Not too long ago, initiating medical therapy in patients with open-angle glaucoma was a fairly simple procedure. In the absence of any contraindications to using beta-adrenergic blocking agents, one of these would ordinarily be chosen as the first line drug. If it lowered IOP, but not as low as necessary, then the ophthalmologist would probably add a cholinergic agent, such as pilocarpine or carbachol, and this would usually show additivity. If that combination didn’t lower IOP to the desired level, then dipivefrin and/or an oral carbonic anhydrase inhibitor (CAI) would be added. Unsuccessful medical therapy was then followed by argon laser trabeculoplasty and then filtering surgery.

The situation is much more complicated at the present time. We currently have six different classes of antiglaucoma medications. Clearly, the introduction of the alpha-2 adrenergic agonists and the protaglandin analog, latanoprost, represent major breakthroughs in treatment, while the use of carbonic anhydrase inhibitors is much more popular now that they can be applied topically. The once-a-day beta-blocker also adds to our choices. Let's take a second to list the various agents so that there is no confusion:

• beta-blockers
• cholinergic agents
• topical and oral carbonic anhydrase inhibitors
• sympathomimetics, e.g., epinephrine, dipivefrin
• alpha-2 adrenergic agonists, e.g., apraclonidine and brimonidine
• prostaglandin analogs

Dr. Ritch has asked me to look at the initiation of therapy in a newly diagnosed glaucoma patient and then progress to maximum medical therapy. Current market research shows that most of us, in the absence of contraindications, are still beginning with a beta-blocker. This trend is being eroded somewhat as we get more familiar and comfortable with the alpha-2 adrenergic agonist, brimonidine, and the prostaglandin analog, latanoprost. Both of these drugs have excellent profiles and are heartily vying for the coveted position of "initial drug of choice" which has been held by the beta-blockers for more than twenty years. Certainly, any contraindication to beta-blockers would have us looking more closely at these other agents.

For the sake of argument let's say there are no contraindications and a beta-blocker is started, and that this lowers the IOP, but not as low as felt necessary. At this point, we need a drug to add to the beta-blocker, the idea being to find one that has a good therapeutic index and is additive with beta-blockers. We have three excellent choices: latanoprost, brimonidine, the topical CAI, dorzolamide. Once again, we all know the choice has to be individualized, but the current tendency in the United States is to add the topical CAI. We often prescribe this drug twice daily when adding it to a beta-blocker, as we have shown that the duration of action of dorzolamide is extended to 12 hours with concomitant beta-blocker use. This is most likely due to the decrease in aqueous production which allows a longer residence time for dorzolamide. Another reason for leaning toward this choice is the fact that these two drugs will shortly be available as a combination in the same bottle. A third reason is that we know a tremendous amount about the CAIs and latanoprost and the alpha-2 adrenergic agonists are still new and not as well known. This will change as we gather experience with them.

If the patient is on a combination of a beta-blocker and topical CAI and they are additive but the IOP still isn't as low as we would like, we need yet a third drug. Before we go to that third drug, though, there are many who find an excellent effect and good patient acceptability by using Timoptic-XE once daily in the morning and latanoprost in the evening. This amounts to two drops per eye per day, which can give excellent additivity and should afford excellent compliance and patient acceptability. This combination is growing in popularity according to marketing surveillance.

Now, back to the patient that we currently have on a beta-blocker and a topical CAI but who still needs a lower IOP. At this point you may say, "but, what about our old friends epinephrine, pilocarpine, and diamox?" Boldly, let us say that I think they have gone the way of the bison. There are still going to be some patients in some situations where these drugs will be useful, but not many. They are certainly not going to be in the mainstream of treating the glaucoma patient. Pilocarpine has many side effects and is not dependably additive with latanoprost. Because of the preferred therapeutic index of latanoprost, it will be added long before one would consider pilocarpine. Epinephrine and DPE are not usually additive with beta-blockers and, therefore, will not be commonly used in glaucoma medical management. The oral CAIs may be better in some cases at lowering IOP than dorzolamide, but the plethora of side effects far outweigh their usefulness for the 1-2 mmHg difference. So, we have basically concluded that there is nowhere in our general scheme for the cholinergic agents, such as pilocarpine and carbachol, the sympathomimetics, such as epinephrine and DPE, or any of the oral CAIs. In fact, in general, if we see someone on an oral CAI, we switch them immediately to the topical one in order to achieve a more favorable therapeutic index. Should that patient not be controlled, then we go on to the next step. We do not go back to the oral CAI. It seems sad that our old friends are gone, but I think all of us will agree they've been replaced by much better options.

