Glaucoma management: relative value and place in therapy of available drug treatments

Abstract

Lowering intraocular pressure (IOP) is the only proven therapeutic intervention for glaucomatous optic neuropathy. Despite advances in laser and microsurgical techniques, medical IOP reduction remains the first-line treatment option for the majority of patients with open-angle glaucoma. Prostaglandin analogs are the most efficacious topical agents and carry a remarkable safety profile. Topical beta-blockers, alpha-agonists, and carbonic anhydrase inhibitors are often employed as adjunctive agents for further IOP control. Newer preserved and nonpreserved formulations are available and appear to be less toxic to the ocular surface. Oral carbonic anhydrase inhibitors, miotic agents, and hyperosmotics are infrequently used due to a host of potentially serious adverse events. Medical therapies on the horizon include rho-kinase inhibitors, neuroprotective interventions, and gene therapies.

Keywords

anterior chamber glaucoma ocular hypertension ophthalmic solutions optic nerve diseases trabecular meshwork vision disorders

Introduction

Glaucoma is an optic neuropathy resulting in a characteristic pattern of optic nerve and visual field deterioration [AAO, 2003]. The disease affects 66.8 million individuals and is the second leading cause of blindness worldwide [Leske, 1983; Quigley, 1996]. Increased intraocular pressure (IOP) is a treatable risk factor for the disease, but an elevation in IOP is not required for diagnosis [Kass et al. 2002]. Primary open-angle glaucoma (POAG), which accounts for the majority of disease cases, primarily results from impaired or suboptimal drainage of aqueous humor out of the eye via the trabecular meshwork and/or uveoscleral pathways [Congdon et al. 1992]. Aqueous humor is produced by the ciliary body and serves to provide nutritional support to anterior segment structures before physiologic filtration.

All currently available treatment modalities for POAG are aimed at lowering IOP by manipulating physiologic aqueous humor dynamics and a concise summary is provided in Table 1. The central role of IOP reduction in decreasing the risk of development or progression of POAG has been borne out in several landmark randomized controlled trials [AGIS Investigators, 2000; Collaborative Normal-Tension Glaucoma Study Group, 1998; Heijl et al. 2002; Kass et al. 2002; Lichter et al. 2001]. Medical, laser, and incisional surgical therapies may be indicated for this purpose.

Table 1.

Currently available glaucoma drugs and their mechanism of action.

