Intracellular regulators

Cyclic adenosine monophosphate plays an important role in the intracellular secretory processes of rabbit ciliary body.226–228

Perhaps cyclic guanosine monophosphate is a secondary messenger for regulation of aqueous secretion.229 As Brubaker points out, the challenge is to determine how to link what happens on the cellular

and tissue levels with the observed phenomena in the intact eye.42 Cherksey and co-workers230,231 have found an anion-selective

channel in cultured human non-pigmented ciliary epithelial cells. Although aqueous humor formation appears normal in eyes of patients with cystic fibrosis (a disease with defective adrenergicallyregulated chloride channels), it is possible that some endogenous humoral or neural factor regulates the activity of this channel and thus is responsible for diurnal variation and the effect of adrenergic agents on aqueous flow.232

Clinical aspects of aqueous humor formation

Clinical conditions

Many conditions affect the rate of aqueous humor production, including ocular and systemic conditions. The known conditions are summarized in Tables 2-5 and 2-6. Although Goldmann calculated from tonographic data that eyes with primary open-angle glaucoma (POAG) had decreased aqueous formation rates, subsequent data strongly suggest that aqueous formation is unaffected by POAG and by pigmentary and exfoliative glaucoma.42 Aqueous flow was not significantly reduced by Fuchs’ heterochromic iridocyclitis.233 Similarly, some conditions with low IOP, such as

low-tension glaucoma or myotonic dystrophy, do not affect aqueous formation.69,205 A long-held assumption has been that retinal

detachment, cyclodialysis, and ocular inflammation are conditions that reduce the rate of aqueous formation. Many of these assumptions are based on tonographic evidence.234 However, no studies using modern techniques have been published to confirm them.

As might be expected, systemic conditions that slow metabolism

also reduce aqueous formation. Hypothermia and systemic acidosis decrease aqueous production.98,127,190 Conversely, hyperthermia

and alkalosis increase the rate of aqueous formation.98,191 Insulindependent diabetes mellitus also seems to decrease aqueous flow.235

Pharmacologic agents

Many drugs have an effect on aqueous humor formation. Some stimulate secretion, others inhibit it. Only two classes of drugs have any significant role in stimulating aqueous secretion. They are -adrenergic agents and endogenously administered corticosteroids. Contrary to early conceptions based on tonographic data that epinephrine reduces aqueous formation, acutely administeredadrenergic agents seem to increase aqueous formation rates, especially during sleep, as noted above.42 This effect may diminish with chronic administration.Topical corticosteroids do not seem to have any effect on aqueous secretion. However, systemically administered hydrocortisone may significantly increase aqueous flow.236 Pilocarpine may increase aqueous formation, but only slightly and not enough to be clinically significant.58 Intracameral atrial natri­ uretic factor also increases aqueous flow, but only transiently.237

Table 2-7  Agents that affect aqueous humor formation

Although only a small number of agents increase aqueous production, over a dozen have been shown to decrease the rate of production. These are listed in Table 2-7. Because of toxicity or route of administration, most of these agents have not been found to be useful therapeutically in humans. Systemically administered carbonic anhydrase inhibitors reduce aqueous formation by approximately 40%.These agents decrease the rate of appearance of bicarbonate and water in newly formed posterior chamber aqueous humor.40,97 Topically applied carbonic anhydrase inhibitors lower IOP and also cause a small reduction in aqueous humor formation. Their mechanism of action seems similar to that of the systemic carbonic anhydrase inhibitors.238

The -adrenergic antagonists are also known to reduce aqueous humor formation. Fluorophotometric studies demonstrate a

16–47% decrease in aqueous formation after the administration of topical timolol, betaxolol, bupranolol, or levobunolol.163,172,180,239

Other agents are also effective. Although both carbonic anhydrase inhibitors and -adrenergic agonists decrease aqueous formation during sleep, the -adrenergic antagonists do not.240 An adaptation to the ability of timolol and other antagonists to reduce aqueous formation may occur after chronic use, but this effect seems not to be clinically significant.42 The effect of -adrenergic antagonists may last for one or more weeks after cessation of administration.241

The -adrenergic agonist clonidine, a drug used as an antihypertensive agent, was found to reduce aqueous flow in the human eye.110 A derivative of clonidine, apraclonidine, was later found to be a better-tolerated clinical agent and to lower IOP by reducing aqueous formation.242 Brimonidine, a relatively selective 2 agonist, is effective at decreasing aqueous formation and also increases the uveoscleral (non-pressure-dependent) aqueous outflow.243

It was believed that topical epinephrine preparations reduced aqueous humor formation.244–246 Recent studies are somewhat con-

tradictory but suggest that aqueous humor formation is either slightly increased or relatively unchanged by topical epinephrine.178,182,184,247

Na -K ATPase inhibitors, such as ouabain, decrease aqueous formation in rabbits,75 cats,82 and humans.82 Unfortunately, these drugs