Glaucoma Drugs 2002

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Review of Optometry

GO

May 15, 2002

Current Topic:

Glaucoma

Glaucoma Medications
What's new for 2002? For the first time in a long time, the answer is: "Not much"...and thankfully so.

There are some slight refinements, but there have been no substantial
changes or additions to glaucoma medications in the past year. However, two concerns endure: one-half of all patients with glaucoma remain undiagnosed; and those that are diagnosed generally receive poor care, mostly through overmedication along with its attendant expense (both of which hinder compliance). In 2002, optimum glaucoma care remains achievable, even in modest clinical settings. Here's what you need to safeguard your patients' vision and help them maintain an acceptable quality of life:
1. Sound clinical knowledge, coupled with an intrinsic desire to apply the Golden Rule. 2. Stereoscopic biomicroscopic assessment of the optic nerve head. 3. Static threshold perimetry (Humphrey preferred). 4. Gonioscopy (four-mirror preferred). 5. Goldmann applanation tonometry (both slit lamp mounted and handheld).
Review of Ophthalmology

Patients with glaucoma represent some of the most poorly cared for people in the U.S., and probably worldwide. If there is one area where optometry can make a major contribution to public health, it's in the care of patients with glaucoma. We have "inherited" hundreds of patients with glaucoma over the years, and it has been the rare patient who was not being over-medicated. This leads to increased side effects, poor compliance and excessive costs. This chapter will address these three areas and others that, when understood and embraced in practice, can dramatically elevate the level of care for patients with glaucoma. Nearly all states have improved practice acts to allow for the care of glaucoma patients. Now the challenge before us is to collectively set new standards of excellence in glaucoma care for our patients. We hope the knowledge shared in this chapter will be a significant step in the pursuit of this goal. We now have an acceptable armamentarium of topical ophthalmic medicines

Vision Web

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to manage the vast majority of patients relatively simply. Of course, a thorough understanding of the glaucoma medicines is prerequisite to optimum patient care. And, as if mastering the drugs themselves were not challenge enough, there is the hype of neuroprotection and ocular blood flow, and all the new whiz-bang, high-tech glaucoma image analyzers. We think we can help simplify your life a bit. Put neuroprotection and blood flow out of your mind. It may well be several years before anything clinically meaningful will be available in this area. Just focus on reducing IOP sufficiently and efficiently while trying to minimize expense. Technological advances in objective tissue assessment continues, and one day will cross the threshold of clinical usefulness. As of this writing, there is no objective analyzer technology available that provides the sensitivity and specificity necessary to enable valid clinical judgments. The GDx, HRT and OCT efforts are valiant, and probably very soon will usher in a new wave of sound glaucoma assessment. Right now, we have ripples. The Humphrey OCT-3 appears very close to this threshold. The underlying mechanisms of axonal death in glaucoma remain speculative. One area of research centers around microvascular perfusion to the laminar portions of the optic nerve. Another area of research focuses on apoptosis-genetically programmed cell death. Apoptosis is the centerpiece of neuroprotection research, and its pharmacological manipulation may well be a crucial element in future therapy. According to one study, "These recent discoveries in glaucoma--that retinal ganglion cells can die by apoptosis, that nitric oxide may be implicated, that glutamate excititoxicity can cause cell death, and that autoimmunity has a potential role--provide encouraging new avenues for the development of neuroprotective strategies that may alleviate the ganglion cell loss and blindness that can unfortunately accompany this disease."1 The field of apoptosis inhibition is among the most rapidly growing in scientific research, and certainly provides hope that therapeutically sound interventions will soon be available. Our two prime concerns in selecting a glaucoma drug are efficacy and compliance. Of course, the safety of the medication is a major factor as well. Cost is a less critical concern, since the cost of most glaucoma therapies are not markedly different. Besides, the price of blindness is not measured in dollars.
Beta Adrenergic Receptor Antagonists (Beta-Blockers)

