title: Anticholinergic effects of desloratadine, the major metabolite of loratadine, in rabbit and guinea-pig iris smooth muscle.
abstract: Allergic conjunctivitis is the most common ocular allergic disease. Although very symptomatic it does not endanger vision, and topical antihistamines or chromones are the first choice treatment in clinical practice. Recently, equivalent nanomolar affinities for histamine H and muscarinic M 1 and M3 cloned human receptors have been reported for desloratadine, the active metabolite of loratadine, a widely prescribed antihistamine. This property might enhance its utility in the treatment of asthma, but could induce adverse anticholinergic effects after topical administration. In the present study, we compare the anticholinergic activity of desloratadine with other known muscarinic antagonists and antihistamines on rabbit and guinea-pig iris smooth muscle. Desloratadine was found to be a competitive antagonist (pA2 = 6.67+/-0.09) of carbachol-induced contractions in isolated rabbit iris smooth muscle. Atropine (pA2 = 9.44+/-0.02) and NPC-14695 (pA2 = 9.18+/-0.03) also behaved as competitive antagonists, whereas tiotropium bromide (pD'2 = 9.06+/-0.02) exhibited a non-competitive behaviour in this tissue. Carebastine (pA2 = 5.64+/-0.04) and fexofenadine (pA2 < 4.0) were also studied. After topical administration on the guinea-pig eye conjunctiva, desloratadine produced a potent (ED50 = 2.3 mg/ml) and long lasting mydriasis (> 120 min at the ED50) in conscious animals. Fexofenadine and carebastine were inactive even at the highest concentration tested (10 mg/ml). Atropine (ED50 = 30 microg/ml) and tiotropium bromide (ED50 = 10 microg/ml) were much more potent than desloratadine or pirenzepine (ED50 = 3 mg/ml) in this model. The competitive muscarinic antagonism of desloratadine in vitro, and its potency and duration of action in vivo, suggest that topical treatment of allergic conjunctivitis and rhinitis with desloratadine could produce undesirable peripheral anticholinergic side effects such as mydriasis and xerostomia.
authors.affiliation: Almirall Prodesfarma, Research Center, Pharmacology Department, Barcelona, Spain. icardelu@almirallprodesfarma.com
authors.forename: I
authors.initials: I
authors.lastname: Cardelús
authors.forename: F
authors.initials: F
authors.lastname: Antón
authors.forename: J
authors.initials: J
authors.lastname: Beleta
authors.forename: J M
authors.initials: JM
authors.lastname: Palacios
mesh_terms: D000818:Animals; D018680:Cholinergic Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D066298:In Vitro Techniques; D007498:Iris / Q000187:drug effects*; D017336:Loratadine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000009:adverse effects / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D015878:Mydriasis / Q000139:chemically induced*; D011817:Rabbits; D013997:Time Factors
chemical_list: D018680:Cholinergic Antagonists; D018727:Muscarinic Antagonists; D017336:Loratadine; C121345:desloratadine