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Review Article |

β-Blocker–Induced Complications and the Patient With Glaucoma:  Newer Treatments to Help Reduce Systemic Adverse Events FREE

William C. Stewart, MD; Patricia M. Garrison
[+] Author Affiliations

From the Department of Ophthalmology, University of South Carolina Medical School, Columbia (Dr Stewart); and Wang Associates, New York, NY (Ms Garrison).


Arch Intern Med. 1998;158(3):221-226. doi:10.1001/archinte.158.3.221.
Text Size: A A A
Published online

Primary 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 80000 are legally blind as a result of the disease.2 Glaucoma 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 β-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 originates with the ophthalmologist, it may be the primary care physician who first observes the systemic effects of glaucoma medication. This is, at least in part, because the population of patients with glaucoma is older and is likely to seek medical attention for a variety of other disorders that are treated by the primary care physician or internist. This comanagement by the primary care physician and ophthalmologist, while necessary to effectively treat elderly patients with diseases of diverse origin, may cause several problems. First, elderly patients may be receiving multiple medications, a circumstance that is confusing and difficult to track, even for the most attentive physician. Second, patients may not fully inform their primary care physicians about their glaucoma therapy, unless they are specifically asked about "eye medication." When this is the case, systemic symptoms produced by topical β-blockers, such as wheezing, shortness of breath, arrhythmia, or even depression, may be falsely attributed to coexisting disease, the use of other systemic medication, or advanced age. As a result, patients may be pharmacologically treated for a disorder without the underlying factor that caused or aggravated the condition being removed.

Fortunately, the ophthalmic community has long recognized the safety concerns involved in the use of β-blockers and new treatment options, with favorable adverse event profiles recently having become available. However, there remains a great need for increased awareness of the potential adverse effects of topical β-blocker therapy. The purpose of this review is to discuss the clinical adverse events associated with topical β-blockers and to provide information regarding newer glaucoma products and their systemic safety profiles.

Currently, the most common agents used in treating glaucoma are the topical β-adrenergic antagonists. There are a number of commercially available drugs in this category, all of which reduce aqueous humor formation by means of β-adrenergic blockade.4 These drugs differ in structure and in their β1 or β2 selectivity, which may affect both efficacy and adverse effects. In general, β1 selectivity is associated with cardiac adverse effects and β2 selectivity with pulmonary and vascular adverse effects and hypoglycemia, especially in the patient with diabetes.

Topical medication may enter the systemic circulation via the nasolacrimal ducts, where it can be absorbed through the nasal, oropharyngeal, and gastrointestinal mucosa.5 Access to the systemic compartment is also possible through the conjunctival vascular system. Although blood levels of topical medication are not as high as those detectable after oral administration, small amounts of systemically absorbed β-blockers can produce significant adverse events in predisposed patients.68 Soon after the introduction of topical β-blockers in the late 1970s, their potential for systemic activity was apparent. Topical timolol maleate therapy was suspected of contributing to 32 deaths within 7 years of its initial commercial production. Several more common, although less severe, adverse effects were also reported, including reduced exercise tolerance, CNS symptoms, psychological changes, and altered serum lipid levels.9

Cardiovascular Effects

It has long been recognized that potentially serious cardiovascular events may occur from topical β-blockade. β-Blockers have been found to contribute to congestive heart failure and arrhythmia, to adversely alter serum lipids, to reduce exercise tolerance, and to decrease nocturnal blood pressure.

Because β-blockers exert a negative inotropic action on the myocardium, they may compromise patients with congestive heart failure, particularly those with significant systemic hypotension, severe pulmonary or systemic edema, or a recent acute decompensation episode.10 Initially, these mechanisms allow cardiac function to continue in the face of poor peripheral perfusion and diminished oxygen delivery to the myocardium.10,11 Cardiac function deteriorates over the long-term, however, thus increasing the impetus for further compensatory mechanisms. The use of timolol maleate has been reported to contribute to congestive heart failure, although such cases are rare, as has the use of betaxolol hydrochloride, the β1-selective blocker that has less β1-binding activity at the cardiac receptors.1114 To our knowledge, the use of topical β-blockers has not been associated with any reported deaths due to cardiac failure.9,15

Recent data have strengthened the hypothesis that oral β-blocker therapy can have a favorable impact on the course of disease in patients with congestive heart failure. A study by Packer et al16 found that patients with mild, moderate, or severe congestive heart failure who were treated with carvedilol had a reduced risk of death, as well as fewer hospitalizations for cardiovascular conditions.

However, carvedilol is a unique, nonselective β-receptor antagonist with an atypical pharmacologic profile; in addition to its antagonistic properties, it also blocks α1-receptors and exerts antioxidant effects, which may contribute to its actions in heart failure. In their discussion, Packer and colleagues16 noted that there is not yet sufficient evidence to conclude that other β-blockers would demonstrate similar clinical benefits on morbidity or mortality or alter the natural history of the disorder.

