Glaucoma is a multifactorial optic neuropathy characterized by retinal ganglion cell apoptosis, of which elevated eye pressure is among one of the risk factors. Eye drops are commonly used as the first line of treatment, whereas laser and glaucoma surgeries are alternative options. Glaucoma medications decrease the pressure of the eye by helping the aqueous fluid drain better and/or by decreasing aqueous production, illustrated in Figure 1.
Figure 1
Drugs that treat glaucoma are classified by their active ingredients: prostaglandin analogs, beta blockers, alpha agonists, carbonic anhydrase inhibitors, rho-kinase inhibitors, and cholinergic agonists. Combination drops are also available when two or more medications are required.
Prostaglandin analogs
Mechanism: Increase uveoscleral outflow
Drops: Xalatan (latanoprost), Travatan Z (travoprost), Lumigan (bimatoprost), Zioptan (tafluprost), Vyzulta (latanoprostene bunod)
Cap Color: Teal
Prostaglandin analogs (PGAs) are typically the first line of topical treatment in IOP control in glaucoma. They may yield a reduction of 30-35% in IOP.1 The most common side effects1 of PGAs are conjunctival hyperemia, ocular irritation, pigmentation of periocular skin, hypertrichosis, periorbital fat loss, and exacerbation of existing inflammatory conditions (macular edema, iritis).
Out of the drops listed above, Vyzulta is unique in that the medication breaks down into latanoprost and nitric oxide. This drug has a dual mechanism of action. Not only does it increase uveoscleral outflow (using Latanoprost), but the nitric oxide relaxes the trabecular meshwork further to increase output. In the past, treatments based on increased outflow through the trabecular pathway were limited to laser trabeculoplasty or miotics.2 In the VOYAGER study, Vyzulta yielded an overall diurnal reduction in IOP by approximately 1.23mmHg compared to Latanoprost.3
Beyond glaucoma: PGAs have gained immense popularity in over the counter and prescription eyelash lengthening products (Latisse). Keep in mind the side effects that come with PGA usage.
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Reference Guide to Glaucoma Medications
A guide to glaucoma medications, dosage, mechanism, contraindications, and more.
ROCK inhibitors
Mechanism: Increase uveoscleral outflow
Drops: Rocklatan (netarsudil and latanoprost), Rhopressa (netarsudil)
Cap Color: White
ROCK inhibitors are a new class of medications, also known as rho kinase inhibitors. As the name suggests, an enzyme called rho kinase is inhibited which regulates cell shape and movements.
ROCK inhibitors have a two-fold effect:1
1) They relax the trabecular meshwork.
2) They lower episcleral venous pressure which increases outflow through Schlemm’s canal.
Rhopressa may also have a role in decreasing aqueous humor production which remains to be further studied.4
Rhopressa is dosed once daily and considered non-inferior to twice daily timolol usage (baseline IOP < 25mmHg), producing mean reduction by up to 5 mmHg.5 The most common side effects of Rhopressa were conjunctival hyperemia (53%), corneal verticillata (~20%), site irritation, and petechial conjunctival hemorrhage (mild). There are no systemic contraindications to this medication.
Rocklatan is a combination of Rhopressa and Latanoprost, dosed qhs. In phase 3 clinical trials, Rocklatan decreased IOP by up to 3mmHg vs its individual components.6 Nearly 60% of Rocklatan patients had IOP of <16mmHg vs 37% of latanoprost patients. The side effects are similar to Rhopressa.
Beyond glaucoma: Rhopressa has shown impressive benefits, off-label, for patients with corneal endothelial dystrophies (i.e., Fuchs' dystrophy). Studies show that Rhopressa enhances cell proliferation, promotes cell adhesion after corneal surgeries, and suppresses apoptosis of corneal endothelial cells.7
Beta blockers
Mechanism: Decrease aqueous production
Drops: Timolol, Betaxolol, Levobunolol
Cap Color: Yellow, White*, Blue*
*Betaxolol is available with a white or blue top
Beta blockers, or adrenergic agonists, inhibit aqueous production. This class of medication may reduce IOP by 20-30%.1 These medications can be nonselective (B1 and B2), or cardioselective (higher affinity for B1 receptors). In the eye, B2 is the predominant adreno-receptor so nonselective agents have a greater impact on IOP. Betaxolol is the only cardioselective option which is good for patients who have mild respiratory comorbidities (i.e., asthma, COPD) because it decreases the likelihood of systemic respiratory side effects as compared to timolol.8 However, it will also be less effective in lowering IOP.
