Meds That Don't Mix with Glaucoma Patients

Many common systemic medications can precipitate acute angle closure or increase intraocular pressure in your glaucoma patients. Here’s a review of the agents you should keep in mind.

By Tammy P. Than, M.S., O.D, and Erin B. Hardie, O.D

Release Date: October 2012
Expiration Date: OCTOBER 1, 2015

Goal Statement:

Many pharmaceutical agents have been known to cause drug-induced glaucoma and/or exacerbate existing glaucoma, but the actual incidence remains undetermined. This article reviews a variety of contemporary medications that eye care practitioners must be aware of in order to more accurately address the question: "With my glaucoma, is it safe to take this drug?"

Faculty/Editorial Board:

Tammy P. Than, M.S., O.D., and Erin B. Hardie, O.D.

Credit Statement:

This course is COPE approved for 2 hours of CE credit. COPE ID 35967-PH. Check with your local state licensing board to see if this counts toward your CE requirements for relicensure.

Joint-Sponsorship Statement:

This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.

Disclosure Statement:

Drs. Than and Hardie have no relationships to disclose.


We all get the occasional call from a patient who has just read the package insert for a specific medication and is worried about the precaution that the particular drug might not be safe for individuals with a known history of glaucoma. However, most drug labels are non-specific and merely list "glaucoma" instead of specifying the type of glaucoma. This should cause the practitioner to take pause and think about the medication, including its pharmacological properties and potential side effects. The practitioner must then review the patient's glaucoma history before rendering a judgment on the safety of the medication in question.

Most medications that could potentially impact a patient with a known history of glaucoma, or even increase the likelihood of glaucoma development, either narrow or close the anterior chamber angle. However, there also are a small number of systemic medications that may cause or exacerbate open-angle glaucoma. Furthermore, systemic medications that may cause optic neuropathy or visual field defects secondary to toxicity confound the monitoring of patients with existing glaucoma.

img1
This is a classic presentation of an eye in acute angle closure. Note the fixed,
mid-dilated pupil in a red eye. Several common systemic medications may increase
your glaucoma patients’ risk of an acute angle-closure attack.

 

If a patient presents with a potentially associated problem, the eye care practitioner must then decide if there is functional/structural glaucomatous progression or if the changes were caused by an adverse drug reaction. Some systemic medications may actually decrease intraocular pressure. While this side effect is not likely to be detrimental, it may give the eye care practitioner a false sense of security that the prescribed glaucoma medication is working more effectively than it truly is.

Many pharmaceutical agents have been known to cause drug-induced glaucoma and/or exacerbate existing glaucoma, but the actual incidence remains undetermined. This article reviews a variety of contemporary medications that eye care practitioners must be aware of in order to more accurately address the question: "With my glaucoma, is it safe to take this drug?"

Ocular Adverse Effects

The eye is prone to drug-related adverse effects due, in part, to its extensive blood supply and relatively small mass.1 Because most glaucoma patients are older, likely use multiple systemic agents for chronic conditions and exhibit an impaired ability to metabolize and excrete medications, they are at increased risk for ocular adverse drug events.

Often, it is very challenging to determine if a systemic medication is likely to exacerbate or cause glaucoma. A very useful resource is "Clinical Ocular Toxicology" by Frederick T. Fraunfelder, Frederick W. Fraunfelder and Wiley A. Chambers.2 This text is written specifically to help eye care practitioners determine if a visual condition is related to a medication, an herbal supplement or other chemical.

In general, documented ocular side effects are gathered from reports obtained by MedWatch: The FDA Safety Information and Adverse Event Reporting Program, the National Registry of Drug-Induced Ocular Side Effects and the World Health Organization (WHO). "Clinical Ocular Toxicology" uses the WHO Causality Assessment Guide of Suspected Adverse Reactions to classify reported adverse drug-related events.2

A recent study questioned the clinical reproducibility of adverse events documented in these causality assessments, but the WHO classification system continues to be widely utilized.3 With the ever increasing number of systemic medications, it is extremely difficult for the literature to address every potential complication. If, however, you observe a previously undocumented ocular adverse event caused by a systemic medication, you should report it to MedWatch (www.fda.gov/safety/medwatch).

