Although timolol seems to cause systemic side-effects which can be serious, it seems to be locally tolerated better than prostaglandin analogues.
Systemic adverse effects
A historical cohort study by Kirwan. was performed to determine the incidence of airways obstruction in subjects with no previous history of airways obstruction, following treatment with topical beta antagonists for glaucoma for the period 1993–7.
For selective topical beta antagonists 12 of 324 treated subjects developed airways obstruction, compared with 112 of 9 094 controls (adjusted hazard rate 3.0, 95% confidence interval 1.6 to 5.4). For non-selective topical beta antagonists, the corresponding figures were 69 of 2321 subjects compared with the same control group (adjusted hazard rate 2.2, CI 95% 1.6 to 3.0). There was no significant difference between groups, p = 0.47, chi(2) test, both being associated with a significantly increased risk of airways obstruction.
Selective topical beta antagonists do appear to have an excess risk of airways obstruction in this population setting and should be subject to the same prescribing caveats as unselective topical beta antagonists «Kirwan JF, Nightingale JA, Bunce C ym. Do selectiv...»1.
Waldock ate al recruited 141 newly diagnosed glaucoma patients who underwent a full ocular, cardiovascular, and respiratory examination, including an electrocardiogram (ECG) and spirometry.
At the initial examination, 17 patients (13%) had ECG evidence of first degree heart block, seven were prescribed latanoprost, six with brimonidine, and four with betaxolol. Eight patients were found to have arespiratory wheeze, four were prescribed brimonidine and the other four latanoprost. They were reviewed 3 months later. One eye of each patient was randomly chosen for analysis, performed using analysis of variance and the chi(2) test.
Timolol was associated with lowered pulse rates and reductions in the spirometry measurements. 41% of patients using brimonidine complained of systemic side effects and over 55% of patients using betaxolol complained of ocular irritation including dry eye. 28% of patients required an alteration in their glaucoma management «Waldock A, Snape J, Graham CM. Effects of glaucoma...»2.
Local side-effects
Twelve studies involving 3048 patients with open-angle glaucoma or ocular hypertension were included in the meta-analysis comparing timolol with prostaglandin analogs. Participants received either travoprost, other prostaglandin analog or timolol.
Ocular hyperaemia was the most common side-effect of prostaglandin analogues. The combined results suggested that travoprost 0.004% caused a higher percentage of ocular hyperaemia than timolol 0.5% (OR = 6.76, 95% CI 4.93-9.25, P < 0.00001), or latanoprost 0.005% (OR = 2.03, 95% CI 1.49-2.75, P = 0.00001) and travoprost 0.0015% (OR = 1.64, 95% CI 1.32-2.04, P = 0.00001). However, there was no statistically significant difference between travoprost 0.004% and bimatoprost 0.03% (OR = 0.65, 95% CI 0.42.1.00, P = 0.05) in hyperaemia.
There was an increased incidence of pigmentation with travoprost 0.004% when compared to timolol 0.5% (OR = 11.06, 95% CI 2.07-59.08, P = 0.005). There was no statistically significant difference between travoprost 0.004% and latanoprost 0.005% (OR = 0.74, 95% CI 0.38-1.46, P = 0.4) in iris pigmentation.
Travoprost 0.004% caused a higher percentage of eyelash changes than timolol 0.5% (OR = 38.81, 95% CI 20.65-72.93, P < 0.00001). There was also an increased incidence of eyelash changes with travoprost 0.004% than latanoptost 0.005% (OR = 3.82, 95% CI 2.50-5.84, P < 0.00001), or travoprost 0.0015% (OR = 1.79, 95% CI 1.40-2.27, P < 0.00001) «Li N, Chen XM, Zhou Y ym. Travoprost compared with...»3.
In a meta-analysis comparing latanoprost with timolol in patients with open-angle glaucoma, latanoprost caused hyperaemia and iris pigmentation more often than timolol (RR = 2.20, 95% CI 1.33-3.65). The number needed to harm was 21 (CI 14-42) when compared to timolol. Moreover, of 478 patients who were treated with latanoprost, 21 (4.39%) developed iris pigmentation. In contrast, none of the patients treated with timolol showed this effect (0/387). Four studies compared systemic adverse reactions to timolol versus latanoprost, such as their effects on systolic blood pressure and heart rate. Timolol caused slowing of heart rate after 3 or 6 months of treatment, and this returned to the baseline level after switching to latanoprost «Zhang WY, Po AL, Dua HS ym. Meta-analysis of rando...»4.
In a systematic review comparing timolol with brimonidine(α2 adrenergic agonist), prostaglandin analogs (travoprost, latanoprost), other β adrenergic antagonists, and placebothere was a twofold increase in the odds of participant drop out due to drug-related adverse events among participants randomized to timolol versus betaxolol (OR. 2.40; 95% CI, 1.04-5.53, five trials), and the odds of dropping out were lower among participants randomized to timolol when compared to those receiving brimonidine (OR, 0.21; 95% CI 0.14-0.31, three trials). As to the comparison of timolol with prostaglandin analogs, participants receiving either travoprost or latanoprost had six times the odds and twice the odds (OR, 6.76, CI 4.93-9.25 and OR 2.03, CL 1.49-2.75), respectively, of dropping out of the study due to conjuctival hyperemia, compared to patients receiving timolol. Both drugs also significantly increased iris pigmentation (travoprost OR 11.06, CI 2.07-59.08 and latanoprost OR 8.01, Cl 1.87-34.30) «Boland MV, Ervin AM, Friedman DS ym. Comparative e...»5.