Cisapride

Absorption

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

Description

Cisapride is a gastroprokinetic useful in the treatment of reflux esophagitis, constipation, and a variety of gastro-intestinal motility disorders. Its novel mechanism of action is thought to involve the enhancement of acetylcholine release in the mysenteric plexus of the gut. It is reportedly devoid of CNS and cardiac side-effects.

Chemical properties

White Solid

Originator

Janssen (Belgium)

The Uses of Cisapride

Cisapride Monohydrate is a cardioactive drug that causes prolongation of cardiac repolarization in human; selective serotonin 5-HT4 receptor agonist.

The Uses of Cisapride

A Serotonin 5-HT4 receptro agonist. Used as a Gastroprokinetic

The Uses of Cisapride

Peristaltic stimulant;5-HT antagonist

The Uses of Cisapride

isoflavone used as a cholagogue and cathartic

Indications

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

Background

In many countries (including Canada) cisapride has been either withdrawn or has had its indications limited due to reports about long QT syndrome due to cisapride, which predisposes to arrhythmias.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

What are the applications of Application

Cisapride is a SR-4 agonist also known as Enteropride

Definition

ChEBI: The amide resulting from formal condensation of 4-amino-5-chloro-2-methoxybenzoic acid with cis-1-[3-(4-fluorophenoxy)propyl]-3-methoxypiperidin-4-amine. It has been used (as its monohydrate or as its tartrate) for the treatment of gastro-oeso hageal reflux disease and for non-ulcer dyspepsia, but its propensity to cause cardiac arrhythmias resulted in its complete withdrawal from many countries, including the U.K., and restrictions on its use elsewhere.

Indications

Cisapride (Propulsid) is serotonin-4 (5-HT4) receptor agonists that stimulate GI motility. Cisapride appears to act by facilitating the release of acetylcholine from the myenteric plexus. It has no antiadrenergic, antidopaminergic, or cholinergic side effects. Following oral administration, peak plasma levels occur in 1.5 to 2 hours; the drug’s half-life is 10 hours.

Manufacturing Process

A mixture of 1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinone (140 mg), benzylamine (61 mg), Pd 10% on charcoal (100 mg) and a 0.02% solution of thiophene in THF was reacted under hydrogen gas for 3 hours at 50°C. The catalyst was filtered off and fresh palladium 10% on charcoal (100 mg) was added. Debenzylation of the formed intermediate took place under hydrogen atmosphere for 18 hours at 50°C. The reaction mixture was filtered and evaporated under a stream of nitrogen to yield 1-[3-(4-fluorophenoxy)- propyl]-3-methoxy-4-piperidinamine having a cis/trans ratio of about 93/7. 1-[3-(4-Fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine (50 g) was dissolved in methyl isobutylketone (250 ml) and a nitric acid solution (65%, 12.8 ml) was carefully added so that the temperature of the solution did not exceed 45°C. The reaction mixture was stirred at a temperature of 30°C and seeded. When crystallisation started, the reaction mixture was cooled to 0°C and stirred for another 2 hours. The product was filtered off, washed with a small amount of toluene and dried, yielding 1-[3-(4-fluorophenoxy)-propyl]-3- methoxy-4-piperidinamine nitrate (m.p. 60°C).
1-[3-(4-Fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine nitrate was dissolved in water (95 ml). The reaction mixture was stirred and toluene (95 ml) was added. A NaOH solution (50%, 10.3 ml) was slowly added and the temperature of the reaction mixture was raised to 75°C. After 30 min, the aqueous layer was discarded and the organic layer was evaporated, yielding 1-[3-(4-fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine having a cis/trans ratio equal to or higher than 98/2.
To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (20.2 g) in methyl isobutylketone (250 ml) and triethyl amine (15.3 ml) was slowly dropped ethyl chloroformate (9.6 ml). The reaction mixture was stirred for 30 min at room temperature. To the formed mixed anhydride was then added 1-[3-(4- fluorophenoxy)-propyl]-3-methoxy-4-piperidinamine (28.2 g) and the reaction mixture was stirred for 2 hours at room temperature. Subsequently, the reaction mixture was washed with water (80 ml) and a NaOH solution (6.5% w/v, 50 ml). The organic layer was warmed to 65°C and methanol (50 ml) and water (8.5 ml) were added. The solution was cooled slowly and stirred for 2 days during which crystallisation occurred, yielding benzamide, 4-amino-5- chloro-N-(1-(3-(4-fluorophenoxy)propyl)-3-methoxy-4-piperidinyl)-2-methoxy- , monohydrate, cis- (Cisapride) having a cis/trans ratio higher than 99/1.

brand name

Propulsid (Janssen);Calmax;Cisapid;Cismotil;Digenol;Prepulsid.

Therapeutic Function

Gastrointestinal drug

Biological Activity

5-HT 4 receptor agonist and gastrokinetic agent. Stimulates intestinal acetylcholine release, possibly via 5-HT 4 receptor-dependent and -independent mechanisms, leading to increased intestinal motility.

Pharmacokinetics

Cisapride is a parasympathomimetic which acts as a serotonin 5-HT4 agonist; upon activation of the receptor signaling pathway, cisapride promotes the release of acetylcholine neurotransmitters in the enteric nervous system. Cisapride stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. Cisapride 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. Cisapride does not induce muscarinic or nicotinic receptor stimulation, nor does it inhibit acetylcholinesterase activity.

Clinical Use

Cisapride has been successfully used to treat gastroparesis and mild gastroesophageal reflux disease.

Side Effects

The most frequent side effect has been diarrhea. A few patients had seizure activity that was reversible after medication was discontinued. Cisapride was pulled from the U. S. market after deaths from drug-associated cardiac arrhythmias, including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation.

Veterinary Drugs and Treatments

Proposed uses for cisapride in small animals includes esophageal reflux and treatment of primary gastric stasis disorders. Cisapride has been found to be useful in the treatment of constipation and megacolon in cats.

Metabolic pathway

Cisapride 14C labeled at the carbonyl carbon and 3H labeled at the fluorophenyl moiety or at the piperidine ring is investigated using some animals. N- Dealkylation at the nitrogen of the piperidine ring, resulting in the main urinary metabolite norcisapride, and aromatic hydroxylation of the fluorinated phenyl ring are the major metabolic pathways in dogs and humans. Norcisapride excretion accounts for 14% of the dose in dogs and 41-45% in humans. Minor metabolic pathways are O-dearylation of the 4- fluorophenyl group and oxidation on the piperidine ring (rat, rabbits and dogs: Lavrijsen et al. (1986)15).

Metabolism

Hepatic. Extensively metabolized via cytochrome P450 3A4 enzyme.

storage

Store at RT