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 caution—or avoided entirely—in herding breeds (e.g., Collies, Australian Shepherds) due to the **ABCB1-1Δ (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.
Mecanismo: Loperamide exerts its antidiarrheal effects through multiple mechanisms within the gastrointestinal tract: * **μ-opioid receptor agonism:** Binds to mu-receptors in the myenteric plexus of the intestinal wall → inhibits the release of acetylcholine and prostaglandins → reduces peristalsis and increases intestinal transit time, allowing for greater fluid absorption. * **δ-opioid receptor agonism:** Binds to delta-receptors → 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.
Dosificación por especie
- Diarrhea · 0.04-0.06 mg/kg · PO · twice daily · Using the suspension. Use is controversial; may react with excitatory behavior.
- Diarrhea · 0.08-0.16 mg/kg · PO · q12h · Use is controversial.
- Management of non-specific acute and chronic diarrhoea, and irritable bowel syndrome · 0.04-0.2 mg/kg · PO · q8-12h · As needed · Use with care; excitability may be seen.
- Antidiarrheal (Rabbits) · 0.1 mg/kg in 1 mL of water · PO · q8h for 3 days, then once daily for 2 days · 5 days total
- Antidiarrheal (Mice, Rats, Gerbils, Hamsters, Guinea pigs, Chinchillas) · 0.1 mg/kg in 1 mL of water · PO · q8h for 3 days, then once daily for 2 days · 5 days total
- Antidiarrheal · 0.08 mg/kg · PO · three times daily · Collies and related breeds (MDR1 mutation) may be overly sensitive
- Antidiarrheal · 0.1-0.2 mg/kg · PO · q8-12h
- Antidiarrheal · 0.1 mg/kg · PO · three times a day · Maximum 5 days · Potentially contraindicated when diarrhea is suspected to be caused by enteric infections
- Adjunctive treatment for diarrhea associated with chemotherapy · 0.08 mg/kg · PO · three times daily
Vías de administración
Contraindicaciones
- Dogs tested positive for the ABCB1-1Δ (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
Efectos adversos
- 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)
Interacciones farmacológicas
- Amiodarone · Inhibits P-glycoprotein (P-gp), which may increase loperamide plasma concentrations and risk of CNS toxicity.
- Carvedilol · Inhibits P-glycoprotein (P-gp), which may increase loperamide plasma concentrations and risk of CNS toxicity.
- Erythromycin · Inhibits P-glycoprotein (P-gp), which may increase loperamide plasma concentrations and risk of CNS toxicity.
- Ketoconazole · Inhibits P-glycoprotein (P-gp), which may increase loperamide plasma concentrations and risk of CNS toxicity.
- Itraconazole · Inhibits P-glycoprotein (P-gp), which may increase loperamide plasma concentrations and risk of CNS toxicity.
- Quinidine · Inhibits P-glycoprotein (P-gp), which may increase loperamide plasma concentrations and risk of CNS toxicity.
- Tamoxifen · Inhibits P-glycoprotein (P-gp), which may increase loperamide plasma concentrations and risk of CNS toxicity.
- Verapamil · Inhibits P-glycoprotein (P-gp), which may increase loperamide plasma concentrations and risk of CNS toxicity.
- Other antimotility drugs · Additive reduction in GI motility, increasing risk of ileus · moderate
- P-glycoprotein inhibitors (e.g., ketoconazole, cyclosporine, spinosad) · May increase CNS penetration of loperamide, leading to neurotoxicity · major
- CNS depressants · Additive sedation if loperamide crosses the blood-brain barrier · moderate
Monitorización
- 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
Sobredosis
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 (ABCB1-1Δ) 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.
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