The effects of tolterodine on anterior segment and choroidal thickness in patients with overactive bladder syndrome

Abstract

Background:

To evaluate the effects of tolterodine on anterior segment and choroidal thickness by using the Pentacam system and optical coherence tomography (OCT) (Pentacam).

Methods:

A total of 122 eyes of 61 patients (34 female; 27 male) were included in the study. All patients underwent a regular ocular examination and intraocular pressure measurements before and after 3 months of antimuscarinic drug tolterodine treatment, in addition, pupil diameter, anterior chamber depth, anterior chamber volume, anterior chamber angle, and lens thickness were measured through Pentacam (Oculus Inc., Wetzlar, Germany) system. Measurements of choroidal thickness were performed by OCT (Spectralis^®, Heidelberg Engineering, Heidelberg, Germany).

Results:

The mean age was 58.4 ± 7.3 years and 56.5 ± 11.1 years for female and male patients. The mean intraocular pressure was 15.10 ± 2.75 mmHg before treatment and 15.18 ± 2.65 mmHg after treatment. Pupil diameters were 3.09 ± 0.48 mm before treatment and 3.12 ± 0.43 mm after treatment. Anterior chamber depth, before and after treatment were 2.68 ± 0.65 mm and 2.70 ± 0.61 mm. The mean value for subfoveal choroidal thickness was 267.92 ± 81.35 μm before the administration of tolterodine, whereas the mean choroidal thickness was 271.83 ± 75.42 μm after the administration of tolterodine. The alterations in the subfoveal choroidal thickness were not statistically significant (p = 0.862).

Conclusions:

After 3 months of therapy with tolterodine, there were no significant changes in anterior segment parameters and choroidal thickness.

Keywords

anterior segment choroidal thickness OCT pentacam tolterodine

Introduction

Iris sphincter muscle, ciliary muscles and trabecular cells have been found to have extensive expression of muscarinic receptors.^1–3 Stimulation of the receptors results in meiosis through the contraction of sphincter muscle;⁴ relaxing of zonulas between the lens and the ciliary body through the contraction of ciliary muscles; and accommodation is achieved by changing the position of the lenses to relaxing or spherical.⁵ Muscarinic receptors, which create contracting or relaxing of the trabecular network can also lead to changes in the intraocular pressure by changing the aqueous humor drainage.⁶

Studies with selective antagonists showed that muscarinic M3 receptor subtypes were present in iris sphincter and ciliary muscle cells.^2,7 Moreover, Ishizaka et al.. identified in evaluating immune reactivity of muscarinic receptors in the tissues of the iris that M3 was the predominant receptor subtype, but other subtypes (M1, M2, M4 and M5) were also present in lower levels.⁸

Systemic antimuscarinic drugs are frequently used in the treatment of overactive bladder syndrome. In the treatment of this syndrome, tolterodine, a nonselective, pure receptor antagonist, is one of the most preferred antimuscarinic drugs.^9–11 Tolterodine exerts its activity in the treatment of overactive bladder through the inhibition of binding of acetylcholine to M2 and M3 receptors on the detrusor muscle. Antimuscarinic drugs act mainly during the storage phase, exerting their effect on the receptors on the detrusor smooth muscle, reducing the spontaneous myocyte activity.¹² Other studies also reported that these agents have an inhibitory effect on afferent nerve fibres.¹³

Ocular effects of tolterodine is uncertain. To our knowledge, only one study on the ocular effects of tolterodine is available in the literature.

The aim of the present study is to evaluate of the effects of tolterodine, a systemic antimuscarinic drug of choice in overactive bladder syndrome, on the parameters of anterior ocular segment, characterized by extensive expression of muscarinic receptors, through the Pentacam (Oculus Inc., Wetzlar, Germany) system and, on choroidal thickness through optical coherence tomography (OCT).

Methods

This study was performed between July 2014 and February 2015 after obtaining the approval of Ankara Training and Research Hospital’s Local Ethics Committee. All patients gave their written informed consent.

The study group was composed of patients who were admitted to the Urology Clinic with complaint of urinary incontinence, frequent urination and urinary urgency, and diagnosed with overactive bladder syndrome, due to be treated with tolterodine (Detrusitol SR 4 mg, Pfizer).

