Expiration Date: February
Statement: This course reviews two case
histories in which therapeutic flexibility prompted
regimen changes that brought about favorable outcomes.
It includes a discussion of the four main classes
of glaucoma medications currently available.
Statement: COPE approval is granted
for this program. This course is COPE-qualified
for 2 hours of CE credit. COPE ID: 6991-GL
check with your state licensing board to see if
this approval counts toward your CE requirement
Statement: This continuing education course is
joint-sponsored by the University of Alabama School
Statement: Dr. Fingeret has no relationships
course is supported by an unrestricted educational
grant from Alcon Laboratories Inc.
Selection of an appropriate
ocular hypotensive agent hinges on many factors. Among these are
the patient's intraocular pressure, optic nerve appearance and visual
fields. These, in turn, help establish an appropriate target pressure.
The patient's family history, age and general health also enter
into the decision-making.
The introduction of several new topical glaucoma agents over
the past decade allows us greater flexibility in tailoring a treatment
regimen to each patient's specific situation. It also means that
the task of selecting an appropriate therapy plan has become considerably
more complicated than in the past, when topical beta-blockers
and pilocarpine were our chief therapeutic weapons. Clinicians
are becoming increasingly adept at mixing and matching agents,
or substituting one for another, to achieve maximal efficacy,
safety and tolerability. Ongoing clinical investigations likewise
provide useful information to help guide us in crafting effective,
individualized treatment plans.
What follows are two case histories in which the demand for
therapeutic flexibility prompted changes in treatment regimens
that led to favorable outcomes. No doubt, we have all seen cases
like these. As you read through them, see if my treatment plan
accords with what you might do in a similar situation. The sidebars
review what we know to date about the four main classes of glaucoma
Case 1: Glaucoma Suspect Treated With
Alpha-2 Agonist, Prostaglandin
A 76-year-old black female
presented for a comprehensive examination with complaints of blurred
vision at near. She was correctable to 20/20 in each eye with
a mild hyperopic prescription. Goldmann tonometry at 9 a.m. revealed
elevated intraocular pressures of 28mm Hg O.D. and 26mm Hg O.S.
The patient denied a family history of glaucoma. She was taking
Tenormin (atenolol), an oral beta-blocker, for atrial fibrillation,
along with Coumadin (warfarin).
FDT screening C 20-5 visual fields were full in each eye. Gonioscopy
revealed grade-3 open angles in each eye with scant pigmentation.
Pachymetry measured corneal thickness of 556m O.D. and 553m O.S.
Stereoscopic optic nerve and retinal examination revealed suspicious
optic nerves, with a large diffuse cup in an average-size optic
disc. There was slight cup-disc asymmetry; the right cup appeared
larger and deeper with a thinner neuro-retinal rim. The nerve
fiber layer, easily visualized, appeared robust in each eye with
no evident defects. There was zone-alpha peripapillary atrophy
in both eyes, but no zone-beta peripapillary atrophy.
examination revealed suspicious optic nerves, with a large
diffuse cup in an average-size optic disc. The right cup (left)
appeared larger and deeper with a thinner neuroretinal rim
than the left.
Peripapillary atrophy (PPA) refers to a thinning and change in
pigmentation in the chorioretinal tissues surrounding the optic
nerve. There are two forms of PPA: zone-alpha and zone-beta. Zone-alpha
is characterized by hypo- or hyperpigmentation, along with thinning
of the chorioretinal tissues, and is found in almost all normal
eyes. Zone-beta bears a relationship with glaucoma, and may change
and enlarge over time. Its characteristics include significant
retinal pigment epithelium loss, chorioretinal tissue thinning,
and visibility of choroidal vessels. Zone-beta appears in up to
20% of normal individuals. It is closer to the optic disc while
zone- alpha is adjacent to the retina.1,2
Two weeks later, this patient returned for follow-up. Her IOPs
were now 26mm Hg O.D. and 24mm Hg O.S. at 2 p.m. Humphrey SITA
Standard 24-2 perimetry produced full visual fields in each eye.
Fields were also full on FDT Threshold N-30 perimetry.
We diagnosed ocular hypertension, noting elevated IOP and a
cardiac arrhythmia as the main risk factors for glaucoma. We talked
with the patient about the best course of action. The management
plan ranged from careful monitoring for the development of glaucomatous
damage without therapy, to initiating topical medications to reduce
the IOP and minimize the chance of glaucomatous optic neuropathy.
