of relatively insoluble medications.

Don't back off too soon. With powerful inflammation, it's not advisable to withdraw aggressive steroid drop therapy until the last cell has disappeared. Many doctors rapidly withdraw topical steroids when the first hint of improvement is noted. This temptation is driven by cost, compliance, commitment, and toxicity issues. Nevertheless, a rebound can occur, particularly in younger patients, which will bring the entire inflammatory episode back to ground zero when withdrawal is undertaken too early.

Thus, the glaucomatous 25-year-old patient with acute unilateral anterior uveitis, using loteprednol etabonate 0.5% for example, shouldn't be withdrawn from q.1.h therapy until all cells and all active keratic precipitates have resolved.

The rapidity of the weaning process depends on numerous factors, including the patient's historical response to similar episodes, age, presence of flare and thus severe blood aqueous barrier breakdown, physician confidence, physician experience, and the underlying diagnosis.

An ounce of prevention is worth a pound of cure. Inflammatory cascades are well-coordinated, evolutionarily conserved enzyme families resident in most cells. Precursors, including arachadonic acid, are readily available in the lipid bipolar cell membrane. The actual mediators of the inflammatory process, including leukotrienes, prostaglandins, and cytokines, aren't instantly available to create inflammatory havoc in ocular cells.

Instead, the precursors must be processed and transmembrane signals activated to upregulate both nuclear transcription and cytoplasmic synthesis before high levels become available. Therefore, pretreatment before an anticipated inflammatory insult can optimally down-regulate these omnipresent cascades.

By far the most common inflammatory insult to the eye is iatrogenic: elective surgery. We can reduce post- operative inflammation as well as the cumulative need for postoperative medications by pretreating with anti-inflammatory agents, including steroids when appropriate. Q.i.d. steroid drops for 3 days prior to elective cataract surgery, laser refractive surgery, or corneal transplantation can go a long way in reducing postoperative medications and complications in selected individuals.

Patients with an unfortunate predisposition to intense inflammation may require even more vigorous preoperative preparation, such as every 2 hours for 2 weeks before scheduled surgery. These patients may also benefit from a pre-emptive posterior sub-Tenon's injection of triamcinolone acetonide (40 mg in 1 cc) 2 to 4 weeks prior to surgery.

Patients with a marked tendency to inflammation following surgery include those with uveitis, previous surgery, previous trauma, synechiae, corneal transplants, systemic inflammatory disease, or chronic allergic conjunctivitis.

All steroids aren't created equally. Although generic prednisolone acetate 1% drops are labeled identically to the proprietary preparation, potency is significantly reduced. The generic preparation consists of suspension particles about 10 microns in diameter, while the proprietary preparation consists of particles averaging between 2 and 3 microns. Thus, there's far less surface area per microgram of drug in the proprietary preparation, providing correspondingly superior absorption characteristics with higher tissue levels and clinical efficacy.

In addition, the generic preparation often becomes clogged at the narrow dispensing tip, creating bothersome particulate matter in the patient's eyes and variable degrees of potency when vehicle escapes around the tip blockage. Generally speaking, with prednisolone acetate 1%, a 2-for-1 substitution is advisable: q.i.d. generic is roughly equivalent to b.i.d. brand name of the same nominal concentration.

Safety first isn't so elusive. Steroids are notorious for their side effects, including cataract, glaucoma, immunosuppresion, herpetic reactivation, and delayed wound healing. Physicians are paid well to treat appropriately, watch their patients closely, and advise regarding the symptoms of these devastating problems.

Newer steroid preparations have recently become available with FDA established potency as well as an improved safety profile. Ester steroids currently available commercially only as loteprednol etabonate 0.5% (Lotemax) and 0.2% (Alrex) provide an added margin of safety for the steroid glaucoma responder. Because these ester steroids are rapidly metabolized to inactive molecules by omnipresent esterase enzymes, unbound drug causes no harm, while drug bound to the ocular steroid receptor continues desirable clinical effects.

Ointments aren't for everyone. Most patients detest ophthalmic ointment use, particularly if they're elderly, arthritic, hypermetropic, or have Parkinson's. We can usually address their needs adequately with drop therapy.

Emergency room and primary care physicians seem to possess a special affinity to ointments, which are perceived as more potent or longer-lasting. This is only partially true because solution and suspension medications are generally far more soluble than ointments, thereby providing superior penetration and target tissue concentrations.

Furthermore, most of the available ophthalmic ointments are combinations, often paired with an undesirable antibiotic partner. The only readily available ophthalmic steroid stand-alone ointment is fluorometholone (FML), which can be extremely useful as an HS preparation or for light lid applications in selected allergic patients.

Injection therapy solves compliance problems. Patients who require high anti-inflammatory levels in the posterior segment, for cystoid macular edema for instance, may benefit more from depot injections rather than drop therapy. Systemic steroid prescriptions portend side effects with potential diabetes mellitus, gastric ulceration, acne, Cushingoid facies, sleep disturbance, mood swings, or hypertension, among other problems.

Although short-term pulse systemic steroid therapy is relatively safe, higher intraocular levels can be achieved with sub-Tenon triamcinolone acetate injections (40 mg in 1 cc), given periodically with close supervision and follow-up. This technique may create steroid glaucoma, but many authorities feel that truly posterior injections reduce this risk.

Serial sub-Tenon injections may be effective in patients with severe or chronic posterior segment inflammation, poor compliance, drop toxicity, or systemic therapy intolerance. Also, a new genetic test (Ocugene) taken from a simple in-office buccal mucosal swab can detect the presence of myocilin gene variants predisposing some individuals to steroid glaucoma.

A new sustained-release intraocular depot device (Envision), currently in Phase III trials, is another compliance problem solver that also allows us to circumvent some systemic steroid side effects. This platform provides sustainable high vitreous levels of fluocinolone for 36 months. The technology, developed by Controlled Delivery Systems and marketed by Bausch & Lomb, is applicable to other medications and ocular disease entities.

MUCH TO MASTER

Steroids are the mainstay of ocular anti-inflammatory therapy. Mastery of topical, injection, and systemic steroid therapy is essential to the cornea, external disease, uveitis, retina, and surgical subspecialist who regularly deals with severe inflammation.

And informed use of steroid alternatives can benefit the patient with chronic disease, compliance difficulties, ocular surface toxicity, preservative hypersensitivity, or steroid-induced glaucoma.

Dr. Sheppard is clinical director of the Tommy Lee Center for Ocular Pharmacology, Ophthalmology Residency Program Director, and Professor of Ophthalmology, Microbiology, and Immunology at Eastern Virginia Medical School in Norfolk. You can contact him at docshep@hotmail.com.