Patients were referred to the Ophthalmology Clinic before treatment with tolterodine was started. Patients underwent a thorough ophthalmologic examination and analyses by the Pentacam system. Ophthalmologic examinations and Pentacam analyses were repeated after 3 months of treatment with tolterodine. Ophthalmologic examination involved visual acuity measurement by Snellen scale and refraction examination, anterior segment examination by slit-lamp biomicroscopy, intraocular pressure measurement by applanation tonometry, angle examination by Goldmann lenses, fundus examination by 90 Diopter lens, anterior segment analysis by Pentacam, and choroidal thickness measurement by OCT.

Inclusion criteria: Absence of systemic diseases such as diabetes, hypertension, congestive heart disease, acute or chronic renal insufficiency; any ophthalmologic disease; history of ocular surgery; ocular injury; high refractive error (>± 6 D); intraocular drug injection; photodynamic or photocoagulation laser treatment; use of topical ophthalmologic drops; urinary tract infection.

Pupil diameter, anterior chamber depth, anterior chamber volume, anterior chamber angle and lens thickness were obtained by Pentacam. The mean value for the pupil diameter was determined in millimeters, from the results of at least three measurements obtained during the scan. Pupil diameters were measured without dilation. As pupil diameter is known to be dynamic, affected by various factors, including accommodation, complex neural factors and responses, all measurements before, and after the administration of the drug were conducted under the same conditions of illumination.¹⁴

Findings of ocular examinations before and after treatment and of the Pentacam analyses were compared statistically. For statistical analyses, paired t test was used. A p value of 0.05 or below was considered statistically significant.

Choroid imaging was assessed with EDI-OCT (enhanced depth imaging optical coherence tomography; Spectralis^®, Heidelberg Engineering, Heidelberg, Germany). For all measurements, OCT images were obtained from a single horizontal section through the foveal center. Choroidal thickness was measured at 500 micron intervals of the section from 3 mm nasal and temporal to the foveal center. Choroidal thickness was measured from the outer border of the retinal pigment epithelium to the inner scleral border.

A preliminary estimate of sample size was based on choroidal thickness between pre- and postmeasurements, based on previous studies, for which a study with an effect size 0.5, type I error of 0.05 and a type II error of 0.2 would require approximately 60 patients with two-sided significance testing.

For the analyses of the choroidal thicknesses, statistical package for the Social Sciences for Windows version 16.0 was used. Categorical variables were given with numbers and ratios, and continuous variable values were given with mean, standard deviation (SD), minimum and maximum values. Ocular values before and after the administration of tolterodine were compared by a paired t test (two-tailed paired sample t test). Statistics were expressed as mean ± SD. In this study, a p value < 0.05 was considered significant.

Results

A total of 122 eyes of 61 patients (34 female; 27 male) were included in the study. The mean age was 58.1 ± 13.5 years (age range was 38–79 years). The mean age was 58.4 ± 7.3 years for females, and 56.5 ± 11.1 years for males.

Visual acuity for both eyes were determined as 10/10. None of the patients have been reported to have any subjective findings, including blurred vision. Anterior segment examinations revealed normal findings for all patients with intact conjunctiva and cornea, anterior chamber of normal depth, pupil at the center with smooth borders and response to light stimulation was present, clear lenses. No changes were observed in ophthalmologic examinations after the drug was administered. In fundus examinations, optic disc, macula and visible retinal surfaces were natural in all patients. No significant changes were observed in fundus examinations after 3 months of drug administration compared with the results of the examinations before drug administration.

Intraocular pressure was measured by Goldmann applanation tonometry in all patients before and after drug administration. Mean values of intraocular pressure obtained were 15.10 ± 2.75 mmHg before treatment and 15.18 ± 2.65 mm Hg after treatment.

