Wednesday, March 29, 2023
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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.
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]
With a long clinical experience of more than 30 years, topical beta-blockers have a proven efficacy and known 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.
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 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.
