Drugdrug Interactions

While not generally considered an interaction, additivity of IOP-lowering medications is a topic of considerable interest. More than 50% of glaucoma patients in the United States are taking multiple IOP-lowering medications. The OBBs are now commonly used as an adjunct to prostaglandins and are a component of all modern fixed-combination products (see chapter 7).

As the first available OBB, timolol maleate solution became a de facto gold standard against which new drugs are compared for regulatory approval. Usually, phase III drug development trials include a study demonstrating drug efficacy compared to timolol and often another demonstrating drug additivity to timolol. These tend to be well-designed, large, prospective studies. In general, after the drug is approved, there remains little incentive for its sponsor to initiate similar studies exploring its additivity to other compounds. Therefore, most additivity data for OBBs examine the efficacy of a second drug to timolol. This no longer reflects common practice, where prostaglandins are a more popular initial monotherapy. It is worth emphasizing that the mean IOP response of a study population does not predict how a drug will act in an individual. While we have previously advocated using a one-eye trial to determine efficacy and additivity within an individual, new data about spontaneous and unilateral IOP fluctuations open valid debate about the value of the one-eye trial. At present, the best strategy to determine efficacy is to measure IOP a few times before and a few times after a change in therapy rather than base efficacy judgment on single IOP measurements.73-75

Reports have provided mixed results concerning the additivity of nonselective OBBs and nonselective adrenergic agonists. In a short-term study, the additivity of timolol to epinephrine was transient.76 Although the majority of patients taking either drug did not have a clinically significant reduction of IOP with the addition of the other, about one-fifth to one-third had an additional reduction of 3 mm Hg in IOP when epinephrine was added to timolol.77,78 Epinephrine compounds had greater additivity with betaxolol than with timolol, but the former combination had about the same IOP-lowering effect as timolol alone.79,80 These studies were performed when topical glaucoma therapy consisted of OBBs, epinephrine compounds, and parasympathomimetic drugs. The nonselective adrenergic agonists have been largely replaced by newer classes of drugs.

The OBBs have been demonstrated to be additive in combination with all other classes of IOP-lowering drugs, including parasympathomimetics, topical and oral CAIs, alpha-2-adrenergic agonists, and prostaglandin analogues.81-89 It is interesting to note that while the prostaglandin analogues latanoprost and travoprost have been shown to be additive in subjects receiving OBBs, similar studies demonstrating additivity of OBBs in patients already on prostaglandins are lacking.

It was the observation that oral beta blockers lower IOP that stimulated development of OBBs. With the common use of oral beta blockers, there is a possibility for some patients to be prescribed both oral and topical beta blockers. Ophthalmic timolol lowered IOP to an equal extent in subjects taking oral placebo and 80 mg propranolol but had no additive effect on subjects taking 160 mg propranolol.90 Similarly, while 20 mg oral timolol administered twice daily lowered IOP, the addition of topical timolol did not further reduce IOP.91 Clinically, this finding can be important. A patient taking oral beta blockers may have little or no additional IOP effect from OBBs. With the advent of new drugs for systemic hypertension, a patient in whom an oral beta blocker is discontinued may appear to have loss of IOP control. In such patients, OBBs may restore IOP to previous levels. It is important to maintain an accurate and current history of systemic medications.

OBBs can have significant interactions with drugs used to treat cardiac disease. Severe bradycardia has been reported in patients taking OBBs in combination with verapamil or quinidine.92 In one case, a patient who was stable when taking quin-idine developed symptomatic bradycardia when timolol was added. Normal sinus rhythm returned when both drugs were discontinued. Timolol alone did not induce a recurrence of the bradycardia, but it returned when quinidine was added.93 Qui-nidine inhibits the CYP2D6 enzyme of the cytochrome P-450 system involved in the metabolism of timolol.94

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