Ocular Betaxolol

Summary

Synopsis

Betaxolol is a lipophilic β-adrenoceptor antagonist relatively selective for β₁-adrenoceptors with only weak β2-blocking activity. Used topically in glaucoma and ocular hypertension, betaxolol 0.5% solution produces a reduction in intraocular pressure of between 13 and 30%, an effect comparable with that of ocular timolol. It may usefully be combined with other types of anti-glaucoma agents. The most notable feature of its adverse effect profile is transient local stinging or irritation, occurring in 25 to 40% of patients. Following ocular administration, betaxolol appears to be largely devoid of adverse bronchopulmonary or cardiac effects, in comparison with nonselective ocular β-adrenoceptor antagonists, which may be more likely to exert systemic effects. Betaxolol has negligible local anaesthetic activity, so that corneal desensitisation does not occur with its use. Thus, betaxolol is an alternative therapeutic option available to the physician for the management of chronic open-angle glaucoma and ocular hypertension. Its apparently lower propensity to affect the cardiopulmonary system represents a significant advantage over other ocular β-adreno-ceptor antagonists.

Pharmacodynamic Properties

Betaxolol is a lipid-soluble (lipophilic) β-adrenoceptor antagonist which is relatively cardioselective, with no intrinsic sympathomimetic activity and little or no membrane stabilising activity. In common with other ocular β-adrenoceptor antagonists, the mechanism of the reduction in intraocular pressure observed with betaxolol is generally considered to be decreased production of aqueous humour by the ciliary body, with no apparent effect on aqueous outflow. The precise mechanism of this effect remains to be elucidated. Retinal and ciliary perfusion pressures in patients have been reported to be unaltered by betaxolol treatment. Betaxolol 0.5% was less toxic to regenerating corneal epithelium in rabbits than was timolol 0.5% or levobunolol 0.5%. Similarly, corneal healing rates were faster with betaxolol (and levobunolol) than with timolol.

Although ocularly administered betaxolol may be absorbed from the nasopharyngeal and conjunctival mucosa into the systemic circulation, betaxolol appears to possess minimal systemic β-blocking activity — approximately 5% that of timolol in 1 radioreceptor assay in rabbits. Ocular betaxolol also failed to antagonise the isoprenaline-induced increase in heart rate in monkeys, an index of systemic β-blockade.

Betaxolol appears to have less propensity for adverse effects on pulmonary function than nonselective ocular β-adrenoceptor antagonists. In studies in patients with respiratory disease or timolol-induced bronchoconstriction, betaxolol has not had any effect on FEV₁, forced vital capacity, or relative forced expiratory volume. However, in an investigation in 85 patients followed for up to 2 years, symptomatic pulmonary obstruction was apparent in 5 patients after 1 to 554 days’ betaxolol treatment. All patients had glaucoma and chronic obstructive pulmonary disease, asthma, or timolol-induced bronchoconstriction at baseline. In 1 study, no statistically significant difference was apparent between betaxolol and placebo in the histamine concentration necessary to produce a 15 to 20% reduction in FEV₁.

Despite its cardioselectivity, betaxolol has had minimal effects on resting or exercise heart rate, blood pressure or double product, after ocular administration, in several placebo-controlled studies. This is in contrast to timolol, which effects significant reductions in these parameters. In 1 study in healthy volunteers, the incidence of CNS effects, including insomnia, depression, hypochondriasis and hysteria, tended to be less with betaxolol than with timolol. In 2 further studies, 16 of 18, and 5 of 7 patients experiencing CNS effects while receiving timolol improved after betaxolol treatment.

Pharmacokinetic Properties

There are no published data detailing the pharmacokinetic properties of betaxolol following ocular administration in humans; such information is important to assess the extent of systemic availability.

The bioavailability of oral betaxolol is 80 to 90% - it does not undergo extensive first pass metabolism. Excretion is mainly via O-dealkylation followed by aliphatic hydroxylation, yielding 2 major inactive metabolites. Betaxolol and its metabolites are excreted renally with an elimination half-life of between 14 and 22 hours, which is prolonged in neonates and the elderly. Total body clearance does not appear to be affected by liver disease but is reduced in patients with severe renal failure.

Therapeutic Trials

In comparisons with placebo, betaxolol has proven superior in reducing intraocular pressure. Mean reductions have ranged between 13 and 27% with betaxolol compared with about 2 to 13% with placebo. Trials comparing betaxolol with timolol reported reductions in intraocular pressure at the end of 6 months’ treatment of between 26 and 36% with betaxolol, and between 29 and 37% with timolol. These 3 trials involved a total of 101 patients.

In a noncomparative trial a reduction of intraocular pressure was obtained within several hours of instillation of betaxolol 0.25%, was maximal at 2 weeks, at 30 to 35%, and was sustained for the duration of the study ( 1 year). In a second noncomparative trial, patients previously administered pilocarpine showed a nonsignificant reduction in intraocular pressure of 8.4% following substitution with betaxolol; in newly diagnosed patients, mean diurnal intraocular pressure was significantly reduced with betaxolol by 17%. In 17 of 20 patients with open-angle glaucoma or ocular hypertension receiving betaxolol 0.5% alone (n=15) or in combination with pilocarpine (n=5), who had been treated with timolol, an additional mean reduction in intraocular pressure of 2.4mm Hg was apparent after 2 weeks, and was maintained for the 12 weeks of study. In specific investigations of combination use, betaxolol therapy resulted in small incremental reductions in intraocular pressure over those obtained with other monotherapies.

After 2 weeks’ treatment with dipivefrine 0.1% alone, intraocular pressure was reduced by 12%, and addition of betaxolol resulted in a total reduction of 15% at 4 weeks. Betaxolol 0.5% twice daily added to oral acetazolamide resulted in an incremental reduction in outflow pressure (intraocular pressure minus an episcleral venous pressure assumed to be 10mm Hg) of 17.6%. With acetazolamide alone the reduction was 42.5%. With betaxolol alone the reduction was 27.3% below baseline, decreased by an additional 35.1% with acetazolamide.

Adverse Effects

The most frequent adverse effect of topical betaxolol treatment is transient local irritation, which occurs in 25 to 40% of patients. A double-blind comparison indicated a higher incidence of ocular symptoms with betaxolol (89%), than with timolol (48%). Ocular symptoms reported include burning, stinging or irritation, pruritus, hyphaemia, vitreous separation and blurred vision. As a cardioselective agent, betaxolol is less likely to be associated with adverse respiratory effects than nonselective β-adrenoceptor antagonists. While adverse respiratory effects have been observed in a small number of patients with underlying respiratory disease followed for up to 2 years on betaxolol, their relationship to treatment is uncertain. Of a total of 56 spontaneous reports of adverse drug experience attributed to betaxolol during its first year of marketing in the US, postmarketing surveillance identified 11 cases of asthma, 8 requiring hospitalisation.

During a clinical trial in 101 patients treated with betaxolol for up to 2 years, cardiac arrhythmia and shortness of breath occurred in 1 patient and bundle branch block in a second. There are case reports describing myocardial infarction, sinus arrest, and congestive heart failure in association with ocular betaxolol. Of the 56 spontaneous reports mentioned above, there were 4 instances of bradycardia, 1 with syncope, and 1 of cardiac arrhythmia. Other adverse effects reported in association with ocular betaxolol include depression, disorientation, vertigo and sleepwalking; and rhinitis, dysuria, alopecia, and prolonged prothrombin time.

Dosage and Administration

The recommended dosage of ocular betaxolol in glaucoma or ocular hypertension is one drop of 0.5% solution in each eye twice daily.