Directed drug therapy addresses glaucoma’s origins

Researchers are asking what happened before the rise in IOP.

NEW YORK — An increasing understanding of the origin of glaucoma and emphasis on treatment approaches other than lowering intraocular pressure (IOP) — along with the introduction of several innovative glaucoma drugs — have combined to produce some interesting ideas about directed drug therapy.

“Prevention of elevated IOP should take precedence over trying to lower it once damage has been done,” said Robert Ritch, MD, professor and chief of glaucoma services at the New York Eye and Ear Infirmary.

“There are many other steps in the glaucoma disease process prior to the elevation of IOP,” Dr. Ritch said. “For instance, pigment dispersion syndrome, exfoliation syndrome or neovascular glaucoma each lead to trabecular dysfunction through a specific series of events. Intervention could be applied at each of these steps,” he said.

Dr. Ritch said he approaches different types of glaucoma differently. “For instance, if it’s high-tension, primary open-angle glaucoma (POAG), I will usually start with a beta-blocker. With exfoliation syndrome, I will usually start with latanoprost and pilocarpine at bedtime. Most ophthalmologists would start with aqueous suppressants, but all that does is further sludge-up the trabecular meshwork when you really need to increase aqueous outflow,” he said.

Drugs that could open the trabecular meshwork temporarily, such as latrunculin 100, might allow dispersal of exfoliation material, according to Dr. Ritch.

The same argument applies for pigment dispersion syndrome and pigmentary glaucoma. “By giving aqueous suppressants, you’re allowing more pigment to come off, and you’re actually going to make the disease worse in the long run,” said Dr. Ritch, “So I will start with Xalatan (latanoprost; Pharmacia) to try to increase the uveoscleral outflow, and it really works well on these patients. I also put them on Ocuserts [pilocarpine; Akorn] — these younger patients can’t tolerate pilocarpine drops — because you want to get the iris away from the zonules,” he said.

Dr. Ritch pointed out that the use of Propine (dipivefrin HCl, Allergan) appears to have fallen by the wayside, with so many new drugs from which to choose. “However, I find that Propine works better in people with pigmentary glaucoma than other types of glaucoma. It may be due to some adrenergic hypersensitivity that exists in these patients.”

Dr. Ritch stresses that his unconventional choices are based completely on clinical impressions derived from his practice. “This is all empirical, simply from what I have found in my practice,” he said. “Essentially, you want to interfere with the mechanism rather than waiting until these patients have glaucomatous damage.”

Variable side effects

A recent study published in the British Journal of Ophthalmology (2000;84:710-713) indicates that, when initiating therapy in new patients, ophthalmologists should consider the variable effects of different glaucoma medications not only on IOP, but on the cardiovascular and respiratory systems, as well.

Andrew Waldock, MD, of Bristol Eye Hospital, U.K., and colleagues evaluated the short-term cardiovascular, respiratory and IOP effects of four glaucoma medications — latanoprost, timolol, brimonidine and betaxolol. Study participants included 134 elderly patients with newly diagnosed primary open-angle glaucoma or presumed normal tension glaucoma (NTG).

Fifteen patients had pre-existing chronic obstructive pulmonary disease. Fourteen patients had congestive heart failure. At initial examination, 17 patients were found to have undiagnosed first-degree heart block, according to the report. However, second-degree heart block was discovered in one patient.

After 3 months of treatment, latanoprost brought the greatest lowering of IOP, followed closely by timolol for primary open-angle glaucoma and brimonidine for normal tension glaucoma, the investigators reported. Betaxolol was relatively weak in reducing IOP in both diagnostic groups, according to the study.

They concluded that, “the evidence from this short-term study suggests that latanoprost is a useful primary treatment for both new POAG and ‘presumed’ NTG patients.

This is based upon its substantial IOP-lowering effects in both of these groups, in conjunction with its relatively ‘clean’ side effect profile.”

What’s ahead?

By the time 2010 comes around, glaucoma researcher, Murray Fingeret, OD, predicts glaucoma management may still center on topical medications and trabecular procedures, but that advances will come in the approach not only to lowering IOP, but to preserving blood flow, visual function and the optic nerve head.

“Predicting how practitioners will treat glaucoma over the next 10 years is an uncertain exercise,” Dr. Fingeret stated in his 6th Annual Glaucoma Report.

“Perhaps, in the decade to come, scientists and pharmaceutical companies will develop effective therapeutic modalities that will allow us to increase blood flow to the retina and optic nerve. Maybe we’ll get agents that provide some means of protecting the retinal ganglion cells.” What’s certain, he said is the probability of seeing more effective IOP-lowering agents, such as new-generation prostaglandins.

Dr. Ritch stresses the need for researchers to focus their attention on the specific disorders that produce glaucoma and further the amount of research being done on their etiologies and mechanisms. “Rapidly increasing understanding of the origin of disease states on a molecular genetic and biochemical level is opening new doors for treatment options, if not eventual cures,” Dr. Ritch said.

Sayoko E. Moroi, MD, PhD, is one of the scientists whose research just might result in alternative treatment strategies for glaucoma. Dr. Moroi’s main research interest is to understand the molecular pathways that regulate IOP in the ciliary body and trabecular meshwork. Ultimately, the results may lead to development of more receptor-specific drugs to lower IOP and perhaps lead to investigative models of elevated IOP using mutated receptors. Her second area of research related to aqueous humor regulation is production of neurotrophins.

By understanding the regulation of neurotrophins in the aqueous humor, alternative treatments to protect the cornea and trabecular meshwork may be created. Her third research interest combines both an understanding of the molecular targets of glaucoma medications in the eye and individual patient response to a variety of the glaucoma drugs.

Ultimately, the three related research areas will facilitate further detailed understanding of currently used glaucoma medications.

For Your Information:

• Robert Ritch, MD, can be reached at Glaucoma Associates, 310 E 14th St., Ste. 304, New York, NY 10003; (212) 673-5140; fax: (212) 420-8743. Dr. Ritch has no direct financial interest in any product mentioned in this article. He is a paid consultant for Akorn.
• Murray Fingeret, OD, can be reached at New York Harbor Health Care System, Brooklyn Campus, 800 Poly Place, Brooklyn, NY 11209; (718) 526-1000; e-mail: murray@liii.com. Dr. Fingeret has no direct financial interest in any product mentioned in this article. He did not disclose if he is a paid consultant for any company mentioned
• Sayoko E. Moroi, MD, PhD, can be reached at the U-M Kellogg Eye Center Department of Ophthalmology and Visual Sciences, 1000 Wall St., Ann Arbor, MI 48105; (734) 763-1415; fax: (734) 936-2340.
• Andrew Waldock, MD, can be reached at Bristol Eye Hospital, Lower Maudlin St., Bristol, UK, BS1 2LX; (44) 117-958-6477; fax: (44) 870-137-5901.