Drug-Induced Glaucoma

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Background

Several different drugs have the potential to cause the elevation of intraocular pressure (IOP), which can occur via an open-angle mechanism or a closed-angle mechanism. Steroid-induced glaucoma is a form of open-angle glaucoma that usually is associated with topical steroid use, but it may develop with inhaled, oral, intravenous, periocular, or intravitreal steroid administration. Medications prescribed for a variety of systemic conditions (eg, depression, allergies, Parkinson disease) can produce pupillary dilation and precipitate an attack of acute angle-closure glaucoma in anatomically predisposed eyes that have narrow angles.[1] Dietary supplements have also been reported to induce acute angle-closure glaucoma.[2]

Open angle

Drug-induced elevation of IOP is more common by an open-angle mechanism. Corticosteroids are a class of drugs that may produce IOP elevation by this mechanism. Not all patients taking corticosteroids will develop elevated IOP. Risk factors include preexisting primary open-angle glaucoma, a family history of glaucoma, high myopia, diabetes mellitus, and history of connective tissue disease (especially rheumatoid arthritis).

Additionally, the number of people responding with an elevated IOP varies with the route of administration. More people respond from topically applied drops (including topically applied creams to the periorbital area) or intravitreal injection. In order of decreasing frequency, incidence of elevated IOP is less with intravenous, parenteral, and inhaled routes of administration. Patients on chronic corticosteroid therapy can remain undiagnosed with an elevated IOP, which can result in glaucomatous optic nerve damage.

Steroid-induced IOP elevation typically occurs within a few weeks of beginning steroid therapy. In most cases, the IOP lowers spontaneously to the baseline within a few weeks to months upon stopping the steroid. In rare instances, the IOP remains elevated. Additionally, there may be some patients whose underlying condition necessitates the continued use of corticosteroids despite the elevated IOP. These patients are treated identically to those with primary open-angle glaucoma.

Closed angle

Most categories of drugs that list glaucoma as a contraindication or adverse effect are concerned with inducing acute angle-closure glaucoma. These medications will incite an attack only in those individuals with occludable angles (ie, very narrow anterior chamber angles). The classes of medications that have the potential to induce angle closure are topical anticholinergic or sympathomimetic dilating drops, tricyclic antidepressants, monoamine oxidase inhibitors, antihistamines, antiparkinsonian drugs, antipsychotic medications, and antispasmolytic agents.[3]

Sulfa containing medications may induce angle-closure glaucoma by a different angle-closure mechanism, involving anterior rotation of the ciliary body. Typically, the angle closure is bilateral and occurs within the first several doses of the sulfonamide-containing medication. Patients with narrow or wide open angles are potentially susceptible to this rare and idiosyncratic reaction.

Pathophysiology

Open angle

Exact pathophysiology of steroid-induced glaucoma is unknown. It is known that steroid-induced IOP elevation is secondary to increased resistance to aqueous outflow. Some evidence indicates that the defect could be increased accumulation of glycosaminoglycans or increased production of trabecular meshwork-inducible glucocorticoid response (TIGR) protein, which could mechanically obstruct outflow. Other evidence points toward corticosteroid-induced cytoskeletal changes that could inhibit pinocytosis of aqueous humor or inhibit the clearing of glycosaminoglycans, resulting in the accumulation of this substance.

Closed angle

The pathophysiology of drug-induced angle-closure glaucoma is usually increased pupillary block (ie, increased iris-lens contact at the pupillary border) from pupillary dilation. Medications have a direct or secondary effect, either to stimulate sympathetic or inhibit parasympathetic activation causing pupillary dilation, which can precipitate acute angle-closure glaucoma in patients with occludable angles. The other possible mechanism is dilation in patients with plateau iris syndrome. See Glaucoma, Angle Closure, Acute.

A notable exception is the angle closure resulting from sulfa containing medications. The mechanism involves anterior rotation of the ciliary body and/or choroidal effusions, resulting in shallowing of the anterior chamber and blockage of the trabecular meshwork by the iris. Pupillary dilation and a preexisting shallow anterior chamber angle are not necessary. The exact defect that causes the ciliary body swelling is unknown.