Atenolol, a cardioselective beta-blocker, was probably exerting
some effect on the IOP; it would be higher without the medication.
We decided to institute therapy with a target IOP range of 16-18mm
Hg. Because she was already taking an oral beta-blocker, we did
not consider a topical counterpart, for this would likely provide
negligible additional reduction. Instead, the choice for the primary
agent was between the prostaglandins and alpha-agonists. Topical
carbonic anhydrase inhibitors, which are less effective at lowering
IOP, are usually reserved as a second-line or supplementary agent.
We chose Alphagan (brimonidine), an alpha-2 adrenergic receptor
agonist, and initiated therapy in the right eye bid. We explained
the potential side effects of Alphagan and how to instill the
medication, and gave her a written dosage schedule. We also instructed
the patient to return in one month.
After one month of Alphagan therapy in the right eye, IOPs were
21mm Hg O.D. and 26mm Hg O.S. at 8 a.m., one hour after instillation.
The IOP reduction was 5-7mm Hg O.D. (20-25%), with little carryover
in the left eye. This reduction was considerable, and the patient
reported no side effects.
The next management question: Should we have her use Alphagan
in both eyes and accept an IOP in the low 20s (hoping for additional
reduction over time); or add a second medication; or substitute
a different medication to lower IOP to the target level with a
single agent? A trend in glaucoma management is to try to use
as few medications as possible, and to switch when one medication
is effective but does not reach the target goal.
Because the target IOP may have been within reach only by switching
to a topical prostaglandin, we decided to do a monocular trial
with Travatan (travoprost) in the right eye. We told the patient
not to discard the remaining brimonidine, because we might need
it later for further IOP reduction. For now, she was to use only
Travatan in the right eye at bedtime.
We counseled the patient that hyperemia may occur at the outset,
but that the redness should decrease over the first weeks of therapy.
This should not be a major concern unless the eye becomes painful
or photophobic. Because her iris color was a homogenous dark brown,
cosmetic iris color changes were not a concern. We also told her
that her eyelashes might lengthen and darken. (She liked that
She returned two weeks later with IOPs of 17mm Hg O.D. (a 35%
reduction) and 25mm Hg O.S. She had a trace amount of hyperemia
in the treated eye. This did not bother her, because she said
it was improving every day.
We now instructed her to use Travatan in both eyes at bedtime
and to return in a month. At that visit, IOPs were 16mm Hg O.D.
and 14mm Hg O.S. There was evidence of trace hyperemia O.U., but
without symptoms. The patient was to continue on the medication
and return in three months.
Case 2: Primary Open Angle Glaucoma
Treated With Beta-Blocker, CAI
A 52-year-old black male
presented for a routine comprehensive examination, his first in
four years. He wore reading glasses, and his chief complaint was
blurred vision at near. The patient was in excellent health. He
denied allergies to any medications, and reported that his older
sister has glaucoma. His uncorrected visual acuity was 20/20 in
each eye at distance and near.
FDT screening perimetry unveiled repeatable defects in both
eyes. Goldmann applanation tonometry measured intraocular pressures
of 26mm Hg O.D. and 24mm Hg O.S. at 9:30 a.m.
eye displays large optic discs with thin neuroretinal rim
tissue. Rim tissue in the temporal quadrants was absent, with
thin surrounding nerve fiber layer. The right eye (left) displayed
a small area of peripapillary atrophy (zone-beta) temporally.
Dilated optic nerve examination showed large optic discs with
thin neuroretinal rim tissue in each eye. Rim tissue in the temporal
quadrants was absent in each eye, with thin surrounding nerve
fiber layer. A small area of peripapillary atrophy (zone-beta)
was evident temporally in the right eye.
When the patient returned the next day, IOPs were 25mm Hg O.D.
and 24mm Hg O.S. at 11 a.m. Humphrey 24-2 SITA Standard visual
fields revealed a dense inferior arcuate scotoma O.D. and diffuse
loss O.S., probably on the way to developing double arcuate scotomas.
Gonioscopy revealed wide-open angles with ciliary body in all
quadrants of both eyes.
We diagnosed primary open angle glaucoma, and started the patient
on Timoptic (timolol 0.5%) O.D. bid as a monocular trial. The
pulse rate was 76 bpm and regular before therapy began. We counseled
the patient to close his eyes for three minutes after instilling
the drop, and taught him how to do that. We described the nature
of glaucoma, the side effects of Timoptic and the reasons for
using it. The target IOP goal, based upon the extent of damage
and highest IOP readings, was 15-16mm Hg. We instructed the patient
to return in two weeks for follow-up.
