Nevertheless, beta blockers are still in wide use. With that in mind, we asked three ophthalmologists with extensive knowledge of beta blockers to provide an update on how and why beta blockers are being used today—and how clinicians could make even better use of them.
Prostaglandins vs. Beta Blockers
"Beta blockers are good drugs that have gotten a bad rap," says Toni Realini, MD, associate professor in the department of ophthalmology at the West Virginia University Eye Institute. "When they were all we had, we loved them. Today, with the advent of prostaglandins and other drug classes, beta blockers are less popular. Nevertheless, they're still completely appropriate for many patients as first-line therapy."
Dr. Realini notes that prostaglandins have come to the fore in recent years because they offer a rare constellation of advantages. "Prostaglandins are unique in medicine in that they are the most powerful drug in the arsenal, and also the safest," he says. "That rarely happens in medicine. To get the most power, you almost invariably have to go to an unfavorable safety profile. But prostaglandins have essentially no systemic side effects that occur with any significant frequency.
"Nevertheless, some patients will respond better to a beta blocker," he continues. "In most comparative studies the difference between beta blockers and prostaglandins is small to moderate,1-3 and in at least one study the effects were equivalent."4
Robert D. Fechtner, MD, FACS, director of the glaucoma division at the University of Medicine and Dentistry of New Jersey, observes that the popularity of particular treatments as first-line therapy depends on whether you're considering the United States or the world as a whole. "In the U.S. where patients usually have easy access to medications, prostaglandins have largely taken over as initial first-line therapy," he says. "We select them because they're once-daily and they have a very favorable adverse-effect profile; they're very well-tolerated systemically. Also, as a class they probably lower pressure a little better than beta blockers. But when patients don't have access to prostaglandins, beta blockers are the logical alternative."
Ehsan Sadri, MD, assistant clinical professor of ophthalmology at University of California, Irvine, agrees. "We often must treat patients who are already on two or three eye drops and still getting worse," he says. "In that situation you have to consider taking the patient to surgery. However, if the patient hasn't already tried beta blockers and his history shows no contraindication, I would trying switching to a beta blocker and then adding other medications as required, before resorting to surgery. Studies say that prostaglandins lower pressure better, but I've had patients who responded better to beta blockers."
"Beta blockers have positives and negatives," he adds. "If you've got a young patient with light irides who doesn't want long eyelashes, a beta blocker is an excellent choice, especially if you use it one drop per day. Also, cost is a huge factor. Many patients on a lipid analog ask me when they can go back to a beta blocker again. And I've known pharmacists to encourage patients to use a less expensive beta blocker when the patient has a prescription for a prostaglandin analog. We ought to provide the patient with something he can be economically compliant with as well as clinically compliant."
The Side Effects Factor
Dr. Sadri notes that possible systemic side effects are usually seen as the main "negative" of beta blockers. "This class of medications has to be used in select patients," he says. "Some clinicians overlook this and use them on everybody—they don't think about the cardiovascular issues. Other doctors are leery of beta blocking patients if there's any hint of a cardiac issue.
"The most important thing to remember is that you have to get a good history," he continues. "The number one rule is: Know your patient. Beta blockers are contraindicated in anyone with a previous myocardial infarction, a history of arrhythmia or bradycardia, pulmonary issues such as chronic obstructive pulmonary disease, or emphysema. On the other hand, if the patient is already on beta blockers systemically, which many of our patients are, adding a topical eye drop is not going to throw him into sinus bradycardia; systemic levels of oral beta blockers are much higher than topically administered beta blockers."
"It's the safety issue that has propelled prostaglandins to the front line," agrees Dr. Realini. "Beta blocker eye drops have a minimal systemic effect in healthy people, but you can detect it in the blood stream—some of it does get in. I've heard one clinician say, 'I like to use a prostaglandin because I don't have to bother to take a careful medical history.' I wouldn't want to be that doctor's patient, but I understand why he said that. With a beta blocker there are a number of important comorbidities that you have to rule out beforehand. With prostaglandins, you don't have to ask all of those questions."
However, Dr. Fechtner notes that there are situations in which he would also hesitate to choose prostaglandins as first-line therapy because of possible side effects. "I'm cautious about using the prostaglandins when a patient has uveitis, cystoid macular edema or herpes simplex keratitis," he says. "While there's no proven causal link between them, the question of an association has been raised. So in those patients I might choose a beta blocker as first-line therapy."
