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`Lowering IOP With Medical Therapy in Patients With Glaucoma
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`Lowering IOP With Medical Therapy in
`Patients With Glaucoma: Concomitant
`Treatment of Glaucoma
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`Lowering IOP With Medical Therapy in Patients With Glaucoma
`
`Concomitant Treatment of
`Glaucoma
`
`Table of Contents
`
`Introduction
`
`First-Line Agents -- Prostaglandin Analogs
`
`Concomitant Treatment of Glaucoma
`
`Fixed Combinations
`
`Conclusion
`
`References
`
`Three classes of drugs, topical beta-
`blockers, topical carbonic anhydrase
`inhibitors (CAIs), and alpha-agonists, are
`used concomitantly as second-line treatment
`or as an alternative if prostaglandins are
`insufficiently effective or poorly tolerated.
`With so many alternatives, the optimal
`sequencing of therapy is less obvious than
`ever before. Indeed, when the first
`prostaglandin was approved, it was not
`approved for initial monotherapy. As a
`result, a number of well-designed
`studies[20,21] demonstrated the additivity of
`prostaglandins to patients already on
`monotherapy (most commonly a beta-
`blocker). Unfortunately, the converse is not
`true: There are few well-designed and
`sufficiently powered studies in regard to the
`efficacy of adding other medications to
`patients who are already on a prostaglandin.
`In fact, no clear consensus or body of
`evidence exists to favor one class of drugs
`over another as second-line therapy. The
`challenge then for practitioners is to keep
`medical therapy reasonable and understand
`that additional therapy does not always
`result in added efficacy, but will result in
`additional cost and possible adverse effects.
`A good general principle is to use the least
`amount of medication necessary to achieve
`the desired IOP reduction. Sometimes this
`approach will mean switching drugs rather
`than adding them.
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`Lowering IOP With Medical Therapy in Patients With Glaucoma
`All 3 classes work by lowering IOP through
`a reduction in aqueous formation. In
`addition, the alpha-agonist brimonidine is
`believed to possibly increase uveoscleral
`outflow.[22] The mechanisms of action are
`complementary to the prostaglandins, and
`good additivity could be expected with all 3
`classes.[23-25] Indeed, all 3 classes have
`demonstrated added efficacy to
`prostaglandins,[24,26,27] and they have
`become commonly used combinations. For
`example, a prostaglandin is often used at
`bedtime in combination with a beta-blocker
`used once daily in the morning. Timolol, the
`most commonly used beta-blocker, is
`available at 0.25% and 0.5% formulations.
`As monotherapy, beta-blockers are often
`used twice daily, although clinical studies
`and practical clinical experience have shown
`that once-daily use may be as effective and
`in fact preferred.[28,29] However, sleep lab
`testing has revived questions of whether a
`once-daily dose of beta-blockers in the
`morning has nocturnal efficacy.[30] Alpha-
`agonists and topical CAIs, which are used 3
`times daily as monotherapy, are often used
`off-label twice daily when added to a
`prostaglandin. Additivity to prostaglandins
`has been demonstrated for brimonidine and
`brinzolamide.[31,32]
`
`Strengths of Beta-Blockers, Topical CAIs,
`and Alpha-Agonists
`
`With a long clinical experience of more than
`30 years, topical beta-blockers have a
`proven efficacy and known
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`Lowering IOP With Medical Therapy in Patients With Glaucoma
`contraindications. They are indicated for
`once- or twice-daily use. Topical CAIs are
`also effective adjunctive agents with a very
`favorable systemic safety profile. The alpha-
`agonist brimonidine has a proven efficacy as
`well, and in laboratory models has
`demonstrated neuroprotective properties. In
`animal models, it enhanced retinal ganglion
`cell survival.[33] A neuroprotective benefit
`in humans beyond IOP reduction remains to
`be demonstrated. Brimonidine, initially
`launched at 0.2% concentration, was
`reformulated at 0.15% and 0.1% with Purite
`preservative (Allergan, Irvine, California)
`instead of BAK.
`
`Weaknesses of Beta-Blockers, Topical
`CAIs, and Alpha-Agonists
`
`Beta-blockers are systemically absorbed,
`and are of particular concern for patients
`with cardiopulmonary disease.[28]
`Relatively strong contraindications exist
`against the use of beta-blockers in patients
`with reactive airway disease (asthma and
`emphysema), uncompensated congestive
`heart failure, and symptomatic bradycardia.
`[34] Some risk may be reduced by
`employing passive eyelid closure or
`nasolacrimal occlusion when using the
`drops.[35] In addition, the additive effect of
`beta-blockers to prostaglandins is not as
`simple as previously thought; some studies
`have demonstrated limited additive efficacy.
`Of note, there was less than 1-mm Hg
`difference between the fixed combination
`latanoprost/timolol and latanoprost alone in
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`Lowering IOP With Medical Therapy in Patients With Glaucoma
`one study.[36] It appears that timolol may
`have variable additivity to prostaglandins
`for many patients.[24,37]
`
`The alpha-agonist brimonidine as
`monotherapy has shown similar peak
`efficacy compared with timolol 0.5%, but
`trough efficacy seems to be less than occurs
`with timolol. Twice-daily dosing as
`monotherapy may be associated with diurnal
`or nocturnal IOP fluctuations.[38] These
`properties may not accurately represent the
`IOP-lowering profile of brimonidine when
`used as an adjunct to a prostaglandin.
`Brimonidine has been associated with some
`systemic adverse effects. These include dry
`mouth and drowsiness. Some patients
`develop allergy or a chronic follicular
`reaction, although these side effects have
`been less common with the newer
`formulations.
`
`The efficacies of brinzolamide and
`dorzolamide seem to be equivalent, with the
`range of IOP reductions of the 2 topical
`CAIs generally lower than timolol 0.5%.
`[39,40] Topical CAIs can cause a metallic
`taste, particularly with carbonated
`beverages. They can cause stinging
`(dorzolamide) or blurring (brinzolamide)
`upon installation. It has been recommended
`that they should be avoided in patients with
`known sulfonamide allergy. In addition, they
`may worsen keratopathy in patients with
`corneal endothelial disease by interfering
`with the endothelial pump. They are
`generally well tolerated systemically.
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`Lowering IOP With Medical Therapy in Patients With Glaucoma
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`Fixed
`Combinations
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`References
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