Timolol

Summary

The extent of impairment of respiratory function in a group of 52 elderly, glaucomatous patients receiving topical timolol therapy was investigated. To predict those patients who were likely to benefit from changing therapy, symptoms were elicited by direct questioning, and lung spirometry was measured before and after inhalation of salbutamol. Changing from timolol to either pilocarpine or the cardioselective betaxolol produced improvement in lung function tests. Mean peak flow increased from 278 1/min to 328 1/min (p [less than] 0.001), forced expiratory volume in 1s ([FEV.sub.1]) from 1.66 1 to 1.85 1 (p [less than] 0.001) and forced vital capacity (FVC) from 2.4 1 to 2.64 1 (p [less than] 0.001). Spirometry in a control group of 20 subjects was unchanged. Nineteen of 47 patients demonstrated a clinically significant (defined as 15% of more) increase in all values of lung function tests. Change to pilocarpine or betaxolol was equally effective in producing improvement but betaxolol had fewer side-effects. The presence of exertional dysponea, cough with sputum, raised dysponea score and improved lung function tests after salbutamol identified those patients experiencing clinically significant bronchospasm with an 89% specificity and 74% sensitivity.

Introduction

In the wester world glaucoma affects 6-7% of elderly people and is responsible for some 16% of blindness registrations in those over 65 years [1-3]. The nonselective beta-adrenergic antagonist timolol, administered topically, is the mainstay of medical therapy. Topical timolol lowers intraocular pressure without changing pupillary size and has few ocular side-effects [4, 5].

Administration of beta-adrenergic blocking agents may impair respiratory function, even in those without history of respiratory disease, especially if non-selective preparations are used. Oral timolol 10 mg given to patients, with no history of astrhma or chronic respiratory disease, following myocardial infarction significantly impairs respiratory function tests [peak flow, forced expiratory volume in 1s ([FEV.sub.1]) and forced vital (FVC)] without causing complaints of dysponea [6].

Significant amounts of topically administered timolol gain access to the circulation by drainage through the nasolacrimal duct and absorption from the nasal mucosa, thus avoiding first-pass metabolism. A dose of one drop of 0.5% timolol solution to each eye approximates to a 10 mg oral dose [7, 8]. This is known to cause respiratory impairment amongst those with a tendency to bronchospasm [9-11], but topical therapy is considered safe in those without such history.

Firstly this study aimed to ascertain the prevalence of clinically significant, unrecognized airflow obstruction affecting those already using topical timolol. Secondly we hoped to find a simple method, based on respiratory symptoms obtained by direct questioning and the response to inhalation of beta-agonists, of identifying those experiencing significant airflow obstruction. Finally we hoped to see if there was a parallel improvement in respiratory symptoms and lung function tests on changing therapy.

Change to the cholinergic agent pilocarpine was used to observe changes in lung function tests in a group once beta-antagonists had been withdrawn. Substitution for timolol by the relatively cardioselective betaxolol [12] was used to see if patients given a cardioselective beta-antagonist might improve their respiratory function tests.

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Materials and Methods

Fifty-two patients, 25 men (mean height 1.68 m, range 1.57-1.85 m) and 27 women (mean height 1.57 m, range 1.48-1.78 m) aged 65-92, mean 77.5 years, receiving topical timolol for glaucoma were recruited from ophthalmology clinics. A control group of patients, five men (mean height 1.64 m, range 1.55-1.73 m) women (mean height 1.55 m, range 1.43-1.8 m) aged 66-91, mean 75.5 years, was also recruited simultaneously from the same clinics, so as to allow exclusion of a learning effect with the spirometer for any changes in lung function tests.

None of the patients or controls was spontaneously complaining of shortage of breath. All were ambulant, none was receiving other beta-blocker or bronchodilator therapy and none was know to have asthma or obstructive airways disease. Subjects with cognitive impairment, defined as a mental test score of less than 9 out of 10 [13] had been excluded. There was no history of recent respiratory tract infection or heart failure and intraocular pressures were stable in all subjects.