Class	Mechanism of action	Average IOP reduction	Nocturnal efficacy	Side effects	Agent	Dosage	Availability
Prostaglandin analogs	Enhance uveoscleral outflow due to relaxation of the ciliary muscle and remodeling of extracellular matrix tissue within the ciliary body	18–31% during day time and about 8% during night time in supine position [Nordmann et al. 2002; Orzalesi et al. 2000; van der Valk et al. 2005]	More effective than beta blockers with IOP reductions of about 8.5–17% [Liu et al. 2004; Orzalesi et al. 2000]	Mild conjunctival hyperemia, darkening of the irides, hypertrichosis and hyperpigmentation of the eye lashes, periorbital fat atrophy	Latanoprost	Once daily	Xalatan (Pfizer, Inc.)
					Bimatoprost	Once daily	Lumigan (Allergan, Inc.)
					Travoprost	Once daily	Travatan (Alcon Laboratories, Inc.)
					Tafluprost	Once daily	Zioptan (Merck Sharp & Dohme Corp.)
					Unoprostone	Twice daily	Rescula (Sucampo Pharma Americas)
Beta-blockers	Reduce the production of aqueous humor	20–27% during day time [Orzalesi et al. 2000; Stewart et al. 1986; Stewart et al. 1996]	Little or no effect [Orzalesi et al. 2000]	Local irritation, dryness, conjunctival hyperemia, stinging, and blurring. Systemic effects on respiratory, cardiovascular and excretory systems	Timolol	Twice daily	Timoptic (Merck Sharp & Dohme Corp.)
							Betimol (Santen Pharmaceutical Co.)
							Istalol (Bausch & Lomb Pharmaceuticals, Inc.), Timoptic in Ocudose (Valeant Ophthalmics)
					Levobunolol	Twice daily	Betagan (Allergan, Inc.)
					Carteolol	Twice daily	Ocupress (CIBA Vision)
					Metipranolol	Twice daily	OptiPranolol (Bausch & Lomb, Inc.)
					Betaxolol	Twice daily	Betoptic (Alcon Laboratories, Inc.)
Alpha-agonists	Constriction of afferent ciliary process vasculature leading to decreased aqueous humor production; increased uveoscleral outflow	12.5–29% [Katz, 1999; Liu et al. 2010; Stewart et al. 1996; Toris et al. 1999; van der Valk et al. 2005]	Little or no effect	Blepharitis, blepharoconjunctivitis, conjunctivitis, hyperemia, blurry vision, dry mouth, ocular allergy, systemic hypotension, fatigue	Brimonidine tartrate	Thrice daily	Alphagan P (Allergan, Inc.)
					Dipivefrin hydrochloride	Twice daily	Propine (Alcon Laboratories, Inc.)
					Apraclonidine hydrochloride	Thrice daily	Iopidine (Alcon Laboratories, Inc.)
Carbonic anhydrase inhibitors	Reduction of aqueous humor production	13.2–22% [Sall, 2000; van der Valk et al. 2005]	Modest efficacy [Orzalesi et al. 2000]	Ocular surface irritation, ocular allergy, transient blurred vision	Brinzolamide	Thrice daily	Azopt (Alcon Laboratories, Inc.)
					Dorzolamide	Twice daily	Trusopt (Merck Sharp & Dohme Corp.)
Miotics	Ciliary muscle and scleral spur contraction, facilitating trabecular aqueous humor outflow			Pupillary constriction, ocular burning, brow ache, reduced night vision.	Pilocarpine hydrochloride	Thrice daily	IsoptoCarpine, (Alcon Laboratories, Inc.)
							Pilocarpine HCl Ophthalmic Solution USP (Bausch & Lomb, Inc.)
							Pilopine HS Gel, (Alcon Laboratories, Inc.)
					Carbachol	Thrice daily	Isopto Carbachol, (Alcon Laboratories, Inc).
					Echothiophate	Once daily and change the dose and frequency based on patient’s response	Phospholine Iodide (Wyeth Pharmaceuticals, Inc.)
					Demecarium	Twice daily to twice weekly depending on response	Humorsol (Merck Sharpe & Dohme Corp.)
Hyperosmotics	Lowering of aqueous fluid volume in the eye			Fluid and electrolyte imbalances, metabolic acidosis, dry mouth, marked diuresis, urinary retention, peripheral edema, headache, blurred vision, convulsions, nausea, vomiting, dehydration, hypotension, tachycardia	Glycerin	Orally at 1–1.5 g/kg of body weight as a single dose	Osmoglyn (Alcon Laboratories, Inc.)
					Isosorbid	1–3 g/kg of body weight orally	Ismotic (Alcon Laboratories, Inc.)
					Mannitol	0.5–2 g/kg body weight intravenously	Mannitol injection solution (Hospira, Inc.)
							Osmitrol (Baxter International, Inc.)
Fixed combinations	Decrease aqueous fluid production and/or increase drainage depending on the individual ingredients in the formulation	27–35.5% reduction		Similar to respective monotherapy counterparts	Timolol maleate and dorzolomide HCI	Twice daily	Cosopt (Merck Sharp & Dohme Corp.)
					Brimonidine tartrate & timolol maleate	Twice daily	Combigan (Allergran, Inc.)
					Brinzolamide and brimonidine	Thrice daily	Simbrinza (Alcon Laboratories, Inc.)
					Latanoprost and timolol	Once daily	Xalacom (Pfizer Ltd.)
					Bimatoprost and timolol	Once daily	Ganfort (Allergan, Inc.)
					Travoprost	One daily	Duotrav (Alcon Canada)
					And timolol

Medical therapies were first introduced for the treatment of glaucoma in 1862, with the discovery of miotic agents [Realini, 2011]. In 1901, epinephrine was discovered as an adrenergic agent with IOP-lowering effects. Systemic carbonic anhydrase inhibitors were discovered the early 1950s [Becker, 1954]. Glaucoma drug therapy development accelerated after the approval of topical timolol for the treatment of glaucoma in 1978. Prostaglandin analogs were incidentally discovered to have IOP-lowering effects and became available in 1996 [Camras and Bito, 1981]. Medical therapy remains the first-line intervention in most cases of glaucoma [Higginbotham, 1998]. This article aims to provide an evidence-based review of the most current medical therapies available for the treatment of POAG.

Prostaglandin analogs

Prostaglandins are a group of lipid compounds derived from arachidonic acid. Within the eye, prostaglandins lower IOP by allowing for enhanced uveoscleral outflow. Possible mechanisms include relaxation of the ciliary muscle and remodeling of extracellular matrix tissue within the ciliary body leading to increased aqueous outflow via this route [Toris et al. 2008]. Prostaglandin analogs are administered as topical eye drops. Currently available agents include latanoprost (Xalatan; Pfizer, Inc., New York, NY, USA), bimatoprost (Lumigan; Allergan, Inc., Irvine, CA, USA), travoprost (Travatan; Alcon Laboratories, Inc., Fort Worth, TX, USA), tafluprost (Zioptan; Merck Sharp & Dohme Corp, North Wales, PA, USA), and unoprostone (Rescula; Sucampo Pharma Americas, LLC, Bethesda, MD, USA). The agents are dosed once daily except for unoprostone which requires twice-daily administration.

