ANNALS OF GASTROENTEROLOGY 2000, 13(4):269-289 Review Prokinetic agents: current aspects with focus on cisapride G.T. Georgiadis1, S. Markantonis-Kyroudis1, J.K. Triantafillidis2 1. INTRODUCTION SUMMARY Gastrointestinal hypomotility includes a number of Prokinetic agents are substances which, through various clinical disorders very commonly faced by gastroenter- mechanisms, stimulate gastrointestinal motor activity, e.g. ologists, such as: Gastro-Oesophageal Reflux Disease cholinergic agonists, macrolide antibiotics (such as eryth- (G.E.R.D), gastroparesis (idiopathic or diabetic), irrita- romycin), dopamine receptors antagonists (metoclopra- ble bowel syndrome, chronic and acute colonic pseudo- mide) and substituted benzamides (domperidone and cis- obstruction (Ogilvies syndrome), chronic idiopathic con- apride). Cisapride is the only prokinetic agent which in- stipation. The medical management of patients with gas- creases the motility of both the small and large bowel. Since trointestinal hypomotility usually includes the adminis- 1993 when it was introduced to the pharmaceutical market, tration of a prokinetic agent. Prokinetic agents are sub- cisapride has been widely used with remarkable success in stances which, through various mechanisms, stimulate a variety of gastrointestinal diseases such as: gastro- gastrointestinal motor activity, e.g. metoclopramide, oesophageal reflux disease, gastric ulcer, chronic idiopathic domperidone and cisapride. The cholinergic agonist be- constipation, irritable bowel syndrome, intestinal pseudo- tanechol is known to improve postoperative ileus but its obstruction. Its major side-effects are gastrointestinal (ab- clinical use is very limited because of its side-effects. The dominal pain, diarrhoea) and cardiovascular. Although it motilin agonist erythromycin is used in the treatment of has always been considered an effective and rather safe med- diabetic gastroparesis, colonic pseudo-obstruction and ication, the large number of reports referring to serious and postoperative ileus. Naloxone, an opioid antagonist, gave even fatal adverse effects on the cardiovascular system (Q- hopeful results when administered to patients with irri- T interval extension, torsades de pointes, ventricular fibril- table bowel syndrome, small intestinal pseudo-obstruc- lation) have prompted manufacturing company to withdraw tion and constipation. Dopamine antagonists such as the drug from the U.S. market as of July 12, 2000, pending domperidone are very effective when administered to hy- further research. pomotility disorders of the proximal gastrointestinal tract, Key words: prokinetic agents, gastrointestinal hypomotility, such as gastro-oesophageal reflux disease and gastropare- pharmacodynamics, pharmacokinetics, drug interactions, sis, but their pharmacodynamic effects on the colon are side-effects minimal. Metoclopramide (combines cholinergic agonist and dopamine antagonist action) is used in current ther- apeutics for upper gastrointestinal tract hypomotility dis- orders only. Finally, cisapride is unique among the other prokinetic agents, for it can be administered to hypomo- tility disorders of both the proximal and distal gastroin- 1Laboratory of Biopharmaceutics and Pharmacokinetics, School of testinal tract with equally good results. 2 Pharmacy, University of Athens, Greece, Department of Gastroen- Cisapride is a substituted piperidinyl benzamide with terology, Saint Panteleimon General State Hospital, Nikaia, Greece a chemical structure that is related to the procainamidic Author for correspondence: derivative metoclopramide. It appears to exert its phar- Sophia Markantonis-Kyroudis Ph.D., Laboratory of Biopharma- macological actions in the gastrointestinal tract as a par- ceutics and Pharmacokinetics, School of Pharmacy, University of tial agonist of 5-HT serotonin receptors, thus stimulat- Athens, Panepistimiïupolis, 157 71, Athens, Greece ing the release of acetylcholine from the postsynaptic 270 G.T. GEORGIADIS, et al nerve endings of the myenteric plexus in the lengthwise C) Agents that act as agonists on gastrointestinal hor- muscle of the gastrointestinal tract. The fact that these mones receptors: Agonists of motilin receptors (mac- actions are demonstrated throughout the entire length rolide antibiotics), somatostatin agonists (octreotide). of the gastrointestinal tract, from oesophagus to rectum, makes cisapride unique amongst the rest of the proki- 2.1. Cholinergic agonists 1-5 netic agents. Cholinergic agonists act on muscarinic cholinergic M2 type receptors which can be found throughout the length Since September 1993 when cisapride was introduced of the gastrointestinal tract. They act by increasing the into the pharmaceutical market by Janssen-Cilag (Pro- muscular