The patients' age, sex, drug and smoking histories were recorded together with the results of questioning about previous respiratory disease.

Inquiry was made, using standardized phrases, about the regular presence of cough with sputum, exertional dysponea, wheeze and nocturnal dysponea. A dysponea score, based upon patients comparing themselves with others of their own age and reporting how breathless they felt when undertaking activities of daily living [14] was derived for each patient. The score ranged from 0 (normal) to 4 (dysponeic or slightest exertion). The aim was to correlate the presence of these symptoms with those affected by clinically significant bronchospasm and so provide a method of identifying patients who might benefit from change in therapy. To reverse beta blockade and so identify those experiencing bronchospasm, peak flow, [FEV.sub.1] and FVC were recorded, using a Micromedical Pocket spirometer, before and after the inhalation, through a nebulizer, of 2.5 mg of the beta-2 receptor agonist salbutamol. A 15% improvement in all three values was taken as evidence of bronchospasm. Those with inconsistent technique with the spirometer were excluded from the study. The recorded values were the best of three attempts. The lung function tests were performed at least 6 hours and less than 8 hours after the administration of topical therapy.

Timolol therapy was changed and patients were randomly allocated topical pilocarpine 2% qds or betaxolol 0.5% bd to both eyes. Exception was made for one patient with pilocarpine allergy and two patients using both timolol and pilocarpine who were given betaxolol. The controls were assessed similarly but no change was made to their topical medication.

Lung function tests were repeated after a 4-week wash-out period on the new therapy, by an observer unaware of the patientsJ enrolment values. Those who had improved peak flow, [FEV.sub.1] and FVC by 15% (i.e. all three values) were adjudged to demonstrate clinically significant improvement in lung function tests [15]. Inquiry was made as to subjective change in perception of breathing. The specific symptom inquiry and dyspnoea scores were repeated with a view to correlating changes in symptoms with changes in lung function tests. Previous therapy was reinstated and the patients returned to their ophthalmologist for review in the light of changes in lung function tests.

For statistical analysis, independent t tests were used to test significance of differences between the group changes in mean peak flow, [FEV.sub.1], FVC between enrolment and review. Discriminant function analysis [16] using smoking, enrolment symptoms, dysponea score and 15% improvement with salbutamol was used to establish a best set of binary predictors of clinically significant improvement in lung function tests on changing therapy.

Results

Of 52 patients enrolled, 27 were changed to betaxolol and 25 to pilocarpine. Forty-seven completed the trial; four subjects using pilocarpine and one betaxolol withdrew because of ocular side-effects. Three of 20 controls failed to attend follow-up and one developed left ventricular failure.

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As reported previously [17] amongst those completing the study there was significant improvement in mea peak flow, from 278 1/min to 328 1/min (t = 5.73, p [less than] 0.001), mean [FEV.sub.1], from 1.66 to 1.85 1 (t = 7.09, p [less than] 0.001), and mean FVC from 2.40 1 to 2.64 1 (t = 5.07, p [less than] 0.001) on changing to betaxolol or pilocarpine. Controls showed no significant changes in lung function tests with mean peak flow falling from 225 1/min on enrolment to 253 1/min on review, [FEV.sub.1] increasing from 1.47 to 1.49 1 and FVC from 2.10 1 to 2.14 1 between enrolment and review. Change to either betaxolol or pilocarpine was associated with improved lung function tests with no significant difference in changes in mean values between the two groups. Both showed significant improvement compared with controls (Table I).

In addition, 19 (40%) of 47 completing the study demonstrated clinically significant (15% or more) improvement in all recorded measures of lung function on changing therapy. Proportionally more patients improved all lung function tests by 15% or more when changed to pilocarpine. Ten (48%) of 21 allocated pilocarpine improved and 9 (35%) of 26 given betaxolol did so (Table II).

