The Canadian Journal of Hospital Pharmacy - Volume 44, No. 4, August, 1991 175

Cisapride: A Novel Gastroprokinetic V. Arora and M. Spino

ABSTRACT RESUME Impaired gastrointestinal motility underlies a multitude of Une motilite gastro-intestinale pathologique est le signe digestive complaints. , 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 , the second prokinetic drug marketed in indesirables a limite son usage, surtout chez !es nourrissons. Canada, is a potent peripheral 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. 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 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 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 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 (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_ 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 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 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 renal function, pramide in the GI tract2. in plasma 1,2,6,14,16_ the half-life may increase mar­ Metabolism and : The kedly. It has been suggested that Human metabolism and excretion profiles this is not due to decreased elim­ Absorption: All three drugs are of these three drugs are quite dif­ ination of metoclopramide in the rapidly absorbed from the GI tract ferent. Cisapride is extensively me­ urine, but possibly to reduced me­ following oral administration, but tabolized via two principal routes: tabolism or enterohepatic recy­ absorption may be postponed or oxidative-N-dealkylation and aro- cling 16. Domperidone's interme- The Canadian Journal of Hospital Phannacy - Volume 44, No. 4, August, 1991 177 diate half-life of 7 to 12 hours may pramide and domperidone have motility. When metoclopramide or be prolonged in patients with se­ little, if any, effect on colonic mo­ domperidone could be used, the vere renal dysfunction2. tility I. latter has generally become the Effects on the Dopaminergic preferred agent because it is well Pharmacodynamics in System: Metoclopramide blocks tolerated and has a much lower Therapeutic trials dopaminergic receptors in the me­ potential for extrapyramidal side Gastrointestinal: Cisapride and dullary CTZ. It causes antiemetic effects. metoclopramide appear to exert and sedative effects while blocking : Gastroparesis re­ similar effects on the lower eso­ the hypertensive actions of dopam­ sults from poor gastric emptying. phageal sphincter (LES) pressure ine. As a result of its dopamine It may be idiopathic or due to a and esophageal motility. They receptor blocking activity, prolac­ variety of conditions including di­ raise the amplitude but not the tin release is increased 1,2. Hyper­ abetes mellitus, progressive sys­ velocity of esophageal contrac­ prolactinemia occurs with dom­ temic sclerosis (PSS), myotonic tions6. Studies indicate domperi­ peridone therapy as well, and is dystrophy, or postoperative GI at­ done's effect on LES pressure to likely due to blockade of endogen­ ony. Gastroparesis typically pre­ be inconsistent; some find in­ ous dopamine release from the sents as early satiety, epigastric creased pressure whereas others do pituitary 16. The advantages of cisa­ burning or pain, , , not. In general, cisapride has shown pride is its specificity of action and vomiting and anorexia6. to be as effective as, or superior lack of affinity for dopamine re­ Long-term metoclopramide to metoclopramide and domperi­ ceptors. It is devoid of dopaminer­ therapy provides symptomatic re­ done in enhancing LES tone and gic effects and does not appear to lief of diabetic gastric stasis by esophageal motor function2,t9-21. stimulate prolactin release6. enhancing gastric emptying, pe­ Results of a few comparative Metabolic and Endocrine Ef­ ristalsis of the duodenum and jeju­ trials with healthy subjects and fects: Metoclopramide and dom­ num, transit time, and increasing dyspepsia patients indicate that peridone do not alter gastric se­ the resting LES tone27. Metoclo­ cisapride is similar or superior to cretions. Metoclopramide may pramide is widely used to prevent metoclopramide in shortening or cause slight decreases in serum nausea and vomiting and to im­ normalizing both liquid and solid growth hormone, luteinizing hor­ prove gastric emptying in patients gastric emptying rates. It also mone and follicle-stimulating hor­ with postoperative gastric statis 1. appears to be as effective as me­ mone concentrations, while in­ Domperidone possesses GI pro­ toclopramide in relieving the creasing