"We've shied away from the beta blockers a little because of their potential for systemic side effects," he adds. "But with 30 years of experience we should be very comfortable with this class of drugs."
Dr. Sadri also points out that some minor side effects favor beta blockers. "In my experience, the most important factor affecting compliance is that the majority of medicines now used to treat glaucoma contain benzalkonium chloride or other preservatives which can cause chronic hyperemia," he says. "Every day I see patients who don't like having chronic red eyes; they want to switch to something else. Also, chronic hyperemia is bad for the eye; it can cause leakage of fluid and chronic edema that can also lead to other deleterious effects such as scarring, making future glaucoma surgeries more difficult.
"Relative to other medications, beta blockers tend to cause less hyperemia," he continues. "I see 60 patients a day, and I can tell the difference when patients use beta blockers; their eyes aren't as red. This difference ultimately translates into patients being more compliant about taking their medications."
Beta Blockers: Less is More?
Dr. Fechtner points out that twice-a-day use of beta blockers, while commonplace, isn't the only option. "Many ophthalmologists recognize that 0.5% timolol is approved for once-daily usage," he points out. "Prostaglandins came out with the convenience of once-daily dosing in a marketplace in which we were almost uniformly using beta blockers twice a day. That was our habit. But if you go back to the FDA-approved label for Timoptic and read it carefully, it says, 'If the intraocular pressure is maintained at satisfactory levels [with twice-daily dosing], the dosage schedule may be changed to one drop once a day in the affected eye(s).' That dosing also has a very favorable side-effect profile.
"In fact, this may be the appropriate way to use it: once daily in the morning," he continues. "There's reason to believe that 0.5% twice a day is way too much beta blocker. When the original dose response research on beta blockers was being done, people didn't know that it takes several weeks to get the full beta-blocker effect. Today, however, we have data suggesting that the nighttime effect of timolol is minimal. If we were going to do it all over again, we'd probably try lower doses, less frequent dosing and having patients stay on it longer before determining the lowest dose that's effective."
He notes that the price differential between prostaglandins and once-a-day beta blockers can also make a difference to patients. "Our clinic has many patients with no insurance," he says. "They have to pay for their own medicines, and they have very limited resources. Once-daily beta blockers can be very cost-effective."
"In medicine, we're taught to 'start low and go slow' when we're prescribing a new medication," notes Dr. Realini. "In the case of beta blockers, there are lots of ways to minimize exposure while still reaping the benefits of the drug. For example, I think a very large subset of the glaucoma population can be just as well controlled on once-daily beta blockers as on twice-daily, whether the drug is used as monotherapy or adjunctive therapy. In addition, there are various preparations that are thicker than solutions, designed to stick to the eye longer and get more drug absorbed before they're washed away by tears and blinking. And many patients would be just as well controlled on timolol 0.25% as on timolol 0.5%, yet that formulation is very infrequently used."
One current product that is approved for once-daily use is Istalol (Ista Pharmaceuticals). "Ista did their homework," says Dr. Fechtner. "They did their clinical trials right and showed that you can start patients on beta blockers once a day. The fact that this data exists is a good reason to view Istalol for initial once-a-day use." However, Dr. Fechtner notes that Istalol isn't the first beta blocker to be approved for once-daily use. "Timoptic XE was approved for once-daily use. Betagan is recommended for use once or twice daily. And timolol maleate solution, once a patient is stable, is also indicated for once-daily use."
Dr. Sadri says he particularly likes Istalol because of the once-a-day approval. "Another major advantage is that it causes less blur in my patients," he says. "That's a big difference between the regular or generic formulations and Istalol. It tends to be a little more expensive, but given what it provides, it's a very good medication to use in lieu of topical prostaglandin analogues. That's especially true with a young person who doesn't want the side effects of a prostaglandin."
Getting Combinations Approved
As every ophthalmologist knows, combination drug eye drops have several significant advantages over using multiple separate drops when patients need a second medication to lower intraocular pressure. Today, beta blockers seem to be an inevitable part of this concept. "Every fixed-combination drug that's in development includes a beta blocker," notes Dr. Fechtner. "Elsewhere in the world, timolol has been combined with bimatoprost, travoprost, latanoprost, pilocarpine, dorzolamide, and recently brimonidine. Of the drugs in my toolbox, the only one I haven't seen combined with timolol is brinzolamide."