As a medication class, prostaglandin analogs offer exceptional IOP-lowering efficacy. In a well-designed meta-analysis of randomized clinical trials comparing the efficacy of the most frequently prescribed glaucoma drugs with placebo, van der Valk and colleagues reported that the prostaglandin analogs, bimatoprost, travoprost, and latanoprost were most effective in reducing IOP [van der Valk et al. 2005]. These agents achieved an IOP percentage reduction ranging from 28% to 31% from trough to peak time points, respectively. This percentage lowering translated to a range of 6.5–8.4 mmHg of reduction at trough and peak time points, respectively. The majority of trials comparing the efficacy of bimatoprost, travoprost, and latanoprost have reported an equivalent degree of IOP reduction. Parrish and colleagues performed a 12-week, randomized, masked-evaluator, multicenter study comparing the three agents at four time points in the diurnal period in 410 patients. Importantly, baseline IOPs were similar in each treatment group at each time point [Parrish et al. 2003]. The overall mean IOP-lowering achieved by the respective agents was similar throughout the diurnal period (8.6 ± 0.3 mmHg, 8.7 ± 0.3 mmHg, 8.0 ± 0.3 mmHg lowering for patients treated with latanoprost, bimatoprost, and travoprost, respectively; p = 0.128). In addition, similar time-matched IOP lowering was achieved by each of the agents at 08:00, 12:00, 16:00, and 20:00. Few studies have reported greater IOP-lowering efficacy with bimatoprost compared with latanoprost [Cheng and Wei, 2008; DuBiner et al. 2001; Gandolfi et al. 2001; Noecker et al. 2003]. However, some of these studies may have been limited by a post hoc nature of analysis and differences in baseline IOPs among treatment groups [DuBiner et al. 2001; Gandolfi et al. 2001]. Tafluprost is the most recently introduced prostaglandin analog and is therefore less well studied. Studies performed to date suggest similar IOP-lowering efficacy when compared to latanoprost and travoprost [Mizoguchi et al. 2012; Uusitalo et al. 2010b]. Schnober and colleagues did report slightly greater IOP reduction with travoprost compared with tafluprost after 6 weeks of therapy, but respective baseline IOPs in each of the treatment groups were not reported [Schnober et al. 2010].

The IOP reduction achieved with unoprostone, which requires a twice-daily dosing regimen, is less than other agents within the prostaglandin class. Jampel and colleagues compared the IOP-lowering efficacy of latanoprost and unoprostone in a prospective, 8-week, randomized clinical trial in 165 patients among 24 clinical sites [Jampel et al. 2002]. The group reported mean IOP reduction of 28% for patients randomized to latanoprost compared with 15% for patients randomized to unoprostone (p ≤ 0.001). Further study revealed similar observations, where approximately 18% mean IOP reduction from baseline was achieved with unoprostone monotherapy [Nordmann et al. 2002].

Prostaglandin analogs have also been found to be efficacious during the nocturnal period. Liu and colleagues reported that latanoprost provided significant IOP reduction compared with time-matched values throughout the nocturnal period in 18 patients undergoing a sleep laboratory study with IOP measured by pneumotonometry in the supine position [Liu et al. 2004]. Further studies have confirmed that prostaglandin analogs are effective in providing 24-hour IOP reduction [Gulati et al. 2012].

As a class, the prostaglandin analogs are relatively well tolerated. The most common ocular adverse events occurring in association with prostaglandin analog therapy include mild conjunctival hyperemia, darkening of the irides, hypertrichosis and hyperpigmentation of the eyelashes [Novack et al. 2002]. The agents may potentiate the development of macular edema in patients that have undergone cataract surgery with a compromised posterior capsule [Halpern and Pasquale, 2002]. Recent case series suggest an association between prostaglandin use and periorbital fat atrophy, which may be partially reversible upon discontinuation of the offending agent [Filippopoulos et al. 2008; Jayaprakasam and Ghazi-Nouri, 2010].

Conjunctival hyperemia and ocular surface effects may relate to the vasodilatory properties of the prostaglandin molecule [Alm et al. 2008] or to preservatives present in the solution [Labbe et al. 2006; Uematsu et al. 2010]. Latanoprost, travoprost, and bimatoprost are preserved with benzalkonium chloride (BAK), which has been implicated as a potentially toxic molecule to the conjunctival and corneal epithelium [Labbe et al. 2006; Uematsu et al. 2010]. A more recent formulation of travoprost (Travatan-Z; Alcon Laboratories, Inc., Fort Worth, TX, USA) does not contain BAK, but rather a proprietary preservative (SofZia; Alcon Laboratories Inc., Fort Worth, TX, USA), which may be less toxic to the ocular surface. Aihara and colleagues reported a significantly lower incidence of corneal and conjunctival epitheliopathy in patients treated with SofZia-preserved travoprost compared with BAK-preserved latanoprost in a prospective randomized single-masked study of 220 subjects [Aihara et al. 2013]. Tafluprost is a prostaglandin analog that is available as a preservative-free formulation (Zioptan; Merck Sharp & Dohme Corp., North Wales, PA, USA). Uusitalo and colleagues reported a decrease in the signs and symptoms of ocular surface disease in 158 patients switched from a preserved prostaglandin analog to preservative-free tafluprost [Uusitalo et al. 2010a]. Recently, preservative-free formulations of bimatoprost and latanoprost have also become available. These agents have shown similar efficacy to preserved agents in the same medication class [Cucherat et al. 2013; Day et al. 2013]. Systemic adverse effects related to topical prostaglandin use are relatively rare and include flu-like symptoms, muscle/joint pain, and allergic skin reaction [Novack et al. 2002]. Owing to their superior IOP-lowering efficacy, minimal risk of ocular and systemic side effects, and convenient once daily dosing regimen, prostaglandin analogs are often employed as first-line agents in the treatment of POAG.

