²-Blocker Induced Complications and the Patient With

REVIEW ARTICLE ␤-Blocker–Induced Complications and the Patient With Glaucoma Newer Treatments to Help Reduce Systemic Adverse Events

William C. Stewart, MD; Patricia M. Garrison

rimary open-angle glaucoma is a condition associated with an elevated intraocular pressure (IOP) that is defined as optic nerve degeneration with a slowly progressive deterioration of the visual field that may lead to blindness.1 More than 1 million Americans are being treated for glaucoma, and 80 000 are legally blind as a result of the disease.2 PGlaucoma has its highest prevalence among the elderly population, with an incidence of approximately 1% in those older than 60 years, 3% in those between the ages of 70 and 80 years, and more than 9% in those older than 80 years.3 Treatment is directed at lowering high ocular pressures. The initial treatment, in most cases topical therapy with a ␤-adrenergic blocking agent, reduces the IOP to help preserve sight. But such topical agents may also have adverse systemic effects on cardiac, pulmonary, central nervous system (CNS), and endocrine functions.

Although treatment of glaucoma origi- other systemic medication, or advanced nates with the ophthalmologist, it may be age. As a result, patients may be pharma- the primary care physician who first ob- cologically treated for a disorder without serves the systemic effects of glaucoma the underlying factor that caused or ag- medication. This is, at least in part, be- gravated the condition being removed. cause the population of patients with glau- Fortunately, the ophthalmic commu- coma is older and is likely to seek medi- nity has long recognized the safety con- cal attention for a variety of other disorders cerns involved in the use of ␤-blockers and that are treated by the primary care phy- new treatment options, with favorable ad- sician or internist. This comanagement by verse event profiles recently having be- the primary care physician and ophthal- come available. However, there remains a mologist, while necessary to effectively great need for increased awareness of the treat elderly patients with diseases of di- potential adverse effects of topical ␤- verse origin, may cause several prob- blocker therapy. The purpose of this re- lems. First, elderly patients may be receiv- view is to discuss the clinical adverse ing multiple medications, a circumstance events associated with topical ␤-blockers that is confusing and difficult to track, even and to provide information regarding for the most attentive physician. Second, newer glaucoma products and their sys- patients may not fully inform their pri- temic safety profiles. mary care physicians about their glaucoma therapy, unless they are specifi- TOPICAL ␤-ADRENERGIC cally asked about “eye medication.” When ANTAGONISTS this is the case, systemic symptoms produced by topical ␤-blockers, such as Currently, the most common agents used wheezing, shortness of breath, arrhyth- in treating glaucoma are the topical ␤- mia, or even depression, may be falsely at- adrenergic antagonists. There are a num- tributed to coexisting disease, the use of ber of commercially available drugs in this category, all of which reduce aqueous hu- From the Department of Ophthalmology, University of South Carolina Medical School, mor formation by means of ␤-adrenergic Columbia (Dr Stewart); and Wang Associates, New York, NY (Ms Garrison). blockade.4 These drugs differ in struc-

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Downloaded From: https://jamanetwork.com/ on 09/30/2021 ture and in their ␤1 or ␤2 selectiv- thus increasing the impetus for fur- some patients from the antiarrhyth- ity, which may affect both efficacy ther compensatory mechanisms. The mic activity of ␤-blockers, which are and adverse effects. In general, ␤1 se- use of timolol maleate has been re- all classified as class II agents ex- lectivity is associated with cardiac ported to contribute to congestive cept for sotalol hydrochloride (class 20,21 adverse effects and ␤2 selectivity with heart failure, although such cases are III). If there is a benefit, it may pulmonary and vascular adverse ef- rare, as has the use of betaxolol hy- stem from the ability of ␤-blockers fects and hypoglycemia, especially drochloride, the ␤1-selective blocker to blunt the effect of excessive sym- in the patient with diabetes. that has less ␤1-binding activity at the pathetic drive, to prolong the action Topical medication may enter cardiac receptors.11-14 To our knowl- potential of the cardiac membrane, the systemic circulation via the na- edge, the use of topical ␤-blockers has and to reduce mean sympathetic tone solacrimal ducts, where it can be ab- not been