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Antihistamines at a Glance
  • H1 are first-line therapy for chronic idiopathic and physical urticarias.
  • H1 may be useful in treating other conditions with histamine-driven pruritus.
  • Limited evidence supports the use of H1 in treatment of atopic dermatitis.
  • Certain special patient populations, including children, the elderly, and patients with renal or hepatic impairment, may require dosage adjustments when using H1 antihistamines.
  • The use of H1 is contraindicated in patients who have narrow angle glaucoma or who are also taking monoamine oxidase inhibitors.
  • H2 antihistamines may be a useful adjunct to H1 antihistamine therapy in refractory cases of chronic idiopathic urticaria/angioedema and pruritus.

Histamine is a low-molecular-weight amine derived from l-histidine that is produced throughout the body. By means of four known types of receptors, histamine affects cellular growth and proliferation, modulates inflammation, and acts as a neurotransmitter. Both H1 and H2 histamine receptors are widely expressed. H1 receptors are found on neurons, smooth muscle, epithelium and endothelium, and multiple other cell types. H2 receptors are located in the gastric mucosa parietal cells, smooth muscle, epithelium and endothelium, heart, and other cell types as well. H3 and H4 receptors have more limited expression. H3 receptors are found primarily on histaminergic neurons, whereas H4 receptors are highly expressed in bone marrow and on peripheral hematopoietic cells.

Mechanism of Action

H1 antihistamines are inverse agonists that reversibly bind and stabilize the inactive form of the H1 receptor, thereby favoring the inactive state1 (Box 229-1). The backbone structure of H1 antihistamines is depicted in Fig. 229-1. By means of the H1 receptor, H1 antihistamines decrease production of proinflammatory cytokines, expression of cell adhesion molecules, and chemotaxis of eosinophils and other cells (Fig. 229-2).2 H1 antihistamines may also decrease mediator release from mast cells and basophils through inhibition of calcium ion channels. In addition to having antihistamine actions, first-generation H1 antihistamines can also act on muscarinic, α-adrenergic, and serotonin receptors and cardiac ion channels. Some of the more serious adverse effects associated with first-generation H1 antihistamines, such as urinary retention, hypotension, and cardiac arrhythmias, are mediated through these other receptors. The first-generation antihistamines are divided into six groups on the basis of chemical structure: (1) ethylenediamines, (2) ethanolamines, (3) alkylamines, (4) phenothiazines, (5) piperazines, and (6) piperidines3 (see Fig. 229-1). The presence of multiple aromatic or heterocyclic rings and alkyl substituents enhances the lipophilicity of these compounds, which allows penetration of the blood-brain barrier.

Box 229-1 Basic Pharmacology of Antihistamines

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