Primary Drug Treatment for Glaucoma

SURVEY OF OPHTHALMOLOGY VOLUME 47 • NUMBER 1 • JANUARY–FEBRUARY 2002

VIEWPOINTS THOMAS L. SLAMOVITS AND JONATHAN J. DUTTON, EDITORS

Primary Drug Treatment for Glaucoma: Beta-Blockers Versus Other Medications I. Individualize Initial Therapy Robert L. Stamper, MD II. Choosing Beta-Blockers for Initial Medical Therapy for Glaucoma Stephen A. Wigginton, MD and Eve J. Higginbotham, MD Abstract. This set of Viewpoints articles examines the merits of beta-blockers versus other medications as the primary drug treatment for glaucoma. Ophthalmologists must balance issues such as efficacy, compliance, cost, and side effects when deciding on the appropriate medication to prescribe. Dr. Stamper stresses the advantages of tailoring the choice of medication to the needs of the individual patient. Drs. Wigginton and Higginbotham review the benefits of beta-blockers and present some of the disadvantages of the non-beta-blocker class of medications. (Surv Ophthalmol 47:63–73, 2002. © 2002 by Elsevier Science Inc. All rights reserved.) Key words. beta-blockers • compliance • cost • glaucoma • side effects

I. Individualize Initial Therapy Robert L. Stamper, MD Department of Ophthalmology, University of California, San Francisco, California, USA

Prior to 1978, only three classes of medications were available for the treatment of chronic glaucoma (both open- and closed-angle). These were topical miotics, topical nonselective sympathomimetics, and oral carbonic anhydrase inhibitors. Topical miotics were generally effective but often poorly tolerated because of induced myopia, poor night vision, fluctuating vision, or headache. Topical epinephrine or its analogs were useful but frequently associated with tachycardia, nervousness, and unsightly rebound hyperemia. Oral carbonic anhy-

drase inhibitors were also quite effective but often exacted a major price in systemic side effects such as lethargy, depression, gastrointestinal disturbances, and renal lithiasis. Stevens–Johnson syndrome and aplastic anemia were rare but devastating problems. We are fortunate today in having many new alternative medications with which to treat chronic glaucoma. The purpose of this article is to review the medical therapeutic choices for treating chronic glaucoma and to strongly urge that ophthalmologists and others who treat glaucoma individualize 63

© 2002 by Elsevier Science Inc. All rights reserved.

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initial therapy to suit the medical, social, and psychological status of each patient.

side effects are probably more common than generally acknowledged or appreciated because ophthalmologists usually don’t ask about them and patients do not associate systemic side effects with topical agents. Alopecia has also been reported (package insert, Timoptic Ophthalmic Solution, Merck & Co., West Point, PA). The concurrent administration of quinidine may reduce the metabolism of beta-blockers so as to induce higher levels of beta-blockade.14 Furthermore, the use of topical beta-bocking agents is a risk factor for falls in the elder population.17 Timolol should be avoided in women who are lactating, as it does cross into breast milk and its effect on infants has not been determined.26 Topical beta-blockers can be associated with dry eyes and superficial punctate keratopathy.4,29 Finally, topical beta-blockers may have a diminished effect if the patient is already using a systemic beta-blocker.31 Contrary to our initial hopes, the use of topical beta-blockers may be associated with side effects that take a long time to develop and may not be easily identifiable as such by the ophthalmologist, primary care physician, or patient. Yet these side effects may have a profound effect on the patient’s quality of life. Therefore, their initial use requires careful history taking to assess medical, social, psychological, vocational, and avocational factors. Furthermore, their continued use demands constant monitoring of these factors as our patients age and their medical, social, and psychological situations change. Prudence would dictate that one start with the lowest possible doses (e.g., 0.25% of timolol or l-bunalol once daily) and increase those doses only if intraocular pressure (IOP) is not controlled at these low doses.

Beta-Adrenergic Antagonists Topical beta-blocking agents revolutionized the medical therapy of glaucoma. For the first time, a topical medication was available that had few visual or ocular side effects. Systemic side effects also seemed few and mild, at least in the healthier volunteers reported on in the initial studies.41 Over twenty years later, beta-blockers are still among the most popular anti-glaucoma agents, and they have far surpassed any of their predecessors as the first therapy of choice in open-angle glaucoma. However, the initial hope of a side effect–free class of drugs has proven illusory. Although the topical side effects were few, the long-term systemic side effects of the beta-blocking agents have been shown to be many, often profound and, yet, frequently subtle. Exacerbation of asthma and chronic obstructive pulmonary disease due to induced bronchospasm are well known side effects; therefore, these agents are usually avoided in those patients with a history of bronchospastic disorders.30 Although the selective beta-blocker, betaxolol, is much less likely than a nonselective beta-blocker to induce bronchospasm, it still has that potential and should be used with great caution, if at all, in someone with active disease.2 Less well known is the fact that, even in someone with no history of asthma or obstructive airway disease, topical nonselective beta-blockers can be associated with a reduction in pulmonary function.11,12 If possible, nonselective beta-blockers should be avoided in patients who smoke, as most of them already have some compromise of pulmonary function, and the beta-blocking agents have the potential of further reducing pulmonary function, often to the point of causing symptoms. Bradycardia is another potential side effect, as are other forms of conduction defects. Since myocardial contractility is reduced, these agents can exacerbate congestive heart failure. Hayreh et al have recently reported that beta-blocking agents are associated with nocturnal hypotension, which may be a risk factor in progression of glaucomatous optic nerve damage.19 Most of the nonselective beta-blockers have the potential to adversely affect the plasma cholesterol levels, which may increase the risk of coronary artery disease.9 In younger patients, tolerance to excercise may be reduced.10 This is of concern to competitive athletes because they may find a decrement in their performance due to loss of maximum cardiac output, heart rate, and endurance. After prolonged use, depression, mood alterations, memory loss, hallucinations, decreased libido, and impotence can all occur.34 These types of

