Timolol: A Review of its Therapeutic Efficacy in the Topical Treatment of Glaucoma

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Synopsis: Timolol maleate1is a nonselective β-blocking drug used for the topical treatment of increased intraocular pressure in patients with chronic open angle glaucoma. In comparative studies it has had a somewhat greater ocular hypotensive effect than the sympathomimetic agent adrenaline (epinephrine), or lower to medium concentrations (up to 4%) of the miotic drug pilocarpine, usually lowering intraocular pressure by about 30 to 35% (absolute pressure reduction). Timolol has been well tolerated by most patients, producing fewer subjective complaints than the comparison drugs, and objective measurements of ophthalmic status have not revealed any marked changes. Although some patients have been treated for extended periods without serious adverse effects or loss of effectiveness, further published reports in larger numbers of patients treated over several years are needed to confirm the drug's apparent long term safety and continued efficacy. Nevertheless, on the basis of present evidence, timolol appears to represent an important advance in the topical treatment of glaucoma.

Pharmacodynamic Studies: Following topical administration, timolol significantly lowered intraocular pressure in healthy volunteers or in patients with open angle glaucoma or ocular hypertension. In studies using a range of concentrations, the maximum effect on intraocular pressure appeared to occur with a 0.5% solution. The mechanism by which topical timolol reduces intraocular pressure is apparently primarily through a reduction in aqueous humour production. Whether or not an increase in facility of outflow of aqueous humour also occurs is unclear, divergent findings in this area having been reported.

Haemodynamic changes during timolol administration have involved only small decreases in heart rate and slight, statistically insignificant decreases in blood pressure, which were not considered to be clinically important. However, such findings were usually in patients without history of cardiac disease, bradycardia or similar disorders which might make them susceptible to β-adrenoceptor antagonists. Similarly, patients with asthma have been excluded from most studies. Thus, the safety of timolol in these patient populations needs further investigation in carefully conducted studies.

Pharmacokinetic Studies: There is no published information on the pharmacokinetic properties of timolol during ocular administration in man. Such studies are needed to determine the extent of systemic absorption. In single dose studies in rabbits, peak blood and aqueous humour levels (0.188μg/ml and 2.47μg/ml, respectively) occurred 30 minutes after ocular administration of a 0.5% solution.

Systemically absorbed timolol appears to be widely distributed in body tissues, the apparent volume of distribution being about 1.3 to 1.7L/kg after oral or intravenous doses (0.1 and 0.02mg/kg, respectively) administered to healthy volunteers. Following gastrointestinal absorption timolol was excreted primarily in the urine (73% of administered radioactivity), mainly as unidentified metabolites. The elimination half-life appeared to be about 2 to 5 hours after a 4 to 10mg oral dose in healthy subjects.

Therapeutic Trials: Timolol has been studied primarily in comparative trials with adrenaline or pilocarpine in patients with chronic open angle glaucoma. Its use in acute closed angle glaucoma has not been reported in published studies. Although a few studies have involved some patients who were treated with timolol for 2 years or longer, the number of patients who have received the drug for extended periods is relatively small.

Timolol was slightly more effective than pilocarpine (1 to 4%) in lowering intraocular pressure (about a 26 to 38% reduction versus 20 to 29%) and was usually significantly more effective than adrenaline (about a 32 to 39% and a 22 to 31% decrease with timolol and adrenaline, respectively). Although a slight reduction in the initial magnitude of the hypotensive effect of timolol occurs during the first 1 to 2 weeks of treatment, marked tachyphylaxis (as has been reported in some patients with some other topically administered β-blocking drugs, e.g. atenolol) has apparently not been a problem with timolol. Further studies in which larger numbers of patients are treated for long periods are needed before it can be definitively stated whether or not tachyphylaxis is likely to occur in some patients.

Side Effects: Timolol has been well tolerated in most patients treated to date. The incidence of subjective complaints such as burning eyes, browache, dryness of the eyes, etc. with timolol (usually about 5 to 10% of patients) was often similar to that seen with no treatment, while adrenaline and pilocarpine produced such reactions much more frequently (usually about 20 to 30%, each).

Objective measurements of ophthalmic status during topical timolol treatment showed few changes. Importantly, no marked reduction in tear production occurred, as has been produced by systemic administration of the β-blocking agent practolol as 1 aspect of a systemic mucocutaneous disorder. However, studies reporting such data were usually only of a few months duration, and further published reports in which larger numbers of patients are treated for extended periods are needed to confirm its apparent lack of serious adverse effects.

Dosage and Administration: The recommended starting dosage of timolol is 1 drop of 0.25% solution in the affected eye(s) twice daily. If response is inadequate the 0.5% solution may be substituted in the same manner. When intraocular pressure is established at a satisfactory level, many patients can be adequately maintained using once daily administration.

Substitution of timolol for other glaucoma regimens should be done using both the previous regimen and timolol (0.25%, 1 drop twice daily) on the first day and thereafter timolol alone, subsequently substituting the 0.5% solution if necessary.

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