Assessment of receptor affinities of ophthalmic and systemic agents in dry eye disease

Purpose of review To explore our current understanding of receptor profiles acted upon by medications used to treat dry eye disease (DED). Recent findings Research into histaminic and muscarinic receptor affinities for drugs targeting the ocular surface has not kept up with bench research pertaining to the receptor profile of the ocular surface. These insights are necessary for better evaluation of medications used in DED and other allergic disorders. At the H1 receptor, Ketotifen (pK(a) = 9.2), pyrilamine (pK(a) = 9.0), and epinastine (pK(a) = 8.0) had the highest affinities, whereas ranitidine (pK(a) = 4.2) and cimetidine (pK(a) = 4.9) had the lowest. Ketotifen, a second-generation antihistamine, was found to have a pK(a) of 6.7 at muscarinic receptors which was higher than that of diphenhydramine (pK(a) = 6.4), a first-generation antihistamine. Additionally, second-generation antihistamines have higher affinity for H3 receptors, which have been linked to urticaria, compared to first-generation. Azelastine, a second-generation, demonstrated significant affinity (pK(a) = 7.1) at the H3 receptor compared to all other drugs. Antazoline (pK(a) = 4.4) and diphenhydramine (pK(a) = 4.6), both first-generation antihistamines, had the lowest affinities for the H3 receptor. These findings raise questions about the use of antihistamines in the treatment of DED and allergic disorders.