Prostaglandin Analogs In the last few years, three new classes of topical agents for the medical treatment of glaucoma have appeared: prostaglandin analogs, selective alphaadrenergic agonists, and topical carbonic anhydrase inhibitors. They have added significantly to our ability to manage glaucoma and have widened the choices of initial and continuing therapy. Latanoprost (Xalatan, [Pharmacia & Upjohn, Kalamazoo, MI]) and its chemical cousins, unoprostone isopropyl (Rescula, [CibaVision, Duluth, GA]), travaprost (Travatan [Alcon, Fort Worth, TX]) and bimatoprost (Lumigan [Allergan, Irvine, CA]) are prostaglandin-related, prostaglandin-like or, as may be the case with bimatoprost, prostamide, medications. They appear to lower intraocular pressure by increasing the uveoscleral outflow of aqueous humor, although not all of them may work via the same receptor systems. Unoprostone has been in use in Ja-

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pan for many years. It appears to be safe but not as effective in lowering intraocular pressure as latanoprost or the other agents in this class. Unoprostone is less likely to change iris color. It may work on different receptors than latanoprost, but the mechanism of action (increasing uveoscleral [non-pressure-sensitive] outflow) is the same. Unoprostone may even be additive to latanoprost. As best as can be determined, it is useful as a first-line drug only in those cases that do not need large pressure reduction. Little has been published about travaprost at this time, but preliminary reports are very promising. Bimatoprost does not seem to activate the same receptors as latanoprost but does act to improve both pressure-sensitive and pressure-insensitive outflow and is at least as potent (and perhaps slightly more so) than latanoprost.5,13 Bimatoprost once a day is more potent than timolol twice a day and seems to maintain a flatter diurnal curve.25,33 Both bimatoprost and travoprost have been approved by the FDA. The efficacy and side effects of these two medications seem to be similar to latanoprost. The prostaglandin-like or prostaglandin-related medications are our most potent topical pressurelowering agents.20,27 They work in almost minute concentration with once-daily dosing. Minor side effects include hyperemia, foreign body sensation, hypertrichosis, increased lower eyelid pigmentation, and superficial punctate keratopathy.1,21 More significant but uncommon side effects include herpes simplex or herpes simplex-like keratopathy, muscle aches, and flu-like symptoms.23,35,37,40 Use of latanoprost has been reported to be associated with exacerbation of uveitis and cystoid macular edema, but these associations have not been proven to be causal.28,38 Of some concern is the ability of these agents to cause an increase in the melanin granule population of melanocytes in the iris stroma, resulting in permanent iris color changes.39 Although no cellular proliferation or other dangerous sequelae of this effect have been seen, long-term consequences of prostaglandin use especially in young patients are of concern. Certainly, these agents should be avoided if possible in young patients who need unilateral treatment because of the risk of increased iris pigmentation and its increased recognizability when used in only one eye. Latanoprost and travaprost should also be avoided in pregnant women because prostaglandins are known to induce labor; although there are no reports of premature labor associated with the use of latanoprost, it seems prudent at this time to refrain from its use during pregnancy. Bimatoprost does not seem to have an effect on uterine muscle in vitro, but its effects in vivo have not been determined (Allergan, Irvine, CA, data on file).

Alpha-Adrenergic Agonists The selective alpha2-adrenergic agonist brimonidine is a potent intraocular pressure-lowering agent with efficacy about the same as timolol.22 It works by both increasing uveoscleral outflow and by decreasing aqueous formation. Usually, it is effective at twice-daily dosing but, in some cases, three-timesa-day dosing may be required. Side effects include the typical rebound hyperemia of adrenergic agonists along with conjunctival follicle formation. True allergy is less common but may have significant geographical variations. In some areas, topical allergy may approach an incidence rate of 25% or more. It is unknown how much of the concern regarding the imputed allergenicity of brimonidine is due to seasonal allergy exacerbated by brimonidine or true allergic reactions to brimonidine itself. However, because of this, brimonidine may not be the best agent to use as a first choice in someone with a strong history of seasonal allergic conjunctivitis. A new formulation, brimonidine with Purite as the preservative (Alphagan-P, [Allergan, Irvine, CA]) may decrease the incidence and severity of allergic reactions with brimonidine usage, and it has been approved by the FDA.38 Somnolence, dry mouth, headache, and dizziness are uncommon but potentially significant problems. The somnolence could interfere with the function of someone who operates machinery, drives for a living, or pilots an airplane. Cardiovascular and pulmonary side effects are rare.18,32 Very young children may be exceptions to this; severe hypotension and other cardiovascular side effects have been reported in infants and toddlers. Therefore, until further information is available, brimonidine should be avoided in children under 5 years of age.7,36 Apraclonidine (Iopidine [Alcon, Fort Worth, TX]) is a relatively nonselective alpha-adrenergic agent. Although it is a potent IOP-lowering agent in the short term, its high rate of tachyphylaxis and high incidence of allergy have made it less useful for long-term therapy.

