The Diurnal and Nocturnal Effects of Pilocarpine on Intraocular Pressure in Patients Receiving Prostaglandin Analog Monotherapy

Abstract

Purpose: The purpose of the study was to determine the 24-h effects of pilocarpine 2% ophthalmic solution on intraocular pressure (IOP) and ocular perfusion pressure (OPP) when used in addition to prostaglandin analog (PGA) therapy.

Methods: Twenty-seven patients with ocular hypertension (OHTN) or open angle glaucoma who were receiving stable monotherapy with a PGA were admitted to an inpatient sleep laboratory for 24-h monitoring of IOP, blood pressure (BP), and heart rate over 2 separate visits. The first baseline visit was performed under PGA monotherapy only. During the second 24-h visit, pilocarpine 2% was administered four times daily in addition to their normal PGA dosing. For each study visit, measurements of all study metrics were performed every 2 h in the habitual position. OPP was calculated as 2/3[diastolic BP +1/3(systolic BP – diastolic BP)] – IOP.

Results: During the diurnal period, pilocarpine significantly reduced IOP from a baseline of 18.2 ± 0.5 mmHg on PGA monotherapy to 17.1 ± 0.4 mmHg, P < 0.01. Similarly, pilocarpine significantly lowered IOP during the nocturnal period from 21.1 ± 0.7 to 20.0 ± 0.6 mmHg, P < 0.01. Mean OPP was unchanged from baseline levels after the addition of pilocarpine in both the diurnal and nocturnal periods. Mean systolic BP was significantly reduced during the nocturnal period only (−3.16 ± 1.5 mmHg, P = 0.03).

Conclusions: In patients taking PGA monotherapy, the addition of pilocarpine can significantly lower IOP throughout the diurnal and nocturnal periods, but has no effect on OPP.

Introduction

Intraocular pressure (IOP) is a major risk factor for the development and progression of glaucoma.¹ Furthermore, IOP continues to be the only modifiable factor in the prevention and treatment of glaucomatous optic neuropathy with all treatments aimed at reduction of IOP.² Despite a growing number of surgical options, topical medications remain the most common initial therapy chosen by clinicians.³ Prostaglandin analogs (PGAs), which predominantly lower IOP through increased uveoscleral outflow, have become the most frequently utilized drug class for first-line therapy due to a number of advantages.⁴ These include high efficacy, excellent tolerability, and once daily dosing.

Increasing importance is being placed on glaucoma treatments that not only reduce IOP during office or daytime hours, but throughout the nocturnal period as well to cover a full 24-h.⁵ Glaucoma patients with progressive disease despite controlled daytime IOP may have significant elevation in IOP during the nocturnal period.⁶ Medications that provide IOP reduction throughout the diurnal and nocturnal periods include PGAs and carbonic anhydrase inhibitors (CAIs), while alpha agonists and beta-blockers have minimal overnight effect.⁷

Initially used in the late 1800s and approved by the FDA in 1974, pilocarpine has a long history as a topical glaucoma therapy. The cholinergic agent works as a direct muscarinic agonist of the ciliary muscles, resulting in contraction and tension on the scleral spur that increases trabecular outflow facility with a 15%–25% reduction of IOP.⁸

The effects of adjunct pilocarpine therapy in patients taking a PGA have not been completely explored. A coexistent decrease in uveoscleral outflow has been shown with pilocarpine, which may alter the combined effect in these patients.⁸ Furthermore, the nocturnal effects of pilocarpine itself or the combination are unknown. In this study, we determine the IOP and ocular perfusion pressure (OPP) effects of adjunct pilocarpine in patients being treated with a PGA.

Methods

Before enrollment, this prospective clinical study was approved by the Colorado Multiple Institutional Review Board and followed the tenets of the Declaration of Helsinki. Written informed consent was obtained from all subjects. Patients meeting defined criteria were recruited at the conclusion of their regularly scheduled outpatient clinic visits at the University of Colorado Health Eye Center, Aurora, CO. The inclusion criteria were any patient ≥18 years of age with a diagnosis of open angle glaucoma (OAG), including pigmentary and pseudoexfoliative glaucoma, or ocular hypertension (OHTN) that were currently on monotherapy with a topical PGA medication (latanoprost, travoprost, bimatoprost, or tafluprost) for at least 6 weeks. Exclusion criteria include diagnosis of any other form of glaucoma other than OAG, IOP readings <14 mmHg in either eye during routine office visits in the past 12 months, Schaffer angle grade <2 in either eye on gonioscopy, intraocular surgery within 6 months or laser surgery within 3 months, history of retinal tear or detachment in either eye, active iritis in either eye on most recent examination, patients who smoke or have irregular sleep patterns, new or change in dose of glucocorticoid therapy, current use of any form of marijuana, and females who were pregnant or planning to become pregnant.

