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Effect of timolol on central corneal thickness

Abstract

Purpose

Timolol is an effective and safe medication that is widely used in glaucoma treatment. Although it is known that it is quickly taken up by the cornea following topical administration and that the cornea exhibits -adrenergic receptors, there are few studies available on the clinical impact of timolol on central corneal thickness (CCT).

Methods

Twenty healthy subjects were tested in a double-blind, prospective, and randomized study. Intraocular pressure (IOP) and CCT were measured before and during administration of timolol 0.5% eyedrops over 28 days.

Results

Administration of timolol 0.5% resulted in a reduction of IOP from an initial value of 16 ± 2 mm Hg to 13 ± 0 mm Hg (p<0.001, R2 = 0.7033) as well as an increase in CCT from 555 ± 11 µm from the time of the baseline examination to 567 ± 9 µm (p = 0.005, R2 = 0.8754), an increase of epithelial thickness from 53 ± 2 µm to 59 ± 3 µm (p<0.001, R2 = 0.5063), and an increase of stromal thickness from 494 ± 4 µm to 498 ± 9 µm (p = 0.045, R2 = 0.4352) after 9 days each. From day 10 on, a decrease in CCT (R2 = 0.6164), epithelial thickness (R2 = 0.2216), and stromal thickness (R2 = 0.2092) was observed. At the end, the values had returned toward the initial values measured (CCT 553 ± 8 µm, p = 0.391; epithelial thickness, 50 ± 2 µm, p = 0.214; and stromal thickness, 493 ± 8 µm, p = 0.483). In contrast, endothelial thickness did not vary following administration of timolol 0.5% (p = 0.727, R2 = 0.009).

Conclusions

Topical administration of timolol 0.5% results in a reversible increase in CCT. These modest changes are unlikely to influence tonometry or clinical decision-making.

Eur J Ophthalmol 2013; 23(6): 784 - 788

Article Type: ORIGINAL RESEARCH ARTICLE

DOI:10.5301/ejo.5000307

Authors

Matthias Grueb, Jens Martin Rohrbach

Article History

Disclosures

Financial Support: No financial support was received for this submission.
Conflict of Interest Statement: None of the authors has conflict of interest with this submission.

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INTRODUCTION

Timolol is a T-adrenergic antagonist and has been successfully used in glaucoma therapy for more than 30 years. A decrease in intraocular pressure (IOP) is achieved by reducing chamber water production in the region of the ciliary body epithelium. Despite the fact that there are some potentially significant cardiovascular and respiratory side effects, this therapy is considered to be safe and effective. Clinically manifest side effects on the eye like, for example, irreversible corneal anesthesia are rare, which is why not much importance has been paid to aspects like interaction with ocular tissues other than the ciliary body epithelium in the pertinent literature (1-2-3).

This is notable because, in addition to ciliary body epithelium, the cornea also has T- and --adrenergic receptors, the functionality of which was often described in in vitro studies (4-5-6). Blocking of -adrenergic receptors of corneal epithelial and endothelial cells by timolol results in a decrease of intracellular cyclic adenosine monophosphate (cAMP) concentration and inhibition of protein kinase A activity and this was brought into context with an increase in corneal thickness (5). While proof of long-term clinical effects of timolol on the cornea was furnished in isolated cases only (7, 8), there are some reports that describe a short-term increase of central corneal thickness (CCT) in subjects on local therapy with timolol (9, 10).

The aims of the current study were to examine whether local administration of timolol might result in interaction with corneal, T-adrenergic receptors in the form of an increase in CCT; whether such an increase in CCT in subjects on therapy with timolol is reversible; and whether there are differences regarding the response to timolol among the corneal epithelium, stroma, and endothelium.

MATERIALS AND METHODS

Twenty healthy subjects (10 women and 10 men) aged 34 ± 9 years (range 23-61 years) were tested by carrying out a double-blind, prospective study. All subjects had a normal ophthalmologic history. Subjects with serious medical or neurologic conditions, on local or systemic therapy with drugs, and contact lens wearers were excluded from the study. All subjects granted consent to participating in the study, and were informed about the purpose and course of the study, as well as about the fact that they had the right to quit the study at any time for whatever reason. The regulations of the Declaration of Helsinki were strictly followed.