Beta-blockers

Epithelial cells of the ciliary body express beta-1 and beta-2 adrenergic receptors. Interaction of catecholamines with the beta adrenergic receptors leads to the activation of cAMP, a second messenger involved in the activation of protein kinase A, which results in the production and secretion of aqueous humor in an energy-dependent manner [Coca-Prados and Escribano, 2007]. Beta-blockers are synthetic organic molecules that inhibit the binding and action of endogenous catecholamines, epinephrine, and nor-epinephrine to beta-1 and/or beta-2 receptors. Those that bind to both classes of beta adrenergic receptors are termed as nonselective and those that bind to only one type are termed selective beta-blockers [Gupta et al. 2008]. Currently available nonselective topical beta-blockers include timolol (Timoptic 0.25% and 0.5%; Aton Pharma, Lawrenceville, NJ, USA), Betimol 0.25% and 0.5% (Vistakon Pharmaceuticals, LLC, Jacksonville, FL, USA), and Istalol 0.5% (Bausch & Lomb Pharmaceuticals, Inc., Tampa, FL, USA), Levobunolol (Betagan 0.25% and 0.5%; Allergan, Inc., Irvine, CA, USA), Carteolol 1% (Ocupress; CIBA Vision Sterile Mfg., Mississauga, ON, Canada), and Metipranolol 0.3% (OptiPranolol; Bausch & Lomb Pharmaceuticals, Inc., Tampa, FL, USA). Betaxolol is a selective beta-blocker and is marketed as Betoptic 0.25% and 0.5% (Alcon Laboratories, Inc., Fort Worth, TX, USA).

Although the standard starting dose for Timoptic and Betimol is one drop of 0.25% in the affected eye(s) administered twice daily, clinicians may often start therapy with a single daily dose. If the clinical response is not adequate, the dosage may be increased to one drop of 0.5% solution in the affected eye(s) administered twice daily.

Beta-blockers have been successfully employed in reducing IOP by an average of 20–30% from baseline levels. In a recent meta-analysis examining several randomized placebo-controlled trials which employed glaucoma drugs, van der Valk and colleagues have shown that timolol reduces IOP by 27% at peak and 26% at trough, translating to an IOP reduction of 6.9 mmHg at both time points [van der Valk et al. 2005]. Betaxolol was found to reduce IOP by 26% and 23% at peak and trough, resulting in IOP reductions of 6.0 and 5.2 mmHg at peak and trough, respectively. In a six-month, double-masked, multicenter clinical trial, Camras compared the efficacy of timolol and latanoprost in 268 patients with ocular hypertension and POAG. The patients received either latanoprost once daily or timolol 0.5% twice daily for 6 months [Camras, 1996]. While IOP was significantly reduced from baseline (p < 0.001) and maintained over 6 months in both treatment arms, latanoprost reduced IOP by 6.7 ± 3.4 mmHg when compared with timolol which reduced IOP by 4.9 ± 2.9 mmHg (p < 0.001). Patients treated with timolol were more likely to experience a decrease in pulse rate, but experienced milder conjunctival hyperema when compared with patients treated with latanoprost. In a 6-month double-blind study of 29 patients, Stewart and colleagues compared the effect of timolol 0.5% with betaxolol 0.5% and found that both were similarly effective in reducing IOP [Stewart et al. 1986]. Timolol reduced IOP from a baseline level of 27.6 ± 0.3 mmHg by 7.4 ± 0.8 mmHg (p < 0.001) and betaxolol reduced IOP from a baseline level of 29.0 ± 1.00 mmHg by 7 ± 0.8 mmHg at 26 weeks (p < 0.001). Both drugs were well tolerated with similar systemic side effects. Hence, betaxolol has clinical benefits in reducing IOP similar to timolol with no statistically significant between the two treatments (p = 0.235).