Findings of the Pentacam analyses

Pentacam analysis data obtained before and after treatment for pupil diameter, anterior chamber depth, anterior chamber volume, anterior chamber angle, and lens thickness were compared for all eyes. Mean pupil diameter was measured as 3.09 ± 0.48 and 3.12 ± 43 mm for all patients, respectively, before and after the treatment. Pre- and post-treatment mean values of anterior chamber depth for all patients were 2.68 ± 0.65 and 2.70 ± 0.61 mm. Pre- and post-treatment mean values of anterior chamber volume for all patients were 161.2 ± 44.9 and 168.3 ± 46.5 mm.³ Pre- and post-treatment mean values of anterior chamber angle for all patients were 38.56 ± 6.7° and 38.036 ± 9.1°. Pre- and post-treatment mean values of lens thickness for all patients were 2308.8 ± 601.3 and 2313.4 ± 608.1 µm (Table 1). In all measurements, there were no significant differences between pre- and post-treatment mean values (p = 0.711, p = 0.501, p = 0.665, p = 0.518, p = 0.759, respectively).

Table 1.

Mean values for all patients.

	Before tolterodine treatment(Mean ± SD)	After tolterodine treatment(Mean ± SD)	p value
Intraocular pressure (mmHg)	15.10 ± 2.75	15.18 ± 2.65	0.732
Pupil diameter (mm)	3.09 ± 0.48	3.12 ± 0.43	0.711
Anterior chamber depth (mm)	2.68 ± 0.65	2.70 ± 0.61	0.501
Anterior chamber volume (mm³)	161.2 ± 44.9	168.3 ± 46.5	0.665
Anterior chamber angle (°)	38.56 ± 6.7	38.036 ± 0.9,1	0.518
Lens thickness (^)	2308.8 ± 601.3	2313.4 ± 608.1	0.759

Choroidal thickness values by optical coherence tomography

Mean choroidal thickness of the subfoveal region before the administration of tolterodine was 267.92 ± 81.35 µm, and 271.83 ± 75.42 µm after the administration of tolterodine. No statistically significant differences in the choroidal thickness was obtained for the subfoveal region (p = 0.862). Mean choroidal thickness values for the nasal region before and after the administration of tolterodine were 191.27 ± 82.49 µm and 198.49 ± 94.62 µm, respectively. No statistically significant difference in the choroidal thickness was detected for nasal region (p = 0.658). Mean choroidal thickness values for temporal region before and after the administration of tolterodine were 231.85 ± 81.46 µm and 233.51 ± 79.13 µm, respectively. No statistically significant differences were detected in the choroidal thickness for the nasal region (p = 0.497) (Table 2).

Table2.

Choroidal thickness values of patients before and after tolterodine treatment.

Choroidal thickness	Choroidal thickness before tolterodine(Mean ± SD)	Choroidal thickness after tolterodine(Mean ± SD)	p value
Subfoveal	267.92 ± 81.35	271.83 ± 75.42	0.862
Nasal	191.27 ± 82.49	198.49 ± 94.62	0.658
Temporal	231.85 ± 81.46	233.51 ± 79.13	0.497

SD, standard deviation.

Discussion

M3 receptor subtype was identified as the most predominant receptor subtype in the studies exploring immune reactivity of muscarinic receptors. In addition to M3, other muscarinic receptor subtypes, M2 and M5, were established to be present in ciliary muscle. The stimulation of these receptors has particular well known effects on eyes.^1,2

Tolterodine is a nonselective antimuscarinic drug and its binding affinities to antimuscarinic M1, M2, M3, M4 and M5 receptors are established as 3.0, 3.8, 3.4, 5.0 and 3.4, respectively. The rates of affinities of solifenacin for M1, M2 and M3 were reported as 25, 125 and 10, respectively and the rates of oxybutynin for M1, M2, M3, M4 and M5 were reported as 1.0, 6.7, 0.67, and 11, respectively.¹¹

Tolterodine is expected to have effects on muscarinic receptors, located in the organs and the tissues other than the bladder, due to its systemic use and nonselective antimuscarinic activity. These effects appear through the inhibition of the M3 receptor in the parotid gland, in the gastrointestinal tract, and in the anterior segment of the eye. The most common side effect is dry mouth. The incidence of dry mouth in patients treated with tolterodine varies between 8% and 18% in various studies. The second most common side effect is constipation and was reported with an incidence of 2–6%. Headache is also a frequently observed side effect, with an incidence rate of 1–7%.¹¹ Blurred vision is another side effect that is the leading cause of discontinuation of the drug. The incidence of blurred vision has been reported in varying rates in various studies. In the study by Jonas et al.., it was reported as 5%.¹⁵ The incidence was reported as 2% by Abrams et al..¹⁶ and as 1% by Zinner et al..¹⁷ On the other hand, in their study, Rackley et al.. reported no side effects related to vision.¹⁸ Likewise, in our study, no complaints of blurred vision were reported in any of the patients.

