Eyedrop overview
The topical treatment landscape in glaucoma
What is the relationship between IOP and glaucoma?
IOP is the only readily modifiable risk factor for glaucoma, and the only approach shown to be effective in preserving visual function is by lowering IOP.1,2
Each 1 mmHg reduction in IOP could lower the risk of disease progression by between 10–20%.1,3–5
What are the topical treatment options available for patients?
Eyedrops may be the initial topical treatment option for patients with most forms of open-angle glaucoma. There are several different classes of topical treatments, including prostaglandin analogs and prostamides, β-receptor antagonists (non-selective and selective), α-2 adrenergic agonists, topical carbonic anhydrase inhibitors, cholinergic drugs, and rho kinase inhibitors.2
Considerations when choosing first-line glaucoma treatment
A first-choice medical treatment is one which an eyecare professional, also known as an ECP, prefers to use as initial IOP-lowering therapy as opposed to the first line treatment approved by policymakers.2
ECPs must take the following factors into consideration when choosing which treatment is best for each individual patient:2
Adapted from European Glaucoma Society Terminology and Guidelines for Glaucoma. 5th edition. 2020.2
It is essential that patients are involved in decisions regarding the management of their condition.2
Monotherapy
Treatment is recommended to begin with monotherapy in most patients, as the least amount of medication required to achieve the desired therapeutic response should be given to minimize the frequency of adverse events.2
The below therapeutic algorithm may be used as a guide for patients whose IOP is insufficiently controlled, or their first-choice treatment option is not well tolerated.2
Glaucoma topical therapy – therapeutic algorithm
Adapted from European Glaucoma Society Terminology and Guidelines for Glaucoma. 5th edition. 2020.2
Prostaglandin analogues and prostamides
Prostaglandin analogues and prostamides have become the first-choice therapy amongst the available medical treatments due to their efficacy, once-daily dosing, and safety profile.2
Mode of action
Topical prostaglandin analogues and prostamides reduce IOP by enhancing uveoscleral outflow of aqueous humor.2
1 – Enhances uveoscleral outflow of aqueous humor2
Adapted from European Glaucoma Society Terminology and Guidelines for Glaucoma. 5th edition. 2020.2
Side effects2
| Local | Systemic |
|---|---|
| Conjunctival hyperemia, burning, stinging, foreign body sensation, itching, increased pigmentation of periocular skin, periorbital fat atrophy, eyelash changes, increased iris pigmentation (in green-brown, blue/grey-brown or yellow-brown irides), cystoid macular edema (aphakic/pseudophakic patients) with posterior lens capsule rupture or in eyes with known risk factors for macular edema, reactivation of herpes keratitis, uveitis | Dyspnea, chest pain/angina, muscle-back pain, exacerbation of asthma |
Non-selective β-receptor antagonists
Non-selective β-receptor antagonists can be used for the treatment of glaucoma.2
Mode of action
β-receptor antagonists reduce IOP by decreasing the production of aqueous humor.2
Contraindications
Currently known contraindications for non-selective β-receptor antagonists have been outlined below:2
asthma
history of COPD
sinus bradycardia (<60 beats/min)
heart block
cardiac failure
Side effects2
| Local | Systemic |
|---|---|
| Conjunctiva hyperemia, superficial punctate keratitis, dry eye, corneal anesthesia, allergic blepharo-conjunctivitis | Bradycardia, arrhythmia, heart failure, syncope, bronchospasm, airways obstruction, distal edema, hypotension, masking of hypoglycemia in insulin-dependent Diabetes Mellitus, nocturnal systemic hypotension, depression, erectile dysfunction |
Selective β-receptor antagonists
β-1-selective antagonists are also used in the treatment of glaucoma.2
Mode of action
They lower IOP by decreasing production of aqueous humor.2
Contraindications
Currently known contraindications for selective β-receptor antagonists have been outlined below:2
