Medical Management for Primary Open-Angle Glaucoma
According to the American Academy of Ophthalmology Preferred Practice Patterns, primary open angle glaucoma (POAG) is defined as an optic neuropathy with associated visual field loss for which elevated intraocular pressure (IOP) is a major risk factor. As a result, most of our treatment strategies are directed at reducing IOP, either with medical therapy, laser surgery, or incisional surgery, with medical therapy being the most common initial course of treatment. Two important questions often confront eye care professionals when initiating therapy: Who needs to be treated and how? With advent of newer drugs with improved efficacy, reduced frequency of dosing, and fewer ocular and systemic side effects, our treatment options have been expanded. While it is important to have more choices, it also adds confusion as to which medication may be best suited for a particular patient. In general, the goal of treatment is to choose a therapeutic agent that is effective, safe, tolerable, and affordable to ensure patient acceptance and adherence. This brief review provides a summary of various classes of drugs available at present for glaucoma treatment. Their mechanisms of action and side effects are described to help clinicians choose primary therapy or adjunctive therapy to lower IOP and to ultimately slow down the progression of glaucoma to preserve visual function.
Glaucoma refers to a group of disorders which causes progressive optic neuropathy with the major risk factor being elevated intraocular pressure. Glaucoma can exist at any level of intraocular pressure; however, prevalence increases with uncontrolled IOP affecting the optic nerve and resulting in subsequent loss of visual function. Glaucoma is the leading cause of irreversible blindness worldwide and the 2nd leading cause of blindness in the United States.
Primary open angle glaucoma is characterized by the presence of an anatomically open angle on gonioscopy; characteristic optic nerve changes, such as cupping and/or thinning or the neuroretinal rim; and characteristic patterns of visual field loss.
According to the Preferred Practice Patterns of AAO, two of the three findings (elevated IOP, optic nerve damage, or visual field loss) must be present for the diagnosis of primary open angle glaucoma.
Family history, Age, Race (Increased prevalence in African American population, Ocular Conditions (increased intraocular pressure, thin central corneal thickness). Other possible risk factors include: perfusion pressure, coronary artery disease, diabetes, myopia
Not entirely understood. Two commonly discussed theories are:
- Mechanical theory -direct pressure induced-damage to the retinal ganglion cell axons at the level of the lamina cribrosa.
- Vascular theory -microvascular changes and resultant ischemia in the optic nerve head.
The only way we currently know to prevent and/or delay progression of primary open angle glaucoma is by reducing the intraocular pressure.
POAG is diagnosed by taking a comprehensive history, clinical exam, and visual field testing. Optic nerve and nerve fiber layer imaging, such as optical coherence tomography (OCT), can aid in the evaluation and diagnosis.
Elevated Intraocular pressure, corneal edema (typically only seen with acutely elevated IOP), optic nerve asymmetry, optic nerve cupping, neuroretinal rim thinning or notches.
Symptoms are typically only experienced with acutely elevated IOP or with advanced optic nerve damage, resulting in visual field loss.
Comprehensive eye exam including evaluation of visual acuity, afferent pupillary defect, gonioscopy, slit lamp examination, dilated fundoscopic exam, and visual field assessment.
- Physiologic optic nerve cupping: Large optic nerves, and static appearance
- Congenital disc anomalies: optic nerve coloboma, congenital pit, and tilted disc syndrome
- Low (Normal) Tension Glaucoma
- Ocular hypertension (high IOP in the presence of normal optic nerves and visual field)
- Secondary open-angle glaucoma: e.g. pseudoexfoliation, pigmentary, steroid-induced, lens particle, etc
- Previous glaucomatous damage: Due to prior episodes of elevated intraocular pressure, e.g. from trauma, uveitis, steroid use, that have resolved. IOP is normal and optic nerve appearance remains static.
