The introduction of several new topical glaucoma agents over the past decade allows us greater flexibility in tailoring a treatment regimen to each patient's specific situation. It also means that the task of selecting an appropriate therapy plan has become considerably more complicated than in the past, when topical beta-blockers and pilocarpine were our chief therapeutic weapons. Clinicians are becoming increasingly adept at mixing and matching agents, or substituting one for another, to achieve maximal efficacy, safety and tolerability. Ongoing clinical investigations likewise provide useful information to help guide us in crafting effective, individualized treatment plans.

What follows are two case histories in which the demand for therapeutic flexibility prompted changes in treatment regimens that led to favorable outcomes. No doubt, we have all seen cases like these. As you read through them, see if my treatment plan accords with what you might do in a similar situation. The sidebars review what we know to date about the four main classes of glaucoma medications.

Case 1: Glaucoma Suspect Treated With Alpha-2 Agonist, Prostaglandin

A 76-year-old black female presented for a comprehensive examination with complaints of blurred vision at near. She was correctable to 20/20 in each eye with a mild hyperopic prescription. Goldmann tonometry at 9 a.m. revealed elevated intraocular pressures of 28mm Hg O.D. and 26mm Hg O.S. The patient denied a family history of glaucoma. She was taking Tenormin (atenolol), an oral beta-blocker, for atrial fibrillation, along with Coumadin (warfarin).

FDT screening C 20-5 visual fields were full in each eye. Gonioscopy revealed grade-3 open angles in each eye with scant pigmentation. Pachymetry measured corneal thickness of 556m O.D. and 553m O.S.

Stereoscopic optic nerve and retinal examination revealed suspicious optic nerves, with a large diffuse cup in an average-size optic disc. There was slight cup-disc asymmetry; the right cup appeared larger and deeper with a thinner neuro-retinal rim. The nerve fiber layer, easily visualized, appeared robust in each eye with no evident defects. There was zone-alpha peripapillary atrophy in both eyes, but no zone-beta peripapillary atrophy.

Retinal examination revealed suspicious optic nerves, with a large diffuse cup in an average-size optic disc. The right cup (left) appeared larger and deeper with a thinner neuroretinal rim than the left.

Peripapillary atrophy (PPA) refers to a thinning and change in pigmentation in the chorioretinal tissues surrounding the optic nerve. There are two forms of PPA: zone-alpha and zone-beta. Zone-alpha is characterized by hypo- or hyperpigmentation, along with thinning of the chorioretinal tissues, and is found in almost all normal eyes. Zone-beta bears a relationship with glaucoma, and may change and enlarge over time. Its characteristics include significant retinal pigment epithelium loss, chorioretinal tissue thinning, and visibility of choroidal vessels. Zone-beta appears in up to 20% of normal individuals. It is closer to the optic disc while zone- alpha is adjacent to the retina.^1,2

Two weeks later, this patient returned for follow-up. Her IOPs were now 26mm Hg O.D. and 24mm Hg O.S. at 2 p.m. Humphrey SITA Standard 24-2 perimetry produced full visual fields in each eye. Fields were also full on FDT Threshold N-30 perimetry.

We diagnosed ocular hypertension, noting elevated IOP and a cardiac arrhythmia as the main risk factors for glaucoma. We talked with the patient about the best course of action. The management plan ranged from careful monitoring for the development of glaucomatous damage without therapy, to initiating topical medications to reduce the IOP and minimize the chance of glaucomatous optic neuropathy. Atenolol, a cardioselective beta-blocker, was probably exerting some effect on the IOP; it would be higher without the medication.

We decided to institute therapy with a target IOP range of 16-18mm Hg. Because she was already taking an oral beta-blocker, we did not consider a topical counterpart, for this would likely provide negligible additional reduction. Instead, the choice for the primary agent was between the prostaglandins and alpha-agonists. Topical carbonic anhydrase inhibitors, which are less effective at lowering IOP, are usually reserved as a second-line or supplementary agent.

We chose Alphagan (brimonidine), an alpha-2 adrenergic receptor agonist, and initiated therapy in the right eye bid. We explained the potential side effects of Alphagan and how to instill the medication, and gave her a written dosage schedule. We also instructed the patient to return in one month.

