Over-the-Counter Ocular Decongestants in the United States - Mechanisms of Action and Clinical Utility for Management of Ocular Redness

Abstract

To manage ocular redness effectively, health-care practitioners require an understanding of the pathophysiology, clinical features and differential diagnosis of ocular redness, as well as comprehensive knowledge of medical therapies available and their pharmacologic properties. This review aims to provide a clinically relevant summary of the current literature on the mechanism of action, efficacy, and safety of current over-the-counter (OTC) decongestants available for reduction of ocular redness due to minor irritations. Currently marketed OTC products indicated for such use in the United States include topical solutions of tetrahydrozoline 0.05%, naphazoline 0.012% to 0.03%, and brimonidine 0.025%. All 3 agents are adrenergic receptor agonists but vary in their receptor-binding profiles: tetrahydrozoline is a selective α1 receptor agonist; naphazoline is a mixed α1/α2 receptor agonist; and brimonidine is a selective α2 receptor agonist. These OTC decongestants produce vasoconstriction of conjunctival blood vessels, which results in a rapid reduction in ocular redness. In general, ocular adverse events reported in published studies of these OTC decongestants were minimal, mild, and transient, with no significant adverse systemic effects. However, ocular decongestants with α1-adrenergic receptor agonist activity can be associated with loss of effectiveness with continued use (ie, tachyphylaxis) and rebound redness upon treatment discontinuation. In clinical trials of the selective α2-adrenergic receptor agonist brimonidine 0.025%, tachyphylaxis was not observed, and rebound redness was rarely reported.

Keywords: brimonidine; naphazoline; ocular decongestant; ocular redness; over-the-counter; tetrahydrozoline.

Figure 1

Schematic illustration of the regulation of ocular vascular tone and potential vasoactive effects of topical ophthalmic vasoconstrictors, mediated by adrenergic receptors found on vascular smooth muscle, vascular endothelium, and nerve cell terminals. Norepinephrine released from the nerve cell terminal diffuses to vascular smooth muscle cells and endothelial cells. Stimulation of α1- and/or α2-adrenergic receptors on vascular smooth muscle cells leads to vasoconstriction; whereas, stimulation of α1-, α2- and/or β-adrenergic receptors on vascular endothelial cells, stimulation of β-adrenergic receptors on vascular smooth muscle cells, and stimulation of α2- and/or β-adrenergic receptors on nerve cell terminals, leads to vasodilation. Adapted with permission from Sheng Y, Zhu L. The crosstalk between autonomic nervous system and blood vessels. Int J Physiol Pathophysiol Pharmacol. 2018;10(1):17–28. Abbreviation: NE, norepinephrine.

Figure 2

Current understanding of the difference in mechanism of action of α-adrenergic receptor agonists for relief of ocular redness. (A) Blood vessels in the conjunctiva under normal conditions (without ocular redness). (B) Ocular redness results from the dilation of arterioles and venules. (C) α1-adrenergic receptor agonists primarily constrict arterioles to reduce redness, whereas mixed α1/α2-adrenergic receptor agonists can impact both arterioles and venules. (D) Selective α2-adrenergic receptor agonists primarily constrict the venules to reduce redness. Of relevance to potential side effects, constriction of arterioles through use of α1- or mixed α1/α2-adrenergic receptor agonists can reduce oxygen delivery to the conjunctiva and lead to ischemia, which, in turn, can be associated with rebound redness following discontinuation. Selective α2-adrenergic receptor agonists effect venular constriction thereby preventing ischemia and subsequent rebound redness. Further research is needed on vascular tone in conjunctival tissue to gain a better understanding of the change(s) in caliber of conjunctival arterioles and venules in ocular redness and their differential response to ocular decongestants.

Figure 3

Investigator-evaluated ocular redness (0- to 4-unit scale) on Day 1 of a randomized clinical trial of brimonidine ophthalmic solution 0.025%. *P<0.0001 vs vehicle at the indicated time point (last observation carried forward). ^#P≤0.01 vs vehicle at the indicated time point (observed data only). Error bars represent standard error of the mean. Reprinted with permission from McLaurin E, Cavet ME, Gomes PJ, Ciolino JB. Brimonidine ophthalmic solution 0.025% for reduction of ocular redness: a randomized clinical trial. Optom Vis Sci. 2018;95(3):264–271. Available from: https://journals.lww.com/optvissci/Fulltext/2018/03000/Brimonidine_Ophthalmic_Solution_0_025__for.13.aspx.