asthma
history of COPD
sinus bradycardia
heart block
cardiac-coronary failure
Side effects2
| Local | Systemic |
|---|---|
| Burning, stinging, more pronounced than with non-selective compounds | Cardiac and respiratory side effects less pronounced than with non-selective compounds, depression, erectile dysfunction |
α-2 adrenergic agonist eye drops
Another class of drugs available for the treatment of glaucoma are α-2 adrenergic agonist eye drops.2
Mode of action
α-2 adrenergic agonists reduce IOP by decreasing aqueous humor production, and brimonidine may also increase uveoscleral outflow of aqueous humor.2
1 – Decreasing aqueous humor production1
2 – Increasing uveoscleral outflow of aqueous humor (brimonidine only)2
Adapted from European Glaucoma Society Terminology and Guidelines for Glaucoma. 5th edition. 2020.2
Contraindications
Currently known contraindications for α-2 adrenergic agonists have been outlined below:2
- oral MAO inhibitor users
- pediatric age
- very low body weight in adults
Side effects2
| Local | Systemic |
|---|---|
| Lid retraction, conjunctival blanching, limited mydriasis (apraclonide), allergic blepharoconjuntivitis, periocular contact dermatitis, allergy or delayed hypersensitivity (apraclonidine and clonidine>brimonidine) | Dry mouth and nose (apraclonidine), fatigue, sleepiness (brimonidine) |
Topical carbonic anhydrase inhibitors
Topical carbonic anhydrase inhibitors can also be used in the treatment of glaucoma.2
Mode of action
Topical carbonic anhydrase inhibitors lower IOP by decreasing production of aqueous humor.2
Contraindications
Currently known contraindications for topical carbonic anhydrase inhibitors are patients with low corneal endothelial cell count, due to increased risk of corneal edema.2
Side effects1
| Local | Systemic |
|---|---|
| Burning, stinging, bitter taste, superficial punctate keratitis, blurred vision, tearing | Headache, urticaria, angioedema, pruritus, asthenia, dizziness, paresthesia, transient myopia |
Cholinergic drugs
Cholinergic drugs can be either direct-acting or indirect-acting.2
Mode of action
Cholinergic drugs lower IOP by facilitating aqueous outflow by contraction of the ciliary muscle, tension on the scleral spur and traction on the trabecular meshwork.2
Contraindications
Cholinergic drugs are contraindicated in patients with or at risk for:2
- post-operative inflammation
- uveitis neovascular glaucoma
- spastic gastrointestinal disturbances
- peptic ulcer
- pronounced bradycardia
- hypotension
- recent myocardial infarction
- epilepsy
- Parkinsonism
- retinal detachment
Side effects2
| Local | Systemic | |
|---|---|---|
| Direct-acting | Reduced vision due to miosis and accommodative myopia, conjunctival hyperemia, retinal detachment, lens opacities, precipitation of angle closure, iris cysts | Intestinal cramps, bronchospasm, headache |
| Indirect-acting | Local and systemic side effects are similar but more pronounced than with direct acting compounds | |
Rho kinase inhibitors
Another class of drops used in glaucoma treatment are the rho kinase inhibitors.2
Mode of action
Rho kinase inhibitors lower IOP by increasing outflow via the trabecular meshwork, and some drugs within this class also elicit reductions in episcleral venous pressure.2
Side effects2
| Local | Systemic | |
|---|---|---|
| Netarsudil | Conjunctival hyperemia, cornea verticillata, instillation site pain, conjunctival haemorrhage, instillation site erythema, corneal staining, blurred vision, increased lacrimation and erythema of eyelid | Headache, nasal discomfort, rhinalgia, dermatitis allergic, dermatitis contact, lichenification, petechiae, polycondritis, escoriation |
| Ripasudil | Conjunctival hyperemia, conjunctivitis, blepharitis, eye irritation, corneal epithelial disorder, eye pruritus, abnormal sensation in eye, eye discharge, eye pain, conjunctival follicles, intraocular pressure increase, contact dermatitis | Gastro-intestinal disorders, dizziness, headache, nasal congestion, allergic rhinitis |
COPD, chronic obstructive pulmonary disease; IOP, intraocular pressure; MAO; monoamine oxidase.
