Healio
Healio
August 23, 2011
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Adjunctive Medical Therapy in Glaucoma

Prostaglandin analogues are the first-line agents of choice for glaucoma monotherapy since these medications demonstrate superior 24-hour diurnal pressure reduction, approximately 30% from baseline, convenient daily dosing, and the best overall safety profile.1 Unfortunately, not all patients with glaucoma achieve successful control with prostaglandin monotherapy. An unsuccessful monotherapeutic response is considered to be an IOP reduction of < 10%from baseline at 2 or more readings.2 Other indicators of insufficient IOP reduction are disc hemorrhage, increased cupping, or visual field progression. When monotherapy fails, ophthalmologists should consider in-class switching to another prostaglandin or adding a second medication.

Substitution Monotherapy

Ophthalmologists might not commonly consider in-class switching of therapeutic agents, referred to as substitution monotherapy. In 2008, a panel of experts could not agree on the practice.2 In one study, the three prostaglandins investigated were equal in efficacy.3 In contrast, a review of 300 patients switched from latanoprost to bimatoprost found that 13% had at least a 3 to 4 mm Hg drop in IOP after the switch, while only 5% had a similar increase, suggesting that some patients may benefit from an in-class medication switch.4,5 The most common side effects of prostaglandins, conjunctival hyperemia and eyelash growth, are more common with bimatoprost than latanoprost or travoprost.2,5

If preservative toxicity is a concern, travoprost is available both with and without benzalkonium chloride (BAK). The formulations are therapeutically equivalent throughout the 24-hour cycle.6 Bimatoprost is available in therapeutically equivalent 0.01% and 0.03% solutions.7 The only clinical concern with 0.01% bimatoprost is that it contains about 300% more BAK than is found in the 0.03% solution. BAK has a dose-related, toxic effect on the ocular surface.8-10 Whether this higher BAK concentration becomes clinically significant remains to be seen.

Any benefit to “piggybacking” two prostaglandins is unclear. One study, in monkeys, showed greater IOP reduction when administering two prostaglandins.11 Another reported successfully adding a rarely used prostaglandin, unoprostone (Rescula) 0.12%, to latanoprost 0.005% with reduced peak and trough pressures of 2 to 3 mm Hg and an overall 50% reduction in mean diurnal fluctuation.12 However, increases in IOP, up to 23 mm Hg, with the concurrent use of latanoprost and bimatoprost have been reported.13

Adjunct Options

If substitution monotherapy is unsuccessful, the next step is adjunctive therapy.1,3 The provider should consider whether the adjunct will offer a complementary mechanism of action (an aqueous suppressant versus augmentation of the prostaglandin’s increased outflow effect), provide maximum additivity for IOP reduction, maximize or enhance both diurnal and nocturnal IOP fluctuation, and alter the ocular or systemic side-effect profile.

Beta-Blockers

Selective and nonselective beta-blockers, such as betaxolol and timolol, respectively, are aqueous production suppressors. Timolol is slightly more effective than betaxolol, lowering mean IOP about 25%.14 In addition, daily timolol 0.5% added to latanoprost was found to be more effective in reducing mean peak and trough IOPs than beta-agonists, topical carbonic anhydrase inhibitors (CAIs) and brimonidine added to latanoprost.15

Adjunctive beta-adrenergic medications augment prostaglandin effects only during the daytime diurnal period, with almost no nocturnal effect. These agents can induce tachyphylaxis, with an upward IOP drift after several years. Patients on systemic beta-blockers may respond less well to topical beta-blockers.14 Beta-blockers also have numerous side effects, such as clinical depression, bradycardia, altered lipid profile, and reduced exercise tolerance.2,14

Alpha2-Adrenergic Agonists

Alpha2-adrenergic agonists, such as brimonidine and apraclonidine, are both aqueous suppressors and outflow-enhancing agents. Apraclonidine has demonstrated rapid tachyphylaxis. Brimonidine has demonstrated a dose-dependant IOP-lowering efficacy similar to that of a beta-adrenergic agonist. When brimonidine is added to a prostaglandin, daytime diurnal suppression is augmented; however, its effect on nocturnal IOP is minimal. The chronic use of alpha2-adrenergics may be limited by side effects, such as dry mouth, fatigue, drowsiness and dose-dependant follicular conjunctivitis.15

Brimonidine with the preservative Purite is available in concentrations of 0.15% and 0.1%—with a lower concentration of the active agent than brimonidine 0.2% with BAK. The lower concentration does not affect efficacy, but has reduced the incidence of allergic reactions from about 20% with 0.2% to about 10% with 0.15%.16 The incidence of dry mouth and conjunctival hyperemia remain unchanged.16 If a patient demonstrates an allergic reaction to brimonidine with BAK, switching to the Purite-preserved drug is not recommended.

