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REVIEW ARTICLE
Update on the Medical Treatment of Primary
Open-Angle Glaucoma
Anjum Cheema, MD,* Robert T. Chang, MD,† Anurag Shrivastava, MD,‡ and Kuldev Singh, MD, MPH†
Abstract: Glaucoma comprises a group of progressive, neurodegenerative disorders characterized by retinal ganglion cell death and nerve
fiber layer atrophy. Several randomized controlled trials have consistently demonstrated the efficacy of intraocular pressure lowering to
slow or halt the measurable progression of the disease. Medical therapy,
in places where it is easily accessible, is often the primary method to
lower intraocular pressure. We review the medical options currently
available and possible future options currently in development. The
5 contemporary classes of topical agents in use include prostaglandin
analogs, beta blockers, carbonic anhydrase inhibitors, alpha agonists,
and cholinergics. In addition, several fixed combination agents are commercially available. Agents from each of these classes have unique mechanisms of action, adverse effects, and other characteristics that impact
how they are used in clinical practice. Despite the plethora of medical
options available, there are limitations to topical ophthalmic therapy
such as the high rate of noncompliance and local and systemic adverse
effects. Alternate and sustained drug delivery models, such as injectable agents and punctal plug delivery systems, may in the future alleviate some such concerns and lead to increased efficacy of treatment
while minimizing adverse effects.
Key Words: glaucoma, topical therapy, adverse effects,
sustained drug delivery, rho kinase
(Asia Pac J Ophthalmol 2016;5: 51–58)
T
he term glaucoma comprises a large number of primary and
secondary causes of progressive retinal ganglion cell death
and nerve fiber layer atrophy leading to increasing peripheral
and central visual field loss over time and, in some cases, leading
to blindness. The hallmark of glaucoma is the presence of
cupping of the neuroretinal rim, particularly superiorly and inferiorly, and has among its risk factors advanced age, thin central corneal thickness, high intraocular pressure (IOP), and
positive family history. There are other potential risk factors
whose role is not yet clearly defined, among which notably are
reduced ocular perfusion pressure and the possibility that lower
intracranial pressure or increased translaminar cerebrospinal
fluid (CSF) gradient differential may be associated with increased risk of glaucomatous progression. Among all glaucoma
population-based studies around the world, the prevalence of
glaucoma increases with age and with increasing IOP. In 2013,
a meta-analysis of 50 population-based studies estimated the
From the *Department of Ophthalmology, Kaiser Permanente, Atlanta, GA;
†Department of Ophthalmology, Stanford University School of Medicine,
Stanford, CA; and ‡Department of Ophthalmology, Albert Einstein College
of Medicine/Montefiore Medical Center, Bronx, NY.
Received for publication October 7, 2015; accepted December 22, 2015.
Supported by a grant from Research to Prevent Blindness (to the Ophthalmology
Department at the Albert Einstein College of Medicine/Montefiore
Medical Center).
The authors have no conflicts of interest to declare.
Reprints: Anjum Cheema, MD, 1412 Bellsmith Dr, Roswell, GA 30076. E-mail:
[email protected].
Copyright © 2016 by Asia Pacific Academy of Ophthalmology
ISSN: 2162-0989
DOI: 10.1097/APO.0000000000000181
global prevalence of open-angle glaucoma (OAG) in people
aged 40 to 80 years to be 3.54% (95% confidence interval,
2.09–5.82) or approximately 64.3 million, rising to an estimated
76 million by 2020.1 The total affected population is much
larger when considering all types of glaucomas, including
angle-closure, neovascular, uveitic, steroid-induced, postsurgical,
etc. In fact, a Market Scope research report expects the global
glaucoma pharmaceutical market to climb from roughly $4.7
billion in revenues in 2015 to nearly $6.1 billion in 2020 at a
compounded annual rate of 5.1%.2 Ideally, glaucoma needs to
be diagnosed as early as possible to preserve the most vision
during a patient’s lifetime. At present, there is no way to functionally restore vision lost from glaucoma but regenerative therapy may be possible in the future. The goal of medical treatment
for glaucoma is to lower an individual’s eye pressure to a level
that preserves visual function to reduce morbidity such as diminished psychosocial functioning3 and falls,4 while maintaining a
good quality of life. Because of the asymptomatic and insidious
nature of most forms of glaucoma, particularly early in the disease
process, screening eye examinations including IOP checks and
examination of the optic nerve are commonly used to first make
a diagnosis. Intraocular pressure is a well-established, modifiable
risk factor for glaucomatous optic neuropathy, and medical therapy to reduce IOP has been proven to slow disease progression
and reduce vision loss. However, occasionally, some patients
still worsen despite maximal IOP lowering, underpinning the
complex pathophysiology of accelerated ganglion cell loss in
this multifactorial neurodegenerative disease process. This
update on the medical treatment of primary OAG (POAG) will review the rationale for medical therapy, describe a practical clinical approach to deciding whether medical therapy should be
initiated or changed, and provide an overview of current and
new glaucoma agents on the horizon.