associated with any reported with long-term dosing.21,22 sorbed through the nasal, oropha- deaths due to cardiac failure.9,15 Topical ␤-blockers may also in- ryngeal, and gastrointestinal Recent data have strengthened fluence serum lipid levels. Several mucosa.5 Access to the systemic the hypothesis that oral ␤-blocker studies have previously evaluated the compartment is also possible therapy can have a favorable impact effect of topical ␤-blockers on lipid through the conjunctival vascular on the course of disease in patients levels, prompted by reports that oral system. Although blood levels of with congestive heart failure. A study nonselective ␤-blockers have been topical medication are not as high by Packer et al16 found that patients found to affect triglyceride, low- as those detectable after oral admin- with mild, moderate, or severe con- density lipoprotein (LDL), and high- istration, small amounts of systemi- gestive heart failure who were treated density lipoprotein (HDL) levels and cally absorbed ␤-blockers can pro- with carvedilol had a reduced risk of total cholesterol–HDL ratios.23-26 duce significant adverse events in death, as well as fewer hospitaliza- Coleman et al27 treated 28 healthy predisposed patients.6-8 Soon after tions for cardiovascular conditions. volunteers (age range, 21-60 years; the introduction of topical ␤- However, carvedilol is a unique, mean age, 35.2 years) with 0.5% blockers in the late 1970s, their po- nonselective ␤-receptor antagonist timolol maleate for an average of 76 tential for systemic activity was ap- with an atypical pharmacologic days. Baseline HDL levels decreased parent. Topical timolol maleate profile; in addition to its antagonis- by 1.45±0.29 (mean [±SD]) mmol/L therapy was suspected of contribut- tic properties, it also blocks ␣1- (56.1±11.2 mg/dL), with the largest ing to 32 deaths within 7 years of its receptors and exerts antioxidant ef- declines occurring in those with the initial commercial production. Sev- fects, which may contribute to its highest baseline values. The au- eral more common, although less se- actions in heart failure. In their dis- thors found no change in total cho- vere, adverse effects were also re- cussion, Packer and colleagues16 lesterol, LDL, or triglyceride levels. ported, including reduced exercise noted that there is not yet suffi- A second study, conducted by West tolerance, CNS symptoms, psycho- cient evidence to conclude that other and Longstaff,28 involved 17 pa- logical changes, and altered serum ␤-blockers would demonstrate simi- tients with elevated IOP who were be- lipid levels.9 lar clinical benefits on morbidity or ing treated with timolol. No changes mortality or alter the natural his- in total cholesterol or lipid fractions Cardiovascular Effects tory of the disorder. were found after 15 weeks of moni- The physiologic activity of ␤- toring. Freedman et al29 compared the It has long been recognized that po- blockers also creates a potential for effects of topical 1.0% carteolol hy- tentially serious cardiovascular possibly causing conduction distur- drochloride and 0.5% timolol male- events may occur from topical ␤- bances, such as arrhythmias. These ate in 58 healthy adult men. A cross- blockade. ␤-Blockers have been agents reduce sinus node automatic- over design resulted in patients being found to contribute to congestive ity; prolong sinoatrial, intra-atrial, and treated with both drugs. Both drugs heart failure and arrhythmia, to atrioventricular conduction times; produced a decrease in HDL levels, adversely alter serum lipids, to and increase atrioventricular nodal although it was significantly smaller reduce exercise tolerance, and to refractoriness.17 Thus, topical ␤- for those taking carteolol (−3.3%, decrease nocturnal blood pressure. blockade may cause bradycardia and −0.04 mmol/L [−1.5 mg/dL]) than for Because ␤-blockers exert a nega- heart block in patients with under- for those taking timolol maleate tive inotropic action on the myocar- lying conduction system disease. It (−8.0%, −0.10 mmol/L [−3.9 mg/ dium, they may compromise pa- may also limit cardiac ability to com- dL]). There were no significant tients with congestive heart failure, pensate for lost pacemaker func- changes in other lipid fractions or to- particularly those with significant sys- tion. Case reports in the literature re- tal cholesterol levels. temic hypotension, severe pulmo- late the use of topical ␤-blockers to The results of a recent multi- nary or systemic edema, or a recent syncope, bradycardia, systemic hy- center trial with women aged 60 years acute decompensation episode.10 Ini- potension, palpitation, arrhythmia, or older diagnosed with ocular hy- tially, these mechanisms allow car- and heart block.11,18,19 When admin- pertension or glaucoma found that diac function to continue in the face istered with quinidine, timolol ma- treatment with topical timolol ad- of poor peripheral perfusion and di- leate has produced bradycardia and versely affected HDL levels (PϽ.001) minished oxygen delivery to the myo- syncope.20 and total cholesterol–HDL ratios cardium.10,11 Cardiac function dete- As in patients with congestive (P=.001) from baseline, although riorates over the long-term, however, heart failure, there may be benefit in there was no significant change from

