Cardiac effects of different eyedrop preparations of timolol in rabbits

Coadministration of phenylephrine and increasing solution viscosity can decrease systemic timolol absorption after eyedrop application. In this study, changes in the heart rate of rabbits after non-viscous (1 cP) and viscous timolol-phenylephrine (330 cP) solution were compared with those after control timolol eyedrops. The resting heart rate of rabbits was not influenced by control timolol eyedrops (0.6 mg/ml, 25 microliters in both eyes). In contrast, control timolol eyedrops antagonized greatly isoproterenol-induced tachycardia for 120 min. Timolol (0.6 mg/ml)-phenylephrine (0.8 mg/ml) eyedrops (25 microliters in both eyes) antagonized the chronotropic effect of isoproterenol less than control timolol eyedrops for the first 10 min. Compared to control timolol eyedrops, administration of viscous timolol (0.3 mg/ml)-phenylephrine (0.8 mg/ml) solution (25 microliters in both eyes) lowered systemic beta-blocking activity of timolol for 120 min. Previously we have shown that compared to non-viscous (1 cP) timolol (5.0 mg/ml) eyedrop (25 microliters), viscous (330 cP) timolol (2.5 mg/ml)-phenylephrine (0.8 mg/ml) solution (25 microliters) results in equal or increased timolol concentrations in the ocular tissues. All three timolol eyedrops antagonized the isoproterenol-induced tachycardia more than buffer solution but the onset of significant beta-blocking effect induced by eyedrops varied from 3 min (control eyedrop) to 40 min (viscous eyedrop). Our results indicate that possible cardiac effects of ophthalmic timolol can be diminished by phenylephrine coadministration and increased solution viscosity.