40 years of topical beta-blockers for glaucoma

Abstract

The introduction of topical beta-blockers in 1978 was a major breakthrough in the treatment of ocular hypertension and glaucoma, and although no longer first-line, beta-blockers remain a commonly prescribed and important intraocular pressure (IOP) lowering medication. On the 40^th anniversary of their introduction we critique the current role of topical beta-blockers, with particular regard to their efficacy, side effects, and role in fixed-dose combinations. While beta-blockers are effective at lowering IOP during the day, sleep laboratory studies have shown that they have minimal effect overnight, likely due to the physiological nocturnal reduction in aqueous production. Cardiac and respiratory side effects are especially important to consider in elderly patients with multiple comorbidities or in those using multiple systemic medications, which may affect beta-blocker metabolism. The increasing number of alternative medical and minimally invasive surgical options for glaucoma treatment is likely to see a reduction in beta-blocker prescribing.

Introduction

This year marks the 40^th anniversary of the introduction of topical beta-blockers for the treatment of glaucoma. Before 1978, the medical treatment of glaucoma relied on the non-selective adrenergic agonist, epinephrine, and the cholinergic agonist, pilocarpine; consequently, the availability of topical timolol maleate represented a major breakthrough in intraocular pressure (IOP) lowering therapy. Timolol became the first-line medical treatment for glaucoma and ocular hypertension (OHT) and remained the undisputed initial choice until the introduction of prostaglandin analogs in 1996.

Although, for most patients, prostaglandin analogs are now the first-line medical treatment, topical beta-blockers remain a widely prescribed and valuable medication, particularly as constituents of fixed-dose combination treatments. However, many patients have contraindications to beta-blockers, which can be associated with potentially serious systemic side effects, and there are concerns regarding their potentially adverse effect on ocular blood flow and lack of 24-h efficacy. On the 40^th anniversary of the introduction of topical timolol and given the wide range of alternative medical, laser, and minimally invasive surgical options, it seems appropriate to consider the role of topical beta-blockers in glaucoma treatment today.

Pharmacology

Beta-blockers act on the post-synaptic β1- and β2-adrenergic receptors of the sympathetic division of the autonomic nervous system.^[1] Blockade of β1-receptors in the ciliary body leads to reduced aqueous humour production; however, β1-blockade also leads to reduced heart rate, reduced cardiac output, and lower blood pressure.^[2,3] Blockade of β2 receptors results in bronchoconstriction and vasoconstriction, leading to potential side effects including dyspnea, worsening of Raynaud's syndrome, and erectile dysfunction. β2-blockade also affects the liver and pancreas, with consequent decreased gluconeogenesis and lipolysis and reduced insulin secretion.^[4] When a patient instills an eye drop, only 2-10% reaches the site of action at the ciliary body. The remainder enters the systemic circulation through conjunctival vessels, nasal mucosa through the nasolacrimal duct, and upper gastrointestinal tract. Therefore, similar to intravenous administration, drugs given topicallybypass first-pass metabolism and can reach relative highplasma concentrations. Topical timolol achieves peak plasmaconcentration within 5-30 min and has a half-life of 4 h, with onedrop of 0.5% timolol equivalent to a 10 mg oral dose. Althoughsystemic absorption can be reduced with nasolacrimal ductocclusion, the amount of drug entering the systemic circulationremains high.

Timolol is eliminated from the body largely throughmetabolism by CYP2D6, a cytochrome P450 enzyme. Itis estimated that 6-10% of Caucasians, 2-5% of African-Americans and 1% of Asians have an inherited deficiencyof CYP2D6, which may lead to increased susceptibility totimolol-related side effects. At least one study has shown poormetabolizers have higher plasma concentrations of timolol andmore pronounced bradycardia after administration of timololeye drops.^[5] Older age, hepatic impairment, and medications,including tricyclic antidepressants, codeine, and tramadol, whichare also metabolized by CYP2D6, may also increase the risk ofsystemic side effects with ophthalmic β-blockers.^[6,7] Althoughthe selective β1-blocker betaxolol has a lower risk of causingrespiratory side effects, it has a similar effect on cardiac functionand blood pressure, with the magnitude of systemic side effectssimilarly affected by variation in metabolism.^[6]

