Coordinated by Bobby Christensen, O.D., F.A.A.O.

Therapeutic Insights
Sea of Options
We've never had so many glaucoma therapies to choose from. Here's how to navigate the choices.
By J. James Thimons, O.D., F.A.A.O., Fairfield, Conn.

The glaucoma clinical care protocols that we've had in place for more than 2 decades may be on the verge of change.

We've never had so many choices of new glaucoma therapies. Just within the last month, three more -- travoprost ophthalmic solution, 0.004% (Travatan), bimatoprost ophthalmic solution, 0.03% (Lumigan) and brimonidine tartrate 0.15% (Alphagan P) were approved.

On the one hand, we're fortunate to have so many medica-tions to choose from, but on the other hand, the numerous choices create challenges for us.

How do we sift through the myriad claims made by manufacturers and choose the best therapy combinations?

Here, I'll review some of the recently available glaucoma medications to help you sort out the best treatment tactics.

Sorting out choices

Prostaglandins are the first new class of pharmaceutical therapy for glaucoma since the introduction of beta-blockers in the late '70s. Although they're effective and relatively safe agents for our patients, questions arise regarding their long-term efficacy as well as the best way to use them when treating patients.

Incidentally, this occurs with any new therapy. These issues were reasonably well defined until the recent development of several agents in this general class. These new agents all offer potentially new and unique applications, but they bring into question the position of prostaglandins in the general treatment of glaucoma.

Xalatan

Latanoprost 0.005% (Xalatan) certainly entered the market with much success. It was the first prostaglandin drop approved for therapy, and it has rapidly accounted for more than 35% of prescriptions.

Latanoprost is a prostanoid- selective prostaglandin (FP receptor agonist) that's best prescribed qd at bedtime. This dosing allows clinicians to take advantage of the prolonged pharmacologic effect and the impact on early morning intraocular pressure (IOP) rise. The typical IOP reduction is between 25% and 30%.

Latanoprost was initially approved by the FDA for second-line or adjunctive therapy, but it's now being used as initial treatment based on a number of studies that have demonstrated efficacy and safety. Animal studies suggest that latanoprost increases uveoscleral outflow.

The drug has had excellent long-term activity when the initial course of therapy is effective. As with any other glaucoma agent, a certain percentage of patients (2% to 5%) are non-responsive to initial therapy and require other methods of control. Because there have been reports of anterior uveitis in some patients with prior histories of the condition, consider possible side effects.

Pseudophakes may have a greater risk of cystoid macular edema (CME) when using latanoprost, especially immediately after cataract surgery. Consider discontinuing it for 2 weeks before surgery and waiting 6 to 8 weeks after surgery before resuming the medication. During that time, you might want to substitute betaxolol HCl (Betoptic S) or brimonidine tartrate (Alphagan). The newly approved Alphagan P is a different concentration than Alphagan and has fewer side effects. The dose rate is also slightly different.

There's also evidence that latanoprost may increase eyelash growth in some patients as well as re-activate Herpes simplex lesions in patients who've had prior infections. Also, latanoprost may change iris color in hazel-, blue- and green-eyed patients.

Travatan

Travoprost is another topical drop. This drug received FDA approval in mid March, and it has demonstrated mean IOP reductions of up to 9 mm Hg and 33.1% across all studies. Travoprost is an FP agonist much like latanoprost, but it had some interesting variations in the initial clinical evaluations that may make it a competitive agent with current prostaglandin analogs.

One of the most important is the difference noted in IOP response compared to latanoprost in African Americans. Travoprost showed approximately 1.5 mm Hg lower IOP compared to latanoprost and 4.0 lower IOP compared to timolol. Additionally, increased optic nerve head (ONH) blood flow has been reported. The relative side effects seem similar to latanoprost, but the population of patients is too small to extrapolate any significant data at this time.

Rescula

Isopropyl unoprostone 0.15% (Rescula) is a docosanoid, which is a separate class of drugs in this group that's not reactive to FP receptors. Isopropyl unoprostone has been approved for b.i.d. dosage and produces less IOP lowering than latanoprost (15%). It has been released as a second-line drug for adjunctive use and has the unique status of being additive to latanoprost.

Therefore, you could start a patient on latanoprost and if IOP isn't well controlled, then add isopropyl unoprostone as your next additive step. Also, the drug has similar additivity with beta-blockers, but reportedly slightly less IOP lowering effect than latanoprost.

One of the interesting aspects of isopropyl unoprostone is the claim that it possesses some level of neuroprotection secondary to a possible role as a metabolite of DHA, an essential element in signal transmission in the retina.

Because the drug was only recently released, the side effects haven't been completely profiled. Its mechanism of action is unknown, but it's thought to enhance trabecular outflow. The following are some interesting differences between isopropyl unoprostone and the FP agonists:

Significant decrease in iris pigmentation. In clinical trials, only one patient demonstrated pigment increase for a rate of occurrence of less than 0.01%, compared to latanoprost, which has a rate of occurrence of approximately 7%.

Lower rate of local ocular side effects seen in the clinical trials, most notably less hyperemia. Isopropyl unoprostone lowers the IOP less than latanoprost and this will present a challenge to its acceptance. The key factor in its favor is its additivity with latanoprost, potentially making it the first adjunctive agent with this drug.

Lumigan

Also approved in mid March is the new drug bimatoprost, which has shown significant promise as an initial agent in glaucoma therapy. It's classified as a prostamide, which is a different class of drugs than either FP agonists or docosanoids. Prostamides are naturally occurring substances found in ocular tissues that play an intrinsic role in IOP regulation.

In Phase III clinical trials compared to timolol 0.5%, bimatoprost showed average IOP lowering of 9.2 mm Hg vs 6.7 mm Hg for timolol. The study also indicates that once-a-day dosing is the most effective.

Another interesting aspect of the study is that twice as many patients showed significant IOP reduction compared to timolol and achieved a goal pressure of 15 mm Hg or less. This class of agents is termed ocular hypotensive lipids and represents a potentially significant addition to our current armamentarium.

Now's the time

The treatment of glaucoma has evolved dramatically in the last year and will only continue to grow this year. The most interesting aspect of this change is the role of the new and exciting category of prostaglandins that has significant chemical differences, but similar applications in treating glaucoma. They may well change the clinical care protocols that have been in place for more than 2 decades.

It's an exciting time to be actively involved in glaucoma therapy. These agents offer great hope for our patients and their successful management in the future. So, don't let all the choices overwhelm you. Get to know more about them and embrace their benefits.

Dr. Thimons is the medical director of Ophthalmic Consultants of Connecticut. He's also a clinical professor at the New England College of Optometry.

Dr. Christensen has a partnership practice in Midwest City, Okla. He's a diplomate in the Cornea and Contact Lens Section of the American Academy of Optometry. He's also a member of National Academies of Practice.