The physiologic activity of β-blockers also creates a potential for possibly causing conduction disturbances, such as arrhythmias. These agents reduce sinus node automaticity; prolong sinoatrial, intra-atrial, and atrioventricular conduction times; and increase atrioventricular nodal refractoriness.17 Thus, topical β-blockade may cause bradycardia and heart block in patients with underlying conduction system disease. It may also limit cardiac ability to compensate for lost pacemaker function. Case reports in the literature relate the use of topical β-blockers to syncope, bradycardia, systemic hypotension, palpitation, arrhythmia, and heart block.11,18,19 When administered with quinidine, timolol maleate has produced bradycardia and syncope.20

As in patients with congestive heart failure, there may be benefit in some patients from the antiarrhythmic activity of β-blockers, which are all classified as class II agents except for sotalol hydrochloride (class III).20,21 If there is a benefit, it may stem from the ability of β-blockers to blunt the effect of excessive sympathetic drive, to prolong the action potential of the cardiac membrane, and to reduce mean sympathetic tone with long-term dosing.21,22

Topical β-blockers may also influence serum lipid levels. Several studies have previously evaluated the effect of topical β-blockers on lipid levels, prompted by reports that oral nonselective β-blockers have been found to affect triglyceride, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels and total cholesterol–HDL ratios.2326 Coleman et al27 treated 28 healthy volunteers (age range, 21-60 years; mean age, 35.2 years) with 0.5% timolol maleate for an average of 76 days. Baseline HDL levels decreased by 1.45±0.29 (mean [±SD]) mmol/L (56.1±11.2 mg/dL), with the largest declines occurring in those with the highest baseline values. The authors found no change in total cholesterol, LDL, or triglyceride levels. A second study, conducted by West and Longstaff,28 involved 17 patients with elevated IOP who were being treated with timolol. No changes in total cholesterol or lipid fractions were found after 15 weeks of monitoring. Freedman et al29 compared the effects of topical 1.0% carteolol hydrochloride and 0.5% timolol maleate in 58 healthy adult men. A crossover design resulted in patients being treated with both drugs. Both drugs produced a decrease in HDL levels, although it was significantly smaller for those taking carteolol (−3.3%, −0.04 mmol/L [−1.5 mg/dL]) than for for those taking timolol maleate (−8.0%, −0.10 mmol/L [−3.9 mg/dL]). There were no significant changes in other lipid fractions or total cholesterol levels.

The results of a recent multicenter trial with women aged 60 years or older diagnosed with ocular hypertension or glaucoma found that treatment with topical timolol adversely affected HDL levels (P<.001) and total cholesterol–HDL ratios (P=.001) from baseline, although there was no significant change from baseline in total cholesterol, LDL, and total glucose levels. Over 12 weeks of monitoring, patients receiving timolol had a reduction in HDL (6.3%, −0.09 mmol/L [−3.4 mg/dL]). Patients treated with carteolol, however, experienced no adverse effects on plasma lipid levels.30 These findings may be clinically important in patients with preexisting lipid disorders and in patients requiring long-term topical β-blocker therapy.30

Topical β-blockers have at least 2 other potential cardiovascular side effects: diminished exercise tolerance and nocturnal hypotension. β-Adrenergic blockers may reduce maximum tachycardia and cardiac output as well as limit peripheral vasodilation.31,32 These effects are directly counter to the physiologic changes produced by exercise and can lead to reduced oxygen uptake and decreased exercise tolerance. Limitations of peripheral vasodilation may affect sweating and core temperature regulation, increasing the risk for dehydration and hyperthermia. In fact, topical timolol therapy has demonstrated some of these effects in 3 studies involving healthy individuals. Doyle et al33 found a reduction in maximum heart rate and time to exhaustion after topical timolol therapy. The patients of Leier et al34 demonstrated decreased maximum heart rate in both the short-term and the long-term after timolol administration. Atkins35 also found that patients' heart rates were significantly reduced from baseline with timolol therapy. The β1-selective activity of betaxolol has not been associated with these effects.36

Not only is exercise generally beneficial for health, but it can also reduce IOP, at least temporarily. Even regular walking has been shown to produce such reductions in patients with glaucoma.36 Thus, it may be that topical β-blockers with less influence on exercise tolerance will be preferred in the future.

The significance of nocturnal hypotension, which has been noted in some patients taking oral β-blockers for systemic hypertension, is not clearly understood at this point. Certain agents cause reduced nocturnal pressure (metipranolol, sotalol) and others do not (atenolol, pindolol, and labetalol).37,38 In terms of patients with glaucoma, the results of several studies suggest that nocturnal hypotension may play a role in the progression of chronic open-angle glaucoma.3941 However, to our knowledge, no clear association exists as yet, and further study is required to characterize this effect.

Pulmonary Effects

One of the most serious potential adverse effects of β-blockade is an exacerbation of reactive airway disease, possibly leading to respiratory arrest. β-Blockers act on β2 receptors that are in the lung.42 However, β-blocker therapy does not produce bronchoconstriction in normal individuals.43 Thus, the activity at the receptor site may not be a complete explanation for how these drugs affect the pulmonary system. The precise mechanism is not known.