serum thyrotropin levels. kinetic activity comparable to me­ symptoms of gastric motility dis­ Both metoclopramide and dom­ toclopramide14. It significantly im­ orders6,22,23. Cisapride is likely to peridone stimulate a transient rise proves gastric emptying rates and command a definite place in the in plasma aldosterone secretion via symptoms in patients with diabetic treatment of delayed gastric emp­ a direct effect on adrenal tissues1-2. and post-vagotomy gastroparesis2. tying of idiopathic, diabetic or Single doses of cisapride result in Cisapride effectively enhances postsurgical origin. significant but temporary increases gastric emptying in scleroderma Effects on the Small and Large in cholecystokinin and human patients with gastroparesis, but Intestines: All three drugs enhance pancreatic polypeptide levels, but symptomatic relief in these patients small bowel transit in normal in­ do not alter gastrin, insulin or glu­ is undertermined28. Trials support dividuals and those with deficient cose concentrations6,25 . Metabolic a prominent role for cisapride to intestinal propulsive activity. Cisa­ control of insulin-dependent dia­ promote gastric emptying and to pride decreases mouth to cecum betes mellitus remains unaltered by alleviate GI symptoms in diabetic transit time since it increases pro­ cisapride therapy26_ gastroparesis and postoperative pulsive activity of the ileum and patients6,12,29_ colon as well as the upper GI tract; Indications Gastroesophageal Reflux: Gas­ metoclopramide and domperidone The majority of indications for troesophageal reflux (GER) is a only decrease small intestinal tran­ prokinetic drugs involve GI mo­ complex disorder involving several sit time and augment peristalsis1,6,9. tility disorders, but the drugs with factors: low resting LES pressure, By accelerating whole gut transit, a broader pharmacologic profile, transient relaxation of the LES, cisapride promotes stool frequency i.e., metoclopramide and domper­ poor esophageal clearance, ele­ and output in most individuals24. idone, have some additional indi­ vated intraabdominal pressure, and It has the added effect of improving cations. The newer drug, cisapride delayed gastric emptying. The colonic transit and may increase (PrepulsidR) has a narrower phar­ main symptoms of GER are heart­ the number of bowel movements macologic profile and is indicated burn, regurgitation, nausea, vom­ in constipated subjects3. Metoclo- specifically for disorders of GI iting and postprandial discomfort 178 The Canadian Journal of Hospital Phannacy - Volume 44, No. 4, August, 1991

in adults. Chronic and excessive disease, or abuse3 4• Pa­ tinal transit of barium. It reduces spitting, and vomiting are charac­ tients with chronic the total procedure time and also teristic features in infants. Al­ which is unresponsive to standard prevents the nausea or regurgita­ though the majority of infants with dietary and therapeutic measures, tion which may follow 1,36. Based chronic GER are symptom-free by or which results from laxative on its mechanism of action, it is two years of age, this benign self­ abuse may benefit from cisapride likely that cisapride will have a limiting disease is recognized as therapy. similar effect. causing failure to thrive. It is not To date, cisapride has shown Prevention of Cancer Chemo­ surprising that multiple treatment some clinical efficacy in improving therapy-induced Emesis: Metoclo­ modalities have been tried in pa­ constipation. It enhances colonic pramide, like other dopaminergic tients with this disease 13,30. Al­ propulsive activity and progres­ antagonists, acts centrally on the though most patients with GER are sively increases the consistency CTZ to prevent emesis. Oral or treated with a combination of and frequency of stools. This agent parenteral metoclopramide in high positional and dietary measures promotes good bowel habits while doses is especially useful for pa­ along with lifestyle changes, or reducing laxative consumption. It tients receiving cisplatin or other histamine-2 blockers, some pa­ is not yet known if all types of antineoplastic agents. By blocking tients are refractory. It is this group constipation may benefit from cis­ stimulation of the CTZ, domper­ of patients which may respond to apride therapy, or if long-term idone also prevents nausea and GI prokinetic agents. maintenance therapy is safe and vomiting associated with emetic Metoclopramide is beneficial for effective.6. Metoclopramide and cytotoxic drugs1,14,16. symptomatic treatment of