Glaucoma is a progressive optic neuropathy, and the only modifiable risk factor is intraocular pressure (IOP) 1)3). Current pharmacotherapy aims to lower IOP and suppress the progression of optic nerve damage.
For chronic glaucoma, pharmacotherapy is the first-line treatment, with the principle of achieving maximum effect with the minimum necessary number of drugs and side effects. Since lifelong daily eye drop treatment is required, the basic approach is to “start with monotherapy and limit combination therapy to a maximum of two agents whenever possible.”
Glaucoma eye drops lower IOP either by suppressing aqueous humor production or by facilitating aqueous humor outflow 1)2)3).
| Mechanism of Action | Drug Class |
|---|---|
| Facilitates aqueous outflow (uveoscleral pathway) | PGA (FP receptor agonists), EP2 receptor agonists |
| Facilitates aqueous outflow (trabecular pathway) | ROCK inhibitors, miotics |
| Aqueous humor outflow enhancement (main pathway + accessory pathway) | EP2 receptor agonist |
| Aqueous humor production suppression | Beta-blockers, CAIs, alpha-2 agonists |
| Aqueous humor production suppression + outflow enhancement | Alpha-2 agonists, alpha-1 beta-blockers |
Prostaglandin analogs (PGAs), which have the strongest intraocular pressure-lowering effect and fewer systemic side effects, are the first-line treatment 1)2)3). If the effect is insufficient, a beta-blocker is added, followed by a CAI, alpha-2 agonist, or ROCK inhibitor. The drug treatment for ocular hypertension follows the same steps as for POAG, but the decision to start treatment is made considering individual risk factors 4).
According to the Tajimi Study, the prevalence of glaucoma in people aged 40 and older is 5.0%, of which about 70% is normal-tension glaucoma 1). The prevalence of primary open-angle glaucoma (broad definition) is reported to be 3.9–4.0%. As of 2020, the number of POAG patients worldwide is estimated at approximately 53 million 3).
In glaucoma, a chronic disease with few subjective symptoms, adherence to eye drop treatment is known to be extremely poor. Many patients who are prescribed glaucoma eye drops for the first time discontinue treatment about one year after starting 1). To improve adherence, simplification of the treatment regimen (choosing formulations with fewer instillations or fixed combinations), patient education, and effective communication are recommended 2).
Glaucoma drug treatment began with pilocarpine (a parasympathomimetic agent), which was used as the first eye drop for many years. In the 1970s, timolol (a beta-blocker) emerged and was widely used as a first-line drug despite issues with systemic side effects. After latanoprost (PGA) was approved in the 1990s, the position of first-line drug shifted to PGAs due to their strong intraocular pressure-lowering effect and convenience of once-daily administration. In 2014, ripasudil (ROCK inhibitor) was approved for the first time in the world, and in 2018, omidenepag isopropyl (EP2 receptor agonist) was approved, expanding the range of drug options.
Primary open-angle glaucoma is a chronic progressive disease, and in principle, eye drop treatment must be continued for life. Lowering intraocular pressure is the only evidence-based treatment, and discontinuing eye drops carries the risk of increased intraocular pressure and progression of optic nerve damage. Data show that many patients drop out about one year after the first prescription, making adherence maintenance extremely important. Using fixed-combination eye drops and learning proper instillation techniques are effective for continuation.
The main conditions for which drug therapy is indicated are as follows:
Before starting treatment, it is important to thoroughly assess baseline data such as intraocular pressure, angle, optic disc, and visual field 1).
| Stage of Glaucoma | Target Intraocular Pressure |
|---|---|
| Early | 19 mmHg or less |
| Moderate | 16 mmHg or less |
| Advanced | 14 mmHg or less |
A target of 20–30% reduction from untreated intraocular pressure is also recommended (2B)1).
Target intraocular pressure is not absolute. Some cases progress rapidly even when target pressure is achieved, while others do not progress or progress very slowly even without achieving target pressure1). Even with sufficient intraocular pressure-lowering treatment, some cases, especially advanced ones, may still progress, so early detection and treatment are important (1A)1).
In ocular hypertension, thin central corneal thickness, large vertical cup-to-disc ratio, older age, and high intraocular pressure are risk factors for conversion to glaucoma. The decision to start treatment is made by comprehensively assessing these factors4).
Intraocular pressure is determined by the balance between aqueous humor production and outflow. There are two outflow pathways: the conventional pathway and the uveoscleral pathway.
