Ocular Metipranolol

Summary

Synopsis

Metipranolol is a non-selective β-adrenoceptor blocking agent used for the topical treatment of elevated intraocular pressure in patients with chronic open angle glaucoma or ocular hypertension. In double-blind comparative studies of up to 4 months duration, metipranolol 0.1 to 0.6% produced comparable reductions in intraocular pressure to timolol 0.25 to 0.5% and levobunolol 0.5%, lowering pressure by about 20 to 29% from baseline. Metipranolol has been well tolerated by most patients, producing only minor changes in objective measurements of ophthalmic status and systemic parameters. Similarly, subjective ophthalmic complaints have been minimal although reports of initial stinging or burning upon instillation have occurred. Further published reports, in which larger numbers of patients are treated over extended periods, are needed to confirm the drug’s apparent long term comparative efficacy.

Studies of ocular metipranolol to date are encouraging, and the drug demonstrates a lasting intraocular pressure reducing effect with good tolerability. Thus, ocular metipranolol provides a viable alternative to ocular timolol and levobunolol in the topical treatment of chronic open angle glaucoma or ocular hypertension.

Pharmacodynamic Studies

Following ocular instillation, metipranolol produced a significant reduction in intraocular pressure in healthy subjects and in patients with open angle glaucoma. The maximum effect on intraocular pressure occurred with metipranolol 0.6%, with peak effects appearing approximately 2 hours following instillation and intraocular pressure reductions persisting for at least 24 hours. In comparative single-dose studies in patients with chronic open angle glaucoma, metipranolol 0.6% produced comparable reductions in intraocular pressure to timolol 0.5%, and to levobunolol 0.5 to 1% and befunolol 0.25 to 0.5%. The mechanism by which topical metipranolol reduces intraocular pressure appears to be primarily related to suppression of aqueous humour formation. Although the effects of the drug on corneal sensitivity have varied, it has been suggested that caution be exercised in patients wearing contact lenses.

Haemodynamic changes following ocular application of metipranolol have been limited to small statistically insignificant reductions in heart rate and systemic blood pressure, which were not considered to be clinically important.

Pharmacokinetic Studies

There is no published information available on the pharmacokinetic properties of metipranolol following ocular administration in man — such studies are needed to ascertain the extent of systemic absorption of the drug after ocular administration.

Metipranolol is rapidly absorbed after oral administration in healthy volunteers, with mean peak plasma concentrations occurring approximately 1 hour after administration. The drug undergoes complete and rapid deacetylation in plasma to form the biologically active metabolite, deacetyl metipranolol. This metabolite appears to be extensively distributed in body tissues, with an apparent volume of distribution of 3.5 L/kg after a 6 to 25mg intravenous dose of metipranolol in healthy subjects. Following oral administration, 4% of the dose appeared in the urine as deacetyl metipranolol. There are no published data available regarding the faecal excretion, if any, of this metabolite. The elimination half-life appears to be approximately 2.5 to 4 hours, with a total clearance of 0.94 L/h/kg in healthy volunteers.

Therapeutic Trials

Metipranolol has been evaluated in uncontrolled and in double-blind comparative trials with timolol and levobunolol in patients with chronic open angle glaucoma or ocular hypertension. However, the controlled comparative studies reporting such data were usually relatively small and only of a few months duration. Further trials in which larger numbers of patients are treated over extended periods are required to confirm the comparative efficacy of metipranolol in the treatment of patients with these conditions.

In uncontrolled studies of up to 12 months duration, metipranolol 0.1 to 0.6% produced a mean decrease in intraocular pressure of 25 to 34% from baseline. Furthermore, in short to medium term comparative studies, twice daily ocular instillation of metipranolol 0.1 to 0.6% reduced intraocular pressure by 15 to 24% from baseline, which was not statistically different from the 12 to 26% pressure reduction produced by timolol 0.25 to 0.5%. A 3-month study comparing metipranolol 0.6% with levobunolol 0.5% demonstrated a mean decrease in intraocular pressure of 29% with both drugs with no significant differences between treatment groups over the course of the study. In addition, the percentage of patients who achieved satisfactory intraocular pressure control with metipranolol was equivalent to that with timolol and levobunolol. Although the initial magnitude of the reduction in pressure diminished slightly after the first 1 to 2 weeks of metipranolol therapy, subsequent long term therapy did not produce a further decrease in effect.

While placebo-controlled trials involving the administration of metipranolol to patients with glaucoma have not been published, the prophylactic use of metipranolol has been compared with placebo in patients undergoing extraction of senile cataracts. In a 10-day double-blind study, only 10% of patients receiving metipranolol 0.6% experienced an elevation of intraocular pressure within the first 24 hours of cataract removal, compared with 65% receiving placebo.

Side Effects

The ocular instillation of metipranolol (0.1 to 0.6%) has generally been well tolerated in studies of up to 12 months duration. However, the comparative tolerability of metipranolol with timolol or levobunolol has been restricted to short term studies in relatively small numbers of patients and additional comparative studies involving larger patient numbers over extended periods are needed to confirm its side effect profile in relationship to other similar agents. The most frequent subjective complaint, reported by approximately 12 to 56% of patients, was initial stinging or burning upon instillation of the drug, which was more common with metipranolol than with timolol or levobunolol although this difference was not significant. Other ocular side effects, such as hyperaemia of the lid and conjunctiva, and a slight reduction in tear production, occurred in isolated cases and were of insufficient severity to necessitate discontinuation of metipranolol. Systemic adverse reactions such as respiratory difficulty and hypersensitivity were reported infrequently (occurring in up to 6% of patients) and in 1 study were responsible for 1 and 2 out of 47 patients, respectively, being withdrawn from treatment. Changes in heart rate and blood pressure following metipranolol administration were usually small and not clinically significant although subjects with cardiovascular or bronchospastic disease were excluded from these studies. Consequently, these findings of minimal systemic effects of ocular metipranolol cannot be assumed in such patients and caution should therefore be exercised.

Dosage and Administration

The most commonly administered dosage of metipranolol is 1 drop of 0.3% solution in the affected eye(s) twice daily. If response is inadequate, the 0.6% solution may be administered in the same manner. Carefully conducted studies in patients with conditions which might be aggravated by β-blockade are needed before the safety of this drug in such patients can be established.