Comparative Study of Topical Application of Timolol and Verapamil in Patients With Glaucoma Within 6 Months

Introduction

Glaucoma is the third most common cause of blindness in the world. According to the data collected by World Health Organization, the incidence of primary open-angle glaucoma was estimated at 2.4 million people per year.

The different types of glaucoma are responsible for 15% of blindness, placing glaucoma as the third leading cause of blindness worldwide, following cataract.1 In fact glaucoma is an optic neuropathy that occurs with partial visual field loss. High intraocular pressure (IOP) is considered as a primary risk factor for glaucoma.1 ^, 2

Different groups of drugs such as β-blockers,3 carbonic anhydrase inhibitors,4 pilocarpin,5 ^, 6 prostaglandin analogs2 that are used topically besides other methods of surgery (eg, trabeculectomy) are used in the treatment of glaucoma.1 ^, 2

Calcium channel blockers inhibit the passage of calcium in tissues such as smooth muscle cells, cardiac cells, sinoatrial and atrioventricular node cells where it has the main role for depolarization.7 In this way, they reduce peripheral vascular resistance and blood pressure.7

As we know, vasospasm2 and hypoperfusion8 have a significant role in the pathogenesis of open-angle glaucoma. Calcium channel blockers increase outflow facility by suggested mechanisms such as reducing peripheral vascular resistance, relaxing smooth muscle cells of capillaries, reducing the tonicity of vessels, and increasing the blood flow.9 However, the mechanisms of increasing outflow facility of the aqueous remain to be determined and there is no exact evidence that reducing peripheral vascular resistance or listed mechanisms may increase aqueous humor outflow. And so they are considered in the treatment of glaucoma.

Among them verapamil is a calcium channel blocker that is used when possible vasospasm is considered in the pathogenesis of low-tension glaucoma.10 ^, 11

Verapamil as a calcium channel blocker has little effect in lowering IOP in systemic use. However, it reduces IOP when used topically.9

It is demonstrated that calcium channel blockers are effective in treating the early stages of adrenalin-induced glaucoma.12

In previous examinations done on normal individuals, topical administration of verapamil 0.125% and 0.25% has reduced IOP.9 ^, 13 ^, 14

Previous reports emphasize on the effectiveness of 0.25% and 0.125% concentrations of topical verapamil in reducing IOP.7

Methods

Out of 59 patients, 31 patients were male and 28 were female (52.5% and 47.5%, respectively). Patients’ age was between 27 and 81. In timolol group, there were 30 patients (mean age = 54.73) and in verapamil group there were 29 patients (mean age = 54.16).

It was a double-blinded prospective study in which the patients with open-angle glaucoma had already been diagnosed by perimetry (visual field examination), gonioscopy (evaluation of anterior chamber angle), tonometry (measuring the IOP), and fundoscopy (optic nerve examination). Their disease was also confirmed by inspection of optic nerve atrophy and increase in disc cupping.

Patients who had taken topical or systemic drugs during the past 24 h that could alter IOP, and those with IOP 22 mmHg or less, were omitted from the study. So among the whole patients with open-angle glaucoma who were referred to our ophthalmology clinics, 59 patients were chosen for the study. The patients were divided into 2 groups; the first group with 30 patients and the second with the remaining 29 patients.

Early in the first step, the IOPs of patients were measured by applanation tonometry and those with the IOP of 23 mmHg and more were chosen for the study. Pachymetry was done to adjust the IOPs. Informed consents were obtained and the research was approved by the institutional review board. The research was based on the tenets of the Declaration of Helsinki, as it was a clinical trial study on patients with glaucoma. We used SPSS v.15 and P value was defined significant <0.05. We analyzed the data by independent t-test after they were checked for normality by one-sample Kolmogorov–Smirnov test.

As timolol and verapamil were chosen for the study, we measured patients’ blood pressure and asked their age, gender, and cardio-bronchial situation. Thus no patients with cardio-bronchial problems or hypotension were chosen for the study.

In our questionnaire, we asked patients about any drugs they use that could alter IOP and history of asthma, as well as history of allergic reactions to drugs or other agents.

A pharmacologist provided the examiner with drugs that were labeled A and B with similar shapes, so the examiner was unaware about the content of drugs we used.

To prepare the eye drops, we used timolol drop 0.5% and changed the container to make the drugs similar in shape. Verapamil eye drop 0.25% was prepared from a solution of 2.5 mg/mL (Lekopten 5 mg/2 mL, production date: 4/2006, expiration date: 4/2011, product number: 3996704H) by a sterile syringe with the volume of 5 cc. Then it was kept in a similar sterile container. We tried to use the drugs as soon as possible (at most in 2 h). No buffer or preservative was used since we did not have a control group in our study to investigate the possible effects of any preservatives in changing IOP.

