Of all the tools now in the employ of practicing ophthalmologists, eyedrops may seem the most innocuous. But glaucoma clinicians should take care—toxicities, both common and not, are lurking in those little bottles.
As a cardiologist and researcher-in-training in the 1970s, William H. Frishman, MD, observed that the oral beta blockers he used to manage his patients’ cardiovascular disease were also having an effect on the eye. “We noticed with tonometry that we were getting lower ocular pressures,” he recalled. Dr. Frishman is now professor and chairman of medicine and professor of pharmacology at New York Medical College and director of medicine at Westchester Medical Center in Valhalla, N.Y. As is often the case in medical progress, an unintended side effect of a drug had created a fortuitous new therapeutic application. By 1979, topical timolol (Timoptic) became the first beta blocker approved for lowering intraocular pressure. It remains the FDA’s gold standard for glaucoma therapy against which all new medications must be compared.
But soon cardiologists started seeing older patients who were worsening while on the drops. “A lot of people said, ‘What’s happening here?’” said Dr. Frishman, who has written extensively about the impact of glaucoma medications on the cardiovascular and respiratory systems. The problems, he said, were traced to glaucoma drops. The potential adverse effects of beta blockers are now well-described and include dizziness, fatigue, severe asthma attacks and the masking of hypoglycemia.
Some side effects can even be deadly. That warrants thinking beyond the effects a drug has only on the eye. Asthma, for example, is just one of many red flags that ophthalmologists need to consider before prescribing glaucoma medications. Others include bradycardia or a history of syncope. Pregnant women, infants and children need to be considered with extraordinary care. Even the inability to pay for medication may lead to adverse effects. Following is a look at contemporary use of the major glaucoma drugs and some worrisome situations, many of which can be avoided by calibrating the patient’s profile to the appropriate drugs.
Using Prostaglandin Analogs
Until the mid-1990s, the beta blocker timolol was king of ocular antihypertensives. Then along came the prostaglandin analog latanoprost (Xalatan). Doctors liked latanoprost because it had few side effects. “Asthmatic patients are unaffected by it,” said Dr. Frishman, and long-term studies have revealed no major pulmonary or cardiac toxicities.
For a first-line treatment, Ruth D. Williams, MD, in private practice in Wheaton, Ill., prefers one of the three available prostaglandin analogs (Lumigan, Travatan Z or Xalatan) because they’re highly effective and, she said, “Their systemic profile is pretty minimal.”
Because of that profile, Paul J. Lama, MD, director of the Glaucoma Institute of Northern New Jersey and associate clinical professor of ophthalmology at Columbia University, also starts most of his patients on a prostaglandin analog, unless a patient has uveitic glaucoma or there’s some contraindicating ocular reason, such as the patient doesn’t want hazel eyes turning brown (one of the known side effects of the prostaglandin analogs, along with lengthening of lashes). “The easiest prostaglandin is latanoprost, which is least likely to cause a red eye or immediate symptoms,” Dr. Lama said.
Using Beta Blockers
Beta blockers are generally Dr. Lama’s second choice after prostaglandin analogs, though he considers them a reasonable first-line therapy. “Most patients are good candidates for topical beta blocker therapy,” he said.
If Dr. Williams is looking for a modest drop in IOP, she may choose beta blockers as a second-line therapy because they’re simple—used once in the morning—and they’re cheap. “But you have to be thoughtful about the side effects,” she said, “Any history of asthma and emphysema—absolutely not.”
Low pulse rate that hasn’t been clinically manifest is another contraindication, said Dr. Lama, who won’t initially prescribe a beta blocker to an elderly patient whose resting pulse rate is 55 or lower, unless historically they are aerobically conditioned. Dr. Lama refers these patients for evaluation for possible sinus node dysfunction or other bradyarrhythmia. If there’s no problem, then a beta blocker is OK, he said.
In fact, after conducting an extensive review of the literature, Dr. Lama has concluded that beta blockers have gotten something of a bad rap.1Over the years, beta blockers have been implicated in everything from worsening intermittent claudication, depression, hypoglycemic unawareness or prolonged hypoglycemia in noninsulin-dependent diabetes, sexual dysfunction and impaired neuromuscular transmission. Yet Dr. Lama concluded that many of these commonly ascribed adverse effects were not supported by published clinical trials. “The take-home message with beta blockers is: Don’t use them in the asthmatic patient or in the patient with chronic obstructive pulmonary disease,” Dr. Lama said.