Among the 19 showing clinically significant improvement, mean peak flow improved 45%, from 224 1/min to 325 1min (t = 8.12, p [less than] 0.001), mean [FEV.sub.1] 27%, from 1.39 1 to 1.77 1 (t = 14.02, p [less than] 0.001), and mean FVC 21%, from 2.12 1 to 2.56 1 (t = 10.66, p [less than] 0.001). The lung function tests of the remaining 28 patients showed small but statistically significant improvement in mean peak flow, 314 1/min to 329 1/min (t = 2.48, p = 0.02) and [FEV.sub.1], 1.83 1 to 1.90 1 (t = 3.58, p = 0.001) and a small but not statistically significant increase in FVC, from 2.60 1 to 2.69 1 (t = 1.55, p NS) after 4 weeks of new therapy.

Review of enrolment symptoms revealed a higher prevalence of respiratory symptoms among those subsequently demonstrating clinically significant improvement in lung function tests with new therapy than among the group who showed no significant change (Table III). Some patients denied exertional dyspnoea but had a raised dyspnoea score and others complained of exertional dyspnoea yet felt their exercise tolerance was as good as others of their own age.

Discriminant function anaylsis of smoking, the enrolment symptoms, a raised dyspnoea score and 15% improvement with salbutamol was used to determine agreement between these possible predictors of clinically significant improvement in lung function tests and actual improvement. The presence in combination on enrolment of a cough with sputum, exertional dyspnoea, a raised dyspnoea score and reversal of bronchospasm by nebulized salbutamol inhalation predicted clinically significant improvement with 83% accuracy (kappa = 0.64), sensitivity 74% and specificity 89%. The addition of any or all of the information regarding smoking, nocturnal dyspnoea or wheeze did not add to the level of agreement. Even using this combination of predictors, five of the 19 patients showing clinically significant improvement in lungf function tests would not have been identified.

On review after 4 weeks there was some improvement in respiratory symptoms, almost exclusively among those demonstrating clinically significant improvement in lung function tests. Of the 19 demonstrating clinically significant improvement in lung function 12 improved their dyspnoea score, eight claimed a subjective improvement in breathing and six no longer complained of exertional dyspnoea. There was little change in symptoms or dyspnoea scores among the other 28 patients or controls. Pilocarpine and betaxolol were equally associated with improved symptoms (Table IV).

Discussion

Elderly people are particularly vulnerable to the effects of beta-antagonists and form the majority of patients with glaucoma, yet previous studies of respiratory side-effects of treatment have not focused specifically upon them.

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Elderly patients commonly have reversible airflow obstruction, often undiagnosed [18-21]. They are less likely to complain of symptoms of shortage of breath than are the young. This may be because other medical conditions predominate and also because breathlessness is too readily accepted as a feature of old age. This might explain why none of our patients felt the need to report respiratory symptoms to a doctor despite the high prevalence that we found on direct questioning.

Many patients had spirometry recordings below their predicted norms but we did not use this as a basis for demonstration of impaired lung function as we feel published norms are unreliable in very elderly people.

This study confirms a high prevalence of unrecognized reversible airflow obstruction in elderly subjects. The substitution of timolol was associated with clinically significant improvement in lung function tests in 40% of patients. This latter group had a high prevalence of respiratory symptoms on direct questioning and showed most symptomatic improvement on changing therapy.

The presence of exertional dyspnoea, cough with sputum, a raised dyspnoea score and 15% improvement in all lung function tests after inhalation of salbutamol were predictors of those likely to demonstrate a clinically significant improvement on changing therapy. Even using such predictors some asymptomatic patients experiencing clinically significant airflow obstruction would be missed. There seems no simple way of identifying all those suffering significant respiratory side-effects.

Reversible airflow obstruction is a contra-indication to beta-antagonist therapy for all but the most pressing of indications. The dose of topically administered drugs reaching the circulation may be reduced by asking the patient temperarily to occlude the nasolacrimal duct with a finger, but few elderly patients are likely to comply. Systemic delivery of topical drug therapy must be assumed. We should include topical therapy as an important part of our routine enquiry about patient medications.

We believe the incidence of unrecognized impairment of lung function tests induced by topical timolol is too high to justify its use for elderly patients. Alternative treatment should be used. If medical therapy with topical beta-antagonists is deemed essential we recommend a more cardioselective agent.

References

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