IOPs at the return visit were 19mm Hg O.D. (a 27% reduction)
and 23mm Hg O.S. The patient reported no side effects. His pulse
rate was now 68 bpm. We now instructed the patient to use Timoptic
O.U. bid, and to return in one month. At this return visit, IOPs
were 20mm Hg O.D. and 18mm Hg O.S. (about a 25% reduction in each
eye). That was a substantial drop, but still not low enough to
meet the target IOP goal of 15-16mm Hg.
We now added dorzolamide to the therapeutic regimen for the
right eye in the form of Cosopt (timolol 0.5%, dorzolamide 2%)
bid, and told the patient to continue using Timoptic bid O.S.
At the next visit, IOPs were 16mm O.D., 19mm Hg O.S. The patient
denied any problems with the use of Cosopt. We now instructed
him to use the medication bid in both eyes.
One month later, IOPs were 16mm Hg O.D. and 15mm Hg O.S. The
medication was well-tolerated, and the IOP was now within the
target pressure range. We instructed the patient to return in
(latanoprost 0.005%), approved in 1996 was the first of
the group of medications referred to as prostaglandin or
prostaglandin-like agents. Latanoprost reduces IOP more
effectively than timolol, up to 35% when used once a day.7
(unoprostone isopropyl 0.15%), FDA-approved in fall 2000,
requires a bid dosage schedule to lower IOP by 16-22%.8
Labeled as a docosanoid, unoprostone reduces IOP by a dual
mechanism of increasing uveoscleral and trabecular meshwork
a metabolite of a prostaglandin,9 unoprostone
does not lower the IOP as much as the other prostaglandin
medications.10 There have been few reports of
iris color darkening, anterior uveitis or other side effects
with unoprostone compared with latanoprost and the other
(travoprost 0.004%) and Lumigan (bimatoprost 0.03%) are
the newest of the prostaglandin-like medications, released
in March 2001. Travoprost is a prostaglandin that enhances
uveoscleral outflow.12 It is an FP prostanoid
receptor agonist with many similarities to latanoprost,
and is at least as effective as latanoprost with an IOP-lowering
efficacy of 26-36%.13 Data show that travoprost
has greater efficacy in blacks than latanoprost and timolol.14
dual mechanism enhances both uveoscleral and trabecular
meshwork outflow. Bimatoprost is a prostamide, and there
is a question as to whether it stimulates the PGF2-alpha
receptor or some other as-yet-unidentified receptor.16
Whatever its mechanism, bimatoprost reduces IOP by 26-36
%.15 Its indications and contraindications are
similar to those of latanoprost and travoprost. Bimatoprost's
concentration exceeds that of latanoprost or travoprost;
whether the increased strength has any undesired systemic
side effects will be seen over time.
IOP-lowering efficacy of latanoprost, bimatoprost and travoprost
is greatest when used once a day; twice-daily use blunts
their effectiveness. Their recommended dosage is at night,
in part due to the hyperemia associated with the medication;
this may be less severe after a night's sleep. Travoprost
and bimatoprost showed no difference in efficacy whether
used at night or in the morning.13,15
medications are additive to other glaucoma medications.
Systemic side effects are rare, but several ocular side
effects have been reported.
conjunctival hyperemia occurs in up to 30% of individuals.17
Pruritus is also common. Increased iris pigmentation has
been observed, especially in lightly pigmented eyes with
mixed color such as green-brown or blue-brown eyes (concentric
of the iris, which has been noted in up to 16% of patients
using prostaglandin-like agents and which appears to be
permanent,18 is due to an increased number of
melanosomes (pigment granules) within melanocytes of the
iris stroma. Clinicians must inform patients about this
potential side effect before initiating therapy, and document
the iris color. If there is a color change, discontinue
treatment if it is bothersome to the patient. No evidence
of further color change has been reported after discontinuation.
changes in the skin around the eye have also been reported
with prostaglandin-like medications.19 Other
reported side effects include corneal pseudodendrites that
disappear after stopping latanoprost, and the potential
exacerbation of herpes simplex viral (HSV) keratitis in
individuals who have had prior HSV infections.16
Eyelashes may lengthen and thicken, and there are reports
of reactivated anterior uveitis and cystoid macula edema.21-23
medications are becoming extremely popular in glaucoma therapy
due to their excellent efficacy, safety index and tolerability.