Epidemiology

Frequency

United States

Open angle

The incidence of steroid-induced IOP elevation in patients on systemic corticosteroids is unknown because most of these patients do not have their IOP checked. These patients may be discovered during a routine eye exam while on their medication, or the glaucoma may have progressed to the point of causing visual symptoms. Patients taking topical steroid drops usually receive follow-up care by an ophthalmologist who monitors IOP.

The risk of developing steroid-induced glaucoma is related to its potency and frequency of administration. People with preexisting primary open-angle glaucoma have a much greater potential to experience an elevated IOP from topical corticosteroids. Patients with primary chronic angle closure and patients with secondary open-angle glaucoma behave similarly to normal eyes with regard to steroid response.

Studies completed by Armaly indicated that approximately one third of normal eyes and more than 90% of patients with primary open-angle glaucoma respond with greater than 6 mm Hg of IOP elevation after receiving a 4-week course of topical dexamethasone 0.1%.[4, 5] Following intravitreal injection of triamcinolone, over 50% of nonglaucomatous eyes will have an increase in IOP; this increase in IOP can occur as long as 6 months after the injection.

Closed angle

Prevalence of occludable angles in whites from the Framingham study is 3.8%.

Narrow angles are more common in the Asian population. A study of a Vietnamese population estimated a prevalence of occludable angles at 8.5%.

Mortality/Morbidity

Glaucoma is the third leading cause of blindness in the United States. The risk of becoming legally blind in one eye from open-angle glaucoma is approximately 20%, with bilateral blindness occurring in 9%.

Race

No racial predilection exists for steroid-responsive IOP.

Sex

No sexual predilection exists for steroid-responsive IOP.

Age

Steroid-responsive IOP elevations can occur in people of all ages, although children less frequently are reported to have IOP elevation with steroids.

Prognosis

A favorable outlook exists if IOP is controlled.

Patient Education

It is recommended that all patients who use chronic corticosteroid medications in any capacity should have a full ophthalmologic evaluation.

For excellent patient education resources, visit eMedicineHealth's Eye and Vision Center. Also, see eMedicineHealth's patient education articles Glaucoma Overview, Glaucoma FAQs, Glaucoma Medications, and Angle Recession Glaucoma.

History

Elicit the patient's current medications, including any recent changes in medications or dietary supplements.

Symptoms

With steroid-induced glaucoma, the pressure elevation is gradual. Therefore, like primary open-angle glaucoma, very few symptoms exist.

Visual symptoms of drug-induced acute angle-closure glaucoma are the same as primary acute angle-closure glaucoma.

If the angle closure is related to anterior rotation of the ciliary body, the patient is also likely to have a significant myopic shift in vision.

Past ocular history/past medical history

Elicit history of systemic medical disease, which could require chronic corticosteroid use (eg, uveitis, collagen vascular disease, asthma, dermatitis).

Inquire about any recent use of sulfa-based medications. In particular, ask about the use of topiramate for migraines or other reasons.

Patients with preexisting primary open-angle glaucoma, a family history of primary open-angle glaucoma, diabetes mellitus, high myopia, or connective tissue diseases are at greater risk to be steroid responders.

Physical

Perform a complete ophthalmic examination.

Vision and refraction

Patients with hyperopia are at an increased risk for narrow angles.

Pupils

Test for the presence of an afferent pupillary defect if topical use has been unilateral or if the attack has only occurred in one eye.

External examination

Use a flashlight test to identify an anatomically narrow angle.

Slit lamp examination

Exclude stigmata of other causes of secondary glaucoma, as follows:

Gonioscopic evaluation

Examine angle anatomy to determine if the angle is at risk for occlusion with dilation.

Dilated examination

Inspect the optic nerve for glaucomatous optic nerve damage. See Glaucoma, Primary Open Angle for a description of glaucomatous patterns. Dilate after potentially occludable narrow angles or plateau iris has been excluded by gonioscopy.

Causes

Drug-induced glaucoma can occur via two mechanisms, as follows: open-angle glaucoma is generally steroid induced, and closed-angle glaucoma is generally from pupillary dilation.

Complications

Untreated glaucoma can lead to permanent visual damage and blindness.

Laboratory Studies

No laboratory studies are indicated.

Imaging Studies

Optical coherence tomography (OCT) is performed as indicated.

Other Tests

Formal visual field testing (ie, Humphrey, Octopus, Goldmann) is performed as indicated.