RATIONALE FOR TREATMENT
As mentioned earlier, IOP lowering is the mainstay of treatment for glaucoma and medical, laser, and surgical methods of
IOP lowering have all been shown in several randomized, controlled trials to reduce progression of vision loss. In a landmark
study entitled “Latanoprost for open-angle glaucoma (UKGTS):
a randomized, multicentre, placebo-controlled trial” in 2015,
Garway-Heath et al5 published the first masked, randomized
controlled trial (N = 516) providing evidence that latanoprost
preserved visual function better than placebo for a 2-year period
in patients with mild to moderate glaucoma. Given the ethical concern for the placebo arm subjects suffering vision loss during the
trial, the authors designated the primary endpoint as a median
visual field change of 1.6 dB in a single eye. All participants
were monitored much more closely than routine clinical practice
(16 fields in 24 months) and time to progression was confirmed
by at least 4 visual fields. This reduced the chance that any progression in the control arm would meaningfully affect a participant’s visual quality of life. In fact, no measurable visual
field deterioration was detected in two thirds of the placebo
group after 2 years (mean IOP, 20.1 ± 4.8 mm Hg). The only other
previously published glaucoma clinical trials with untreated
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control groups were a small study by Holmin et al6 and the multicenter Early Manifest Glaucoma Trial.7
The Early Manifest Glaucoma Trial was a US-Swedish collaborative study performed in the early 1990s, which concluded
that lowering IOP effectively slowed visual field progression in
early stage glaucoma. Before this study, the natural history of
untreated early glaucoma was not well defined, and it was equally
unclear whether early intervention made a difference in terms of
visual preservation. From the 255 patients randomized to either laser trabeculoplasty and topical betaxolol hydrochloride or no
treatment, the investigators found that an IOP reduction by
a mean of 25% (5.1 mm Hg) reduced progression from 62%
to 45% in the treated versus control groups, respectively, at
6-year follow-up. Criteria for visual field progression were
computer based and defined as the same 3 or more test point locations, showing significant deterioration from baseline in glaucoma
change probability maps from 3 consecutive tests. As soon as any
progression was detected in the control group, these individuals
were also offered treatment. On average, it took 4 years to detect
early disease advancement.
Multiple other large glaucoma studies including the Advanced Glaucoma Intervention Study, which reported findings
in 1998,8 the Collaborative Initial Glaucoma Treatment Study
in 2001,9 and the Ocular Hypertension Treatment Study in
2002,10 all had treatment arms that demonstrated the benefit
of lowering eye pressure at various stages of the disease. The primary aim of the Advanced Glaucoma Intervention Study was to
determine whether laser trabeculoplasty or trabeculectomy would
be preferred in patients with uncontrolled, advanced glaucoma.
When IOP was stratified, it was shown that the group with lowest
IOP had less overall change in visual field progression.8 Collaborative Initial Glaucoma Treatment Study sought to clarify whether
surgical therapy or medical therapy was preferable in newly diagnosed glaucomatous patients. Patients were randomized to either
medical therapy or trabeculectomy. Although greater IOP reduction was observed in the surgical arm at all time points, there
was no difference in visual field progression. Notably, both arms
had substantial IOP lowering (46% in the surgical arm, 38% in
the medical arm).9 The Ocular Hypertension Treatment Study explored whether IOP lowering in ocular hypertensive patients decreased the likelihood of developing glaucoma. Patients were
randomized to 20% IOP lowering or no treatment. The treatment
arm had a 50% relative reduction in the incidence of conversion
to glaucoma.10
Likewise, IOP lowering has been observed to be beneficial
in eyes with normal- or low-tension glaucoma. The Collaborative
Normal-Tension Glaucoma Study, published in 1998,11 established
that among more than 140 patients with normal pressure and
either documented progression, fixation-threatening field defects,
or presence of disc hemorrhages, a 30% IOP reduction dropped
the rate of disc or field progression from 35% in the observation
group to 12% in the treated group, after correcting for the effect
of cataract, which was greater in the treated group. More recently
in 2011, the Low-Pressure Glaucoma Treatment Study, consisting of 178 patients randomized to 2 different treatment groups,
determined that the use of brimonidine 0.2% was statistically
less likely to be associated with progressive visual field loss
than treatment with timolol 0.5%, even though there was no significant difference between the IOP-lowering effects of the 2 drugs
in this multicenter, randomized controlled clinical trial.12 All of
these major studies provided evidence in support of IOP reduction therapy in glaucoma. With the discovery of lower cerebral
spinal pressure (CSF) by computed tomography cisternography in a small group of patients with normal-tension glaucoma13 and the retrospective finding of lower CSF pressure in
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POAG patients compared with that in nonglaucomatous controls,14 there is increasing evidence that translaminar (IOP-CSF)
gradient pressures may explain why further IOP lowering helps
even at “normal” pressures.