After one month of Alphagan therapy in the right eye, IOPs were 21mm Hg O.D. and 26mm Hg O.S. at 8 a.m., one hour after instillation. The IOP reduction was 5-7mm Hg O.D. (20-25%), with little carryover in the left eye. This reduction was considerable, and the patient reported no side effects.

The next management question: Should we have her use Alphagan in both eyes and accept an IOP in the low 20s (hoping for additional reduction over time); or add a second medication; or substitute a different medication to lower IOP to the target level with a single agent? A trend in glaucoma management is to try to use as few medications as possible, and to switch when one medication is effective but does not reach the target goal.

Because the target IOP may have been within reach only by switching to a topical prostaglandin, we decided to do a monocular trial with Travatan (travoprost) in the right eye. We told the patient not to discard the remaining brimonidine, because we might need it later for further IOP reduction. For now, she was to use only Travatan in the right eye at bedtime.

We counseled the patient that hyperemia may occur at the outset, but that the redness should decrease over the first weeks of therapy. This should not be a major concern unless the eye becomes painful or photophobic. Because her iris color was a homogenous dark brown, cosmetic iris color changes were not a concern. We also told her that her eyelashes might lengthen and darken. (She liked that prospect.)

She returned two weeks later with IOPs of 17mm Hg O.D. (a 35% reduction) and 25mm Hg O.S. She had a trace amount of hyperemia in the treated eye. This did not bother her, because she said it was improving every day.

We now instructed her to use Travatan in both eyes at bedtime and to return in a month. At that visit, IOPs were 16mm Hg O.D. and 14mm Hg O.S. There was evidence of trace hyperemia O.U., but without symptoms. The patient was to continue on the medication and return in three months.

Case 2: Primary Open Angle Glaucoma Treated With Beta-Blocker, CAI

A 52-year-old black male presented for a routine comprehensive examination, his first in four years. He wore reading glasses, and his chief complaint was blurred vision at near. The patient was in excellent health. He denied allergies to any medications, and reported that his older sister has glaucoma. His uncorrected visual acuity was 20/20 in each eye at distance and near.

FDT screening perimetry unveiled repeatable defects in both eyes. Goldmann applanation tonometry measured intraocular pressures of 26mm Hg O.D. and 24mm Hg O.S. at 9:30 a.m.

Each eye displays large optic discs with thin neuroretinal rim tissue. Rim tissue in the temporal quadrants was absent, with thin surrounding nerve fiber layer. The right eye (left) displayed a small area of peripapillary atrophy (zone-beta) temporally.

Dilated optic nerve examination showed large optic discs with thin neuroretinal rim tissue in each eye. Rim tissue in the temporal quadrants was absent in each eye, with thin surrounding nerve fiber layer. A small area of peripapillary atrophy (zone-beta) was evident temporally in the right eye.

When the patient returned the next day, IOPs were 25mm Hg O.D. and 24mm Hg O.S. at 11 a.m. Humphrey 24-2 SITA Standard visual fields revealed a dense inferior arcuate scotoma O.D. and diffuse loss O.S., probably on the way to developing double arcuate scotomas. Gonioscopy revealed wide-open angles with ciliary body in all quadrants of both eyes.

We diagnosed primary open angle glaucoma, and started the patient on Timoptic (timolol 0.5%) O.D. bid as a monocular trial. The pulse rate was 76 bpm and regular before therapy began. We counseled the patient to close his eyes for three minutes after instilling the drop, and taught him how to do that. We described the nature of glaucoma, the side effects of Timoptic and the reasons for using it. The target IOP goal, based upon the extent of damage and highest IOP readings, was 15-16mm Hg. We instructed the patient to return in two weeks for follow-up.

IOPs at the return visit were 19mm Hg O.D. (a 27% reduction) and 23mm Hg O.S. The patient reported no side effects. His pulse rate was now 68 bpm. We now instructed the patient to use Timoptic O.U. bid, and to return in one month. At this return visit, IOPs were 20mm Hg O.D. and 18mm Hg O.S. (about a 25% reduction in each eye). That was a substantial drop, but still not low enough to meet the target IOP goal of 15-16mm Hg.

