Glaucoma

Glaucoma are ocular disorders that lead to an optic neuropathy characterized by changes in the optic nerve head (optic disc) that is associated with loss of visual sensitivity and field. Ultimately, glaucoma result in irreversible blindness if left untreated. Glaucoma may or may not be accompanied by elevated intraocular pressure (IOP). But the treatment is directed at lowering IOP, regardless of baseline IOP.

PATHOPHYSIOLOGY

There are two major types of glaucoma: primary open-angle glaucoma (POAG) or ocular hypertension, which accounts for most cases and is therefore the focus of this chapter, and closed-angle glaucoma (CAG). Either type can be primary inherited disorder, congenital, or secondary to disease, trauma, or drugs.

In POAG, the specific cause of optic neuropathy is unknown. Increased intraocular pressure (IOP) was historically considered to be the sole cause. Additional contributing factors include increased susceptibility of the optic nerve to ischemia, excitotoxicity, autoimmune reactions, and other abnormal physiologic processes.

Although IOP is a poor predictor of which patients will have visual field loss, the risk of visual field loss increases with increasing IOP. IOP is not constant; it changes with pulse, blood pressure, forced expiration or coughing, neck compression, and posture. IOP demonstrates diurnal variation with a minimum pressure around 6 pm and a maximum pressure upon awakening.

The balance between the inflow and outflow of aqueous humor determines IOP. Inflow is increased by beta-adrenergic agents and decreased by alpha2- and beta-adrenergic blockers, dopamine blockers, carbonic anhydrase inhibitors (CAIs), and adenylate cyclase stimulators. Outflow is increased by cholinergic agents, which contract the ciliary muscle and open the trabecular meshwork, and by prostaglandin analogues and beta- and alpha2-adrenergic agonists, which affect uveoscleral outflow.

Secondary OAG has many causes, including exfoliation syndrome, pigmentary glaucoma, systemic disease, trauma, surgery, ocular inflammatory disease, and drugs. Secondary glaucoma can be classified as pretrabecular (normal meshwork is covered and prevents outflow of aqueous humor), trabecular (meshwork is altered or material accumulates in the intertrabecular spaces), or posttrabecular (episcleral venous blood pressure is increased).

Many drugs can increase IOP (Table 1). The potential to induce or worsen glaucoma depends on the type of glaucoma and on whether it is adequately controlled.

CAG occurs when there is a physical blockage of the trabecular meshwork, resulting in increased IOP.

Table 1. Drugs That May Induce or Potentiate Increased Intraocular Pressure

Open-angle glaucoma

Closed-angle glaucoma

Ophthalmic corticosteroids (high risk) Systemic corticosteroids Nasal/inhaled corticosteroids Fenoldopam Ophthalmic anticholinergics Succinylcholine Vasodilators (low risk) Cimetidine (low risk)

Topical anticholinergics Topical sympathomimetics Systemic anticholinergics Heterocyclic antidepressants Low-potency phenothiazines Antihistamines Ipratropium Benzodiazepine (low risk) Theophylline (low risk) Vasodilators (low risk) Systemic sympathomimetics (low risk) CNS stimulants (low risk) Selective serotonin reuptake inhibitors Imipramine Venlafaxine Topiramate Tetracyclines (low risk) Carbonic anhydrase inhibitors (low risk) Monoamine oxidase inhibitors (low risk) Topical cholinergics (low risk)

CLINICAL PRESENTATION

POAG is slowly progressive and is usually asymptomatic until onset of substantial visual field loss. Central visual acuity is maintained, even in late stages.

Patients with CAG typically experience intermittent prodromal symptoms (eg, blurred or hazy vision with halos around lights and , occasionally, headache). Acute episodes produce symptoms associated with a cloudy, edematous cornea; ocular pain; nausea, vomiting, and abdominal pain; and diaphoresis.

DIAGNOSIS

POAG is confirmed by the presence of characteristic optic disc changes and visual field loss, with or without increased IOP. Normal tension glaucoma refers to disc changes, visual field loss, and IOP less than 21 mmHg. Ocular hypertension refers to IOP greater than 21 mmHg without disc changes or visual field loss.

CAG is usually visualized by gonioscopy. IOP is generally markedly elevated (eg, 40-90 mmHg) when symptoms are present. Additional signs include hyperemic conjunctiva, cloudy cornea, shallow anterior chamber, and occasionally edematous and hyperemic optic disc.