CLINICAL APPROACH
Because there is no perfect biomarker for glaucoma or a
single test that can confirm active disease, the decision to initiate or change therapy for glaucoma is usually based on the following factors: the life expectancy and quality of life of the
patient, the IOP, the optic nerve appearance in combination with
the retinal nerve fiber layer thickness, and visual field results.
The current goal of glaucoma therapy is to lower IOP to a level
that will preserve visual function for a patient’s lifetime.15
There is no way to accurately predict, prospectively, which
level of IOP will guarantee that one will attain such a goal. This
is because a safe IOP range for one patient’s optic nerves may
not be generalizable to all patients. Reliable serial testing
for glaucomatous progression via optic nerve visualization,
optic nerve and retinal nerve fiber layer imaging [optical coherence tomography (OCT) or confocal scanning laser ophthalmoscopy], and visual field examination forms the cornerstone
for personalized glaucoma management. Also, given the limited snapshots of suboptimal “true IOP” data, multiple preferred practice patterns have set forth guidelines for establishing
a baseline IOP and estimated target pressure ranges on the
basis of the severity of glaucoma.16,17 Staging of glaucoma
patients is commonly divided into suspect, mild, moderate, and
severe, on the basis of the estimated vertical cup-to-disc (C/D)
ratio and visual field mean deviation (MD). Many research studies
choose the same visual field mean deviation cutoffs with early
MD better than −6 dB and not within 10 degrees of fixation,
moderate MD −6 to −12 dB, and advanced MD worse than
−12 dB or defect within 10 degrees of fixation. These definitions
are loosely based on the Hodapp Parrish Anderson glaucoma
grading scale criteria.18
The initial target pressure range is a suggested upper limit
of IOP on the basis of longevity, quality of life, and risk factors
for progression. This estimate is constantly adjusted during
the course of follow-up, on the basis of disease stability or progression as determined by serial structure-function testing.19
However, what glaucoma specialists are really after is the estimated rate of glaucoma progression in a given eye, and multiple averaged pressure readings merely provide an estimate of
the response to a given therapy. Thus, an alternate way of looking at target IOP is to follow a more dynamic treatment paradigm20 in which, instead of setting a periodically modified
target IOP goal, a clinician makes an assessment on each patient visit regarding whether lowering a patient’s IOP with additional therapy is justified on the basis of the risk-benefit
tradeoff at a given point in time based on a variety of patientspecific factors. With multiple OCT measurements of the retinal nerve fiber layer and visual field index information for
individually calculated rates of progression, therapy can be personalized to each patient. Thus, requiring every mild, moderate, or severe glaucoma patient to have a specific target IOP
range based on severity may be suboptimal in some circumstances. A cookbook approach to glaucoma patient care, particularly in terms of setting IOP goals, may lead, in some situations,
to inappropriate care.
Medication choices in glaucoma care are affected by efficacy,
safety, tolerability, compliance, persistence, and affordability—
not necessarily in that order. Glaucoma therapy is usually chronic;
and thus, it is important to check IOP multiple times to monitor
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Asia-Pacific Journal of Ophthalmology • Volume 5, Number 1, January/February 2016
a medicine’s therapeutic effect, while concomitantly providing
serial testing for disease progression.21
MEDICAL TREATMENT OPTIONS AVAILABLE
Currently, there are 5 classes of medications available to
lower IOP. The efficacy, mechanism of action, and adverse
effects of each class will be reviewed, followed by a short discussion on how to determine the optimal medicine depending
on patient-specific and disease-specific variables.