Acute Angle Closure

Medications that could induce an acute angle-closure attack often are contraindicated in glaucoma patients. According to one study, over-the-counter and prescription medications account for 33% of acute angle-closure glaucoma.4

Drugs that induce acute angle closure produce this effect in several ways. In predisposed patients, a pupillary block angle closure may occur secondary to forward movement of the lens-iris diaphragm with functional apposition between the iris border and the anterior lens surface.

The restriction in aqueous flow creates excessive pressure in the posterior chamber, which bows the peripheral iris forward and closes the angle.5,6 Any drug that causes pupillary dilation also may precipitate angle closure due to the pulling of the peripheral iris into the anterior chamber angle.7

Individuals who are at the greatest risk for drug-induced angle closure often exhibit one or more of the following characteristics: Asian ethnicity, advanced age, female, hyperopia, positive family history, narrow iridocorneal angle and shallow anterior chamber depth.8,9 It has even been reported that acute angle-closure attacks are more common in fall and winter than spring and summer.7 Angle-closure attacks are often unilateral.

The other mechanism that causes acute angle closure results from forward movement of the lens, rotation of the ciliary body and choroidal effusion. This reaction appears to be an idiosyncratic response to certain medications, which may occur irrespective of anterior chamber angle depth prior to medication use.5

With existing glaucoma patients, eye care practitioners already have evaluated them gonioscopically and can alert them about the risk of certain systemic medication classes. Many patients who experience an acute angle-closure attack secondary to medication use may have been unaware that they were at risk, and it simply is not practical to perform gonioscopy on every patient prior to initiating systemic therapy.

Idiosyncratic reactions are just that--we cannot predict which patients will experience an adverse event. Optometrists should communicate with primary care providers and other physicians who routinely prescribe medications that are known to cause angle closure, so that they may alert patients to seek care if they experience any manifestations of acutely elevated IOP.

* Cholinergic agents. Systemic cholinergic agonists are used to stimulate salivary gland production in patients with xerostomia secondary to Sjögren's syndrome or following head/neck radiation therapy. These agents also may be used off-label for recalcitrant dry eye due to the stimulatory effect on the lacrimal gland.

Salagen (pilocarpine, Eisai) and Evoxac (cevimeline, Daiichi Sankyo) both list narrow-angle glaucoma as a contraindication for use, and may precipitate a pupillary block angle closure. These drugs cause anterior movement of the lens-iris diaphragm. This is more problematic in patients with advancing cataracts who already have shallower anterior chambers. According to package inserts for both medications, the incidence of glaucoma development was less than 1% in clinical trials.

Any medication that exhibits anticholinergic properties should be used with caution in patients with narrow angles. A large number of systemic medications exhibit varying degrees of anticholinergic effect, which may result in pupillary dilation. Should an acute angle-closure attack occur, the suspected medication must be discontinued immediately (in consultation with the prescribing provider) and the individual's IOP should be lowered with ocular hypotensive medications. In addition, laser peripheral iridotomy yields a prophylactic benefit against future events.

* Antidepressants. Selective serotonin reuptake inhibitors (SSRIs) often are a first-line option in the management of depressive and anxiety disorders due to their excellent safety profile and tolerability. Among those used are Prozac (fluoxetine, Eli Lilly), Paxil (paroxetine, GlaxoSmithKline) and fluvoxamine. The therapeutic effect of SSRIs is rendered via a gradual increase in serotonin in the postsynaptic cleft.

The mechanism by which SSRIs result in angle closure is uncertain. It has been postulated that serotonin is responsible for increased pupil dilation and aqueous production.10 Another study suggested that the medications' anticholinergic effects cause pupil dilation.11 In either case, glaucomatous attacks typically occur within the first six months of starting SSRI therapy (although one case was reported as late as five years after treatment).10

img2
Acute angle closure secondary to pupillary block, as seen on Visante OCT (Carl Zeiss
Meditec). Note the dramatic iris bombé. This is a potential side effect of many
systemic medications (including any agents that exhibit anticholinergic properties).

img3
Here is the same eye approximately 90 minutes later, following a laser peripheral
iridotomy. The iris has now returned to a more planar configuration. The debris
resultant from the laser procedure is evident in the anterior chamber.

