The Canadian Journal of Hospital Pharmacy - Volume 44, No. 4, August, 1991 175 Cisapride: A Novel Gastroprokinetic Drug V. Arora and M. Spino ABSTRACT RESUME Impaired gastrointestinal motility underlies a multitude of Une motilite gastro-intestinale pathologique est le signe digestive complaints. Metoclopramide, an antidopaminer­ d 'une multitude de maladies digestives. Le metoclopramide, gic and cholinomimetic agen~ was the first prokinetic drug un agent anti-dopaminergique et cholinomimetique, fut le used to treat such conditions, but a high incidence of premier medicament procinetique utilise pour traiter de adverse effects has limited its use, especially in infants. tel/es conditions mais une frequence elevee des reactions Domperidone, the second prokinetic drug marketed in indesirables a limite son usage, surtout chez !es nourrissons. Canada, is a potent peripheral dopamine receptor an­ Le domperidone, le deuxieme medicament procinetique tagonist which does not cross the blood-brain barrier well commercialise au Canada, est un antagoniste puissant des and, therefore, displays minimal CNS side effects. Cisapride recepteurs dopaminergiques peripheriques qui ne traverse is a gastroprokinetic agent which appears to act mainly pas beaucoup la barriere hemo-encephalique et done, by releasing acetylcholine from the myenteric plexus of provoque peu d'effets secondaires au systeme nerveux the gut. It has no dopamine-blocking activity, and does central (SNC). Le cisapride est un nouvel agent gastro­ not share the serious CNS side effects of other drugs in procinetique qui semble agir principalement par la libe­ its class. These drugs stimulate gastric and small intestinal ration de l'acetylcholine du plexus myenterique de l'intestin. activity, but cisapride also enhances colonic motility. ll ne bloque pas la dopamine, done n 'apporte aucun effet Cisapride is well tolerated, and seems to exhibit a more secondaire serieux au SNC. Ces medicaments stimulent favourable benefit.'risk ratio than metoclopramide or la motilite gastrique et celle de l'intestin grele, mais en domperidone. Further studies will detennine the relative plus, le cisapride augmente la motilite du colon. Le cisapride place ofcisapride in the treatment of GI motility disorders. est bien to/ere et semb/e posseder un rapport avantage: Key Words: cisapride, domperidone, metoclopramide, risque plus favorable que le metoclopramide et le dompe­ prokinetic drugs ridone. D'autres etudes detennineront la place respective du cisapride dans le traitement des troubles de la motilite GI (gastro-intestinale). Mots des: cisapride, domperidone, metoclopramide, pro­ Can J Hosp Pharm 1991; 4: 175-181 cinetique medicament INTRODUCTION sympathetic, parasympathetic and is widely used as an antiemetic and Impaired gastrointestinal (GI) mo­ enteric nervous systems. Input GI motility modifierl.3. Domperi­ tility underlies a multitude of di­ from these systems is modulated done has been on the Canadian gestive complaints including de­ by the central nervous system market for several years, although layed gastric emptying and gastro­ which regulates GI motility2. Cho­ it is still an investigational drug in esophageal reflux. Patients suffer­ linomimetics are a logical choice the United States4. It acts primarily ing from such conditions may for the treatment of GI motility as a peripheral dopamine receptor benefit from enhanced GI motility. disorders since GI motility is lar­ antagonist, and has a lower poten­ The pathophysiology of GI motility gely controlled by cholinergic tial for extrapyramidal side effects. disorders normally involves neural mechanisms. Most agents used, es­ Cisapride is a novel prokinetic rather than primary muscular dis­ pecially for gastroesophageal re­ agent which was developed by turbances. Therapeutically diverse flux (GER), either potentiate the Janssen Pharmaceutica to target pharmacologic and non-pharma­ action of acetylcholine or block effects on the GI system only. Stu­ cologic modalities have been used dopamine receptors. dies indicate that cisapride mod­ in the treatment of such disorders 1• Metoclopramide, an antidopa­ ifies motility along the entire GI The GI tract is innervated by the minergic and cholinomimetic drug, tract5- 10. V. Arora, B.Sc.Phm., is a Staff Phamiacist, Sunnybrook Health Science Centre. M. Spino, Pharrn.D., is a Professor, Faculties of Pharmacy and Medicine, University of Toronto, and Senior Scientist, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario. Address correspondence to: V. Arora, K Wing Pharmacy, Sunnybrook Health Science Centre, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5. 