Glaucoma eye drops lower intraocular pressure by acting on these pathways, either suppressing aqueous production or promoting aqueous outflow1)2).
In open-angle glaucoma, increased outflow resistance in the conventional pathway is considered the main cause of elevated intraocular pressure. Age-related degeneration of the trabecular meshwork, cell loss, and accumulation of extracellular matrix impede aqueous flow into Schlemm’s canal. The uveoscleral pathway is relatively less affected by aging, so even when prostaglandin analogs (PGAs) enhance this pathway, the pressure-lowering effect is less likely to diminish. In contrast, ROCK inhibitors directly act on the main site of outflow resistance in the conventional pathway, making them a treatment that targets the underlying pathophysiology.
Many glaucoma eye drops contain benzalkonium chloride (BAK) as a preservative. Long-term use of BAK can cause corneal epithelial damage, conjunctival epithelial damage, and dry eye-like symptoms2). Patients using multiple eye drops have increased BAK exposure, raising the risk of ocular surface disorders.
Choosing preservative-free formulations (e.g., Tapros® Mini, Alphagan®) or formulations with preservatives other than BAK is especially important for patients with ocular surface disorders. For patients who may require filtration surgery in the future, maintaining a healthy ocular surface before surgery is thought to influence surgical success2).
When introducing eye drops, after establishing baseline intraocular pressure, administer to only one eye, and evaluate the intraocular pressure-lowering effect and early side effects considering the relationship between instillation time and intraocular pressure measurement time (monocular trial). It is desirable to start bilateral administration after confirming the effect (2C)1).
A monocular trial is a method in which a glaucoma eye drop is initially administered to only one eye to confirm its efficacy and side effects. After establishing baseline intraocular pressure (IOP), the drop is given to one eye for 4 to 6 weeks, and the IOP-lowering effect is objectively assessed by comparing with the untreated eye. Once the effect is confirmed, treatment is started in both eyes. The Japanese Glaucoma Guideline 5th edition recommends this with a grade of 2C 1).
FP receptor agonists lower IOP by enhancing aqueous humor outflow through the uveoscleral outflow pathway (alternative pathway) 1)2)3). They induce remodeling of the extracellular matrix and increase outflow pathway permeability through modulation of matrix metalloproteinases. Their IOP-lowering effect is the strongest among all drug classes, achieving a reduction of approximately 25–35% 1)2). A single daily dose (recommended at night) provides 24-hour efficacy.
The list of approved FP receptor agonists is shown below.
| Generic Name | Brand Name | Concentration | Dosing Frequency |
|---|---|---|---|
| Latanoprost | Xalatan® | 0.005% | Once daily |
| Tafluprost | Tapros® / Tapros® Mini | 0.0015% | Once daily |
| Travoprost | Travatan Z® | 0.004% | Once daily |
| Bimatoprost | Lumigan® | 0.03% | Once daily |
| Isopropyl unoprostone | Rescula® | 0.12% | Twice daily |
Latanoprost (Xalatan®) 0.005% is the most widely used. Tafluprost (Taflotan®) is a preservative-free unit dose formulation, useful for patients with ocular surface disorders.
Main side effects of PGAs:
Reports have been made of cystoid macular edema, increased intraocular pressure in the presence of iritis or uveitis, and recurrence of corneal herpes when administered to eyes after cataract surgery. Therefore, caution is required in patients with these conditions.
In a multicenter database study (SOURCE study) involving 67,517 individuals, the incidence of uveitis within 3 months of PGA use was 0.32%, which was significantly lower than that with beta-blockers (1.95%), alpha-agonists (1.63%), and CAIs (1.68%)6). It has been shown that PGA use is not associated with an increased risk of uveitis6).
FP receptor agonist
Mechanism of action: enhances the uveoscleral outflow pathway (alternative pathway)
Representative drugs: latanoprost 0.005%, tafluprost 0.0015%
Intraocular pressure reduction: approximately 25–35% (strongest class)
Main side effects: iris pigmentation (irreversible), DUES, eyelash changes, eyelid pigmentation
EP2 receptor agonist
Mechanism of action: Promotes both the uveoscleral outflow pathway and the trabecular meshwork pathway.
Drug: Omidenepag isopropyl (Eybelis®)
Intraocular pressure reduction: Non-inferior to latanoprost.