 

Other antidepressants are known to demonstrate anticholinergic activity and have precipitated angle closure in patients with a narrow iridocorneal angles. Tricyclic antidepressants (TCADs) that are often associated with ocular sequelae include amitryptiline and imipramine. Non-TCADs that have been linked to acute angle closure include Celexa (citalopram, Forest Laboratories) and Lexapro (escitalopram, Forest Laboratories).

Monoamine oxidate inhibitors (e.g., phenelzine sulfate)--which also are utilized in the management of depressive disorders--have mild anticholinergic effects and pose a risk, albeit less than TCADs.

Additionally, many antipsychotic drugs have anticholinergic activity. Although the anticholinergic activity is weak, several medications in this class, including fluphenazine and chlorpromazine, have been associated with acute angle-closure attacks.8,11

* Antihistamines. H2 receptor agonists, such as Tagamet (cimetidine, Prestige Brands) and Zantac (ranitidine, Boehringer Ingelheim), which are indicated for relief of peptic ulcer disease and gastro-esophageal reflux disease, are weak anticholinergics that may cause angle closure.6

Additionally, H1-blocking agents used for anti-allergy (e.g., diphenhydramine), anti-emesis (e.g., promethazine) and anti-anxiolytic (e.g., hydroxyzine) purposes exhibit significant anticholinergic activity and may cause angle closure.6 Safer H1-blocking agents for high-risk patients include non-sedating antihistamines, such as loratadine, cetirizine or fexofenadine.

* Incontinence control medications. Overactive bladder is thought to affect one-third of adults over age 75. It is frequently associated with urinary incontinence and urgency that can be managed with muscarinic receptor antagonists.

Current medications with anti-cholinergic properties include Detrol (tolterodine, Pfizer), Ditropan (oxybutynin, Ortho-McNeil Pharmaceutical), trospium, pro-pantheline and darifenacin.12 Moreover, the package inserts list uncontrolled, narrow-angle glaucoma as a contraindication. Several small studies have shown no effect on intraocular pressure in patients without glaucoma or those with primary open-angle glaucoma.13

* Adrenergic agonists. Epinephrine, used for anaphylaxis and severe asthma, and ephedrine, which is found in cold remedies, both cause pupillary dilation that may result in acute angle-closure attacks.6 One study evaluated a series of patients with upper respiratory infections who presented with angle closure. The researchers determined that the majority of those affected had used anti-cough mixtures prior to the attack.7

Additionally, amphetamine, which is used to control narcolepsy and attention deficit hyperactivity disorder, may cause mydriasis. Such medications that demonstrate sympathomimetic activity typically cause pupil dilation, and should be used with caution in patients who are known to have narrow angles.

* Nutraceuticals. Ask patients about their use of herbal and nutritional supplements, because these too may affect glaucoma. Jimson weed (datura stramonium) is an annual herb that grows up to five feet tall and produces fragrant, trumpet-shaped flowers. It is used for a wide variety of conditions, including asthma, analgesia and motion sickness. Datura plants contain high concentrations of atropine and scopolamine, and should not be used by patients with narrow angles due to its association with pupil dilation.

Several other dietary supplements have been associated with mydriasis, including valerian root, mandrake and 5-hydroxytryptophan henbane.2

* Other medications. Management of spasms in patients with Parkinson's disease may include the use of orphenadrine citrate (an anticholinergic medication) or trihexyphenidyl (an antimuscarinic agent with a significant amount of anticholinergic activity). These anti-spasm medications may be associated with pupillary dilation and angle closure.5

Atrovent (ipratropium bromide, Boehringer Ingelheim) and Spiriva (tiotropium bromide, Boehringer Ingelheim) are anticholinergic medications for long-term management of bronchospasms associated with COPD and emphysema, and have been reported to cause angle-closure attacks.5

Idiosyncratic Angle Closure

* Sulfonamides. A number of sulfonamide drugs--including topiramate hydrochlorothiazide, acetazolamide, quinine, tetracycline and trimethoprim/sulfamethoxazole--can cause an idiosyncratic non-pupillary block (which often manifests bilaterally).5 In this instance, patients likely experience an allergic reaction to the sulpha moiety, resulting in ciliary body edema with lens zonule relaxation.6 This process, in turn, causes anterior-posterior lens thickening. Then, the ciliary body, lens and iris are shifted forward, which narrows the anterior chamber. Additionally, choroidal effusion likely is a contributing factor.6