Studies with topical agents have shown that timolol maleate, carteolol, and, to a much lesser extent, betaxolol can produce pulmonary effects. Topical therapy, most often with a nonselective β-blocker such as timolol maleate, has been associated with worsening of reactive airway disease and bronchitis, as indicated by symptoms such as wheezing, dyspnea, cough, and bronchial spasm.44,45 In one study, the use of timolol maleate increased the need for bronchodilator therapy in 47% of patients with asthma.46,47 Respiratory arrest occurred in 1 patient with asthma within 20 minutes of receiving a first drop of timolol maleate, and 12 respiratory deaths were recorded in the first 8 years of the commercial production of timolol.48,49

Paradoxically, in another study, 12 patients treated with betaxolol exhibited increased respiratory symptoms without any actual worsening of airway function.50 But the safety of betaxolol therapy is not definitively established in this regard. It may exacerbate asthma sufficiently to lead to hospitalization.51,52

Three studies suggest the possibility that betaxolol can adversely affect the pulmonary system. Hugues46 found no change in vital capacity or forced expiratory volume in 1 second (FEV1) in 9 of 10 patients with asthma treated with betaxolol, but 1 patient had a reduction of FEV1 by more than 15%. In a 2-year follow-up of 101 patients with reactive airway disease conducted by Weinreb et al,53 9 patients were withdrawn because of worsening pulmonary status, and, overall, the mean FEV1–forced vital capacity ratio decreased from 66% to 54%. A third betaxolol study in patients with asthma found that one third had increased asthmatic symptoms, such as wheezing, coughing, and dyspnea, and half had a 15% decrease in FEV1.54 In addition, agents administered systemically with intrinsic sympathomimetic activity may not confer greater protection against respiratory effects. Topical carteolol, which has intrinsic sympathomimetic activity, has demonstrated a detrimental effect on lung function that was greater than that of betaxolol, and oral pindolol has blocked recovery from an asthma attack after terbutaline treatment.46,55,56

CNS and Endocrine Effects

Among the most common adverse effects seen with topical β-blocker use are those associated with the CNS, including depression, fatigue, weakness, confusion, memory loss, headaches, and anxiety.45 Approximately 10% of patients report CNS effects, and 5% have to discontinue taking the medication.11 These drugs can cross the blood-brain barrier and inhibit central β-receptors. They also block serotonin receptors and exert other nonspecific and peripherally mediated CNS effects.57 Such effects seem to be influenced by the selectivity of the agent. For example, Lynch et al58 found that betaxolol produced fewer CNS effects than timolol maleate. Likewise, lipophilic characteristics of β-blockers could influence penetration across the blood-brain barrier and CNS effects. However, to our knowledge, the influence of lipophilic characteristics of β-blockers has not been studied clinically with ophthalmic β-blocker preparations.

A final controversial side effect of β-blockers involves alteration of the endocrine system in patients with diabetes. There is little information on such topical effects in the ophthalmic literature, but oral administration may reduce the awareness of a hypoglycemic crisis and produce a deterioration in glucose tolerance.59,60

The range of potentially serious adverse effects associated with topical β-blockers can pose considerable challenges to the physician in clinical practice. Recognition and management of systemic sequelae, patient intolerance to adverse events, and the impact of these factors on compliance with therapy and quality of life have previously been discussed and reviewed in the literature.6163

Several new glaucoma agents with demonstrated efficacy in reducing IOP have been shown to have systemic adverse effect profiles that appear to be more favorable than those found with traditional therapies, including timolol maleate, These new drugs offer alternatives to the ophthalmologist that also may portend advantages in patient management for both the ophthalmologist and the primary care physician.

Latanoprost

Latanoprost is a prostaglandin analog that lowers IOP by increasing uveoscleral outflow.6466 (It has been recently approved by the Food and Drug Administration under the trade name Xalatan.) Prostaglandins are mediators of inflammation, and were investigated for the treatment of glaucoma because reduced IOP is often associated with ocular inflammation.67 Latanoprost represents a new class of glaucoma medications that have the potential to become first-line agents.68 Recently, 4 large randomized trials proved once-daily dosing of latanoprost to be equal or superior to treatment with timolol maleate.6972 The absence of serious systemic adverse effects with latanoprost therapy was noteworthy.

At the end of 6 months of treatment, Watson et al69 found that treatment with timolol produced a slight but significant reduction in heart rate from a baseline value of 73.8±11.6 (mean[±SD]) beats per minute to 71.8±10.9 beats per minute, with no effect from treatment with latanoprost. Although neither timolol nor latanoprost had a consistent effect on blood pressure, there was a general tendency toward a slight decrease with the use of both agents. Approximately 6.9% of patients receiving timolol maleate reported respiratory or cardiovascular effects, in contrast to 2.0% in the latanoprost group (patients contraindicated to treatment with timolol were excluded from the trial). Thus, there were more patients with shortness of breath, bronchitis, and arterial hypotension in the timolol group.

Alm et al70 found a reduction in heart rate with timolol maleate and negligible systemic adverse effects with latanoprost.Camras et al71 reported relatively few systemic adverse effects with either latanoprost or timolol maleate; however, heart rate was significantly reduced at 6 months with timolol maleate, and there was no change in heart rate with latanoprost. In addition, 13.8% of patients in the timolol maleate group reported headache or lassitude, compared with 6.7% in the latanoprost group.

Finally, in a study comparing the efficacy of 0.005% latanoprost administered once daily with that of 0.5% timolol maleate administered twice daily, Mishima et al72 found that latanoprost was more efficacious than timolol maleate in reducing IOP in patients with open-angle glaucoma and ocular hypertension; the main systemic effect was a slight but statistically significant reduction in mean heart rate in the patients in the timolol group at 4, 8, and 12 weeks (P<.01); of the 83 patients in the timolol group, 2 exhibited bradycardia and 1 had cardiac arrhythmia.

