Mechanism of action
α2-Selective agonists lower IOP primarily by reducing aqueous humor production. The α2-adrenoceptor found on the ciliary epithelium is coupled to an inhibitory G protein. It is thought that when this adrenoceptor is bound by catecholamines or pharmacologically active α2-agonists, an intracellular cascade results in reduction in the activity of adenylate cyclase and the intracellular concentration of cAMP, with a resultant reduction in the rate of aqueous humor production. An alternate or possibly complementary mechanism by which aqueous humor production is reduced may be anterior segment vasoconstriction and reduced blood flow to the ciliary body. After a longer period of therapy, increased uveoscleral outflow was observed with the selective α2-adrenergic agonist brimonidine, but not with apraclonidine. How uveoscleral outflow may be increased with brimonidine is unclear, but evidence points to relaxation of ciliary smooth muscle cells. As with β-blockers, systemic absorption of α2-selective agonists may lead to a crossover effect, although it appears to be small.
Available agents and dosing frequency
Brimonidine tartrate is the most commonly used α2-adrenergic agonist. Apraclonidine hydrochloride (para-aminoclonidine), an α2-adrenergic agonist and clonidine derivative, is used for long-term therapy only in rare instances because of the frequent occurrence of tachyphylaxis and a hypersensitivity reaction that can cause blepharoconjunctivitis. Use of apraclonidine is mostly limited to perioperative administration to blunt acute IOP spikes that may occur after laser iridotomy, laser trabeculoplasty, Nd:YAG laser capsulotomy, and cataract extraction. Brimonidine is similarly effective when used perioperatively.
Tachyphylaxis is less profound with brimonidine than with apraclonidine. Brimonidine’s peak IOP reduction is approximately 26% (2 hours post dose), which is comparable to the reduction achieved by a nonselective β-blocker and superior to that of the selective β-blocker betaxolol. At trough (12 hours post dose), the IOP reduction is only 14%–15%, or less than the reduction achieved with nonselective β-blockers. Studies have shown that brimonidine does not lower nocturnal IOP. Though approved for therapy 3 times daily in the United States, brimonidine is commonly used twice daily, particularly when used in combination with at least 1 other agent.
The incidence of ocular allergic reactions (eg, follicular conjunctivitis and contact blepharodermatitis; Fig 3-12) is lower with brimonidine than with apraclonidine. This is a delayed-type hypersensitivity reaction that is dose dependent, with a 1-year incidence of approximately 15% for brimonidine tartrate 0.2% preserved with benzalkonium chloride (BAK) and 10% for brimonidine tartrate 0.15% preserved with sodium chlorite (Purite). The incidence of allergy continues to increase beyond 1 year. Cross-sensitivity to brimonidine in patients with known hypersensitivity to apraclonidine is minimal. The incidence of long-term intolerance to brimonidine due to local adverse effects, however, is high (>20%). Granulomatous anterior uveitis is rare but has been reported in association with the use of brimonidine.
α2-Selective agonists have some α1-binding activity. The ocular effects of α1-adrenergic agonists include conjunctival vasoconstriction, pupillary dilation, and eyelid retraction. Apraclonidine has a much greater affinity for α1-receptors than does brimonidine and is therefore more likely to produce these effects. In some patients, apraclonidine causes mydriasis, whereas brimonidine commonly causes miosis.
Figure 12-3 Contact blepharodermatitis following α-adrenergic agonist use.
(Courtesy of F. Jane Durcan, MD.)
Systemic adverse effects of α2-selective agonists include xerostomia (dry mouth) and lethargy, both mediated by their clonidine-like CNS activity. Patients taking these medications should be advised to perform punctal occlusion. Brimonidine should not be used in infants and young children because of the risk of CNS depression, apnea, bradycardia, and hypotension, due to a combination of the lower volume of distribution and presumed increased CNS penetration of the drug.
Monoamine oxidase inhibitors and tricyclic antidepressants may interfere with metabolism of apraclonidine and brimonidine, resulting in toxicity.
Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.