The effects of adrenergic stimulation in the eye are mediated by cell-specific transmembrane receptors, which activate a regulatory guanine nucleotide-binding enzyme, or G-protein, and thereby activate various second-messenger systems in the cell. Three main adrenergic-receptor types are recognized: alpha-1, alpha-2, and beta. Each is associated with at least one unique regulatory G-protein: Gq, Gi, and Gs, respectively. Numerous additional receptor subtypes have been identified by a unique response to specific agonists and by the discovery of closely related genes (alpha-lA, -1B, and -1D; alpha-2A, -2B, -C, and -2D). However, the unique properties of these further subtypes are poorly delineated in the eye. An extensive review of adrenergic-receptor physiology as it relates to aqueous dynamics is available elsewhere.2
The cascade of events initiated by adrenoreceptor activation appears to regulate intraocular pressure (IOP) via the activity level of adenylate cyclase in the ciliary epithelium. While the final messengers are still uncertain, the net inhibition of adenylate cyclase and the reduction of intracellular cyclic adenosine monophosphate (cAMP) are implicated as necessary steps in the reduction in aqueous production by the ciliary epithelium. This unified hypothesis explains why both beta-receptor antagonists, which block endogenous stimulation of adenylate cyclase, and alpha-2 agonists, which actively inhibit adenylate cyclase, both effectively reduce IOP. Why, then, do both beta agonists such as epinephrine and beta blockers such as timolol reduce IOP in clinical practice? This apparent paradox may be due to adenylate cyclase down-regulation in response to chronic beta-agonist receptor occupancy.3
Prostaglandins appear to function as the intracellular second messenger for alpha-2 agonists in animal models,4 but not in humans. Although the nonsteroidal anti-inflammatory drug flurbiprofen blocks apraclonidine's IOP-lowering effect in monkeys,4 topical flurbiprofen pretreatment, at the 0.03% dosage used preoperatively in cataract surgery, does not block apraclonidine's effect on aqueous flow in humans.5,6 The apparent species difference may be explained instead by the lower concentration of flurbiprofen tested clinically in human experiments than that used in animal trials.
Adrenergic agonists can occupy adrenergic and imidazole receptors in the brain and adrenergic receptors concentrated locally in the ciliary body, making the precise site of action unclear. Unilateral application of apraclonidine7-10 or brimonidine8,11 causes a 7% to 19% reduction of contralateral IOP, suggesting that a central mechanism may be responsible for at least part of the alpha-adrenergic drugs' efficacy. This central effect varies among different species. In the rabbit, the central effect of adrenergic drugs appears to be transmitted to the eye directly via the sympathetic nervous system,12 but not, apparently, in humans13 or monkeys.8 Specific local and systemic side effects have been attributed to each receptor subtype (table 4.1).
Table 4.1 Receptor-Specific Side Effects of Adrenergic Agonists
Alpha-1 Receptor Effects
Conjunctival blanching Dry nose and mouth Systemic hypertension Eyelid retraction Mydriasis
Alpha-2 Receptor Effects
Central nervous system depression Sedation, confusion Growth hormone release Peripheral vasodilation Systemic hypotension
Electrolyte absorption in gut Miosis
Reduced aqueous formation Lipolysis
Inhibition of insulin release Renin release
Beta Receptor Effects
Source: Information on alpha-2 receptor effects is from Coleman AL, Robin AL, Pollack IP, et al. Cardiovascular and intraocular pressure effects and plasma concentrations of apraclonidine. Arch Ophthalmol. 1990;108:1264-1267.
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