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Downloaded From: https://jamanetwork.com/ on 09/30/2021 baseline in total cholesterol, LDL, and others do not (atenolol, pindolol, and pacity or forced expiratory volume in 37,38 total glucose levels. Over 12 weeks labetalol). In terms of patients with 1 second (FEV1) in 9 of 10 patients of monitoring, patients receiving glaucoma, the results of several stud- with asthma treated with betaxolol, timolol had a reduction in HDL iessuggestthatnocturnalhypotension but 1 patient had a reduction of FEV1 (6.3%, −0.09 mmol/L [−3.4 mg/ may play a role in the progression of by more than 15%. In a 2-year fol- dL]). Patients treated with carteo- chronic open-angle glaucoma.39-41 low-up of 101 patients with reactive lol, however, experienced no ad- However, to our knowledge, no clear airway disease conducted by Wein- verse effects on plasma lipid levels.30 association exists as yet, and further reb et al,53 9 patients were with- These findings may be clinically im- study is required to characterize this drawn because of worsening pulmo- portant in patients with preexisting effect. nary status, and, overall, the mean lipid disorders and in patients requir- FEV1–forced vital capacity ratio de- ing long-term topical ␤-blocker Pulmonary Effects creased from 66% to 54%. A third be- therapy.30 taxolol study in patients with asthma Topical ␤-blockers have at least One of the most serious potential ad- found that one third had increased 2 other potential cardiovascular side verse effects of ␤-blockade is an ex- asthmatic symptoms, such as wheez- effects: diminished exercise toler- acerbation of reactive airway dis- ing, coughing, and dyspnea, and half 54 ance and nocturnal hypotension. ␤- ease, possibly leading to respiratory had a 15% decrease in FEV1. In ad- Adrenergic blockers may reduce arrest. ␤-Blockers act on ␤2 recep- dition, agents administered systemi- maximum tachycardia and cardiac tors that are in the lung.42 How- cally with intrinsic sympathomi- output as well as limit peripheral va- ever, ␤-blocker therapy does not metic activity may not confer greater sodilation.31,32 These effects are di- produce bronchoconstriction in nor- protection against respiratory ef- rectly counter to the physiologic mal individuals.43 Thus, the activ- fects. Topical carteolol, which has in- changes produced by exercise and ity at the receptor site may not be a trinsic sympathomimetic activity, has can lead to reduced oxygen uptake complete explanation for how these demonstrated a detrimental effect on and decreased exercise tolerance. drugs affect the pulmonary system. lung function that was greater than Limitations of peripheral vasodila- The precise mechanism is not that of betaxolol, and oral pindolol has tion may affect sweating and core known. blocked recovery from an asthma at- temperature regulation, increasing Studies with topical agents have tack after terbutaline treatment.46,55,56 the risk for dehydration and hyper- shown that timolol maleate, carteo- thermia. In fact, topical timolol lol, and, to a much lesser extent, be- CNS and Endocrine Effects therapy has demonstrated some of taxolol can produce pulmonary ef- these effects in 3 studies involving fects. Topical therapy, most often Among the most common adverse ef- healthy individuals. Doyle et al33 with a nonselective ␤-blocker such fects seen with topical ␤-blocker use found a reduction in maximum heart as timolol maleate, has been associ- are those associated with the CNS, in- rate and time to exhaustion after ated with worsening of reactive air- cluding depression, fatigue, weak- topical timolol therapy. The pa- way disease and bronchitis, as indi- ness, confusion, memory loss, head- tients of Leier et al34 demonstrated cated by symptoms such as aches, and anxiety.45 Approximately decreased maximum heart rate in wheezing, dyspnea, cough, and 10% of patients report CNS effects, both the short-term and the long- bronchial spasm.44,45 In one study, and 5% have to discontinue taking term after timolol administration. At- the use of timolol maleate in- the medication.11 These drugs can