Cisapride

Prokinetic agent Benzamide derivative

Dosage & Administration Guidelines

Species Route Dose Frequency Duration & Clinical Notes
Dog PO 0.1-0.5 mg/kg q8-12h Duration: As needed; typically 2-4 weeks for chronic conditions
Notes: Start at lower end for constipation; adjust based on response.
Cat PO 0.1-0.5 mg/kg (up to 1 mg/kg in refractory cases) q8-12h Duration: As needed; may be long-term for megacolon
Notes: Commonly used dose: 2.5 mg per cat q12h (approx. 0.5 mg/kg).
Horse PO 0.1-0.2 mg/kg q8-12h Duration: 3-5 days or as needed
Notes: Use with caution; monitor for colic.
Rabbit PO 0.5 mg/kg q8-12h Duration: Until gastrointestinal motility improves
Notes: Often used in combination with fluids and syringe feeding.
Cattle PO 0.1 mg/kg q12h Duration: 2-3 days
Notes: Off-label; limited data.

Clinical Indications & Species Uses

General Indications
  • Prokinetic agent for gastrointestinal motility disorders
  • Treatment of gastroesophageal reflux
  • Management of delayed gastric emptying
  • Treatment of constipation and megacolon
Dog (Canine)
  • Gastroesophageal reflux disease (GERD)
  • Gastric dilatation-volvulus (adjunctive therapy)
  • Delayed gastric emptying
  • Chronic constipation
  • Megacolon (adjunctive therapy)
  • Postoperative ileus
Cat (Feline)
  • Chronic constipation
  • Megacolon (idiopathic)
  • Gastroesophageal reflux disease
  • Delayed gastric emptying
  • Hairball management (adjunctive)
Horse (Equine)
  • Postoperative ileus
  • Gastric emptying disorders
  • Equine grass sickness (supportive)
Cattle (Bovine)
  • Abomasal displacement (adjunctive)
  • Ruminal atony (off-label)
Rabbit & Small Mammals
  • Gastrointestinal stasis (ileus)
  • Gastric dilation
  • Postoperative ileus
Exotic & Other Species
  • Reptiles: gastrointestinal stasis (off-label)
  • Small mammals (ferrets, guinea pigs): gastrointestinal stasis (off-label)

Pharmacology & Mechanism of Action

Drug Class: Prokinetic agent | Pharmacological Group: Benzamide derivative

Mechanism of Action: Cisapride is a substituted benzamide that enhances gastrointestinal motility by increasing the release of acetylcholine from the myenteric plexus. It acts primarily as a 5-HT4 receptor agonist, which facilitates cholinergic transmission in the gut. This results in increased lower esophageal sphincter pressure, improved gastric emptying, and enhanced small and large intestinal transit. Unlike metoclopramide, cisapride has minimal dopamine receptor antagonism, thus fewer central nervous system effects.

Pharmacodynamics: Cisapride stimulates motility throughout the gastrointestinal tract, from the esophagus to the colon. It increases the amplitude of esophageal peristalsis, raises lower esophageal sphincter tone, accelerates gastric emptying, and shortens small and large intestinal transit time. It also enhances antroduodenal coordination. The drug's effects are most pronounced in the stomach and small intestine, but it also stimulates colonic motility, making it useful for constipation. The prokinetic effect is dose-dependent and is more potent than metoclopramide in many species.

⚑ Pharmacokinetics Summary

Absorption: Cisapride is rapidly and well absorbed after oral administration. Peak plasma concentrations are reached within 1-2 hours in most species. Food may increase the rate of absorption but not the extent. Bioavailability is approximately 40-50% in dogs due to first-pass metabolism.
Distribution: Cisapride is widely distributed in tissues, with a volume of distribution of about 2-4 L/kg. It crosses the blood-brain barrier to a limited extent. Protein binding is approximately 97-98% in plasma, primarily to albumin and alpha-1-acid glycoprotein.
Metabolism: Cisapride is extensively metabolized in the liver via the cytochrome P450 system, primarily by CYP3A4 in humans and analogous enzymes in animals. It undergoes N-dealkylation and hydroxylation to form inactive metabolites. There is significant first-pass metabolism, reducing systemic bioavailability.
Excretion: Metabolites are excreted primarily in the urine (about 50%) and feces (about 40%). Only a small fraction (less than 1%) is excreted unchanged. The elimination half-life varies by species: approximately 1-2 hours in dogs, 2-3 hours in cats, and 1-2 hours in horses.
Half-Life: Dog: 1-2 hours; Cat: 2-3 hours; Horse: 1-2 hours
Bioavailability: Oral: ~40-50% in dogs; ~50-60% in cats
Protein Binding: 97-98%

Available Formulations & Strengths

Oral Tablet 5 mg, 10 mg, 20 mg (PO)
Oral Suspension 1 mg/mL (compounded) (PO)