tone, the tension of contractions and the peri- pulsid® in USA - Alimix® in Greece), it has been widely staltic activity of the bowel. Their prime representative used by clinicians, principally because of its lack of anti- is bethanehol, which acts principally on the upper sec- dopaminergic or cholinergic side-effects, which have re- tion of the gastrointestinal system, increasing the pres- stricted the extensive use of other prokinetic agents. sure of the lower oesophageal sphincter and the strength Numerous researchers have documented the effica- of oesophageal peristaltic contractions. Clinical trials cy of cisapride (greater than placebo and similar to or involving betanechol in the treatment of gastro-oesopha- superior to other therapeutic agents) in the symptomat- geal reflux disease have demonstrated both symptomat- ic relief of patients with gastric dysmotility. Todate it has ic and endoscopic improvement in oesophagitis. It was been considered to be a significant agent for the medical also found that although betanechol has a minor effect management of gastro-oesophageal reflux disease (es- on accelerating small bowel transit, it improves the symp- pecially accompanied by oesophagitis), functional dys- toms of postoperative ileus. It must be emphasized that pepsia, gastroparesis and chronic idiopathic constipa- although betanechol could have a place in the therapeu- tion.2,6,7 Furthermore, it has been proven to be effective tic management of gastro-oesophageal reflux disease and in the therapy of other pathological conditions, such as postoperative ileus, currently its use is limited by the many chronic intestinal pseudo-obstruction, irritable bowel side effects evoked by its cholinergic action.1,8,12 Cholin- syndrome and gastric ulcer. Overall, cisapride has exhib- ergic agonists do not have a role in the treatment of in- ited a low incidence of undesirable side-effects but con- testinal pseudo-obstruction or chronic idiopathic consti- cern over the growing numbers of reports pertaining to pation. serious adverse effects on the heart prompted a large scale study of this problem by its manufacturing compa- 2.2. Macrolide antibiotics ny Janssen-Cilag, culminating in its pending withdrawal Macrolide antibiotics act as agonists of motilin re- from the market. ceptors that can be found throughout the length of the gastrointestinal tract, from the oesophagus to the large The present article presents a brief report on proki- bowel. Motilin is released by stimulation of the vagus netic agents in general, followed by a more detailed re- and by the transit of food through the duodenum. It in- view of the pharmacokinetics, clinical uses, side-effects creases both the motility of the stomach (not after a meal) and drug interactions of cisapride which account for its and the small bowel while simultaneously increasing gall- current status in the therapy of gastrointestinal hypomo- bladder contractions. The main representative of the tility. macrolide antibiotics is erythromycin. Erythromycin (af- ter I.V. infusion) binds with motilin receptors on the gas- 2. CLASSIFICATION OF PROKINETIC trointestinal smooth muscle membranes, inhibiting mo- AGENTS tilin binding. In this way it causes powerful dose-depend- Prokinetic agents are classified into three categories, ent peristaltic contractions in the antrum, accelerating according to their mechanisms of action.4,5,7-11 the gastric emptying of both solids and liquids in healthy volunteers and in patients with diabetic gastroparesis. A) Agents that increase the release of stimulating neu- Erythromycin also accelerates colonic transit and stool rotransmitters: Cholinergic agonists, 5 HT recep- 4 frequency. Therefore it can be used successfully in the tor agonists. treatment of gastrointestinal dysmotility due to diabetic B) Agents that inhibit the action of inhibitory neuro- gastroparesis, intestinal pseudo-obstruction, chronic id- transmitters: Antidopaminergic agents, opioid an- iopathic constipation and postoperative ileum.1,8 On the tagonists. contrary, erythromycin administration did not produce remarkable results in the treatment of gastro-oesopha- Prokinetic agents: current aspects with focus on cisapride 271 geal reflux disease. Prolonged per os use causes a signif- primarily used as an antiemetic agent. Later it was found icant incidence of gastrointestinal side-effects (abdomi- to be capable of stimulating the motility of the upper nal cramping, nausea, vomiting and diarrhea) and may gastrointestinal tract. In larger dosages it exhibits neu- result in bacterial or mycotic hyperplasia and allergic roleptic action as well.1,18 The pharmacodynamic poten- reactions (urticaria, cutaneus eruptions, anaphylaxis).13 cy of metoclopramide and its extrapyramidal unwanted Also,