European Glaucoma Society. Terminology and Guidelines for Glaucoma. 5th edition. EGS. 2020.2
Combination therapy
If monotherapy is tolerated but does not lower IOP to the target pressure, an additional drug from a different class should be considered. Fixed combination therapy is preferable to the use of two separate instillations to help maintain adherence and reduce exposure to preservatives.2 Fixed combination medications usually have clinical equivalence to unfixed combinations.2
Most fixed combination therapies available in Europe contain a β-receptor antagonist. These may improve local tolerability of the other agent but can be associated with systemic side effects especially in patients with relevant contraindications.2
The most common combination therapy is a prostaglandin analog with a β-receptor antagonist. Also available are CAIs with α-2-adrenergic agonist or prostaglandin analog with rho kinase inhibitor combinations.2
The benefits of fixed combination therapies
Fixed combination therapies offer many benefits over the separate use of two different topical therapies for several reasons:6
Convenience – it is more convenient (easier and faster) to administer one drop of a fixed combination than two drops from separate bottles of the component medications2
Adherence – up to 80% of glaucoma patients may not take their medication as prescribed, and the inconvenience of the need to administer multiple drops is one of the primary reasons for this2
Cautions with combination therapy
Combination therapy is not recommended as a first choice treatment.2
If a patient’s IOP is insufficiently controlled with two drugs then a third drug, laser, or incisional surgery may be considered.2
Preservative-free eye drops
Preserved topical glaucoma medications may cause and/or exacerbate pre-existing OSD disease such as dry eye disease and Meibomian gland dysfunction, which has a high prevalence in adults.2
Patients that may benefit from preservative-free formulations include patients who are likely to need long-term treatment with multiple medications, those who are allergic to preservatives, and those with clinically significant OSD.7
Potential benefits of preservative free formulations include:8
Reduced occurrence of some topical adverse events
Increased adherence to treatment
Improved quality of life by reducing the incidence of
preservative-associated adverse events
Reduced risk of ocular surface toxicity from long-term treatment leading to or exacerbating existing OSD, especially in the elderly population
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References and abbreviations
1. MacIver, S., MacDonald, D., & Prokopich, C. L. (2019). Screening, Diagnosis, and Management of Open Angle Glaucoma: An Evidence-Based Guideline for Canadian Optometrists. Canadian Journal of Optometry, 79(1), 5–71
2. European Glaucoma Society. Terminology and Guidelines for Glaucoma. 5th edition. EGS. 2020.
3. Heijl A and Brandel M. If we don't change direction soon, we'll end up where we're going: a description of the SSY Engine. Acta Ophthalmol 2020; 99(4): 357–361.
4. Leske C, Hejil, Bengtsson et al. Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol 2003; 141(1): 48–56.
5. Chauhan B, Mikelberg, Balaszi et al. Canadian Glaucoma Study: 2. risk factors for the progression of open-angle glaucoma. Arch Ophthalmol 2008; 126(8): 1030–1036.
6. Higginbotham E,. Considerations in glaucoma therapy: fixed combinations versus their component medications. Clin Ophthalmol 2010; 4: 1–9.
7. Stalmans I, Megevand, Cordeiro et al. Preservative-free treatment in glaucoma: who, when, and why. Eur J Ophthalmol 2013; 23(4): 518–525.
8. Thygesen J. Glaucoma therapy: preservative-free for all? Clin Ophthalmol 2018; 12: 707–717.
ECP, eyecare professional; IOP, intraocular pressure. OSD, ocular surface disease. CAI, carbonic anhydrase inhibitor; CIGTS, collaberative initial glaucoma treatment study; IOP, intraocular pressure
SE-OPHTHG-240006 v1.0 July 2024