Richard G. Fiscella, RPh, MPH, agreed. “If a patient has a history of asthma or COPD, doctors should be very careful because beta blockers cause bronchoconstriction,” he said. “If a patient had three ER admissions in the last year for asthma, you’ll be very cautious. Who knows what will push them over?” Prof. Fiscella is clinical professor of pharmacy practice and adjunct professor of ophthalmology at the University of Illinois in Chicago.
Medications for the Management of Elevated Intraocular Pressure and Glaucoma
EyeNet has found that the most comprehensive and convenient source of information on drugs approved by the FDA is “DailyMed,” a service of the National Library of Medicine (www.dailymed.nlm.nih.gov). As described by the NLM: “DailyMed provides high quality information about marketed drugs. Drug labeling on this Web site is the most recent submitted to the Food and Drug Administration and currently in use; it may include, for example, strengthened warnings undergoing FDA review or minor editorial changes.”
The search engine works best by entering the generic name of a drug in the search field. When “timolol” is entered, for example, all 13 formulations of that medication that are marketed in the United States are called up, including combinations of medications that contain timolol. Clicking on any one formulation then leads to all relevant prescribing information, including mechanism of action, dosing, precautions, drug interactions, adverse effects and recommendations for use in children or pregnant women.
For patients, a similarly good source of prescription drug information can be found at another NLM site—MedlinePlus (www.nlm.nih.gov/medlineplus/druginformation.html).
The notes on each class of medication below are adapted from the Academy’sBasic and Clinical Science Course,Section 10 (Glaucoma), chapter 7 (Medical Management of Glaucoma).
Caution is urged in patients who are taking monoamine oxidase inhibitors or tricyclic antidepressants. Apraclonidine may cause tachyphylaxis and topical sensitivity. Use in children under 2 years of age is contraindicated.
|<width="35%">Apraclonidine Iopidine (apraclonidine hydrochloride) solution.Alcon|
Brimonidine Alphagan P (brimonidine tartrate) solution.Allergan
Brimonidine tartrate solution.Akorn, Alcon, Bausch & Lomb
Combigan (brimonidine tartrate and timolol maleate) solution. Allergan
Carbonic anhydrase inhibitors
Side effects include bitter taste, blurred vision and punctate keratopathy.
|Brinzolamide Azopt (brinzolamide) suspension.Alcon|
Dorzolamide Cosopt (dorzolamide hydrochloride and timolol maleate) solution.Merck
Dorzolamide hydrochloride solution.Apotex, Hi Tech Pharmacal, Teva Pharm
Dorzolamide hydrochloride and timolol maleate solution.Apotex, Hi Tech Pharmacal
Trusopt (dorzolamide hydrochloride) solution. Merck
Hypotensive lipids, including prostaglandin analogs
Side effects may include darkening of the iris and periocular skin, conjunctival hyperemia and hypertrichiasis. Latanoprost and travoprost are prostaglandin analogs.
Bimatoprost Lumigan (bimatoprost) solution.Allergan
Latanoprost Xalatan (latanoprost) solution.Pfizer/Pharmacia & Upjohn
Travoprost Travatan (travoprost) solution.Alcon
Travatan Z (travoprost) solution. Alcon
Parasympathomimetic (miotic) agents
Induced myopia is a common side effect. Retinal detachments have been reported in some patients, and a peripheral retinal evaluation is recommended before therapy.
|Carbachol Isopto carbachol solution.Alcon|
Echothiophate Phospholine iodide (echothiophate iodide) solution.Pfizer/Wyeth
Beta-adrenergic antagonists (beta blockers)
Side effects of beta blockers include bronchospasm, bradycardia, increased heart block, hypotension, reduced exercise tolerance and CNS depression. Patients with diabetes may experience reduced glucose tolerance and masking of hypoglycemic signs and symptoms. Abrupt withdrawal of ocular beta blockers can exacerbate symptoms of hyperthyroidism. Betaxolol may be safer, if somewhat less effective, than other beta blockers for some patients.