- Acquired conditions: e.g. arteritic anterior ischemic optic neuropathy, compressive lesions such as intracranial aneurysm (characteristic patterns on the visual field testing help to distinguish glaucoma from various neurological diseases)
Current treatment of glaucoma is limited to lowering the intraocular pressure to a level that will decrease the likelihood of further optic nerve damage. Many ophthalmologists initially try medical management or selective laser trabeculoplasty (SLT) if the glaucoma progression is not rapid. If conservative therapy fails, then incisional surgery with microinvasive glaucoma surgery (MIGS), trabeculectomy, or glaucoma drainage implant may be required. Once the decision to treat has been made, one has to determine the target IOP pressure range. Factors such as age of patient, life expectancy, and other risk factors must be kept in mind. It is essential to obtain a full history of concomitant systemic diseases to avoid side effects. The goal of treatment should be preservation of vision as well as quality of life.
Glaucoma clinical trials over the past 20 years have provided critically important, evidence-based guidelines in the management of patients with glaucoma. Whether treatment is provided with medical therapy, laser, or surgery, these trials have shown that glaucoma development and progression can be controlled by lowering IOP, a well-established modifiable risk factor for glaucomatous optic neuropathy. IOP lowering has been found to be beneficial even in eyes with normal tension glaucoma. The Collaborative Normal Tension Study Group found that a 30% IOP reduction dropped the rate of progression from 35% in the observation group to 12% in the treated group. The Early Manifest Glaucoma Trial (EMGT) found that an IOP reduction by at least 25% reduced progression from 62 %to 45% in the treated group compared to an untreated group. Setting an initial target of 20-30% IOP reduction is recommended; however, it is very important to constantly reassess for optic nerve or visual field changes, and change target pressure, as needed.
The medications currently used to treat glaucoma work by lowering the intraocular pressure by two main mechanisms 1) reducing aqueous humor production and/or 2) increasing aqueous humor outflow.
Medications that suppress aqueous humor production
Mechanism of action
Lower IOP by suppressing aqueous humor production. They inhibit synthesis of cyclic adenosine monophosphate (c-AMP) in the ciliary epithelium and lead to a decrease in aqueous secretion.
Ocular side effects of topical beta-blockers are minor and include burning and decreased corneal sensation. Systemic side effects can be more severe. They include bradycardia; arrhythmia; heart failure; heart block; syncope; bronchospasm or airway obstruction; central nervous system effects (depression, weakness, fatigue, or hallucinations); impotence, and elevation of blood cholesterol levels. Topical beta-blockers have been shown to decrease HDL and increase cholesterol. Diabetics may experience reduced glucose tolerance and hypoglycemic signs and symptoms can be masked. Beta-blockers may aggravate myasthenia gravis and abrupt withdrawal can exacerbate symptoms of hyperthyroidism. The beta-1 selective antagonist, betaxolol, has fewer pulmonary side effects.
Mechanism of action
Lower IOP through alpha 2 agonist mediated aqueous suppression and a secondary mechanism that increases aqueous outflow.
- Nonselective adrenergic agonists such as epinephrine lower IOP by several different mechanisms. Initially, a vasoconstrictive effect decreases aqueous production and c-AMP synthesis increases the outflow facility.
Ocular side effects include follicular conjunctivitis, burning, reactive hyperemia, adrenochrome deposits, mydriasis, maculopathy in aphakic eyes, corneal endothelial damage, and ocular hypoxia. Systemic side effects include hypertension, tachycardia and arrhythmia. Dipivefrin is a prodrug that is hydrolyzed to epinephrine as it traverses the cornea. It has significantly fewer systemic side effects than epinephrine. The potential side effects of nonselective adrenergic agonists has led to decline in their use.
Selective adrenergic agonists
- include apraclonidine and brimonidine (0.1-0.2%) with the latter having much greater selectivity at the alpha 2 receptor.
Brimonidine (0.1-0.2%) appears to also increase uveoscleral outflow and lower IOP by about 26%.
