Additivity Of Medications

How well two or more medications achieve IOP reduction also depends upon drug class, or their mechanisms of action. Two beta blockers used together will have little added IOP-lowering effect, since they both decrease aqueous humor formation by the same mechanism. Likewise, two PAs used simultaneously will add little to IOP lowering and, in fact, may be less effective than either medication alone.5 On the other hand, a beta blocker and a CAI both decrease aqueous humor production, but by different mechanisms, the beta blocker by occupying adrenergic receptors and the CAI by reducing the activity of the enzyme carbonic anhydrase, which is responsible for catalyzing the reaction converting bicarbonate to carbon dioxide and water. In fact, IOP may drop an additional 13-21% when dorzolamide 2% (Trusopt) is added to timolol 0.5%.6 Alpha-adrenergic agonists can also effectively reduce IOP in patients on maximal medical therapy.7

The PAs contribute positively to the IOP-lowering effect of beta blockers, alpha agonists, and CAIs, which all act by decreasing aqueous production. Studies investigating the addition of a beta blocker to a PA showed an IOP reduction of 15-35%.8,9 The mechanism of action for all PAs contributes to this additivity by increasing pressure-independent (uveoscleral) outflow, and to some extent, pressure-dependent

Table 11.1 General Guidelines for Combination Therapy for Glaucoma

If medication is not working or significant side effects occur, stop the drug! If a medication is working, but is not adequate, switch to or add another drug. A monocular therapeutic trial can determine if a drug is effective. Use the lowest dose and frequency possible, and increase as needed. If medications are not adequate, move on to laser trabeculoplasty or filtration surgery.

outflow (facility), as well. As a result, however, this class of agents is less effective when used in conjunction with cholinergic agents. Drugs such as pilocarpine decrease uveoscleral outflow and therefore are antagonistic to PAs, as indicated by several clinical studies.10,11

Multiple studies have verified the IOP-lowering effect of adding a CAI to a PA.12-14 This result appears to be similar to combining a beta blocker with a PA but greater than that of combined alpha-agonist-PA therapy. These differences are yet to be unequivocally proven, and future prospective randomized studies are needed to determine the differences in additive therapy with the various PA agents.

In view of the apparent additive IOP-lowering effect of beta blockers to the PA class of glaucoma medications, newer drop formulations containing both medications in one bottle are currently being studied.15-17 Published data indicate that fixed combinations of a PA and a beta blocker appear to provide near-equal IOP-lowering effects compared to concomitant use of the two drugs while providing the benefit of decreasing dosing frequency, reducing preservative exposure, and possibly improving compliance. These medications may prove advantageous in treating patients while offering the added benefit of saving on cost of medications (depending on drug pricing).

A monocular therapeutic trial of 3 or 4 weeks can determine if a drug is effective; however, beta blockers and brimonidine can have significant crossover activity (you may see IOP lowering in the eye not being treated). An in-office monocular therapeutic trial can be used for all glaucoma medications except PAs. The drop is given in one eye, and IOP is checked 2 hours after dosing. Other general guidelines for combination medical therapy are given in table 11.1.

While there is no hard-and-fast rule determining which drugs should be used as first-line agents and in which order new drugs should be added or substituted, figure 11.1 provides some general guidelines. It is important to remember that this is only a general strategy for combination therapy, which may vary dramatically from patient to patient depending upon individual response, systemic considerations, side effects, and patient lifestyle.


In an attempt to control IOP and prevent progression of glaucomatous optic nerve damage, clinicians often place patients on multiple medications. Using every avail-

Figure 11.1. General strategy for combination therapy for glaucoma.

able glaucoma medication that the patient can topically or systemically tolerate is considered maximal medical therapy. The word "tolerate" is key, since the number of medications a patient may simultaneously use is often limited by surface irritation, allergy, systemic side effects, or inconvenience. Some patients simply do not want to take five different eye drops a day, and there is often very little the clinician can do to change their minds.

An important implication of the term "maximal medical therapy'' is that it is the last resort before surgical interventions, such as laser trabeculoplasty (LTP) or trabeculectomy. If patients are cognizant of this, they are often prompted to be more compliant with their medications. On the other hand, some would rather have laser surgery, in the hopes that it will obviate the need for multiple medications, even if the effect is not permanent.

Just as no two cases of glaucoma are the same, no two patients are the same with regard to their response to medications. Each patient's eye drop regimen, therefore, should be constructed and then modified to meet the individual patient's needs. When it was widely used, pilocarpine might not have been a good choice for a healthy, young professional, due to not only accommodative effects but also frequent dosing. Now, for such an individual, a PA at bedtime may be best tolerated until additional medications are needed. Particularly for noncompliant patients, a fixed-dose combination drug may be appropriate early in treatment. Communication with the patient and the patient's primary care physician is instrumental in assuring a safe and acceptable drug regimen.

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