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Acenalin

Acenalin - 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In many countries (including Canada) cisapride has been either withdrawn or has had its indications limited due to reports about long QT syndrome due to cisapride, which predisposes to arrhythmias.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 Acenalin

Acenalin is a parasympathomimetic which acts as a serotonin 5-HT4 agonist. Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous system. Acenalin stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. Acenalin 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. Acenalin does not induce muscarinic or nicotinic receptor stimulation, nor does it inhibit acetylcholinesterase activity.

 

Acenalin for patients

 

Acenalin 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.

 

Acenalin 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 Acenalin

Acenalin Indication: For the symptomatic treatment of adult patients with nocturnal heartburn due to gastroesophageal reflux disease.
Mechanism Of Action: Acenalin 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
Amiodarone Increased risk of cardiotoxicity and arrhythmias
Amitriptyline Increased risk of cardiotoxicity and arrhythmias
Amoxapine Increased risk of cardiotoxicity and arrhythmias
Amprenavir Amprenavir increases the effect and toxicity of cisapride
Anisindione Increases the anticoagulant effect
Aprepitant Increased risk of cardiotoxicity and arrhythmias
Astemizole Increased risk of cardiotoxicity and arrhythmias
Atazanavir Increased risk of cardiotoxicity and arrhythmias
Bepridil Increased risk of cardiotoxicity and arrhythmias
Bretylium Increased risk of cardiotoxicity and arrhythmias
Chlorpromazine Increased risk of cardiotoxicity and arrhythmias
Clarithromycin Increased risk of cardiotoxicity and arrhythmias
Clomipramine Increased risk of cardiotoxicity and arrhythmias
Delavirdine Increased risk of cardiotoxicity and arrhythmias
Desipramine Increased risk of cardiotoxicity and arrhythmias
Dicumarol Increases the anticoagulant effect
Dihydroquinidine barbiturate Increased risk of cardiotoxicity and arrhythmias
Diltiazem Diltiazem increases the levels of cisapride
Disopyramide Increased risk of cardiotoxicity and arrhythmias
Doxepin Increased risk of cardiotoxicity and arrhythmias
Efavirenz Increased risk of cardiotoxicity and arrhythmias
Encainide Increased risk of cardiotoxicity and arrhythmias
Erythromycin Increased risk of cardiotoxicity and arrhythmias
Ethopropazine Increased risk of cardiotoxicity and arrhythmias
Fexofenadine Increased risk of cardiotoxicity and arrhythmias
Flecainide Increased risk of cardiotoxicity and arrhythmias
Fluconazole Increased risk of cardiotoxicity and arrhythmias
Fluphenazine Increased risk of cardiotoxicity and arrhythmias
Fosamprenavir Amprenavir increases the effect and toxicity of cisapride
Imipramine Increased risk of cardiotoxicity and arrhythmias
Indinavir Increased risk of cardiotoxicity and arrhythmias
Itraconazole Increased risk of cardiotoxicity and arrhythmias
Josamycin Increased risk of cardiotoxicity and arrhythmias
Ketoconazole Increased risk of cardiotoxicity and arrhythmias
Maprotiline Increased risk of cardiotoxicity and arrhythmias
Mesoridazine Increased risk of cardiotoxicity and arrhythmias
Methdilazine Increased risk of cardiotoxicity and arrhythmias
Nelfinavir Increased risk of cardiotoxicity and arrhythmias
Mibefradil Mibefradil increases levels of cisapride
Nefazodone Nefazodone increases serum levels of cisapride
Acenocoumarol Increases the anticoagulant effect
Nifedipine Increases the effect and toxicity of nifedipine
Nortriptyline Increased risk of cardiotoxicity and arrhythmias
Perphenazine Increased risk of cardiotoxicity and arrhythmias
Posaconazole Contraindicated co-administration
Procainamide Increased risk of cardiotoxicity and arrhythmias
Prochlorperazine Increased risk of cardiotoxicity and arrhythmias
Promazine Increased risk of cardiotoxicity and arrhythmias
Promethazine Increased risk of cardiotoxicity and arrhythmias
Propafenone Increased risk of cardiotoxicity and arrhythmias
Propiomazine Increased risk of cardiotoxicity and arrhythmias
Protriptyline Increased risk of cardiotoxicity and arrhythmias
Quinidine Increased risk of cardiotoxicity and arrhythmias
Quinidine barbiturate Increased risk of cardiotoxicity and arrhythmias
Quinupristin This combination presents an increased risk of toxicity
Ritonavir Increased risk of cardiotoxicity and arrhythmias
Saquinavir Increased risk of cardiotoxicity and arrhythmias
Sotalol Increased risk of cardiotoxicity and arrhythmias
Telithromycin Increased risk of cardiotoxicity and arrhythmias
Terfenadine Increased risk of cardiotoxicity and arrhythmias
Thiethylperazine Increased risk of cardiotoxicity and arrhythmias
Thioridazine Increased risk of cardiotoxicity and arrhythmias
Trifluoperazine Increased risk of cardiotoxicity and arrhythmias
Triflupromazine Increased risk of cardiotoxicity and arrhythmias
Trimeprazine Increased risk of cardiotoxicity and arrhythmias
Trimipramine Increased risk of cardiotoxicity and arrhythmias
Troleandomycin Increased risk of cardiotoxicity and arrhythmias
Voriconazole Increased risk of cardiotoxicity and arrhythmias
Warfarin Increases the anticoagulant effect
Zafirlukast Increased risk of cardiotoxicity and arrhythmias
Ziprasidone Increased risk of cardiotoxicity and arrhythmias
Ibutilide Increased risk of cardiotoxicity and arrhythmias
Methotrimeprazine Increased risk of cardiotoxicity and arrhythmias
Food Interactions: Increases absorption, take 30 minutes before a meal.
Grapefruit and grapefruit juice should be avoided throughout treatment, grapefruit can significantly increase serum levels of this product.
Generic Name: Cisapride
Synonyms: Not Available
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%.
Toxicity (Overdose): Not Available
Protein Binding: 97.5%
Biotransformation: Hepatic. Extensively metabolized via cytochrome P450 3A4 enzyme.
Half Life: 6-12 hours
Dosage Forms of Acenalin: Tablet Oral
Suspension 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: http://en.wikipedia.org/wiki/Cisapride
Organisms Affected: Humans and other mammals