Adrenergic agents lower IOP primarily through their alpha-2 stimulation, which lowers adenylate cyclase activity and reduces intracellular cAMP levels. Secondary mediators may include prostaglandins, but topical nonsteroidal anti-inflammatory drugs do not interfere with the efficacy of adrenergic agents in humans. Epinephrine, a nonspecific adrenergic agonist, increases aqueous flow and may raise IOP transiently, but long-term use lowers IOP and is additive to acetazolamide and pilocarpine. Dipivefrin is a more lipophilic prodrug of epinephrine that is converted by ciliary body esterases to epinephrine. Both dipivefrin and epinephrine are contra-indicated in patients at risk for pupillary-block glaucoma and in patients with aphakia, hypertension, arrhythmia, or ischemic heart disease. Long-term therapy is discontinued in many patients because of a delayed allergy-like reaction.

Among alpha agonists, clonidine can lower IOP but is unpopular because of its side effects of severe systemic hypotension and sedation. Apraclonidine, a hydro-philic derivative of clonidine, lowers IOP by decreasing aqueous flow and reducing episcleral venous pressure. Apraclonidine 0.5% three times daily is safe and effective in the management of ocular hypertension and advanced glaucoma, although long-term use is hampered in many patients by a delayed allergy-like reaction. Apraclonidine 1% is indicated in the preoperative prophylaxis of acute IOP spikes associated with ALT, iridotomy, Nd:YAG laser capsulotomy, and cataract and glaucoma surgery. Apraclonidine reduces anterior segment blood flow and is therefore contraindicated in anterior segment ischemia and in advanced diabetic eye disease.

Brimonidine is an alpha-2-selective agonist. Brimonidine acts on alpha-2 and imidazole receptors and lowers IOP by decreasing aqueous flow and increasing uveoscleral outflow. The safety profile for long-term use of brimonidine 0.2% is similar to that for apraclonidine 0.5%, and the incidence of severe allergy-like reaction is somewhat lower. In very young children, it should be used with caution since the incidence of serious side effects increases (see chapter 13 for discussion of pediatric glaucoma). Lower concentrations of brimonidine available with newer preservative formulations have reduced the side effect profile further, without significantly reducing the IOP reducing effectiveness.

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