Cisapride: An Updated Review of its Pharmacology and Therapeutic Efficacy as a Prokinetic Agent in Gastrointestinal Motility Disorders

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Abstract

Synopsis

Cisapride is an orally administered prokinetic agent which facilitates or restores motility throughout the length of the gastrointestinal tract. It is a substituted piperidinyl benzamide, chemically related to metoclopramide, but unlike metoclopramide, cisapride is largely devoid of central depressant or antidopaminergic effects.

Synopsis

In placebo-controlled trials, cisapride improved healing rates and symptoms in both adults and children with reflux oesophagitis. Maintenance therapy with cisapride at half the healing dose is effective in reducing the incidence of relapse. Symptoms are also alleviated in patients with functional dyspepsia, and gastric emptying and symptoms are improved in most patients with gastroparesis, an effect which is sustained during long term administration. However, the efficacy of cisapride in end-stage gastroparesis remains less clear. Cisapride increases stool frequency in patients with chronic constipation, and limited data suggest that the drug may also be beneficial in treating chronic intestinal pseudo-obstruction and irritable bowel syndrome. Cisapride demonstrated efficacy comparable with or superior to that of metoclopramide, and was at least as effective as cimetidine and ranitidine in patients with reflux disease. In patients with functional dyspepsia, cisapride has shown at least equal efficacy to domperidone, metoclopramide and ranitidine, and superior efficacy to cimetidine in the small comparative trials conducted to date.

Synopsis

Adverse effects in patients receiving cisapride are generally transient and mild, with abdominal cramping, borborygmi, diarrhoea or loose stools most frequently reported. Central nervous system adverse effects are rare.

Synopsis

Thus, with its favourable tolerability profile and demonstrated efficacy in a variety of gastrointestinal motility disorders, the position of cisapride as a valuable agent in the management of patients with gastrointestinal motility disorders is strengthening. However, larger well-controlled comparative trials of the drug with other agents are necessary before the relative position of cisapride in therapy can be categorically defined.

Pharmacological Properties

Cisapride stimulates gastrointestinal motor activity through an indirect mechanism involving the release of acetylcholine mediated by postganglionic nerve endings in the myenteric plexus of the gut. It is an agonist of serotonin (5-hydroxytryptamine; 5-HT) at the 5-HT4 receptor as well as an antagonist at the 5-HT3 receptor. Studies indicate that the intestinal effect is most likely to result from activation of 5-HT4 receptors, although other, as yet unidentified serotonin receptors may also be involved.

Pharmacological Properties

Cisapride has been shown to reduce the exposure of the oesophagus to gastric acid - an action which can be attributed to its effects on the lower oesophageal sphincter pressure (LOSP), oesophageal clearing peristalsis and gastric emptying. Cisapride administration generally increases LOSP and oesophageal motility by about 20 to 50% in healthy adult volunteers and patients with gastro-oesophageal reflux disease (GORD). Increases in LOSP and oesophageal motility have also been found in infants with GORD after administration of the drug and in some patients with systemic sclerosis. Cisapride reduces the duration of oesophageal pH < 4 in adults and children during both day and night.

Pharmacological Properties

In comparative studies, cisapride demonstrated an efficacy similar or superior to that of metoclopramide in reducing oesophageal acid exposure in patients with GORD, and had a more prolonged effect. When administered together with ranitidine, cisapride caused a significantly greater reduction in acid reflux than ranitidine alone.

Pharmacological Properties

Cisapride accelerated gastric emptying of both solids and liquids to a significantly greater extent than placebo in healthy adults, and patients with idiopathic or diabetic gastroparesis, or GORD. In children with GORD and delayed gastric emptying of solids, final gastric emptying time was significantly reduced from 145 to 95 minutes after 8 weeks' treatment with cisapride 0.3 mg/kg 3 times daily. An improvement in gastric emptying has been observed in adults with intestinal pseudo-obstruction and in patients with primary anorexia nervosa after cisapride administration. Cisapride was more effective than metoclopramide in accelerating gastric emptying in patients with diabetic gastroparesis and demonstrated similar efficacy to that of domperidone. Increased gastric emptying was sustained in patients with idiopathic or diabetic gastroparesis treated with cisapride and followed for up to 3 years.