Prostaglandin Analogs
Prostaglandin analogs (PGAs) or hypotensive lipids, first
introduced into the US market in 1996, have become the most
common choice for initial therapy for glaucoma. Although
the exact mechanism of action remains to be definitively elucidated, it is thought that these agents increase uveoscleral outflow by binding to receptors on the ciliary body, leading to
upregulation of metalloproteinases and subsequent remodeling of the extracellular matrix to allow for increased aqueous
humor outflow.22
There are 5 commercially available PGAs, including latanoprost, bimatoprost, travoprost, unoprostone, and tafluprost. Each
is dosed nightly, with the exception of unoprostone, which is
dosed twice daily. The most commonly used PGAs in clinical
practice are latanoprost, bimatoprost, and travoprost. Each of
these has been shown in prospective randomized controlled
trials to be more efficacious as monotherapy compared with
timolol, which was the most common first-line therapy before
the introduction of PGAs. Latanoprost administered nightly
produced a mean IOP reduction of 6.7 ± 3.4 mm Hg (27%)
compared with 4.9 ± 2.9 mm Hg (20%) with twice daily timolol
after 6 months of treatment.23 Similarly, in a meta-analysis
of studies involving the use of latanoprost, monotherapy in
patients with angle-closure glaucoma showed a 32.5% IOP reduction (−7.9 mm Hg).24 Travoprost 0.004% lowered IOP
from a mean baseline of 26.8 mm Hg to 17.7 to 19.1 mm Hg
(29%–34%) at 1 year, compared with a final IOP of 19.4 to
20.3 mm Hg from a similar baseline of 27.0 mm Hg (25%–28%)
with timolol 0.5%.25 Similarly, bimatoprost produced a greater
mean IOP reduction compared with timolol [8.1 (33%) vs
5.6 (23%) mm Hg, P < 0.001] after 6 months of treatment.26
Although some studies have suggested slightly greater IOP reduction with bimatoprost compared with latanoprost and travoprost,27
other studies have shown similar efficacy among all 3 agents.28
In contrast, tafluprost and unoprostone have less impressive
results. Tafluprost, a preservative-free PGA, was shown to be
noninferior to preservative-free timolol after a 12-week treatment
period, reducing IOP from a baseline of 23.8–26.1 mm Hg to
17.4–18.6 mm Hg compared with a reduction from a baseline
of 23.5–26.0 mm Hg to 17.9–18.5 mm Hg with preservativefree timolol.29 Unoprostone is associated with the least IOP
lowering in this class of outflow drugs. This agent, although
shown to produce clinically significant IOP reductions, was
outperformed by timolol in a 6-month study, lowering IOP
by 4.3 (17.8%) versus 5.8(24.0%) mm Hg with timolol.30
In addition to their impressive efficacy, PGAs tend to be
well tolerated with less than 5% of patients discontinuing treatment due to adverse effects.31 Although systemic adverse
effects are rare, local adverse effects are fairly common, including
conjunctival hyperemia, eyelash growth, and rarely, irreversible
increased iris pigmentation.31 Prostaglandin-associated periorbitopathy, a condition characterized by periorbital fat loss, involution
of dermatochalasis, and deepening of the upper eyelid sulcus, has
increasingly been recognized as a common adverse effect of PGA
© 2016 Asia Pacific Academy of Ophthalmology
Medical Therapies for Primary Open-Angle Glaucoma
therapy.32 Other possible but less definitive adverse effects include
exacerbations of anterior uveitis, herpetic keratitis, and cystoid
macular edema after cataract surgery.31
Beta Blockers
Topical beta blockers (BBs) have been a mainstay of glaucoma treatment since their introduction in 1978. Their mechanism of action is reduced aqueous production via blockade
of β-adrenoreceptors in the ciliary epithelium.33 These agents
are most effective during waking hours but have little effect
during sleep because of naturally reduced aqueous humor
production at night.33 Another factor that sometimes limits
their clinical use as long-term therapy is the relatively high rate
of tachyphylaxis, approaching 50% at 2 years in 1 study.34
Nonselective β1 and β2 antagonists along with selective β1
antagonists are commercially available. Nonselective agents include timolol, levobunolol, metipranolol, and carteolol. Betaxolol
is a selective β1 antagonist. Of these choices, timolol was the
first introduced and remains the most commonly used agent.
