Despite beta-blockers' efficacy and local tolerability, practitioners have become increasingly concerned that these agents' chronic use could result in potentially serious systemic side effects. The complete and indiscriminate avoidance of beta-blocker therapy, however, ignores a substantial proportion of patients who may benefit from these agents. It is therefore incumbent upon the clinician to know beta-blockers' potential systemic interactions as evident from scientifically available data rather than unproven dogma or non–peer-reviewed sources, especially those peddled by competing pharmaceutical companies.
CARDIOVASCULAR DISEASE
Beta-blockers have long played an integral role in the management of cardiovascular disease, but, traditionally, medical education has held that these agents should be avoided in patients with congestive heart failure (CHF) and symptomatic bradycardia as well as more advanced degrees of heart block. Recent data from randomized placebo-controlled trials, however, prove that beta-blockers actually benefit patients with compensated heart failure.2-8 The evidence demonstrating a reduction in mortality and improved functional status is incontrovertible. In fact, even patients with the most advanced degrees of heart failure, including some awaiting heart transplantation, may benefit from beta-blocker therapy.2 The American College of Cardiology currently recommends that all patients with depressed left ventricular function, when clinically stable, begin beta-blocker therapy, regardless of whether or not they had a myocardial infarction.2-8 Studies conducted more than 20 years ago showed that all patients who have suffered myocardial infarction should undergo beta-blocker therapy for at least 3 years.9-11
How does this information affect ophthalmologists? First, we now know that certain heart conditions not only do not preclude beta-blocker therapy but actually necessitate it. Second, because patients on systemic beta-blockers will have plasma levels of the drug far greater than those achieved by topical administration, concomitant topical administration will not appreciably affect their total plasma levels. Initiating beta-blockers for glaucoma, therefore, will neither interfere in the management of patients' underlying cardiac condition nor appreciably increase their risk of dose-related toxicity. No data are available regarding whether the beta-blockers approved for the treatment of CHF affect aqueous production, thus negating the IOP-lowering effect of ophthalmically administered beta-blockers.
PULMONARY DISEASE
Asthma affects roughly 5% of the US population. Recurrent episodes of airway obstruction with periods of essentially normal lung function are characteristic of this syndrome. Affected individuals demonstrate hyperresponsiveness to stimuli that have little or no effect in normal individuals.11 During an attack, airway resistance increases at all levels. Spirometric changes occur, as demonstrated by a reduction in the peak expiratory flow rate, 1-second forced expiratory volume (FEV1), and maximal mid-expiratory flow rate.12 Blockade of beta-adrenergic receptors—specifically the beta-2 subtype—may precipitate or potentiate an attack. In fact, several case reports have described beta-adrenergic blocker-induced bronchospasm leading to death.13 Nonfatal attacks have also been reported. Interestingly, in the nonfatal attacks, the degree of pulmonary obstruction was unpredictable.13 It is thus apparent that small doses can trigger an attack or affect airway resistance.
A study comparing timolol with placebo eye drops in 15 asthmatics and 10 nonasthmatics demonstrated a drop in FEV1 in 13 of 15 asthmatics.14 In four of these individuals, the reduction exceeded 20%. Although a 20% reduction in FEV1 is clinically significant, such a change follows acute administration of the drug, and the long-term effects of beta-adrenergic blockers on FEV1 may not necessarily be constant. Salpeter et al15 performed a meta-analysis of 29 clinical trials studying acute (single dose) and chronic (up to 4 weeks) systemic administration of beta-1 selective beta-blockers in patients with mild-to-moderate asthma and in patients with chronic obstructive pulmonary disease (COPD). The investigators found that acute administration caused a drop in FEV1 by 7.46% versus no effect on FEV1 from chronic administration of up to 4 weeks in asthmatics. This finding may be due to an upregulation of beta-2 receptors after chronic administration. Individuals with COPD did not experience a change in FEV1 when the agent was administered acutely or chronically.
Although such data suggest that internists may safely prescribe a systemic beta-1 selective beta-blocker for patients with controlled, mild-to-moderate asthma or COPD and a history of myocardial infarction or CHF because of the agent's life-saving potential, they do not imply that topical nonselective beta-blocker therapy is not potentially harmful to patients with asthma or COPD. Glaucoma patients with concomitant pulmonary disease, therefore, generally should not receive these agents until further data are available from randomized, placebo-controlled, clinical trials that look specifically at topical administration in these conditions.
DEPRESSION
The association between beta-blockers and depression is largely based on published case reports and short case series.16 By contrast, the cumulative evidence from prospective placebo-controlled clinical trials, case-controlled studies, and large population-based surveys of patients receiving systemic beta-blocker therapy overwhelmingly failed to identify such an association.16 Many of these studies concluded that beta-blockers, as a group, pose no greater risk of causing depression than other antihypertensive agents not known to be associated with depression. More specifically, 16 of 19 studies failed to support this association; three of them were randomized prospective clinical trials involving moderate-to-high doses of oral agents.
OTHER CLINICAL SITUATIONS
Overall, either the literature fails to support many of the traditionally cited negative effects of beta-blockers, including worsening symptoms of peripheral vascular disease (ie, intermittent claudication or prolonged hypoglycemia in type II diabetics), or there exists only supportive evidence when beta-blockers are administered systemically.17,18 For example, systemic doses of beta-blockers have been shown to reduce individuals' exercise tolerance and exercise work output. These effects are not simply the result of a reduction in heart rate or blood pressure, such as ophthalmic doses may cause during exercise, but are due to complex alterations in energy and electrolyte metabolism.19-22 Dickstein et al23,24 demonstrated that timolol solution, timolol gellan, and betaxolol reduce the heart rate and systolic arterial blood pressure at baseline and during exercise (the effect on the heart rate was statistically more significant than the effect on systolic arterial blood pressure), but they found no difference in work output. These data provide additional support for the concepts that heart rate and blood pressure alone do not account for differences in exercise capacity and that ophthalmically administered doses may be insufficient to affect work output, despite the statistically significant changes in hemodynamic parameters.
FINAL THOUGHTS
Ophthalmic beta-blockers are an important part of the glaucoma pharmacological armamentarium. The call for more aggressive IOP control makes the need for combination drug therapy inescapable, despite the advent of potent prostaglandin agents. Rather than summarily avoid beta-blockers as a class due to often unwarranted fears about triggering unwanted systemic side-effects and the associated risks of litigation, ophthalmologists need to reappraise the role of these agents in the management of glaucoma. This reassessment should involve evidence-based data instead of traditional dogma. Numerous individuals may achieve a significant therapeutic response with this form of treatment, and the available evidence suggests that many patients previously considered to be inappropriate candidates for beta-blocker therapy can safely take these agents. Patients with asthma, symptomatic bradycardia, or newly diagnosed nonphysiologic bradycardia should not receive an ophthalmic beta-blocker, however.
Paul J. Lama, MD, is Assistant Professor of Ophthalmology at the New Jersey Medical School in Newark. Dr. Lama is on the Speakers Bureau for Merck & Co., Inc., Pfizer Inc., and Alcon Laboratories, Inc., and he is a consultant to ISTA Pharmaceuticals, Inc. He disclosed no direct financial interest in the products mentioned herein. Dr. Lama may be reached at (973) 972-9467; lamapj@umdnj.edu.
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