In addition to taking each subject’s history, his or her basic examination included a check of his or her visual faculty as well as tests like slit-lamp microscopy, funduscopy, measurements of IOP, and spectral optic coherence tomography (SOCT) of the anterior eye section. After that, randomized administration of timolol 0.5% eyedrops (Timo Comod 0.5%; timolol hydrogen maleate 6.84 mg = timolol 5 mg, sodium dihydrogen phosphate dihydrate, sodium monohydrogen phosphate dodecahydrate, water; Ursapharm, Saarbruecken, Germany), a commercial therapeutic agent for glaucoma patients, to one eye and placebo eyedrops (Hylo Comod; sodium hyaluronate 1 mg, water; Ursapharm) to the other eye took place. Neither the subject nor the examiner were informed about the result of randomization. The use of preparations that contain preservative agents was deliberately avoided. The bottles that contained the original drops were masked with a neutral adhesive film, which in accordance with randomization was labeled as right or left only. Pouring the material into new bottles was abstained from for reasons of sterility. Spectral OCTs and measurements of IOP were repeated 10 minutes later. The subjects were asked to continue to apply both eyedrops for another 28 days BID. Follow-up SOCTs and measurements of IOP were carried out at 8:00 each morning of the following 28 days. At the same time, the subjects were asked to make statements regarding compliance with the administration of the eyedrops. All tests and follow-ups as well assessment of the SOCT scans were carried out by one examiner. To check corneal thickness and the individual corneal layers, SOCT (Copernicus, EyeTec, Lübeck, Germany), which takes measurements of corneal thickness by means of a noncontrast procedure with an accuracy of <5.0 µm, was used (11). Two measurements taken at a time interval of 1 minute were averaged. Measurements of IOP were taken using Goldmann applanation tonometry; again, 2 measurements taken at a time interval of 1 minute were averaged. Statements regarding significance of the results were made using analysis of variance and the R2 coefficient of determination.

RESULTS

Central corneal thickness of the placebo group at an initial value of 554 ± 19 µm (mean difference between both measurements: 0 ± 0 µm) did not differ from corneal thickness of the timolol group at a value of 555 ± 11 µm (mean difference between both measurements: 2 ± 3 µm) (p = 0.924) (Fig. 1). The placebo group showed no significant change in CCT (p = 0.292). In contrast, CCT of the timolol group significantly increased to 567 ± 9 µm compared to the placebo group within the first 9 days (p = 0.005, R2 = 0.8754). From the 10th day onward, a decrease in CCT of the timolol group to 553 ± 8 µm (R2 = 0.6164) was noted, which means that corneal thickness no longer significantly differed from corneal thickness of the placebo group (p = 0.391) (Fig. 1).

Central corneal thickness before (day 1) and during (day 0-28) application of timolol 0.5% eyedrops in one eye (n = 20) and placebo eyedrops in the fellow eye (n = 20).

Also with regard to corneal epithelial thickness, no difference between the placebo group at a value of 55 ± 2 µm and the timolol group at a value of 53 ± 2 µm (p = 0.110) (Fig. 2) was noted at the beginning of the study. Epithelial thickness of the placebo group did not change significantly during the period of the study (p = 0.856). In contrast, epithelial thickness of the timolol group significantly increased to 59 ± 3 µm (p<0.001, R2 = 0.5063) within the first 9 days. From the 10th day onward, epithelial thickness of the timolol group decreased again (R2 = 0.2216) and finally did not significantly differ from epithelial thickness of the placebo group (p = 0.214) (Fig. 2). Initial stromal thickness of the placebo group (494 ± 18 µm) did not significantly differ from stromal thickness of the timolol group (494 ± 4 µm, p = 0.961) and, in addition, did not significantly change in the further course of the study (p = 0.589).

Epithelial thickness before (day 1) and during (day 0-28) application of timolol 0.5% eyedrops in one eye (n = 20) and placebo eye drops in the fellow eye (n = 20).

Similar to total thickness and epithelial thickness, stromal thickness of the timolol group also increased within the first 9 days (498 ± 9 µm, p = 0.045, R2 = 0.4352). By the end of the study period, stromal thickness had decreased to 493 ± 8 µm again (p = 0.483).

Endothelial thickness did not significantly vary between the timolol group and the placebo group, either at the beginning of the study or in its further course (p = 0.727). In contrast, endothelial thickness did not vary following administration of timolol 0.5% (p = 0.727, R2 = 0.009).

At the beginning of the study, there was no significant difference in IOP between the timolol group (16 ± 2 mm Hg) (mean difference between both measurements: 1 ± 1 µm) and the placebo group (16 ± 3 mm Hg, p = 0.867) (mean difference between both measurements: 1 ± 1 µm). While IOP in the placebo group remained stable over 28 days (p = 0.881), IOP in the timolol group on therapy with timolol eyedrops significantly decreased (p<0.001, R2 = 0.7033) and remained significantly below the values measured in the placebo group during the study period (p<0.001).