Pharmacological Properties

Antroduodenal motility and its coordination were improved following single or multiple doses of cisapride in healthy volunteers and patients with dyspepsia during fasting and fed conditions. Antroduodenal coordination was enhanced in patients with diabetic gastroparesis and the post-prandial duodenal motility index improved in children with chronic intestinal pseudo-obstruction.

Pharmacological Properties

Cisapride reduced transit time through the small and large bowel in healthy volunteers and patients with deficiencies in propulsive activity, including patients with diabetic autonomic neuropathy, quadriplegics and patients with gas bloat syndrome. Colonic transit time was reduced by cisapride in healthy volunteers and patients with diabetes and in patients following cholecystectomy, and the number of bowel movements increased in healthy volunteers and patients with constipation.

Pharmacological Properties

Peak plasma concentrations of cisapride are achieved 1 to 2 hours after oral administration of a single 5 to 20mg dose. The absolute bioavailability of the oral formulation of the drug is 40 to 50%. The volume of distribution is 2.4 L/kg and cisapride is 98% bound to plasma proteins in vitro. The drug is extensively metabolised; however, the metabolites do not appear to contribute significantly to the pharmacological activity of the drug. An elimination half-life of approximately 10 hours has been found in healthy volunteers, which may be prolonged in patients with hepatic disease and in the elderly. Renal dysfunction does not appear to affect the pharmacokinetics of cisapride and the drug is not removed by haemodialysis.

Therapeutic Efficacy

In patients with GORD, endoscopically confirmed response rates after administration of cisapride 10mg 4 times daily or placebo ranged from 57 to 73% and from 12 to 53%, respectively, Cisapride therapy was associated with greater symptomatic improvement than placebo, with good or excellent responses in 57 to 91% and in 13 to 52% of patients, respectively. Cisapride 10mg 4 times daily or 20mg twice daily demonstrated similar efficacy to cimetidine 400mg 4 times daily or ranitidine 150mg twice daily in comparative trials. No significant differences were found in mucosal healing rates or symptomatic improvement between cisapride and histamine H2 receptor antagonists, whereas metoclopramide 10mg 3 times daily appeared less effective in healing mucosal lesions. Coadministration of cisapride 40mg daily with ranitidine or cimetidine improved healing rates vs either agent as monotherapy.

Therapeutic Efficacy

Cisapride treatment may be beneficial in children with reflux disease, with studies showing greater improvement in reflux parameters vs placebo and further improvement when cisapride was administered in combination with postural and dietary therapy. In preliminary comparative studies, cisapride demonstrated similar efficacy to cimetidine or a combination of Gaviscon® and Carobel®, and its efficacy was similar or superior to that of metoclopramide, although the onset of symptom relief was more rapid in cisapride recipients. Cisapride improved symptoms in some children with cystic fibrosis-associated reflux; however, further larger trials of the drug in this disease are warranted.

Therapeutic Efficacy

Long term treatment with a low dosage of cisapride was effective in prolonging the duration of symptomatic and endoscopic remission, consequently reducing the incidence of relapse after endoscopically-proven healing of oesophagitis with cisapride or histamine H2 receptor antagonists. After 12 months, relapse rates were significantly lower in patients treated with cisapride vs placebo (32 vs 51%; p < 0.01). The duration of remission tended to be longer in patients with a lower initial degree of oesophagitis.