Timolol has been shown to reduce IOP by 20% to 35% on average and remains the US Food and Drug Administration’s “criterion standard” drug for glaucoma therapy against which new
medications are commonly judged before approval.31 It is available in 0.25% and 0.5% concentrations used either once daily or
twice daily and once daily gel-forming solutions. Levobunolol,
available in 0.25% and 0.5% solutions typically administered
twice daily, and metipranolol 0.3% administered twice daily
have similar efficacy to timolol.35,36 Carteolol is unique in that
its use is associated with intrinsic sympathomimetic activity
producing an early, transient β-agonist response, which may
partially protect against the systemic adverse effects of other
β antagonists, including reduced pulse and blood pressure.31
Betaxolol is a cardioselective β1 antagonist, formulated to
reduce the incidence of pulmonary β2-mediated adverse
effects. This agent, however, is less effective in terms of IOP
lowering, compared with other nonselective agents, with mean
IOP reductions of 18% to 26%.31,37
Local adverse effects of BBs include conjunctival hyperemia, stinging, superficial punctate keratitis, and dry eye
syndrome.31 They have also been shown to cause transient
blurry vision by inducing higher order aberrations.38 Systemic
adverse effects are an important consideration limiting the usefulness of these agents in certain patients, particularly those
with severe heart disease, asthma, or chronic obstructive pulmonary disease. These possible effects include bradycardia,
arrhythmia, cardiac conduction block, congestive heart failure, bronchospasm, masking of hypoglycemic symptoms in
diabetics, depression, anxiety, impotence, and exacerbation
or unmasking of myasthenia gravis.31
Carbonic Anhydrase Inhibitors
Carbonic anhydrase inhibitors (CAIs) were first introduced in systemic form in 1954 and in topical form more recently in 1994. These agents selectively inhibit carbonic
anhydrase isoenzyme II in the ciliary epithelium, leading to decreased aqueous production.31
Systemic CAIs include acetazolamide and methazolamide. Both are quite effective at lowering IOP, but adverse
effects limit their utility for chronic IOP lowering. In clinical
practice, they are often used as temporizing measures before
surgery. Common adverse effects seen with systemic agents
include paresthesias of the extremities, nausea, vomiting, and
fatigue. More severe adverse effects include renal stones, electrolyte imbalances such as metabolic acidosis, hypokalemia, and
hyponatremia. Rarely, the use of oral CAIs has been associated
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with bone marrow depression resulting in thrombocytopenia,
agranulocytosis, and aplastic anemia. Carbonic anhydrase inhibitors should be avoided in patients with renal dysfunction and in
patients with a sulfa allergy because CAIs are sulfonamides.
The first topical CAI to be introduced was dorzolamide
in 1994, followed by brinzolamide in 1998. Dorzolamide is
approved for thrice a day usage in the United States but is often
used twice a day in other countries. Three times a day dosing
has been found to result in IOP lowering of 18% to 22%
and has been found to be equivalent to betaxolol but slightly
inferior to timolol as monotherapy.39 Brinzolamide is available in suspension form with a physiologic pH of 7.4, causing it to be better tolerated than dorzolamide, which has a
relatively acidic pH of 5.5.40 Brinzolamide has similar efficacy
to dorzolamide.41
Topical CAIs have been found to be systemically safe,
avoiding many of the significant systemic adverse effects of oral
CAIs. Local adverse effects include bitter taste, stinging, burning,
itching, and foreign body sensation. Brinzolamide in particular
has been associated with transient blurry vision, attributed to
increased light scattering.38 There have also been reports of irreversible corneal decompensation in patients with marked endothelial compromise, so topical CAIs should be used with caution
or avoided in this patient group.31,42 Topical CAIs should be used
with caution in patients with sulfa allergies. A recent retrospective study, interestingly, showed that patients with sulfa allergies
had similar rates of adverse reactions to topical CAIs as patients
with nonsulfa-related allergies, suggesting the possibility that
patients with medication allergies of any kind may be more likely
to develop allergies to other agents, without necessarily indicating
that a self-reported sulfa allergy is a contraindication to topical
CAI therapy.43
Adrenergic Agonists
Adrenergic agonists (AAs) are available in both nonselective forms, which target both α- and β-adrenergic receptors,
and selective forms, which target only α-adrenergic receptors.