TREATMENT OF OCULAR HYPERTENSION AND OPEN-ANGLE GLAUCOMA

Goal of Treatment: The goal is to preserve visual function by reducing IOP to a level at which no further optic nerve damage occurs. IOP can be lowered by pharmacologic therapy, laser therapy, and/or surgery.

Treat ocular hypertension if the patient has a significant risk factor such as IOP greater than 25 mmHg, vertical cup:disc ratio grater than 0.5, or central corneal thickness less than 555 micrometer. Additional risk factors to be considered include family history of glaucoma, black race, severe myopia, and presence of only one eye. The goal of therapy is to lower IOP by 20-30% from baseline to decrease the risk of optic nerve damage.

Treat all patients with elevated IOP and characteristic optic disc changes or visual field defects. An initial target IOP reduction of 30% is desired in patients with POAG.

Multiple medications are available (Table 2). But topical agents are preferred. The most popular are prostaglandin analogs, followed by beta-blockers (particularly timolol). Other medications include alpha-2-selective adrenergic agonists, carbonic anhydrase inhibitors, rho kinase inhibitors, and cholinergic agonists. Systemic carbonic anhydrase inhibitors are effective, but adverse effects limit their use.

Table 2. Overview of Glaucoma Medications

CHF = congestive heart failure; CNS = central nervous system; FDA = Food and Drug Administration; IOP = intraocular pressure
* Data from the Heijl A, Traverso CE, eds. Terminology and Guidelines for Glaucoma. European Glaucoma Society. 4th ed. Savona, Italy: PubliComm; 2014:146-51. Available at: http://www.icoph.org/dynamic/attachments/resources/egs_guidelines_4_english.pdf Accessed October 16, 2020.
† FDA Pregnancy Category B = Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies on pregnant women. FDA Pregnancy Category C = Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.
‡ Latanoprostene bunod is a new IOP-lowering agent that is rapidly metabolized to latanoprost (a prostaglandin analog) and butanediol mononitrate (a nitric oxide-donating moiety). It enhances aqueous humor outflow through both the uveoscleral and trabecular meshwork pathways.
** The FDA replaced the ABCDX drug pregnancy categories with descriptive information regarding medication risks to the developing fetus, breastfed infant, and individual of reproductive potential under the Pregnancy and Lactation Labeling Rule in 2015. Rho-kinase inhibitors are therefore not assigned a pregnancy category. No data exist on the use of netarsudil in pregnant women. Animal studies did not demonstrate adverse effects on the developing fetus with clinically relevant intravenous exposures

Drug Classification	Mechanism of Action	IOP Reduction*	Potential Side Effects	Potential Contraindications	FDA Pregnancy Category†
Prostaglandin analogs‡ Bimatoprost Latanoprost Latanoprostene bunod Tafluprost Travoprost	Increase uveoscleral and/or trabecular outflow	25%-30%	Increased and misdirected eyelash growth Periocular hyperpigmentation Conjunctival injection Allergic conjunctivitis/contact dermatitis Keratitis Possible herpes virus Possible herpes virus activation Increased iris pigmentation Uveitis Cystoid macular edema Periobitopathy Migraine-like headache Flu-like symptoms	Macular edema History of herpetic keratitis Active uveitis	C
Beta-adrenergic antagonists (beta-blockers) Nonselective Carteolol Levobunolol Timolol Selective Betaxolol	Decrease aqueous production	20%-25%	Allergic conjunctivitis/contact dermatitis Keratitis Bronchospasm Bradycardia Hypotension CHF Reduced exercise tolerance Depression Impotence	Chronic obstructive pulmonary disease Asthma CHF Bradicardia Hypotension Greater than first-degree heart block	C
Alpha-adrenergic agonist Apraclonidine Brimonidine	Decrease aqueous production; decrease episcleral venous pressure or increase uveoscleral outflow	20%-25%	Allergic conjunctivitis/contact dermatitis Follicular conjunctivitis Dry mouth and nose Hypotension Headache Fatigue Somnolence	Monoamine oxidase inhibitor therapy Infants and children (for brimonidine)	B
Parasympathomimetic agents Cholinergic agonist Pilocarpine Anticholinesterase agent Echothiophate	Increase trabecular outflow	20%-25%	Increase myopia Decreased vision Cataract Periocular contact dermatitis Allergic conjunctivitis/contact dermatitis Conjunctival scarring Conjunctival shrinkage Keratitis Paradoxical angle closure Retinal tears/detachment Eye or brow ache/pain Increased salivation Abdominal cramps	Areas of peripheral retina that predispose to break The need to regularly assess the fundus Neovascular, uveitis, or malignant glaucoma	C
Rho kinase inhibitors Netarsudil	Increase trabecular outflow; Decrease episcleral venous pressure; Decrease aqueous production	10%-20%	Conjunctival hyperemia Corneal verticillata Instillation site pain Conjunctival hemorrhage Keratitis	None	...**
Topical carbonic anhydrase inhibitors Brinzolamide Dorzolamide	Decrease aqueous production	15%-20%	Allergic dermatitis/conjunctivitis Corneal edema Keratitis Metallic taste	Sulfonamide allergy Sickle cell disease with hyphema	C
Systemic carbonic anhydrase inhibitors Acetazolamide Methazolamide	Decrease aqueous production	20%-30%	Stevens-Johnson syndrome Malaise, anorexia, depression Serum electrolyte imbalance Renal calculi Blood dyscrasias (aplastic anemia, thrombocytopenia) Metallic taste Enuresis Parasthesia Diarrhea Abdominal cramps	Sulfonamide allergy Kidney stones Aplastic anemia Thrombocytopenia Sickle cell disease	C
Hyperosmotic agents Glycerol Mannitol	Dehydration of vitreous	No data	Headache CHF Nausea, vomiting Diarrhea Renal failure Diabetic complications Mental confusion	Renal failure CHF Potential CNS pathology	C