Topical Carbonic Anhydrase Inhibitors The topical carbonic anhydrase inhibitors, dorzolamide (Trusopt [Merck & Co, West Point, PA]) and brinzolamide (Azopt [Alcon, Fort Worth, TX]) decrease intraocular pressure by reducing aqueous formation, and they have few systemic side effects. Rarely, transient gastrointestinal symptoms are seen. A metallic or distorted taste, particularly with carbonated beverages, may be experienced. Although slightly less effective than the beta-blockers, these agents are usually well tolerated.3 If used as monotherapy, they may require three-times daily dosing, but twice-daily dosing is usually efffective when they

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TABLE 1

Choices for Initial Therapy in Chronic Glaucoma Choose Once-a-day Beta-blocker Rx When . . .

Choose Latanoprost, Bimatoprost or Travaprost When . . .

Compliance is an issue Past history of CME, HSV, etc. Cosmetic concerns

Choose Brimonidine When . . .

Compliance is an issue Drowsiness a potential problem No cosmetic issues Beta-blocker concerns

Others a problem Patient is younger Past history of CME, HSV, etc.

CME  cystoid macular edema; HSV  Herpes simplex virus.

are used as adjunctive treatment. Recently, a combination of timolol and dorzolamide (Cosopt [Merck & Co, West Point, PA]) has been released for twicedaily dosing.8 Although the medication seems to be effective and by combining two medications into one bottle compliance should be improved, twicedaily dosing may be more beta-blocker than needed in many patients. Topically, allergic reactions may be seen. Dorzolamide may induce transient burning on administration, whereas brinzolamide may be associated with a white deposit or debris on the eyelids. Serious side effects are rare, but nephrolithiasis, corneal decompensation, hypotony, and choroidal detachment have been reported in patients using topical carbonic anhydrase inhibitors, although a causal relationship has not been firmly established for any of these.6,15,16,24 Corneal decompensation may occur in patients with already compromised endothelium, as these agents inhibit carbonic anhydrase which is required for the pumping action of corneal endothelial cells. Aplastic anemia and Stevens–Johnson syndrome have not been reported with the topical agents although they have been seen with oral carbonic anhydrase inhibitors; they remain a theoretical risk as with any sulfa-derived drug.

dorzolamide (Cosopt). However, combinations of latanoprost and timolol as well as brimonidine and timolol are being studied and may become available soon. Generally speaking, combinations should be avoided for initial therapy. Often, combinations may require overdosing with one of its ingredients in order to maintain adequate therapeutic levels for the other.

Conclusions We are blessed today with a variety of reasonable choices for medical treatment of chronic glaucoma. Given the long-term systemic side effect profile of topical beta-blockers, as well as the subtle nature of some of these side effects, it seems unwise to choose them automatically to begin therapy of glaucoma. In fact, good arguments can be made in many and perhaps most cases to choose either a prostanoid—such as latanoprost, bimatoprost, or travaprost—or brimonidine as the first medical therapeutic agent in chronic glaucoma. Each of our patients is an individual and our approach to treatment should reflect our understanding of and respect for their complex medical, ocular, social, psychological, and environmental history. Tables 1 and 2 may be helpful in choosing both initial therapy as well as secondary and adjunctive therapy.

References

Combinations Currently, only one combination (of the newer agents) has been approved by the FDA—timolol and

1. Alm A, Camras CB, Watson PG: Phase III latanoprost studies in Scandinavia, the United Kingdom and the United States. Surv Ophthalmol 41(Suppl 2):S105–10, 1997

TABLE 2

Choosing Initial Therapy for Chronic Glaucoma Avoid -Blockers When . . . COPD or Asthma Heart disease Dizziness Impotence Athlete Systemic beta-blocker Rx Lactating

Avoid Latanoprost When . . .

Avoid Brimonidine When . . .

Recent intra-ocular surgery Past history of CME, uveitism, HSV or high risk for them Cosmetic concerns Pregnant

Dry mouth Risky job where drowsiness could be a problem Under 5 years old

COPD  chronic obstructive pulmonary disease; CME  cystoid macular edema; HSV  Herpes simplex virus.

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The author has no commercial or proprietary interest in any product or concept discussed in this article. Reprint address: Robert L. Stamper, MD, UCSF Deptartment of Ophthalmology, 10 Kirkham Street, Room K-301, San Francisco, CA 94121. PII S0039-6257(01)00286-7