Propulsin: Full Drug Profile

Propulsin - General Information

In many countries (including Canada) cisapride has been either withdrawn or has had its indications limited due to reports about long QT syndrome due to cisapride, which predisposes to arrhythmias. The FDA issued a warning letter regarding this risk to health care professionals and patients.

Pharmacology of Propulsin

Propulsin is a parasympathomimetic which acts as a serotonin 5-HT₄ agonist. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous system. Propulsin stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. Propulsin increases the tone and amplitude of gastric (especially antral) contractions, relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the resting tone of the lower esophageal sphincter. It has little, if any, effect on the motility of the colon or gallbladder. Propulsin does not induce muscarinic or nicotinic receptor stimulation, nor does it inhibit acetylcholinesterase activity.

Propulsin for patients

Propulsin Interactions

Cisapride is metabolized mainly via the cytochrome P450 3A4 enzyme. In some cases where serious ventricular arrhythmias, QT prolongation, and torsades de pointes have occurred when cisapride was taken in conjunction with one of the cytochrome P450 3A4 inhibitors, elevated blood cisapride levels were noted at the time of the QT prolongation.

Antibiotics: In vitro and/or in vivo data show that clarithromycin, erythromycin, and troleandomycin markedly inhibit the metabolism of cisapride, which can result in an increase in plasma cisapride levels and prolongation of the QT interval on the ECG.

Anticholinergics: Concurrent administration of certain anticholinergic compounds, such as belladonna alkaloids and dicyclomine, would be expected to compromise the beneficial effects of cisapride.

Anticoagulants (Oral): In patients receiving oral anticoagulants, the coagulation times were increased in some cases. It is advisable to check coagulation time within the first few days after the start and discontinuation of cisapride therapy, with an appropriate adjustment of the anticoagulant dose, if necessary.

Antidepressants: In vitro data indicate that nefazodone inhibits the metabolism of cisapride, which can result in an increase in plasma cisapride levels and prolongation of the QT interval on the ECG.

Antifungals: In vitro and/or in vivo data indicate that fluconazole, itraconazole, and oral ketoconazole markedly inhibit the metabolism of cisapride, which can result in an increase in plasma cisapride levels and prolongation of the QT interval on the ECG. Human pharmacokinetic data indicate that oral ketoconazole markedly inhibits the metabolism of cisapride, resulting in a mean eight-fold increase in AUC of cisapride. A study in 14 normal male and female volunteers suggests that coadministration of cisapride and ketoconazole can result in prolongation of the QT interval on the ECG.

H2 Receptor Antagonists: Cimetidine coadministration leads to an increased peak plasma concentration and AUC of cisapride, there is no effect on cisapride absorption when it is coadministered with ranitidine. The gastrointestinal absorption of cimetidine and ranitidine is accelerated when they are coadministered with cisapride.

Protease Inhibitors: In vitro data indicate that indinavir and ritonavir markedly inhibit the metabolism of cisapride which can result in an increase in plasma cisapride levels and prolongation of the QT interval on the ECG.

Other: Coadministration of grapefruit juice with cisapride increases the bioavailability of cisapride and concomitant use should be avoided.

Cisapride should not be used concomitantly with other drugs known to prolong the QT interval: certain antiarrhythmics, including those of Class IA (such as quinidine and procainamide) and Class III (such as sotalol); tricyclic antidepressants (such as amitriptyline); certain tetracyclic antidepressants (such as maprotiline); certain antipsychotic medications (such as sertindole); astemizole, bepridil, sparfloxacin, and terodiline. The preceding lists of drugs are not comprehensive.

The acceleration of gastric emptying by cisapride could affect the rate of absorption of other drugs. Patients receiving narrow therapeutic ratio drugs or other drugs that require careful titration should be followed closely; if plasma levels are being monitored, they should be reassessed.

Propulsin Contraindications

Serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation have been reported in patients taking cisapride with other drugs that inhibit cytochrome P450 3A4. Some of these events have been fatal. Concomitant oral or intravenous administration of the following drugs with cisapride may lead to elevated cisapride blood levels and is contraindicated. Antibiotics: Oral or IV erythromycin, clarithromycin (Biaxin), troleandomycin (TAO). Antidepressants: Nefazodone (Serzone). Antifungals: Oral or IV fluconazole (Diflucan), itraconazole (Sporanox), oral ketoconazole (Nizoral). Protease Inhibitors: Indinavir (Crixivan), ritonavir (Norvir).Cisapride is Also Contraindicated for Patients With: History of prolonged electrocardiographic QT intervals or known family history of congenital long QT syndrome; renal failure; history of ventricular arrhythmias, ischemic heart disease, and congestive heart failure; clinically significant bradycardia; uncorrected electrolyte disorders (hypokalemia, hypomagnesemia); respiratory failure; and concomitant medications known to prolong the QT interval and increase the risk of arrhythmia, such as certain antiarrhythmics, certain antipsychotics, certain antidepressants, astemizole, bepridil, sparfloxacin, and terodiline. The preceding lists of drugs are not comprehensive. Cisapride should not be used in patients with uncorrected hypokalemia or hypomagnesemia or who might experience rapid reduction of plasma potassium such as those administered potassium-wasting diuretics and/or insulin in acute settings. Cisapride should not be used in patients in whom an increase in gastrointestinal motility could be harmful, e.g., in the presence of gastrointestinal hemorrhage, mechanical obstruction, or perforation. Cisapride is contraindicated in patients with known sensitivity or intolerance to the drug.

Additional information about Propulsin

Propulsin Indication

For the symptomatic treatment of adult patients with nocturnal heartburn due to gastroesophageal reflux disease.

Mechanism Of Action

Propulsin acts through the stimulation of the serotonin 5-HT₄ receptors which increases acetylcholine release in the enteric nervous system (specifically the myenteric plexus). This results in increased tone and amplitude of gastric (especially antral) contractions, relaxation of the pyloric sphincter and the duodenal bulb, and increased peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit.

Drug Interactions

Acetophenazine Increased risk of cardiotoxicity and arrhythmias

Food Interactions

Increases absorption, take 30 minutes before a meal.

Generic Name

Cisapride

Drug Category

Gastrointestinal Agents; Anti-Ulcer Agents; Prokinetic Agents; Serotonin Agonists

Drug Type

Small Molecule; Approved; Withdrawn

Other Brand Names containing Cisapride

Acenalin; Alimix; Cipril; Enteropride; Kinestase; Prepulsid; Pridesia; Propulsid; Propulsid Quicksolv; Propulsin; Risamal; Syspride;

Absorption

Cisapride is rapidly absorbed after oral administration, with an absolute bioavailability of 35-40%.

Protein Binding

97.5%

Biotransformation

Hepatic. Extensively metabolized via cytochrome P450 3A4 enzyme.

Half Life

6-12 hours

Dosage Forms of Propulsin

Tablet Oral

Chemical IUPAC Name

4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-yl]-2-methoxybenzamide

Chemical Formula

C23H29ClFN3O4

Cisapride on Wikipedia

https://en.wikipedia.org/wiki/Cisapride

Organisms Affected

Humans and other mammals