Initiate drug therapy in stepwise manner, starting with lower concentrations of single well-tolerated topical agent (Table 3). Historically, beta-blockers (eg, timolol) were the treatment of choice provided no contraindications existed. Prostaglandin analogs (eg, latanoprost, bimatoprost, and travoprost) offer once-daily dosing, better IOP reduction, good tolerance, and, recently availability of lower-cost generics. Prostaglandins have lower rates of systemic side effects and may have somewhat better efficacy than beta blockers. Prostaglandins are the preferred choice for first-line therapy. Brimonidine and topical CAIs are also suitable for first-line therapy.

Combining drops from different classes (ie, beta blocker plus prostaglandin or beta blocker plus carbonic anhydrase inhibitor) can cause a greater reduction in the IOP than monotherapy. Adding a second medication is reasonable if initial monotherapy is not effective.

Pilocarpine and dipivefrin, a prodrug of epinephrine, are used as third-line therapies because of adverse events or reduced efficacy as compared with newer agents.

Carbachol, topical cholinesterase inhibitors, and oral CAIs (eg, acetazolamide) are used as last-resort options after failure of less toxic options.

Netarsudil, approved in 2017, is a rho kinase inhibitor; it is believed to reduce IOP by increasing the outflow of aqueous humor through the trabecular meshwork. Netarsudil is a third-line choice because its ocular hypotensive effect may be inferior to latanoprost and slightly inferior to timolol.

Optimal timing of laser trabeculoplasty or surgical trabeculectomy is controversial, ranging from initial therapy to after failure of third- or fourth-line drug therapy. Antiproliferative agents such as fluorouracil and mitomycin C are used to modify the healing process and maintain patency.

TREATMENT OF CLOSED-ANGLE GLAUCOMA

Acute CAG with high IOP requires rapid reduction in IOP. Iridectomy is the definitive treatment producing a hole in the iris that permits aqueous humor flow to move directly from the posterior to the anterior chamber.

Drug therapy of an acute attach typically consists of an osmotic agent and secretory inhibitor (eg, beta-blocker, alpha2-agonist, latanoprost, or CAI), with or without pilocarpine.

Osmotic agents are used to rapidly decrease IOP Examples include glycerin, 1-2 g/kg orally, and mannitol, 1-2 g/kg IV.

Although traditionally the drug of choice, pilocarpine use is controversial as initial therapy. Once IOP is controlled, pilocarpine should be given every 6 hours until iridectomy is performed.

Topical corticosteroids can be used to reduce ocular inflammation and synechiae.

EVALUATION OF THERAPEUTIC OUTCOMES

Successful outcomes require identifying an effective, well-tolerated regimen; closely monitoring therapy; and patient adherence. Whenever possible, therapy for open-angle glaucoma should be started as a single agent in one eye to facilitate evaluation of drug efficacy and tolerance. Many drugs or combinations may need to be tried before the optimal regimen is identified.

Monitoring therapy for POAG should be individualized. Assess IOP response every 4-6 weeks initially, every 3-4 months after IOPs become acceptable, and more frequently if therapy is changed. Visual field and disc changes are monitored annually, unless glaucoma is unstable or worsening.