They flatten the diurnal curve significantly and achieve
the greatest IOP reduction of any class of topical medication.
often can get to the desired target pressure with a single
agent, as in the first case presented here.
the drugs may cause side effects such as hyperemia and pruritus,
for many individuals their once-a-day schedule makes it
easy to adhere to a treatment regimen. Many clinicians use
prostaglandin-like medications as their primary therapy.
Adrenergic Receptor Agonists
initial agent in this drug class was Iopidine (apraclonidine
1%), followed by apraclonidine 0.5%. Two significant problems
occurred with apraclonidine.3 Allergic blepharoconjunctivitis
developed in 20-50% of users, and tachyphylaxis occurred
in up to 50%.4 Today, the medication is seldom used.
the FDA approved Alphagan (brimonidine 0.2%), a relatively
selective alpha-2 adrenergic receptor agonist that has become
the alpha-2 agonist of choice. Recently, we witnessed the
release of Alphagan P (brimonidine 0.15%), using the preservative
Purite to reduce the incidence of hyperemia, toxicity and
has a dual mechanism for decreasing the IOP: It suppresses
aqueous production and enhances uveoscleral outflow.5,6
Brimonidine may cross the blood-brain barrier, leading to
potential central nervous system (CNS) side effects such
as fatigue; this is why brimonidine should never be used
in children. Brimonidines penchant for inducing allergic
conjunctivitis is less than with apraclonidine, though still
considerable (10-15%). Tachyphylaxis has not been a problem
new Alphagan P replaces the preservative benzalkonium chloride
(BAK) with Purite, an oxychloro complex that breaks down
to natural components when exposed to light. A neutral pH
further minimizes toxicity, and enhanced bioavailability
allows a reduced concentration of the drug to achieve efficacy
equivalent to that of the original Alphagan. Clinicians
are seeing fewer instances of allergic conjunctivitis associated
with Alphagan P, most likely owing to its lower concentration.
efficacy is similar to that of timolol at its peak effect.
Brimonidine loses its IOP-lowering effect more quickly than
timolol, so that at trough (8-12 hours after instillation),
its efficacy is diminished.5 This is why the FDA labeled
the medication with a tid dosage, though most clinicians
use it bid.
clinical concern for individuals using Alphagan as a sole
agent is that you need an afternoon IOP reading to determine
whether you are getting adequate diurnal control. Alphagan
P should become the alpha-2 agonist of choice since its
cost and efficacy are believed to be comparable to Alphagan
but with fewer side effects.
Topical beta-blockers first became available
in 1978 with the introduction of Timoptic (timolol), which
decreases aqueous production. Topical nonselective beta-blockers
reduce IOP 22-26%, and patients may use them either once
or twice daily.24 The onset of this class of
drugs starts 30 minutes after instillation, with a peak
effect in one to two hours. Since aqueous production is
reduced naturally while a person sleeps, most of the drug's
efficacy occurs during waking hours. Many individuals can
successfully use topical beta-blockers once a day (in the
Topical beta-blockers are comfortable when
instilled, but side effects, predominantly systemic ones,
are a concern. They relate to the blockade of the beta-adrenergic
receptors. When cardiac or pulmonary receptors are involved,
pulmonary capacity or heart rate is reduced; bronchospasm,
weakness and lethargy may ensue. Cardiovascular complications
include bradycardia, hypotension, elevated cholesterol levels,
syncope and heart failure.25 When the medication
crosses the blood-brain barrier, CNS side effects may include
general lethargy, anxiety, confusion, decreased libido and
depression. Individuals using calcium channel blockers when
placed on beta-blockers have the risk of developing severe
Patients at greatest risk for developing
systemic side effects are the elderly and frail, and those
with severe illness. Contra-indications to topical beta-blockers
include chronic obstructive pulmonary disease (COPD), asthma,
emphysema and other pulmonary conditions; cardiovascular
conditions, including bradycardia, congestive heart failure
or heart block; and depression. One way to reduce systemic
absorption is to have patients close their eyes or occlude
the puncta for three minutes after instilling the drop.
Oral beta-blockers used to treat hypertension
or other cardiovascular conditions may reduce IOP. When
someone is already using a systemic beta-blocker, a topical
one adds little to IOP reduction; it only increases the
risk for side effects.
