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I know that first generation H1 antagonists, commonly known as antihistamines have anticholinergic effects. Their sedative side effects go away due to tolerance, but as for their anticholinergic side effects well that's something that is unknown to me at least. You might say use second generation H1 antagonists, but for this application the antiemetic effects that are unique to H1 antagonists that cross the BBB (i.e., first generation H1 antagonists) are desired.

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The tolerance to antihistamines is an ongoing debate in the community. Although there were early studies citing that tolerance to therapeutic effects of antihistamines could occur, more recent data, especially studies involving nonsedating antihistamines, indicate that tolerance to the therapeutic effects of these drugs does not occur.

Overall, it seems like the mechanism driving the sedation vs. the therapeutic effects are two separate down stream effects of regulating the inflammatory response. Neuronal tolerance and synaptic transformation is a fairly fluid and ongoing process, whereas the inflammatory response is much more robust. Meaning, the neuronal response is, theoretically, more able to adapt to chronic use of the anihistmaine while still giving the therapeutic effect. This hypothesis is supported by data, but yet to be confirmed, thus creating polarization on the topic.

Also see, Goodman and Gillman Pharmacological Principles of Therapeutics

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