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AT-A-GLANCE

AT-A-GLANCE

  • H1 antihistamines are first-line therapy for chronic idiopathic and physical urticarials.

  • H1 agents may be useful in treating conditions with histamine-associated pruritus.

  • Limited evidence supports the use of H1 in the 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 antihistamines.

  • H2 antihistamines may be a useful adjunct to H1 antihistamine therapy in refractory cases of chronic idiopathic urticaria/angioedema.

Histamine is a low-molecular-weight amine that is synthesized from L-histidine by histidine decarboxylase, an enzyme expressed by numerous cells throughout the body. Histamine exerts its effects through 4 different receptors that play a role in embryonic development, cellular growth and proliferation, hematopoiesis and immunity, inflammation, and wound healing. This amine is an important neurotransmitter in the CNS and is produced in neurons located in the tuberomammillary nucleus of the posterior hypothalamus. Nerves arising from this area regulate the sleep–wake cycle, endocrine homeostasis, cognition and memory. Histamine also exerts anticonvulsant effects. Histamine is metabolized by 2 major pathways: diamine oxidase and histamine methyl transferase.1,2

Histamine receptors are heptahelical transmembrane molecules that transmit extracellular signals to intracellular second messengers via G proteins. These receptors have constitutive activity, and thus are able to trigger downstream events in the absence of ligand stimulation. Active and inactive states of histamine receptors exist in equilibrium and can be shifted to a greater proportion of active or inactive states by histamine and antihistamines, respectively.3,4 Both H1 and H2 histamine receptors are widely expressed on neurons, smooth muscle, epithelium, endothelium, and multiple immune cells. H2 receptors also exist on gastric mucosal parietal cells; consequently, occupation by specific H2 antihistamines inhibits gastric acid secretion. H3 and H4 receptors have more limited expression in the body with H3 receptors occurring primarily on histaminergic neurons and immune cells, whereas H4 receptors are highly expressed in the bone marrow and on peripheral hematopoietic cells.2,5

H1 ANTIHISTAMINES

The first H1 antihistamines were introduced in the 1940s after groundbreaking work by Bovet in the 1930s. The H1 antihistamines—diphenhydramine, chlorpheniramine, and promethazine—all became available for clinical use during this time, and these and other agents were the primary source of antihistamine therapy until the 1980s when less-sedating, second-generation antihistamines were developed. First-generation antihistamines are divided into 6 groups on the basis of chemical structure: (a) ethylenediamines, (b) ethanolamines, (c) alkylamines, (d) phenothiazines, (e) piperazines, and (f) piperidines. The presence of multiple aromatic or heterocyclic rings and alkyl substituents enhances the lipophilicity of these compounds, permitting penetration of the blood–brain barrier, thereby leading to sedation. Second-generation antihistamines are less capable of accumulating in the CNS, and thus are less sedating. Compared to first-generation antihistamines, these second-generation agents also have the added advantage of ...

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