Main side effects: Conjunctival hyperemia (approximately 25%). Does not cause eyelash abnormalities or eyelid pigmentation.
Omidenepag isopropyl (Eybelis®) is an EP2 receptor-selective agonist approved in September 20181). It binds to the EP2 receptor rather than the FP receptor of prostaglandins and acts on both the uveoscleral outflow pathway and the trabecular meshwork pathway. It has been reported to be effective even in cases where FP receptor agonists are ineffective.
The intraocular pressure-lowering effect is considered non-inferior to latanoprost1). Conjunctival hyperemia occurs in about 25% of cases, but eyelash abnormalities and eyelid skin pigmentation do not occur.
Important contraindications and precautions:
Beta-blockers block beta receptors on the ciliary epithelium, reducing aqueous humor production and lowering intraocular pressure by approximately 20–25%2)3).
The list of approved beta-blockers is shown below.
| Generic name | Brand name | Concentration | Frequency of instillation |
|---|---|---|---|
| Timolol maleate | Timoptol® | 0.25%, 0.5% | 2 times/day |
| Timolol maleate (sustained-release) | Timoptol XE®, Rysmon TG® | 0.25%, 0.5% | 1 time/day |
| Carteolol hydrochloride | Mikelan® | 1%, 2% | 2 times/day |
| Carteolol hydrochloride (sustained-release) | Mikelan LA® | 1%, 2% | 1 time/day |
| Betaxolol hydrochloride (β₁-selective) | Betoptic® S | 0.25% | 2 times/day |
Timolol maleate is the most widely used. Nighttime administration has limited efficacy and may contribute to visual field progression through nocturnal blood pressure reduction 3).
Carteolol vs Timolol: Carteolol hydrochloride has α₂ receptor stimulatory action in addition to β-receptor antagonism, and is said to have milder systemic side effects. Compared to timolol, it causes less corneal epithelial damage, and because it is water-soluble, central nervous system side effects (such as depressive symptoms) are less likely to occur.
β₁-selective blockers (betaxolol): The intraocular pressure-lowering effect is inferior to non-selective β-blockers, but since the contraindication is limited to poorly controlled heart failure, it is an alternative for patients in whom non-selective β-blockers are contraindicated. Caution is needed regarding blood pressure reduction.
They inhibit carbonic anhydrase in the ciliary epithelium, reducing aqueous humor production1)2).
Topical CAI:
Both lower intraocular pressure by approximately 15–20%. Severe renal impairment is a contraindication, and caution is needed in cases of severe corneal endothelial damage.
Oral CAI (acetazolamide, Diamox®): Used for short-term management of acute intraocular pressure elevation, but systemic side effects such as metabolic acidosis, paresthesia, and fatigue are common. Not suitable for long-term use; cases requiring oral medication are considered for surgery1).
α₂-adrenergic receptor agonists lower intraocular pressure by approximately 20–25% through a dual mechanism: suppression of aqueous humor production and enhancement of uveoscleral outflow2)3).
Contraindications: Use in low birth weight infants, newborns, infants, and children under 2 years of age. Risk of sedation and apnea due to CNS depression3).
Characteristic side effects: Allergic conjunctivitis and blepharitis occur in 10–25% of patients, typically appearing after 3 months or more rather than immediately after use. Caution is also needed for orthostatic hypotension, dizziness, drowsiness, and bradycardia due to systemic absorption.
ROCK inhibitors act on trabecular meshwork cells, extracellular matrix, and Schlemm’s canal endothelial cells, directly promoting aqueous humor outflow through the conventional (trabecular) pathway1). They represent a completely new class of drugs targeting the main outflow pathway, and their future role is of interest1).
Characteristics of side effects: Conjunctival hyperemia after instillation disappears in about 90 minutes, but unlike prostaglandin-related drugs, the hyperemia does not disappear even with continued use. Maximum intraocular pressure lowering effect is achieved 2 hours after administration. Conjunctivitis and blepharitis may also occur.
Using fixed-combination eye drops allows the use of multiple drugs without increasing the number of eye drops or instillation frequency, which is advantageous for maintaining adherence (1B)1). Only fixed-combination preparations containing two ingredients exist1).