persist­ domperidone do not promote co­ ent GER unresponsive to conven­ lonic motility and, therefore, are Adverse Effects tional therapy, but its clinical use not useful for the symptomatic re­ As expected, broader pharmaco­ has often been limited by a high lief of constipation. logical profiles yield a wider range incidence of CNS side effects. In Intestinal Pseudo-obstruction: of indications but also a wider particular, marked infant irritabil­ This may be induced by motility range of adverse drug reactions. ity with metoclopramide therapy dysfunction associated with im­ Metoclopramide produces a mul­ has been noted5,30. Usually, short­ paired propulsion of the bowel, or titude of side effects, primarily as­ term treatment up to 12 weeks stasis of the stomach or intestinal sociated with the CNS and the GI provides symptomatic relief in contents. Cisapride acts selectively system. These are usually mild, adult patients. 1• within the gut wall to facilitate or transient and reversible upon dis­ Although domperidone does not correct motility along the entire GI continuation of the drug. The in­ improve or endoscopic tract3,5, 12. It restores colonic pro­ cidence is most often related to healing, it is successful in relieving pulsive motility and may be useful dosage and duration of therapy 1• regurgitation, and also shows in conditions where normal move­ Being a cholinomimetic and an­ evidence of improved symptoms in ment of bowel contents is im­ tidopaminergic drug, metoclo­ infants2. paired8,35. Metoclopramide and pramide can cause psychotropic, Cisapride enhances LES tone domperidone have no role in re­ extrapyramidal, dystonic, and dys­ and accelerates emptying of gastric storing normal colonic motility. kinetic reactions which may limit contents. The number of reflux Intubation of the Small Intes­ its long-term use, especially in episodes as well as incidence of tine: Parenteral metoclopramide children. These particular side ef­ side effects are decreased with cis­ has been used to facilitate intuba­ fects may be independent of dose apride therapy6, 31 . tion when the tube does not pass and duration of therapy3. Parkin­ Non-ulcer Upper Gastrointes­ through the pylorus with conven­ sonian symptoms may occur, along tinal Discomfort: Cisapride is at tional maneuvers. However, the with the possibility of irreversible least as effective as metoclopra­ drug does not improve patient tol­ tardive dyskinesia. Restlessness, mide and domperidone in relieving erance of the procedure'. drowsiness, sedation and fatigue symptoms of postprandial epigast­ Radiographic Examination of are obvious in about 10% of pa­ ric discomfort such as bloating, the Upper : tients, while insomnia, headache, belching, nausea, vomiting, heart­ Metoclopramide is used frequently and dizziness are less frequently burn and abdominal distention32,33. to aid in radiological examination reported. Other adverse effects in­ Chronic Constipation: This of the stomach and small intestine. clude transient flushing, constipa­ common complaint may be idio­ When delayed gastric emptying tion, diarrhea, rash, edema, and pathic or associated with diabetic interferes with the procedure, par­ methemoglobinemia. Metoclo­ autonomous neuropathy, intestinal enteral metoclopramide will stim­ pramide may cause galactorrhea, pseudo-obstruction, Hirchsprung's ulate gastric emptying and intes- gynecomastia, amenorrhea, and The Canadian Journal of Hospital Pharmacy - Volume 44, No. 4, August, 1991 179 impotence. Most of these effects developing fluid retention or hypo­ , thereby enhancing their are probably due to its potent stim­ kalemia should be initiated on re­ depressant effects. Caution is ulation of prolactin release. Al­ duced dosages and monitored therefore advised when prescribing though devoid of clinically impor­ closely. This is important because cisapride and CNS depressants tant cardiovascular activity, metoclopramide has the ability to concomitantly6. Careful monitor­ transient antiarrhythmic effects increase plasma aldosterone and ing is suggested for elderly patients have been reported with therapeu­ sodium retention. It may also ex­ and those with hepatic insuffici­ tic doses1. acerbate hypertension by elevating ency. During clinical trials, domperi­ concentrations of circulating cate­ Cisapride should not be given to done had an overall side effect cholamines 1. infants less than 36 weeks of age incidence of less than 7%16. Most Pediatric patients are at in­ unless the benefits clearly out­ adverse reactions are due