kins35 also found that patients’ heart creased the need for bronchodila- cross the blood-brain barrier and in- rates were significantly reduced from tor therapy in 47% of patients with hibit central ␤-receptors. They also baseline with timolol therapy. The asthma.46,47 Respiratory arrest oc- block serotonin receptors and exert ␤1-selective activity of betaxolol has curred in 1 patient with asthma other nonspecific and peripherally not been associated with these ef- within 20 minutes of receiving a first mediated CNS effects.57 Such effects fects.36 drop of timolol maleate, and 12 res- seem to be influenced by the selec- Not only is exercise generally piratory deaths were recorded in the tivity of the agent. For example, beneficial for health, but it can also first 8 years of the commercial pro- Lynch et al58 found that betaxolol reduce IOP, at least temporarily. duction of timolol.48,49 produced fewer CNS effects than Even regular walking has been Paradoxically, in another study, timolol maleate. Likewise, lipo- shown to produce such reductions 12 patients treated with betaxolol ex- philic characteristics of ␤-blockers in patients with glaucoma.36 Thus, hibited increased respiratory symp- could influence penetration across it may be that topical ␤-blockers with toms without any actual worsening the blood-brain barrier and CNS ef- less influence on exercise tolerance of airway function.50 But the safety fects. However, to our knowledge, will be preferred in the future. of betaxolol therapy is not defini- the influence of lipophilic character- The significance of nocturnal hy- tively established in this regard. It istics of ␤-blockers has not been potension, which has been noted in may exacerbate asthma sufficiently studied clinically with ophthalmic some patients taking oral ␤-blockers to lead to hospitalization.51,52 ␤-blocker preparations. for systemic hypertension, is not Three studies suggest the pos- A final controversial side ef- clearly understood at this point. Cer- sibility that betaxolol can adversely fect of ␤-blockers involves alter- tain agents cause reduced nocturnal affect the pulmonary system. ation of the endocrine system in pa- pressure (metipranolol, sotalol) and Hugues46 found no change in vital ca- tients with diabetes. There is little

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Downloaded From: https://jamanetwork.com/ on 09/30/2021 information on such topical effects from a baseline value of 73.8±11.6 ter melanocytes, but an increase in in the ophthalmic literature, but oral (mean[±SD]) beats per minute to melanin has been observed. In fol- administration may reduce the 71.8±10.9 beats per minute, with no low-up, patients who developed a awareness of a hypoglycemic crisis effect from treatment with latano- darkening of the iris have not re- and produce a deterioration in glu- prost. Although neither timolol nor vealed any adverse effects on the eye cose tolerance.59,60 latanoprost had a consistent effect or vision. on blood pressure, there was a gen- NEW AGENTS WITH eral tendency toward a slight de- Brimonidine POTENTIALLY REDUCED crease with the use of both agents. SYSTEMIC EFFECTS Approximately 6.9% of patients re- Another new agent, brimonidine tar- ceiving timolol maleate reported res- trate (Alphagan), is a relatively se- The range of potentially serious ad- piratory or cardiovascular effects, in lective ␣2-agonist that lowers IOP by verse effects associated with topical contrast to 2.0% in the latanoprost reducing aqueous humor produc- ␤-blockers can pose considerable group (patients contraindicated to tion and, probably, by increasing challenges to the physician in clini- treatment with timolol were ex- uveoscleral outflow as a secondary ef- cal practice. Recognition and man- cluded from the trial). Thus, there fect.73 It is a highly lipophilic drug agement of systemic sequelae, pa- were more patients with shortness that can pass the blood-brain bar- tient intolerance to adverse events, of breath, bronchitis, and arterial hy- rier and therefore has some poten- and the impact of these factors on potension in the timolol group. tial for causing CNS adverse events. compliance with therapy and qual- Alm et al70 found a reduction in To date, fatigue and dry mouth ap- ity of life have previously been dis- heart rate with timolol maleate and pear to be the most significant sys- cussed and reviewed in the litera- negligible systemic adverse effects temic side effects noted, occurring ture.61-63 with latanoprost.Camras et al71 re- mostly at doses higher in concentra- Several new glaucoma agents ported relatively few systemic ad- tion than those available commer- with demonstrated efficacy in reduc- verse effects with either latano- cially. In