Efficacy

Numerous prospective randomized trials have proven thatlowering IOP reduces the risk of glaucomatous visual loss,with the recent United Kingdom Glaucoma Treatment Study,the first study showing the effectiveness of medical treatment(latanoprost) compared to placebo.^[8,9] Studies establishing thevalue of topical beta-blockers in OHT and glaucoma include thelandmark Ocular Hypertension Treatment Study^[8] and EarlyManifest Glaucoma Treatment Trial,^[9] which were initiatedbefore prostaglandin analogs became available. Although betablockersare effective IOP lowering medications, they are lesseffective than prostaglandin analogs. Pooled results from studiesincluding over 800 patients found an average 26% reductionin IOP with timolol 0.5% twice per day, compared to a 31%reduction with latanoprost, with the advantage that latanoprostrequires once-daily administration and has fewer systemic sideeffects.^[5,10]

An additional concern regarding beta-blockers, which isnow well established from studies in the sleep laboratory, is thatthey lack 24-h efficacy, with their effect diminished during thenocturnal period.^[11] A recent prospective, randomized, doublemaskedcrossover study found that, while both prostaglandinanalogs and beta-blockers reduced mean 24-h IOP,prostaglandin analogs were more effective than beta-blockersduring the night, and patients using beta-blockers had reducedblood pressure, heart rate, and ocular perfusion pressure, whichmay have important consequences for glaucoma progression.^[11] Furthermore, when used as a second line agent in patientsalready using a prostaglandin analogue, although timolol 0.5%twice per day further lowered IOP during the day, it had noeffect on nocturnal IOP. The likely explanation for the lack ofnocturnal efficacy is that beta-blockers' mechanism of actionrelies on impeding the effects of endogenous catecholamines,which drive aqueous humor formation in the ciliary epithelia. Innormal individuals, aqueous production decreases to half of thedaytime levels during sleep, reducing the opportunity for betablockersto further reduce aqueous production.^[12]

Due to lower efficacy and higher risk of systemic side effectscompared to prostaglandin analogs, topical beta-blockers areno longer the first-choice treatment for most patients withglaucoma or OHT. Yet, patients frequently require more thanone medication and beta-blockers are the foremost secondlinetreatment, particularly given their availability in fixed-dosecombination formulations. Furthermore, although beta-blockersare no longer first line for all, the most appropriate first choicemedication will differ according to the individual ocular andsystemic comorbidities and beta-blockers or an alternativemay be preferable to prostaglandin analogs in patients withcomorbidities such as herpetic eye disease or cystoid macularedema. It is, therefore, crucial to tailor treatment according topatients' individual needs.^[13]

Adherence to treatment is also essential to treatment success,and previous studies have shown decreasing adherence withincreasing numbers of medications.^[14,15] An advantage of topicalbeta-blockers is that they are available in fixed combinationformulations which are likely to improve adherence in thoseneeding more than one agent. A recent study examiningadherence to glaucoma medications found that, over a 1-yearperiod, patients using two separate IOP-lowering medicationsinstilled their drops within 24 h of expected on only 43 ±27% of days compared to 60 ± 28% of days for those usingfixed combination medications. No patients using separatedrops were adherent for >95% of days.^[16] Due to the effectof complex dosing regimens on adherence and the greaterexposure to preservatives with a greater number of drops, it isrecommended to use fixed-dose combination medications whenavailable.^[17] A disadvantage of beta-blocker containing fixeddosecombinations, however, is that they contain timolol at aconcentration of 0.5%, which may expose the patient to greaterrisk of systemic side effects, with no greater IOP-loweringefficacy compared to lower concentrations such as 0.25% and0.1%. Furthermore, in countries where prostaglandin analog- beta-blocker fixed combination medications are available, thereis controversy regarding the optimal timing of administration.While prostaglandin analogs are typically taken in the evening,due to the lack of nocturnal IOP lowering and the potential forreduced blood pressure and ocular perfusion pressure, there isa preference among many ophthalmologists for beta-blockersto be administered in the morning. Furthermore, prostaglandinanalog - beta-blocker fixed combination medications are notcurrently available in the United States as the U.S. Food andDrug Administration has stipulated, new combinations mustdemonstrate a 2 mmHg further reduction in IOP than providedby either individual component. When beta-blockers are usedas a second-line agent, a meta-analysis examining the additiveeffect of alpha-agonists, beta-blockers, and carbonic anhydraseinhibitors combined with prostaglandin analogs showed asimilar mean additional IOP-lowering effect of approximately2.3-3 mmHg for each medication.^[18] However, no individualstudies of prostaglandin analog - beta-blocker fixed combinationmedications - have met the FDA criteria for approval.