Side Effects of selective adrenergic agonists
Common ocular side effects include contact dermatitis (40% with apraclonidine, < 15% for brimonidine, and <0.2% for brimonidine-Purite), follicular conjunctivitis, eyelid retraction, mydriasis, and conjunctival blanching. Systemically, they can cause headache, dry mouth, fatigue, bradycardia, and hypotension. Long-term use of topical apraclonidine is frequently associated with allergy and tachyphylaxis. The use of brimonidine is contraindicated in infants and young children (especially those with low body weight) due to an increased risk of somnolence, hypotension, seizures, and apnea, believed to be due to increased CNS penetration of the drug secondary to high lipophilicity. Generally, brimonidine seems to produce fewer ocular side effects than apraclonidine.
Carbonic Anhydrase Inhibitors (CAI)
Mechanism of action
Lower IOP by decreasing aqueous production by direct antagonist activity on the ciliary epithelial carbonic anhydrase. Over 90% of ciliary epithelial enzyme activity needs to be abolished to decrease aqueous production and lower IOP. Systemic CAI include acetazolamide (Diamox) and methazolamide (Neptazane). Topical CAIs include brinzolamide 1% (Azopt) and dorzolamide 2% (Trusopt). A 14-17% reduction in IOP is seen with these agents.
Systemic CAIs are associated with numerous side effects, including transient myopia; paresthesia of the fingers, toes, and perioral area; urinary frequency; metabolic acidosis; malaise; fatigue; weight loss; depression; potassium depletion; gastrointestinal symptoms; renal calculi formation; and rarely, blood dyscrasia. Due to the side effects of the systemic CAIs, they are most useful in acute situations or as a temporizing measure before surgical intervention. The topical CAIs have significantly fewer systemic side effects than oral carbonic anhydrase inhibitors and have been reported to have clinical efficacy comparable to that of timolol. Common side effects of topical CAIs include bitter taste, blurred vision, punctate keratopathy, and lethargy.
Medications that increase aqueous outflow
Mechanism of action
Lower IOP by increasing aqueous outflow through the unconventional outflow pathway or uveoscleral outflow. The exact mechanism by which prostaglandins improve uveoscleral outflow is not full understood, but may involve relaxation of the ciliary muscle and remodelling of the extracellular matrix elements of the ciliary muscle. These agents have been shown to increase the outflow by as much as 50%.
Latanoprost and travaprost, and bimataprost (prostamide), represent the newest, the most effective, and most commonly used class of medications. Latanoprost 0.005% and travaprost 0.004% are pro-drugs that penetrate the cornea and become biologically active after being hydrolyzed by corneal esterases. Bimataprost 0.03% decreases IOP by increasing uveoscleral outflow by 50% and increasing trabecular outflow by approximately 25-30%. Both latanoprost and travaprost reduce IOP by approximately 25-30%.
Ocular and systemic side effects such as conjunctival injection, hypertrichosis, trichiasis, hyperpigmentation of periocular skin and hair growth around the eyes are generally were well-tolerated. These tend to be reversible with cessation of the drug. A unique side effect is increased iris pigmentation which is thought to be secondary to increased melanin content in the iris stromal mealnocytes without proliferation of cells. This tends to occur in 10-20% of blue irides within 18-24 months of initiating therapy, and 60% eyes with mixed green-brown or blue-brown irides. Use of prostaglandin analogs and prostamides have also been associated with exacerbations of herpes keratitis, anterior uveitis, and cystoid macular edema in susceptible individuals. Photos Courtesy of Anjana Jindal, MD, Wills Eye Hospital
Mechanism of action
Lower IOP by increasing aqueous outflow related to contraction of the ciliary muscle in eyes with open angles and pupillary constriction in cases of pupillary block glaucoma.
