Mechanism Of Action Of First Generation (Sedating) Antihistamines

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Pharmacology of Antihistamines

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Published by Max Ignatius Atlas on February 21, 2020

Classification of First Generation Antihistamines

Geo Contents

First generation antihistamines include the following drugs

Chlorpheniramine
Cyclizine
Diphenhydramine
Dimenhydrinate
Doxylamine
Hydroxyzine
Meclizine
Promethazine
Doxepine

Histamine

Histamine is an important neurotransmitter that is synthesised from L-histidine exclusively by histidine decarboxylase, an enzyme found in the human brain gastric mucosa parietal cells, mast cells, basophils, and other cells throughout the body. On activation, these neurons stimulate H1-receptors in all of the major parts of the cerebellum, posterior pituitary, cerebrum and spinal cord where they reinforce learning and memory, and have roles in fluid balance, suppression of feeding control of the cardiovascular system, increase arousal in the circadian sleep/wake cycle, control of body temperature and mediation of stress-induced adrenocorticotrophic hormone release and endorphin from the pituitary gland. The release of histamine during the day results in arousal whereas the production of histamine is reduced at night which results in a reduction of the arousal response.

The Histamine H1-Receptor

The histamine H1-receptor in humans is a member of the superfamily of G-protein coupled receptors. This superfamily contains at least 500 individual membrane proteins that share a similar structure of seven transmembrane helical segments. Like other G-protein coupled receptors, the histamine H1-receptor may be viewed as “cellular switches,” which exist as an equilibrium between the active or “on” state and the inactive or “off” state. Histamine stabilizes the receptor in its active conformation by cross-linking with sites present on transmembrane domains III and V that leads to equilibrium to swing to the on position 12. H1-antihistamine do not antagonise the binding of histamine if they are not structurally related to histamine but they bind to different sites on the H1 histamine receptor to produce the opposite effect. So H1-antihistamines are considered as inverse agonists rather than receptor antagonists but in that they produce the opposite effect on the receptor to histamine. Therefore, the preferred term to define these drugs is“H1-antihistamines” rather than “histamine antagonists.”

Mechanism of Action of First-Generation H1-Antihistamines

The mechanism of action of all the H1-receptor blockers is almost similar. H1 antihistamines drugs act as inverse agonists that shifts the equilibrium toward the inactive state by binding with H1 receptor and stabilise the receptor in inactive state.

First-generation H1-antihistamines have poor selectivity for receptors and are derived from the same chemical stem from which cholinergic muscarinic antagonists, tranquillizers, antipsychotics and antihypertensive agents are developed. They also interact with receptors of other biologically active amines which induces antiadrenergic, antimuscarinic and anti serotonin activity. It blocks the receptor-mediated response of a target tissue. First-generation H1-antihistamines are more effective in preventing symptoms than reversing them

The drawback of first generation antihistamines is that they interfere with histaminergic transmission because they easily cross the blood-brain barrier. Even if taken in recommended doses during the day, first-generation H1-antihistamines frequently cause sedation, drowsiness, fatigue, daytime somnolence, impaired concentration and memory. When taken at night, first-generation H1-antihistamines increase the timing of onset of rapid eye movement sleep and decrease the duration of rapid eye movement sleep. The residual effects of poor sleep, including vigilance, working memory, impaired attention and sensory-motor performance still persist next morning.

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