|Betaxolol Betaxolol hydrochloride solution.Falcon|
Betoptic (betaxolol hydrochloride) solution.Alcon
Betoptic S (betaxolol hydrochloride) suspension.Alcon
Carteolol Carteolol hydrochloride solution.Bausch & Lomb, Falcon
Ocupress (carteolol hydrochloride) solution.Novartis
Levobunolol Betagan (levobunolol hydrochloride) solution.Allergan
Levobunolol hydrochloride solution.Bausch & Lomb, Falcon
Metipranolol Metipranolol hydrochloride solution.Falcon
Optipranolol (metipranolol hydrochloride) solution.Bausch & Lomb
Timolol Betimol (timolol) solution.Santen/Vistakon
Combigan (brimonidine tartrate and timolol maleate) solution.Allergan
Cosopt (dorzolamide hydrochloride and timolol maleate) solution.Merck
Dorzolamide hydrochloride and timolol maleate solution.Apotex, Hi Tech Pharmacal
Istalol (timolol maleate) solution.Ista
Timolol maleate solution.Bausch & Lomb, Falcon, Pacific Pharma, Akorn
Timoptic (timolol maleate) solution.Merck
Timoptic-XE (timolol maleate) solution, gel forming, extended release. Merck
Polypharmacy, common in the elderly, can be a recipe for disaster. It’s in this context that ophthalmologists will want to use the most caution with beta blockers.
As Dr. Frishman elucidated in an article on the pharmacotherapy of glaucoma, the growing advocacy for the use of beta blockers in the treatment of congestive heart failure, a disease widely prevalent in the elderly, creates a significant subset of ophthalmic patients already on systemic beta blocker therapy.2“It is unclear,” he writes, “what the impact of additional topically administered beta blockers would have under these circumstances.” In the same article, Dr. Frishman underscores the importance of recognizing which patients with glaucoma may have other concomitant conditions that would contraindicate the use of beta blockers.
Dr. Frishman warned that the additive effects of oral and systemic beta blockers can create a very low pulse rate. Or patients may be treated presumptively for an underlying cardiac or pulmonary disorder, when the true causative factor is that they’re on a beta blocker for their glaucoma, he said. To prevent such situations, physicians must be aware of all systemic or oral drugs that patients are taking.
Dr. Lama, however, suggested that a patient on a systemic beta blocker “would only have a miniscule increase in plasma concentration of beta blocker after receiving a topical beta blocker.” On the other hand, he said that “if a patient is on a topical beta blocker and a systemic beta blocker is started, then plasma concentrations will be significantly elevated.” Having said that, he agreed that ophthalmologists need to know a patient’s complete medication history. “Be a patient’s doctor. There’s no excuse not to know their medical history,” he said. “Work with the patient and know your therapeutic goal. That’s how you should choose your medication.”
Dr. Lama’s mantra is safety, efficacy, cost, tolerability. “If you can answer yes to all of them, you have a pretty good drug in your hand.”
There are not many studies of these drugs conducted in pregnant women, so there are no simple solutions as to how to treat them, Prof. Fiscella said. But the systemic carbonic anhydrase inhibitor (CAI) acetazolamide is definitely contraindicated, he said. “That one is associated with teratogenic effects,” and so caution is advised with the topical CAIs, he said.
Prostaglandins are a potential concern, he continued, because systemic administration may initiate uterine contractions, creating a theoretical risk for spontaneous abortion, although no cases have ever been reported with the use of topical agents.
The FDA classifies glaucoma medications according to their effect on pregnancy, mainly during the first trimester, said Eydie G. Miller-Ellis, MD, who lectures on glaucoma and pregnancy and is director of the glaucoma service and professor of clinical ophthalmology at the Scheie Eye Institute at the University of Pennsylvania. All glaucoma medications fall into category C, meaning the drug should be given only if the potential benefit justifies the potential risk to the fetus. Only brimonidine and dipivefrin are in category B, which means studies have failed to demonstrate a risk to the fetus. Here are some of Dr. Miller-Ellis’ recommendations for treating glaucoma during pregnancy:
- Avoid the use of medication, or use a minimum number of drugs, especially during the first trimester.
- If medication is necessary, brimonidine is the best choice. If a beta blocker is used, timolol gel-forming solution has less systemic absorption than the aqueous solution.
- Use punctal occlusion to minimize systemic absorption.
- IOP is lower during pregnancy, so control of IOP may well be achieved with fewer medications.
- Consider laser trabeculoplasty or filtering surgery in high-risk cases. The second trimester is the optimal time for surgery.
