During my introductory lecture to residents, I explain that the goal of all glaucoma treatments is to stave off functional vision loss, currently by lowering IOP. With medical treatment, the aim is to maximize IOP lowering while minimizing therapy’s impact on the patient’s quality of life, an effort that entails reducing side effects, using the least medication necessary, and prescribing the simplest dosing regimen that will achieve a consistent, “safe” IOP. Target IOP, I explain, is the level at which the practitioner can reasonably expect that pressure-related damage to the optic nerve will cease or slow to an acceptable level. During the remainder of their 3-year glaucoma training, residents learn how to apply these principles practically, and they soon discover that doing so is not as easy as it sounds.

Clearly, the ideal glaucoma medication does not exist. The perfect therapeutic agent would be 100% effective at achieving the target pressure in all patients, cause no side effects, and require only a single dose by the patient in his lifetime. Instead, contemporary drugs have varying efficacy, involve dosing regimens as frequent as q.i.d, and lead to side effects such as chronic hyperemia, fatigue, symptomatic bradycardia, and breathing problems. We are certainly fortunate that several agents are highly effective in most patients without causing more than minimal side effects or requiring administration more frequent than q.d. Nevertheless, in order to achieve patients’ target pressures, practitioners often must use multiple medications. This article focuses on how to associate these agents to the patients’ best advantage.

DECIDING TO USE MULTIPLE MEDICATIONS
For background on this and related topics, I suggest reading two articles written for this publication by Tony Realini, MD, of Morgantown, West Virginia, on selecting adjunctive therapy in glaucoma1 and fixed-combination glaucoma medications.2 He discussed the issues of switching versus adding medications, choosing a second or third agent, and building a combination of medications into the treatment regimen.

Deciding to use multiple medications implies that a single agent is effective but insufficient for achieving the desired IOP. Further, the decision indicates that the practitioner has established a target IOP for the patient and has a sense of his actual diurnal IOP in relation to the target. This process is easier (but by no means simple) when a single physician has made the diagnosis of glaucoma and then followed the patient for a period of time. The situation is more complicated when the presenting patient is already on treatment; before adding more medications, it is worthwhile in such cases to review carefully the patient’s records and discuss with him his previous treatment experiences.

CONSOLIDATING MEDICATIONS
When a presenting patient is already undergoing treatment with multiple medications, it is sometimes easy to simplify his regimen without sacrificing efficacy. If he is using both timolol and dorzolamide b.i.d., then an obvious choice is to switch the medications for a combination drop (other fixed-combinations will likely become available in the future). Another method for simplifying drug regimens is using the same medications in both eyes, if appropriate. It may also be worth considering the nontraditional or off-label use of certain medications, for instance, a beta-blocker solution q.a.m., a miotic t.i.d. or b.i.d., and a topical carbonic anhydrase inhibitor (CAI) or brimonidine b.i.d. After adjusting a patient’s drug regimen, the practitioner should recheck the patient’s pressure at the time of trough effect (just before the next dose) in order to ensure the maintenance of proper IOP control.

If it is uncertain whether a particular agent is effective or responsible for a given side effect, conducting a reverse monocular trial is often reasonable. Eliminating the suspect medication for 2 to 4 weeks may be necessary in order to determine whether it is responsible for systemic side effects. The results of this trial often surprise the physician and patient. A medication taken for years may no longer be effective or may compromise the patient’s quality of life in some manner.

ADJUNCTIVE THERAPY
At present, beta-blockers and prostaglandin analogs are the most commonly prescribed agents for the initial treatment of glaucoma. If a single agent is effective but insufficient to achieve the target IOP, then switching the medication for another in the same class is generally fruitless. In such cases, the practitioner often must instead decide which medication should supplement the beta-blocker or prostaglandin monotherapy.

Prostaglandin analogs are additive to beta-blockers. Several studies have demonstrated an additional 13% to 36% reduction in IOP when latanoprost has been added to timolol monotherapy.3-5 Other agents are also clearly supplemental to beta-blocker monotherapy. Topical CAIs may provide an additional 13% to 22% reduction in mean IOP.6-8 Brimonidine can provide an additional 20% mean IOP reduction7 and as much as a 23% additional IOP reduction at peak effect.5 These were randomized, prospective, masked, parallel-design trials, although outcome measures differed. When evaluating studies, it is important to closely examine their methodology. For example, it is helpful to examine mean diurnal IOP reduction rather than peak effect, because it better reflects how well the medications work for patients over the course of an entire day. To date, no study has directly compared the effect of all these drugs when added to beta-blockers.