Nonselective agents, including epinephrine and its prodrug
dipivefrin, work primarily by increasing aqueous outflow through
the trabecular meshwork (TM) and the uveoscleral pathway. These
agents have been associated with 15% to 25% IOP reductions,
but their use has declined greatly in modern clinical practice.44
Systemic adverse effects include headache, palpitations, high
blood pressure, and anxiety, whereas local effects include pupillary dilation, conjunctival hyperemia, and conjunctival adrenochrome deposits with long-term administration.31
Selective α-AAs include apraclonidine and brimonidine and
decrease IOP by both enhancing outflow and decreasing aqueous
production.31 Apraclonidine has been shown to produce 20% to
27% mean IOP reductions but has been associated with a high rate
of allergic blepharoconjunctivitis and is typically used for shortterm prophylaxis against IOP spikes after anterior segment laser
surgery.45,46 Brimonidine, available as 0.2%, 0.15%, and 0.1%,
is a highly selective α2 agonist. It is approved for use thrice daily
in the United States but is often used twice daily in some regions
of the world. Brimonidine 0.2% has been shown to be equivalent
to timolol at reducing IOP at peak (2 hours after morning dose;
5.9–7.6 vs 6.0–6.6 mm Hg IOP reduction for brimonidine and
timolol, respectively) but less effective at trough levels (12 hours
after evening dose; 3.7–5.0 vs 5.9–6.6 mm Hg IOP reduction, respectively).47 In another study, brimonidine was shown to reduce
IOP by approximately 24% from a baseline of 23.6 mm Hg.48 In
addition to its IOP-lowering effect, there has been great interest regarding the potentially neuroprotective effects of brimonidine. In
an animal model of rats with laser-induced ocular hypertension,
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it was shown to reduce the rate of retinal ganglion cell loss from
33% to 15%.49 Moreover, in a randomized controlled trial of
low-tension glaucoma patients treated with either brimonidine or
timolol, the eyes treated with brimonidine had slower rates of
visual field progression despite similar IOP lowering in each
group. Subsequent analysis showed that this protective effect
of brimonidine was independent of mean ocular perfusion pressure or IOP-related effects, suggesting a possible neuroprotective
mechanism.50 Systemic adverse effects reported with brimonidine
include dry mouth, fatigue, and headache, whereas local adverse
effects include allergic blepharoconjunctivitis occurring in 12%
to 15% of patients after several months of therapy. An important
and serious systemic adverse effect is central nervous system
and respiratory depression in small children due to the ease with
which these agents cross the blood-brain barrier, making its use
absolutely contraindicated in children younger than 2 years old
and relatively contraindicated in those younger than 6 years.31
Brimonidine 0.15% and 0.1% have been formulated with a stabilized oxychloro complex in place of benzalkonium chloride
(BAK) producing lower yet still significant rates of allergy
(9.2% vs 15.7%, P = 0.007).48
Cholinergics
Cholinergic, or parasympathomimetic agents, were the first
medications introduced for the treatment of glaucoma over 100 years
ago.31 They are available as direct agonists of parasympathetic
receptors in the eye or as indirect agonists, which inhibit
aceteylcholinesterase. Cholinergic agents work by increasing
aqueous outflow through the TM.
Pilocarpine is a direct agonist and is available in various
concentrations from 0.5% to 8%. It is applied 4 times daily because of its short duration of action, and it has been shown to
reduce IOP by 20% to 30%.31 However, it has some notable
adverse effects, including diminished visual acuity due to pupillary constriction and accommodative spasm, brow ache, and
rarely retinal detachment. Systemic adverse effects are uncommon but may include increased salivation, diarrhea, sweating,
vomiting, and tachycardia. Echothiophate iodide is an indirect
agent used twice daily with comparable IOP reduction to pilocarpine. It has similar adverse effects as pilocarpine but is also
associated with a cataractogenic effect and with prolonged respiratory paralysis during general anesthesia if suxamethonium chloride is used as a muscle relaxant.31 In general, cholinergic agents
are used much less frequently because newer agents with improved dosing and side effect profiles have been developed, but
they are still an important part of the medical armamentarium
for glaucoma in select patients, particularly in those who are pseudophakic or aphakic.
Fixed Combinations
Often, multiple medications are necessary for adequate IOP
lowering, and there are several fixed combination therapies available worldwide. In the United States, the currently available
options are Cosopt (dorzolamide 2%-timolol 0.5%), Combigan
(brimonidine 0.2%-timolol 0.5%), and Simbrinza (brinzolamide
1%-brimonidine 0.2%).
Dorzolamide-timolol dosed twice daily has been shown
to be equivalent to instillation of dorzolamide thrice daily and
timolol twice daily [IOP reductions of 5.1 mm Hg (20.5%)
and 4.9 mm Hg (20.0%) with combination and its components
administered separately, respectively].51 Similarly, brimonidinetimolol was found to be equally efficacious to concomitant administration of its components, brimonidine and timolol, producing
an IOP reduction of 4.4 to 5.3 mm Hg for a 12-week period,
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Asia-Pacific Journal of Ophthalmology • Volume 5, Number 1, January/February 2016
with a similar safety profile.52 In a separate randomized trial,
brimonidine-timolol was associated with a 32.3% (−7.7 mm Hg)
IOP reduction from an untreated baseline.53 The most recently approved fixed combination in the United States, brinzolamidebrimonidine administered thrice daily, has been shown to be
superior to monotherapy with either of its components for a period of 6 months (26.7%–36% with combination vs 22.4%–
27.9% with brinzolamide and 20.6%–31.3% with brimonidine).54
Similarly, a randomized trial showed brinzolamide-brimonidine
fixed combination to be noninferior to concurrent application of
both brimonidine and brinzolamide [−8.5 (32.2%) mm Hg for
fixed combination vs −8.3 (31.3%) mm Hg for concurrent
brimonidine and brinzolamide].54
Fixed combination agents offer several advantages of concomitant administration of their components, including increased
patient adherence and persistence with therapy, decreased potential for washout of first medication by instillation of second,
decreased exposure to preservatives and possibly improved tolerability, and potentially decreased costs.55
Which Agent to Choose?
