Adrenergic Stimulators

Like the β-adrenergic receptors, the α-adrenergic receptors are part of the sympathetic nervous system that play a major role to regulate in part aqueous humor dynamics (see Chapter 1). Development of this class of glaucoma medications was based on the observation that a topical formulation of the antihypertensive agent clonidine lowered intraocular pressure (IOP) (1). The clinical value of clonidine as an ocular hypotensive agent was limited by the fact that it penetrates the blood–brain barrier, occasionally causing significant systemic hypotensive episodes, even with topical administration. Further research led to the approval of several α₂-adrenergic agonists for use in managing glaucoma. The nonselective α- and β-adrenergic receptor agonists epinephrine and the prodrug dipivefrin are no longer available but are summarized in this chapter for historical reasons.

MECHANISMS OF ACTION

The mechanism of action by which apraclonidine, clonidine, and brimonidine tartrate lower IOP is through reducing aqueous production (2). These agents have little, if any, effect on blood–aqueous barrier permeability (3). In one clinical trial, there was also a suggestion that apraclonidine may increase outflow facility and reduce episcleral venous pressure (4). Given the presence of α_2A-adrenergic receptors in cultured human trabecular meshwork cells (5), these agents may exert some effect on outflow facility. In contrast, brimonidine does not appear to have an effect on conventional aqueous humor outflow or episcleral venous pressure, but it increases uveoscleral outflow (6).

Another possible mechanism may involve an increase in prostaglandin levels. However, in studies involving healthy volunteers and patients with either ocular hypertension or glaucoma, pretreatment with flurbiprofen had no influenc on the IOP-lowering effect of apraclonidine (7,8).

Epinephrine, a neurohumoral transmitter, and norepinephrine, a neurotransmitter, stimulate adrenergic receptors and mediate the physiologic sympathetic actions on aqueous humor dynamics. Early studies of epinephrine and the prodrug dipivefrin showed multiple effects on aqueous humor dynamics. The effects of epinephrine have been described in three phases. In the early phase, within minutes after instillation of epinephrine, aqueous inflow is reduced, presumably due to the α-adrenergic effect of vasoconstriction, which reduces the ultrafiltration of plasma into the stroma of the ciliary processes (9). This α-adrenergic effect on aqueous production, however, is transient and not of sufficient magnitude to significantly influence IOP. The middle phase overlaps with the first phase and is believed to be an early, moderate-sized α-adrenergic effect on true outflow facility. Fluorophotometric and tonographic studies in healthy (10,11) and ocular hypertensive human eyes suggest that IOP reduction for at least the first several hours after topical instillation of epinephrine is associated with improved facility of outflow (12). The late phase is believed to occur weeks to months after continued administration of epinephrine. The mechanism is thought to be related to metabolism of glycosaminoglycans in the trabecular meshwork (13).

SPECIFIC AGENTS

Apraclonidine

Apraclonidine is a para-amino derivative of clonidine, an α₂-adrenergic agonist that is used clinically as a potent systemic antihypertensive agent. Topical apraclonidine hydrochloride is available in a 1% concentration for the treatment of short-term IOP elevation, especially after anterior segment laser procedures, and in a 0.5% preparation for the long-term management of glaucoma. In a 90-day study comparing apraclonidine, 0.25% or 0.5%, three times a day and timolol, 0.5%, twice a day, the apraclonidine, 0.5%, reduced IOP more than apraclonidine, 0.25%, but no significant difference was observed between apraclonidine, 0.5%, and timolol, 0.5% (14).

Brimonidine

Brimonidine tartrate, 0.2%, has been similar to timolol, 0.5%, and greater than betaxolol, 0.25%, in IOP-lowering efficacy (15). As with apraclonidine, brimonidine is useful in controlling the IOP rise after anterior segment laser surgery. In two vehicle-controlled, multicenter trials involving 480 patients undergoing 360% argon laser trabeculoplasty, brimonidine, 0.5%, provided effective postoperative pressure control, whether it was given before, after, or before and after the procedure (16). Brimonidine, 0.2%, is as effective as apraclonidine, 0.5%, in preventing postoperative IOP elevation after anterior segment laser procedures (17).

In addition to lowering the IOP, brimonidine may prevent optic nerve damage through a neuroprotective mechanism. Brimonidine reduces loss of retinal ganglion cells in an optic nerve crush injury model in rats and mice (18). These findings have been supported by later studies examining the effect of brimonidine on retinal ganglion cell death in retinal ischemia models and laser-induced glaucoma models (19). However, these models of optic nerve injury are not directly comparable to glaucoma occurring in humans. Whether brimonidine provides neuroprotection in humans with glaucoma remains unknown.

Dipivefrin and Epinephrine

Dipivefrin, a prodrug of epinephrine, is a direct-acting sympathomimetic that stimulates both α- and β-adrenergic receptors. Neither dipivefrin nor epinephrine is currently available. Dipivefrin, or dipivalyl epinephrine, was a modification of epinephrine in which two pivalic acid groups were added to the parent drug. It was significantly more lipophilic than epinephrine, which increases the corneal penetration 17-fold (20). Dipivefrin was hydrolyzed to epinephrine after absorption into the eye, with most of the hydrolysis occurring in the cornea (21). Clinical trials indicate that the pressure-lowering effect of dipivefrin, 0.1%, is similar to that of betaxolol, 0.5% (22).

ADMINISTRATION

Topical 1% apraclonidine is indicated for short-term use generally to prevent and to manage postlaser IOP elevation. In a double-masked, randomized, 90-day trial involving patients with chronic open-angle glaucoma (COAG), apraclonidine, 0.25% and 0.5%, given three times daily, reduced the IOP an average of 3.6 and 5.4 mm Hg, respectively, compared with 5.0 mm Hg with timolol, 0.5%, administered twice daily (14). Apraclonidine also had a similar effect to β-adrenergic antagonists on daytime aqueous flow, with an average reduction of 30% (23). Unlike timolol, however, which does not affect aqueous flow during sleep, apraclonidine caused a 27% reduction of the spontaneous nocturnal rate (23).

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