We now added dorzolamide to the therapeutic regimen for the right eye in the form of Cosopt (timolol 0.5%, dorzolamide 2%) bid, and told the patient to continue using Timoptic bid O.S. At the next visit, IOPs were 16mm O.D., 19mm Hg O.S. The patient denied any problems with the use of Cosopt. We now instructed him to use the medication bid in both eyes.

One month later, IOPs were 16mm Hg O.D. and 15mm Hg O.S. The medication was well-tolerated, and the IOP was now within the target pressure range. We instructed the patient to return in three months.

 

Prostaglandin-like Agents Xalatan (latanoprost 0.005%), approved in 1996 was the first of the group of medications referred to as prostaglandin or prostaglandin-like agents. Latanoprost reduces IOP more effectively than timolol, up to 35% when used once a day.7 Rescula (unoprostone isopropyl 0.15%), FDA-approved in fall 2000, requires a bid dosage schedule to lower IOP by 16-22%.8 Labeled as a docosanoid, unoprostone reduces IOP by a dual mechanism of increasing uveoscleral and trabecular meshwork outflow. As a metabolite of a prostaglandin,9 unoprostone does not lower the IOP as much as the other prostaglandin medications.10 There have been few reports of iris color darkening, anterior uveitis or other side effects with unoprostone compared with latanoprost and the other prostaglandins.11 Travatan (travoprost 0.004%) and Lumigan (bimatoprost 0.03%) are the newest of the prostaglandin-like medications, released in March 2001. Travoprost is a prostaglandin that enhances uveoscleral outflow.12 It is an FP prostanoid receptor agonist with many similarities to latanoprost, and is at least as effective as latanoprost with an IOP-lowering efficacy of 26-36%.13 Data show that travoprost has greater efficacy in blacks than latanoprost and timolol.14 Bimatoprost's dual mechanism enhances both uveoscleral and trabecular meshwork outflow. Bimatoprost is a prostamide, and there is a question as to whether it stimulates the PGF2-alpha receptor or some other as-yet-unidentified receptor.16 Whatever its mechanism, bimatoprost reduces IOP by 26-36 %.15 Its indications and contraindications are similar to those of latanoprost and travoprost. Bimatoprost's concentration exceeds that of latanoprost or travoprost; whether the increased strength has any undesired systemic side effects will be seen over time. The IOP-lowering efficacy of latanoprost, bimatoprost and travoprost is greatest when used once a day; twice-daily use blunts their effectiveness. Their recommended dosage is at night, in part due to the hyperemia associated with the medication; this may be less severe after a night's sleep. Travoprost and bimatoprost showed no difference in efficacy whether used at night or in the morning.13,15 Prostaglandin-like medications are additive to other glaucoma medications. Systemic side effects are rare, but several ocular side effects have been reported. Increased conjunctival hyperemia occurs in up to 30% of individuals.17 Pruritus is also common. Increased iris pigmentation has been observed, especially in lightly pigmented eyes with mixed color such as green-brown or blue-brown eyes (concentric heterochromia). Darkening of the iris, which has been noted in up to 16% of patients using prostaglandin-like agents and which appears to be permanent,18 is due to an increased number of melanosomes (pigment granules) within melanocytes of the iris stroma. Clinicians must inform patients about this potential side effect before initiating therapy, and document the iris color. If there is a color change, discontinue treatment if it is bothersome to the patient. No evidence of further color change has been reported after discontinuation. Pigmentary changes in the skin around the eye have also been reported with prostaglandin-like medications.19 Other reported side effects include corneal pseudodendrites that disappear after stopping latanoprost, and the potential exacerbation of herpes simplex viral (HSV) keratitis in individuals who have had prior HSV infections.16 Eyelashes may lengthen and thicken, and there are reports of reactivated anterior uveitis and cystoid macula edema.21-23 Prostaglandin-like medications are becoming extremely popular in glaucoma therapy due to their excellent efficacy, safety index and tolerability. They flatten the diurnal curve significantly and achieve the greatest IOP reduction of any class of topical medication. Patients often can get to the desired target pressure with a single agent, as in the first case presented here. While the drugs may cause side effects such as hyperemia and pruritus, for many individuals their once-a-day schedule makes it easy to adhere to a treatment regimen. Many clinicians use prostaglandin-like medications as their primary therapy.