All subjects completed a total of 2 study visits after enrollment. On each study visit, subjects were admitted to an inpatient private room at the University of Colorado Hospital Clinical and Translational Research Center for a continuous 24-h period. The initial or baseline visit was completed while patients were taking their typical daily PGA medication. On the second study visit, patients continued to take their PGA medication at the usual time but were also given 1 drop of pilocarpine hydrochloride 2% by study staff at 0600, 1000, 1600, and 2200 h. This visit was completed up to 4 weeks after the initial visit, according to subject and study availability.

At each time point, proparacaine hydrochloride 0.5% was administered for topical anesthesia, and a Model 30 pneumatonometer (Reichert, Inc., Depew, NY) was utilized to measure IOP. Measurements with standard deviations >1.0 were discarded and remeasured. Both eyes were included as long as the eye met inclusion criteria. Measurements of heart rate (HR) and blood pressure (BP) were completed with a standard automated sphygmomanometer at the time of each IOP measurement. OPP was defined as the difference between two-third of the mean arterial blood pressure (MAP) and IOP (OPP = 2/3MAP–IOP).⁹

The means (±standard error) for all study measurements were compared between the baseline visit on PGA monotherapy and the follow-up visit on PGA and pilocarpine for each 2-h period, 16-h diurnal period, 8-h nocturnal period, as well as the entire 24-h period. A linear model with generalized estimating equations using an unstructured correlation structure was used to compare the mean values for each outcome at each time point accounting for repeated measures over time and across both eyes. Data analysis was conducted in SAS version 9.4 (SAS Institute, Inc.: Cary, NC, 2014). A P-value <0.05 was considered to be statistically significant.

Results

A total of 27 patients were enrolled in the study and completed all study visits. The study population had a mean age of 68.3 years (range 45–85) with a preponderance of females (74%). Primary OAG was the most frequent diagnosis (78%), and a majority was phakic (70%). The complete patient and ocular demographics are included in Table 1.

Table 1.

Patient Demographics and Ocular Characteristics

Variable	N (%) or mean (SD)
Age, years	68.3 (10.8)
Female	20 (74%)
Race
White	19 (70%)
Black	5 (19%)
Hispanic	2 (7%)
Asian	1 (4%)
Diagnosis
Primary open angle glaucoma	21 (78%)
Ocular hypertension	4 (15%)
Pseudoexfoliation glaucoma	2 (7%)
Lens status
Phakic	19 (70%)
Pseudophakic	8 (30%)
Prior laser surgery
Laser peripheral iridotomy	5 (62%)
Selective laser trabeculoplasty	3 (38%)
PGA
Latanoprost	26 (96%)
Bimatoprost	1 (4%)

PGA, prostaglandin analog.

The 24-h IOP profiles are displayed in Fig. 1 for both the baseline visit on PGA only and the follow-up visit with the addition of pilocarpine. The mean IOP was significantly reduced at each 2-h time point except at 0500, 0700, 1100, and 1300. Table 2 includes the mean IOP for the diurnal and nocturnal periods for each study visit. During the diurnal period, mean IOP was significantly reduced from 18.23 ± 0.45 to 17.12 ± 0.40 mmHg (P < 0.01). For the nocturnal period, mean IOP was significantly reduced from 21.13 ± 0.66 on PGA alone to 20.01 ± 0.55 mmHg on PGA plus pilocarpine (P < 0.01). These differences did not change significantly after adjusting for gender, race, age, lens status, and history of laser surgery.

FIG. 1.

The 24-h mean IOP curves at baseline of PGA monotherapy and after the addition of pilocarpine. IOP, intraocular pressure; PGA, prostaglandin analog.

Table 2.

