Loperamide have negative effects from rebound constipation. If a suspicion exists of diarrhea associated with organisms that can penetrate the intestinal walls, such as or "Salmonella", loperamide is contraindicated as a primary treatment. Loperamide treatment is not used in symptomatic "C. difficile" infections, as it increases the risk of toxin retention and precipitation of toxic megacolon. Loperamide should be administered with caution to people with liver failure due to reduced first-pass metabolism. Additionally, caution should be used when treating people with advanced HIV, as cases of both viral and bacterial toxic megacolon have been reported. If abdominal distension is noted, therapy
Loperamide first-pass metabolism by the liver. Loperamide metabolizes into an MPTP-like compound, but is unlikely to exert neurotoxicity. Efflux by P-glycoprotein also prevents circulating loperamide from effectively crossing the blood–brain barrier, so it can generally only antagonize muscarinic receptors in the peripheral nervous system, and currently has a score of 1 on the anticholinergic cognitive burden scale. Concurrent administration of P-glycoprotein inhibitors such as quinidine potentially allows loperamide to cross the blood–brain barrier and produce central morphine-like effects. Loperamide taken with quinidine was found to produce respiratory depression, indicative of central opioid action. Loperamide has been shown to cause a mild