Side effects and Contraindications

Topical administration of beta-blockers may cause systemicside effects as β-adrenergic receptors are expressed by cardiacmuscles, airways, arteries, and kidneys and in the sympatheticnervous system. However, due to strict inclusion criteria,the systemic side effects of topical beta-blockers may beunderestimated in pivotal Phase 3 trials compared to real-worldexperiences. The medication package insert for timolol, inwhich patients often read when first prescribed the medication,lists systemic side effects including low blood glucose levels,insomnia, depression, anxiety, nightmares, memory loss,slow heart rate, palpitations, heart failure, heart block, lowblood pressure, Raynaud's phenomenon, cold hand and feet,constriction of the airways of the lings, nasal congestion, cough,loss of appetite, nausea, dry mouth, indigestion, fainting, muscleweakness, stroke, reduced blood supply to the brain, worseningmyasthenia gravis, hair loss, worsening of psoriasis, muscle pain,and sexual dysfunction. Although many of these potential sideeffects are rare, it is important to be aware of the potential forharm when prescribing.

The use of topical beta-blockers is contraindicated in patientswith asthma or chronic obstructive pulmonary disease (COPD),hypotension, bradycardia, or Raynaud's disease, and theyshould be used in caution in diabetes due to the risk of maskingsigns and symptoms of hypoglycemia. They are also relativelycontraindicated in patients using systemic beta-blockers and, aspreviously discussed should, be used in caution in patients usingother CYP2D6 inhibitors such as paroxetine and fluoxetine.Due to the large number of contraindications, it is essential forprescribers to take a comprehensive past medical history andmedication history before initiating any glaucoma treatment.Glaucoma patients are often elderly with multiple comorbiditiesand hence are on multiple systemic medications. It is alsoimportant to be aware that some patients may have undiagnosedcomorbidity and it is, therefore, prudent to check the patient'spulse rate and blood pressure before prescribing a beta-blockerand to provide a warning of potential side effects of treatment, somedication can be discontinued promptly if side effects occur.

Cardiac Safety

The effect of topical timolol on heart rate and blood pressureis well established.^[19] For example, a double-masked crossoverstudy including 43 subjects with glaucoma evaluated the effectof timolol 0.5% eye drops twice per day on 24-h heart ratecompared to placebo.^[20] There was a significant decrease in heartrate, with an average decline of 6 beats per minute, although thedecline was more pronounced if patients were coprescribed anoral beta-blocker. As previously noted, bradycardia was alsomore marked in those with impaired CYP2D6 function.^[5,21]The effects of bradycardia may go unnoticed by the patient;however, bradycardia it may lead to tiredness on exertion,breathlessness, and combined with hypotension; lower ocularand brain perfusion and increased risk of falls. A study fromAustralia, including over 6000 patients, found that recentcommencement with timolol eye drops was a significant riskfactor for hospitalization due to bradycardia.^[22]

Another recognized side effect is orthostatic hypotension,defined as a decrease in systolic BP of >20 mm Hg or diastolic>10 mm Hg within 3 min of standing or head up tilt.^[23] Orthostatichypotension can lead to falls, which are a serious problem in theelderly. 30% of people above the age of 65 years old fall at leastonce per year,^[24] with falls associated with increased morbidityand mortality, as well as reduced quality of life, in part due topatients limiting normal daily activities. It is important to considerthe risk of falls when prescribing elderly patients with topical betablockers.A retrospective study of 500 patients with glaucoma aged65 years or more found that 10% of patients using timolol hadexperienced an injurious fall in the previous year compared to only3% of patients not using antiglaucoma medications.^[25] Although itdid not control for different levels of activity, a recent prospectivestudy including 2400 patients followed for 2-3 years found thatthe risk of falls in those using topical timolol was very similar tothose using oral beta-blockers, with patients using either topical orsystemic beta-blockers at higher risk of falls than those not treatedwith beta-blockers.^[26] Topical timolol was associated with a 1.37-fold (95% confidence interval [CI] 0.99-1.90) increased risk offalls, whereas non-selective systemic beta-blockers were associatedwith 1.4-fold (95% CI 1.12-1.78) increased risk. To reduce therisk of orthostatic problems, the authors recommended using alower concentration of 0.1% timolol.^[26,27]

