Effects of topical nipradilol, a beta blocking agent with alpha blocking and nitroglycerin-like activities, on intraocular pressure and aqueous dynamics in humans

Abstract

Aims-To study the eVects of topical nipradilol, a non-selective blocker with blocking and nitroglycerin-like activities, on intraocular pressure (IOP) and aqueous humour dynamics in normal humans and in patients with ocular hypertension. Methods-Nipradilol (0.06%, 0.125%, 0.25%, 0.5%) was applied to normal volunteers (n = 12) to test for IOP lowering eVects. In a second group of normal volunteers (n = 11), nipradilol (0.125% and 0.25%) and timolol (0.5%) were compared for IOP lowering eVects. After a single administration of 0.25% nipradilol, IOP, flare intensity in the anterior chamber, aqueous flow, uveoscleral outflow, tonographic outflow facility, and episcleral venous pressure were either directly measured or mathematically calculated. Topical nipradilol (0.25%) was administered to 24 patients with ocular hypertension twice daily for 8 weeks. Results-Administration of 0.25% nipradilol decreased IOP with a maximum reduction of 4.2 mm Hg lasting 12 hours. A single instillation of both 0.25% nipradilol and 0.5% timolol reduced the IOP in normotensive human subjects to the same degree. A single instillation of 0.25% nipradilol decreased the aqueous flow rate in the treated eye by 20%. Nipradilol produced no significant eVect in tonographic outflow facility or episcleral venous pressure, but uveoscleral outflow was increased.In patients with ocular hypertension, twice daily instillation of 0.25% nipradilol decreased IOP without tachyphylaxis for the 8 week test period. Conclusion-Topical nipradilol (0.25%) reduced IOP by decreasing the aqueous flow rate and probably also by increasing uveoscleral outflow. Nipradilol should be further investigated as a new antiglaucoma drug. (Br J Ophthalmol 2000;84:293-299) Nipradilol is a non-selective blocker with 1 blocking and nitroglycerin-like vasodilating activities that are attributed to its nitroxyl moiety.

Effects of Nipradilol on Alpha-Adrenoceptor Function in Ocular Arteries

“…Together with the data of ß-adrenoceptorblocking properties reported in our previous study [8], the vascular actions of nipradilol in dog central retinal arteries are summarized in table 3. Nipradilol is now used as a potential therapeutic agent for the treatment of glaucoma, since it has been demonstrated to lower intraocular pressure by decreasing aqueous humor formation [5,6] and by increasing aqueous humor outflow [5,6], and to increase ocular blood flow [5][6][7]. The lowering of aqueous humor formation by nipradilol is reportedly associated with ß-adrenoceptor-blocking activity, whereas the stimulation of aqueous humor outflow and ocular blood flow are associated with · 1 -adrenoceptor-blocking and NO-releasing activities [5,6].…”

“…Nipradilol is now used as a potential therapeutic agent for the treatment of glaucoma, since it has been demonstrated to lower intraocular pressure by decreasing aqueous humor formation [5,6] and by increasing aqueous humor outflow [5,6], and to increase ocular blood flow [5][6][7]. The lowering of aqueous humor formation by nipradilol is reportedly associated with ß-adrenoceptor-blocking activity, whereas the stimulation of aqueous humor outflow and ocular blood flow are associated with · 1 -adrenoceptor-blocking and NO-releasing activities [5,6]. Therefore, if the results of the potency order of nipradilol obtained from the vascular tissue can be applied to other ocular tissues, the decrease in aqueous humor formation appears to be more sensitive in lowering intraocular pressure than the increase in aqueous humor outflow.…”

“…However, this cannot be the case, because the magnitude of the vasorelaxation induced by ß-adrenoceptor agonists such as isoproterenol is much less than that by nipradilol in ocular arteries; 10 -6 mol/l isoproterenol and 10 -8 mol/l nipradilol are equipotent [8], therefore relaxations induced by nipradilol at low concentrations can easily overcome the contractions, if any, due to ß-adrenoceptor blockade. Nipradilol increases retinal blood flow in anesthetized cats [6] and optic nerve head tissue blood velocity in anesthetized rabbits [5]. The circulatory actions appear to be mediated with its direct action through liberating NO from the molecule and · 1 -adrenoceptor inhibition against endogenous adrenoceptor agonists.…”

“…Since nipradilol does not penetrate the blood-brain barrier [4], topical application is necessary for the treatment. The drug has been demonstrated to decrease aqueous humor formation [5,6], to increase aqueous humor outflow [5,6] and ocular blood flow [5][6][7], and to relax isolated dog central retinal arteries [8]. Nipradilol is known to possess ß-adrenoceptor- [9] and · 1 -adrenoceptor-blocking activities [10] and to have an NO 2 moiety in its chemical struc-ture.…”

“…Nipradilol, developed as an anti-anginal [1] or systemic hypotensive agent [2], is now being applied for the treatment of glaucoma and high ocular pressure [3]. Since nipradilol does not penetrate the blood-brain barrier [4], topical application is necessary for the treatment.…”