DISCUSSION

Glaucoma is one of the most important illnesses of the eye. When this condition is not diagnosed and remains untreated, irreversible blindness may result (1-2-3). Corneal thickness in healthy adults is 540 ± 30 µm and associated with a risk that glaucoma might develop and/or progress (12-13-14-15-16-17-18-19). A number of studies have dealt with the effect of various antiglaucoma drugs on corneal thickness. Local therapy with prostaglandin analogs results in a decrease of CCT (20-21-22-23-24), while topical administration of carboanhydrasis inhibitors may result in at least a short-term increase in corneal thickness (25, 26). Local administration of the n2-adrenergic agonist brimonidine results in a reversible increase in CCT (27, 28). This is particularly interesting because with regard to corneal epithelium and endothelium, i2- and 2-adrenergic receptors act as opponents on the same signal pathway. Stimulation of corneal o-adrenergic receptors results in an increase in intracellular cAMP concentration as well as an increase in protein kinase A activity; stimulation of 2-adrenergic or blocking of 2-adrenergic receptors of the cornea results in a decrease in intracellular cAMP and inhibition of protein kinase A (5). Correspondingly, it is assumed that subjects on local therapy with the p-adrenergic antagonist timolol also show an at least reversible increase in corneal thickness, as was demonstrated by the current study (Fig. 1).

Previous studies have furnished proof that there is a rapid increase in CCT in subjects on therapy with timolol eyedrops (9, 10.) However, the study period, ranging from 3 to 5 days, was short, and unlike in the current study, unsuitable to furnish proof of the reversibility of this effect. This reversibility also explains the apparent contradiction between the short-term increase in CCT (9, 10) and the fact that no significant change in corneal thickness was demonstrable in other studies after 6 and 12 months, respectively (7, 8).

In the current study, the maximum extent of the increase in corneal thickness was reached after 9 days and corneal thickness afterwards returned to its initial value (Fig. 1). It is assumed that the reason for this is desensitization/sensitization by the agonist/antagonist typically seen in a- and --adrenergic receptors (29-30-31). However, because desensitization/sensitization does not only depend on time factors but also on the dosage used, it currently remains open whether a changed concentration of the active ingredient might also result in a deferral of the effect in time. Compared with the i2-adrenergic agonist brimonidine, which reaches a maximum increase in corneal thickness after 2 days (27, 28), it should be considered that the binding affinity of the ligand also has an effect on the desensitization/sensitization process. In addition, it should be discussed whether an increased amount of other receptors that counteracted the effect of f-adrenergic blocking by timolol were activated/inhibited from the ninth day onward.

The effect timolol has on the different individual corneal layers as tested by means of SOCT in the current study has not been considered previously. It is hardly surprising that an increase in corneal stromal thickness is most pronounced in subjects on therapy with timolol. However, corneal stroma does not have any o-adrenergic receptors (4, 5), so this effect must be considered to be a secondary one. Corneal thickness is the result of corneal homeostasis, which is controlled by interaction of epithelial and endothelial receptors (4-5-6, 9, 10, 27, 28). In 1985, Nielsen und Nielsen (9) claimed that administration of timolol inhibits the endothelial pump-leak mechanism by blocking endothelial d-adrenergic receptors and thus results in an increase in corneal thickness. As in previous studies, endothelial thickness did not change in the current study (10, 25, 27, 28, 32, 33). However, the absence of an increase in endothelial thickness in subjects on topical therapy with timolol does not allow us to conclude that activity or functionality is absent. The same applies to the absence of changes in endothelial cellular density in subjects on therapy with timolol, which are reported to be present in the pertinent literature (7, 8, 10). What is also of interest in this context is the fact that epithelial thickness distinctly increases during the first 9 days in subjects on local therapy with timolol and that corneal epithelial thickness then decreases within the next few days (Fig. 2). The question whether this means a fluid shift from the outside to the inside or, instead, active or passive transport of fluid from the stroma to the outside cannot be clearly answered at the present time. If this increase in total corneal thickness is due to blocking of the endothelial pump-leak mechanism, the early increase and subsequent decrease in epithelial thickness might also demonstrate an attempt of (receptor-controlled) adjustment of homeostasis, which then has the effect that corneal thickness again decreases from the ninth day onward.

In summary, local therapy with 0.5% timolol results in a reversible increase in CCT. At the present time, it remains a matter of speculation which physiologic processes cause this increase and subsequent decrease in thickness. However, it is unlikely that the mild changes described by the current study have an effect on measurements of IOP (using applanation tonometry) or clinical decision-making.

Disclosures

Financial Support: No financial support was received for this submission.
Conflict of Interest Statement: None of the authors has conflict of interest with this submission.
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Authors

Affiliations

  • Villa im Lindengarten, Breisach am Rhein - Germany
  • University of Tuebingen, Department of Ophthalmology, Tuebingen - Germany

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