Increased pigmentation of the iris has been noted in 5% to 15% of patients using latanoprost, occurring in patients with multicolored irises, ie, blue-brown, gray-brown, green-brown, and yellow-brown.6972 Although the safety of this eye-color change is under investigation, it appears to lack clinical significance; histologically, it has been shown that the change does not alter melanocytes, but an increase in melanin has been observed. In follow-up, patients who developed a darkening of the iris have not revealed any adverse effects on the eye or vision.

Brimonidine

Another new agent, brimonidine tartrate (Alphagan), is a relatively selective α2-agonist that lowers IOP by reducing aqueous humor production and, probably, by increasing uveoscleral outflow as a secondary effect.73 It is a highly lipophilic drug that can pass the blood-brain barrier and therefore has some potential for causing CNS adverse events. To date, fatigue and dry mouth appear to be the most significant systemic side effects noted, occurring mostly at doses higher in concentration than those available commercially. In a study designed to evaluate the cardiovascular and respiratory effects of brimonidine, Nordlund et al74 showed that this drug was associated with a mild, statistically significant, decrease in systolic blood pressure at rest and also during exercise recovery. Unlike timolol maleate, however, it has not been shown to limit exercise tolerance.

Dorzolamide

A third new agent, dorzolamide (introduced under the trade name Trusopt), is the first commercially available topical carbonic anhydrase inhibitor (eg, Diamox). It has been found to lower IOP 18% to 20% throughout the day (mean pressure, 4.5-6.1 mm Hg) from baseline, by suppressing aqueous humor production.75,76 The oral carbonic anhydrase inhibitors have traditionally been reserved as last-resort treatment, because adverse systemic effects occur in as many as 50% of patients. Such effects include general malaise, fatigue, depression, loss of libido, paresthesias, tinnitus, nausea, anorexia, gastrointestinal disturbances, blood dyscrasias, and metabolic and respiratory acidosis.77,78 No such effects have been reported thus far (to our knowledge) with dorzolamide. There have been no reports of bone marrow depression or aplastic anemia, both of which are rare occurrences with oral carbonic anhydrase inhibitors, although red blood cell carbonic anhydrase activity was shown to be reduced by 21% in one study.77 In a large, multicenter trial comparing dorzolamide with betaxolol and timolol maleate, a frequently reported side effect in the dorzolamide group was bad taste, which occurred in 27% of patients.79 Dorzolamide produced fewer headaches than betaxolol and more gastrointestinal disturbances than either of the other 2 drugs. Patients receiving betaxolol had significantly more cardiovascular adverse events, including angina, hypertension, and bradycardia, than did those in the dorzolamide group. Fatigue and rashes have been reported infrequently. Because dorzolamide is a sulfonamide, it is prudent to remain vigilant in watching for the adverse reactions that are sometimes seen with systemic administration, particularly hypersensitivity.80

Apraclonidine

Research has also shown that a new drug, apraclonidine, is an effective adjunct to treatment with timolol maleate in reducing IOP, with few nonocular adverse effects. Similar to brimonidine, apraclonidine is an α2-adrenergic agonist. In a study by Stewart et al,81 0.5% apraclonidine administered adjunctively with 0.5% timolol maleate produced IOP reductions from baseline that were as significant as those produced with 1.0% apraclonidine treatment and 0.5% timolol maleate. However, sensitivity to apraclonidine treatment at 1.0% was greater than at 0.5% (13.8% vs 20.3%), and treatment was discontinued owing to ocular or nonocular adverse effects in 21.5% of patients receiving 0.5% apraclonidine, which is available commercially, and in 25% of patients receiving 1.0% apraclonidine.

As primary therapy, apraclonidine lowers the IOP approximately 20% 12 hours after dosing, but the percentage is statistically lower than with timolol.82 Unfortunately, ocular intolerance has been a problem with apraclonidine in 13% to 36% of cases. The patients present with asymptomatic or mild ocular pruritis. However, they subsequently are found to have conjunctival erythema and potential periorbital infection. The intolerance subsides quickly on discontinuation of the therapy.83

New topical agents for the treatment of glaucoma offer significant promise, both in terms of efficacy and in the absence of systemic events. Nevertheless, topical β-blockers are currently the most commonly used therapy for glaucoma. Therefore, increased communication within the medical community is warranted. Careful attention on the part of the primary care physician to the systemic effects of topical β-blockade is paramount for several reasons. These medications must be remembered and ordered correctly on inpatient orders. Many hospitalized patients are treated for glaucoma, yet a small retrospective survey found that as many as 37% do not receive the correct medicine or amount.84 Recognizing the importance of these medications can help to ensure that their use is not indiscriminately discontinued without communication with the prescribing ophthalmologist. And, finally, these topical medications may partly or wholly explain an alteration in a patient's systemic condition. Conversely, ophthalmologists can benefit from consultation with the primary care physician to refine the choice of agents for certain patients. Ultimately, more studies and new agents may provide clear-cut guidelines for patient prescription; in the meantime, however, it is critical that ophthalmologists and primary care physicians communicate about the safest, most efficacious usage of such medicine.

Accepted for publication July, 17, 1997.

Reprints: William C. Stewart, MD, 1639 Tatum St, Charleston, SC 29412.