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Topical beta-blockers are the most commonly prescribed drugs to treat glaucoma, and traditionally have been the first-line drug for most glaucoma patients. Because this class of drugs has a successful 20-year track record and continues to be the most cost-effective therapy, it should remain initial therapy for most patients most of the time. All beta-blockers act by a similar mechanism--they inhibit aqueous formation by blocking beta2 receptors on nonpigmented ciliary epithelium. Non-selective beta- blockers block both beta1 and beta2 receptors; selective beta-blockers mostly block beta1 receptors. The non-selective beta-blockers are all similar in efficacy, causing about a 25% reduction in IOP. We now know that the most commonly prescribed betablockers--timolol and levobunolol, because of their half-lives--are just as effective taken as one drop of 0.25% solution once daily in the morning as 0.5% solutions taken bid. (An exception is a patient of African descent, who
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may require 0.5% qd.) Simple math shows the bid 0.5% regimen, which most glaucoma patients take, amounts to considerable overdosage, not to mention twice the expense and dosage complexity compared to qd therapy. Choosing the most appropriate beta-blocker sometimes simply comes down to personal preference. There are some distinctions, however, which we will point out here. Keep in mind that 10-20% of patients do not respond to betablockers. (See "Therapy on Trial," page 14A.) Also bear in mind that these drugs are not without potential side effects. Because beta receptor blockage of the pulmonary tissues can result in bronchospasm, use of beta-blockers is contraindicated in asthmatic patients. It is also wise to avoid these with patients having significant heart disease. At least consult with such a patient's physician prior to prescribing a betablocker. Also, keep in mind that if the patient is taking a betablocker systemically, the efficiency of topical beta-blocker therapy can be significantly muted. To minimize the patient's cost of therapy, we recommend using sample bottles for all initial therapeutic trials. Be sure to have the manufacturer of your drug(s) of choice keep you well supplied with adequate samples in order to be able to conduct these preliminary trials. This may require written and verbal inquiries to the drug companies, but this is an achievable goal. Once a course of therapy has been selected, write a prescription for the largest bottle available; this is either a 10ml or 15ml bottle. Although 5ml bottles are available, we rarely write for them, because they are relatively more expensive. The Timolols
q q

Timoptic and Timoptic-XE (timolol maleate) and generics Betimol (timolol hemihydrate)

Timoptic (Merck), the first beta-blocker, came to market in 1978. It is a nonselective beta receptor antagonist that is available in both a conventional solution and a gel-based delivery system (marketed as Timoptic-XE in a gellan gum-based vehicle). Timoptic and Timoptic-XE are now available generically, i. e., timolol maleate ophthalmic solution and timolol maleate in a xanthan gumbased vehicle. Of note, a "Dear Doctor" letter from Merck dated February 1, 2002 announced "product supply shortages" of Timoptic-XE that would preclude its availability only "intermittently through the first half of 2002." We recommend substituting Betimol for those patients; it will likely work as well and be considerably less expensive. We are constantly searching for ways to minimize the impact of glaucoma therapy on our patients. An excellent study in the December 1998 issue of Journal of Glaucoma confirmed what we have believed for years, that traditional solutions of timolol, instilled once daily in the morning, were as effective as the gel-forming delivery systems.2 What's more, gentle lid closure was not employed in this study. We wonder what additional benefits of IOP and side-effect reduction would be achieved if gentle eyelid closure had been used.

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Following the simple guidelines of 0.25% once daily beta-blocker therapy with gentle lid closure, one would have to question the wisdom of using the more expensive gel-forming solutions. Betimol (Santen Pharmaceutical) is a brand name of timolol hemihydrate that is not generically substitutable, yet is about the same cost as generic timolol maleate. It is well established that Betimol is equivalent in efficacy to Timoptic. Betimol, like Timoptic, is available in both 0.25% and 0.5% concentrations and is prescribed exactly as traditional timolol. Remember, good studies have shown that once-daily administration is equally effective as twice-daily. Using drugs with long half-lives, like timolol or levobunolol, once a day instead of twice would cut the price in half, and undoubtedly reduce the potential for side effects as well. Levobunolol This drug, marketed as Betagan by Allergan and also available generically, is very similar to timolol. It has the longest half-life of all the beta-blockers, and may be used very successfully once daily in many patients. The 0.5% concentration is approved by the FDA for once-daily dosing, but studies have clearly demonstrated that 0.25% works as well administered only once a day. We suggest trying the lower concentration, once daily first. Carteolol Carteolol (Ocupress, Novartis Ophthalmics and generics) is a highly hydrophilic compound which does not cross the bloodbrain barrier as readily as the lipophilic non-selective betablockers. This may protect against depression, a common side effect of non-selective beta-blockers. It also possesses "intrinsic sympathomimetic activity," which, for reasons not fully understood, may provide some systemic and ocular benefits over other types of beta-blockers. It also does not aggravate cholesterol or lipid profiles as much as the bid use of first-generation, non-selective beta-blockers. Therefore, it may be more appropriate for patients at risk for coronary or atherosclerotic disease and those with dyslipidemia. However, it is our belief that when traditional beta-blockers are used only qd, this advantage would be muted or eliminated. One way to mark these patients is a historical review of antihyperlipidemic drugs such as Questran, niacin, Zocor, Pravachol, Lopid, Mevacor, Lescol, Lipitor or other such therapeutic agents. Ocupress also tends to sting less than most of the other beta-blockers, which may help with compliance. This is especially true for patients with dry eyes. Carteolol is used q12h. Betaxolol

