Certain foods, medications, chemicals, plants — even sunlight — are known to trigger urticaria (hives). About half of the time, though, the itchy wheals appear and last anywhere from a few hours to a few days with no known explanation. Chronic hives, though, are a little different. Hives that last for six weeks or longer are considered chronic, and they're called chronic idiopathic urticarial. These hives are usually tied to an autoimmune response, causing mast cells — cells that are involved in our allergic reactions — to inappropriately produce histamine.
Most antihistamines, such as hydroxyzine (Atarax) and diphenhydramine (Benadryl), are H1 histamine receptor antagonists. That means they target one of the four types of histamine receptors in the body, called H1 receptors, and block their production of histamine. H1 receptors are located throughout the body in our smooth muscles and in the cells that make up the lining of our blood and lymphatic vessels.
A much smaller percent of antihistamines are histamine H2 receptor antagonists, which means they block H2 histamine receptors from producing histamine. H2 receptors are found in gastrointestinal parietal cells (the stomach cells that produce gastric acid). Medications used to treat heartburn, including ranitidine (Zantac) and cimetidine (Tagamet), are also used as H2-blocking antihistamines. (H3 receptors are found throughout the nervous system, and H4 receptors are located in the immune system.)
While an acute outbreak of hives is often treated effectively with antihistamines, the most common second-line treatment for chronic hives is actually better known for its treatment of depression and insomnia: the tricyclic antidepressant doxepin (Sinequan). Doxepin, it turns out, is a pretty potent antihistamine, acting on both the H1 and H2 receptors simultaneously and preventing hives and pruritus (itchiness).