Loperamide

Loperamide, a synthetic piperidine derivative, is a drug effective against diarrhea resulting from gastroenteritis or inflammatory bowel disease. In most countries it is available generically and under brand names such as Lopex, Imodium, Dimor and Pepto Diarrhea Control. It was discovered at Janssen Pharmaceutica in 1969.

Mode of action
Loperamide is an opioid receptor agonist and acts on the μ-opioid receptors in the myenteric plexus large intestines; it does not affect the central nervous system like other opioids.

It works by decreasing the activity of the myenteric plexus which decreases the motility of the circular and longitudinal smooth muscles of the intestinal wall. This increases the amount of time substances stay in the intestine, allowing for more water to be absorbed out of the fecal matter. Loperamide also decreases colonic mass movements and suppresses the gastrocolic reflex.

Loperamide molecules do not cross the blood-brain barrier in significant amounts, and thus it has no analgesic properties. Any that do cross the blood-brain barrier are quickly exported from the brain by P-glycoprotein (Pgp), also known as multidrug resistance protein (MDR1). Tolerance in response to long-term use has not been reported.

However, loperamide can cause physical dependence. Symptoms of opiate withdrawal have been observed in patients abruptly discontinuing long-term therapy with loperamide. For this reason, the drug was briefly classified as a Schedule V controlled substance upon its introduction.

Contraindications
Treatment should be avoided in the presence of fever or if the stool is bloody. Treatment is not recommended for patients who could suffer detrimental effects from rebound constipation. If there is a suspicion of diarrhea associated with organisms that can penetrate the intestinal walls, such as E. coli O157:H7 or salmonella, loperamide is contraindicated.

Crossing the blood-brain barrier
When loperamide is taken by itself, it cannot readily cross the blood-brain barrier; however, when loperamide-containing nanoparticles are coated with polysorbate 80 and injected, the results were the same as typical opiates and opioids -- long, effective analgesia. A solution prepared using loperamide coated with polysorbate 80 resulted in a very short duration of action and less effective analgesic effect. The same study concluded that loperamide does not cause any analgesic effects when taken by itself.

Concurrent administration of P-glycoprotein inhibitors such as quinidine with loperamide has been found to produce respiratory depression, indicative of central opioid action.

Side-effects
Side effects can include drowsiness, constipation, abdominal pain or discomfort, dry mouth, fatigue, and in rare cases toxic megacolon, mild euphoria and mild stimulation (at high doses).