a study designed to evalu- ing IOP have been shown to have sys- prost or timolol maleate; however, ate the cardiovascular and respiratory temic adverse effect profiles that ap- heart rate was significantly re- effects of brimonidine, Nordlund et pear to be more favorable than those duced at 6 months with timolol ma- al74 showed that this drug was asso- found with traditional therapies, in- leate, and there was no change in ciated with a mild, statistically sig- cluding timolol maleate, These new heart rate with latanoprost. In ad- nificant, decrease in systolic blood drugs offer alternatives to the oph- dition, 13.8% of patients in the timo- pressure at rest and also during ex- thalmologist that also may portend lol maleate group reported head- ercise recovery. Unlike timolol ma- advantages in patient management ache or lassitude, compared with leate, however, it has not been shown for both the ophthalmologist and the 6.7% in the latanoprost group. to limit exercise tolerance. primary care physician. Finally, in a study comparing the efficacy of 0.005% latanoprost Dorzolamide Latanoprost administered once daily with that of 0.5% timolol maleate administered A third new agent, dorzolamide (in- Latanoprost is a prostaglandin ana- twice daily, Mishima et al72 found troduced under the trade name Tru- log that lowers IOP by increasing that latanoprost was more effica- sopt), is the first commercially avail- uveoscleral outflow.64-66 (It has been cious than timolol maleate in reduc- able topical carbonic anhydrase recently approved by the Food and ing IOP in patients with open- inhibitor (eg, Diamox). It has been Drug Administration under the trade angle glaucoma and ocular found to lower IOP 18% to 20% name Xalatan.) Prostaglandins are hypertension; the main systemic ef- throughout the day (mean pressure, mediators of inflammation, and were fect was a slight but statistically sig- 4.5-6.1 mm Hg) from baseline, by investigated for the treatment of glau- nificant reduction in mean heart rate suppressing aqueous humor produc- coma because reduced IOP is often in the patients in the timolol group tion.75,76 The oral carbonic anhy- associated with ocular inflamma- at 4, 8, and 12 weeks (PϽ.01); of the drase inhibitors have traditionally tion.67 Latanoprost represents a new 83 patients in the timolol group, 2 been reserved as last-resort treat- class of glaucoma medications that exhibited bradycardia and 1 had car- ment, because adverse systemic ef- have the potential to become first- diac arrhythmia. fects occur in as many as 50% of pa- line agents.68 Recently, 4 large ran- Increased pigmentation of the tients. Such effects include general domized trials proved once-daily dos- iris has been noted in 5% to 15% of malaise, fatigue, depression, loss of ing of latanoprost to be equal or patients using latanoprost, occur- libido, paresthesias, tinnitus, nau- superior to treatment with timolol ring in patients with multicolored sea, anorexia, gastrointestinal distur- maleate.69-72 The absence of serious irises, ie, blue-brown, gray-brown, bances, blood dyscrasias, and meta- systemic adverse effects with latano- green-brown, and yellow-brown.69-72 bolic and respiratory acidosis.77,78 No prost therapy was noteworthy. Although the safety of this eye- such effects have been reported thus At the end of 6 months of treat- color change is under investiga- far (to our knowledge) with dorzol- ment, Watson et al69 found that treat- tion, it appears to lack clinical sig- amide. There have been no reports ment with timolol produced a slight nificance; histologically, it has been of bone marrow depression or aplas- but significant reduction in heart rate shown that the change does not al- tic anemia, both of which are rare oc-

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Downloaded From: https://jamanetwork.com/ on 09/30/2021 currences with oral carbonic anhy- found to have conjunctival ery- 2. Gordon ME, Kass MA. Validity of standard com- drase inhibitors, although red blood thema and potential periorbital in- pliance measures in glaucoma compared with an electronic eyedrop monitor. In: Cramer JA, Spilker cell carbonic anhydrase activity was fection. The intolerance subsides B, eds. Patient Compliance in Medical Practice and shown to be reduced by 21% in one quickly on discontinuation of the Clinical Trials. New York, NY: Lippincott-Raven; study.77 In a large, multicenter trial therapy.83 1991:163-173. comparing dorzolamide with betaxo- 3. Bankes JLK, Perkins ES, Tsolakis S, Wright JE. Bedford Glaucoma Survey. BMJ. 1968;30:791- lol and timolol maleate, a frequently CONCLUSIONS 796. reported side effect in the dorzol- 4. Coakes RL, Brubaker RS. The mechanism of timo- amide group was bad taste, which oc- New topical agents for the treat- lol in lowering intraocular pressure. Arch Oph- curred in 27% of patients.79 Dorzol- ment of glaucoma offer significant thalmol. 