Antimuscarinic actions of antihistamines on the heart

Abstract

SummaryAntimuscarinic side-effects, which include dry mouth, tachycardia, thickening of mucus possibly sedation, of the antihistamines limited the usefulness of these drugs. The advent of newer agents has reduced the sedative effect of the antihistamine. The data presented here show that one of the newest antihistamines, desloratadine, and a first generation drug, diphenhydramine, are both competitive inhibitors of muscarinic receptor mediated slowing of the heart as measured using a Langendorff preparation. Both agents have apparent sub-micromolar affinities for the muscarinic receptor. Two other agents, cetirizine and fexofenadine, do not interact with muscarinic receptors in the heart at the concentrations used in this study. Structural similarities of the drugs suggest that substitution of a group with a high dipole moment or charge on the side chain nitrogen decreases the binding with muscarinic receptors. We conclude that of the compounds tested fexofenadine and cetirizine have little or no interaction with muscarinic receptors.The newest antihistamines, desloratadine, fexofenadine and cetirizine, are metabolites of the older antihistamines, loratadine, terfenadine and hydroxyzine [1]. All these compounds are selective H1-histamine receptor antagonists. The newer agents also cause less drowsiness than first generation antihistamines (e.g., diphenhydramine) [2]. In addition, the newest compounds do not interact with HERG channels in the heart to cause a prolonged QT syndrome as did terfenadine, the parent compound of fexofenadine [3,4].Another potential interaction of antihistamines with cardiac function is at receptors involved in modifying heart rate and contraction. The first generation compounds were known to be competitive inhibitors of muscarinic receptors [5] and caused tachycardia by impairing vagal tone on the heart and xerostomia by inhibiting muscarinic stimulation of salivary function. Desloratadine is reported to inhibit muscarinic receptors at submicromolar concentrations [6] and therefore could potentially interact on the heart through inhibition of M2-muscarinic receptors. In this report we examine the interaction of antihistamines with muscarinic receptor-induced reduction of cardiac function in a working rat heart model using a Langendorff apparatus. Methods LangendorffFemale Sprague-Dawley rats weighing 300-350 g were used in these experiments. They were housed within the animal facility of University of Mississippi Medical center, and supplied with standard chow and water ad libitum. All experimental procedures were approved by the institutional animal care and use committee.The basic procedures are similar to those used by Vergely et al. [7]. Rats were anesthetized with phenobarbital sodium (65 mg/kg body wt., i.p.),

Identification of an Ascaris G protein-coupled acetylcholine receptor with atypical muscarinic pharmacology

“…Some histamine receptor antagonists are widely known to have anticholinergic effects but we found their activity at AsGAR-1 to be different to that at muscarinic receptors. Promethazine, an H1 receptor antagonist, diphenhydramine, an H1 antagonist, and cimetidine, an H2 antagonist, all display varying degrees of vertebrate muscarinic receptor antagonism (Kubo et al, 1987; Gwee and Cheah, 1990; 1991; Orzechowski et al, 2005; Liu et al, 2006). Only promethazine was an effective antagonist of AsGAR-1.…”

Histamine H1 Receptor Induces Cytosolic Calcium Increase and Aquaporin Translocation in Human Salivary Gland Cells

“…This hypothesis, in general, was applied to classical antihistamines (for instance, chlorpheniramine and promethazine) that have been shown to inhibit muscarinic receptors (Brown and Eckberg, 1997;Yasuda and Yasuda, 1999;Shelton and McCarthy, 2000;Liu et al, 2006). However, recently developed "second-generation" antihistamines, such as astemizole and fexofenadine, also induce xerostomia (Wilson et al, 1987;Sreebny and Schwartz, 1997;Elad et al, 2006), despite their extremely low affinity for muscarinic receptors (Laduron et al, 1982;Liu et al, 2006). These observations suggest that xerostomia is not related solely to muscarinic receptor inhibition.…”

“…Even though the xerostomia-inducing effect of antihistamines strongly suggests that histaminergic Ca 2ϩ signaling is functional in human salivary glands, there is no solid evidence for the expression of any histamine receptors. The current consensus is that antihistamine-induced xerostomia comes from an antimuscarinic effect; indeed, a number of studies have shown that first-generation histamine H1 receptor antagonists possess antimuscarinic activity (Yasuda and Yasuda, 1999;Liu et al, 2006).…”

New antihistamines: a critical view

“…As evidências indicam que a FEX é segura e bem tolerada [44][45][46][47]50 , mesmo em doses até 11 vezes maiores do que as terapêuticas 40 . É destituída de efeitos anticolinérgicos clinicamente significativos 51 .…”