Despite this, none of the fixed combination prostaglandin/beta blockers have been approved in the United States. "One reason for this," says Dr. Fechtner, "is that in the clinical trials the prostaglandin monotherapy was very effective, and the combination drug was not tremendously more effective than the prostaglandin alone at the study endpoints." However, he notes that this may not reflect some practical realities. "In some individuals, adding a beta blocker to a prostaglandin can be very effective," he says. He also notes that real-world use may differ from use in clinical trials. "For example, our experience with the timolol/dorzolamide combination (Cosopt)—which is the only approved fixed combination in the United States—suggests that in real life it can work better than it did in controlled clinical trials.
"Also, key factors may be very different when you put the two drops in the same bottle, particularly when you're giving the drops at night, when beta blockers work least well," he continues, noting that this was done in many of the combination trials. "We typically dose prostaglandins at night, but if we use beta blockers as monotherapy, we dose them in the morning. If they're both in the same bottle, I'm not sure when you should dose them to get the best efficacy profile."
"There's fairly compelling evidence that prostaglandins can be dosed with essentially equal efficacy in the morning or at night,"5,6 comments Dr. Realini. "There are small differences, but overall the diurnal blood pressure profile seems to be fairly comparable either way. So I think that morning dosing of a beta blocker/prostaglandin combination product would be perfectly reasonable."
Dr. Realini notes that the Food and Drug Administration's reluctance to approve a combination of beta blocker and prostaglandin may be having more negative effects than positive. "Right now, the majority of patients who need an adjunct to a prostaglandin are prescribed a beta blocker," he points out. "So the FDA's argument that the combination doesn't appear efficacious enough to justify the risk of topical beta blockers becomes somewhat spurious. They're not really protecting patients from that combination; that combination is already available in two separate bottles and in wide use. These components are not experimental; they're already FDA-approved.
"On the other hand," he continues, "if the FDA approved these combinations, it would facilitate compliance, minimize exposure to vehicle components such as preservatives that can be toxic to the eye in chronic therapy, and reduce the number of co-pays for people who have a prescription drug benefit. So the lack of approval isn't protecting patients from the two drugs; it's just depriving patients of the benefits of combination therapy."
Despite prostaglandins currently being favored as first-line therapy in the United States, beta blockers clearly will remain part of the clinicians' armamentarium for the foreseeable future. "We're not giving up on them," notes Dr. Fechtner.
"We use beta blockers because they're good drugs," adds Dr. Realini. "You just have to carefully select the patients you use them in."1. Netland PA, Landry T, et al; Travoprost Study Group. Travoprost compared with latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension. Am J Ophthalmol 2001;132:4:472-84.
2. Camras CB. Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma: A six-month masked, multicenter trial in the United States. The United States Latanoprost Study Group. Ophthalmology 1996;103:1:138-47.
3. Sherwood M, Brandt J; Bimatoprost Study Groups 1 and 2. Six-month comparison of bimatoprost once-daily and twice-daily with timolol twice-daily in patients with elevated intraocular pressure. Surv Ophthalmol 2001;45 Suppl 4:S361-8.
4. Watson P, Stjernschantz J. A six-month, randomized, double-masked study comparing latanoprost with timolol in open-angle glaucoma and ocular hypertension. The Latanoprost Study Group. Ophthalmology 1996;103:1:126-37.
5. Denis P, Andrew R, Wells D, Friren B. A comparison of morning and evening instillation of a combination travoprost 0.004%/timolol 0.5% ophthalmic solution. Eur J Ophthalmol 2006;16:3:407-15.
6. Konstas AG, Mikropoulos D, Kaltsos K, Jenkins JN, Stewart WC. 24-hour intraocular pressure control obtained with evening- versus morning-dosed travoprost in primary open-angle glaucoma. Ophthalmology. 2006;113:3:446-50.
7. Herndon LW, Asrani SG, Williams GH, Challa P, Lee PP. Paradoxical intraocular pressure elevation after combined therapy with latanoprost and bimatoprost. Arch Ophthalmol 2002;120:6:847-9.