Contraindications & Clinical Warnings

Contraindications:
  • Known hypersensitivity to cisapride or other benzamide derivatives
  • Gastrointestinal hemorrhage, obstruction, or perforation
  • Concurrent use with drugs that inhibit CYP3A4 (e.g., ketoconazole, itraconazole, erythromycin, clarithromycin, fluconazole, grapefruit juice) due to risk of QT prolongation and cardiac arrhythmias
  • Severe hepatic impairment
  • Hypokalemia or hypomagnesemia (risk of QT prolongation)
Warnings & Clinical Precautions:
  • Use with caution in patients with cardiac disease, especially those with pre-existing QT prolongation or arrhythmias.
  • Monitor serum electrolytes (potassium, magnesium) before and during therapy.
  • May cause extrapyramidal signs in some animals, though less common than with metoclopramide.
  • Use with caution in pregnant or lactating animals; safety not established.
  • In food animals, withdrawal times must be observed; extra-label use requires veterinary oversight.
  • Do not use in animals with known gastrointestinal obstruction.
  • In horses, monitor for signs of colic.

Adverse Effects & Reactions

Common:

  • Diarrhea
  • Abdominal cramping
  • Flatulence
  • Increased salivation

Serious / Severe:

  • Cardiac arrhythmias (ventricular tachycardia, QT prolongation)
  • Seizures (rare)
  • Extrapyramidal signs (muscle tremors, restlessness)

Rare:

  • Hepatotoxicity
  • Blood dyscrasias
  • Allergic reactions (rash, urticaria)

Key Drug Interactions

Interacting Drug / Class Clinical Effect & Mechanism Severity
Ketoconazole, Itraconazole, Fluconazole Inhibits CYP3A4 metabolism of cisapride, leading to increased plasma levels and risk of QT prolongation and cardiac arrhythmias. High
Erythromycin, Clarithromycin Inhibits CYP3A4 and may also prolong QT interval; increased risk of arrhythmias. High
Grapefruit juice Inhibits intestinal CYP3A4, increasing cisapride bioavailability and risk of toxicity. High
Anticholinergics (e.g., atropine) May antagonize the prokinetic effects of cisapride. Moderate
Opioids May reduce gastrointestinal motility, counteracting cisapride's effects. Moderate
Tricyclic antidepressants (e.g., amitriptyline) Additive QT prolongation; increased risk of arrhythmias. Moderate
Cimetidine May increase cisapride levels (inhibits CYP3A4), but less severe than azole antifungals. Moderate

Overdose & Toxicity Management

Signs of Toxicity:

  • Abdominal pain
  • Diarrhea
  • Hypotension
  • Tachycardia or bradycardia
  • QT prolongation
  • Ventricular arrhythmias
  • Seizures (in severe cases)

Emergency Treatment Protocol: Treatment is symptomatic and supportive. Induce emesis if recent ingestion and animal is conscious. Administer activated charcoal to reduce absorption. Monitor cardiac function with ECG and treat arrhythmias with appropriate antiarrhythmic agents (e.g., lidocaine for ventricular tachycardia). Correct electrolyte imbalances (potassium, magnesium). Provide intravenous fluids for hypotension. Seizures may be controlled with diazepam or barbiturates. There is no specific antidote.

Food Animal Withdrawal Times

πŸ₯© Meat: 7 daysπŸ₯› Milk: 3 days

Cisapride is not approved for food animals; extra-label use requires extended withdrawal times. The values provided are conservative estimates; consult FARAD for specific guidance.

Storage, Handling & Regulatory Information

Storage Temperature: Store at room temperature (20-25Β°C) in a tight, light-resistant container.

Light Sensitivity: Light-sensitive β€” protect from direct exposure.

Handling & Special Conditions: Protect from moisture. Compounded suspensions should be refrigerated and used within 30 days.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: Not FDA-approved for veterinary use; approved for human use but restricted due to cardiac risks. Veterinary use is extra-label.

Extra-Label (Off-Label) Use: In the US, cisapride is not approved for veterinary use but can be prescribed under AMDUCA for animals. It is a prescription drug for humans; extra-label use in animals is permitted by a veterinarian. In food animals, a valid VCPR is required, and withdrawal times must be extended.

Clinical Pearls & Practice Notes

πŸ’‘ Clinical Insights: Cisapride is a potent prokinetic agent used primarily in small animals for gastrointestinal motility disorders, especially chronic constipation and megacolon in cats. It is often preferred over metoclopramide for colonic motility because it stimulates the entire GI tract. However, its use has declined due to cardiac safety concerns in humans, but in veterinary medicine, it remains a valuable option when used cautiously. It is important to screen for potential drug interactions, especially with CYP3A4 inhibitors. In cats with megacolon, cisapride may be used long-term, but response can vary. In rabbits, it is a common treatment for GI stasis. Always monitor for adverse effects and adjust dosing based on clinical response. For food animals, extra-label use is rare and requires careful consideration of withdrawal times.

References & Literature

  • πŸ“š Plumb's Veterinary Drug Handbook
  • πŸ“š Papich Veterinary Pharmacology and Therapeutics
  • πŸ“š Compendium of Veterinary Products (CVP)