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Betaxolol is a unique, beta1 selective beta-blocker, and is probably the "safest" beta-blocker available. This drug must also be used q12h. Although beta receptors in the ciliary body are almost exclusively beta2, the common theory is that betaxolol is such a profound and potent blocker of beta1 receptors that it causes override to the beta2 receptors, decreasing aqueous production. Put another way, beta selectivity is heavily influenced by the concentration of the beta-blocker. Betaxolol, by Alcon, is available as either a 0.5% solution (Betoptic) or 0.25% suspension (Betoptic-S). The latter rarely stings upon instillation--a common problem with the solution form--yet achieves the same efficacy as the solution. Betoptic-S also requires only minimal shaking to maintain the proper concentration. This drug does not decrease IOP as effectively as a nonselective beta-blocker, but may do an equal or better job of preserving the visual field. This is, of course, the ultimate goal in glaucoma therapy. If long-term studies confirm this, betaxolol should enjoy even more widespread use. Even though it is a beta1-selective blocker, patients with active chronic obstructive pulmonary disease, emphysema or asthma should use an alternative, such as latanoprost, brimonidine or one of the topical CAIs. In addition, recent research indicates that non-selective betablockers may cause vasoconstriction of the microvasculature at the laminar level, which might offset some of the benefits of lowering pressure. Betaxolol via its partial calcium channel-blocking activity appears not to cause this side effect, which may explain how it is able to preserve visual field without lowering IOP as much as its non-selective counterparts. It's still theoretical, therefore we'll have to wait to see if this effect is shown to be real. Levobetaxolol Born under the shadow of its superstar sibling, Travatan, we foresee a relatively small role for Betaxon. This levo-isomer of betaxolol has a slightly enhanced therapeutic profile over its prototype betaxolol. Overall, it probably reduces IOP about 1 or 2 mm more than original betaxolol, and has the same excellent safety profile. Like betaxolol, it must be used q12h. While levobetaxolol is an upgrade over its predecessor, we feel all the flurry over the three prostaglandins will subdue its clinical use. Levobetaxolol--to be marketed as Betaxon 0.5% ophthalmic suspension, by Alcon--was approved by the FDA, but is yet to be launched. Metipranolol Available as Optipranolol by Bausch & Lomb Pharmaceuticals and generically, this non-selective beta-blocker is similar to timolol and levobunolol. A few cases of metipranolol-associated granulomatous uveitis have been reported. While this is very rare, it should be considered in the differential diagnosis should a patient develop the condition. This is an excellent, affordable drug. No studies have been done to show its efficacy when administered once daily.
Prostaglandin Analogs