Only one study on the ocular effects of tolterodine is available in the literature. In that study by Altan-Yaycıoğlu et al.., 104 eyes of 52 patients were included. Patients who were diagnosed with overactive bladder syndrome and were to receive treatment with either tolterodine or oxybutynin, were examined before, and 3 months after, the treatment. The evaluation of intraocular pressure revealed a mean value of 16.86 mmHg before and 15.96 mmHg after the administration of the drug, and the difference was not statistically significant.¹⁹ Compatible with the literature, there was no change in the measurements of visual acuity, and in the findings of ocular examination in patients, who received 3 months of treatment with tolterodine in our study.

In our study, there was no change between the pre- and post-treatment values of visual acuity in patients. Similar results have also been reported in the study by Altan-Yaycıoğlu et al.. The authors reported that the pre- and post-treatment measurements of visual acuity in patients treated with tolterodine remained the same.¹⁹

Frischmeyer et al.., in their study of dogs treated with systemic anticholinergic agents, reported that there was no change in intraocular pressure from baseline values and no difference between the values of dogs treated with anticholinergic agents and of those treated with saline.²⁰ However, systemic anticholinergic agents have been suggested to increase intraocular pressure in patients with narrow-angle glaucoma.²¹

In many studies of reliability and reproducibility of Pentacam measurements, the Pentacam system has been demonstrated to have high reliability and reproducibility.^15,22,23

In our study, the parameters of ocular anterior segment were measured with Pentacam before and after 3 months of administration of tolterodine, one of the most commonly used drugs in overactive bladder syndrome. These measurements involved the structures in which muscarinic receptors are located in high density, or those that are affected most from these receptors, such as the pupil, anterior chamber angle, anterior chamber depth, anterior chamber volume and lens thickness. In these parameters, no difference between pre- and post-treatment was found in all patient groups. In the evaluation of the patients’ subgroups, no statistically significant difference was obtained between pre- and post-treatment parameters of male and female patient groups. Evaluations involved choroidal thickness measurements with OCT as well.

In their study on the ocular effects of tolterodine, Altan-Yaycıoğlu et al.. found that pupil diameter in bright light did not alter, whereas pupil diameter in darkened conditions was significantly larger.¹⁹ This finding is different from ours. However, in that study, pupil diameter was measured by biomicroscopic scale. We, on the other hand, used the Pentacam system, an objective method free from human error for measurements.

Different views on the pupillary effects of systemic anticholinergic agents have been suggested in the literature. Some authors have demonstrated in dogs that these agents did not alter pupil diameter.²⁰ In humans, systemic anticholinergic drugs are established to cause mydriasis.²¹ In our study, tolterodine did not alter pupil diameter after 3 months of treatment. Besides, in our study, for the first time in published literature, measurements of anterior chamber angle, anterior chamber depth, anterior chamber volume and lens thickness have been demonstrated as unaltered.

In our study, tolterodine did not alter the parameters of visual acuity, ocular examination, intraocular pressure, and anterior ocular segment, measured by Pentacam after 3 months of administration. This result can be explained by tissue and functional selectivity of the drug. Studies in animal and human tissue cultures showed that tolterodine was more selective to antimuscarinic receptors in bladder than to the antimuscarinic receptors in salivary glands, like parotid or submandibular glands. However, there is no study demonstrating the involvement of muscarinic receptors in eyes, bladder or in other tissues that have taken place in published literature. Therefore, the finding we have detected in the clinical environment needs to be established experimentally.