to do­ creased risk of developing extra­ weigh the potential risks. Women pamine receptor blocking activity pyramidal reactions, and should who are pregnant or breastfeeding and are reversible upon disconti­ be prescribed metoclopramide should not take cisapride simply nuation of the drug. The incidence only when clearly indicated. Pa­ because there is a lack of trials to of adverse endocrine effects is tients on MAO inhibitors and sym­ demonstrate safe and efficacious 1.3%. Blockade of the inhibition of pathomimetics are also targets for use in such patients6. Animal stu­ prolactin release and the resultant careful monitoring. Due to lack of dies have shown an absence of higher levels of serum prolactin adequate studies, metoclopramide mutagenic and carcinogenic ef­ may cause gynecomastia, galac­ should be used during pregnancy fects with cisapride therapy.s torrhea and menstrual irregular­ only when the risk:benefit ratio ities. Unlike metoclopramide, has been considered. Since it is Drug Interactions domperidone does not appear to distributed into breast milk, the Cisapride, metoclopramide and affect growth hormone or thyroid­ same caution applies to nursing domperidone theoretically have stimulating hormone2,16. women. No studies to date have the potential to alter the absorption Side effects with cisapride ther­ shown evidence of metoclo­ and the bioavailability of some apy are few and are related to its pramide-induced mutagenicity, drugs. Changes in GI motility, spe­ primary pharmacological action in but clinicians should be aware that cifically enhanced gastric empty­ the GI system. Most commonly, about one-third of human breast ing may modify absorption of some patients experience transient ab­ carcinomas are prolactin-depen­ drugs. For example, the absorption dominal cramping, borborygmi dent, and metoclopramide and of digoxin may be diminished (rumbling noises), and diarrhea or domperidone are known prolactin while the absorption of acetamin­ loose stools. Less commonly, head­ secretors 1. ophen, , ethanol, cimet­ ache, dizziness, or lightheadedness Absolute contraindications in­ idine and acenocoumarol may be occur. Although it crosses the clude GI hemorrhage (except to increased 1. Two studies reported blood-brain barrier, cisapride is not clear the stomach of blood prior significant reductions of digoxin antidopaminergic and therefore to endoscopy), mechanical ob­ plasma peak concentrations only displays no CNS effects. The ad­ struction or perforation, pheochro­ with cisapride therapy. Products verse effects that occur do not seem mocytoma (since the tumor may that rapidly dissolve and therefore to increase in incidence with long­ be induced to release catechola­ are readily absorbed such as La­ term therapy unlike metoclopram­ mines and precipitate a hyperten­ noxinR avoid this problem of re­ ide6. In most studies reviewed, few sive crisis), concurrent use of drugs duced peak levels. It is still recom­ or no side effects were reported likely to cause extrapyramidal re­ mended to monitor patients closely with cisapride3,5,9,12,24,2s,32. actions such as or when any of the above combina­ butyrophenones, and patients in tions are prescribed37. Precautions and whom increased GI motility might Metoclopramide has greater po­ Contraindications be dangerous1,34. tential for drug interactions than Patients on metoclopramide ther­ Domperidone is a drug requiring cisapride. drugs apy are subject to potential impair­ few precautions. As with metoclo­ and narcotics may antagonize me­ ment of mental alertness or phys­ pramide, it should be avoided in toclopramide's GI motility effects. ical activity. As well, enhanced patients with GI hemorrhage, ob­ Metoclopramide may enhance the sedation can occur with concom­ struction or perforation2. actions of other CNS depressants, itant administration of alcohol, Although cisapride itself does , or alcohol when used barbiturates, and other CNS de­ not cause sedation or drowsiness, concomitantly. Appropriate pre­ pressants. Patients with impaired it may increase the absorption cautions should be given to patients renal function, or those at risk of rate of drugs such as diazepam and on these combinations14. 180 The Canadian Journal of Hospital Pham1acy - Volume 44, No. 4, August, 1991