1978;96:2045-2048. promise, both in terms of efficacy 5. Shields MB. Textbook of Glaucoma. 2nd ed. Bal- amide produced fewer headaches timore, Md: Williams & Wilkins; 1987:361-373. than betaxolol and more gastrointes- and in the absence of systemic 6. Kaila T, Karhuvaara S, Huupponen R, Iisalo E. The tinal disturbances than either of the events. Nevertheless, topical ␤- analysis of plasma kinetics and ␤-receptor– other 2 drugs. Patients receiving be- blockers are currently the most com- binding and –blocking activity of timolol follow- taxolol had significantly more car- monly used therapy for glaucoma. ing its small intravenous dose. Int J Clin Pharma- col Ther Toxicol. 1993;31:351-357. diovascular adverse events, includ- Therefore, increased communica- 7. Kaila T. A sensitive radioligand binding assay for ing angina, hypertension, and tion within the medical commu- timolol in plasma. J Pharm Sci. 1991;80:296-299. bradycardia, than did those in the nity is warranted. Careful attention 8. Irvine NA, Lipworth BJ, McDevitt DG. A dose- dorzolamide group. Fatigue and on the part of the primary care phy- ranging study to evaluate the ␤-adrenoceptor se- sician to the systemic effects of topi- lectivity of single doses of betaxolol. Br J Clin Phar- rashes have been reported infre- macol. 1990;30:119-126. quently. Because dorzolamide is a sul- cal ␤-blockade is paramount for sev- 9. Nelson WL, Fraunfelder FT, Sills JM, Arrowsmith fonamide, it is prudent to remain vigi- eral reasons. These medications must JB, Kuritsky JN. Adverse respiratory and cardio- lant in watching for the adverse be remembered and ordered cor- vascular events attributed to timolol ophthalmic rectly on inpatient orders. Many hos- solution,1978-1985. Am J Ophthalmol. 1986;102: reactions that are sometimes seen 606-611. with systemic administration, par- pitalized patients are treated for glau- 10. Eichnorn EJ. Do ␤-blockers have a role in pa- ticularly hypersensitivity.80 coma, yet a small retrospective tients with congestive heart failure? Cardiol Clin. survey found that as many as 37% 1994;12:133-142. Apraclonidine do not receive the correct medicine 11. Zimmerman TJ, Baumann JD, Hetherington J. Side 84 effects of timolol. Surv Ophthalmol. 1983;28 or amount. Recognizing the im- (suppl):243-249. Research has also shown that a new portance of these medications can 12. Polansky JR. Comparison of plasma blocking ac- drug, apraclonidine, is an effective help to ensure that their use is not tivity of betaxolol and timolol. Int Ophthalmol Clin. adjunct to treatment with timolol indiscriminately discontinued with- 1989;29(suppl):17-18. out communication with the pre- 13. Vuori M-L, Ali-Melkkila¨ T, Kaila T, Iisalo E, Saari maleate in reducing IOP, with few KM. ␤1- and ␤2-antagonist activity of topically ap- nonocular adverse effects. Similar to scribing ophthalmologist. And, fi- plied betaxolol and timolol in the systemic circu- brimonidine, apraclonidine is an ␣2- nally, these topical medications may lation. Acta Ophthalmol. 1993;71:682-685. adrenergic agonist. In a study by partly or wholly explain an alter- 14. Ball S. Congestive heart failure from betaxolol. Arch Stewart et al,81 0.5% apraclonidine ation in a patient’s systemic condi- Ophthalmol. 1987;105:320. 15. Van Buskirk EM, Fraunfelder FT. Ocular ␤- administered adjunctively with 0.5% tion. Conversely, ophthalmolo- blockers and systemic effects. Am J Ophthal- timolol maleate produced IOP re- gists can benefit from consultation mol. 1984;98:623-624. ductions from baseline that were as with the primary care physician to 16. Packer M, Bristow M, Cohn JN, et al. The effect significant as those produced with refine the choice of agents for cer- of carvedilol on morbidity and mortality in pa- tain patients. Ultimately, more stud- tients with chronic heart failure. N Engl J Med. 1.0% apraclonidine treatment and 1996;334:1349-1355. 0.5% timolol maleate. However, sen- ies and new agents may provide 17. Kastor JA, ed. Arrhythmias. Philadelphia, Pa: WB sitivity to apraclonidine treatment at clear-cut guidelines for patient pre- Saunders Co; 1994;1. 1.0% was greater than at 0.5% scription; in the meantime, how- 18. Fraunfelder FT, Meyer SM. Systemic adverse re- (13.8% vs 20.3%), and treatment was ever, it is critical that ophthalmolo- actions to glaucoma medications. Int Ophthal- mol Clin. 1989;29:143-146. discontinued owing to ocular or no- gists and primary care physicians 19. Charap AD, Shin DH, Petursson G, et al. 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