Conversely, once-daily beta-blockers can serve as additives to prostaglandin monotherapy. One study reported an additional 16% reduction in IOP at trough when investigators added a morning dose of timolol solution to an evening dose of latanoprost.9 The only study comparing the additive effect of different medications with a prostaglandin was a retrospective evaluation of 73 patients.10 When added to latanoprost, dorzolamide (25 patients) lowered IOP by 20% compared with beta-blockers (23 patients) and brimonidine (25 patients), which decreased IOP by 12% and 9%, respectively. The researchers observed no difference in the degree of IOP reduction with dorzolamide dosed b.i.d. versus t.i.d. These findings have influenced some practitioners to consider topical CAIs rather than beta-blockers when supplementing prostaglandin monotherapy, but a prospective study is needed to confirm these results.

At my own practice, the most common association of medications is a once-daily beta-blocker in the morning and a prostaglandin analog in the evening. I have found that this therapeutic regimen conveniently and effectively lowers the IOP of a significant number of patients while minimizing ocular and systemic side effects.

LIFESTYLE FACTORS
Besides obvious demographics such as age, race, and family history, I also inquire about patients’ occupations, hobbies, daily routines, travel schedules, and other factors that may influence their treatment regimen. For example, a contact lens wearer probably does not want to remove his lenses in the middle of the day in order to instill a t.i.d. medication. Even spacing doses of b.i.d. medications by 12 hours may be difficult for patients who wear their lenses for 16 hours or more each day. People who are busy at work and with other activities may find midday or early-evening dosing similarly difficult.

When speaking with a patient, the physician may need to reconstruct the entire treatment strategy if the patient works the night shift or has other scheduling conflicts. Those who travel may also have concerns about how to cope with time zone changes, store their medications, and access medications in other states or countries.

Every treatment plan must be customized for each patient. Fortunately, practitioners may combine glaucoma medications in a multitude of ways. The art of practicing medicine involves working with patients to determine which combination will best achieve the ultimate goal of preserving their vision. When associating glaucoma medications, I attempt to ensure that every drop counts.
1
Geoffrey T. Emerick, MD, is Director of the Glaucoma Service at Loyola University Medical Center in Maywood, Illinois. He holds no financial interest in the products mentioned herein. Dr. Emerick may be reached at (708) 216-3408; gemeric@lumc.edu.
n
1. Realini, Tony. Selecting adjunctive therapy in glaucoma. Glaucoma Today [serial online]. 2003;1(1).
2. Realini, Tony. Fixed-combination glaucoma medications. Glaucoma Today [serial online]. 2003;1(2).
3. Alm A, Widengård I, Kjellgren D, et al. Latanoprost administered once daily caused a maintained reduction of intraocular pressure in glaucoma patients treated concomitantly with timolol. Br J Ophthalmol. 1995;79:12-16.
4. Rulo AH, Greve EL, Hoyng PF. Additive effect of latanoprost, a prostaglandin F2 alpha analogue, and timolol in patients with elevated intraocular pressure. Br J Ophthalmol. 1994;78:899-902.
5. Simmons ST, Earl ML; Alphagan/Xalatan Study Group. Three-month comparison of brimonidine and latanoprost as adjunctive therapy in glaucoma and ocular hypertension patients uncontrolled on beta-blockers: tolerance and peak intraocular pressure lowering. Ophthalmology. 2002;109:307-314; discussion:314-315.
6. Strahlman ER, Vogel R, Tipping R, Clinieschmidt CM. The use of dorzolamide and pilocarpine as adjunctive therapy to timolol in patients with elevated intraocular pressure. The Dorzolomide Additivity Study Group. Ophthalmology. 1996;103:1283-1293.
7. Simmons ST. Alphagan/Trusopt Study Group. Efficacy of brimonidine 0.2% and dorzolamide 2% as adjunctive therapy to beta-blockers in adult patients with glaucoma or ocular hypertension. Clin Therapeutics. 2001;23:604-619.
8. Michaud JE, Friren B, International Brinzolamide Adjunctive Study Group. Comparison of topical brinzolamide 1% and dorzolamide 2% eye drops given twice daily in addition to timolol 0.5% in patients with primary open-angle glaucoma or ocular hypertension. Am J Ophthalmol. 2001;132:235-243.
9. Stewart WC, Day DG, Sharpe ED, et al. Efficacy and safety of timolol solution once daily vs timolol gel added to latanaprost. Am J Ophthalmol. 1999;128:692-696.
10. O’Connor DJ, Martone JF, Mead A. Additive intraocular pressure lowering effect of various medications with latanoprost. Am J Ophthalmol. 2002;133:836-837.