Loperamide
Loperamide is a synthetic, peripherally acting piperidine-derivative opiate agonist primarily used as an antidiarrheal and gastrointestinal (GI) motility modifier in veterinary medicine. Unlike many other opioids, loperamide is a substrate for the **P-glycoprotein (P-gp)** efflux pump at the blood-brain barrier. In normal animals, this prevents the drug from accumulating in the central nervous system (CNS), thereby minimizing typical opioid neurological effects. > **Clinical Pearl:** Loperamide is highly effective for symptomatic relief of non-infectious diarrhea (such as chemotherapy-induced diarrhea from drugs like toceranib). However, it must be used with extreme cautionโor avoided entirelyโin herding breeds (e.g., Collies, Australian Shepherds) due to the **ABCB1-1ฮ (MDR1) mutation**. In these dogs, the defective P-gp pump allows loperamide to cross the blood-brain barrier, leading to profound and potentially fatal neurotoxicity even at standard doses.
Mechanism: Loperamide exerts its antidiarrheal effects through multiple mechanisms within the gastrointestinal tract: * **ฮผ-opioid receptor agonism:** Binds to mu-receptors in the myenteric plexus of the intestinal wall โ inhibits the release of acetylcholine and prostaglandins โ reduces peristalsis and increases intestinal transit time, allowing for greater fluid absorption. * **ฮด-opioid receptor agonism:** Binds to delta-receptors โ decreases intestinal secretion induced by cholera toxin and prostaglandins. * **Calcium channel modulation:** Inhibits diarrheas caused by factors utilizing calcium as a second messenger (non-cAMP/cGMP mediated). * **Mucosal absorption:** Directly enhances the mucosal absorption of water and electrolytes.
Dosing by species
- Diarrhea ยท 0.04-0.06 mg/kg ยท PO ยท twice daily ยท Using the suspension. Use is controversial; may react with excitatory behavior.
- Diarrhea ยท 0.08-0.16 mg/kg ยท PO ยท q12h ยท Use is controversial.
- Management of non-specific acute and chronic diarrhoea, and irritable bowel syndrome ยท 0.04-0.2 mg/kg ยท PO ยท q8-12h ยท As needed ยท Use with care; excitability may be seen.
- Antidiarrheal (Rabbits) ยท 0.1 mg/kg in 1 mL of water ยท PO ยท q8h for 3 days, then once daily for 2 days ยท 5 days total
- Antidiarrheal (Mice, Rats, Gerbils, Hamsters, Guinea pigs, Chinchillas) ยท 0.1 mg/kg in 1 mL of water ยท PO ยท q8h for 3 days, then once daily for 2 days ยท 5 days total
- Antidiarrheal ยท 0.08 mg/kg ยท PO ยท three times daily ยท Collies and related breeds (MDR1 mutation) may be overly sensitive
- Antidiarrheal ยท 0.1-0.2 mg/kg ยท PO ยท q8-12h
- Antidiarrheal ยท 0.1 mg/kg ยท PO ยท three times a day ยท Maximum 5 days ยท Potentially contraindicated when diarrhea is suspected to be caused by enteric infections
- Adjunctive treatment for diarrhea associated with chemotherapy ยท 0.08 mg/kg ยท PO ยท three times daily
Routes of administration
Contraindications
- Dogs tested positive for the ABCB1-1ฮ (MDR1) mutation
- Untested dogs of herding breeds susceptible to the MDR1 mutation
- Diarrhea caused by toxic ingestion (until the toxin is eliminated)
- Known hypersensitivity to narcotic analgesics
- Infectious enteritis (relative contraindication, as decreased motility can delay pathogen clearance)
- Intestinal obstruction
- Dogs likely to be ivermectin-sensitive (MDR1/ABCB1 mutation, e.g., Collies, Australian Shepherds)
- Infectious enteritis (where decreased motility may delay pathogen clearance)
- Toxigenic diarrhea
Adverse effects
- Constipation
- Bloat
- Sedation
- Paralytic ileus
- Toxic megacolon
- Pancreatitis
- CNS depression (especially in MDR1-mutant dogs)
- Excitatory behavior (cats)
- Excitability (especially in cats)
- Profound sedation and ataxia (in MDR1 mutant dogs)
Drug interactions
- Amiodarone ยท Inhibits P-glycoprotein (P-gp), which may increase loperamide plasma concentrations and risk of CNS toxicity.
- Carvedilol ยท Inhibits P-glycoprotein (P-gp), which may increase loperamide plasma concentrations and risk of CNS toxicity.
- Erythromycin ยท Inhibits P-glycoprotein (P-gp), which may increase loperamide plasma concentrations and risk of CNS toxicity.
- Ketoconazole ยท Inhibits P-glycoprotein (P-gp), which may increase loperamide plasma concentrations and risk of CNS toxicity.
- Itraconazole ยท Inhibits P-glycoprotein (P-gp), which may increase loperamide plasma concentrations and risk of CNS toxicity.
- Quinidine ยท Inhibits P-glycoprotein (P-gp), which may increase loperamide plasma concentrations and risk of CNS toxicity.
- Tamoxifen ยท Inhibits P-glycoprotein (P-gp), which may increase loperamide plasma concentrations and risk of CNS toxicity.
- Verapamil ยท Inhibits P-glycoprotein (P-gp), which may increase loperamide plasma concentrations and risk of CNS toxicity.
- Other antimotility drugs ยท Additive reduction in GI motility, increasing risk of ileus ยท moderate
- P-glycoprotein inhibitors (e.g., ketoconazole, cyclosporine, spinosad) ยท May increase CNS penetration of loperamide, leading to neurotoxicity ยท major
- CNS depressants ยท Additive sedation if loperamide crosses the blood-brain barrier ยท moderate
Monitoring
- Clinical efficacy (resolution of diarrhea)
- Fluid and electrolyte status (especially in severe diarrhea)
- CNS effects (sedation, ataxia, depression), particularly if using high dosages or in susceptible breeds
- Fecal consistency and frequency
- Signs of constipation or paralytic ileus
- Neurological status (watch for sedation or ataxia, especially in at-risk breeds)
- Hydration status
Overdose
In dog toxicity studies, doses of 1.25-5 mg/kg/day produced **vomiting, depression, severe salivation, and weight loss**. > **CRITICAL WARNING:** Breeds with a defective MDR1 (ABCB1-1ฮ) gene are profoundly more sensitive to CNS depression with loperamide than other breeds and have shown clinical signs of toxicity at doses as low as **0.06 mg/kg**. Common clinical signs of overdose include diarrhea, vomiting, lethargy, anorexia, weakness, and hypersalivation. **Treatment:** * Follow standard GI decontamination protocols. * **Avoid apomorphine** for emesis, as it can have additive CNS or respiratory depressant effects. * **Naloxone** may be used to treat severe CNS/respiratory depression; higher than usual doses of naloxone may be required to reverse loperamide toxicity.
VetSheet drug reference is intended for licensed veterinary professionals as a clinical decision-support aid, not a substitute for professional judgement or the manufacturerโs current label.