Margolis et al.. studied 54 eyes of 30 healthy subjects with a mean age of 50.4 years, in the choroidal region at 500 µm intervals of a horizontal section from 3 mm to the fovea by Spectralis^® EDI-OCT and found that the choroid was thickest in the subfoveal region (mean 287 ± 76 µm), choroidal thickness decreased rapidly in the nasal direction (mean 145 ± 57 µm), and choroidal thickness decreased with increasing age. They found that choroidal thickness decreased by approximately 15.6 µm for each decade.²⁴ Manjunath et al.. found the mean subfoveal choroidal thickness was 272 ± 81 µm. In this study, a negative correlation was found between subfoveal choroidal thickness and age (r = 0.61, p < 0.001).²⁵ McCourt et al.. measured subfoveal choroidal thickness of 194 healthy eyes (subjects’ mean age 55.50 years) was 246.59 µm and noted a decrease of 3.09 µm for each year.²⁶

Yamashite et al.. performed choroidal thickness measurements in 43 healthy subjects using three different OCT instruments and found subfoveal choroidal thicknesses as 272.6 ± 63.0 with Spectralis^®, 272.8 ± 64.7 with Cirrus (Cirrus, Carl Zeiss Meditec Inc., Dublin, CA), and 269.2 ± 61.0 µm with Topcon (Topcon, Topcon Corp., Tokyo, Japan).²⁷

Branchini et al.. studied choroidal thicknesses of 28 healthy subjects (mean age 35.2 years) using three different OCT instruments and measured subfoveal choroidal thicknesses as 347.46 ± 97.92 µm with Spectralis^®, 347.51 ± 94.37 µm with Cirrus, and 337.67 ± 89.01 µm with RTVue (Optovue Inc., Fremont, CA).²⁸ Decreasing choroidal thickness with increasing age has already been shown by previous histologic studies.²⁴ Ramrattan et al.. showed a decrease in choriocapillary density beginning from the first decade of life (choriocapillary density for the first decade: 0.75) with a linear decreasing trend with age (at 10th decade: 0.41) in enucleated 95 healthy eyes (aged between 6 and 100 years; mean age 61 years). They showed a decrease in choriocapillary density and diameter, and in choroidal thickness with age.²⁹

In our study, examinations of the horizontal choroidal sections to foveal center revealed that choroid were the thickest subfoveally, and the mean nasal choroidal thickness was lower than the mean temporal choroidal thickness. This correlation was found to be present both in pre- and in postadministration of tolterodine. Moreover, in this study, the difference between the choroidal thickness in subfoveal, nasal, and temporal quadrants before, and 3 months after, the administration of tolterodine was not found to be statistically significant.

In conclusion, tolterodine did not alter subjective findings reported by the patients and findings of ocular examination, and of intraocular pressure after 3 months of treatment. After 3 months of treatment, tolterodine did not create any statistically significant change in the parameters of anterior segment measured by Pentacam, including pupil diameter, anterior chamber depth, anterior chamber volume, anterior chamber angle and lens thickness. Moreover, no statistically significant changes were observed in the values of choroidal thickness in subfoveal, nasal, and temporal quadrants, measured by OCT. This could be the result of tissue selectivity characteristic of the agent to the bladder. However, these findings need to be supported by clinical and experimental studies involving ocular antimuscarinic receptors.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare that there is no conflict of interest.

References

Gupta

Drance

McAllister

. Localization of M3 muscarinic receptor subtype and mRNA in the human eye. Ophthalmic Res 1994; 26: 207–213.

Woldemussie

Feldmann

Chen

Characterization of muscarinic receptors in cultured human iris sphincter and ciliary smooth muscle cells. Exp Eye Res 1993; 56: 385–392.

Zhang

Hernandez

Yang

. Expression of muscarinic receptor subtype mRNA in the human ciliary muscle. Invest Ophthalmol Vis Sci 1995; 36: 1645–1657.

Newsome

Loewenfeld

IE.

Iris mechanics. II. Influence of pupil size on details of iris structure. Am J Ophthalmol 1971; 71: 553–573.

Koretz

Kaufman

Neider

. Accommodation and presbyopia in the human eye –aging of the anterior segment. Vision Res 1989; 29: 1685–1692.

Selbach

Gottanka

Wittmann

. Efferent and afferent innervation of primate trabecular meshwork and scleral spur. Invest Ophthalmol Vis Sci 2000; 41: 2184–2191.

Gil

Krauss

Bogardus

. Muscarinic receptor subtypes in human iris-ciliary body measured by immunoprecipitation. Invest Ophthalmol Vis Sci 1997; 38: 1434–1442.