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Harris  LSGreenstein  SHBloom  AF Respiratory difficulties with betaxolol. Am J Ophthalmol. 1986;102274
Link to Article
Nelson  WLKuritsky  JN Early postmarketing surveillance of betaxolol hydrochloride, September 1985–September 1986. Am J Ophthalmol. 1987;103592
Weinreb  RNVan Buskirk  EMCherniack  RDrake  MM Long-term betaxolol therapy in glaucoma patients with pulmonary disease. Am J Ophthalmol. 1988;106162- 167
Spiritus  EMCasciari  R Effects of topical betaxolol, timolol, and placebo on pulmonary function in asthmatic bronchitis. Am J Ophthalmol. 1985;100492- 494
Svedmyr  NRönn  O Undersökning av den Kliniska Relevansen av β-1-Selektivitet och Egenstimulering för Adrenerga β-Blockerare hos Astmatiker. Sandoz Tidsskrift. 1981;8118- 21
Lammers  JWJFolgering  HTMMuller  MEvan Herwaarden  CL Ventilatory effects of long-term treatment with pindolol and metipranolol in hypertensive patients with chronic obstructive lung disease. Br J Clin Pharmacol. 1985;20201- 210
Link to Article
Koella  WP CNS-related (side-)effects of β-blockers with special reference to mechanisms of action. Eur J Clin Pharmacol. 1985;28(suppl)55- 63
Link to Article
Lynch  MGWhitson  JTBrown  RHNguyen  HDrake  MM Topical β-blocker therapy and central nervous system side effects: a preliminary study comparing betaxolol and timolol. Arch Ophthalmol. 1988;106908- 911
Link to Article
Tse  WYKendall  M Is there a role for β-blockers in hypertensive diabetic patients? Diabet Med. 1994;11137- 144
Link to Article
Houston  DC Adverse effects of antihypertensive drug therapy on glucose intolerance. Cardiol Clin. 1986;4117- 135
Monane  MBohn  RLGurwitz  JHGlynn  RJChoodnovskiy  IAvorn  J Topical glaucoma medications and cardiovascular risk in the elderly. Clin Pharmacol Ther. 1994;5576- 83
Link to Article
Diggory  PHeyworth  PChau  GMcKenzie  SSharma  A Unsuspected broncospasm in association with topical timolol—a common problem in elderly people. Age Aging. 1994;2317- 21
Link to Article
Patel  SCSpaeth  GL Compliance in patients prescribed eyedrops for glaucoma. Ophthalmic Surg. 1995;26233- 236
Stjernschantz  JResul  B Phenyl substituted prostaglandin analogs for glaucoma treatment. Drugs Future. 1992;17691- 704
Resul  BStjernschantz  JNo  K  et al.  Phenyl-substituted prostaglandins: potent and selective antiglaucoma agents. J Med Chem. 1993;36243- 248
Link to Article
Stjernschantz  J Prostaglandins as ocular hypertensive agents: development of an analogue for glaucoma treatment. Adv Prostaglandin Thromboxane Leukotrine Res. 1995;2363- 68
Camras  CB Prostaglandins. Ritch  RShields  MBKrupin  Teds.The Glaucomas. St Louis, Mo Mosby–Year Book Inc1996;1449- 1462
Higgenbotham  E Will latanoprost be the wonder drug of the ‘90s for the treatment of glaucoma? Arch Ophthalmol. 1996;114998
Link to Article
Watson  PStjernschantz  JThe Latanoprost Study Group, A six-month randomized double-masked study comparing latanoprost with timolol in open-angle glaucoma and ocular hypertension. Ophthalmology. 1996;103126- 137
Link to Article
Alm  AStjernschantz  JThe Scandinavian Latanoprost Study Group, Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning. Ophthalmology. 1995;1021743- 1752
Link to Article
Camras  CBThe United States Latanoprost Study Group, Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma: a six-month, masked, multicenter trial in the United States. Ophthalmology. 1996;103138- 147
Link to Article
Mishima  HKMasuda  KKitazawa  YAzuma  IAraie  M A comparison of latanoprost and timolol in primary open-angle glaucoma and ocular hypertension: a 12-week study. Arch Ophthalmol. 1996;114929- 932
Link to Article
Serle  JBSteidl  SWang  RMittag  JPodos  S Selective α2-adrenergic antagonists B-HT920 and UK14304-18: effects on aqueous humor dynamics in monkeys. Arch Ophthalmol. 1991;1091158- 1162
Link to Article
Nordlund  JRPasquale  LRRobin  AL  et al.  The cardiovascular, pulmonary, and ocular hypotensive effects of 0.2% brimonidine. Arch Ophthalmol. 1995;11377- 83
Link to Article
Lippa  EACarlson  LEEhinger  B  et al.  Dose response and duration of action of dorzolamide, a topical carbonic anhydrase inhibitor. Arch Ophthalmol. 1992;110495- 499
Link to Article
Maren  TH The rates of movement of Na+, Cl, and HCO−3 from plasma to posterior chamber: effect of acetazolamide and relation to the treatment of glaucoma. Invest Ophthalmol. 1983;28(suppl)280- 284
Epstein  DLGrant  MW Carbonic anhydrase inhibitor side effects: serum chemical analysis. Arch Ophthalmol. 1977;951378- 1382
Link to Article
Berson  FGEpstein  DL Carbonic anhydrase inhibitors. Perspect Ophthalmol. 1980;491- 95
Strahlman  ETipping  RVogel  RThe International Dorzolamide Study Group, A double-masked, randomized 1-year study comparing dorzolamide (Trusopt), timolol, and betaxolol. Arch Ophthalmol. 1995;1131009- 1016
Link to Article
Not Available, Dorzolamide hydrochloride ophthalmic solution [product insert].  West Point, Pa Merck & Co Inc1995;
Stewart  WCRitch  RShin  D  et al.  The efficacy of apraclonidine as an adjunct to timolol therapy: Apraclonidine Adjunctive Therapy Study Group. Arch Ophthalmol. 1995;113287- 292
Link to Article
Stewart  WCLaibovitz  RHorwitz  BStewart  RHRitch  RKottler  MThe Apraclonidine Primary Therapy Study Group, A 90-day study of the efficacy and side effects of 0.25% and 0.5% apraclonidine vs 0.5% timolol. Arch Ophthalmol. 1996;114938- 942
Link to Article
Stewart  WC Apraclonidine. Klin Monatsbl Augenheilkd. 1996;209A7- A13
Link to Article
Price  NC Importance of asking about glaucoma. BMJ. 1983;286349
Link to Article