Latanoprost

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It has become clear, now with nearly six years of widespread clinical use, that Xalatan (Pharmacia Corporation) was the most significant medical milestone in glaucoma therapy since the introduction of Timolol in 1978. The prostaglandins continue to enjoy the distinction of being the systemically safest drugs to treat glaucoma. Latanoprost's predominant mechanism of action is the enhancement of uveoscleral aqueous outflow. Approximately 10% of aqueous outflow in humans is via the uveoscleral pathway. It is generally thought that this prostaglandin analog biochemically loosens the intercellular spaces within the face of the ciliary body, enabling enhancement of uveoscleral aqueous outflow. This shifts the outflow dynamics such that perhaps 30% exits via the uveoscleral pathway and 70% exits via the trabecular meshwork. Studies have shown that latanoprost 0.005%, at one drop per day, reduces IOP more than timolol 0.5% bid, with a much better safety profile. About 90% of patients respond to latanoprost therapy, a rate similar to that of all other topical glaucoma medications. Latanoprost comes in a 2.5ml bottle containing about 90 drops, which provides about six weeks of bilateral therapy. Instruct patients to squeeze the thinwalled bottle gently to avoid spilling the solution. Initially, the dropper tip allowed overly easy egress; it has since been redesigned to rectify this problem. The average price to the patient is about $50 to $60 per bottle. That translates to about $450-$500 per year for bilateral therapy. Latanoprost is additive to all other glaucoma drugs with the exception of pilocarpine. The cholinergic agonist pilocarpine enhances trabecular outflow by contracting the longitudinal muscle of the ciliary body. This contraction also tightens the intercellular junctions on the face of the ciliary body, thus potentially reducing uveoscleral outflow and dampening the effectiveness of latanoprost. All medicines seem to have an Achilles' heel, and the prostaglandin class is no exception. Years of clinical experience have shown that while prostaglandins can cause iris darkening, especially in mixed-colored irides, it is considerably less than originally predicted. These changes are largely cosmetic and carry no known pathological implications. The pigmentary changes represent enhanced production of melanin pigment within the stromal melanocytes and not an increase in the number of melanocytes. There is no "leakage" of pigment from the iris into other ocular tissues. In practice, this color change potential is rarely a concern to patients, as most of them are thrilled at the success and the simplicity of latanoprost therapy. The key is to educate the patient about this potential side effect prior to initiation of therapy (some may even like having browner eyes). In general, these irreversible yet subtle pigmentation changes begin to occur six to 12 months into therapy. Such iris color changes are observed in less than 5% of our patients. Now that latanoprost has been used extensively, its side effect profile, while minimal, is beginning to show itself. Approximately 5% of patients in one study developed uveitis, and approximately 2% of patients developed CME. The latanoprost-associated iritis was generally low grade and did not develop until after two months of therapy. Iritis or CME, on the rare occasions when it occurs, almost always does so in patients with a history of these conditions, and hardly ever in patients without prior disease. A recent article has reported a few cases of herpes simplex keratitis thought to be causally related to topical latanoprost. It therefore seems prudent to try other therapies for this small subset of patients until this association is more
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thoroughly investigated.3 Based on published literature, it seems reasonable to use Xalatan with caution in patients with:
q q q q q

a history of uveitis or CME aphakia YAG posterior capsulotomy an anterior chamber IOL a history of herpes simplex keratitis

Hypertrichosis, a darkening, lengthening and thickening of eyelashes, seems to be the most common side effect seen with latano- prost. Whether this is a desired or undesired side effect may be in the eye of the glaucoma patient, much like the iris color change. Migraine headache can be triggered by Xalatan, according to a case report published in the February 2001 issue of Archives of Ophthalmology. While this is definitely rare, consider it if migraine headache occurs in temporal association with use of any prostaglandin or prostaglandin-like drug. Lastly, be aware that vague flu-like symptoms can be caused by latanoprost, and possibly by other prostaglandin drugs. Again, these are rare, but the astute clinician is always cognizant and vigilant. It generally takes about two weeks for the prostaglandins to achieve maximum, or near-maximum, therapeutic effect. For this reason, start the patient on a monocular therapeutic trial and reevaluate the patient in two to three weeks. Once a therapeutic benefit has been established, continue with bilateral therapy, if indicated. Travoprost Of the prostaglandins, travoprost most closely mimics all the characteristics of latanoprost. Just as the obsession with refrigeration of latanoprost has been moderated, so too, we predict, will be the current foil-packaging requirement for Travatan. We like the clear bottles of Xalatan and Travatan so patients can monitor their supply, however, it is important to preemptively explain to patients that both are purposefully halffilled to facilitate "dropper-ability." This will curb some whining about, "This little bottle isn't but half-full!" One interesting outcome from the phase III studies was a disproportionate decrease of IOP in the patients of African descent. On average, this subset of patients had an IOP 1.8 mm lower than the white subset. Whether this finding is spurious or real will only be known after a year or so of widespread clinical use. At this time, we think the drug will prove to be equally effective across race and ethnic groups. It is interesting that in the May 15, 2001 Ophthalmology Times, Wiley Chambers, M.D., Chief of Ophthalmology for the FDA, says, "If you cross-compare Xalatan, Travatan, and Lumigan, they all have a similar profile. They're comparable." Dr. Chambers said travoprost's claim regarding its effectiveness in black patients probably could be applied to bimatoprost and latanoprost. He said all three effectively reduce pressure and have similar side effects, including sometimes turning blue or green eyes brown. In summary, travoprost is a very similar drug to latanoprost, and is thought to have a similar performance and side effect profile. Travoprost is available in a 2.5 ml clear bottle which is packaged in a foil wrap similar to Bion Tears and TheraTears unit-dose containers.

