GLAUCOMA MEDICATION
| GLAUCOMA MEDICAL THERAPY: INDIVIDUALIZED PATIENT CARE—James C. Tsai, MD, Associate Professor of
Ophthalmology, Columbia University College of Physicians and Surgeons, and Director, Glaucoma Division, Edward S.
Harkness Eye Institute, Columbia University Medical Center, New York City
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Clinical Relevance of Target IOP
| Current concepts: target intraocular pressure (IOP) upper boundary of ideal range; American Academy of Ophthalmology
(AAO) preferred practice pattern (1989) based on retrospective outcome studies; choice of 1) percentage of IOP
reduction or 2) absolute IOP level, as target depends on severity of disease and patient
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| Ocular Hypertension Treatment Study (OHTS): initial IOP 24 to 32 mm Hg; findings—20% IOP reduction leads to
60% decreased risk of developing glaucoma (4.4% vs 9.5% over 5 yr); visual field confirmation in 45% of patients with
progressive glaucoma; European Glaucoma Prevention Study—initial IOP 22 to 29 mm Hg; findings—placebo-associated
reduction in IOP; no treatment effect (dorzolamide [15%-22% reduction in IOP]); placebo (9%-19% reduction)
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| Early open-angle glaucoma (OAG): Collaborative Initial Glaucoma Treatment Study (CIGTS; Lichter et al): medication
vs surgery; aggressive target IOP (≥35% reduction); medication comparable to surgery; in medication group, decreased
visual fluctuation, cataract formation, and ptosis over first year; Early Manifest Glaucoma Trial (EMGT)—
25% decrease in IOP (visual field worsened in 45%); almost 50% had normal-tension glaucoma [NTG])
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| Advanced Glaucoma Intervention Study (AGIS): moderate or advanced OAG; with IOP <18 mm Hg at all times, no
loss in visual field (average 12.3 mm Hg)
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| Collaborative Normal Tension Glaucoma Study (CNTGS): goal 30% reduction in IOP (average 16-11 mm Hg); risk
decreased from 60% to 20%
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| Conclusion: 20% reduction in IOP minimum required to prevent further progression
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| CIGTS revisited: in medication group, IOP decreased ≈38% (in surgery group, decrease slightly greater); mean visual
field scores comparable over 5 yr
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| AGIS 7: looked at percentage of visits with IOP <18 mm Hg; with mean IOP 12.3 mm Hg over 8 yr, no visual field progression;
greater diurnal fluctuation associated with increased risk for progression
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| AAO recommendations: IOP reduction 20% to 30%; monitor for progression; if target IOP met, but glaucoma
progresses, further reduction ≥15% recommended; does not emphasize IOP fluctuations
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Diurnal Fluctuation
| Overview: much energy expended to autoregulate blood flow when fluctuation range 12 mm Hg to 18 mm Hg; IOP
swings may occur throughout 24-hr circadian cycle
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| Home monitoring of IOP fluctuation (Asrani et al): group that ranged in highest 25% had more significant rate of visual
field progression, compared to patients whose IOP did not fluctuate (mean IOPs comparable); with least fluctuation (mean
diurnal range 3.1 mm Hg), relative risk for glaucoma progression 1.0; greatest fluctuation (5.4 mm Hg) associated with almost
6-fold greater risk for progression; risk factors for progression (AGIS; Nouri-Mahdavi et al)—most important factors
increased age and greater IOP fluctuation (not mean IOP)
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Central Corneal Thickness
| OHTS findings: central corneal thickness (CCT) ≤555 µm; if vertical cup-to-disc ratio 0.3 to 0.5, risk of developing
OAG with normal or thin cornea 26% over 5 yr; managing patients at risk—optical coherence tomography (OCT);
Heidelberg Retinal Tomography (HRT)-II or -III evaluation; follow patients closely (especially those with normal or
thin corneas); 40 µm decrease in CCT—associated with 71% increase in relative risk (more studies needed)
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| Study (Shih et al): regardless of algorithm, ≥50% of patients need IOP adjustment ≥1.5 mm Hg; CCT affects clinical
management (edema possible confounding factor)
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Adherence to Medication
| Overview: compliance increases with simpler treatment regimen and better patient education
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| Reasons for noncompliance (study by Tsai et al): regimen factors (eg, side effects); patient factors (eg, arthritis and
forgetfulness); environmental or situational factors
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| Improving compliance: have staff inform physician when patients comment about obstacles; use illustrated fact and