- During surgery, avoid antimetabolites and systemic anesthesia.
- During breastfeeding, CAIs and beta blockers are acceptable, but dosing should be done immediately after nursing to minimize the concentration in breast milk.
|Keep Drops In The Eye And Out Of Circulation|
They’re dropped in the eye, but topical glaucoma medications are absorbed systemically via the nasopharyngeal mucosa, after passage through the nasolacrimal duct. For this reason, topical ophthalmic dosing is more akin to intravenous delivery than to oral dosing, Dr. Frishman said, adding that the hepatic first-pass effect in a drug’s metabolism that happens after oral dosing may be negated by topical delivery.
But there are ways to lessen systemic side effects from topical mediation. Punctal occlusion can reduce absorption topical medication by 60 to 65 percent, Prof. Fiscella said. He advised telling patients to put a finger in the corner eye and keeping it there for three minutes. This prevents pumping action into the lacrimal sac and reduces absorption down the nasopharyngeal mucosa. If a physician is really concerned about an adverse systemic reaction, added Dr. Williams, he or she should prescribe a different drug.
Just a single drop of medication can have an adverse effect on children. “With drops we don’t have the ability to change the dosing. A drop is the same concentration no matter how big you are,” said pediatric ophthalmologist K. David Epley, MD, who warned ophthalmologists to be aware of issues with certain classes of medications in children. Dr. Epley is in private practice in Kirkland, Wash.
Of biggest concern are the two alpha-adrenergic agonists, brimonidine and apraclonidine, which have been linked to reports of death in infants. “The alpha agonist suppressed their drive to continue to take breaths,” Dr. Epley said. “They just stopped breathing.” Dr. Epley said to avoid alpha agonists in children under age 6, and definitely don’t use them in children younger than 2 years of age.
Instead, he said, consider timolol in young children. Its known side effect of lowering the heart rate is not a big concern for most children, Dr. Epley said. On the other hand, he cautioned that it can potentially aggravate a child’s asthma, a condition that children have more frequently than adults. If timolol is contraindicated, Dr. Epley advised topical CAIs. Latanoprost, the most popular first-line drug in adults, has not been well studied in children, he added.
The prevailing thinking is that most drops are not effective in infantile glaucoma, Dr. Epley said. Rather, drugs are used primarily to stabilize children prior to surgery.
When kids are on medication, Dr. Epley advised asking parents specific questions about side effects. For example, if a child is on dorzolamide, is he or she having trouble going to the bathroom, or are they complaining of a funny taste in the mouth? A general question may not yield answers, he said, explaining that parents might not make the connection between an eyedrop and their child’s condition. “As an ophthalmologist, you need to be aware to ask questions that put those associations together,” Dr. Epley said. “It seems so innocuous to put a drop in the eye.” ___________________________
1Am J Ophthalmol 2002;134(5):749–760. 2Cardiol Rev2008;16:95–108.
|When Healthy Vision Has A Dollar Sign|
Since adherence is a crucial ingredient in the long-term success of glaucoma management, obstacles to adherence spell trouble. And the high cost of American branded pharmaceuticals can be just such an obstacle.
Dr. Williams knows firsthand what happens when patients can’t afford their drops. She has one patient who was taking Xalatan every other day. Another patient was watering down her drops to make them last longer. “It’s our job to make sure our patients can afford the meds,” said Dr. Williams, who initiates the conversation about cost. “People are feeling the financial crunch more than ever, but they’re afraid to talk to the doctor,” she said. “When I bring it up, it’s a real relief to the patient.”
Many of the large pharmaceutical chains heavily discount generic drugs. When cost is a factor, and the patient’s a good candidate, Dr. Lama prescribes beta blockers. “Beta blockers are very, very versatile drugs,” he said. “There’s not one kind of glaucoma that you can’t prescribe a beta blocker for.” He stressed that many more patients may be eligible for beta blockers than conventional wisdom holds. Obtain a careful medical history and check pulse rate and rhythm in the office to identify the vast majority of patients with potential cardiopulmonary contraindications.
For the patient who can’t tolerate a beta blocker and can’t afford a more costly alternative, Dr. Lama prefers laser. “It’s a beautiful option,” he said. “If they respond well for a long enough time, it helps them with the cost.”
The bot***** *****ne, said Dr. Lama: “If they can’t afford it, they’re not buying it.”