β2-Adrenergic agonists lower IOP by improving trabecular outflow and possibly by increasing uveoscleral outflow. The beneficial effect on outflow more than compensates for a small increase in aqueous inflow as detected by fluorophotometry. The effect on outflow facility seems to be mediated by β2-receptors.
β2-Receptors linked to adenylate cyclase are present in the ciliary epithelium and processes as well as in the trabecular meshwork. Treatment with l-epinephrine, a nonselective mixed α-and β-agonist, increases intracellular levels of cyclic adenosine monophosphate (cAMP) in these tissues and in the aqueous humor. In other tissues, β-receptor–mediated generation of cAMP in turn activates cAMP-dependent enzymes, which results in responses such as glycogenolysis and gluconeogenesis in the liver and lipolysis in adipose tissue. However, the biochemical mechanisms responsible for lowering IOP remain to be determined.
Figure 16-5 Synthesis and release of norepinephrine from the adrenergic neuron. COMT = catechol-O-methyltransferase; DOPA = dihydroxyphenylalanine; MAO = monoamine oxidase inhibitor.
(Reproduced with permission from Mycek MJ, Harvey RA, Champe PC, eds.
2nd ed. Lippincott’s Illustrated Reviews. Philadelphia: Lippincott-Raven; 1997:57.)
Topical l-epinephrine is no longer commercially available in the United States or used in most countries (see Table 16-7). Local and systemic adverse effects are common (see BCSC Section 10, Glaucoma). Clinically, nonselective adrenergic drugs have been replaced by the selective α2-adrenergic agonists because of their improved efficacy and adverse effect profiles. In an animal model, long-term therapy with epinephrine was shown to downregulate the number of β-receptors. This phenomenon may underlie the loss of some of the drug’s therapeutic effectiveness over time (tachyphylaxis).
β-Adrenergic antagonists, also known as β-blockers, lower IOP by reducing aqueous humor production by as much as 50% (Table 16-9). Six β-blockers are approved for use in the treatment of glaucoma: timolol maleate, levobunolol, metipranolol, carteolol, betaxolol, and timolol hemihydrate. Although it is likely that the site of action is the ciliary body, it is not known whether the vasculature of the ciliary processes or the pumping mechanism of the ciliary epithelium is primarily affected. A possible mechanism may be an effect on the β-adrenergic receptor–coupled adenylate cyclase of the ciliary epithelium.
Table 16-9 β-Adrenergic Antagonists
Although systemic administration of β-blockers has been reported to elevate blood lipid levels, such elevation has not been demonstrated with topical β-blockers such as timolol. All β-blockers can inhibit the increase in pulse and blood pressure that is exhibited in response to exertion. For this reason, they may be poorly tolerated in elderly patients during routine activities, as well as in young, physically active individuals. Nonselective β-blockers inhibit the pulmonary β2-receptors that dilate the respiratory tree. The induced bronchospasm may be significant in patients with asthma or chronic obstructive lung disease. In patients with bradycardia and second- or third-degree atrioventricular block, the underlying cardiac condition may be exacerbated with use of these drugs.
The traditional teaching that topical β-blockers are contraindicated in patients with congestive heart failure is being challenged. Indeed, current cardiologic evidence strongly demonstrates that β-blockage is an important component of treatment for heart failure, except in advanced cases. Therefore, ophthalmologists should maintain continuous communication with patients’ internists or cardiologists regarding the systemic effects of ophthalmic therapy.
Timolol maleate, 0.25% or 0.5%, and levobunolol, 0.25% or 0.5%, are mixed β1-/β2-antagonists. Tests of more specific β-blockers suggest that β2-antagonists have a greater effect on aqueous secretion than do β1-antagonists. For example, comparative studies have shown that the specific β1-antagonist betaxolol, 0.5%, is approximately 85% as effective as timolol in lowering IOP.
Metipranolol hydrochloride is a nonselective β1- and β2-adrenergic receptor–blocking drug. As a 0.3% topical solution, it is similar in effect to other topical nonselective β-blockers, in addition to reducing IOP.
Carteolol hydrochloride demonstrates intrinsic sympathomimetic activity; in other words, while acting as a competitive antagonist, it also causes a slight to moderate activation of receptors. Thus, even though carteolol has β-blocking activity, it may be tempered, reducing the effects on cardiovascular and respiratory systems. Carteolol is also less likely than other β-blockers to adversely affect the systemic lipid profile.
Betaxolol is a selective β1-antagonist that is substantially safer than the nonselective β-blockers when pulmonary, cardiac, CNS, or other systemic conditions are considered. Betaxolol may be useful in patients with a history of bronchospastic disorders, although other therapies should be tried first because betaxolol’s β selectivity is relative and not absolute, and some β2 effects can therefore remain. In general, the IOP-lowering effect of betaxolol is less than that of the nonselective β-adrenergic antagonists.
Betaxolol is available as a generic 0.5% solution and as a 0.25% suspension. The 0.25% suspension causes less irritation on instillation yet maintains its clinical efficacy compared with the brand-name 0.5% solution (now discontinued), a finding that is generally extrapolated to the currently available generic 0.5% solution.
Prodrugs of nonselective β-blockers are being developed. They may offer higher potency of β1-/β2-blocking medications while reducing their systemic adverse effects.
Curiously, both β-agonist and β-antagonist drugs can lower IOP. This paradox is compounded by the observation that β-agonist and β-antagonist drugs have slightly additive effects in lowering IOP.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.