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Bimatoprost Lumigan is the third member of this elite drug class. Because of its somewhat unique chemical structure, it has to be more concentrated, i.e., 0.03% (versus 0.005% latanoprost and 0.004% travoprost). Lumigan reduces IOP very similarly to Xalatan and Travatan--about 30%. It is to be used once daily and, like Xalatan and Travatan, may be ever so slightly more effective if used in the evening. Lumigan acts by enhancing aqueous outflow, probably via the uveoscleral pathway and possibly the trabecular pathway, as well.4 They are all thought to "loosen" the intercellular connections of the uveoscleral tissues, thereby allowing more aqueous to be shunted down this secondary outflow pathway. A careful read of the package inserts of Lumigan, Travatan and Xalatan shows virtually identical language regarding their side effect profiles. Widespread clinical use of these three drugs will allow subtle differences among these drugs to be appreciated. In summary, Lumigan is a potent prostaglandin drug that, when used once daily, can reduce IOP about 30% with minimal side effect potential. It does have the greatest tendency of the three to cause transient conjunctival hyperemia. Patients should be advised upfront of this possibility to avoid unnecessary panicked call-backs. The redness generally abates over a few weeks and does not cause harm. Since the three prostaglandin drugs are roughly clinically equivalent, the main deciding factor may be as simple as price. Lumigan is the only prostaglandin to come in an opaque bottle. This has the advantage of preventing patients from complaining about the bottle being only half-full, as some do who use the clear-bottled prostaglandins. The disadvantage is that patients cannot judge when the bottle is nearly empty, and may cause some patients who fail to plan ahead to occasionally miss dosing. Another uniqueness of Lumigan is its availability in 2.5ml, 5.0ml, and soon-tobe-released 7.5ml sizes. There are some insurance plans which cover medicines for up to a three-month supply with only one co-pay. Having 7.5ml of solution available in one bottle could prove very cost-saving for patients with such plans. Otherwise, an out-of-pocket estimate charge of $140 for that size bottle could create serious sticker-shock at the pharmacy check-out counter.
Docosanoid Compounds

A new class of IOP-lowering compounds was ushered into American medicine by the FDA in August 2000. Docosanoid drugs have been in clinical use in Japan and other countries since 1994. Unoprostone Docosahexaenoic acid (DHA) is the prototypic docosanoid (unoprostone isopropyl) known by the band name Rescula (0.15% ophthalmic solution) by Novartis Ophthalmics. While docosanoids share similarities with prostaglandins, they behave differently. We have developed a table (see page 21) to succinctly characterize these two classes. Although Rescula is not indicated for first-line therapy, studies

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have shown that it is equitherapeutic to brimonidine, beta-blockers and topical CAIs as adjunctive therapy. As monotherapy, it reduces IOP similarly to betaxolol. Currently, there are no known systemic side effects, which makes Rescula the safest known topical glaucoma drug. Only when drugs leave the relatively protected harbor of phase III studies and enter the waters of widespread clinical use is their full character known, but all assessments at this time give Rescula an excellent safety profile. Because of its efficacy and safety, we foresee Rescula's main role as additive to primary therapy of all drug classes when monotherapy fails to achieve target IOP, and combination therapy is needed.
Alpha Adrenergic Receptor Agonists (Alpha Agonists)

