Cisapride

Usage

Cisapride is a gastrointestinal prokinetic agent. It was primarily used to treat symptoms of gastroesophageal reflux disease (GERD), gastroparesis, and other conditions involving impaired gastrointestinal motility. Its pharmacological classification is gastroprokinetic agent. It works by increasing the release of acetylcholine in the myenteric plexus, which enhances gastrointestinal motility and transit. However, due to its potential for serious cardiac side effects, its use is now severely restricted, and it’s generally unavailable except under a very limited access program in some countries.

Alternate Names

Cisapride is also known by the brand name Propulsid. There are no widely recognized international or regional variations of the name.

How It Works

Pharmacodynamics: Cisapride acts as a serotonin 5-HT4 receptor agonist. It stimulates the release of acetylcholine, increasing the frequency and strength of esophageal contractions, improves lower esophageal sphincter pressure, and accelerates gastric emptying. It also enhances motility in the small intestine and colon.

Pharmacokinetics: Cisapride is readily absorbed after oral administration. It undergoes hepatic metabolism, primarily via the cytochrome P450 3A4 enzyme system. It’s eliminated primarily through the liver and bile, with a small fraction excreted in the urine. Its elimination half-life is around 7 hours.

Mode of Action: Cisapride binds to and activates 5-HT4 receptors on enteric neurons, increasing the release of acetylcholine. This, in turn, stimulates smooth muscle contraction and enhances gastrointestinal motility and transit. It doesn’t block dopamine receptors and has no antiemetic effect.

Elimination Pathways: Cisapride is primarily metabolized in the liver, with a smaller portion renally excreted. The specific CYP enzyme responsible for its metabolism is CYP3A4.

Dosage

It is crucial to note that cisapride is only accessible through a limited access program due to serious safety concerns. Any cisapride prescription and dosage must be overseen by a specialist registered with the program and strictly adhere to its guidelines. The following historical dosage information is for reference only:

Standard Dosage

Adults:

Historically, the standard adult dose was 10 mg orally, four times a day, 15 minutes before meals and at bedtime. This dose could be increased to 20 mg four times a day if needed. However, doses above 40 mg per day are contraindicated.

Children:

Historically, the pediatric dosage was 0.2-0.3 mg/kg/dose orally three to four times a day for children older than one year. Pediatric dosing is generally no longer recommended.

Special Cases:

• Elderly Patients: Dose reduction may be necessary.
• Patients with Renal Impairment: Careful monitoring is needed.
• Patients with Hepatic Dysfunction: Dose reduction may be necessary.
• Patients with Comorbid Conditions: Individualized dosing is required based on the specific condition.

Clinical Use Cases

Cisapride is not recommended for use in any of these clinical settings due to the risk of serious cardiac side effects.

Dosage Adjustments:

Dosage adjustments may be required for patients with liver or kidney dysfunction and those taking other medications metabolized by CYP3A4.

Side Effects

Common Side Effects:

Diarrhea, abdominal pain, headache, nausea, rhinitis, and fatigue.

Rare but Serious Side Effects:

Serious cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, torsades de pointes, QT prolongation, syncope, cardiac arrest, and sudden death.

Long-Term Effects:

Data on the long-term effects of cisapride are limited due to its restricted use.

Adverse Drug Reactions (ADR):

The most serious ADRs associated with cisapride are cardiac arrhythmias, which can be fatal.

Contraindications

Cisapride is contraindicated in patients with:

• Hypersensitivity to cisapride
• A history of QT prolongation or a family history of long QT syndrome
• Concomitant use of medications that inhibit CYP3A4 or prolong the QT interval
• Electrolyte imbalances (hypokalemia, hypomagnesemia)
• Pre-existing cardiac conditions (e.g., congestive heart failure, ventricular arrhythmias)
• Renal or hepatic impairment

Drug Interactions

Cisapride interacts with a wide range of medications, including:

• CYP3A4 inhibitors (e.g., azole antifungals, macrolide antibiotics)
• QT-prolonging agents (e.g., certain antiarrhythmics, antipsychotics)
• Certain antacids
• Alcohol

Pregnancy and Breastfeeding

Cisapride is contraindicated during pregnancy and should be used with caution during breastfeeding.

Drug Profile Summary

• Mechanism of Action: 5-HT4 receptor agonist, increases acetylcholine release, enhances GI motility.
• Side Effects: Diarrhea, abdominal pain, potentially fatal cardiac arrhythmias.
• Contraindications: QT prolongation, CYP3A4 inhibitors, electrolyte imbalances, cardiac conditions.
• Drug Interactions: Numerous, particularly with CYP3A4 inhibitors and QT-prolonging drugs.
• Pregnancy & Breastfeeding: Contraindicated in pregnancy, caution advised during breastfeeding.
• Dosage: Historically, 10-20 mg four times daily for adults, but use is now severely restricted.
• Monitoring Parameters: ECG (QT interval), serum electrolytes.

Popular Combinations

The use of cisapride in combination with other drugs is highly discouraged due to the elevated risk of adverse effects.

Precautions

Pre-screening for cardiac conditions, electrolyte imbalances, and concomitant medication use is essential. Cisapride use is generally limited to specialized settings under strict medical supervision.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Cisapride?

A: Due to the high risk of adverse cardiac events, cisapride is only available through a restricted access program. The dosage is determined by a specialist registered with the program, based on the patient’s specific condition and clinical response, and cannot exceed 40mg daily for adults. Historical dosage information is for reference only and should not guide current practice.

Q2: What are the most serious side effects of Cisapride?

A: The most serious side effects are cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, torsades de pointes, QT prolongation, which can lead to syncope, cardiac arrest, and even sudden death.

Q3: Who should not take Cisapride?

A: Cisapride should not be taken by individuals with long QT syndrome, a history of cardiac arrhythmias, electrolyte imbalances, or those taking medications that inhibit CYP3A4 or prolong the QT interval.

Q4: Can Cisapride be used during pregnancy?

A: No, Cisapride is contraindicated during pregnancy due to potential risks to the fetus.

Q5: How does Cisapride work?

A: Cisapride is a 5-HT4 receptor agonist that increases acetylcholine release in the gut, leading to increased gastrointestinal motility.

Q6: What are the common side effects of Cisapride?

A: The most common side effects include diarrhea, abdominal pain, headache, and nausea.

Q7: What should I do if I miss a dose of Cisapride?

A: If you miss a dose, take it as soon as possible. If it’s almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not double the dose.

Q8: What are the signs of a Cisapride overdose?

A: Signs of an overdose may include severe diarrhea, irregular heartbeat, dizziness, and fainting. Seek immediate medical attention if an overdose is suspected.

Q9: How is Cisapride metabolized?

A: Cisapride is primarily metabolized in the liver by the CYP3A4 enzyme system.

Q10: Are there any drug interactions with Cisapride?

A: Yes, Cisapride has numerous drug interactions, notably with medications that inhibit or induce CYP3A4 (e.g. macrolide antibiotics, antifungals) and drugs that prolong the QT interval. These interactions can increase the risk of serious cardiac side effects. Therefore, it is important to inform your doctor about all other medications you are taking, including over-the-counter drugs and herbal supplements.