dosing sheets; train patients to administer drops correctly; enlist others in household to assist patient; link dosing
schedules to daily activities; address work-related issues; choose treatments that enhance compliance
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| Patients at risk for noncompliance with follow-up (Kosoko et al): glaucoma-suspect hypertensives may mistakenly
rely on normal visual field; patients dissatisfied with waiting times; patients who are nonadherent to prescribed treatment
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| Prostaglandin analogues: advantages—efficacy; tolerability; reduced dosing; studies suggest that prostaglandins blunt
diurnal IOP fluctuation; diurnal IOP fluctuation range (Drance)—in normal eyes, ≈3.7 mm Hg; in typical patient with
glaucoma, 11 mm Hg; with prostaglandin therapy, 3.5 to 4.5 mm Hg
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| More management tips: diurnal fluctuation important in determining IOP goals, based on AGIS and CIGTS; more aggressive
IOP reduction indicated in younger patients; based on OHTS and EMGT, older patients at greater risk for
progression at same IOP level; initial IOP decrease needs to be ≥20% (perhaps 30%); 40% reduction may be indicated
in severe disease; adjust for CCT
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| Speaker’s treatment algorithm: ocular hypertension—if good adherence anticipated, IOP reduction ≥20%, IOP in normal
range, and diurnal fluctuation range ≤5 mm Hg; early OAG—25% IOP reduction, IOP in mid-to-upper teens, and
decreased diurnal fluctuation; moderate or advanced OAG—may need IOP of 12 mm Hg and fluctuation range ≤3 mm;
NTG—may need ≥30% reduction and IOP consistently <12 mm Hg
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| Fixed drug combinations: dorzolamide and timolol (Cosopt) helpful; awaiting Food and Drug Administration (FDA)
approval—brimonidine and timolol (Combigan); bimatoprost and timolol (Xalcom); travoprost and timolol (Extravan)
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| EFFECT OF GLAUCOMA THERAPY ON THE OCULAR SURFACE—Robert J. Noecker, MD, Associate Professor of
Ophthalmology and Vice Chair of Clinical Affairs, University of Pittsburgh School of Medicine; Director, Glaucoma
Service, Eye and Ear Institute, University of Pittsburgh Medical Center
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| Classes of ophthalmic preservatives: detergents; oxidizing agents; alcohol-based (echothiophate [Phospholine Iodide])
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Detergent Preservatives
| Specific vehicles: benzalkonium chloride (BAK); benzododecinium bromide (BDD); polyquaternium-1 (Polyquad); mechanism
of action—disruption of cell membrane permeability; lipid dispersion; lysing of cell contents causes bacterial
death
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| Adverse effects: denaturing of proteins; lysis of nontargeted membranes; damage to ocular surface cells (epithelial or
subconjunctival); high doses of BAK disrupt structure of corneal epithelium; at lower doses—intercalation into cell
membranes; change in epithelial ionic resistance; increased cell permeability; with BAK, corneal epithelial permeability
2.7 times greater than controls
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| Increased epithelial permeability: no benefit
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| Type and extent of damage: depends on amount of exposure; low-level BAK exposure—epithelial cells stop flowing;
medium concentrations (0.01%)—apoptosis (not much inflammation; neighbor cells not adversely affected); higher
doses—cell necrosis; much inflammation; local damage; long-standing effects on ocular surface
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| Accumulation in tissues: severity of adverse effects correlates with duration of treatment; 1 or 2 wk—effects clinically
insignificant; long-term use—BAK tends to penetrate deeper into eye; adverse effects on lens; with multiple medications,
inflammation and cell necrosis more likely
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Oxidizing Agents in Artificial Tears
| Overview: benign; preservative converted to sodium chloride and water once exposed to light; types—1) sodium perborate
(preservative in GenTeal [artificial tears]); 2) sodium chloride (Purite); in healthy corneal epithelium of rabbit, normal
hexagonal structure after exposure; Polyquad—more shriveling and damage; BAK—cell destruction
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| Sodium chloride: no long-term or mutagenic effect; Purite moderately stable and nontoxic; kills bacteria through oxidation
of glutathione; mammals have renewable supply of glutathione (mammalian cells not oxidized)
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| Sodium perborate: not much hydrogen peroxide needed to kill bacteria (used effectively in low doses); slightly higher
dose may cause stinging; penetrates cell walls and affects membrane enzymes; disrupts protein synthesis
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| Summary: vehicle and amount of preservative in artificial tears vary (avoid BAK)