Monitor patients for loss of control of IOP (tachyphylaxis), especially with beta-blockers or apraclonidine. Treatment can be temporarily discontinued to monitor benefit.

There is no specific target IOP because the correlation between IOP and optic nerve damage is poor. Typically, a reduction of 25-30% is desired.

The target IOP also depends on disease severity and is generally less than 21 mmHg for early visual field loss or optic disc changes, with progressively lower targets for greater damage. Targets as low as less than 10 mmHg are desired for very advanced disease, continued damage at higher IOPs, normal-tension glaucoma, and pretreatment pressure in the low to midteens.

Monitor medication adherence because it is commonly inadequate and a cause of therapy failure.

Table 3. Topical Drugs Used in the Treatment of Open-Angle Glaucoma

Drug	Pharmacologic properties	Common brand names	Dosage form	Strength (%)	Usual dose	Pharmacologic class and mechanism of action
Betaxolol	Relative beta1-selective	Generic	Solution	0.5	1 drop BID	Beta-Adrenergic Blocking Agents reduce aqueous production of ciliary body
		Betoptic-S	Suspension	0.25	1 drop BID
Carteolol	Nonselective, intrinsic sympathomimetic activity	Generic	Solution	1	1 drop BID
Levobunolol	Nonselective	Generic	Solution	0.5	1 drop BID
Timolol	Nonselective	Timoptic; Betimol; Istalol; or Generic	Solution	0.25; 0.5	1 drop Daily or BID
		Timoptic-XE or Generic	Gel forming solution	0.25; 0.5	1 drop Daily
Apraclonidine	Specific alpha2-agonists	Generic	Solution	0.5	1 drop BID to TID	Specific alpha2-agonists reduce aqueous humor production, brimonidine known to also increase uveoscleral outflow; only brimonidine has primary indication.
		Iopidine	Solution	1	1 drop BID to TID
Brimonidine		Alphagan P or Generic	Solution	0.1; 0.15; 0.2	1 drop BID to TID
Pilocarpine	Irreversible	Generic	Solution	1; 2; 4	1 drop BID to QID	Direct Acting Cholinergic Agonists increase aqueous humor outflow through trabecular meshwork
Echothiophate		Phospholine iodide	Solution	0.125	1 drop Daily to BID	Cholinesterase Inhibitors increase trabecular outflow
Brinzolamide	Carbonic anhydrase type II inhibition	Azopt or Generic	Suspension	1	1 drop BID to TID	Topic Carbonic Anhydrase Inhibitors reduce aqueous humor production of ciliary body
Dorzolamide		Generic	Solution	2	1 drop BID to TID
Latanoprost	Prostanoid agonist	Xalatan; Xelpros; Iyuzeh; or Generic	Solution	0.005	1 drop QHS	Prostaglandin Analogs increase aqueous uveoscleral outflow and to a less extent trabecular outflow
Bimatoprost		Lumigan	Solution	0.01	1 drop QHS
		Durysta	Implant	10mcg	For ophthalmic intracameral administration
Travoprost		Travatan Z; or Generic	Solution	0.004	1 drop QHS
		Idose TR	Implant	75mcg	For ophthalmic intracameral administration
Tafluprost		Zioptan; or Generic	Solution	0.0015	1 drop QHS
Latanoprostene bunod		Vyzulta	Solution	0.024	1 drop QHS
Netarsudil	Rho kinase inhibition	Rhopressa	Solution	0.02	1 drop QHS	Rho kinase inhibitors increase trabecular outflow, decrease episcleral venous pressure, and decrease aqueous production
Netarsudil Latanoprost	Combination	Rocklatan	Solution	0.02/0.005	1 drop QHS
Brimonidine Timolol	Combination	Combigan; or Generic	Solution	0.2/0.5	1 drop BID
Dorzolamide Timolol	Combination	Cosopt; or Generic	Solution	2/0.5	1 drop BID
Dorzolamide Timolol Preservative Free	Combination	Cosopt PF; or Generic	Solution	2/0.5	1 drop BID
Brimonidine Brinzolamide	Combination	Simbrinza	Suspension	0.2/1	1 drop TID

Clincal Guidelines

• American Academy of Ophthalmology 2020
  Gedde SJ, Vinod K, Wright MM, et al. Primary Open-Angle Glaucoma Preferred Practice Pattern®. Ophthalmology. 2021;128(1):P71-P150. doi:10.1016/j.ophtha.2020.10.022

Useful Links

Glaucoma in Merck Manual