Do mammals develop tolerance to anticholinergics?

Question

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.

Answer 1

Tolerance is associated with declining effects to the drug over time while the dose remains the same. Since muscarinic receptors are GPCRs, tolerance can be a real thing. Long term use of a drug that antagonizes a GPCRs will result in an increase in the receptor number over time. This is the body's attempt to restore homeostasis. From a clinical perspective, I wonder why someone would need to be on a long-term H1 blockers like diphenhydramine. Clinical practice shows the antimuscarinic effects are bothersome for just this reason. If you want anti-emetic effects, use other receptor-blocking drugs like Zofran (blocking serotonin) or metoclopramide (blocking dopamine).