Beta blockers should be avoided in patients with asthma, COPD, congestive heart failure, bradycardia as they have the potential to cause serious side effects. Keep note that concurrent use of systemic beta-blocker along with a topical dose may reduce the overall efficacy of the medication.
Beyond glaucoma: Topical timolol 0.5% dosed twice daily has shown effectiveness in decreasing and/or eliminating pyogenic granulomas after 4-6 weeks of therapy.9
Alpha-adrenergic agonists
Mechanism: Decrease aqueous production, increase uveoscleral outflow
Drops: Brimonidine, Apraclonidine
Cap Color: Purple
Alpha-adrenergic agonists decrease aqueous production and increase uveoscleral outflow. They are typically adjunctive therapies after PGAs and beta-blockers.
Common side effects of these medications are follicular conjunctivitis (20%1), dizziness, drowsiness, dry mouth, hypotension, and central nervous system depression.10
Beyond glaucoma: Brimonidine can be dosed once daily to decrease pupil size for glare and/or higher order aberrations purposes. Brimonidine can also be used as a vasoconstrictor for conjunctival hyperemia. Lumify is the first and only OTC drop for this purpose.
Carbonic anhydrase inhibitors
Mechanism: Decrease aqueous production
Drops: Brinzolamide, Dorzolamide
Cap Color: Orange
Also known as CAIs, these lower IOP by reducing aqueous production. Similar to alpha-adrenergic agonists, these medications are typically used as adjunctive therapy. They are available in topical and oral form (Diamox).
Diamox is often used for patients with acute elevated IOP > 40mmHg. Side effects of oral therapy are fatigue, paresthesia, and metabolic acidosis.10
Topical therapy is known to cause stinging, and dysgeusia. These agents are contraindicated in patients with corneal endothelial dysfunction as it can reduce the function of the endothelial pumps. They are also cautioned in patients with sulfa allergies. Oral and topical should be used very cautiously in sickle cell patients as it may cause systemic acidosis and/or exacerbate sickling.
Beyond glaucoma: Diamox is used in idiopathic intracranial hypertension (IIH, pseudotumor cerebri) and is thought to decrease cerebrospinal fluid.
Miotics
Mechanism: Increase aqueous outflow
Drops: Pilocarpine
Cap Color: Green
Miotics are cholinergics that stretch the trabecular meshwork to increase aqueous outflow. IOP may be decreased by 20%1 when dosed qid. It is not used much because of the tendency to cause ciliary muscle spasm, miosis, corneal toxicity, uveitis, cataracts, respiratory depression, and gastrointestinal distress. Newer classes of medications listed above have much better safety profiles with greater IOP-lowering effects. Still, miotics are beneficial in use during acute angle closure glaucoma.
Combination therapy
Drops: Simbrinza (brinzolamide/brimonidine), Cosopt (dorzolamide/timolol), Combigan (brimonidine/timolol), Rocklatan (rhopressa/latanoprost)
Cap Color: Blue, White
Combination drops are used to achieve further IOP reduction. Along with the combination therapies mentioned above, compounding pharmacies may customize drops to include other agents. For example, with ImprimisRx, you may order a quad therapy which combines four agents (brimonidine, dorzolamide, timolol, and latanoprost).