The pH of both solutions was measured by a pH meter article. It was 6 for verapamil and 6.5 for timolol. Timolol and verapamil drops were put in containers totally similar with the same volume of 5 cc. Containers were labeled A and B, so both the examiners and patients were unaware about the content of drugs. Intraocular pressure was measured again after 90 min and was recorded in the file with mentioning which drug (A or B) was used. Finally the data were collected and analyzed.

Results

Irrespective of sex there were 59 patients, ranged from 27 to 81 years old. As mentioned before statistically, there was no significant difference relating to their age (P = 0.955).

Before instillation of eye drops, the range of IOP was 22–51 in the right eyes and 22–52 in the left. After instillation, the range changed from 22 to 47 in the right eyes and 20 to 46 in the left.

Before administration of drug, mean IOPs in the right eyes (50 eyes) and left eyes (49 eyes) were measured 31.04 and 34.61, respectively. In general, mean IOPs before and after instillation of eye drop in 99 eyes were 32.8081 and 30.4747, respectively. Then we used t-test and compared the results. Among the whole patients, 11 patients had hypertension (HTN), eight had diabetes mellitus (DM), and four had both HTN and DM. The remaining 36 patients had no other diseases rather than glaucoma. Mean pressure in timolol group in 52 eyes (27 right eyes and 25 left eyes) before and after instillation of eye drop was 32.545 and 30.230, respectively, and in verapamil group in 47 eyes (22 right eyes and 25 left eyes) it changed from 33.195 to 30.835.

Considering the comparable decrease in IOP in both timolol and verapamil groups after 90 min, we compared the results by t-test. So comparing the mean pressures between 2 groups showed there is no significant difference in IOPs (P = 0.27).

Discussion

Calcium channel blockers through possible mechanisms such as increasing outflow facility9 and reducing vasospasm2 ^, 11 are effective in lowering IOP. However, the mechanisms of increasing outflow facility of the aqueous remain to be determined and there is no exact evidence that reducing peripheral vascular resistance or listed mechanisms may increase aqueous humor outflow.

This group of drugs has dual effect on the aqueous humor dynamics. It depends on the way they are administered.15 Topical use of calcium channel blockers is more effective in decreasing IOP than their systemic use.15 Besides the possible mechanisms mentioned above, verapamil can also improve optic nerve circulation in glaucoma patients.

According to Payne and colleagues verapamil, diltiazem, and nifedipine are not effective in reducing IOP in rabbits.16 However, Segarra and colleagues have stated topical application of verapamil and nifedipine lowers IOP in conscious rabbits.17 Another study demonstrates that calcium channel blockers in combination with antiglaucoma medications significantly lower IOP in the primate eye.18

There are other studies that show calcium channel blockers like verapamil are effective in reducing IOP in open-angle glaucoma.10 ^, 15 ^, 19

So among all calcium channel blockers, topical verapamil was chosen to be compared with timolol. Both drugs reduced aqueous humor secretion through different mechanisms.20

Topical verapamil 2% does not change IOP in healthy human eyes.19 However, 0.25% and 0.125% concentrations of verapamil reduce IOP.11 ^, 14 ^, 21 ^, 22

Single-dose administration of verapamil 0.125% reduced IOP 3–4 mmHg in hypertensive eyes in 12 patients that lasted up to 10 h.14 Also a slight decrease in IOP (about 1.5 mmHg) has been reported in normal individuals.13

According to Netland and colleagues, verapamil 0.25% has been more effective in lowering IOP and increasing capillary blood flow, compared with the 0.063% and 0.125% concentrations.22 So in our study, we applied topical verapamil 0.25%.

Aqueous humor flow seems to be increased 30 min after topical application of verapamil19 and most drugs used to treat glaucoma show their maximum effect within 1 h. Also topical β-blockers such as timolol eye drop reduce aqueous humor secretion in ciliary epithelial cells through inhibiting cAMP production and lower IOP 20% to 30% after an hour.23 Therefore based on the previous studies, we measured the IOP 90 min after we applied topical verapamil.24

Cul de sac has a maximum capacity of 30 µL so an eye drop with a volume of 50–70 µL exceeds its capacity. The extra volume enters gastrointestinal system and may cause systemic side effects.25

According to Goyal and colleagues, application of topical verapamil for 2 weeks and 3 times daily reduced blood pressure and heart rate. This indicated the hypotensive effects of topical verapamil due to its systemic absorption.21 However, Netland and colleagues found no systemic effects on heart rate or blood pressure after administration of topical verapamil.22 In our study we measured blood pressure and heart rate after the administration of topical verapamil and the results were similar to those in Netland and colleagues’ study.22

Considering the possible change in heart rate or blood pressure with administration of calcium channel blockers, patients with low blood pressure and heart rate were not chosen for the study.

According to our findings about comparable therapeutic effects of timolol 0.5% and verapamil 0.25% after 90 min in reducing IOP, further studies about administration of verapamil in more glaucoma patients and with longer duration would be helpful.