Carbonic anhydrase inhibitors (CAIs) inhibit carbonic anhydrase isozyme II in the non-pigmented epithelium of the ciliary body, suppressing aqueous humor production and lowering intraocular pressure4)5).
Oral CAIs (acetazolamide) have been used as intraocular pressure-lowering agents since the 1950s, but they caused many systemic side effects such as fatigue, paresthesia, metabolic acidosis, and kidney stones5). Topical CAIs were developed to ensure corneal permeability while significantly reducing systemic side effects.
Currently available topical CAIs include dorzolamide hydrochloride (Trusopt®) and brinzolamide (Azopt®)6). In addition to monotherapy, they can be used in combination with beta-blockers or prostaglandin analogs to achieve additive intraocular pressure reduction.
| Drug | Concentration | Frequency |
|---|---|---|
| Dorzolamide | 0.5–2% | 2–3 times daily |
| Brinzolamide | 1% | Twice daily |
Oral CAI (acetazolamide) has a strong intraocular pressure-lowering effect of 30–40%, but systemic side effects (paresthesia, fatigue, kidney stones, metabolic acidosis, blood disorders, etc.) are frequent, making it unsuitable for long-term use 5). Topical CAI (dorzolamide, brinzolamide) lowers intraocular pressure by 15–20%, which is weaker than oral, but systemic side effects are greatly reduced, allowing long-term use 4)5). Oral CAI is limited to emergency intraocular pressure reduction, and the principle is to use eye drops for long-term management.
The main indications for topical CAI are primary open-angle glaucoma (POAG) and ocular hypertension. It is also used as an aqueous humor suppressant in inflammatory glaucoma.
In glaucoma pharmacotherapy, prostaglandin analogs are often used as first-line therapy and beta-blockers as second-line therapy 6). Topical CAI is positioned as a second-line agent and is added as an adjunct when monotherapy is insufficient 4)6).
When multiple drugs are used, fixed-combination eye drops are useful for improving adherence 6). If the effect of a single agent is insufficient, consider changing the drug first, aiming for monotherapy. If still insufficient, perform multidrug therapy (including fixed combinations) 6).
| Combination | Brand Name | Frequency |
|---|---|---|
| Dorzolamide + Timolol | Cosopt® | Twice daily |
| Brinzolamide + Timolol | Azarga® | Twice daily |
Dorzolamide is sometimes used off-label for the treatment of macular cystic diseases. Its efficacy has been reported for cystoid macular edema in retinitis pigmentosa, X-linked retinoschisis, and resolution of subfoveal fluid associated with dome-shaped macula 2). Case reports have also shown the effectiveness of dorzolamide for cystoid macular edema related to taxane-based anticancer drugs 3).
Dorzolamide Hydrochloride (Trusopt®)
Concentration: 0.5%, 1%, 2% ophthalmic solution
Frequency of instillation: Three times daily when used alone, twice daily when used in combination 6)
Features: Contains a viscoelastic agent to enhance intraocular penetration. Characteristic stinging sensation upon instillation.
Main side effects: Ocular irritation, conjunctival hyperemia, bitter taste 5)
Brinzolamide (Azopt®)
Concentration: 1% suspension eye drops
Frequency: Twice daily 6)
Features: As a suspension, may cause blurred vision after instillation. When used with other drops, administer last.
Main side effects: Blurred vision, foreign body sensation, dysgeusia 5)
Ocular side effects: Burning/stinging sensation, bitter (metallic) taste, superficial punctate keratitis (SPK), blurred vision, conjunctival hyperemia, allergic conjunctivitis/dermatitis, corneal edema 4)5)
Systemic side effects: Although infrequent, headache, urticaria, angioedema, paresthesia, and transient myopia have been reported 5). Since small amounts reach systemic circulation, rare cases of thrombocytopenia have also been reported.
Contraindications: Sulfonamide allergy, severe renal impairment 6)
Caution: Patients with low corneal endothelial cell count (increased risk of corneal edema) 5), hepatic impairment 6)
In patients with low corneal endothelial cell count, CAI eye drops increase the risk of corneal edema 5). The Japanese Glaucoma Practice Guidelines also consider severe corneal endothelial damage as a condition requiring cautious administration 6). In cases with significantly reduced corneal endothelial function (e.g., Fuchs corneal endothelial dystrophy), switching to other glaucoma medications should be considered.