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Preservatives in Glaucoma Medications
| Benzalkonium chloride: latanoprost (Xalatan)—highest BAK content; potential for necrotic cell death; relatively unstable
in solution (reason for higher concentration); timolol (Timoptic)—intermediate concentration (lower ranges
available in bimatoprost [Lumigan] and levobunol [Betagan])
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| Non-BAK formulations: 1) preservative-free Timoptic (effective); 2) Timoptic XE (for some patients, benzododecinium
too closely related to BAK); Phospholine Iodide contains chlorobutanol (alcohol-based preservative); Alphagan P
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Effects of Glaucoma Medications on Corneal Epithelium
| Histologic findings (rabbit model): dorzolamide (Trusopt)—on staining, area correlates clinically to punctate erosion;
not many microvilli present; dehydrated; more barren; areas of disruption; Xalatan—loss of superficial cells; more
corneal staining; not as organized; many microvilli lost; Lumigan—moderate or intermediate amount of damage to
surface; Timolol—lost one cell; Alphagan P—appearance similar to cornea that received artificial tears only; normal
hexagonal structure; slightly fewer microvilli
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| Alphagan vs Alphagan P: Alphagan had 60% higher rate of ocular damage; both relatively effective and gentle to ocular
surface, but Alphagan-P surface looks as good or better than controls
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Effects of Glaucoma Medications on
Conjunctival Epithelium
| Initial observations (rabbit model): Trusopt—at 1 mo, epithelial region greatly thickened; many inflammatory lymphocytic
cells; hypercellularity at epithelial and superficial stromal level; Timolol—some thickening of epithelium
(tends to be hypercellular); Xalatan—epithelium thick (2 or 3 times normal); hypercellular stroma; Lumigan—similar
but less thickening in epithelium (some areas normal); Alphagan P—similar to control population; may be few more
superficial stromal cells; epithelium not thickened by inflammation
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| Preservative concentration and lymphocyte count (rabbit model): hypercellularity or thickening in epithelium and
superficial stroma correlated well with amount of BAK; Xalatan—highest amount of BAK (0.02%) and greatest hypercellularity;
Timolol—half the BAK (0.01%) (half the thickening and hypercellularity); Trusopt—0.0075%;
Lumigan—0.005%; hypercellularity correlated well; Alphagan P—not different from control
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| Effect on human conjunctiva: Xalatan—thickening similar to that in rabbits; much more hypercellularity in superficial
stroma; Alphagan P—epithelium not significantly different from controls; no increase in hypercellularity
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| Reversing changes: case—patient on glaucoma medication; increase in hyperemia; corneal staining; redness with
long-term glaucoma therapy; treatment short dose of mild steroid, then long-term cyclosporine (Restasis); consider—
pretreatment with steroids before trabeculectomy; Restasis avoids IOP spike; bleb may develop in patient with dry
eye or chronic inflammation (tends to be localized and thin); case—candidate for second surgery pretreated with
Restasis; initially, bleb not localized or thin; with treatment, much quieter; problem of mitomycin C (inflammatory
cells stop at end of region, dumping proteases and thinning stroma)
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| Summary: detergent-containing medications cause significant changes in cornea and conjunctiva; changes correlate
with whether patients on multidrug therapy or drugs containing higher amounts of BAK (drug pH another factor);
Trusopt—on staining, most corneal damage; probably related to pH and vehicle used; in contrast, conjunctival
changes correlate well with long-term use of BAK (greater exposure associated with more chronic inflammation);
consider Purite (benign; long history of use)
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| Clinical pearls: side effects of long-term topical glaucoma therapy include hyperemia and chronic inflammation; consider
cost/benefit ratio; newer oxidative preservatives on horizon kill bacteria well with fewer harmful effects; trabeculectomy
candidates—duration of previous topical therapy important; patients on glaucoma medication, eg, 20 yr,
tend to have more inflammation initially, higher rates of failure in short term, and thinner blebs that do not do as well
long-term; pretreatment with, eg, topical cyclosporine can minimize complications
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Educational Objectives
The goal of this program is to educate the listener about glaucoma medical therapy. After hearing and assimilating this
program, the clinician will be better able to:
 | 1. Describe the clinical relevance of target intraocular pressure (IOP) in managing glaucoma.