Now, if the patient is on a beta-blocker, a topical CAI, and as a third agent, either latanoprost or brimonidine, and is still not at the target pressure, do you add a fourth drug? I think this is a call that can only be answered by a therapeutic trial. Often, adding a fourth drug will significantly lower IOP and not too terribly complicate the drug regimen. If the IOP is not lowered significantly by the fourth agent, then switching of drugs and/or consideration of going on to laser trabeculoplasty should be considered. At this point we must stop and think about the cost to the patient, the compliance from a complicated regime, etc.

In sum, we consider the "core" maximum medical therapy to be the beta-blocker, the topical CAI, and latanoprost and/or brimonidine. This may be further simplified in the future with the introduction of a combination of a topical CAI and timolol maleate in the same bottle and also the possible combination of levobunolol and brimonidine in the same bottle. Similarly, a beta-blocker and latanoprost might be combined. That might move the core maximum medical therapy to simply three drops of medication in each eye daily.

As much as everybody would like to have a cookbook scheme to manage a patient from initial therapy through maximum medical therapy, we all know that is simply not possible. The therapist's dilemma is always to pick the right medication for that particular patient. That includes combinations, consideration of systemic health, other ocular problems, interaction with other medications, both topically and systemic, etc., etc. It's through knowing everything you can about the patient and everything that you can about all the drugs available that the proper therapeutic intervention occurs.

Instead of an introduction to Dr. Zimmerman’s column, I feel that an extroduction (sic?) is more appropriate. I would argue in defense of pilocarpine, which has been much maligned since the introduction of the newer classes of antiglaucoma agents. Maybe I stand alone, but it won’t be the first time I’ve done that, and it won’t be the last. Pilocarpine has been in use for over a century. It is safe and generally well tolerated and not all patients have side effects. Systemic side effects are rare. It does not have to be used four times daily, since with nasolacrimal occlusion, Dr. Zimmerman himself has shown that twice a day can be sufficient. Pilocarpine and latanoprost are additive in many patients. Patients who cannot tolerate the induced miosis, or younger patients who are prone to accommodative spasm and marked refractive changes may do well with pilocarpine Ocuserts. We have patients between the ages of 8 and 95 using them successfully.

So when is pilocarpine indicated? Remember that in 1998, it is not sufficient merely to attempt to lower IOP when we can accomplish more than that. The “more” here is interference with the mechanism of the glaucoma to retard its progression or even reverse it. Patients with pigmentary glaucoma and exfoliative glaucoma, the latter being the most common identifiable cause of glaucoma worldwide, have blockage of the trabecular meshwork by pigment liberated from the iris as a result of iridozonular contact and iridolenticular contact, respectively. In these patients, elimination of such contact can prevent further pigment liberation and allow the trabecular meshwork to clear itself to a greater or lesser degree and to regain function. Aqueous suppressants do not accomplish this, whereas miotics do. Further, aqueous suppressants, by decreasing clearance through the meshwork, may speed progression of these diseases, although this has not been formally proven. Patients who cannot tolerate miotics during the day may benefit from 2% pilocarpine at bedtime; this may be enough to retard pupillary movement for 24 hours. Patients with exfoliation syndrome undergoing ALT are prone to sudden, late rises in IOP when miotics are not continued postlaser. It is also theoretically possible, although again the study has not been done, that treatment with miotics may prevent the development of elevated IOP in eyes with pigment dispersion syndrome or exfoliation syndrome.

Do I use miotics invariably? No. One also has to be practical. In patients with pigment dispersion who do not have lattice degeneration, I try to initiate treatment with Ocuserts. Latanoprost is an alternate choice. I do not, however, initiate aqueous suppressants as my first choice in patients who are still in the active pigment liberation stages (around 20-45 years of age). In patients with exfoliation syndrome, who tend to be older, I don’t force miotics, but may start treatment with an aqueous suppressant. However, a miotic is often my choice for the second drug in these patients.

We’d like to hear what others think about this matter. You can write to me directly or better, e-mail to ritch@inx.net. If we get enough feedback, we can compile your comments and preferences for future publication in this column.