What is the recommended first‑line pharmacologic treatment and dosing regimen for open‑angle glaucoma, including alternatives if prostaglandin analogues are contraindicated or insufficient?

First-Line Pharmacologic Treatment for Open-Angle Glaucoma

Prostaglandin analogues are the recommended first-line treatment for open-angle glaucoma, with latanoprost 0.005%, bimatoprost 0.03%, or travoprost 0.004% administered once daily in the evening as the preferred agents. 1

Primary Recommendation: Prostaglandin Analogues

• Initiate prostaglandin analogues as first-line therapy unless specific contraindications exist, as they demonstrate superior IOP reduction compared to all other drug classes, require only once-daily dosing, and have the best efficacy and tolerability profile. 1

• The American Academy of Ophthalmology recommends prostaglandins as first-line medical therapy based on network meta-analysis showing they had the highest ranking for IOP reduction from 1999 onward. 2

• Prostaglandin analogues reduce IOP by 25-35% (approximately 7-8 mmHg from baseline pressures of 25-27 mmHg), achieving reductions of 22-39% over 1-12 months of treatment. 1

Specific Drug Selection and Dosing

Latanoprost 0.005%:

• Administer one drop (1.5 μg) in the affected eye(s) once daily in the evening. 3
• IOP reduction begins approximately 3-4 hours after administration with maximum effect at 8-12 hours. 3
• Do not exceed once-daily dosing, as more frequent administration may decrease the IOP-lowering effect or cause paradoxical IOP elevations. 3

Bimatoprost 0.03%:

• Provides the best IOP-lowering effect among all monotherapy regimens and ranks highest in network meta-analyses from 2004 and 2009. 2, 1
• Increases mean ocular perfusion pressure compared to timolol. 4
• Do not use bimatoprost 0.01% as this lower concentration is absent from treatment recommendations and lacks supporting evidence from randomized clinical trials. 4

Travoprost 0.004%:

• Equivalent efficacy to bimatoprost and superior to timolol in lowering IOP. 2
• Administered once daily in the evening. 1

Critical Implementation Points

• Check IOP response within 2-4 weeks of initiation to confirm adequate pressure reduction. 1
• Target IOP should be approximately 20% lower than baseline. 1
• If using multiple eye drops, instruct patients to wait at least 5 minutes between different medications to prevent washout and ensure proper absorption. 1, 3

Second-Line Option: Beta-Blockers

If prostaglandin analogues are contraindicated or not tolerated, use topical beta-adrenergic antagonists as the next best option. 1

• Timolol 0.5% solution twice daily or timolol 0.1% gel once daily are the standard dosing regimens. 1
• Timolol achieves IOP reductions of approximately 7-9 mmHg. 1
• Avoid nighttime dosing of beta-blockers, as this is associated with limited efficacy and may contribute to visual field progression via nocturnal reduction of systemic blood pressure. 1
• Beta-blockers lack the cardiopulmonary adverse effects compared to systemic agents but can still cause systemic side effects. 5

Third-Line Options

Alpha-2 adrenergic agonists (brimonidine):

• Reduce IOP but are less effective than prostaglandins. 1
• Latanoprost is more effective than brimonidine, with mean IOP reduction differences of 1.22 mmHg (95% CrI 0.56 to 1.88) favoring latanoprost. 2

Topical carbonic anhydrase inhibitors (dorzolamide, brinzolamide):

• Achieve 15-20% IOP reduction and can be used as adjunctive therapy. 1
• Latanoprost is more effective than dorzolamide as monotherapy. 2

Rho kinase inhibitors (netarsudil):

• Provide 10-20% IOP reduction through increased trabecular outflow. 1

Combination Therapy

• The fixed combination of latanoprost plus timolol provides better IOP reduction than either agent alone and is more effective than dorzolamide-timolol combinations. 1, 5
• The combined use of two or more prostaglandins or prostaglandin analogues is not recommended. 3
• When prostaglandin monotherapy is insufficient, adding a beta-blocker, carbonic anhydrase inhibitor, or alpha-2 agonist provides significant additive effects. 5

Oral Therapy (Reserved for Acute Situations Only)

• Oral carbonic anhydrase inhibitors (acetazolamide 250-500 mg) are reserved for acute angle-closure glaucoma or severe IOP elevation requiring rapid reduction. 1
• Acetazolamide carries significant risks including Stevens-Johnson syndrome, electrolyte imbalances, renal calculi, and blood dyscrasias. 1
• Contraindications include sulfonamide allergy, kidney stones, aplastic anemia, and sickle cell disease. 1

Critical Pitfalls to Avoid

Do not use unoprostone as first-line therapy despite its prostaglandin classification—it was the least effective drug in network meta-analyses and has uncertain classification as a prostaglandin analogue. 2, 1, 6

• Unoprostone produces less IOP reduction than timolol or latanoprost and may require three times daily dosing to approach timolol's effectiveness. 7

Avoid more frequent than once-daily dosing of prostaglandin analogues, as this decreases efficacy or causes paradoxical IOP elevations. 3

Use caution with prostaglandin analogues in patients with:

• Active uveitis (due to pro-inflammatory mode of action). 8
• History of cystoid macular edema (case reports of association exist). 8, 7
• Recent intraocular surgery (increased risk of macular edema). 8

Preservative-free formulations are preferred when available, particularly for patients with ocular surface disease or those requiring multiple medications. 1

Expected Adverse Effects

Prostaglandin analogues:

• Conjunctival hyperemia (3-15% of patients, mild to moderate). 5
• Iris color change (2-9%, may be permanent, most common in green-brown, yellow-brown, and blue/grey-brown eyes). 5, 7
• Hypertrichosis and hyperpigmentation of eyelashes. 7
• Minimal systemic adverse events. 5