Prostaglandin analogs are the most commonly used topical
agents for initial medical treatment of glaucoma and ocular
hypertension due to excellent efficacy and relatively favorable
side effect profiles, particularly with regard to systemic adverse
effects, relative to several other classes of drugs. However, despite the excellent efficacy of PGAs, a large percentage of patients will require additional therapy to meet IOP reduction
goals. Thirty-nine percent of eyes in the Ocular Hypertension
Treatment Study required 2 or more medications to reach a
20% IOP reduction, and at least 50% of patients in the Collaborative Initial Glaucoma Treatment Study required 2 or more
medications to reach treatment goals.9,56 If PGA use does not
allow adequate IOP reduction, the most common agents to consider next would be BBs, CAIs, or AAs. The most important
factors to consider when beginning adjunctive therapy are efficacy, ease of administration, side effect profile, and tolerability.
It is important to note that the efficacy of each of these agents
when used in conjunction with a PGA is significantly different
than when each is used as monotherapy. A systematic review
and meta-analysis of the adjunctive effect of BBs, CAIs, or AAs
with concomitant use of PGAs reported a statistically similar
mean diurnal IOP-lowering efficacy (2.3–3.0 mm Hg) among all
agents, whereas CAIs and BBs were more efficacious at intermediate (4–9 hours after administration) and trough (9–12 hours after
administration) levels compared with AAs.57 In patients with
ocular allergy and intolerance to multiple medications, consideration should be given to either preservative-free formulations
or BAK-free formulations. Timolol, dorzolamide-timolol, and
tafluprost are available without preservatives, whereas travoprost
and brimonidine are available in formulations preserved with an
alternative to BAK. Finally, as mentioned previously, fixed combinations offer several advantages such as ease of administration
and increased compliance. However, the law of diminishing returns
applies as third and fourth IOP-lowering medications are added,
as 1 study has shown only 14% of patients achieving an additional 20% IOP reduction with the addition of third or fourth
adjunctive IOP-lowering agents.58 In such patients, surgery or laser
trabeculoplasty should be considered.
NEW MEDICAL TREATMENTS ON THE HORIZON
There are several novel medications currently under investigation, which may potentially increase the armamentarium of
glaucoma therapies in the future. Additionally, in response to the
many limitations associated with traditional topical ophthalmic
© 2016 Asia Pacific Academy of Ophthalmology
Medical Therapies for Primary Open-Angle Glaucoma
agents, there has been a rapid expansion and development of
technologies to circumvent common limitations, such as poor
compliance, adnexal adverse effects, and difficulties in the selfadministration of eye drops. It is hoped that novel drug delivery
devices currently in trials will alleviate many of these concerns.
Indeed, sustained release (SR) systems represent one of the most
exciting aspects of research to improve glaucoma care.59
Novel Medications
Rho Kinase Inhibitors
Rho kinase inhibitors, also known as ROCK inhibitors, may
be the next potential class of glaucoma medications. Agents are
being tested in late phase multinational trials alone and in combination with existing classes of medications such as BBs and
PGAs. ROCK inhibitors are thought to work by multiple mechanisms, and the most common adverse effect is hyperemia. The
IOP-lowering effects are achieved primarily by increasing trabecular outflow and improving optic nerve perfusion via complex
interactions with the contractile properties of outflow tissues and
possibly by decreasing episcleral venous pressure.60,61 There are
several ROCK inhibitors that have undergone extensive study,
with Rhopressa (Aerie Pharmaceuticals) currently in phase 3 trials, which initially failed to meet the primary endpoint in Rocket
1, but met a modified primary endpoint in Rocket 2, and with
Rockets 3 and 4 in the pipeline.62 Other ROCK inhibitors have
been abandoned in the past because of both efficacy and tolerability
issues. Given the multiple potential benefits of ROCK inhibitors,
there has been considerable interest in this class of medications.
It has been postulated that these agents have potential neuroprotective benefits as well, which will require further study.
Trabodenoson (Selective α-1 Adenosine Mimetic)
Trabodenoson (Inotek Pharmaceuticals, Lexington, Mass)
has recently completed promising phase 2 trials, reporting not
only impressive IOP lowering, but also excellent tolerability.63
The medication is thought to improve trabecular outflow by enhancing and upregulating protease activity (protease A and
MMP-2), thereby augmenting the normal physiology of the
TM. Of significance as well is the potential for a neuroprotective effect of trabodenoson on retinal ganglion cells, a function
that has remained largely elusive in the current armamentarium
of glaucoma therapies.