A rarer side effect is the impact of beta-blockers on cardiacconduction, and there are several reports of previously healthypatients developing complete heart block following treatmentwith topical timolol, with some patients requiring implantationof permanent pacemakers.^[19]

Pulmonary Safety

Topical beta-blockers may also exacerbate asthma and COPDand are contraindicated in these patients. A retrospectiveanalysis of prescribing habits, examined using a UK electronicpatient record, identified almost 5000 asthmatics who werenewly prescribed topical IOP lowering medication between2000 and 2012.^[28] Approximately 1 in 5 was given a non-selectivebeta-blocker, disagreeing with known contraindications,which was similar to previous reports of high frequency ofbeta-blocker prescription in asthmatics.^[29] This suggests thatprescribers are not enquiring about patients' comorbidities. Ofthe 1369 patients prescribed a topical beta-blocker, 128 had asevere asthma exacerbation requiring hospital admission duringfollow-up, while another 298 had moderate exacerbationsrequiring treatment with oral steroids. The risk of asthmaexacerbation was highest within 30 days of starting topical betablockers(IRR = 4.83, 95% CI 1.56-14.9); however, there was nosignificant increase in exacerbations with chronic use, perhaps aspatients at risk of exacerbation had already discontinued topicalbeta-blockers. Interestingly, the risk of asthma exacerbationwas similar between selective and non-selective beta-blockers,similar to the results of Kirwan et al. study discussed below.^[30]

The general decline in beta-blocker prescribing seems tohave resulted in a reduction in the number of asthmatic patientsprescribed beta-blockers. In the UK study, non-selective andselective topical beta-blocker prescribing decreased from 23%to 13.4% and 10.5% to 0.9% respectively between 2000 and2012, however the level of topical beta-blocker prescribingin patients with asthma remains remains high with >1 in10 patients with asthma and OHT or glaucoma prescribeda topical beta-blocker.^[31] The reason for the fall in betaxololprescribing, despite its better safety profile, was perhaps dueto the increased availability of fixed combination preparationscontaining non-selective beta-blockers. In addition to anincreased risk of exacerbation of known obstructive pulmonarydisease, there is a evidence of previously undiagnosed patientsdeveloping symptoms of obstructive airway disease aftercommencing topical beta-blockers. Specifically, Kirwan etal. reported an increase in new prescriptions for obstructiveairways disease after starting topical beta-blockers with a hazardratio of 2.22 (95% CI 1.63 to 3.02) for non-selective topicalbeta-blockers compared to controls and a similarly high hazardratio of 3.06 (95% CI 1.63-5.36) for selective topical betablockers,suggesting that selective beta-blockers may not be assafe for asthmatics as initial thought.^[30]

Studies examining the respiratory effects of topical betablockersin terms of repository function have also shown anadverse effect. Acute non-selective beta-blocker eye dropexposure has been shown to result in a significant mean fall inforced expiratory volume 1, with an average fall of almost 11%,and a decrease in pulmonary function similar to the effectof exposure to oral beta-blockers.^[28] A recent populationbasedstudy of almost 100,000 patients newly prescribed IOPlowering treatment found that patients using medication forpulmonary disease had a significantly higher chance of stoppingbeta-blockers within 90 days of commencement compared tothose without pulmonary disease (8% vs. 4%).^[32] The rate ofdiscontinuation of other IOP lowering medications was similarregardless of whether the patient had asthma or COPD.

Other Side Effects

Other side effects reported with topical beta-blockers includeeffects on the central nervous system such as depression,hallucinations, or confusion, which may be misattributedto dementia in elderly patients. Just as it is important forophthalmologists to be aware of a patient's systemic medication,it is important that family doctors and physicians are aware ofthe patient's ophthalmic medications and their potential sideeffects so that symptoms, due to medication side effects, are notattributed to old age or systemic disease.

