Download Effect of timolol on central corneal thickness

Eur J Ophthalmol 2013; 23 ( 6 ): 784-788
DOI: 10.5301/ejo.5000307
ORIGINAL ARTICLE
Effect of timolol on central corneal thickness
Matthias Grueb1,2, Jens Martin Rohrbach1
1
2
Villa im Lindengarten, Breisach am Rhein - Germany
University of Tuebingen, Department of Ophthalmology, Tuebingen - Germany
Villa im Lindengarten, Breisach am Rhein and University of Tuebingen, Department of Ophthalmology, Tuebingen - Germany
Villa im Lindengarten, Breisach am Rhein
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 β-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.
Keywords: Central corneal thickness, Cornea, Receptor, Timolol
Accepted: April 11, 2013
INTRODUCTION
Timolol is a β-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
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with ocular tissues other than the ciliary body epithelium in
the pertinent literature (1-3).
This is notable because, in addition to ciliary body epithelium, the cornea also has α- and β-adrenergic receptors,
the functionality of which was often described in in vitro
studies (4-6). Blocking of β-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
© 2013 Wichtig Editore - ISSN 1120-6721
Grueb and Rohrbach
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, β-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).
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
© 2013 Wichtig Editore - ISSN 1120-6721
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Timolol and CCT
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).
Fig. 2 - 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).
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).
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
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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 (1-3). Corneal
thickness in healthy adults is 540 ± 30 μm and associated
with a risk that glaucoma might develop and/or progress
(12-19). 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 (20-24), while topical administration of carboanhydrasis inhibitors may result in at least a short-term
increase in corneal thickness (25, 26). Local administration of the α2-adrenergic agonist brimonidine results in
a reversible increase in CCT (27, 28). This is particularly
interesting because with regard to corneal epithelium
© 2013 Wichtig Editore - ISSN 1120-6721
Grueb and Rohrbach
and endothelium, α2- and β-adrenergic receptors act as
opponents on the same signal pathway. Stimulation of
corneal β-adrenergic receptors results in an increase in
intracellular cAMP concentration as well as an increase in
protein kinase A activity; stimulation of α2-adrenergic or
blocking of β-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 β-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 α- and β-adrenergic receptors (29-31). 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 α2-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 β-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 β-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 (4-6, 9, 10, 27, 28). In 1985, Nielsen und
Nielsen (9) claimed that administration of timolol inhibits the
endothelial pump-leak mechanism by blocking endothelial
β-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.
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.
Address for correspondence:
Priv. Doz. Dr. Matthias Grueb
Villa im Lindengarten
Bahnhofstr. 7-9
D-79206 Breisach am Rhein
Germany
[email protected]
© 2013 Wichtig Editore - ISSN 1120-6721
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Timolol and CCT
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
788
Volotinen M, Hakkola J, Pelkonen O, Vapaatalo H, Mäenpää J. Metabolism of ophthalmic timolol: new aspects
of an old drug. Basic Clin Pharmacol Toxicol 2011;108:
297-303.
Mittag TW. Adrenergic and dopaminergic drugs in glaucoma. In:
The Glaucomas. St. Louis: CV Mosby; 1989;1409-24.
Gieser SC, Juzych M, Robin AL. Clinical pharmacology of
adrenergic drugs. In: The Glaucomas. St. Louis: CV Mosby;
1989;1425-48.
Grueb M, Wallenfels-Thilo B, Denk O, et al. Monoamine receptors in human corneal epithelium and endothelium. Acta Ophthalmol Scand 2006; 84:110-5.
Grueb M, Bartz-Schmidt KU, Rohrbach JM. Adrenergic regulation of cAMP/protein kinase A pathway in corneal epithelium
and endothelium. Ophthalmic Res 2008;40:322-8.
Walkenbach RJ, Chao WT, Bylund DB, Gibbs SR. Characterization of beta-adrenergic receptors in fresh and primary cultured
bovine corneal endothelium. Exp Eye Res 1985; 40:15-21.
Lass JH, Khosrof SA, Laurence J, Horwitz B, Ghosh K, Adamsons I; Dorzolamide Corneal Effects Study Group. A doublemasked, randomized, 1-year study comparing the corneal effects of dorzolamide, timolol, and betaxolol. Arch Ophthalmol
1998;116:1003-10.
Lass JH, Eriksson GL, Osterling L, Simpson CV; Latanoprost
Corneal Effects Study Group. Comparison of the corneal effects
of latanoprost, fixed combination latanoprost-timolol, and timolol: a double-masked, randomized, one-year study. Ophthalmology 2001;108:264-71.
Nielsen CB, Nielsen PJ. Effect of alpha- and beta-receptor active
drugs on corneal thickness. Acta Ophthalmol 1985; 63:351-4.
Grüb M, Leitritz M, Mielke J, Reinthal E, Bartz-Schmidt KU,
Rohrbach JM. Einfluss von Timolol auf die zentrale Hornhautdicke und Endothelzelldichte. Klin Monatsbl Augenheilkd
2006;223:894-8.
