Ocular penetration of β-adrenergic blocking agents. An experimental study with atenolol, metoprolol, timolol and propranolol

Abstract

A comparison was made between the ocular penetration of topically applied 14C-atenolol, 14C-timolol, 14C-propranolol and 3H-metoprolol by means of liquid scintillation counting. Only one eye was treated, the fellow eye served as a control. Blood plasma levels were measured as well. We could detect a relationship between the ocular penetration and the degree of lipophilicity of the drugs used, as was to be expected. Drugs with a higher degree of lipophilicity penetrated more readily into the eye, whereas they also achieved higher blood plasma levels. Relatively high concentrations of atenolol were found in the nicitating membrane, thus reflecting its poor ocular penetration. The concentrations detected in the untreated eye were low and probably cannot explain the marked reduction in intraocular pressure observed after unilateral instillation of active beta-adrenergic blocking drugs, as for instance timolol. Our findings suggest that the ocular penetration of beta-adrenergic blocking agents on topical application only plays a minor part in their ocular hypotensive effect.

The Comparative Multiple‐dose Intraocular Pressure Responses of Nadolol and Timolol in Glaucoma and Ocular Hypertension

“…Since there is a positive relationship between ocular penetration and lipophilicity of the drug used this can be a pharmacokinetic feature in favour of timolol (Ros et al 1979). How important this aspect is was demonstrated with a pro-drug version of Nadolol, the DiacetateNadolol.…”

“…The virgin eye in terms of betablockers is very sensitive towards this group of compounds, so even a very weak betablocker can give an excellent initial response which however may wear off within days or weeks. Since there is a positive relationship between ocular penetration and lipophilicity of the drug used this can be a pharmacokinetic feature in favour of timolol (Ros et al 1979). How important this aspect is was demonstrated with a pro-drug version of Nadolol, the Diacetate-Nadolol.…”

Molecular Design for Enhancement of Ocular Penetration

“…Huang et al 80 compared the penetration of three b-blockers, bufuralol, timolol and acebutolol, into aqueous humor. Ros et al 81 also investigated the drug exposure of four b-blockers: atenolol, timolol, propranolol, and metoprolol. Both studies revealed that timolol showed higher AUC values than the more lipophilic compounds bufuralol and propranolol.…”

“…Both studies revealed that timolol showed higher AUC values than the more lipophilic compounds bufuralol and propranolol. 80,81 The lipophilic nature of these drugs led to the wide tissue distribution and lowered the aqueous humor drug levels. The less IOP reducing efficacy of propranolol relative to timolol may be due to the low unbound fraction caused by high lipophilicity.…”

Cassette analysis of eight beta-blockers in bovine eye sclera, choroid–RPE, retina, and vitreous by liquid chromatography–tandem mass spectrometry

“…Beta-blockers, when applied as an eye drop, are useful pharmacological agents in treating elevated intraocular pressure associated with glaucoma [1]. Beta-blockers are also commonly used as markers to study the influence of drug lipophilicity on permeability of various tissues because a series of beta-blockers are available with a wide range of lipophilicity (log P ranging from −1.0 to 3.0) and similar molecular weights (∼300) and pK a s (∼9.2) [2,3].…”