Procedures

No procedures are indicated for glaucoma.

Medical Care

Open angle

If the patient's underlying medical condition can tolerate discontinuation of corticosteroids, then cessation of the medication will usually result in normalization of IOP.

In the case of topical corticosteroid drops, using a lower potency steroid medication, such as the phosphate forms of prednisolone and dexamethasone, rimexolone, loteprednol etabonate, fluorometholone, or medrysone, should be considered. These lower potency drugs have a lesser chance of raising IOP, but they are usually not as effective as an anti-inflammatory drug. Topical nonsteroidal anti-inflammatory medications (eg, diclofenac, ketorolac) are other alternatives that have no potential to elevate IOP, but they may not have enough anti-inflammatory activity to treat the patient's underlying condition.

In the occasional cases in which the patient's IOP does not normalize upon cessation of the steroid or in those patients who must continue on corticosteroid medications, use standard antiglaucoma medications, as described in Glaucoma, Primary Open Angle.

Closed angle

If the etiology is because of sulfa containing medications, the increase in IOP generally will resolve upon stopping the medication. However, severe cases of sulfonamide-induced angle closure (ie, IOP >45 mm Hg) may not respond to simply discontinuing the offending medication. These cases may respond to intravenous Solu-Medrol and mannitol.

For other etiologies, treat the same as primary acute angle-closure glaucoma.

In addition, in laser peripheral iridotomy is typically counterproductive in patients with drug-induced glaucoma. Pupil dilation benefits this cohort of patients, as it stimulates posterior rotation of the ciliary body, which can break the angle closure.

Surgical Care

Open angle

When medical therapy is ineffective at lowering the IOP to target pressure or the patient is intolerant of medical therapy, then surgical therapy is indicated.

In patients with an open angle and the absence of ocular inflammation, argon laser trabeculoplasty can be attempted to lower the IOP.

In patients whom both medical and laser therapy have failed to lower the IOP adequately, surgical therapy is warranted. Historically, trabeculectomy (guarded filtration procedure), with or without intraoperative antimetabolites, was the primary procedure of choice. Recently, the rise of microinvasive glaucoma surgery (MIGS) has allowed for safer, more effective surgical options. In cases of eyes with active neovascularization or inflammation, a glaucoma drainage implant may be used as the primary procedure.

Closed angle

Treat the same as primary acute angle-closure glaucoma.

Consultations

If not able to control IOP, refer the patient to a glaucoma specialist.

Prevention

Drugs that have the potential of inducing glaucoma should only be used if truly indicated.

If drugs must be used, IOP should be monitored closely.

Further Outpatient Care

Open angle

It is recommended that all patients who use chronic corticosteroid medications in any capacity should have a full ophthalmologic evaluation.

Patients on topical corticosteroid therapy should receive follow-up care at regular intervals by an ophthalmologist to monitor their ocular condition and IOP. Steroid-induced IOP elevation typically occurs within 2-6 weeks of beginning steroid therapy.

Upon stopping corticosteroids, the IOP usually normalizes in a few weeks to months. For patients on medical therapy alone, the interval of follow-up care is determined by the extent of the IOP elevation and the degree of optic nerve and visual field damage.

Patients who have had surgical intervention should have follow-up care consistent with routine postoperative care for the appropriate procedure.

Closed angle

It is recommended that people older than the 40 years should have routine eye examinations to screen for various conditions. One of these conditions should be the presence of narrow anterior chamber angles.

Treat the same as primary acute angle-closure glaucoma.

Medication Summary

The goal of pharmacotherapy is to reduce morbidity and to prevent complications.

Many treatment options are available, summarized below. In general, one medication is started at a time, but additional medications or combinations of medications may be needed depending on the presentation.

Because of their efficacy and once-daily dosing, the prostaglandin analogues are typical first-line agents, although others can also be used as a primary choice. The wider choice of eye drops makes it even more important to select the most appropriate therapy for the individual patient. However, multiple topical medications or a systemic carbonic anhydrase inhibitor is less desirable.

Brimonidine (Alphagan P)

Clinical Context:  Selective alpha2-receptor agonist that reduces aqueous humor formation and possibly increases uveoscleral outflow.