Glaucomatous individuals are often elderly and may be afflicted with co-existing systemic hypertension and treated with systemic beta-blocker therapy. The efficacy of topical brimonidine 0.2%, an alpha-2 selective adrenergic agonist, and timolol 0.5%, was investigated in glaucoma patients on concurrent systemic beta-blocker therapy in two prospective multicenter, randomized, double-masked, 12-month clinical trials [Schuman, 2000]. Patients treated with systemic beta-blocker therapy and also receiving topical timolol experienced a mean IOP reduction of 4.41 ± 0.51 mmHg (19%) from baseline at peak; however, patients who were not on systemic beta-blocker therapy and received timolol experienced a greater IOP reduction of 6.23 ± 0.18 mmHg (25%). The reductions in IOP were similar when measured at trough. Patients treated with brimonidine while on concurrent systemic beta-blocker therapy did not experience a similar reduction in IOP-lowering efficacy. The patients treated with concurrent topical and systemic beta-blocker therapies experienced a significantly greater reduction in heart rate when compared with corresponding patients that received only local therapy. These findings suggest that concurrent systemic beta-blocker therapy reduces the efficacy of topical beta-blockers and compromises their safety profile.

In a study investigating both the diurnal and nocturnal efficacy of timolol, Liu and colleagues measured IOP in 18 patients treated with either latanoprost or timolol over a 24-hour period [Liu et al. 2009]. During the nocturnal period, timolol had no impact on IOP reduction from baseline while latanoprost treatment significantly lowered baseline IOP.

Ocular tolerability of both nonselective and selective beta-blockers is generally good although the formulation of the active ingredient may increase the risk of local irritation. Results from a small clinical study of 30 patients indicated that timolol maleate in potassium sorbate was associated with more ocular stinging and/or burning when compared to timolol hemihydrate and timolol gel-forming solution. However, timolol gel-forming solution was associated with an increased frequency of blurred vision when compared with the other two formulations [Sonty et al. 2009]. These findings were further confirmed in a recent patients’ comfort survey indicating that timolol hemihydrate is associated with less ocular stinging and tearing than timolol maleate in sorbate [Stewart et al. 2013].

Since beta adrenergic receptors are expressed by heart muscles, smooth muscles, airways, arteries, kidneys, and other tissues which are part of sympathetic nervous system, local administration of these agents may cause adverse events upon entering the systemic circulation. Hence, treatment with beta-blockers is generally contraindicated in patients with cardiovascular and/or pulmonary diseases. In a randomized, placebo-controlled double-masked study consisting of 20 healthy subjects, the effect of topical ocular administration of timolol on heart rate, oxygen consumption, exercise duration, systemic blood pressure at rest, and maximal exercise was investigated. A total of 10 subjects received timolol 0.5% twice daily for 4 weeks and 10 subjects received artificial tears as placebo. The timolol group experienced a significant reduction in heart rate (p < 0.05) at rest and maximum exercise after first dose as well as at maximum exercise after chronic dosing for 4 weeks. Similarly, the timolol group experienced a modest albeit statistically significant decrease in oxygen consumption at first dose as well after chronic dosing (p > 0.05). There was no significant impact on systemic blood pressure by timolol [Leier et al. 1986]. To assess the effect of timolol on patients with obstructive pulmonary disease (OPD), Avron and colleagues conducted a case-control study to investigate the effect of timolol on OPD patients receiving bronchodilation treatment. In their study, 47% of glaucoma patients who were on a bronchodilation treatment regimen consisting of xanthines or inhaled steroids who also received timolol experienced an increased risk of pulmonary side effects and need for a different class of bronchodilator than those patients on no glaucoma therapy (odds ratio = 1.47; 95% confidence interval [CI] 1.04–2.09; p = 0.03). These results were not observed with other classes of glaucoma drugs [Avorn et al. 1993]. To examine whether topical administration of beta-blockers had an effect on hospitalization and emergency room visits in glaucoma patients with OPD, Kaiserman and colleagues conducted a historical cohort study of 693 patients with the two co-existing diseases [Kaiserman et al. 2009]. Of all hospitalized and emergently treated glaucoma patients, 544 (78.5%) were treated with topical beta-blockers. Furthermore, only 169 received a selective beta-1 blocker, while the remainder received a nonselective agent. These findings indicate that glaucoma patients with OPD are more likely to be either hospitalized or require an emergency room visit when treated with topical beta-blockers compared with other IOP-lowering agents. Patients treated with a nonselective beta-blocker are at least twice likely to seek hospital care than those treated with a selective agent. Owing to the potential occurrence of these adverse events, caution must be exercised while treating patients with co-existing underlying medical conditions that may be aggravated by topical beta-blockers.