Alpha-2 Adrenergic Receptor Agonists The initial agent in this drug class was Iopidine (apraclonidine 1%), followed by apraclonidine 0.5%. Two significant problems occurred with apraclonidine.3 Allergic blepharoconjunctivitis developed in 20-50% of users, and tachyphylaxis occurred in up to 50%.4 Today, the medication is seldom used. In 1996 the FDA approved Alphagan (brimonidine 0.2%), a relatively selective alpha-2 adrenergic receptor agonist that has become the alpha-2 agonist of choice. Recently, we witnessed the release of Alphagan P (brimonidine 0.15%), using the preservative Purite to reduce the incidence of hyperemia, toxicity and allergic reactions. Brimonidine has a dual mechanism for decreasing the IOP: It suppresses aqueous production and enhances uveoscleral outflow.5,6 Brimonidine may cross the blood-brain barrier, leading to potential central nervous system (CNS) side effects such as fatigue; this is why brimonidine should never be used in children. Brimonidine’s penchant for inducing allergic conjunctivitis is less than with apraclonidine, though still considerable (10-15%). Tachyphylaxis has not been a problem with brimonidine. The new Alphagan P replaces the preservative benzalkonium chloride (BAK) with Purite, an oxychloro complex that breaks down to natural components when exposed to light. A neutral pH further minimizes toxicity, and enhanced bioavailability allows a reduced concentration of the drug to achieve efficacy equivalent to that of the original Alphagan. Clinicians are seeing fewer instances of allergic conjunctivitis associated with Alphagan P, most likely owing to its lower concentration. Brimonidine’s efficacy is similar to that of timolol at its peak effect. Brimonidine loses its IOP-lowering effect more quickly than timolol, so that at trough (8-12 hours after instillation), its efficacy is diminished.5 This is why the FDA labeled the medication with a tid dosage, though most clinicians use it bid. The clinical concern for individuals using Alphagan as a sole agent is that you need an afternoon IOP reading to determine whether you are getting adequate diurnal control. Alphagan P should become the alpha-2 agonist of choice since its cost and efficacy are believed to be comparable to Alphagan but with fewer side effects.