Mean Intraocular Pressure During the Diurnal (0600–2200) and Nocturnal (2200–0600) Periods for Each Study Visit

	Mean ± SE	95% confidence limits		P
Nocturnal PGA monotherapy	21.1 ± 0.7	19.833	22.431
Nocturnal PGA + pilocarpine	20.0 ± 0.6	18.925	21.096
Nocturnal difference	−1.1 ± 0.3	−1.776	−0.467	<0.01
Diurnal PGA monotherapy	18.2 ± 0.5	17.346	19.116
Diurnal PGA + pilocarpine	17.1 ± 0.4	16.340	17.898
Diurnal difference	−1.1 ± 0.3	−1.612	−0.612	<0.01

The 24-h OPP profiles are displayed in Fig. 2 for both the baseline and follow-up visits. Mean OPP for the diurnal period was 44.1 ± 1.2 mmHg at baseline and 44.3 ± 1.1 mmHg after the addition of pilocarpine (P = 0.78). During the nocturnal period, mean OPP was 37.2 ± 1.3 mmHg at baseline and 37.1 ± 1.2 mmHg after the addition of pilocarpine (P = 0.87). No significant difference between study visits was found at any 2-h time point, or for the entire diurnal or nocturnal periods.

FIG. 2.

The 24-h mean OPP curves at baseline of PGA monotherapy and after the addition of pilocarpine. OPP, ocular perfusion pressure.

During the nocturnal period, there was a significant decrease in mean systolic BP (SBP) from 125.8 ± 2.9 mmHg at baseline to 122.7 ± 2.9 mmHg with the addition of pilocarpine (P = 0.03). A similar but nonsignificant decline in mean SBP was found during the diurnal period from 132.5 ± 2.8 at baseline to 130.8 ± 2.9 mmHg on pilocarpine (P = 0.16). For diastolic BP, a small but nonsignificant change occurred during the nocturnal and diurnal periods after the addition of pilocarpine (−1.31 ± 0.7 and −1.14 ± 0.9 mmHg, respectively). HR was not significantly changed between study visits at any study time point.

Discussion

In our study, we demonstrate the IOP and OPP effects of adjunctive pilocarpine therapy in OAG and OHTN patients treated with a topical PGA. While this combination of topical glaucoma medications has been studied previously in a limited fashion, our findings significantly identify the additional IOP lowering effects of pilocarpine in these patients over a 24-h period. Pilocarpine 2% dosed 4 times a day achieved a significantly lower IOP than PGA therapy alone not only during the diurnal period but during the nocturnal period as well in the habitual position. Despite the long-standing use of pilocarpine in the treatment of glaucoma, to our knowledge, this is the first study of its efficacy throughout a 24-h period.

PGA medications have been established as the first-line therapy for primary open angle glaucoma and OHTN for several years now.⁴ This status has been achieved due to the convenience of once daily dosing, outstanding efficacy (25%–33% IOP lowering), and excellent tolerability. Furthermore, the effect has been shown to be significant throughout the diurnal and nocturnal periods.^10–12 PGAs achieve IOP reduction primarily through an increase in aqueous outflow through the uveoscleral pathway with a demonstration of as much as a 50% increase in uveoscleral outflow.¹³ The mechanism of action is thought to be primarily through a matrix metalloprotease-induced change in the extracellular matrix but may also work through relaxation of ciliary muscle.¹⁴

Despite the use of PGAs in initial medical therapy, glaucoma patients often require additional therapy to better control their IOP. The most appropriate additional therapy is not nearly as well defined and can vary greatly from one clinician to the next. The addition of an alpha-agonist, beta-blocker, or CAI to PGA monotherapy can all achieve further IOP reduction, through reduction in aqueous humor production. While all 3 classes produce different reductions in IOP as monotherapy, they all produce similar additive IOP lowering effects as adjunct agents to PGAs during the diurnal period.¹⁵ However during the nocturnal period, a beta-blocker, timolol, failed to lower IOP, while brinzolamide, a CAI, significantly lowered IOP overnight.¹⁶ While alpha-agonists have not been studied overnight in this capacity, other studies have failed to show a nocturnal effect as monotherapy.^17,18

When latanoprost was approved, there was concern about the interaction of pilocarpine with PGAs. This was based on the drugs' potentially conflicting mechanisms of action; PGAs increase uveoscleral outflow across the ciliary body, and pilocarpine causes constriction of these ciliary muscle fibers with an increase in outflow facility.¹⁹ Several studies have since proven the additive effect of these 2 medications on IOP reduction. In a study of 20 OHTN patients, pilocarpine achieved a 7% IOP reduction when added to PGA therapy, while latanoprost achieved a 14% reduction when added to pilocarpine therapy.²⁰ Shin et al. assessed the efficacy of latanoprost in 61 glaucoma patients with uncontrolled IOP despite maximum medical therapy.²¹ While latanoprost achieved a significant reduction in mean IOP and was successful in avoiding glaucoma surgery, the authors found that presence of low- or high-dose pilocarpine therapy or its absence had no impact on its efficacy. Kent et al. found that pilocarpine achieved an additional IOP reduction in latanoprost-treated patients, but only when dosed 4 times a day with the bedtime dose occurring 1 h after latanoprost administration.²² Toris et al. studied the combined effects of pilocarpine and latanoprost, added in alternating order, on outflow facility and IOP.⁸ They found that latanoprost predominantly increased uveoscleral outflow and pilocarpine increased outflow facility resulting in a reduction of IOP. Furthermore, when used in combination, the effects of outflow facility and uveoscleral outflow were additive with a further reduction in IOP over monotherapy with either drug. Due to the action of pilocarpine on the iris and trabecular outflow pathway, it is conceivable that there may be a differential effect in eyes that are phakic versus pseudophakic as well as eyes with and without prior history of laser trabeculoplasty. However, when these characteristics were analyzed in our study, no significant difference in IOP lowering effects of pilocarpine was identified.