Sustained Drug Delivery
Compliance
Compliance with commonly prescribed eye drop regimens
has been repeatedly demonstrated to be suboptimal across a multitude of studies. Poor compliance to medical regimens accounts
for substantial worsening of disease and increased healthcare
costs, irrespective of how compliance is measured. To further
add to the problem, studies have concluded that physicians are
poor at predicting the degree of patient compliance and patients
consistently overrepresent their degree of adherence.10,64–67 A
large retrospective review of more than 18,000 glaucoma patients
in California demonstrated that less than one third of glaucoma
patients were considered “highly compliant” and found that adherence during the first 2 years of treatment was the best predictor of future adherence.65
Punctal Plug Delivery Systems
The concept of punctal occlusion to improve local absorption of topical medications has been examined for decades with
variable and contradictory results.68,69 The demonstration of
successful SR using these devices, however, is a relatively recent
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55
Asia-Pacific Journal of Ophthalmology • Volume 5, Number 1, January/February 2016
Cheema et al
development. A review of preferences of currently available SR
systems in Singapore revealed that patients significantly preferred
punctal plug delivery systems over subconjunctival and intracameral routes, although all 3 were preferred over topical administration by subsets of the population.70
Early phase trials have been conducted by QLT, Mati
Therapeutics, and Ocular Therapeutix on SR punctal plug delivery systems of prostaglandin analogs. These studies have demonstrated promising initial results, with the reported sustained IOP
lowering of punctal plug delivered travoprost similar to topical
timolol at time points during the course of 2 to 3 months. Low
rates of adverse events have been reported to date, and the technology demonstrates significant promise by mitigating the major
limitations of eye drop therapy with a simple delivery system.
Many of the current iterations of this delivery system are made
with absorbable polymers, obviating the need for removal of a
previously inserted device. Larger trials in the future will help
further understand potential limitations and benefits of these
delivery systems.
Injectables
Given major paradigm shifts in intravitreal therapeutics for
macular degeneration, diabetes, and other retinal vasculitides,
the concept of repeated injections of medications has become
more accepted by patients and providers alike. The primary sites
for injectable SR delivery systems include the subconjunctival
space, the anterior chamber, and the vitreous body. Each offers
unique advantages and disadvantages, and trials continue to help
elucidate the differences between the various methods.
In animal models, polyesteramide microfibers have successfully delivered latanoprost in both canine and rabbit models.71
pSivida (Watertown, Mass), in a modification of the already
existing Durasert implantable bioerodable, is examining subconjunctival and intracameral insertion of latanoprost depot injections
in early trials. Envisia (Morrisville, NC) and Ohr Pharmaceucticals (New York City, NY) are both in the preclinical trial phase
with injectable nanoparticle technologies to administer travoprost
and latanoprost, respectively. Nanotechnology offers tremendous
promise in drug delivery because of distinct advantages over standard emulsions in terms of the amount and consistency of the deliverable medication.
Compared with punctal plug and other extraocular drug
delivery methods, direct administration of medication into the
anterior or posterior chamber has the advantage of not relying on corneal penetration. Perhaps the greatest advantage of
intracameral delivery of medications is the potential for major
reductions in adnexal adverse effects. The major disadvantages
include the increased risk of toxicity, the potential for physical
compromise of delicate intraocular structures, and the necessity of lifelong procedures to maintain sustained IOP lowering.
At the time of this publication, SR bimatoprost injections are in
phase 3 clinical trials (Allergan, Irvine, Calif ).
CONCLUSIONS
The art of glaucoma therapy is founded upon an understanding of not only the therapeutic potency of a particular agent, but
also an appreciation of its practical limitations. Our ability to determine and quantify disease progression has vastly improved
with advancements in structural imaging and functional paradigms. Several large randomized clinical trials have validated
the important benefits of IOP lowering in slowing disease progression. Although highly effective when used correctly, topical
therapies have major limitations in clinical practice. Because
interventional procedures continue to advance, it is likely that
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medical and surgical therapy of glaucoma will continue to overlap, and safe and effective drug delivery systems may challenge
the existing paradigm of eye drop therapy. Novel classes of medications may become available to replace and augment our current
therapeutics by allowing for better IOP control and, perhaps in the
future, directly preserving optic nerve health.
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Throughout the centuries there were men who took first steps, down new roads, armed with nothing but their own vision.
— Ayn Rand
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