Timolol is available in two forms: maleate
(Timoptic) and hemihydrate (Betimol). Both have equivalent
efficacy with similar side effects. Timolol also comes in
two different concentrations: 0.25% and 0.5%. The 0.25%
concentration is effective in lightly pigmented individuals;
the 0.5% is usually indicated in patients with darker complexions.
Timolol is also available as a gel (Timoptic-XE, Falcon
gel). This form, used once a day, reduces the amount of
medication absorbed systemically.
||0.25, 0.5% solution
||qd or bid
||0.25, 0.5% solution
||qd or bid
||0.25, 0.5% solution
||qd or bid
||qd or bid
Ocupress (carteolol) is a unique nonselective
beta-blocker with intrinsic sympathomimetic (ISA) activity.
ISA allows blockage of the adrenergic system at certain
receptors and stimulation at others. One advantage of ISA:
Carteolol does not appear to affect the heart rate or cholesterol
level as other beta-blockers do.27 So, one indication
for the use of Ocupress may be in individuals with a history
of cardiovascular disease.
Betoptic (betaxolol) is a cardioselective
beta-blocker that reduces IOP by about 20-22%.28
This beta1-blocker has reduced affinity for the
beta2 receptors of the pulmonary and gastrointestinal
While betaxolol is specific for the beta1
receptors, its affinity for those receptors is less than
that of timolol.29 This makes Betoptic a safer
drug than the nonselective beta-blockers when you are concerned
about cardiovascular, pulmonary or central nervous system
effects. Even so, Betoptic should not be the initial drug
of choice for individuals with pulmonary problems. It may
be used in those with a relative contraindication when other
medications have not performed as required, but only if
approved by the patient's internist.
Betaxolol comes in a 0.25% suspension (Betoptic-S)
and a 0.5% solution (Betoptic). Studies comparing the two
have shown equal clinical efficacy. Both forms are used
every 12 hours. Ocular side effects of Betoptic include
stinging and burning, more so than with Betoptic-S (or timolol).
Several studies have shown that betaxolol enhances blood
flow to the optic nerve.30,31
A new, more efficacious form of betaxolol,
the S-isomer (Betaxon), will shortly become available. This
medication has a side effect and safety profile similar
to other forms of betaxolol, but appears to yield a 22-24%
greater IOP reduction.32
A dissipation phenomenon common to the
beta-blockers is known as short-term "escape" and long-term
"drift." When starting therapy with a topical beta-blocker,
there is an initial IOP reduction that lasts several days
to weeks. "Escape" then occurs, resulting in a small IOP
rise. After 2-4 weeks, the IOP usually stabilizes below
the pre-treatment level. IOP control may then last for weeks
to years. Long-term "drift" refers to a slow, steady rise
in IOP after months to years of treatment, often to a point
where the medication is no longer effective.
Both the oral and topical carbonic anhydrase
inhibitors (CAIs) inhibit the enzyme carbonic anhydrase,
decreasing aqueous humor production. Oral CAIs, most notably
Diamox (acetazolamide), are the most potent ocular hypotensive
Unfortunately, a host of side effects have
been well-documented with Diamox, including nausea, vomiting,
depression, kidney stone formation, gastrointestinal upset
and loss of libido. More severe side effects include aplastic
anemia, Stevens-Johnson syndrome and erythema multiforme.
CAIs are sulfa drugs, and are contraindicated in those allergic
Trusopt (dorzolamide 2%) was the first
topical CAI, released in 1995. In 1998 we saw the introduction
of Azopt (brinzolamide 1%). While not as effective as their
systemic counterparts in lowering IOP, their excellent safety
index makes them a good choice when you need an adjunctive
medication. The dosage for topical CAIs is three times daily,
though some individuals may be controlled on a twice-daily
basis. Trusopt and Azopt reduce IOP by about 16-22%.33
CAIs are additive to beta-blockers and adrenergics.
Rarely do systemic side effects occur with
topical CAIs, but headaches and a metallic taste are common
complaints. Ocular side effects, while infrequent, include
irritation, itching and hyperemia.
Cosopt is a combination medication containing
timolol 0.5% and dorzolamide 2% that is used twice daily.
The convenience of fewer drops per day enhances patient
Fingeret is co-author of the texts Primary Care of the Glaucomas
and Atlas of Primary Eyecare Procedures. He is chair and chief
of the optometry section at the Brooklyn/St. Albans Campus, Department
of Veterans Affairs, and associate clinical professor at the State
University of New York State College of Optometry. He is also
chair of Review of Optometry's Glaucoma 2002 Conference.