176 The Canadian Journal of Hospital Phannacy Volume 44, No. 4, August, 1991 Pharmacology reduced in patients with impaired matic hydroxylation. The pharma­ Cisapride has a unique mechanism gastric emptying1,2,7• Cisapride has cological activity of the metabo­ of action. It is not an antidopami­ an absolute bioavailability of 40 to lites is negligible compared to the nergic or a cholinergic agent9,11 but 50% and undergoes an extensive parent compound. Cisapride and is believed to indirectly enhance first pass metabolism 14. Domperi­ its metabolites are equally excreted the release of acetylcholine by done is also subject to a large first in urine and feces. About 41 to 45% stimulating receptors located on pass effect with only about 15% of a single dose is eliminated as the postganglionic neurons of the of an oral dose reaching the sys­ norcisapride. Less than 1% and myenteric (Auerbach's) plexus of temic circulation. Bioavailability 4-6% of the parent drug is nor­ the gut. This results in stimulation of metoclopramide is extremely mally eliminated in urine and feces, of cholinergic (muscarinic) recep­ variable with reports of 30 to 100% respectively3,6. tors on smooth muscle cells of the of an oral dose reaching the sys­ Metoclopramide has a high first­ gut. There is also some evidence temic circulation as unchanged pass effect. It is conjugated with that cisapride acts as an antagonist drug1,2,1s_ sulfuric acid or glucuronic acid. of serotonin (5-hydroxytrypta­ After oral administration of a Approximately 85% of an oral mine) receptors, however, the clin­ single 10 mg dose, peak plasma dose appears in the urine as parent ical significance of this effect re­ concentrations are reached within drug and conjugates, and 5% is mains to be determinedJ,s,12_ one to two hours for all three drugs. excreted in the feces via bile. Five Metoclopramide's mechanisms Maximal plasma levels obtained to 10% of an oral dose appears in of action is complex. This procai­ are about 45 to 65 µg/L with cisa­ the urine as a metabolite with un­ namide derivative blocks peri­ pride, 30 to 45 µg/L with meto­ determined pharmacological ac­ pheral and central dopaminergic clopramide and 20 µg/L with tivity. In total, about 20% of the receptors, including those at the domperidone. Co-administration drug is excreted unchanged1,11_ vomiting centre. It also has peri­ with food increases the extent of Domperidone undergoes hydro­ pheral cholinergic and direct drug absorption with the Cmax xylation and oxidative N-dealky­ smooth muscle activity 13. Effects about 20% higher after a meal 1,2,6. lation to inactive metabolites ex­ on GI motility are mediated Distribution: In adults, cisapride creted in the urine and feces. Less through enhanced acetylcholine and metoclopramide have compar­ than 5% of a dose is excreted in release from postganglionic neu­ able apparent volumes of distri­ the urine unchanged, although rons in the gut, and sensitization bution: 2.4 L/kg and 2.2 to 3.4 L/ about 30% appears as glucuronide of cholinergic (muscarinic) recep­ kg, respectively. Domperidone's conjugates of the two principle tors of GI smooth muscle to ace­ apparent volume of distribution is metabolites. These metabolites are tylcholine. Metoclopramide re­ about 5 to 6 L/kg. Plasma protein mainly excreted in the feces2. quires inherent neuronal acetyl­ binding is very high for cisapride Cisapride has a terminal half­ choline storage sites to exert phy­ and domperidone at >90% while life of about 15 hours. The half­ siologic release of this neurotrans­ only 25 to 30% of metoclopramide life may be prolonged in some mitter1. is bound1,2,6,14. elderly patients and in those with Although domperidone is struc­ Domperidone has high affinity impaired hepatic function. This turally similar to the butyrophe­ for dopamine receptors. It does not might be expected since cisapride none compounds, it does not cross cross the blood-brain barrier ex­ is mainly eliminated via hepatic the blood-brain barrier well and, tensively but does act at the che­ oxidation. Renal insufficiency does therefore, is not used as a neuro­ moreceptor trigger zone (CTZ) to not appear to significantly affect Ieptic. In vitro, domperidone has inhibit drug-induced vomiting. the elimination of cisapride, how­ high affinity for dopamine recep­ Metoclopramide crosses the blood­ ever, the manufacturer recom­ tors, but low affinity for muscarinic brain barrier and acts at the CTZ mends an initial lower daily and serotonergic receptors. It is a in the area postrema. Although dose4,14,18. Metoclopramide has a peripheral dopamine receptor an­ cisapride also penetrates into the much shorter terminal half-life of tagonist and exhibits many of the CNS, brain tissue concentrations 2.5 to six hours1,15 . In patients with pharmacologic effects of metoclo­ are two or three times less than severely impaired