Topical cholinergic agonists such as pilocarpine cause contraction of the longitudinal ciliary muscle, which pulls the scleral spur to tighten the trabecular meshwork, increasing outflow of aqueous humor. This results in a 15-25% reduction in IOP. The direct agents (pilocarpine) are cholinergic receptor agonists; the indirect agents (echothiophate iodide) inhibit cholinesterase and prolong the action of native acetylcholine. Carbachol is a mixed direct agonist/acetylcholine releasing agent.
Systemic side effects of pilocarpine are rare; however, ocular side effects are common. Ocular side effects include brow ache, induced myopia, miosis (leading to decreased vision), shallowing of the anterior chamber, retinal detachment, corneal endothelial toxicity, breakdown of the blood-brain barrier, hypersensitivity or toxic reaction, cicatricial pemphigoid of the conjunctiva, and atypical band keratopathy. The indirect agents have ocular side effects that are generally more intense than those of the direct agents. In addition, indirect agents can cause iris cysts in children and cataract in adults. Finally, prolonged respiratory paralysis may occur during general anesthesia in patients who are on cholinesterase inhibitors because of their inability to metabolize paralytic agents such as succinylcholine. The use of cholinergic agents has declined in recent years with the availability of newer medications that have comparable efficacy and fewer side effects.
Rho kinase inhibitor
Mechanism of action
Netarsudil 0.02% (Rhopressa; Aerie Pharmaceuticals) was approved by the Food and Drug Administration (FDA) in 2017 as the first Rho kinase inhibitor for the treatment of OAG or ocular hypertension. Netarsudil increases aqueous outflow through the trabecular meshwork and decreases episcleral venous pressure by inhibiting the effect of Rho kinase on actin and myosin contraction. In the ROCKET clinical trials, once daily netarsudil was found to be noninferior to twice daily timolol, reducing IOP by an average of about 4mmHg. Netarsudil may have a particularly important role in treating patients with lower starting IOPs. In addition to its action on the trabecular meshwork to increase outflow, netarsudil’s unique ability to lower episcleral venous pressure can achieve a target beyond the low teens, which is otherwise difficult to achieve with a venous back pressure in the 8-12mmHg range.
In 2019, the FDA approved the combination of netarsudil with latanoprost as a once-daily medication for the treatment of OAG or ocular hypertension (Rocklatan; Aerie Pharmaceuticals: netarsudil and latanoprost ophthalmic solution 0.02%/0.005%). In the MERCURY clinical trials, more than 60% of enrolled patients taking the combination medication achieved an IOP reduction of 30% or more compared to about 30% achieving this target on latanoprost monotherapy.
Netarsudil has a favorable safely profile. Most commonly reported side effects include conjunctival hyperemia (50%), corneal verticillata (20%), and conjunctival hemorrhage (20%). While clinical evident on biomicroscopic exam within the first 4 weeks of treatment, corneal verticillata have not been found to be functionally or visually significant. Most corneal verticillata resolved upon discontinuation of treatment.
Mechanism of action
Latanoprostene bunod 0.024% (Vyzulta; Bausch+Laumb) was approved for reduction of IOP in OAG or ocular hypertension by the FDA in 2017, filling a niche by combining the effects of a prostaglandin analog with the action of nitric oxide on the trabecular meshwork outflow. Nitric oxide (NO) levels are known to be lower in glaucomatous eyes, and NO deficiency may lead to trabecular contraction and decreased outflow facility. Additionally, when instilled into the eye, NO diffuses to the trabecular meshwork to promote cell relaxation and increase outflow to lower IOP. Latanoprostene bunod leverages these effects of NO by releasing the molecule upon metabolizing in the eye. In the VOYAGER study, patients receiving latanoprostene bunod had an average of 1.23mmHg lower reduction in IOP compared to patients receiving latanoprost alone.
The safety profile of latanoprostene bunod is similar to that of other prostaglandin analogs, including increase iris and periorbital skin pigmentation and eyelash growth. Caution should be used in patients with a history of intraocular inflammation or macular edema. The most common adverse effects reported are conjunctival hyperemia (6%), eye irritation (4%), eye pain (3%), and pain at the instillation site (2%).