This class of drugs is represented by apraclonidine (Iopidine) and brimonidine (Alphagan). Since brimonidine is vastly superior to apraclonidine, we will limit our discussion to brimonidine. Brimonidine Brimonidine is now available in two forms: Alphagan 0.2% ophthalmic solution and Alphagan-P 0.15% ophthalmic solution. Very simply, Allergan has replaced the BAK preservative with a much less toxic proprietary preservative, Purite. This is the same non-toxic preservative that is used in their Refresh Tears artificial tear. The 0.15% solution is equieffective to the 0.2% traditional solution. This alpha adrenergic is roughly equivalent to timolol 0.5% bid, yet it has a considerably enhanced safety profile. Like apraclonidine, it is approved for tid therapy. There is some debate on whether tid or bid dosing is better. While tid administration will give maximum IOP reduction, most studies have found that bid administration will adequately reduce IOP in most patients. Since compliance decreases as the complexity of the dosing increases, we generally prescribe brimonidine bid. We tell the patient to instill the first drop within the first hour upon awakening, and the second drop by mid- to late afternoon. This hopefully achieves maximum IOP lowering when it's at its highest, during waking hours. We occasionally recommend three minutes of gentle eyelid closure to maximize ocular absorption and effectiveness, and minimize systemic absorption. (We employ this technique in patients on multiple po medications and/or those who have poorer health when prescribing adrenergic acting medications, i.e., the beta-blockers and the alpha adrenergic receptor agonists.) Brimonidine can be used as a first-line drug or as adjunctive therapy. We generally prefer a trial of low-dose (0.25%) q a.m. Betimol as initial therapy. However, if bid beta-blocker therapy is considered as initial therapy, then we strongly prefer bid brimonidine instead because of its enhanced systemic safety profile. Apraclonidine and brimonidine share many similarities. Both reduce IOP by approximately 20-25%. Both are useful in treating acute rises in IOP such as post-laser spikes and angle closure. Both are relatively safe, their main systemic side effects being dry mouth and fatigue. Uveitis was reported in the September 2000 American Journal of Ophthalmology to be a potential late side effect, so be aware of this relatively newly observed association. This granulomatous uveitis was seen after about one year of brimonidine therapy,
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and subsided upon cessation of the drug. The alpha adrenergic agents primarily inhibit aqueous production, although brimonidine may also enhance uveoscleral outflow somewhat. To us, brimonidine appears to represent a clinically significant advance, and stands as the alpha adrenergic agonist of choice in the management of primary open angle glaucoma. Only because it is a bid drug do we not use it as one of our initial drugs of choice. Of note, most patients who developed an allergic response to apraclonidine can successfully use brimonidine.
Carbonic Anhydrase Inhibitors (CAIs)

CAIs work by reducing the carbonic anhydrase activity in the ciliary processes. In the ciliary epithelium, the production of aqueous humor is a function of the production of bicarbonate. By reducing bicarbonate production, aqueous formation is reduced, thus decreasing IOP. These drugs can be valuable in certain patients. However, with the advent of the more clinically efficacious drugs latanoprost and brimonidine, this class of drugs has a relatively limited role in reducing IOP. Since these drugs inhibit bicarbonate function, there is some concern that corneal endothelial function may be partially compromised. Likewise, mucin production by corneal epithelial cells is somewhat dependent on bicarbonate function. These concerns are gaining more ground in the literature, and until research further elucidates the impact of CAIs on endothelial and epithelial function, it would be wise to use these drugs with caution in patients with clinically significant guttata, endothelial compromise, those with significant ocular surface disease, and especially in eyes that have sustained surgery.5 Although CAIs are sulfa-based compounds, these topical drugs probably do not share sulfa allergy with sulfonamide antibacterials because of significantly different chemical structures. But until widespread use proves this, avoid CAIs in patients with a true sulfa allergy. Also, no measurable amount of these drugs is found in blood plasma, so there is little or no impact on renal physiology. Carbonic anhydrase inhibitors are available in both ocular and systemic forms, although the advent of topical therapy has reduced, but not totally eliminated, the need for oral therapy. Dorzolamide This 2% solution of Trusopt (Merck) reduces IOP about 15-20%. Like latanoprost and brimonidine, dorzolamide may be very useful for asthmatics and patients with normotensive glaucoma where vasoconstrictive effects may be a concern. Dorzolamide is FDA-approved for tid use, but clinical studies have shown that bid administration is nearly as effective as tid dosing, particularly when used in additive therapy. For the rare occasions when a CAI would be used as monotherapy, tid administration may be needed to achieve maximum IOP reduction.

