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Current options in adjunctive therapy

ByE. Randy Craven, MD

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E. Randy Craven, MD

The goal of glaucoma management is to lower intraocular pressure and hinder the progression of the disease. If monotherapy does not provide adequate IOP lowering, then ophthalmologists need to consider treating patients with a different medication or with additional medications to achieve lower IOP.

Switching versus adding

Ophthalmologists who are faced with the decision of switching medication or adding medication to the current treatment need to first look at the pharmacology within the eye. The ideal treatment method is a medication that decreases aqueous production and increases outflow through the trabeculum meshwork. A study by Richard F. Brubaker, MD, looked at the ideal balance between decreasing inflow and increasing outflow.¹ He concluded that if inflow was impeded too much that the uveoscleral outflow mechanism would be sluggish and the patient would lose the effects of the medication.

A good medication to add to initial therapy will provide 10% to 15% IOP reduction when the medications are combined. It is important for ophthalmologists to find complementary mechanisms when trying to lower IOP. For example, adding one beta blocker to another will not provide adequate IOP lowering because they are the same class of medication and work on the same receptor.

Safety and tolerability are an important aspect of choosing a medication to add to initial therapy. Older studies by David Zadok, MD, showed that combinations such as pilocarpine and timolol are highly effective.² The pilocarpine molecule increases flow through the trabecular meshwork, while timolol decreases inflow. When added together they reduce IOP by a few points.

A study by K. A. Parrow, MD and colleagues, demonstrated another good combination: dipivefrin and timolol.³ Dipivefrin is an epinephrine pro-drug that increases the facility of outflow, and when combined with timolol, provides good IOP lowering.

Prostaglandin analogues

Additional options for ophthalmologists include prostaglandin analogues that increase uveoscleral outflow. However, ophthalmologists treating patients with a prostaglandin analogue have a difficult time finding medications that can further lower IOP when initial therapy fails. Beta blockers have not been shown to have a dramatic effect on lowering IOP when combined with a prostaglandin analogue, with the best results being a two-point drop in IOP.

eA study by David A. Lee, MD, looked at adding alpha-adrenergic agonists such as brimonidine to latanoprost.⁴ Brimonidine has a primary effect of increasing the uveoscleral outflow or the facility of outflow. It also has the secondary effect of decreasing the aqueous production. The study showed a 32% reduction in IOP when the combination is used.

Another combination that has shown good results is topical carbonic anhydrase inhibitors (CAIs). Topical CAIs have been found to reduce IOP from 11% to 25% when added to prostaglandin analogues.^5-8

Fixed combination therapy

Ophthalmologists can switch to fixed combination therapy to treat patients when initial monotherapy does not provide adequate IOP lowering. The two options for fixed combination therapy are (1) dorzolamide and timolol and (2) brimonidine and timolol. Advantages of using fixed combination therapy include patients needing only one bottle of medication, fewer drops needed to administer the medication, less exposure to preservatives and only one co-payment. Fixed combination therapy through one bottle is convenient for patients, which increases the likelihood that the treatment method will be followed.

Recent studies looked at the effect of fixed combination of brimonidine and timolol on lowering IOP compared to brimonidine or timolol being used as monotherapy.^9,10 Study results show brimonidine and timolol used separately reduce IOP by 21%. When used in fixed combination therapy, the IOP reduction was 31%, similar to the results found in prostaglandin analogues when they are used as primary treatment.

Fixed combination therapy seems to be a good alternative for patients who are not achieving optimal results on prostaglandin analogue therapy. Further studies will show whether it is an ideal therapy choice for patients.

References

1. Brubaker RF. Targeting outflow facility in glaucoma management. Surv Ophthalmol. 2003;48:S17-S20.
2. Zadok D, Geyer O, Zadok J, et al. Combined timolol and pilocarpine vs. pilocarpine alone and timolol alone in the treatment of glaucoma. Am J Ophthalmol. 1994;117:728-731.
3. Parrow KA, Hong YJ, Shin DH, Shi DX, McCarty B. Is it worthwhile to add dipivefrin HCl 0.1% to topical beta 1-, beta 2-blocker therapy? Ophthalmology. 1989 Sep;96(9):1338-41; discussion 1341-1342.
4. Lee DA, Gombein JA. Effectiveness and safety of brimonidine as adjunctive therapy for patients with elevated intraocular pressure in a large, open-label community trial. J Glaucoma. 2001;10:220-226.
5. Konstas AG, Karabatsas CH, Lallos N, et al. 24-Hour intraocular pressures with brimonidine purite versus dorzolamide added to latanoprost in primary open-angle glaucoma subjects. Ophthalmology. 2005;112:603-608.
6. Rulo AH, Greve EL, Hoyng PF. Additive ocular hypotensive effect of latanoprost and acetazolamide. A short-term study in patients with elevated intraocular pressure. Ophthalmology. 1997 Sep;104(9):1503-1507.
7. Vanlandigham BD, Brubaker RF. Combined effect of dorzolamide and latanoprost on the rate of aqueous humor flow. Am J Ophthalmol. 1998 Aug;126(2):191-196.
8. Shoji N, Ogata H, Suyama H, et al. Intraocular pressure lowering effect of brinzolamide 1.0% as adjunctive therapy to latanoprost 0.005% in patients with open angle glaucoma or ocular hypertension: an uncontrolled, open label study. Curr Med Res Opin. 2005;21:503-508.
9. Craven ER et al. American Academy of Ophthalmology Annual Meeting; October 23-26, 2004. Abstract P58.
10. Sherwood MB, Craven ER, Chou C, et al. Twice-daily 0.2% brimonidine-0.5% timolol fixed-combination therapy vs. monotherapy with timolol or brimonidine in patients with glaucoma or ocular hypertension: a 12-month randomized trial. Arch Ophthalmol. 2006;124:1230-1238.