Preclinical evaluation of brimonidine

Preclinical studies of brimonidine show that it is a potent alpha(2)-adrenoceptor agonist that is 1000-fold more selective for the alpha(2)- vs. the alpha(1)-adrenoceptor, and is 7-12-fold more alpha(2)-selective than clonidine and 23- to 32-fold more alpha(2)-selective than apraclonidine (p-aminoclonidine). Brimonidine decreased intraocular pressure (IOP) in various animal models but, unlike apraclonidine, brimonidine was not mydriatic. The site and pharmacology of the IOP response depends on the animal species. In rabbits, the IOP response to brimonidine is mediated by an ocular alpha(2)-adrenoceptor while in monkeys, a central nervous system (CNS) 'imidazoline' receptor appears to be involved. Brimonidine decreased IOP by suppressing the rate of aqueous humor flow and enhancing uveoscleral outflow. Topical brimonidine resulted in posterior segment drug levels adequate to activate alpha(2)-adrenoceptors, but was not vasoconstrictive in a model designed to assess the vasoactivity of the human retinal microvasculature. Brimonidine protected the rat optic nerve from secondary damage following mechanical injury to the optic nerve and was nontoxic in an array of experiments designed to evaluate ocular and organ toxicity. Taken together, the high alpha(2)-adrenoceptor selectivity, ocular hypotensive efficacy, retinal bioavailability and neuroprotective properties make brimonidine an important addition to the field of antiglaucoma agents.