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Antihistamines are a class of substances that inhibit the action of histamine. Antihistamines are commonly used to relieve allergies and to promote sleep. Recreationally, very high doses can be used to induce delirium and achieve a hallucinogenic effect in which the user sees and hears fully-formed, extremely convincing hallucinations. However, this experience is typically considered highly unpleasant by most users.
H1 antihistamines are classified as first- and second-generation compounds. First-generation compounds cross the blood–brain barrier (BBB) causing sedation and they commonly cause antimuscarinic anticholinergic effects such as delirium, dry mouth and dysfunctional urine voiding. Second-generation compounds cross the BBB to a minimal degree and are less sedating and do not cause delirium.
The toxicity of recreational antihistamine use is poorly understood, although there is some evidence that abuse may cause cognitive deficits and other health issues.
Most antihistamines act as inverse agonists on histamine receptors, meaning they inhibit the action of histamine by preventing it from binding to them. They may also inhibit the enzymatic activity of histidine decarboxylase which catalyzes the transformation of histidine into histamine.
First-generation antihistamines readily cross the blood–brain barrier (BBB) and occupy H1-receptors located on postsynaptic membranes of histaminergic neurons throughout the CNS. Most of these drugs have antimuscarinic anticholinergic effects, some have alpha-adrenergic blocking effects, and others can inhibit both histamine and 5-HT activity. Second-generation H1-antihistamineshave significantly less affinity for muscarinic cholinergic and alpha-adrenergic receptors and cross the BBB to a minimal degree, penetrate poorly into the CNS, and typically occupy fewer than 20% of CNS H1-receptors.
Antihistamines are found throughout organic chemistry and include psychoactive and anti-allergenic compounds.
Toxicity and harm potential
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First-generation H1-antihistamines potentially cause adverse effects in multiple body systems. CNS adverse effects of antihistamines are due to inverse agonism at CNS H1-receptors, inhibition of neurotransmission in histaminergic neurons, and impairment of alertness, cognition, learning, and memory that is not necessarily associated with sedation, fatigue, or somnolence. After an overdose, some first-generation H1-antihistamines potentially lead to sinus tachycardia, prolongation of the QT interval, ventricular arrhythmias, and torsade de pointes.
In contrast to first-generation H1-antihistamines, second-generation H1-antihistamines are relatively free from antihistaminic adverse CNS effects and from antimuscarinic, antiserotonin, and anti–α-adrenergic effects. Massive overdoses of second-generation H1-antihistamines, such as cetirizine, fexofenadine, and loratadine, have not been causally linked with seizures, coma, respiratory depression, or fatality.
- Emanuel, M. B. (1999). Histamine and the antiallergic antihistamines: a history of their discoveries. Clinical & Experimental Allergy, 29(S3), 1-11. https://doi.org/10.1046/j.1365-2222.1999.00004.x-i1
- Sicherer, Scott H. M.D., Understanding and Managing Your Child's Food Allergy. Baltimore: The Johns Hopkins University Press, 2006 ISBN 0-8018-8492-6.
- Histamine and H1-antihistamines: Celebrating a century of progress | https://www.sciencedirect.com/science/article/pii/S0091674911014084