Meds and BAK
products improve comfort and compliance for glaucoma patients?
Coordinated by Bobby
Christensen, O.D., F.A.A.O., written by Michael Chaglasian, O.D.,
are well aware of the many challenges we face with glaucoma patients in trying to
control the disease and prevent progressive loss of vision. But one related problem
that we potentially overlook is the contribution of chronic glaucoma medications
to the development of ocular surface disease. Even when we identify topical medications
as an associated risk factor for dry eye syndrome (DES), the options for change
are limited. This is due to the chronic nature of the disease and the scarcity of
products that are gentle to the cornea and conjunctiva.
How significant is this problem? While there are limited
references in the literature docu- menting glaucoma and DES, a recent survey of
1,077 glaucoma patients indicated the incidence (patient-reported) of dry eye in
that group is 38%. We'll examine the role a common ophthalmic preservative plays
in this problem.
BAK and glaucoma
Glaucoma patients typically remain on their eye drops for years
often a decade or more. So the potential for the therapeutic agent or the
preservatives to cause toxic effects is significant. Of course the development of
ocular surface disease is multifactorial and results from many underlying causes
or conditions. For patients who are on topical medications, a significant contributing
factor in the development of DES is the preservative benzalkonium chloride (BAK).
BAK is the most widely-used preservative in topical ophthal-mic
medications; Alcon claims that 72% of products include it. BAK is a quaternary ammonium
compound with detergent-like surfactant properties. It has been shown effective
in protecting multi-dose containers from microbial contamination; thus it's achieved
Hitting the ocular surface
In recent years, scientists have explored the role of BAK and
its effects on ocular surface disruption. They've found that BAK:
Decreases corneal epithelial cell integrity
Compromises the epithelial barrier
Impairs corneal healing
Causes a secondary increase in corneal and conjunctival inflammatory cells
Causes a loss of goblet cells
Reduces tear function
Decreases Tear Film Break Up Time (TBUT).
Further research is necessary to determine the exact incidence
rates of these conditions in association with BAK. Some researchers have linked
the effects to longer duration of exposure to the preservative, concentration and
use of other products containing this preservative (as most glaucoma patients do).
My clinical experience leads me to believe there is some percentage
of patients with DES who show reduced compliance to their glaucoma medications due
to dryness exacerbated by BAK. However, despite the side effects listed above, the
lack of alternatives leaves BAK as the number one preservative for topical medications.
Current topical therapy for glaucoma includes four different therapeutic
classes. Prosta-glandin analogs (PGA) are now the most frequently used, due to their
efficacy and low incidence of side effects. Second-line agents for patients who
require additional therapy include the carbonic anhydrase inhibitors, alpha adrenergic
agonists and beta blockers. Manufacturers use BAK in nearly all versions of these
agents with the exception of two: Alphagan P (brimonidine 0.1%, Allergan) and Timoptic
XE (timolol maleate 0.5%, Merck).
Because all three of the products in the prostaglandin family
contain BAK, currently there's no option for patients whose ocular surface may show
signs of toxicity and could benefit from a product free of that preservative. Virtually
all of these patients remain on the PGA, potentially aggravating their symptoms
of dryness. Dry eye therapy may help alleviate some of these symptoms, but it would
be preferable to remove one of the underlying causes and still maintain good IOP
control. A BAK-free formulation of an effective IOP-lowering medication that is
well tolerated in multi-dose packaging would be a welcome addition to our armamentarium.
A BAK-free future
A BAK-free version of Travatan (travoprost 0.004%, Alcon Labs)
is currently in development and awaiting FDA approval. This PGA product uses a new
ionic, buffered preservative system that includes sorbitol, zinc and borate. The
system works well in the bottle to prevent contamination. After dosing, it comes
in contact with ions such as potassium and sodium in the tear film, which cause
the preservative system to become inactive. Thus it is safe and gentle on the eye.
In a three-month clinical study on more than 650 patients, Alcon
reports that the new formulation had a mean IOP reduction equal to the existing
product (Lewis, et al). Dosing, administration and other contraindications remain
the same. Keep in mind that the conjunctival hyperemia seen in the PGA class of
glaucoma agents is caused by the active prostaglandin molecule and not by the BAK.
Photographic assay studies conducted earlier this year compared
the effects of the new Travatan, Xalatan (latanoprost, Pfizer), Systane (Alcon)
and gentamicin on live/dead immortalized human corneal epithelial cells following
25 minutes of exposure to each drug. Travatan without BAK demonstrated significantly
less toxicity to the cells compared with latanoprost and gentamicin (Norcom, et
al). Finally, in a separate study, researchers performed in vivo confocal examination
of rabbit corneas and examined them for any changes in epithelial cell dropout,
morphology or thickness. Results showed that the new formulation doesn't cause corneal
epithelial toxicity (Whitson, et al).
Comfort = compliance
Compliance is always an issue in a chronic disease like glaucoma.
While there are many strategies to improve patient compliance, if the medication
contributes to patient discomfort, perhaps the most logical approach would be to
make the drug as safe and well-tolerated as possible. After all, if the patient
experiences reduced symptoms and improved comfort, it will be easier for him or
her to comply with treatment.
We need both advantages
All therapies have risks and benefits. In glaucoma, therapeutic
options for our patients who also have ocular surface disease are somewhat limited.
It would be quite advantageous to have a product in the prostaglandin class that
can help improve the signs and symptoms of dry eye disease and still have excellent
Dr. Chaglasian is Chief of Staff at Illinois Eye
Institute, Illinois College of Optometry. He is a member of Alcon's Speakers Bureau
and has participated in the company's educational programs.
Dr. Christensen has a partnership practice
in Midwest City, Okla. He's a diplomate in the Cornea and Contact Lens Section of
the American Academy of Optometry. He's also a member of National Academies of
Optometric Management, Issue: September 2006