Alpha-agonists

Alpha adrenergic receptors are G-protein-coupled receptors consisting of an alpha-1 receptor present in smooth muscle, heart, and liver and alpha-2 found in the iris, ciliary body, retina and retinal pigment epithelium, platelets, vascular smooth muscle, nerve termini, and pancreatic islets. The physiological ligands are epinephrine and norepinephrine. The activation of alpha-1 receptors leads to vasoconstriction, intestinal relaxation, uterine contraction, and pupillary dilation while the activation of alpha-2 receptors results in vasoconstriction, inhibition of norepinephrine release and insulin secretion. Alpha-2 agonists decrease IOP by constriction of the afferent ciliary process vasculature leading to decreased aqueous humor production and also by increasing uveoscleral outflow [Fudemberg et al. 2008; Toris et al. 1999]. Currently available alpha-agonists include apraclonidine hydrochloride 1% (Iopidine; Alcon Laboratories, Inc., Fort Worth, TX, USA), dipivefrin hydrochloride 0.1% (Propine; Alcon Laboratories, Inc., Fort Worth, TX, USA), and brimonidine tartrate 0.1%, 0.15%, and 0.2% (Alphagan; Allergan, Inc., Irvine, CA, USA). In some markets, topical clonidine is also available. One to two drops of apraclonidine or brimonidine should be instilled in the affected eye(s) two or three times daily; dipivefrin hydrochloride is administered twice daily.

Apraclonidine hydrochloride is a polar derivative of clonidine that has reduced effects on the cardiovascular system. The relatively high frequency of adverse events associated with this agent limit its use in routine clinical care [Stewart et al. 1996]. A substantial proportion of patients treated with apraclonidine 1% for the long term develop ocular allergic reactions presumably related to the adrenergic function of the drug [Butler et al. 1995]. A meta-analysis of published clinical trials indicate that brimonidine is effective as an IOP-reducing agent, demonstrating an ability to reduce baseline IOP by approximately 17% [van der Valk et al. 2005]. Comparative efficacy of brimonidine tartrate 0.2% and timolol 0.5% administered twice daily was investigated in 837 subjects over one year. While IOP reductions were significantly lower (p = 0.04) for the brimonidine-treated group at peak, the timolol-treated group experienced significantly greater reductions at trough (p < 0.001). While 11.5% of brimonidine-treated patients versus only 1% in the timolol-treated group experienced an ocular allergy, timolol-treated subjects were more likely to experience a significant decrease in heart rate (p = 0.001). These findings suggest that brimonidine is a relatively safe long-term IOP-reducing agent, although ocular allergy may lead to discontinuation in some individuals [Katz, 1999].

The effect of brimonidine on IOP during the sleep–wake cycle was investigated prospectively in 15 patients by Liu and colleagues. All patients received bromonidine tartrate 0.1% in both eyes three times a day 8 hours apart in a sleep laboratory and underwent baseline and post-treatment 24-hour IOP measurements in the sitting and supine positions [Liu et al. 2009]. Brimonidine treatment significantly reduced (p < 0.01) mean IOP from a baseline value of 19.2 ± 2.7 mmHg to 16.8 ± 2.8 mmHg (12.5% reduction) during diurnal time points in the seated position. However, the agent had no effect on baseline IOP when post-treatment measurements were obtained in the supine position at night time.

The most common preservatives that are used in ophthalmic preparations for glaucoma medicines include BAK, stabilized oxychloro complex (Purite; Allergan, Inc., Irvine, CA, USA), chlorobutanol, sodium perborate, and others. A meta-analysis of two phase III studies that tested the safety and tolerability of brimonidine 0.2% in BAK, brimonidine 0.15% in Purite, and brimonidine 0.1% in Purite indicated that these preparations have similar efficacy [Cantor et al. 2009]. Treatment-related adverse events were less with the Purite formulation than with BAK-preserved formulations. Furthermore, although the adverse events are similar between 0.1% and 0.15% brimonidine in Purite formulations, treatment-related systemic adverse events were less with 0.1% brimonidine in Purite when compared with 0.15% brimonidine in Purite. In a separate study, brimonidine in Purite demonstrated a more favorable safety and tolerability profile than the BAK formulation with a better satisfaction and comfort rating [Katz, 2002]. The ocular tolerability with Purite formulations may be superior to BAK as the active component in this preservative dissociates into water, sodium and chloride ions, and oxygen when exposed to light at the time of administration.

Common adverse local events with brimonidine 0.2% include blepharitis, blepharoconjunctivitis, conjunctivitis, hyperemia, blurry vision, dry mouth, and ocular allergy. These events may result in discontinuation of treatment in approximately 12% of patients [Fudemberg et al. 2008; Katz, 1999].

Alpha-agonists are structurally similar to medications used for the treatment of systemic hypertension. Hence, the most common systemic effects include chest heaviness or burning, palpitations, systemic hypotension, orthostatic hypotension, rhinitis, dyspnea, pharyngitis, dry nose, facial edema, taste perversion, depression, lethargy, abnormal coordination, asthenia, dizziness, headache, insomnia, malaise, nervousness, and paresthesias.

Carbonic anhydrase inhibitors

Carbonic anhydrase generates Na⁺ and HCO₃^– ions, allowing water to enter the ciliary epithelial cells, leading to aqueous humor production. Carbonic anhydrase inhibitors are small chemical compounds that inhibit the production of aqueous humor production by inhibiting the action of the enzyme carbonic anhydrase. Currently available topical carbonic anhydrase inhibitors include brinzolamide 1% (Azopt; Alcon Laboratories Inc., Fort Worth, TX, USA) and dorzolamide 2% (Trusopt; Merck Sharp & Dohme Corp., Whitehouse Station, NJ, USA) These agents are typically dosed in the affected eye two to three times daily.