Fixed combination medications offer the potential advantage of increased convenience, compliance, efficacy, and cost. Some fixed-combination medications currently on the market in the US include: dorzolamide hydrochloride 2% and timolol maleate ophthalmic solution 0.5% (Cosopt, now available as generic), brimonidine tartrate 0.2%, timolol maleate ophthalmic solution 0.5% (Combigan), brimonidine tartrate 0.2% and brinzolamide 1% (Simbrinza), and netarsudil and latanoprost ophthalmic solution 0.02%/0.005% (Rocklatan). Prior to initiating monotherapy with a fixed-combination medication, it is important to prove the efficacy of the individual components of the medications. The efficacy and ocular side effects for both fixed-combination medications are similar to their individual components. The efficacy and tolerability of both dorzolamide hydrochloride-timolol maleate 2%/0.5% and brimonidine tartrate-timolol maleate 0.2%/0.5% appear to be similar to each other.
Hyperosmotic agents such as oral glycerine and intravenous mannitol can rapidly lower IOP by decreasing vitreous volume. They do not cross the blood-ocular barrier and therefore exert oncotic pressure that dehydrates the vitreous. Side effects associated with the hyperosmotic agents can be severe and include headache, back pain, diuresis, circulatory overload with angina, pulmonary edema and heart failure, and central nervous system effects such as obtundation, seizure, and cerebral hemorrhage. Because of these potentially serious side effects, they are not used as long-term agents. They are typically used in acute situations to temporarily reduce high IOP until more definitive treatments can be rendered.
Summary of glaucoma medications
|Class||Brand Name||Strength/Concentration||Dosing||IOP Reduction||Mechanism of Action||Side Effects|
|Bimataprost||Lumigan||0.03 %||qhs||27-33%||Increase uveoscleral outflow; Increase trabecular outflow||
|Travaprost||Travatan||0.004 %||qhs||25-32%||Increase uveoscleral outflow||same as above|
|Latanaprost||Xalatan||0.005%||qhs||25-32%||Increase uveoscleral outflow||same as above|
|Prostaglandin Analog with Nitric Oxide|
|Latanoprostene bunod||Vyzulta||0.024%||qhs||30-35%||Increase uveoscleral and trabecular meshwork outflow||same as above|
|Rho kinase inhibitor|
|Netarsudil||Rhopressa||0.02%||qd||20%||Increase trabecular meshwork outflow and decrease episcleral venous pressure||Conjunctival hyperemia, corneal verticillata, and conjunctival hemorrhage|
|Beta-adrenergic antagonists (beta blockers)|
|Decrease aqueous humor production||Bronchospasm, bradycardia, decrease blood pressure, adversely alter blood lipid profiles, CNS effect (lethargy, confusion, depression), impotence, exacerbate myasthenia gravis, mask symptoms of hypoglycemia in diabetics|
|Timolol hemihydrate||Betimol||0.25%,0.5%||qd, bid||20-30%||same as above||same as above|
|Levobunolol HCL||Betagan||0.25%,0.5%||qd, bid||20-30%||same as above||same as above|
|Metipranolol||Optipranolol||0.3%||bid||20-30%||same as above||same as above|
(has intrinsic sympathomimetic activity)
|Ocupress||1.0%||qd, bid||20-30%||same as above||same as above|
|Betaxolol||Betoptic||0.25%||bid||15-20%||Decrease aqueous humor production||Less bronchospasm, but otherwise similar to other beta blockers|
|Epinepherine||Epifrin||0.25%, 0.5%, 1.0%, 2.0%||bid||15-20%||Initially, decrease aqueous production and increase outflow; later, further increase outflow||
hypertension, tachycardia, arrhythmia
Ocular: adrenochrome deposits, drug allergy, follicular conujunctivitis, rebound hyperemia, cystoid macular edema in aphakia, madarosis
|Dipivefrin HCL||Propine||0.1%||bid||15-20%||same as above||same as above|
|Apraclonidine HCL||Iopidine||0.5%, 1.0%||bid, tid||20-30%||Decrease aqueous production; decrease episcleral venous pressure||Systemic: dry mouth, decrease blood pressure, bradycardia