The aforementioned sulfonamide medications have been shown to cause acute transient myopia and acute angle closure in approximately 3% of patients.14 The exact mechanism of these ocular side effects is unknown; however, the presentation typically occurs bilaterally, shortly after treatment initiation.4,5 Specific patient symptoms include blur (up to -8.00D of acute myopia), pain and nausea. ("Topamax, Qsymia May Cause Angle Closure")

Topamax, Qsymia May Cause Angle Closure

Topamax (topiramate, Janssen Pharmaceuticals) is a sulfamate-substituted monosaccharide
that is indicated for the management of seizures and migraines.1 Clinicians occasionally
prescribe Topamax off label for a wide variety of applications, including smoking cessation,
bipolar disorder, neuropathic pain and idiopathic intracranial hypertension.

In July 2012, Qsymia (phentermine/topiramate extended release, Vivus) received FDA
approval for chronic weight management in obese patients or those with weight-related
comorbidities.

Patients who use Topamax or Qsymia are at an increased risk for ocular adverse events––
including drug-induced myopia and angle-closure glaucoma.1 Ocular side effects associated
with topiramate typically are experienced within the first month of dosing (85% of symptoms
manifest during the first two weeks after therapeutic initiation).

 

In any suspected case, have the patient discontinue the medication immediately. Then, prescribe ocular hypotensive medications to lower IOP. Because pupillary block is not a contributing factor, a peripheral iridotomy typically is ineffective (although initial management with laser iridoplasty has been shown to help extract the peripheral iris from the occluded angle).15

* Norepinephrine-dopamine reuptake inhibitors. A recent case of bilateral uveal effusion and acute angle closure was reported two weeks after initiating treatment with bupropion hydrochloride (e.g., Wellbutrin, GlaxoSmithKline).16

Structurally, bupropion is not a sulfonamide, but a norepinephrine-dopamine reuptake inhibitor that is used in the management of depressive disorders as well as for smoking cessation. Some research suggests that norepinephrine may play a role in the development of choroidal effusions; this adverse effect also has been reported following the use of venlafaxine hydrochloride--another norepinephrine reuptake inhibitor.16

* Anticoagulants. In rare instances, anticoagulant therapy (e.g., warfarin) has been reported to cause angle closure secondary to large, spontaneous, choroidal or subretinal hemorrhages.4,5 Additional risk factors for associated angle closure include hypertension and artherosclerosis.4,5

Open-Angle Glaucoma

* Oral steroids. When we think of drug-induced IOP elevation or spike, we think of oral steroids. According to a Canadian study, adults treated with oral steroids were 1.41 times more likely to experience an increase in ocular hypertension than non-users.16

Multiple ocular side effects have been associated with oral steroid use, including posterior subcapsular cataracts, poor or incomplete corneal wound healing and, most importantly, glaucoma secondary to increased IOP.17 Acute-onset responses with stronger systemic steroids have been documented within weeks of initial dosing, whereas weaker steroids may not cause an IOP increase for several months.18 While newer topical corticosteroids have been formulated to minimize the potential for secondary IOP increase, oral and injectable steroids still increase an individual's overall risk of ocular hypertension.19

Still, not every patient is a "steroid responder." So, we must accurately identify the most common risk factors for drug-induced glaucoma, including a previous diagnosis of primary open-angle glaucoma, diabetes, myopia and younger age.20

Some published reports indicate that nearly 70% of first-degree offspring from patients with primary open-angle glaucoma exhibit a significant IOP increase following use of topical and/or oral steroids.21

Why Do Steroids Spike Up the Pressure?

What is the underlying pathophysiology of IOP increase with steroid use? All forms of steroids––
even nasal sprays––can increase IOP due to reduced aqueous humor outflow caused
by morphological and biochemical changes in the trabecular meshwork.22

Much of the trabecular meshwork cell function, gene expression and extracellular matrix
metabolism is altered by steroid use, which absolutely limits its ability to function properly.
Clinical experience suggests that higher ocular concentrations of corticosteroids yield proportionately
elevated IOP measurements.

