ABSTRACT.Purpose: To investigate the pharmacological basis of systemic effects of atropine eyedrops, we estimated the bioavailability of ophthalmic 1% atropine solution in healthy volunteers. Methods: In a randomized crossover study we administered 0.3 mg atropine either intravenously or ocularly to six healthy volunteers. The plasma concentrations of the biologically active atropine enantiomer, 1-hyoscyamine, were determined using a muscarinic cholinoceptor binding assay. Results: The mean area under the curve from zero to infinitum (AUC 0-≤) for 1-hyoscyamine was 1.862∫0.580 mg/L ¡ hr after intravenous, and 1.092∫0.381 ml/L ¡ hr after ocular administration (mean∫s.d, nΩ6), respectively. The mean bioavailability was 63.5∫28.6% (mean∫SD, nΩ6; min 19%, max 95%). Large interindividual differences characterized the absorption and elimination phases of 1-hyoscyamine kinetics. The terminal half-life (t 1 / 2 b) of 1-hyoscyamine in plasma was not affected by the route of drug administration. Conclusion: The systemic bioevailability of 1-hyoscyamine was considerable and may explain the systemic anticholinergic side effects reported in association with the clinical use of atropine eyedrops.

Plasma and aqueous humour concentrations and systemic effects of timolol and betaxolol were studied after ocular administration in 45 patients scheduled for extracapsular cataract extraction and intraocular lens implantation. The patients were divided randomly into three groups and received 40 microliters of either 0.5% betaxolol, 0.25% timolol or placebo into the lower cul-de-sacs of both eyes. Blood samples were collected over a period of 4 h and blood pressure and heart rate were monitored during the study. Aqueous humour samples were aspirated at the beginning of the operation. Plasma and aqueous humour concentrations of timolol and betaxolol were analyzed using a sensitive radioreceptor assay. The mean plasma concentrations of betaxolol were lower than those of timolol. The concentration of betaxolol in the aqueous humour was twice as high as the concentration of timolol. Both drugs produced a significant decrease in heart rate. In the timolol group a decrease in heart rate was found 15 min after drug administration, and in the betaxolol group after one hour.

We studied the ocular and systemic absorption of 40 microliters of topical 0.5% timolol in 57 patients using radioligand binding techniques. The mean concentration of timolol in aqueous humour of the treated eye was 1.9 +/- 0.8 micrograms/ml 74 minutes after instillation of the drug. About 18 h after drug instillation the aqueous humour concentration of timolol was 105.5 +/- 60.9 ng/ml. Timolol was found in 15 (42%) contralateral eyes. Concentration of timolol in the contralateral eye increased from 0.04 +/- 0.08 ng/ml at 50 min to 0.3 +/- 0.2 ng/ml at 134 min and was 0.2 +/- 0.4 ng/ml at 18 h after instillation. Timolol concentrations in the aqueous humour of the treated eye appeared to be high enough to occupy beta 1- and beta 2-receptors completely (100%) at 74 min and at 18 h after drug instillation. Timolol concentrations in the contralateral eye were high enough to occupy up to 33.0 +/- 24.7% of the beta 2-receptors and up to 51.7 +/- 35.1% of beta 2-receptors. High drug concentrations and complete beta-receptor occupancy in the aqueous humour of the treated eye after topical timolol are in agreement with the long-lasting ocular hypotensive effects. The low drug concentrations and partial receptor occupancy in the contralateral eye may also be of some clinical significance.