Aqueous humor is secreted by the non-pigmented epithelium of the ciliary body. In this process, carbonic anhydrase II (CA-II) plays an important role 5). CA-II catalyzes the hydration reaction of carbon dioxide (CO2) to produce carbonic acid (H2CO3). Carbonic acid dissociates into bicarbonate ions (HCO3-) and hydrogen ions (H+).
The formation of bicarbonate ions regulates the pH environment necessary for active transport of sodium ions (Na+) and promotes fluid transport. When CAIs inhibit CA-II, bicarbonate ion production decreases, resulting in suppression of ion transport and aqueous humor secretion, thereby lowering intraocular pressure 4)5).
It is hypothesized that CAIs cause vasodilation via increased tissue CO2 concentration or decreased pH, improving ocular blood flow. Several small prospective studies suggest that topical CAIs improve perfusion parameters in the retina, choroid, and retrobulbar circulation. This effect is attracting attention as an intervention for vascular factors in glaucomatous optic neuropathy.
Both agents target the same CA-II, but their formulation characteristics differ. Dorzolamide is an aqueous solution with added viscoelastic agents to improve corneal permeability; its slightly lower pH upon instillation tends to cause stinging. Brinzolamide is a neutral pH suspension with less stinging, but the suspended particles can cause blurred vision. Both agents provide 24-hour intraocular pressure reduction, including during the night.
A randomized double-blind phase IV study compared a 4-drug regimen (TDB-L) adding latanoprost to a triple fixed combination of timolol, dorzolamide, and brimonidine, with a 3-drug regimen (TD-L) adding latanoprost to a dual fixed combination of timolol and dorzolamide 1).
The study included 47 eyes of patients with primary open-angle glaucoma and followed them for 60 days, yielding the following results 1):
TDB-L group (4 drugs)
Baseline IOP: 20.1 ± 1.6 mmHg
IOP at 60 days: 14.0 ± 2.2 mmHg
IOP reduction: 6.3 mmHg (p < 0.0001)
TD-L group (3 drugs)
Baseline IOP: 20.8 ± 1.8 mmHg
IOP at 60 days: 16.8 ± 2.0 mmHg
IOP reduction: 4.5 mmHg (p < 0.0001)
At 60 days, the TDB-L group achieved significantly lower IOP than the TD-L group (between-group difference p = 0.042)1). Both groups had good tolerability, and no drug-related adverse events were observed1).
The application of CAIs to macular diseases is attracting attention. A case was reported in which bilateral macular cysts associated with dome-shaped macula in myopic eyes completely resolved after 4 months of dorzolamide three times daily2). Two cases of cystoid macular edema caused by taxane-based anticancer drugs (nab-paclitaxel) that improved within 5–10 weeks after drug discontinuation combined with dorzolamide eye drops have also been reported3).
The mechanism by which CAIs improve macular edema is thought to involve a decrease in subretinal pH due to inhibition of membrane-bound carbonic anhydrase in the basal membrane of the retinal pigment epithelium, and promotion of reabsorption of subretinal and intraretinal fluid3).
Future challenges:
Combination drugs (e.g., dorzolamide + timolol: Cosopt®) contain two components in a single bottle, reducing the number of eye drops and instillation frequency, thereby improving adherence 6). Advantages also include reduced medication costs, simplified management of instillation intervals, and decreased risk of washout 1). However, combining drugs with the same mechanism of action (e.g., two types of CAIs) should be avoided; drugs with different mechanisms of action should be combined 6).
- Olvera-Montaño O, Mejia-Morales C, Jauregui-Franco RO, et al. Maximum Tolerated Medical Therapy for Glaucoma: Fixed-Dose Combinations of Timolol, Dorzolamide, Brimonidine with Latanoprost Versus Timolol, Dorzolamide with Latanoprost. Clin Ophthalmol. 2025;19:2913-2925.
- Vukkadala T, Gowdar Kuberappa R, Azad SV, et al. Resolution of bilateral foveal cysts in dome-shaped macula after treatment with topical dorzolamide. BMJ Case Rep. 2021;14:e237868.
- Otsubo M, Kinouchi R, Kamiya T, et al. Regression of taxane-related cystoid macular edema after topical dorzolamide treatment: two case reports. J Med Case Reports. 2021;15:355.
- American Academy of Ophthalmology. Primary Open-Angle Glaucoma Preferred Practice Pattern®. 2020.
- European Glaucoma Society. Terminology and Guidelines for Glaucoma, 6th Edition. Br J Ophthalmol. 2025.
- 日本緑内障学会. 緑内障診療ガイドライン（第5版）. 日眼会誌. 2022;126(2):85-177.