A meta-analysis on the efficacy of several ocular hypotensive agents indicated that brinozolamide reduced IOP by 17% from baseline at both peak and trough while dorzolamide reduced IOP by 22% at peak [van der Valk et al. 2005]. Sall and colleagues tested the safety and efficacy brinzolamide 1% ophthalmic suspension given either two or three times daily and dorzolamide 2% given twice daily to patients with open angle glaucoma in a randomized placebo-controlled, multicenter, double-masked clinical trial [Sall, 2000]. Both treatments were found to be similarly effective in reducing IOP, but ocular discomfort (burning and stinging) was experienced in 12.2% versus 3% of patients who received dorzolamide and brinzolamide, respectively.

A recent meta-analysis on the safety and efficacy of carbonic anhydrase inhibitors versus alpha-2 adrenergic agonists versus beta adrenergic antagonists as adjunctive therapy to prostaglandin analogs indicated that the mean diurnal IOP reduction was similar among these three therapeutic combinations. However, IOP reduction at trough was greater in patients treated with either a carbonic anhydrase inhibitor or beta-blocker as adjunctive therapy to a prostaglandin analog, compared with alpha-agonists. Ocular discomfort was more common with alpha-2 adrenergic agonist treatment. Fatigue, weakness, and dizziness were more pronounced with alpha adrenergic agonists and beta adrenergic blockers, while taste disturbances were more common with topical carbonic anhydrase inhibitors [Tanna et al. 2010]. Topical carbonic anhydrase inhibitors have also demonstrated nocturnal IOP-lowering efficacy [Orzalesi et al. 2000].

Barnebey and Kwok conducted a prospective, open-label study to assess patients’ acceptance and comfort when switched from dorzolamide to brinzolamide. Sixty-nine percent of the 447 patients reported an improvement in comfort rating when switched to brinzolamide and 59% preferred brinzolamide to dorzolamide, with 73% continuing with brinzolamide therapy [Barnebey and Kwok, 2000].

Carbonic anhydrase inhibitors such as acetazolamide and methazolamide have been used either orally or parenterally for adjunctive treatment of altitude sickness, drug-induced edema, idiopathic intracranial hypertension, and glaucoma. As sulfonamide derivatives, these agents are associated with severe adverse events including anaphylaxis, fever, rash, crystalluria, renal calculus, bone marrow depression, thrombocytopenic purpura, hemolytic anemia, metabolic acidosis, electrolyte imbalance, leukopenia, pancytopenia, and agranulocytosis. Unlike acetazolamide, methazolamide has a longer half-life and undergoes first-pass hepatic metabolism, reducing the overall risk of adverse events.

Miotics

Miotic agents include pilocarpine, carbachol, echothiophate, and demecarium. These drugs cause contraction of the ciliary muscle and scleral spur leading to mechanical opening of the trabecular meshwork and facilitation of aqueous humor outflow. Several common side effects such as pupillary constriction, ocular burning, brow ache, and reduced night vision limit the widespread use of these agents for glaucoma therapy [Gupta et al. 2008].

Hyperosmotics

The hyperosmotic agents reduce IOP by lowering the aqueous fluid volume in the eye and are typically given in emergency and/or preoperative situations to reduce IOP transiently. This class of drugs includes the orally prepared agents, glycerin and isosorbide, and also mannitol, which is administered intravenously. Glycerin is administered orally at 1–1.5 g/kg of body weight as a single dose and isosorbide is administered 1–3 g/kg of body weight. Mannitol is usually administered intravenously 0.5–2 g/kg of body weight. Potential side effects of this medication class include fluid and electrolyte imbalance, metabolic acidosis, electrolyte loss, dry mouth, marked diuresis, urinary retention, peripheral edema, headache, blurred vision, convulsions, nausea, vomiting, dehydration, hypotension, and tachycardia.

Fixed combinations

Several patients do not respond to one type of medication and need a combination therapy for effective IOP control. It has been demonstrated that fixed combination agents reduce IOP more effectively than either of their component medications used separately as monotherapy [Higginbotham, 2010; Woodward and Chen, 2007]. Several fixed combination glaucoma drugs are currently available in the USA and include: Cosopt (timolol maleate 0.5% and dorzolamide hydrochloride 2%; Merck Sharp & Dohme Corp., North Wales, PA, USA), Combigan (brimonidine tartrate 0.2% and timolol maleate 0.5%; Allergan Inc., Irvine, CA, USA), and Simbrinza (brimonidine tartrate 0.2% and brinzolamide 1%; Alcon Laboratories, Inc., Fort Worth, TX, USA). Cosopt is the only fixed-combination agent available as a preservative-free formulation (Cosopt PF; Merck Sharp & Dohme Corp., North Wales, PA, USA). Other fixed combination drugs that are available outside the USA include: Xalacom (latanoprost 0.005% and timolol 0.5%; Pfizer Ltd, Kent, NJ, USA), Ganfort (bimatoprost 0.03% and timolol 0.5%; Allergan Ltd, Buckinghamshire, UK), and Duotrav (travoprost 0.004% and timolol maleate 0.5%; Alcon Canada, Mississauga, ON, Canada).