Figures

Tables

References

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Gordon  MEKass  MA Validity of standard compliance measures in glaucoma compared with an electronic eyedrop monitor. Cramer  JASpilker  Beds.Patient Compliance in Medical Practice and Clinical Trials. New York, NY Lippincott-Raven1991;163- 173
Bankes  JLKPerkins  ESTsolakis  SWright  JE Bedford Glaucoma Survey. BMJ. 1968;30791- 796
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Coakes  RLBrubaker  RS The mechanism of timolol in lowering intraocular pressure. Arch Ophthalmol. 1978;962045- 2048
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Shields  MB Textbook of Glaucoma. 2nd ed. Baltimore, Md Williams & Wilkins1987;361- 373
Kaila  TKarhuvaara  SHuupponen  RIisalo  E The analysis of plasma kinetics and β-receptor–binding and –blocking activity of timolol following its small intravenous dose. Int J Clin Pharmacol Ther Toxicol. 1993;31351- 357
Kaila  T A sensitive radioligand binding assay for timolol in plasma. J Pharm Sci. 1991;80296- 299
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Irvine  NALipworth  BJMcDevitt  DG A dose-ranging study to evaluate the β-adrenoceptor selectivity of single doses of betaxolol. Br J Clin Pharmacol. 1990;30119- 126
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Nelson  WLFraunfelder  FTSills  JMArrowsmith  JBKuritsky  JN Adverse respiratory and cardiovascular events attributed to timolol ophthalmic solution,1978-1985. Am J Ophthalmol. 1986;102606- 611
Eichnorn  EJ Do β-blockers have a role in patients with congestive heart failure? Cardiol Clin. 1994;12133- 142
Zimmerman  TJBaumann  JDHetherington  J Side effects of timolol. Surv Ophthalmol. 1983;28(suppl)243- 249
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Polansky  JR Comparison of plasma blocking activity of betaxolol and timolol. Int Ophthalmol Clin. 1989;29(suppl)17- 18
Link to Article
Vuori  M-LAli-Melkkilä  TKaila  TIisalo  ESaari  KM β1- and β2-antagonist activity of topically applied betaxolol and timolol in the systemic circulation. Acta Ophthalmol. 1993;71682- 685
Link to Article
Ball  S Congestive heart failure from betaxolol. Arch Ophthalmol. 1987;105320
Link to Article
Van Buskirk  EMFraunfelder  FT Ocular β-blockers and systemic effects. Am J Ophthalmol. 1984;98623- 624
Packer  MBristow  MCohn  JN  et al.  The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996;3341349- 1355
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Kastor  JAed Arrhythmias.  Philadelphia, Pa WB Saunders Co1994;1
Fraunfelder  FTMeyer  SM Systemic adverse reactions to glaucoma medications. Int Ophthalmol Clin. 1989;29143- 146
Link to Article
Charap  ADShin  DHPetursson  G  et al.  Effect of varying drop size on the efficacy and safety of a topical beta blocker. Ann Ophthalmol. 1989;21351- 357
Not Available, Betoptic S. [Product monograph]. Fort Worth, Tex Alcon Laboratories Inc1985;
Coumel  PLeclercq  J-FEscoubet  B β-Blockers: use for arrhythmias. Eur Heart J. 1987;8(suppl A)41- 52
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Hampton  JR Choosing the right β-blocker: a guide to selection. Drugs. 1994;48549- 568
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Roberts  WC Recent studies on the effects of β-blockers on blood lipid levels. Am J Heart. 1989;117709- 714
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Ames  RP Antihypertensive drugs and lipid profiles. Am J Hypertens. 1988;1421- 427
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Lardinois  CKNeuman  SL The effects of antihypertensive agents on serum lipids and lipoproteins. Arch Intern Med. 1988;1481280- 1288
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Grimm  RHFlack  JMGrandits  GA  et al.  Long-term effects on plasma lipids of diet and drugs to treat hypertension: Treatment of Mild Hypertension Study (TOMHS) Research Group. JAMA. 1996;2751549- 1556
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Coleman  ALDiehl  DLCJampel  ADBachorik  PSQuigley  HA Topical timolol decreases plasma high-density lipoprotein cholesterol level. Arch Ophthalmol. 1990;1081260- 1263
Link to Article
West  JLongstaff  S Topical timolol and serum lipoproteins. Br J Ophthalmol. 1990;74663- 664
Link to Article
Freedman  SFFreedman  NJShields  MB  et al.  Effects of ocular carteolol and timolol on plasma high-density lipoprotein cholesterol level. Am J Ophthalmol. 1993;116600- 611