Apraclonidine (Iopidine)

Clinical Context:  Reduces IOP whether or not accompanied by glaucoma. Selective alpha-adrenergic agonist without significant local anesthetic activity. Has minimal cardiovascular effect.

Class Summary

Topical agents (sympathomimetics) decrease aqueous production and reduce resistance to aqueous outflow. Often used with cholinergic agonists like pilocarpine. Adverse effects include dry mouth and allergenicity.

Levobunolol (Betagan)

Clinical Context:  Nonselective beta-adrenergic blocking agent that lowers IOP by reducing aqueous humor production.

Timolol ophthalmic (Betimol, Istalol, Timoptic)

Clinical Context:  May reduce elevated and normal IOP, with or without glaucoma, by reducing production of aqueous humor.

Betaxolol ophthalmic (Betoptic S)

Clinical Context:  Relatively selective in blocking beta1-adrenergic receptors. Reduces IOP by reducing production of aqueous humor.

Carteolol ophthalmic

Clinical Context:  Blocks beta1- and beta2-receptors and has mild intrinsic sympathomimetic effects.

Metipranolol ophthalmic

Clinical Context:  Beta-adrenergic blocker that has little or no intrinsic sympathomimetic effects and membrane stabilizing activity. Has little local anesthetic activity. Reduces IOP by reducing production of aqueous humor.

Class Summary

Topical beta-adrenergic receptor antagonists decrease aqueous humor production by the ciliary body. Adverse effects are due to systemic absorption of the drug, decreased cardiac output, and bronchoconstriction. In susceptible patients, this may cause bronchospasm, bradycardia, heart block, or hypotension. Monitor the patient's pulse rate and blood pressure; patients may be instructed to perform punctal occlusion after administering the drops. Depression or anxiety may be experienced in some patients, and sexual dysfunction may be initiated or exacerbated.

Epinephrine solution

Clinical Context:  Lower IOP by increasing outflow and reducing production of aqueous humor. Used as adjunct to miotic or beta-blocker therapy. Combination of miotic and sympathomimetic will have additive effects in lowering IOP.

Class Summary

Increase outflow of aqueous humor through trabecular meshwork and possibly through uveoscleral outflow pathway, probably by a beta2-agonist action. Up to one third of patients will not respond to these drugs, which are rarely used today for treatment of elevated IOP.

Dorzolamide (Trusopt)

Clinical Context:  Used concomitantly with other topical ophthalmic drug products to lower IOP. If more than one ophthalmic drug is being used, administer the drugs at least 10 min apart.

Dorzolamide is a reversible carbonic anhydrase inhibitor that may decrease aqueous humor secretion, causing a decrease in IOP. Presumably, it slows bicarbonate ion formation with subsequent reduction in sodium and fluid transport.

Systemic absorption can affect carbonic anhydrase in the kidney, reducing hydrogen ion secretion at renal tubule, and increases renal excretion of sodium, potassium bicarbonate, and water.

Brinzolamide 1% (Azopt)

Clinical Context:  Catalyzes reversible reaction involving hydration of carbon dioxide and dehydration of carbonic acid. May use concomitantly with other topical ophthalmic drug products to lower IOP. If more than one topical ophthalmic drug is used, administer drugs at least 10 min apart.

Dorzolamide HCl/timolol maleate (Cosopt)

Clinical Context:  Carbonic anhydrase inhibitor that may decrease aqueous humor secretion, causing a decrease in IOP. Presumably slows bicarbonate ion formation with subsequent reduction in sodium and fluid transport.

Timolol is nonselective beta-adrenergic receptor blocker that decreases IOP by decreasing aqueous humor secretion.

Both agents administered together bid may result in additional IOP reduction compared with either component administered alone, but reduction is not as much as when dorzolamide tid and timolol bid are administered concomitantly.

Class Summary

Reduce secretion of aqueous humor by inhibiting carbonic anhydrase in the ciliary body. In acute angle-closure glaucoma, administer systemically; apply topically in patients with open-angle glaucoma. These drugs are less effective, and their duration of action is shorter than many other classes of drugs. Adverse effects are relatively rare but include superficial punctate keratitis, acidosis, paresthesias, nausea, depression, and lassitude.

Pilocarpine ophthalmic (IsoptoCarpine)

Clinical Context:  Directly stimulates cholinergic receptors in the eye, decreasing resistance to aqueous humor outflow.

