Glaucoma Eye Drops
Chat Highlights
March 21, 2007

On Wednesday, March 21, 2007, Dr. Michael James Pro, a glaucoma specialist at Wills, and the glaucoma chat group discussed "Glaucoma Eye Drops."

Moderator:    Welcome back, Dr. Pro.  Tonight our topic is “Glaucoma Eyedrops”.  What is their main purpose?

Dr. Pro:    All glaucoma drops have one thing in common; they lower intraocular pressure (IOP).

Moderator:  What are the different types of eyedrops for glaucoma?

Dr. Pro:  (1) Cholinergics (miotics) have been used for over 100 years.  Pilocarpine is the oldest and most frequently used. Drawbacks include q.i.d. (four times per day) dosing for the drop form, and side effects, such as reduced vision in dim illumination, induced myopia, and supraorbital and temporal headaches from stimulation of the ciliary muscle. Pilocarpine is poorly tolerated in younger patients due to accommodative myopia.

(2) Epinephrine, the non-selective alpha agonist, was also among the first drugs used for glaucoma.  Significant side effects, including adenochrome deposits and allergy, limited its use. Dipivefrine (Propine) was introduced in 1989; it is the pro-drug of epinephrine and was developed to enhance corneal penetration and minimize surface toxicity.

(3) Systemic carbonic anhydrase inhibitors (CAIs) have been used for over 50 years.  The topical formulations dorzolamide hydrochloride (Trusopt) and brinzolamide hydrochloride (Azopt) were FDA-approved in 1998.

(4) Beta-adrenergic agonists remain a major class of anti-glaucoma drugs.  Timolol, introduced in 1978, was the first.

The adverse effects of the beta-blockers include difficult breathing, impotence, mood changes, and inhibition of cardiac function.

(5) Selective Alpha 2 adrenergic agonists include apraclonidine (Iopidine) and brimonidine (Alphagan). This class came to market in the mid-1990’s.

(6) Prostaglandin analogs (anti-hypertensive lipids) are now the first-line anti-glaucoma drugs with no systemic adverse effects.  Side effects include conjunctival hyperemia and darkening of the peripheral iris stroma.  Latanoprost (Xalatan), launched in 1996, was the first successful prostaglandin.  Bimatoprost (Lumigan) and travaprost (Travatan) followed.

P:  Which of the drops are most frequently prescribed?

Dr. Pro:  We use mostly the newer types, as they have fewer side effects.  Many ophthalmologists have switched to the prostaglandins as the first drug used. That drug is now more popular than the beta-blockers, like timolol.

P:  What percentage of glaucoma patients respond satisfactorily to eyedrops?  For those who respond, do the medications stop progression or only slow it down?

Dr. Pro:  I do not know the exact percentage of response, but it is pretty high, probably over 80%.  To answer your second question:  The drops are all designed to delay progression of glaucoma.

P:  Why do drops stop working?

Dr. Pro:  We think the drops stop working because the patient somehow becomes "tolerant" of the drug.  Each drug usually targets one mechanism for glaucoma in the eye.  For instance, since the beta-blockers cause the eye to produce less fluid, it can help to switch the user to a drug with another mechanism, such as the prostaglandins, which improve the outflow. Sometimes the original drug can be re-started later, and a response can be seen.

P:  How do the prostaglandins work?

Dr. Pro:  They target an alternative pathway, the uveoscleral, for outflow of the aqueous humor. The uveoscleral pathway usually is responsible for about 10% of outflow, but prostaglandins "ramp up" this system, thus lowering the IOP.

P:  Is it correct to say that the “raccoon” appearance of the eyelids and the "hair" on the cheeks is the result of prostaglandin eyedrops directly affecting the skin, and is not a systemic effect?

Dr. Pro:  Yes, those are local effects.  Systemic effects include cardiovascular, etc.

P:  The potential for darkening of iris pigment with the use of prostaglandins disturbs me.  The prostaglandins have been on the market for about 10 years.  Do you think that's really long enough to assess the safety of this class of medications? Is there the slightest evidence that pigment darkening is dangerous?

Dr. Pro:  There is no evidence that this increased pigmentation is harmful.  Ten years is a fairly long time, and I feel comfortable using prostaglandins.

P:  Since my glaucoma is unilateral, using Xalatan in one eye increased the length of my eyelashes only in that eye.  Would it have been okay to instill the eyedrop in the non-glaucomatous eye?

Dr. Pro:  I would get your doctor’s approval first.  I have let my patients do it.

P:  Patients on prostaglandins worry about the change in eye color, but doesn't that occur in only a small percentage of users, and they have hazel or green eyes?

Dr. Pro:  Right. Hazel and green eyes can be affected most, and it is really usually very minor. However, it sounds serious to patients, because eye color seems inviolate to them.

P:  I use Xalatan, have retinal edema, and suffer from light sensitivity.  Could Xalatan cause any of these problems?