The main fixed-combination eye drops are shown below.
| Brand name | Ingredients | Frequency |
|---|---|---|
| Xalacom® | Latanoprost 0.005% + Timolol 0.5% | Once daily |
| Tapcom® | Tafluprost 0.0015% + Timolol 0.5% | Once daily |
| DuoTrav® | Travoprost 0.004% + Timolol 0.5% | Once daily |
| Cosopt® | Dorzolamide 1% + Timolol 0.5% | 2 times/day |
| Azorga® | Brinzolamide 1% + Timolol 0.5% | 2 times/day |
| Mikelna® | Carteolol 1% + Latanoprost 0.005% | 2 times/day |
Although PGA + timolol fixed combinations theoretically reduce the effect of timolol from twice daily to once daily, switching to a fixed combination may improve treatment outcomes in patients who tend to forget eye drops.
Important note: All currently available fixed combinations contain a beta-blocker. Therefore, fixed combinations cannot be used in patients with contraindications to beta-blockers (e.g., bronchial asthma, COPD, heart failure, bradycardia, atrioventricular block).
The stepwise approach to glaucoma medication therapy is as follows.
In elderly patients or those at risk of systemic side effects from beta-blockers, after PGA, choose from CAI, alpha-2 agonists, or ROCK inhibitors 1).
For normal-tension glaucoma (NTG), first-line medication is also PGA, followed by beta-blockers or CAIs. The target is a 20-30% reduction from untreated intraocular pressure. If eye drops are insufficient, surgical therapy is performed.
In late-onset developmental glaucoma, considering side effects such as periorbital pigmentation, treatment may start with beta-blockers. However, if intraocular pressure exceeds 25 mmHg even with mild optic nerve or visual field damage, PGA (latanoprost) is used from the start.
Glaucoma is a chronic disease with few subjective symptoms, so adherence to medication is a major clinical challenge 1)2). The following measures are recommended.
The use of fixed-combination eye drops is particularly effective in improving adherence (1B) 1). Reducing the number of eye drops and instillations not only lessens the patient’s burden but also eliminates the “washout effect” from sequential instillation, potentially achieving better intraocular pressure control than separate administration.
Pigmentation of the eyelid skin often tends to improve after discontinuation. On the other hand, iris pigmentation is due to an increase in the number of melanosomes and is irreversible. DUES (deepening of the upper eyelid sulcus) and changes in eyelashes tend to improve after discontinuation. To prevent pigmentation, compression of the lacrimal sac after instillation and wiping off any excess medication from the skin are effective. It is important to provide sufficient explanation of these side effects before administration and obtain the patient’s consent.
ROCK inhibitors are a new class of glaucoma medications that directly enhance outflow through the trabecular meshwork and Schlemm’s canal, the main outflow pathway. Ripasudil (Glanatec®) was the first to be approved worldwide in 2014. Currently, they are not first-line agents but are often used as add-on therapy when target intraocular pressure is not achieved with PGAs or beta-blockers. Their distinctive feature is a mechanism of action different from other drug classes (direct enhancement of conventional outflow).
Aqueous humor is produced by the non-pigmented epithelium of the ciliary body at a rate of approximately 2–3 μL per day and exits via two main pathways7).
In the conventional pathway (trabecular outflow pathway), aqueous humor drains through the trabecular meshwork → Schlemm’s canal → collector channels → episcleral veins7). This pressure-dependent pathway accounts for 80–90% of total aqueous outflow. In the uveoscleral pathway, aqueous humor flows through the interstices of the ciliary muscle into the suprachoroidal space. This pressure-independent pathway accounts for 10–20% of total aqueous outflow.
| Drug Class | Main Mechanism of IOP Reduction | IOP Reduction Rate |
|---|---|---|
| FP receptor agonists (PGAs) | Enhancement of uveoscleral outflow | 25–35% |
| EP2 receptor agonist | Enhances uveoscleral outflow + trabecular outflow | Non-inferior to latanoprost |
| Beta-blocker | Suppresses aqueous humor production | 20–25% |
| CAI (topical) | Suppresses aqueous humor production | 15–20% |
| Alpha-2 agonist | Suppresses aqueous humor production + enhances uveoscleral outflow | 20–25% |
| ROCK inhibitor | Enhances trabecular outflow (direct) | Mainly additive effect |
| α₁β blocker | Suppression of aqueous humor production + enhancement of uveoscleral outflow | Equivalent to β-blockers |
| Pilocarpine | Enhancement of trabecular outflow (indirect, via miosis) | 15–25% |
PGAs (FP receptor agonists) are prostaglandin F₂α derivatives that improve uveoscleral outflow by remodeling the extracellular matrix of the ciliary muscle 2)3). EP2 receptor agonists also enhance trabecular outflow by relaxing the trabecular meshwork and dilating Schlemm’s canal, in addition to uveoscleral outflow, providing a dual mechanism of outflow enhancement 1).