Ishizaka

Noda

Yokoyama

. Muscarinic acetylcholine receptor subtypes in the human iris. Brain Res 1998; 787: 344–347.

Nilvebrant

Andersson

Gillberg

. Tolterodine – a new bladder-selective antimuscarinic agent. Eur J Pharmacol 1997; 327: 195–207.

10.

Bent

AE.

Etiology and management of detrusor instability and mixed incontinence. Obstet Gynecol Clin North Am 1989; 16: 853–868.

11.

Abrams

Andersson

KE.

Muscarinic receptor antagonists for overactive bladder. BJU Int 2007; 100: 987–1006.

12.

Anderson

Wein

AJ.

Pharmacology of the lower urinary tract: basis for current and future treatments of urinary incontinence. Pharmacol Rev 2004; 56: 581–631.

13.

Yokoyama

Yusup

Miwa

Effects of tolterodine on an overactive bladder depend on suppression of C-fiber bladder afferent activity in rats. J Urol 2005; 174: 2032–2036.

14.

Kawasaki

Moore

Kardon

RH.

Long-term fluctuation of relative afferent pupillary defect in subjects with normal visual function. Am J Ophthalmol 1996; 122: 875–882.

15.

Chen

Lam

AK.

Reliability and repeatability of the Pentacam on corneal curvatures. Clin Exp Optom 2009; 92: 110–118.

16.

Abrams

Kaplan

De Koning Gans

. Safety and tolerability of tolterodine for the treatment of overactive bladder in men with bladder outlet obstruction. J Urol 2006; 175(3 Pt 1): 999–1004.

17.

Zinner

Mattiasson

Stanton

SL.

Efficacy, safety, and tolerability of extended-release once-daily tolterodine treatment for overactive bladder in older versus younger patients. J Am Geriatr Soc 2002; 50: 799–807.

18.

Rackley

Weiss

Rovner

. Night-time dosing with tolterodine reduces overactive bladder-related nocturnal micturitions in patients with overactive bladder and nocturia. Urology 2006; 67: 731–736.

19.

Altan-Yaycıoğlu

Yaycıoğlu

Aydin Akova

. Ocular side-effects of tolterodine and oxybutynin, a single-blind prospective randomized trial. Br J Clin Pharmacol 2005; 59: 588–592.

20.

Frischmeyer

Miller

Bellay

. Parenteral anticholinergics in dogs with normal and elevated intraocular pressure. Vet Surg 1993; 22: 230–234.

21.

Feinberg

The problems of anticholinergic adverse effects in older patients. Drugs Aging 1993; 3: 335–348.

22.

Maruyama

Oki

Otsuka

. Human muscarinic receptor binding characteristics of antimuscarinic agents to treat overactive bladder. J Urol 2006; 175: 365–369.

23.

Shankar

Taranath

Santhirathelagan

. Anterior segment biometry with the Pentacam: comprehensive assessment of repeatability of automated measurements. J Cataract Refract Surg 2008; 34: 103–113.

24.

Margolis

Spaide

RF.

A pilot study of enhanced depth imaging optical coherence tomography of the choroid in normal eyes. Am J Ophthalmol 2009; 147: 811–815.

25.

Manjunath

Taha

Fujimoto

. Choroidal thickness in normal eyes measured using Cirrus HD optical coherence tomography. Am J Ophthalmol 2010; 150: 325–329.

26.

McCourt

Cadena

Barnett

. Measurement of subfoveal choroidal thickness using spectral domain optical coherence tomography. Ophthalmic Surg Lasers Imaging 2010; 41: 28–33.

27.

Yamashita

Shirasawa

Arimura

. Repeatability and reproducibility of subfoveal choroidal thickness in normal eyes of Japanese using different SD-OCT devices. Invest Ophthalmol Vis Sci 2012; 53: 1102–1107.

28.

Branchini

Regatieri

Flores-Moreno

. Reproducibility of choroidal thickness measurements across three spectral domain optical coherence tomography systems. Ophthalmology 2012; 119: 119–123.

29.

Ramrattan

van der Schaft

Mooy

. Morphometric analysis of Bruch’s membrane, the choriocapillaris, and the choroid in aging. Invest Ophthalmol Vis Sci 1994; 35: 2857–2864.