Because the trabecular meshwork accounts for nearly 90% of the aqueous humor drainage,
it is reasonable to conclude that a disruption in its function will result in excess aqueous
volume, decreased outflow facility and higher IOP.8 One retrospective study indicated that
discontinuing a steroid nasal spray (e.g., Flonase [fluticasone, GlaxoSmithKline]) showed a
clinically significant decrease in IOP.24 So, monitor IOP closely in all patients who use any type
and/or dosage of steroidal medication to limit the potential for drug-induced glaucoma.

 

Further, researchers have uncovered a genetic susceptibility to corticosteroid-induced glaucoma via the myocilin gene (formerly known as the trabecular meshwork inducible glucocorticoid response protein, or TIGR).18 Myocilin is highly expressed when trabecular mesh-work cells are exposed to steroids, and mutations in this gene are more commonly found in patients with juvenile- and adult-onset primary open-angle glaucoma.18 In the future, clinicians might be able to use genetic testing to more accurately predict a steroid response.

We must also be familiar with systemic conditions that warrant frequent use of steroids and/ or other anti-inflammatory drugs. Conditions such as asthma, rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus require oral steroid treatment in both children and adults. Primary eye care practitioners must recognize these diseases and educate their patients about the potential ocular complications associated with frequent or long-term steroid use.

* Cancer drugs. Docetaxel and paclitaxel are anticancer agents that work as microtubule inhibitors. These agents frequently are prescribed to combat breast and prostate cancer. Elevated intraocular pressure has been noted following therapy, but the causal mechanism is not clear and might be related to fluid retention.9,25 Additionally, one patient on paclitaxel therapy reported visual field changes that likely presented secondary to neurotoxicity.26 In this case, however, the patient's visual changes resolved upon discontinuation of therapy.26

* Systemic beta blockers. Oral beta blockers are not likely to supplant their topical counterparts in glaucoma management. On the other hand, optometrists must also be aware that titration or outright discontinuation of systemic beta blockers might then cause IOP elevation. This reiterates the notion that communication with primary care physicians is crucial for comprehensive management of glaucoma patients. If a systemic beta blocker is stopped, be sure to monitor the individual's IOP.

* Mydriatics and cycloplegics. While certainly not a systemic medication, it is worth noting that topical tropicamide may cause increased IOP via mechanisms other than angle closure. After examining IOP fluctuations in children given mydriatics, researchers found an average increase of 2mm Hg; however, a potential increase or decrease of 8mm Hg was documented in many patients with open angles.27 The investigators concluded that some alteration in aqueous dynamics occurred upon dilation and, because of the variable effect on IOP (even without the presence of anterior segment complications), all patients who use mydriatics require observation.27

In one published report, 23% of patients with primary open-angle glaucoma experienced a significant increase in IOP following topical installation of cycloplegic agents, compared to just 2% of patients without glaucoma.28 The authors concluded that a significant change in IOP following anticholinergic use should be considered in open-angle glaucoma suspects.28 Here again, the mechanism is not completely understood; however, the researchers suggested that decreased aqueous outflow facility likely contributed to increased IOP.28

* Caffeine. At least one study suggested that large amounts of caffeine (more than 180mg per day) might yield a small spike in IOP of 1mm Hg to 2mm Hg.29 But, more recent studies indicate that one cup of caffeinated coffee per day likely does not have a clinically significant impact on IOP.30

Many medications can exacerbate glaucoma or cause acute angle-closure attacks. So eye care practitioner must be aware of these common associations and keep a high level of suspicion when taking a patient's pharmaceutical history.

We must also realize that many systemic medications that are particularly deleterious to glaucoma patients, yet associated ocular adverse events have yet to be reported. In these instances, optometrists are encouraged to report their findings to the FDA in an effort to alert other clinicians.

Thankfully, most adverse ocular events that impact glaucoma patients occur infrequently. But, if and when a problem arises, you must be adequately prepared to intervene.

Dr. Than is an associate professor at the University of Alabama at Birmingham School of Optometry.
Dr. Hardie is completing an ocular disease residency at VisionAmerica in Birmingham.

References

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