β-blockers block β₂-adrenergic receptors in the ciliary epithelium, suppressing cAMP production and thereby reducing aqueous humor production 2)3). CAIs inhibit carbonic anhydrase type II in the ciliary epithelium, suppressing bicarbonate ion transport and reducing aqueous humor production.
ROCK inhibitors relax the actin-myosin system in trabecular meshwork cells and modulate the barrier function of Schlemm’s canal endothelial cells, directly reducing aqueous humor outflow resistance through the conventional pathway 1). While other drug classes primarily act on the uveoscleral pathway or aqueous humor production, ROCK inhibitors occupy a unique position by directly targeting the trabecular meshwork, the main site of outflow resistance in glaucoma.
α₂ agonists (brimonidine) have a dual action: suppression of aqueous humor production and enhancement of uveoscleral outflow. In the Low-pressure Glaucoma Treatment Study (LoGTS), brimonidine was reported to have significantly less visual field progression compared to timolol (9.1% vs 39.2%), suggesting an intraocular pressure-independent neuroprotective effect 7). However, treatment aimed at neuroprotection is not yet established 2).
α₁β blockers (nipradilol, Hypadil®) lower intraocular pressure by both suppressing aqueous humor production and enhancing uveoscleral outflow. Their ocular hypotensive effect is equivalent to that of β-blockers, and systemic contraindications are the same as for β-blockers. Caution is required because long-term administration in aphakic eyes or eyes with fundus disease may cause macular edema.
When selecting a drug, in addition to the intraocular pressure-lowering effect, the following patient factors should be comprehensively considered.
In the 6-year results of the LiGHT trial, 69.8% of eyes in the group treated with selective laser trabeculoplasty (SLT) as primary therapy maintained target intraocular pressure without additional medication or surgery 5).
The LiGHT trial (633 patients, 6-year follow-up) compared SLT group with eye drop group. The SLT group had less disease progression (19.6% vs 26.8%, P=0.006) and significantly fewer trabeculectomies (13 eyes vs 32 eyes, P<0.001). Cataract surgery was also less frequent in the SLT group (57 eyes vs 95 eyes, P=0.03). No serious laser-related complications were observed 5).
The European Glaucoma Society (EGS) and AAO guidelines recommend SLT as a primary treatment option for open-angle glaucoma and ocular hypertension 2)3). SLT is a strong option for patients with adherence issues or those who cannot continue eye drops due to side effects.
In the 6-year results of the LiGHT trial, 69.8% of patients treated with SLT as primary therapy maintained target intraocular pressure without additional eye drops or surgery. The SLT group showed less disease progression and a significantly lower need for trabeculectomy compared to the eye drop group. The European Glaucoma Society and AAO recommend SLT as a primary treatment option. However, SLT is not indicated for all cases; it is contraindicated in severe cases or those with a history of uveitis. It is important to consult with your doctor and choose a treatment method according to your individual condition.
- 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;126:85-177.
- European Glaucoma Society. Terminology and Guidelines for Glaucoma, 6th Edition. Br J Ophthalmol. 2025.
- American Academy of Ophthalmology. Primary Open-Angle Glaucoma Preferred Practice Pattern®. 2020.
- American Academy of Ophthalmology. Primary Open-Angle Glaucoma Suspect Preferred Practice Pattern®. 2020.
- Gazzard G, Konstantakopoulou E, Garway-Heath D, et al. Laser in Glaucoma and Ocular Hypertension (LiGHT) Trial. Six-Year Results of Primary Selective Laser Trabeculoplasty versus Eye Drops for the Treatment of Glaucoma and Ocular Hypertension. Ophthalmology. 2023;130(2):139-151.
- Chauhan MZ, Elhusseiny AM, Marwah S, et al. Incidence of Uveitis Following Initiation of Prostaglandin Analogs versus Other Glaucoma Medications: A Study from the SOURCE Repository. Ophthalmol Glaucoma. 2025;8:126-132.
- European Glaucoma Society. Terminology and Guidelines for Glaucoma, 5th Edition. 2020.