Zander B, Pemöller E. Technische Daten. SOCT Copernicus+.
Lübeck: Eyetec;2006:7.
Wolfs RC, Klaver CC, Vingerling JR, Grobbee DE, Hofman A,
de Jong PT. Distribution of central corneal thickness and its association with intraocular pressure: The Rotterdam Study. Am J
Ophthalmol 1997;123:767-72.
Su DH, Wong TY, Wong WL, et al. Singapore Malay Eye Study
Group. Diabetes, hyperglycemia, and central corneal thickness:
the Singapore Malay Eye Study. Ophthalmology 2008;115:964-8.
Tomidokoro A, Araie M, Iwase A; Tajimi Study Group. Corneal
thickness and relating factors in a population-based study in Japan: the Tajimi study. Am J Ophthalmol 2007;144:152-4.
Eysteinsson T, Jonasson F, Sasaki H. Central corneal thickness, radius of the central curvature and intraocular pressure in
normal subjects using non-contact techniques: Reykjavik Eye
Study. Acta Ophthalmol 2002;80:11-5.
Zhang H, Xu L, Chen C, Jonas JB. Central corneal thickness
in adult Chinese. Association with ocular and general parameters: The Beijing Eye Study. Graefes Arch Clin Exp Ophthalmol
2008;246:587-92.
17. Pfeiffer N, Torri V, Miglior S, Zeyen T, Adamsons I, Cunha-Vaz J;
European Glaucoma Prevention Study Group. Central corneal
thickness in the European Glaucoma Prevention Study. Ophthalmology 2007;114:454-9.
18. Chauhan BC, Hutchison DM, LeBlanc RP, Artes PH,
Nicolela MT. Central corneal thickness and progression of
the visual field and optic disc in glaucoma. Br J Ophthalmol
2005;89:1008-12.
19. Brandt JD. Central corneal thickness, tonometry, and glaucoma
risk: a guide for the perplexed. Can J Ophthalmol 2007;42:562-6.
20. Zhong Y, Shen X, Yu J. The comparison of the effects of latanoprost, travoprost, and bimatoprost on central corneal thickness.
Cornea 2011;30:861-4.
21. Harasymowycz PJ, Papamatheakis DG, Ennis M, Brady M, Gordon KD; Travoprost Central Corneal Thickness Study Group.
Relationship between travoprost and central corneal thickness in ocular hypertension and open-angle glaucoma. Cornea
2007;26:34-41.
22. Sen E, Nalcacioglu P, Yazici A, et al. Comparison of the effects
of latanoprost and bimatoprost on central corneal thickness. J
Glaucoma 2008;17:398-402.
23. Schlote T, Tzamalis A, Kynigopoulos M. Central corneal thickness during treatment with travoprost 0.004%
in glaucoma patients. J Ocul Pharmacol Ther 2009;25:
459-62.
24. Kim HJ, Cho BJ. Long-term effect of latanoprost on central corneal thickness in normal tension glaucoma. J Ocul Pharmacol
Ther 2011;27:73-6.
25. Wirtitsch MG, Findl O, Heinzl H, Drexler W. Effect of dorzolamide hydrochloride on central corneal thickness in humans
with cornea guttata. Arch Ophthalmol 2007;125: 1345-50.
26. Ornek K, Gullu R, Ogurel T, Ergin A. Short-term effect of topical brinzolamide on human central corneal thickness. Eur
J Ophthalmol 2008;18:338-40.
27. Grueb M, Mielke J, Rohrbach JM, Schlote T. Effect of brimonidine
on corneal thickness. J Ocul Pharmacol Ther 2011; 27:503-9.
28. Grüb M, Mielke J, Schlote T, Rohrbach M. Einfluss von
Brimonidin auf die zentrale Hornhautdicke. Klin Monatsbl Augenheilkd 2012;229:236-40.
29. Hamilton CA, Deighton NM, Reid JL. Rapid and reversible desensitisation of vascular and platelet alpha 2 adrenoceptors.
Naunyn Schmiedebergs Arch Pharmacol 1987;335: 534-40.
30. Scola AM, Chong LK, Suvarna SK, Chess-Williams R, Peachell PT. Desensitisation of mast cell beta2-adrenoceptormediated responses by salmeterol and formoterol. Br J Pharmacol 2004;141:163-71.
31. Scola AM, Chong LK, Chess-Williams R, Peachell PT. Influence
of agonist intrinsic activity on the desensitisation of beta2-adre-
noceptor-mediated responses in mast cells. Br J Pharmacol
2004;143:71-80.
32. Nielsen CB. The effect of carbonic anhydrase inhibition on
central corneal thickness after cataract extraction. Acta
Ophthalmol 1980;58:985-90.
33. Nielsen CB. Prostaglandin inhibition and central corneal
thickness after cataract extraction. Acta Ophthalmol 1982;
60:252-8.
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