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We recommend initial dosing as one drop within one hour of waking and the second before dinner. Since CAIs exhibit some melanin-binding, tid administration may be necessary in patients with dark irides for maximum benefit. In most cases, topical therapy with this CAI can replace systemic CAI therapy with good preservation of IOP control. If you undertake a systemic-to-topical switch (which is a wise therapeutic trial), be sure to monitor IOP to ensure no unacceptable loss of IOP control has occurred. An excellent study in the January 1997 Archives of Ophthalmology demonstrated that systemic acetazolamide reduced aqueous flow by 30% whereas topical dorzolamide reduced flow only 17%. They conclude: "Clinicians who prescribe dorzolamide should expect less of an ocular hypotensive effect than that experienced from systemically administered acetazolamide."6 The judicious use of systemic therapy may well enable the achievement of target IOP with minimal side effects, and remains a viable therapeutic approach in select patients. About 75% of patients taking an oral CAI can switch to dorzolamide with no loss of IOP control. One-quarter of patients notice a bitter taste in their throat when taking dorzolamide. Gentle eyelid closure for three minutes tends to eliminate or minimize systemic absorption. Brinzolamide This newest addition to the CAI family is a 1% ophthalmic suspension marketed as Azopt (Alcon). Trusopt and Azopt perform equally well in clinical use. Clinical data does show that it tends to produce less stinging and burning than dorzolamide does. Although it is a suspension, minimal shaking is required because of Alcon's unique proprietary carbopol suspension system, which is also the suspension vehicle in Betoptic-S and Vexol. While both brinzolamide and dorzolamide are very much interchangeable, we generally use brinzolamide for the above stated reasons. Because topical CAIs can cause corneal decompensation in diseased post-operative corneas, avoid topical CAIs in this tiny subset of patients. Dorzolamide/Timolol Maleate This is the first combination drug for glaucoma (dorzolamide 2% with timolol maleate 0.5% ophthalmic solution) since pilocarpine/epinephrine, and far more advanced. Cosopt (Merck) is intended to be used when beta-blocker therapy alone does not achieve the target IOP. It may reduce IOP about 30% in most patients responsive to each of its component drugs. Cosopt is to be used bid. We are disappointed that Cosopt is only available with 0.5% timolol maleate. This will force the prescriber to needlessly overexpose the patient to the potential adverse effects of beta-blockade. Combining dorzolamide with 0.25% timolol maleate would have honored the knowledge extensively published in the ophthalmic literature. For this reason, our use of Cosopt will be reserved for unique cases where the risk/benefit to our patient is met. For example, a patient taking a beta-blocker who is non-responsive to brimonidine and the prostaglandin class of drugs, yet requires additional topical therapy to achieve target IOP, may benefit from Cosopt. Another exception may be in some patients of African descent where a higher concentration of beta-blocker is occasionally required to achieve maximum
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response to a beta-blocker, and where the 0.25% nearly achieved target IOP. The addition of newer drugs in the anti-glaucoma cauldron does indeed make therapeutic decision-making more complex. Where will Cosopt fit into the algorithm of glaucoma therapy? Our opinion is that it could be used after a therapeutic trial of a beta-blocker where...
1. The target IOP was nearly achieved yet an additional 2 or 3mm Hg of reduction is desired, and... 2. Where a monocular trial of dorzolamide or brinzolamide has been shown to be effective.

Once these two criteria have been met, only then is it prudent to do a trial with Cosopt to determine if it can indeed achieve target IOP. It seems to us much simpler to try this alternative approach: If the beta-blocker comes close, yet is still 2 or 3mm Hg shy of target, stop the beta-blocker and try one of the "big three"--Xalatan, Lumigan or Travatan. One of these less expensive approaches may well achieve target IOP more simply and safely, and less expensively. Alternatively, what if the beta blocker qd combined with one of the "big three"(total daily instillation frequency of bid) does not achieve target IOP? Rather than add brimonidine to the beta-blocker (which would now result in tid therapy), consider a trial of Cosopt bid, based on the principle that the simpler the therapy, the better the patient compliance. There are now several ways to mix and mingle the glaucoma drugs, so try to use the least amount of drug to met the IOP target goal while minimizing the impact on the patients overall quality of life.

— References —
1. Dreyer EB, Lipton SA. New perspectives on glaucoma. JAMA 1999;281 (4):306-8. 2. Stewart WC, et al. Efficacy and safety of timolol solution once daily versus timolol gel in treating elevated intraocular pressure. J Glaucoma 1998;7(6):402-7. 3. Wand M, et al. Latanoprost and herpes simplex keratitis. Am J Ophthalmol 1999;127(5):602-4. 4. Brubaker RF, et al. Effects of AGN 192024, a new ocular hypertensive agent, on aqueous dynamics. Am J Ophthal 2001 Jan;131(1):19-24. 5. Konowal A, Morrison JC, et al. Irreversible corneal decompensation in patients treated with dorzolamide. Am J Ophthalmol 1999;127(4):403-6. 6. Maus TL, Larsson LI, et al. Comparison of dorzolamide and acetazolamide as suppressors of aqueous humor flow in humans. Arch Ophthalmol 1997 Jan;115(1):45-9.

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