Antihistamines are used medicinally to treat allergies, colds, insomnia, and coughs and can be taken with or without a prescription. They can be classified into three categories: sedative, less sedative, and nonsedative based on measurements of antihistamine receptor occupancy in the human brain and depending on the level of penetration into the central nervous system. (1).

They have a long history. First-generation antihistamines (e.g., chlorpheniramine, promethazine, diphenhydramine, hydroxyzine), many of which can be purchased without a prescription, could cause adverse reactions such as drowsiness, tachycardia, decreased cognition, urinary retention, thirst, and more. Second-generation antihistamines have been put on the market since 1979 to overcome the contraindications and adverse reactions that first-generation antihistamines could cause and rarely lead to severe toxicity (2).

Neuronal histamine, a biogenic monoamine, is found throughout the body with high concentrations in the gastrointestinal tract, lungs, and skin and acts as a neurotransmitter, reverse agonist, through activation of H1, H2, H3 receptors, H4 (G protein-coupled receptor (GPCR) family, consisting of 7 transmembrane-spanning helices) in the brain that have influence on various mechanisms both immunological and physiological such as intestinal and vascular smooth muscle and brain (3), gastric secretion, inflammation, vasodilation.

The relationship between histamine and migraine has been debated for decades. Since the 1940s, antihistamines have been considered to play a primary role in the management of vertigo. In 2019, intravenous cetirizine was approved for the treatment of acute urticaria, and compared with intravenous diphenhydramine, cetirizine has fewer contraindications and lower risk on elderly patients (4).

References_____________________________________________________________________

(1) Yanai K, Yoshikawa T, Yanai A, Nakamura T, Iida T, Leurs R, Tashiro M. The clinical pharmacology of non-sedating antihistamines. Pharmacol Ther. 2017 Oct;178:148-156. doi: 10.1016/j.pharmthera.2017.04.004.

(2) Jensen LL, Rømsing J, Dalhoff K. A Danish Survey of Antihistamine Use and Poisoning Patterns. Basic Clin Pharmacol Toxicol. 2017 Jan;120(1):64-70. doi: 10.1111/bcpt.12632.

(3) Hill SJ. Multiple histamine receptors: properties and functional characteristics. Biochem Soc Trans. 1992 Feb;20(1):122-5. doi: 10.1042/bst0200122. 

(4) Blaiss MS, Bernstein JA, Kessler A, Pines JM, Camargo CA Jr, Fulgham P, Haumschild R, Rupp K, Tyler T, Moellman J. The Role of Cetirizine in the Changing Landscape of IV Antihistamines: A Narrative Review. Adv Ther. 2021 Dec 4. doi: 10.1007/s12325-021-01999-x.

Other major studies

Zappia CD, Monczor F. Therapeutic utility of glucocorticoids and antihistamines cotreatment. Rationale and perspectives. Pharmacol Res Perspect. 2019 Dec;7(6):e00530. doi: 10.1002/prp2.530.

Abstract. We hypothesize that the existence of this synergistic effect could contribute in reducing the glucocorticoids clinical doses, ineffective by itself but effective in combination with an antihistamine. This could result in a therapeutic advantage as the glucocorticoid-desired effects may be reinforced by the addition of an antihistamine and, as a consequence of the dose reduction, glucocorticoid-related adverse effects could be reduced or at least mitigated.

Fukui H, Mizuguchi H, Kitamura Y, Takeda N. Patho-Pharmacological Research of Anti-allergic Natural Products Targeting Antihistamine-Sensitive and -Insensitive Allergic Mechanisms. Curr Top Behav Neurosci. 2021 Oct 14. doi: 10.1007/7854_2021_255.

Abstract.  Combination therapy using medicines suppressing both H1R gene expression and IL-9 gene expression is promising for outstanding alleviation of allergic disease. Multifactorial diseases involving H1R gene expression may be treated by the combination therapy with antihistamine and complementary drugs, and diseases involving PKCδ signaling may be treated by drugs targeting Hsp90.