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| 2. Recognize diurnal IOP fluctuation as a risk factor for glaucoma progression.
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| 3. Describe strategies for improving adherence to medication.
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| 4. Describe adverse effects of preservatives in topical glaucoma therapy on the ocular surface.
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| 5. Choose appropriate topical therapy for managing glaucoma.
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Discussed on This Program
Bimatoprost [Lumigan]
Brimonidine tartrate [Alphagan, Alphagan P]
Cyclosporine, ophthalmic [Restasis]
Dorzolamide [Trusopt]
Dorzolamide HCl and timolol maleate [Cosopt]
Echothiophate iodide [Phospholine Iodide]
Latanoprost [Xalatan]
Levobunolol hydrochloride [AKBeta, Betagan Liquifilm]
Timolol maleate [Betimol, Blocadren, Istalol, Timoptic, Timoptic-XE]
Travoprost [Travatan]
Suggested Reading
Asrani S: Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma. J
Glaucoma 9:134, 2000; Bergea B et al: Impact of intraocular pressure regulation on visual fields on open-angle glaucoma.
Ophthalmology 106:997, 1999; Fiscella RG: Persistency with glaucoma medication. Am J Ophthalmol 138:1093,
2004; Gordon MO et al: The Ocular Hypertension Treatment Study: baseline factors that predict the onset of primary
open-angle glaucoma. Arch Ophthalmol 120:714, 2002; Kosoko O et al: Risk factors for noncompliance with glaucoma
follow-up visits in a residents’ eye clinic. Ophthalmology 105, 2105, 1998; Lichter PR et al: Interim clinical outcomes
in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery.
Ophthalmology 108:1943, 2001; Nouri-Mahdavi K et al: Predictive factors for glaucomatous visual field progression
in the Advanced Glacoma Intervention Study. Ophthalmology 111:1627, 2004; Pisella PJ et al: Prevalence of
ocular symptoms and signs with preserved and preservative free glaucoma medication. Br J Ophthalmol 86:418, 2002;
Shih et al: Clinical significance of central corneal thickness in the management of glaucoma. Arch Ophthalmol
122:1270, 2004; Taylor SA et al: Causes of noncompliance with drug regimens in glaucoma patients: a qualitative
study. J Ocul Pharmacol Ther 18:401, 2002; Thygesen J et al: Short-term effect of latanoprost and timolol eye drops on
tear fluid and the ocular surface in patients with primary open-angle glaucoma and ocular hypertension. Acta Ophthalmol
Scand 78:37, 2000; Tsai JC et al: Compliance barriers in glaucoma: a systematic classification. J Glaucoma
12:393, 2003.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. Dr. Tsai has received
research funding from Alcon, Allergan, and Pfizer and has been a consultant or part of the Speaker’s Bureau for
Alcon, Allergan, Merck, and Pfizer.
Dr. Tsai was recorded at the 4th Annual Downeast Ophthalmology Symposium, Practical Solutions in Ophthalmology,
presented September 23-25, 2005, in Bar Harbor, Maine, by the Maine Society of Eye Physicians and Surgeons; Dr. Noecker
was recorded at the Kansas City Society of Ophthalmology and Otolaryngology Annual Clinical Conference, presented
January 7-8, 2005, in Kansas City, Missouri by the Kansas City Society of Ophthalmology and Otolaryngology.
The Audio-Digest Foundation thanks Drs. Tsai and Noecker and the sponsors for their cooperation in the production of
this program.
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