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H2 blockers (eg, ranitidine, famotidine) commonly are used for the treatment of heartburn and gastroesophageal reflux disease.

These antihistamines are more selective on peripheral H1 receptors and have a lower affinity for cholinergic and alpha-adrenergic receptor sites, which reduces the risk of anticholinergic and central nervous system side effects.

Older adults are especially sensitive to the central nervous system- and anticholinergic-related side effects of sedating antihistamines because of decreased cholinergic neurons or receptors in the brain, reduced hepatic and renal function, and increased blood-brain permeability.

In a meta-analysis of 27 studies conducted between 19, in 25 of the studies researchers confirmed a link between anticholinergic medication use and either delirium, cognitive impairment, or dementia.6 Other studies reviewing the effects of diphenhydramine and its use in OTC analgesic plus diphenhydramine products have shown they can significantly increase the risk of delirium.

Because delirium and hallucinations can result from the use of anticholinergics including sedating antihistamines, patients receiving these medications are at risk of being prescribed antipsychotic medications.

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Many physicians believe that the most effective way to treat chronic urticaria is to take a nonsedating second-generation H1 -antihistamine in the morning and a sedating first-generation H1 -antihistamine, usually hydroxyzine, at night to enhance sleep. To test this belief by comparing the effectiveness and prevalence of unwanted sedative effects when treating patients with chronic spontaneous urticaria (CSU) with levocetirizine 15 mg daily plus hydroxyzine 50 mg at night (levocetirizine plus hydroxyzine) vs.

These antihistamines also are potent muscarinic receptor antagonists that can lead to serious anticholinergic side effects, such as sinus tachycardia, dry skin, dry mucous membranes, dilated pupils, constipation, ileus, urinary retention, and agitated delirium.3 The mnemonic “blind as a bat, dry as a bone, red as a beet, mad as a hatter, and hot as a hare” often is used to help describe and identify patients suffering from anticholinergic syndrome (see Table 2 below).

Urinary retention and difficulty urinating can be particularly troublesome in male patients with enlarged prostates, and this retention can increase the risk of urinary tract infections, especially in women.4 The second-generation nonsedating antihistamines generally are considered as safer alternatives for use in older adults who require treatment for allergic rhinitis and other allergy symptoms.

Ongoing research efforts aim to develop potential agents to target the H3 and H4 receptor sites.

H3 receptor antagonists could provide new treatment options for sleep disorders, weight loss, neuropathic pain, obesity, movement disorders, schizophrenia, attention deficit disorders, and Alzheimer’s dementia, while the development of antagonists for H4 receptors may lead to new treatment options for autoimmune inflammatory diseases.1,2 The first H1 sedating antihistamines have been available for more than 60 years and were synthesized based on a chemical structure similar to that used to develop cholinergic muscarinic antagonists, tranquilizers, and antihypertensive agents.

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