Carbonic Anhydrase Inhibitors

Topical CAIs, such as brinzolamide 1.0% or dorzolamide 2.0%, are aqueous suppressors that induce a dose-related IOP reduction. Their effect on IOP is similar after 4 to 6 weeks of use whether dosed twice or three times daily,16 and the effect is slightly less than that of alpha2-adrenergic agents.1

Topical CAIs augment IOP reduction during both the day and night.18 One clinical study demonstrated that topical CAIs, when added to prostaglandins, are more effective at reducing IOP than either beta-blockers or alpha2-agonists.20 The major drawbacks with topical CAI agents are their dosing schedule and burning and stinging on instillation, which may affect adherence. Discomfort on instillation has been more often reported with dorzolamide drops than brinzolamide.21

Parasympathomimetic Miotics

Research on the parasympathomimetic miotic agent pilocarpine 1% to 4% is mixed. One study found 4% pilocarpine gel to be a more effective and convenient 24-hour IOP suppressant than drops of a similar concentration (about 30% for the gel versus 22% for drops).22 Another found pilocarpine to increase facility of outflow, resulting in an additional 25% decrease in IOP when added to latanoprost. A third found neither a positive nor a negative effect from adding pilocarpine 2%, 4% or 6% to bimatoprost.23 Therefore, when adding pilocarpine as an adjunct agent, pilocarpine 4% gel appears to be best. Limitations to adding this agent include frequent dosing and numerous side effects, including miosis, intermittent accommodative paralysis, and increased risk of retinal detachment in susceptible patients. These side effects tend to reduce patient adherence and limit pilocarpine’s usefulness.

Fixed Combination Agents

A panel of glaucoma experts did not recommend fixed combination agents, such as timolol/dorzolamide and timolol/brimonidine, as a first choice for adjunctive therapy.1 Although these agents can augment IOP control, limiting factors include frequency of dosing, medication expense and restricted optimum dosing.24

Selecting the Best Option

Data from two large studies demonstrated the potential vision-sparing benefit of appropriately aggressive reduction of IOP.25,26 Prescribing should be guided by the patient’s overall health status and risk of blindness. In one large study, the mean IOP reduction goal was 22.5%,25 while in another, the goal was to reduce IOP by 38% in the drug group and 46% in the surgery group.26 Both therapeutic interventions resulted in reduced or delayed glaucoma progression. The AGIS-7 Study determined that those patients with IOPs consistently below 18 mm Hg, over the 6-year follow-up period (mean IOP 12.3 mm Hg) had, on average, no visual field progression.27

A literature review failed to find that IOP fluctuation and variation were independent risk factors for glaucomatous progression,27-31 although controlling fluctuating IOPs may have clinical significance since their values add to the value of the mean IOP. The nocturnal increase in IOP associated with a reduced nocturnal systemic perfusion pressure may increase risk for optic nerve damage and development or progression of glaucoma.30,31 The underlying defects in ocular autoregulation due to comorbid diseases, such as hypertension or diabetes, are thought to predispose the optic nerve to this ischemic damage.30 This predisposition may be more clinically significant in patients with advanced glaucoma, low or normal tension glaucoma, or those with vascular comorbidities.

Adjunctive options include adding a beta-blocker, alpha-adrenergic agonist, a topical CAI, or a miotic (parasympathomimetic) agent. Serious side effects and frequent dosing limit the clinical usefulness of miotics. Adjunctive combination agents, such as timolol/latanoprost, derive their effect from their beta-blocker component and provide notable IOP reduction only during the daytime. These combination agents should be reserved for patients with chronically stable, early glaucoma or, for convenience, patients confined to hospitals or nursing homes. These medications offer the convenience and ease of multiple medications, but do not offer the ability to maximize the dosing of either component.

While beta-adrenergics and alpha agonists offer the convenience of once or twice daily dosing, their IOP-lowering efficacy is restricted to the daytime with little nocturnal benefit. Beta-adrenergics and alpha-agonists may be more useful as adjuncts in younger patients, those with earlier disease, and those without comorbid vascular risk factors. Patients with more advanced disease, low-tension glaucoma or other comorbid vasculopathies would benefit most from a topical CAI as adjunct therapy.

References

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