Polypharmacy

Elderly patients commonly use multiple medications, with manyusing either systemic beta-blockers or CYP2D6 inhibitors,which can increase the likelihood systemic side effects and,for systemic beta-blockers, reduce the efficacy of topical betablockers.A recent study which evaluated ophthalmic drugs aspart of polypharmacy in nursing home residents with glaucomafound that patients were prescribed an average of six systemicmedications, with 20% using both a systemic and topicalbeta-blockers.^[33] An Australian study also found a 20% rate ofcoprescribing of topical and systemic beta-blockers.^[34] Severalstudies have shown that concurrent use of a systemic β-blockerreduces the efficacy of a topical β-blocker while increasing the riskof systemic side effects.^{[20,21,34,35]} For this reason, we recommendavoiding concurrent use of topical and systemic beta-blockers.

Of concern, the Blue Mountains Eye Study suggesteda possible increase in cardiovascular mortality for patientspreviously diagnosed with glaucoma, particularly notedamong those using timolol. However, the reason for possibleincreased mortality was not certain and the results have not beencorroborated.^[36] A further important study to consider is the lowpressureglaucoma treatment study,^[37] which is often interpretedas demonstrating a harmful effect of topical timolol 0.5% inpatients with normal tension glaucoma (NTG). The study,which included 178 patients with NTG randomized to timololor brimonidine, found that although there was no significantreduction in IOP between groups, patients using timolol had asignificantly higher risk of progression, with 39.2% of the timololgroup noted to have visual field progression compared to only9.1% of the brimonidine group over an average 30-monthfollow-up period. This suggests that either brimonidine had aneuroprotective effect beyond IOP lowering or that timolol washarmful, perhaps, due to reduced ocular perfusion during thenight. However, the study was affected by a large dropout rate,particularly in the brimonidine arm, which limits our ability todraw definitive conclusions.

In summary, 40 years since their introduction, although nolonger the first-line treatment for most patients, beta-blockersremain a commonly prescribed and important IOP loweringmedication. However, while beta-blockers are effective atlowering IOP during the day, sleep-laboratory studies haveshown that they have minimal effect overnight, likely due to thephysiological nocturnal reduction in aqueous production. Lackof nocturnal IOP lowering, coupled with the propensity to lowerblood pressure, means that topical beta-blockers may reduceocular perfusion pressure at night, with the potential to have adetrimental effect on glaucoma progression. Before prescribingbeta-blockers, it is essential to take a thorough past medicaland medication history, and if beta-blockers are considered,we would recommend checking blood pressure and pulse ratebefore starting treatment. A recent review article went as far asto recommend patients should have their CYP2D6 genotypeassessed prior to commencing treatment with topical betablockers;^[19] however, this is unlikely to be practical in clinicalpractice and advising patients to be aware of possible side effectsand monitoring pulse rate and blood pressure may be morerealistic. The use of topical beta-blockers, while not absolutelycontraindicated, should also be reconsidered if patients arethe elderly, have multiple comorbidities, or are using multiplesystemic medications, particularly systemic beta-blockers. Thereis also a strong argument for the use of weaker beta-blockers, suchas timolol 0.1%, which have similar efficacy but less potentialfor systemic side effects. Fixed combination medications areimportant to consider given the evidence of higher adherencerates than with separate medications; however, more evidence isneeded regarding the optimal timing of fixed-dose prostaglandinanalog - beta-blocker combinations, and there is a need forfixed-dose combinations containing weaker concentrations oftimolol. Therefore, while we have four decades of experienceusing topical beta-blockers for glaucoma, there are still questionsunanswered regarding their optimal use. Given the emergence ofless invasive glaucoma surgical procedures, there are, however,likely to be fewer patients needing multiple eye drops forglaucoma. With the increasing number of therapeutic optionsavailable, it becomes increasingly important to tailor treatmentchoices to the individual needs of each patient.

Disclosure

A.J.T. - speaking honorarium and travel support from Allergan,Novartis, Heidelberg Engineering. Travel support from Santen,Thea, Icare. The remaining authors declare no conflicts ofinterest.

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