Dr. Pro:  Xalatan can cause inflammation and macular edema.  Sometimes Xalatan needs to be stopped and the edema treated with a topical NSAID like Acular.

P:  Do the benefits of the prostaglandins differ?

Dr. Pro:  No, they are all similar.  Some studies, however, found Lumigan to be somewhat more effective for some patients.

P:  How large a percentage drop in IOP can be expected?  Does it differ by the class of drop?

Dr. Pro:  With the prostaglandins, the decrease is about 30%; the others, less so.  It seems that each successive drug lowers the IOP by a smaller percentage.

P:  Three classes of glaucoma eyedrops (several formulations of each) failed to reduce my IOP at all.  Why is it that some eyes don't respond to the medications?

Dr. Pro:  Good question.  We may not know the answer to that until we really start to study the particular genetics for glaucoma.  In the future, drugs may be targeted to an individual, based on that individual’s genetic make-up.  For now, we use drugs that benefit groups of patients in large studies.

P:  If you just learned that you had moderately advanced glaucoma, would you choose to use glaucoma eyedrops, SLT, ALT, or trabeculectomy?

Dr. Pro:  The Glaucoma Laser Trial suggested that starting with ALT was as good as drops in many patients.  Many doctors, including me, usually try drops first. If the pressure is controlled with one drop, I keep the patient on drops.  If the pressure is still high, then I will often try SLT (selective laser trabeculoplasty) or ALT (argon laser trabeculoplasty).

P:  I thought that ALT or SLT were best for pigmentary glaucoma in older patients.

Dr. Pro:  The laser is best for a few groups.  Patients with pseudoexfoliation syndrome do well with SLT.  Patients with pigmented trabecular meshwork usually do better.  Care should be taken with patients who have pigmentary glaucoma. In young patients, the pressure can be higher after ALT.

P:  Are there any new drops on the horizon?

Dr. Pro:  Not really.  There are combination drops that should be coming soon.  Watch for Combigan (timolol 0.5% and brimonidine 0.2%) with twice-a-day dosing, which should be launched soon.

Extravan (TM) ophthalmic solution (a fixed combination of travaprost 0.004% and timolol 0.5%) is currently in Phase III trials.  Fixed combination medications simplify the drop regimen for some patients and may improve compliance.

P:  After bleb revision surgery last week, I had a difficult time finding Pred Forte.  The pharmacies only had a generic.  I finally found Pred Forte at an independent pharmacy. What is your opinion of generic eyedrops?

Dr. Pro:  In general, they are equal.  The manufacturer of generic drugs must prove that to the FDA to be approved.  But it’s true that they can be less comfortable, because sometimes they have different vehicles (liquid that the drug is in).  Generics may contain older-type preservatives, whereas some of the branded drugs use newer, milder preservatives.

P:  Which eyedrops have a cross-over effect?

Dr. Pro:  Well, the only one that makes any sense is the beta-blockers, where the drug has known systemic effects.  So, in theory, putting the drop in one eye could lower the IOP in the other.  That doesn't make sense for the prostaglandins, which really have no systemic effect.

P:  Can beta blockers cause irregular heartbeat?

Dr. Pro:  Yes. That class has respiratory and cardiovascular side effects.

P:  Are any better ways of instilling these expensive eyedrops being studied?  It's hard not to waste a bit.

Dr. Pro:  Some of the drug companies make dispensers that help the patients get the drops in the eyes.  Ultimately, we need a new drug delivery system that is easy for the patient, like a yearly injection.

P:  Is the manufacturer’s estimate of the number of drops per bottle correct?  I get at least double the amount of drops per bottle.

Dr. Pro:  You are probably the first patient to tell me that.  The manufacturer has the drops measured out pretty exact, so they can make the most money.  But the bottles are designed to dispense similar-sized drops, so I doubt that you are getting a half-drop.  Maybe you should hold the bottle higher, so a complete drop forms before you instill it in your eye.

P:  Isn't it possible that one or another of the glaucoma medications could actually cause an increase in IOP and greater damage in the presence of certain physical factors?  For example, if there were some venous constriction or obstruction in the outflow mechanism and the medication was designed to increase fluid outflow, couldn't that increase the IOP?

Dr. Pro:  Some medications can occasionally cause a paradoxical increase in IOP.  Unfortunately, it is never as mechanical as you suggest.  Rather, we usually don't know why some drops don't work for some patients.  The exception is when the angle is scarred shut. In that case, drops like pilocarpine won't work.

P:  Does any prostaglandin come in an ointment form?

Dr. Pro:  No, there is no need for that.  The drop is already used only once a day and lasts over 24 hours.

Moderator:  Thank you, Dr Pro.

Dr. Pro:  You are welcome.

On April 4 Dr. Wilson discussed "What is Glaucoma?" in the Chat room. Click here for highlights of that meeting.

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