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The present study examined 15 patients previously resistant to conventional antihistamines, in which doxepin at doses in the range of 50-75 mg/day was shown to be effective in treatment of chronic urticaria and without significant adverse side effects. However, some controversy remains about its mechanism of action in this particular disease. The aim of the present study was to examine the muscarinic, H1 and H2 blocking activity of doxepin. The following methods were used: a) gastric acid hypersecretion induced by histamine and carbachol in the pylorus-ligated rat preparation; b) contractile dose-response curves to histamine and carbachol in the guinea pig ileum; c) dimaprit-stimulated guinea pig atrium in vitro. pA2 values were determined for atropine, mepyramine, cimetidine and doxepin. As regards histamine, doxepin (50 mg/kg, po) increased gastric pH and decreased secretion volume, gastric acid concentration and total acid output; with carbachol, doxepin weakly antagonized those values. In the ileum, doxepin competitively antagonized carbachol (pA2 = 7.08) and histamine (pA2 = 9.72); pA2 values for atropine and mepyramine against carbachol and histamine were 9.11 and 8.82, respectively. In the atria, the dose-response curve to dimaprit was also competitively displaced by cimetidine (pA2 = 6.69) and doxepin (pA2 = 6.00). Doxepin displayed a very high affinity for H1 histamine receptor, being 8-fold more potent than mepyramine. Doxepin showed significant H2 blocking activity which was 5 times less potent than that of cimetidine. Doxepin competitively antagonized carbachol in the guinea pig ileum, and was 107 times less potent than atropine. The combined H1, H2 and muscarinic blocking activities of doxepin may contribute towards explaining its clinical efficacy in the treatment of chronic urticaria.


A Figueiredo, C A Ribeiro, M Gonçalo, L Almeida, A Poiares-Baptista, F Teixeira. Mechanism of action of doxepin in the treatment of chronic urticaria. Fundamental & clinical pharmacology. 1990;4(2):147-58

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PMID: 2141000

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