Ocular: follicular conjunctivitis, ocular irritation, pruritus, dermatitis, conjunctival blanching, eyelid retraction, mydriasis, drug allergy
Brimonidine tartrate in Purite
|Decrease aqueous production; increase uveoscleral outflow||same as above, but less with brimonidine|
|Direct cholinergic agonist|
|Increase trabecular outflow||Miosis (decrease vision), brow ache, induced myopia and variable refractive error, exacerbate inflammation, shallow anterior chamber, retinal detachment|
|Indirect cholinergic agonist|
|Echothiophate iodide||0.03%-0.25%||qd, bid||15%-25%||Increase trabecular outflow||Above plus, cataractogenic, iris cysts in children, increase pupillary block, prolonged effect of paralyzing agent such as succinylcholine when used concomitantly|
|Demercarium iodide||0.125%, 0.25%||qd, bid||15%-25%||same as above||same as above|
|Physostigmine||0.25%-0.5%||qd, bid||15%-25%||same as above||same as above|
|Isofluorophate||0.25%||qhs||15%-25%||same as above||same as above|
|Carbonic anhydrase inhibitor|
|Diamox||125mg, 250mg, 500mg SR||bid, tid, qid||15%-20%||Decrease aqueous production||Parasthesia of fingers and toes, metallic taste, nausea, malaise, depression, loss of libido, hypokalemia, aplastic anemia, metabolic acidosis, kidney stones|
||15%-20%||same as above||same as above|
|Neptazane||25mg, 50mg||bid, tid||15-20%||same as above||same as above|
|Dorzolamide||Trusopt||2.0%||bid, tid||15-20%||Decrease aqueous humor production||same as above;Systemic side effects less with dorzolamide and brinzolamide|
|Brinzolamide||Azopt||1.0%||bid, tid||15-20%||same as above||same as above|
|Glycerine (oral)||50, 75%||1.0-1.5g/kg||Decrease vitreous volume||Headache, back pain, diuresis, angina, pulmonary edema, heart failure, obtundation, seizure, and subarachnoid hemorrhage; nausea/vomiting (oral agents)|
|Isosorbide (oral)||45%||1.5g/kg||same as above||same as above|
|Mannitol (intravenous)||5%, 10%, 15%, 20%||1-2g/kg||same as above||same as above|
Medical follow up
IOP must be checked after initiation of treatment to determine its efficacy. Depending on the level of IOP and extent of optic nerve damage, the IOP should be checked within 1-2 days or a few weeks. The use of monocular trials has been debated but there is likely a role for monocular trial to establish both efficacy as well as tolerability. Medications should also be added one at a time if possible to avoid confusion regarding efficacy and tolerability.
Future directions in medical therapy
Novel drug delivery platforms may allow for medical therapy beyond topical eye drop administration. Intracameral delivery, such as the bimatorpost sustained release implant, could allow for intermittent office-based drug delivery with less reliance on patient adherence and persistence. Punctal plugs and fornix-based delivery platforms have also been developed and are under investigation as glaucoma drug eluting devices.
Lastly, medical therapy for neuroprotection in glaucoma has been under active study. Neuroprotective medications would aim to reduce retinal ganglion cell death independent of IOP reduction. A number of agents are under investigation for neuroprotective effects in glaucoma, including brimonidine, memantine, antioxidants, and calcium channel blockers.
If initial medical and/or laser therapy fails to improve intraocular pressure to an acceptable level, surgical intervention may be necessary.
Most patients with glaucoma retain useful vision for most of their lives if caught early and treatment is initiated. Incidence of unilateral blindness has been reported to be 27% and bilateral blindness 9% at 20 years following diagnosis.
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