Stewart  WCDubiner  HBLaibovitz  RA  et al.  The effect of carteolol and timolol on plasma lipid profiles in older women with ocular hypertension or primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 1997;38(suppl)S2591
Tesch  PA Exercise performance and β-blockade. Sports Med. 1985;2389- 412
Link to Article
Åström  H Haemodynamic effects of β-adrenergic blockade. Br Heart J. 1968;3044- 49
Link to Article
Doyle  WJWeber  PAMeeks  RH Effect of topical timolol maleate on exercise performance. Arch Ophthalmol. 1984;1021517- 1518
Link to Article
Leier  CVBaker  NDWeber  PA Cardiovascular effects of ophthalmic timolol. Ann Intern Med. 1986;104197- 199
Link to Article
Atkins  JM Effects of topical β-blockers on cardiovascular function during exercise. Int Ophthalmol Clin. 1989;29(suppl)S23
Link to Article
Passo  MSHunt  SCElliot  DLGoldberg  L Regular exercise lowers intraocular pressure in glaucoma patients. Invest Ophthmol Vis Sci. 1994;13(suppl)1254
Raftery  EBCarrageta  MO Hypertension and β-blockers: are they all the same? Int J Cardiol. 1985;7337- 346
Link to Article
Mayer  JWeichler  UHerres-Mayer  BSchneider  HMarx  UPeter  JH Influence of metaprolol and cilazapril on blood pressure and on sleep apnea activity. J Cardiovasc Pharmacol. 1990;16952- 961
Link to Article
Claridge  KGSmith  SE Diurnal variation in pulsatile ocular blood flow in normal and glaucomatous eyes. Surv Ophthalmol. 1994;38(suppl)S198- S205
Link to Article
Hayreh  SSZimmerman  MBPodhajsky  PAlward  WLM Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol. 1994;117603- 624
Graham  SLDrance  SMWijsman  KDouglas  GRMikelberg  FS Ambulatory blood pressure monitoring in glaucoma: the nocturnal dip. Ophthalmology. 1995;10261- 69
Link to Article
McNeill  RS Effect of a β-adrenergic-blocking agent, propranolol, on asthmatics. Lancet. 1964;21101- 1102
Link to Article
Löfdahl  C-G Antihypertensive agents and airway function, with special reference to calcium channel blockade. J Cardiovasc Pharmacol. 1989;14(suppl 10)S40- S51
Link to Article
Schoene  RBMartin  TRCharan  NBFrench  CL Timolol-induced bronchospasm in asthmatic bronchitis. JAMA. 1981;2451460- 1461
Link to Article
Van Buskirk  EM Adverse reactions from timolol administration. Ophthalmology. 1908;87447- 450
Link to Article
Hugues  FC Clinical studies of systemic effects of topical β-blockers. Int Ophthalmol Clin. 1989;29(suppl)S19- S20
Link to Article
Avorn  JGlynn  RJGurwitz  JH  et al.  Adverse pulmonary effects of topical β-blockers used in the treatment of glaucoma. J Glaucoma. 1993;2158- 165
Link to Article
Botet  CGrau  JBenito  PColl  JVivancos  J Timolol ophthalmic solution and respiratory arrest. Arch Intern Med. 1986;105306- 307
Wandel  TCharap  ADLewis  RA  et al.  Glaucoma treatment with once-daily levobunolol. Am J Ophthalmol. 1986;101298- 304
Schoene  RVerstappen  AMcDonald  TO Betaxolol use not related to adverse pulmonary reactions reported in patients with reactive airway disease: a report on 12 double-masked rechallenges. Glaucoma. 1992;1439- 45
Harris  LSGreenstein  SHBloom  AF Respiratory difficulties with betaxolol. Am J Ophthalmol. 1986;102274
Link to Article
Nelson  WLKuritsky  JN Early postmarketing surveillance of betaxolol hydrochloride, September 1985–September 1986. Am J Ophthalmol. 1987;103592
Weinreb  RNVan Buskirk  EMCherniack  RDrake  MM Long-term betaxolol therapy in glaucoma patients with pulmonary disease. Am J Ophthalmol. 1988;106162- 167
Spiritus  EMCasciari  R Effects of topical betaxolol, timolol, and placebo on pulmonary function in asthmatic bronchitis. Am J Ophthalmol. 1985;100492- 494
Svedmyr  NRönn  O Undersökning av den Kliniska Relevansen av β-1-Selektivitet och Egenstimulering för Adrenerga β-Blockerare hos Astmatiker. Sandoz Tidsskrift. 1981;8118- 21
Lammers  JWJFolgering  HTMMuller  MEvan Herwaarden  CL Ventilatory effects of long-term treatment with pindolol and metipranolol in hypertensive patients with chronic obstructive lung disease. Br J Clin Pharmacol. 1985;20201- 210
Link to Article
Koella  WP CNS-related (side-)effects of β-blockers with special reference to mechanisms of action. Eur J Clin Pharmacol. 1985;28(suppl)55- 63
Link to Article
Lynch  MGWhitson  JTBrown  RHNguyen  HDrake  MM Topical β-blocker therapy and central nervous system side effects: a preliminary study comparing betaxolol and timolol. Arch Ophthalmol. 1988;106908- 911