Our findings validate previous work showing an additive effect of pilocarpine and PGAs, and further define the effect over a 24-h period. Despite its efficacy across a 24-h period, the effect of pilocarpine appears to be smallest near the end of the nocturnal period and early morning before the first daily dose but increases quickly by the 0900 measurement. The effect was most sustained during the afternoon and evening hours, and into the first half of the overnight period. Importantly, the medication significantly lowers IOP during the nocturnal period in the habitual supine position. Only one previous study has looked at the 24-h effects of pilocarpine, but this study was only on pseudoexfoliation patients already on timolol and dorzolamide therapy.²³ In that study, the authors also found a significant IOP lowering effect throughout a 24-h period; however, only one overnight reading was taken and was done in the seated position.

Although pilocarpine is not frequently utilized as a second agent due to frequent dosing and side effects, the beneficial characteristic of 24-h efficacy, particularly in the overnight period, should be considered. This may apply particularly when treating normal tension glaucoma patients, or those in whom a significant nocturnal rise in IOP is suspected. A single, bedtime dose of pilocarpine may achieve this nocturnal effect while minimizing common side effects such as blurred vision during the day. When compared with other available agents, only the CAI, brinzolamide, has been shown to result in further IOP reduction overnight when added to a PGA.¹⁶ It should also be noted that while pilocarpine achieved a statistically significant reduction in IOP, the mean 6% decrease in IOP over the diurnal period may not always be clinically significant.

Looking beyond IOP, there is growing interest in medications effect on OPP, which has been identified as a risk factor for glaucoma. There are mixed data regarding the effect of PGAs on OPP with most studies showing an increase.^9,10 In this study, we found a variable but nonsignificant impact on OPP from the addition of pilocarpine to PGA therapy. It is unclear if pilocarpine would have a significant effect on OPP when given as monotherapy. The lack of OPP effect may be largely due to the small but significant decrease in SBP during the nocturnal period with the addition of pilocarpine. The muscarinic agonist properties of the medication have the potential to cause vasodilation resulting in this finding, but it is unclear from this study if this is a true medication effect and should be explored further. Importantly, there was no significant effect on heart rate from pilocarpine. Clinicians should consider this in elderly patients, or those with cardiac or pulmonary issues. It is well known that beta-blockers would be a relative contraindication in many of these scenarios, and alpha-agonists may also result in systemic side effects such as BP lowering and fatigue.²⁴

We recognize a few limitations in our study: First, our findings can only be applied to patients already taking a PGA who then started pilocarpine 4 times daily. This prevents any conclusions about the medications effect as monotherapy, but the study was designed to represent the most common potential use of pilocarpine in modern-day therapy. Second, patients taking any commercially available PGA medication were eligible to enroll. This may account for some variation in response to pilocarpine; however, it should be noted that the vast majority of patients were taking latanoprost. Finally, only 1 day of pilocarpine was administered. Additional effects may have been achieved with several days or weeks of therapy before the second study visit.

In conclusion, pilocarpine can provide significant additional IOP reductions throughout a 24-h period in patients with OAG and OHTN already taking a PGA. The effect is similar during the diurnal and nocturnal periods. The medication had no significant impact on OPP or HR but resulted in a small decrease in SBP. Further studies may be performed to elucidate the 24-h IOP lowering efficacy of pilocarpine as monotherapy as well as its use as a single nightly dose concomitantly with a PGA.

Acknowledgments

The authors acknowledge the support of NIH/NCATS Colorado CTSI, Grant Number UL1 TR001082, David Epstein Clinician-Scientist Research Award, and Research to Prevent Blindness.

Disclaimer

Contents are the authors' sole responsibility and do not necessarily represent official NIH views.

Author Disclosure Statement

No competing financial interests exist.