Topical Beta-Blockers Topical beta-blockers first became available in 1978 with the introduction of Timoptic (timolol), which decreases aqueous production. Topical nonselective beta-blockers reduce IOP 22-26%, and patients may use them either once or twice daily.24 The onset of this class of drugs starts 30 minutes after instillation, with a peak effect in one to two hours. Since aqueous production is reduced naturally while a person sleeps, most of the drug's efficacy occurs during waking hours. Many individuals can successfully use topical beta-blockers once a day (in the morning). Topical beta-blockers are comfortable when instilled, but side effects, predominantly systemic ones, are a concern. They relate to the blockade of the beta-adrenergic receptors. When cardiac or pulmonary receptors are involved, pulmonary capacity or heart rate is reduced; bronchospasm, weakness and lethargy may ensue. Cardiovascular complications include bradycardia, hypotension, elevated cholesterol levels, syncope and heart failure.25 When the medication crosses the blood-brain barrier, CNS side effects may include general lethargy, anxiety, confusion, decreased libido and depression. Individuals using calcium channel blockers when placed on beta-blockers have the risk of developing severe bradycardia.26 Patients at greatest risk for developing systemic side effects are the elderly and frail, and those with severe illness. Contra-indications to topical beta-blockers include chronic obstructive pulmonary disease (COPD), asthma, emphysema and other pulmonary conditions; cardiovascular conditions, including bradycardia, congestive heart failure or heart block; and depression. One way to reduce systemic absorption is to have patients close their eyes or occlude the puncta for three minutes after instilling the drop. Oral beta-blockers used to treat hypertension or other cardiovascular conditions may reduce IOP. When someone is already using a systemic beta-blocker, a topical one adds little to IOP reduction; it only increases the risk for side effects. Timolol is available in two forms: maleate (Timoptic) and hemihydrate (Betimol). Both have equivalent efficacy with similar side effects. Timolol also comes in two different concentrations: 0.25% and 0.5%. The 0.25% concentration is effective in lightly pigmented individuals; the 0.5% is usually indicated in patients with darker complexions. Timolol is also available as a gel (Timoptic-XE, Falcon gel). This form, used once a day, reduces the amount of medication absorbed systemically. Nonselective Beta-Blockers Medication Concentration Dosing Brand name Timolol hemihydrate 0.25, 0.5% solution qd or bid Betimol Timolol maleate 0.25, 0.5% solution qd or bid Timoptic, generic Levobunolol 0.25, 0.5% solution qd or bid Betagan, generic Carteolol 1% solution qd or bid Ocupress Metipranolol 0.3% solution bid OptiPranolol Ocupress (carteolol) is a unique nonselective beta-blocker with intrinsic sympathomimetic (ISA) activity. ISA allows blockage of the adrenergic system at certain receptors and stimulation at others. One advantage of ISA: Carteolol does not appear to affect the heart rate or cholesterol level as other beta-blockers do.27 So, one indication for the use of Ocupress may be in individuals with a history of cardiovascular disease. Betoptic (betaxolol) is a cardioselective beta-blocker that reduces IOP by about 20-22%.28 This beta1-blocker has reduced affinity for the beta2 receptors of the pulmonary and gastrointestinal tissues. While betaxolol is specific for the beta1 receptors, its affinity for those receptors is less than that of timolol.29 This makes Betoptic a safer drug than the nonselective beta-blockers when you are concerned about cardiovascular, pulmonary or central nervous system effects. Even so, Betoptic should not be the initial drug of choice for individuals with pulmonary problems. It may be used in those with a relative contraindication when other medications have not performed as required, but only if approved by the patient's internist. Betaxolol comes in a 0.25% suspension (Betoptic-S) and a 0.5% solution (Betoptic). Studies comparing the two have shown equal clinical efficacy. Both forms are used every 12 hours. Ocular side effects of Betoptic include stinging and burning, more so than with Betoptic-S (or timolol). Several studies have shown that betaxolol enhances blood flow to the optic nerve.30,31 A new, more efficacious form of betaxolol, the S-isomer (Betaxon), will shortly become available. This medication has a side effect and safety profile similar to other forms of betaxolol, but appears to yield a 22-24% greater IOP reduction.32 A dissipation phenomenon common to the beta-blockers is known as short-term "escape" and long-term "drift." When starting therapy with a topical beta-blocker, there is an initial IOP reduction that lasts several days to weeks. "Escape" then occurs, resulting in a small IOP rise. After 2-4 weeks, the IOP usually stabilizes below the pre-treatment level. IOP control may then last for weeks to years. Long-term "drift" refers to a slow, steady rise in IOP after months to years of treatment, often to a point where the medication is no longer effective.

Carbonic Anhydrase Inhibitors Both the oral and topical carbonic anhydrase inhibitors (CAIs) inhibit the enzyme carbonic anhydrase, decreasing aqueous humor production. Oral CAIs, most notably Diamox (acetazolamide), are the most potent ocular hypotensive drugs available. Unfortunately, a host of side effects have been well-documented with Diamox, including nausea, vomiting, depression, kidney stone formation, gastrointestinal upset and loss of libido. More severe side effects include aplastic anemia, Stevens-Johnson syndrome and erythema multiforme. CAIs are sulfa drugs, and are contraindicated in those allergic to them. Trusopt (dorzolamide 2%) was the first topical CAI, released in 1995. In 1998 we saw the introduction of Azopt (brinzolamide 1%). While not as effective as their systemic counterparts in lowering IOP, their excellent safety index makes them a good choice when you need an adjunctive medication. The dosage for topical CAIs is three times daily, though some individuals may be controlled on a twice-daily basis. Trusopt and Azopt reduce IOP by about 16-22%.33 CAIs are additive to beta-blockers and adrenergics. Rarely do systemic side effects occur with topical CAIs, but headaches and a metallic taste are common complaints. Ocular side effects, while infrequent, include irritation, itching and hyperemia. Cosopt is a combination medication containing timolol 0.5% and dorzolamide 2% that is used twice daily. The convenience of fewer drops per day enhances patient compliance.

Dr. Fingeret is co-author of the texts Primary Care of the Glaucomas and Atlas of Primary Eyecare Procedures. He is chair and chief of the optometry section at the Brooklyn/St. Albans Campus, Department of Veterans Affairs, and associate clinical professor at the State University of New York State College of Optometry. He is also chair of Review of Optometry's Glaucoma 2002 Conference.