Instillation frequency and concentration are determined by patient's response. Individuals with heavily pigmented irides may require higher strengths.

If other glaucoma medication also is being used, at bedtime, use drops at least 5 min before gel.

Class Summary

Contract the ciliary muscle, tightening the trabecular meshwork and allowing increased outflow of aqueous. Miosis results from the action of these drugs on pupillary sphincter. Adverse effects include brow ache, induced myopia, and decreased vision in low light.

Bimatoprost (Lumigan, Latisse)

Clinical Context:  Prostaglandin agonist that selectively mimics effects of naturally occurring substances, prostamides. Exact mechanism of action unknown but believed to reduce IOP by increasing outflow of aqueous humor through trabecular meshwork and uveoscleral routes. Used to reduce IOP in open-angle glaucoma or ocular hypertension.

Travoprost (Travatan Z)

Clinical Context:  Prostaglandin F2-alpha analog and selective FP prostanoid receptor agonist. Exact mechanism of action unknown but believed to reduce IOP by increasing uveoscleral outflow.

Latanoprost (Xalatan, Xelpros)

Clinical Context:  F2-alpha analogue that mimics the IOP-lowering activity of prostamides via the prostamide pathway. Decreases IOP by increasing outflow of aqueous humor.

Tafluprost (Zioptan)

Clinical Context:  Tafluprost is a preservative-free, topical, ophthalmic prostaglandin analog indicated for elevated IOP associated with open-angle glaucoma or ocular hypertension. The exact mechanism by which it reduces IOP is unknown, but it is thought to increase uveoscleral outflow.

Class Summary

Increase uveoscleral outflow of aqueous. One mechanism of action may be through induction of metalloproteinases in the ciliary body, which breakdown the extracellular matrix, reducing resistance to outflow through the ciliary body. They can be used in conjunction with beta-blockers, alpha-agonists, or topical carbonic anhydrase inhibitors. Many patients respond well to these agents; others do not respond at all. Adverse effects include iris pigmentation, cystoid macular edema, and uveitis.

Brinzolamide and Brimonidine (Simbrinza)

Clinical Context:  Brinzolamide reduces intraocular pressure by inhibiting carbonic anhydrase, which in turn decreases aqueous humor secretion.

Brimonidine is an alpha2 receptor agonist. Reduces formation of aqueous humor production and increases uveoscleral outflow.

Class Summary

Carbonic anhydrase inhibitors decrease aqueous humor secretion while alpha2-receptor agonists increase uveoscleral flow and decrease aqueous humor production.

Unoprostone (Rescula)

Clinical Context:  This agent differs from other anti-glaucoma drugs in that it is the only available ocular therapy that contains a docosanoid. It may decrease intraocular pressure by increasing outflow of aqueous humor and by increasing trabecular meshwork outflow via stimulation of calcium-activated BK and CIC-2 type channels.

Class Summary

These agents are lipids derived from docosahexaenoic acid, which as been shown to be essential in the development and functioning of the retina.

Author

Michael D Greenwood, MD, Cataract, Refractive, Cornea, Glaucoma Surgeon

Disclosure: Nothing to disclose.

Coauthor(s)

Russell Swan, MD, Fellow in Cornea, Glaucoma, and Refractive Surgery, Vance Thompson Vision

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Hampton Roy, Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences

Disclosure: Nothing to disclose.

Additional Contributors

Andrew I Rabinowitz, MD, Director of Glaucoma Service, Barnet Dulaney Perkins Eye Center

Disclosure: Nothing to disclose.

Douglas J Rhee, MD, Professor and Chair, Department of Ophthalmology and Visual Science, University Hospitals Eye Institute, Case Western Reserve University School of Medicine

Disclosure: Received grant/research funds from Alcon for independent contractor; Received grant/research funds from Allergan for independent contractor; Received consulting fee from Alcon for consulting; Received consulting fee from Allergan for consulting; Received grant/research funds from Merck for independent contractor; Received grant/research funds from Ivantis for independent contractor; Received consulting fee from Glaukos for consulting; Received consulting fee from Ivantis for consulting; Received.

Steven Gedde, MD, Program Director, Assistant Professor, Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine

Disclosure: Nothing to disclose.

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