Glaucoma Medications—Helpful or Harmful?

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The relationship between medications that are used to treat glaucoma and their effect on the corneal endothelium is complex. Given mounting research examining the safety of some widely used glaucoma drops on the layers of the cornea, researchers from the University of Athens, in Greece, conducted a comprehensive review of medical literature looking at the impact of drops on the endothelium to provide insights, including potential risks and benefits, to ophthalmologists who treat glaucoma patients.

“This review was needed,” said lead study author Stylianos A. Kandarakis, MD, PhD, who with colleagues analyzed outcomes from 83 studies—both in vivo and in vitro investigations—involving numerous classes of drugs. The authors concluded that choosing the best pharmacotherapy for patients with glaucoma depends on a range of individual parameters, including stage of glaucoma, IOP, risk factors, and the overall health of the patient.

One class of drugs in particular, carbonic anhydrase inhibitors (CAIs), would benefit from additional in vivo research, Dr. Kandarakis said.¹

Methodology. Using PubMed and Scopus databases, the researchers analyzed studies evaluating beta blockers, CAIs, and alpha₂ agonists, all of which decrease aqueous humor production; rho-kinase inhibitors, a newer class of drugs that increase drainage through trabecular meshwork; and prostaglandin analogues, which increase aqueous humor flow through the uveal sclera tract (alpha₂ agonists also do this).

Key findings. Some medications, including prostaglandin analogues, have minimal impact on the corneal endothelium in in vitro experiments, Dr. Kandarakis said. “They are systemically safer and generally well tolerated,” the authors wrote.

However, beta blockers may affect various physiologic functions in corneal endothelium, possibly via the protein kinase A signaling pathway, the authors wrote. Even more significant, they said beta blockers could regulate cell proliferation and migration, facilitating Na-K ATPase activity.

Only a few studies exist that report the impact of alpha₂ agonists on the corneal endothelium, according to the study authors, and so it was difficult to determine their effect on the corneal endothelial layer.

Studies that examined rho-kinase inhibitors, which include the drugs ripasudil and netarsudil, indicated that these agents can stimulate cell cycle progression, enhance cell migration, and augment barrier and pump function. They can also prevent mesenchymal transition in corneal endothelial cells of patients with Fuchs endothelial corneal dystrophy, leading to thinner central cornea thickness and clearer corneas.

Cautionary note. The effect of CAIs, such as acetazolamide, on the corneal endothelium is an area for clinical caution, Dr. Kandarakis said, and the authors suggested close monitoring of patients who take CAIs. “In vitro experiments have demonstrated that CAIs can significantly reduce fluid pumping by approximately 40% to 60%,” he said.

But these findings have not been consistently replicated in in vivo studies, where, Dr. Kandarakis said, data indicate a transient increase in corneal thickness among patients receiving CAIs. Observed changes in corneal thickness have been relatively small, ranging from 2.5 to 18 μm, he said.

“The current body of scientific literature suggests that CAIs may have some impact on corneal endothelial function and corneal thickness, but the clinical significance of these effects remains unclear,” he said.

Additionally, there have been no randomized controlled trials that specifically examine the effects of CAIs on patients who have undergone corneal transplant or who have compromised corneas, the authors said.

Nonpharmacological treatments. Minimally invasive glaucoma surgery and selective laser trabeculoplasty may provide effective alternative treatments to glaucoma drops in some patients and minimize the side effects of topical treatment, Dr. Kandarakis said.

Study limitations. While this review highlighted important considerations, it also emphasized the need for more research to understand the full scope of the clinical effect of glaucoma medications. The existing literature is limited and most studies are in vitro. They also do not take into account all glaucoma medications used clinically, the authors wrote.

Another limitation: most of the studies reviewed did not distinguish between preservative-free and preservative-containing solutions. This should be taken into consideration because preservatives have been reported to result in corneal endothelial toxicity, Dr. Kandarakis said.

Final note. When physicians prescribe, the authors wrote, it is crucial to distinguish the healthy state of the corneal endothelium in primary open-angle glaucoma patients and the compromised endothelium that may be present in patients with secondary glaucomas such as pseudoexfoliation glaucoma and uveitic glaucoma.

“This review highlights the need for further investigations and a greater follow-up to prove whether the demonstrated effects of glaucoma drugs on corneal endothelium could reach clinical significance,” Dr. Kandarakis said.     

—Patricia Weiser, PharmD 

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1 Kandarakis SA et al. Ophthalmol Ther. 2023;12(3):1457-1478.

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Relevant financial disclosures: Dr. Kandarakis—None.

For full disclosures and the disclosure key, see below.

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