Therapeutic Efficacy

Cisapride is effective in alleviating symptoms of functional dyspepsia (epigastric discomfort or pain, belching, bloatedness, abdominal distension, early satiety). Good or excellent responses have been reported in 63 to 86% of patients in clinical trials after treatment with cisapride 5 or 10mg 3 times daily for 3 to 6 weeks. Cisapride was superior to placebo in alleviating dyspeptic symptoms in most studies, although the placebo response was generally high in patients with functional dyspepsia (20 to 55%). In some trials the superior efficacy of cisapride vs placebo was confined to the subgroup of patients with severe symptoms, or to the first 2-week observation period. Cisapride was more effective than placebo in improving symptoms in patients with dyspepsia refractory to metoclopramide or domperidone. In comparative studies, cisapride demonstrated similar efficacy to metoclopramide, domperidone, clebopride, ranitidine and tripotassium dicitrato bismuthate (bismuth subcitrate) in alleviating dyspeptic symptoms, and was superior to cimetidine in the subgroup of patients with dysmotility-like dyspepsia. In large-scale noncomparative trials, response rates to cisapride were good or excellent in about 80% of patients, generally irrespective of dyspepsia subgroup, concomitant disease and co-medication, but were lower in patients receiving nonsteroidal anti-inflammatory drugs. Dyspeptic symptoms recurred in about 30% of patients during a 6-month follow-up in 1 trial and were associated with pretreatment duration of dyspepsia and mean symptom score at the end of treatment.

Therapeutic Efficacy

Improved gastric emptying after cisapride administration in patients with gastroparesis of various origins was associated with symptom improvement in most short and long term studies. Cisapride was generally superior to placebo in improving symptoms (mainly epigastric pain, bloating and prolonged digestion) although its efficacy in patients with severe disease remains unclear. Long term treatment with cisapride 10 to 20mg 3 times daily generally sustained accelerated gastric emptying and symptom improvement in patients followed for 2 years. Clinical studies indicate that cisapride may be effective in improving gastrointestinal atony in the postoperative phase, accelerating gastric emptying and facilitating bowel recovery; however, further studies are necessary to clarify its role in this indication.

Therapeutic Efficacy

An increase in stool frequency with reduced laxative use has been found in some patients with chronic constipation following treatment with cisapride 5 to 10mg 3 times daily or 20mg twice daily. A significant increase in stool frequency has been reported in children following administration of cisapride 0.2mg/kg 3 times daily for 12 weeks, whereas placebo did not have a significant effect. The efficacy of the drug in alleviating chronic constipation in paraplegic patients remains unclear. Similarly, the possible beneficial effect of cisapride in treatment of chronic intestinal pseudo-obstruction, irritable bowel syndrome and gastric ulcer remains to be defined.

Tolerability

Cisapride is well tolerated by the majority of patients during short and long term treatment, and cessation of therapy due to adverse effects is rarely necessary. Transient abdominal cramping, borborygmi and diarrhoea or loose stools, the most frequently reported adverse events, are extensions of the pharmacological profile of cisapride. The drug is also well tolerated by infants and children, with an incidence of adverse effects similar to that reported in adults. Notably, central nervous system effects, such as somnolence or fatigue, are rare and extrapyramidal reactions do not occur with cisapride. Small trials suggest the incidence of adverse events reported during cisapride therapy is similar to that with cimetidine or ranitidine, but cisapride may be better tolerated than metoclopramide and clebopride.

Tolerability

The acceleration of gastric emptying by cisapride may affect the absorption of other drugs. Concomitant administration of cisapride with ranitidine or cimetidine significantly increases the rate of absorption of the H2 antagonists and the bioavailability of cisapride is increased by cimetidine administration. Cisapride also accelerates absorption of disopyramide, flecainide, cyclosporin, alcohol and morphine, and may increase coagulation time in patients receiving anticoagulant agents concomitantly.

Dosage and Administration

Patients with functional dyspepsia or constipation should receive oral cisapride 5mg 3 times daily, increasing to 10mg 3 times daily if necessary. Cisapride should be administered at the higher dosage of 10mg 4 times daily to patients with GORD or gastroparesis; 0.2 mg/kg (increased to 0.3 mg/kg if necessary) 3 to 4 times daily (suspension formulation) is recommended in infants and children with GORD. The recommended dosage for maintenance treatment of GORD is half that recommended for healing i.e. 10mg twice daily or 20mg once daily, which may be increased to 20mg twice daily. A 50% reduction in initial dosage is recommended in patients with renal or hepatic impairment. In all instances, cisapride should be taken 15 to 30 minutes prior to a meal.

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