Preservative-free therapy

Ocular surface disease (OSD) is relatively prevalent among the elderly population and glaucoma patients in particular. The preservative agents contained in most topical IOP-lowering medical formulations may exacerbate pre-existing OSD leading to ocular symptoms as well as decreased medication compliance [Anwar et al. 2013]. BAK is the most common ophthalmic preservative and also has been most implicated as a causative agent in exacerbation of OSD. Recent studies have suggested that BAK may also be neurotoxic to corneal tissues [Sarkar et al. 2012]. In addition, daily long-term exposure to BAK may adversely affect glaucoma surgical outcomes [Broadway et al. 1994]. The recent availability of preservative-free topical glaucoma therapy has offered an important treatment option in this regard. Preservative-free IOP-lowering medicines include: tafluprost (Zioptan; Merck Sharp & Dohme Corp., North Wales, PA, USA), bimatoprost (Bimatoprost PF; Allergan, Inc., Irvine, CA, USA), latanoprost, timolol (Timoptic in Ocudose; Valeant Ophthalmics, Bridgewater, NJ, USA), and fixed combination dorzolamide/timolol (Cosopt PF; Merck Sharp & Dohme Corp., North Wales, PA, USA). Prior crossover studies have demonstrated a decrease in the signs and symptoms of OSD after switching glaucomatous patients from preserved to nonpreserved topical therapy [Januleviciene et al. 2012]. The degree of IOP-lowering appears to be similar between preserved and nonpreserved agents [Cucherat et al. 2013].

Medical therapies on the horizon

Advances in cellular and molecular biology have aided the development of next-generation target-specific intervention strategies for glaucomatous diseases.

Rho-kinase Inhibitors

Rho-kinases are downstream effectors which regulate smooth muscle contractions [Rao and Epstein, 2007]. A novel class of rho-kinase inhibitors, AR-12286 ophthalmic solution at 0.05%, 0.1%, and 0.25%, was investigated for its ability to reduce IOP in 89 patients with ocular hypertension and glaucoma [Williams et al. 2011]. The three different concentrations of the drug were administered to different groups of patients once daily in the morning for 7 days, then once daily in the evening for 7 days, then twice daily for 7 days. AR-12286 at 0.25% produced the greatest IOP reduction (up to 6.8 mmHg reduction from baseline or 28%). The only minor side effect included a transient conjunctival hyperemia which lasted for 4 hours in a minority of patients.

Neuroprotective agents

Efforts have been directed to identify neuroprotective agents that may reverse neuroretinal axonal cell injury and prevent damage to neighboring axons in order to protect retinal ganglion cells. These agents include those that have direct protective effects such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and the neurotrophins NT-3, NT-4 and NT-5 as well as those which inhibit free radicals and apoptosis [Chang and Goldberg, 2012]. The deprivation and/or dysfunction of ciliary neurotrophic factor (CNTF) have been shown to cause glaucoma and supplementation of CNTF may result in neuroprotection [Johnson et al. 2011; Wen et al. 2012].

Gene therapy

Glaucoma results from a variety of causes including insufficiency or dysfunction of one or more neurotrophic factors and/or the defective cellular function of ciliary muscles or trabecular cells. Any of these specific defects are potential targets for gene therapy [Demetriades, 2011]. Gene therapy has been tried with reasonable successes in other fields of medicine and is being investigated as a potential glaucoma therapy in experimental studies [Alqawlaq et al. 2012]. Viral as well as nonviral tissue-specific vectors have been employed along with nanoparticle delivery systems to target the functional gene of a specific cell and tissue type. Gene therapy along with currently well-accepted therapies holds promise as a potentially safe and long-term effective intervention strategy for the prevention and treatment of glaucoma.

Conclusion

Since the days of epinephrine in the 1900s to treat glaucoma, tremendous advances have been made to develop effective classes of glaucoma drugs designed to provide long-term IOP control for treatment of the disease. These agents are available as monotherapy and fixed combination therapies. Although newer formulations appear safer for the ocular surface, local and systemic adverse effects still may occur. Advances in cellular and molecular biology, gene therapy, and nanotechnology as well as other disciplines have poised the scientific community to explore new approaches that are noninvasive and cell-specific to develop next-generation intervention strategies for glaucoma.

Footnotes

Funding

The authors received an unrestricted departmental grant from Research to Prevent Blindness, New York, USA.

Conflict of interest statement

Dr Aref has served as a paid speaker for Alcon Laboratories Inc. and Merck Sharp & Dohme, Inc. Mr Sambhara has no conflicts of interest to declare.

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