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Loperamide is frequently used to slow gastrointestinal motility. It is available over the counter (in the US, I don't know about elsewhere) without any regulations whatsoever, yet it's derived from an opiate. Knowing that the opiates slow the intestinal motility, it makes sense that it shares the same side effect.

What doesn't make sense to me is why it doesn't share the same primary effect of analgesia? Clearly it binds to opiate receptors in the gut, but are they the same subtype as those in the CNS? Or is it that the structure of the drug is such that hardly any crosses the blood brain barrier?

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up vote 13 down vote accepted

This is more of a chemical question I think, but the gist of it is that, unlike its predecessors difenoxin (Motofen) and diphenoxylate (Lomotil), it was specifically designed by Dr. Paul Janssen and other researchers at Janssen Pharmaceutica to have limited bioavailability from the gut (it is easily first-pass metabolized through cytochromes), as well as being too lipophilic to be dissolved in water and thus administered intravenously (and thus, junkies hoping to get a "hit" from loperamide through injections will be sorely disappointed), while still retaining its ability as a μ-opioid receptor agonist to the receptors in the myenteric plexus (resulting in the slowing of peristalsis). (Difenoxin/diphenoxylate in fact is administered with small doses of atropine to discourage abuse.)

In addition, efflux mediated by P-glycoprotein in the blood-brain barrier helps retard the entry of loperamide into the CNS. The concomitant administration of a P-gp inhibitor like quinidine (a stereoisomer of quinine used as an antiarrythmic) with loperamide, however, will cause respiratory depression and other CNS effects that are characteristic of μ-opioid receptor agonists.

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