Each class of medication has its own potential side effect profile that needs to be considered when choosing this line of therapy. Some effects may also be minimized, as is in the case of follicular conjunctivitis with combination therapy of brimonidine and timolol. It is thought that because timolol causes vessel constriction, this reduces conjunctival hyperemia and subsequently lowers the incidence of the hypersensitivity vs brimonidine alone.11
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Conclusion
Treating glaucoma requires knowing each class of medication and prescribing a drop or combination of which works best for your patient, keeping in mind the contraindications and side effects. If glaucoma is progressing despite drop therapy or the patient has poor compliance, selective laser trabeculoplasty (SLT) is an excellent non-invasive treatment option. SLT may also be used as a first line of treatment. Make referrals as needed for patients for traditional filtering surgeries, and for those patients that need cataract procedures, minimally invasive glaucoma surgeries (MIGS).
References
- Michael Dorkowski, OD. “A Guide to Applying IOP-Lowering Drugs.” Review of Optometry, 15 July 2018, https://www.reviewofoptometry.com/article/a-guide-to-applying-ioplowering-drugs.
- Joseph W. Sowka, OD. “Glaucoma's New Foe, Explained.” Review of Optometry, 15 Feb. 2018, https://www.reviewofoptometry.com/article/ro0218-glaucomas-new-foe-explained.
- Weinreb RN, Ong T, Sforzolini BS, et al. “A randomized, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open angle glaucoma: the VOYAGER study.” Br J Ophthalmol. 2015;99(6):738-45.
- Kazemi, Arash et al. “The Effects of Netarsudil Ophthalmic Solution on Aqueous Humor Dynamics in a Randomized Study in Humans.” Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics vol. 34,5 (2018): 380-386. doi:10.1089/jop.2017.0138
- Sawhney, Gagan. “New Options in Glaucoma Pharmacology.” Ophthalmologymanagement.com, 1 Nov. 2019, https://www.ophthalmologymanagement.com/issues/2019/november-2019/new-options-in-glaucoma-pharmacology.
- Izzo, Michael, et al. “Advances in Therapeutics.” Glaucoma Today, Bryn Mawr Communications, 2021, https://glaucomatoday.com/articles/2021-july-aug/advances-in-therapeutics.
- Okumura, Naoki, et al. “Application of Rho Kinase Inhibitors for the Treatment of Corneal Endothelial Diseases.” Journal of Ophthalmology, Hindawi, 2 July 2017, https://www.hindawi.com/journals/joph/2017/2646904/.
- Tajran, Jahan, and Anju Goyal. “Betaxolol.” National Center for Biotechnology Information, U.S. National Library of Medicine, 21 Apr. 2022, https://www.ncbi.nlm.nih.gov/books/NBK557870/.
- Nair, Akshay, et al. “Topical Timolol for the Treatment of Conjunctival Pyogenic Granuloma.” Indian Journal of Ophthalmology, https://journals.lww.com/ijo/Fulltext/2020/68100/Topical_timolol_for_the_treatment_of_conjunctival.28.aspx.
- Marrelli, Danica. “The Glaucoma Therapy Toolbox.” Optometricmanagement.com, 1 Feb. 2018, https://www.optometricmanagement.com/issues/2018/february-2018/the-glaucoma-therapy-toolbox.
- Yeh, Po-Han, et al. “Brimonidine Related Acute Follicular Conjunctivitis.” Medicine, https://journals.lww.com/md-journal/Fulltext/2021/07230/Brimonidine_related_acute_follicular.48.aspx.
- Chang, Eileen, et al. “Side Effects of Glaucoma Medications.” Glaucoma Today, Bryn Mawr Communications, 2021, https://glaucomatoday.com/articles/2021-jan-feb/side-effects-of-glaucoma-medications-1.
- Thurtell, Matthew J, and Michael Wall. “Idiopathic intracranial hypertension (pseudotumor cerebri): recognition, treatment, and ongoing management.” Current treatment options in neurology vol. 15,1 (2013): 1-12. doi:10.1007/s11940-012-0207-4
- Williams, Steven. “Medical Therapy for Open-Angle Glaucoma.” Steven M. Williams, MD, Steven M. Williams, MD, 29 Nov. 2019, https://www.ophthalmologyexpertservices.com/blog/2019/medical-therapy-for-open-angle-glaucoma.