Link to Article
Tse  WYKendall  M Is there a role for β-blockers in hypertensive diabetic patients? Diabet Med. 1994;11137- 144
Link to Article
Houston  DC Adverse effects of antihypertensive drug therapy on glucose intolerance. Cardiol Clin. 1986;4117- 135
Monane  MBohn  RLGurwitz  JHGlynn  RJChoodnovskiy  IAvorn  J Topical glaucoma medications and cardiovascular risk in the elderly. Clin Pharmacol Ther. 1994;5576- 83
Link to Article
Diggory  PHeyworth  PChau  GMcKenzie  SSharma  A Unsuspected broncospasm in association with topical timolol—a common problem in elderly people. Age Aging. 1994;2317- 21
Link to Article
Patel  SCSpaeth  GL Compliance in patients prescribed eyedrops for glaucoma. Ophthalmic Surg. 1995;26233- 236
Stjernschantz  JResul  B Phenyl substituted prostaglandin analogs for glaucoma treatment. Drugs Future. 1992;17691- 704
Resul  BStjernschantz  JNo  K  et al.  Phenyl-substituted prostaglandins: potent and selective antiglaucoma agents. J Med Chem. 1993;36243- 248
Link to Article
Stjernschantz  J Prostaglandins as ocular hypertensive agents: development of an analogue for glaucoma treatment. Adv Prostaglandin Thromboxane Leukotrine Res. 1995;2363- 68
Camras  CB Prostaglandins. Ritch  RShields  MBKrupin  Teds.The Glaucomas. St Louis, Mo Mosby–Year Book Inc1996;1449- 1462
Higgenbotham  E Will latanoprost be the wonder drug of the ‘90s for the treatment of glaucoma? Arch Ophthalmol. 1996;114998
Link to Article
Watson  PStjernschantz  JThe Latanoprost Study Group, A six-month randomized double-masked study comparing latanoprost with timolol in open-angle glaucoma and ocular hypertension. Ophthalmology. 1996;103126- 137
Link to Article
Alm  AStjernschantz  JThe Scandinavian Latanoprost Study Group, Effects on intraocular pressure and side effects of 0.005% latanoprost applied once daily, evening or morning. Ophthalmology. 1995;1021743- 1752
Link to Article
Camras  CBThe United States Latanoprost Study Group, Comparison of latanoprost and timolol in patients with ocular hypertension and glaucoma: a six-month, masked, multicenter trial in the United States. Ophthalmology. 1996;103138- 147
Link to Article
Mishima  HKMasuda  KKitazawa  YAzuma  IAraie  M A comparison of latanoprost and timolol in primary open-angle glaucoma and ocular hypertension: a 12-week study. Arch Ophthalmol. 1996;114929- 932
Link to Article
Serle  JBSteidl  SWang  RMittag  JPodos  S Selective α2-adrenergic antagonists B-HT920 and UK14304-18: effects on aqueous humor dynamics in monkeys. Arch Ophthalmol. 1991;1091158- 1162
Link to Article
Nordlund  JRPasquale  LRRobin  AL  et al.  The cardiovascular, pulmonary, and ocular hypotensive effects of 0.2% brimonidine. Arch Ophthalmol. 1995;11377- 83
Link to Article
Lippa  EACarlson  LEEhinger  B  et al.  Dose response and duration of action of dorzolamide, a topical carbonic anhydrase inhibitor. Arch Ophthalmol. 1992;110495- 499
Link to Article
Maren  TH The rates of movement of Na+, Cl, and HCO−3 from plasma to posterior chamber: effect of acetazolamide and relation to the treatment of glaucoma. Invest Ophthalmol. 1983;28(suppl)280- 284
Epstein  DLGrant  MW Carbonic anhydrase inhibitor side effects: serum chemical analysis. Arch Ophthalmol. 1977;951378- 1382
Link to Article
Berson  FGEpstein  DL Carbonic anhydrase inhibitors. Perspect Ophthalmol. 1980;491- 95
Strahlman  ETipping  RVogel  RThe International Dorzolamide Study Group, A double-masked, randomized 1-year study comparing dorzolamide (Trusopt), timolol, and betaxolol. Arch Ophthalmol. 1995;1131009- 1016
Link to Article
Not Available, Dorzolamide hydrochloride ophthalmic solution [product insert].  West Point, Pa Merck & Co Inc1995;
Stewart  WCRitch  RShin  D  et al.  The efficacy of apraclonidine as an adjunct to timolol therapy: Apraclonidine Adjunctive Therapy Study Group. Arch Ophthalmol. 1995;113287- 292
Link to Article
Stewart  WCLaibovitz  RHorwitz  BStewart  RHRitch  RKottler  MThe Apraclonidine Primary Therapy Study Group, A 90-day study of the efficacy and side effects of 0.25% and 0.5% apraclonidine vs 0.5% timolol. Arch Ophthalmol. 1996;114938- 942
Link to Article
Stewart  WC Apraclonidine. Klin Monatsbl Augenheilkd. 1996;209A7- A13
Link to Article
Price  NC Importance of asking about glaucoma. BMJ. 1983;286349
Link to Article

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