Dosage and Administration and 0.45% NaCl, Ringer's, and REFERENCES Cisapride, metoclopramide and lactated Ringer's solutions for 24 I. McEvoy GK, ed. American hospital domperidone are dosed according hours at room temperature and up formulary service: Drug Information. Bethesda, MD: Am Soc of Hosp to the severity of the symptoms and to 48 hours if protected from light. Phann 1988: 1664-70. degrees of hepatic and renal func­ Patients with renal impairment, i.e., 2. Spino M. Pharmacologic treatment of tion. The duration of treatment va­ creatinine clearance less than 40 gastrointestinal motility. In: Walker ries with the patient and condition, mL/min, should be started on half WA, Durie PR, Hamilton JR et al but is usually short-term except in the normal dosage1,1 4. (eds). Pediatric . Burlington: BC Decker Inc, the case of cisapride therapy for Domperidone (MotiliumR), also 1990: 1735-46. chronic constipation. This symp­ a Janssen product, is marketed as 3. Rode H, Stunden RJ, Millar AJ, et al. tom may be treated with cisapride a 10 mg oral tablet. It is not Esophageal pH assessment of for several months. available in the parenteral form gastroduodenal reflux in 18 patients Cisapride (PrepulsidR-J anssen) since cardiac and ar­ and the effect of two prokinetic agents: cisapride and is marketed in the following dos­ rest were reported after IV admin­ metoclopramide. J Pediatr Surg 1987; age forms: 5 mg and 10 mg oral istration. Such effects were not 22:931-4. tablets and a 1 mg/mL oral reported with the oral prep­ 4. Reynolds JEF, ed. Martindale: The suspension4,8. aration 14,16,38. Extra Pharmacopoeia. 29th ed. The recommended dose is 5-10 London, England: The Phannaceutical Press, I 989: I 090. mg po three to four times daily. 5. Gilbert RJ, Dodds WJ, Kahrilas PJ, et Resulting diarrhea necessitates a CONCLUSION al. Effect of cisapride, a new reduction in dosage in infants and Prokinetic drugs restore normal , on esophageal children. In all instances of oral motility of the GI tract. Cisapride motor function. Dig Dis Sci 1987; administration, cisapride should be is a unique prokinetic agent with 32:1331-6. 6. McCallum RW, Prakash C, Campoli­ ingested 15 minutes before meals no antidopaminergic activity. It Richards DM, et al. Cisapride: A with a beverage since food in­ acts indirectly to enhance physi­ preliminary review of its creases the rate and extent of drug ological release of acetylcholine in pharmacodynamics and absorption. There are no plans to the gut. In contrast to metoclo­ pharmacokinetic properties, and market a parenteral form of cisa­ pramide and domperidone, cisa­ therapeutic use as a prokinetic agent in gastrointestinal motility disorders. pride. pride enhances motor activity of Dnigs I 988; 36:652-81. No dosage adjustment is neces­ the entire GI tract. 7. Janssen Pharmaceutica. Cisapride sary in patients with renal impair­ Cisapride has greater selectivity booklet. An original oesophageal ment, but it is recommended to for GI motility disorders when gastric and intestinal prokinetic. start at half the usual dose in pa­ compared to metoclopramide and Mississauga, Ont; 1987:1-27. 8 8. Janssen Pharmaceutica. tients with hepatic disease6, . domperidone. Its pharmacological Investigational new drug brochure: Metoclopramide is marketed as specificity is demonstrated by a Cisapride (R51619) an original EmexR by Beecham, MaxeranR by lack of significant CNS side effects. gastric and intestinal prokinetic. Nordic, ReglanR by A.H. Robins In particular, cisapride is effective Mississauga, Ont; 1985. and as Apo-metoclopR by Apotex. and well-tolerated in patients with 9. Lazzaroni M, Sangaletti 0, Parro B. Effect of cisapride on gastric It is available in Canada for oral GER, non-ulcer dyspepsia, and emptying and ilea! transit time of use as 5 mg and 10 mg tablets and gastroparesis. It has also had suc­ balanced liquid meal in healthy as a 1 mg/mL liquid. Injectable cess in the treatment of patients subjects. Digestion 1987; 37: 110-13. solutions are manufactured in with chronic constipation and in­ 10. Reyntjens A, Verlinden M, Aerts T. concentrations of 5 mg/mL and testinal pseudo-obstruction. Stu­ Development and clinical use of the 15 mg/mL38,39. new gastrointestinal prokinetic drug dies indicate that cisapride com­ cisapride (RS 1619). Dnig Dev Res Metoclopramide is taken orally pares favourably with metoclo­ 1986; 8:251-5. 30 minutes prior to meals. The IV pramide and domperidone in many 11. Valori RM, Kumar D, Wingte DL. preparation should be injected aspects of drug disposition. Effects of different types of stress slowly over a one to two minute Cisapride is a useful alternative and of 'prokinetic' drugs on the control of the fasting motor complex period, or infused over at least 15 to metoclopramide and domperi­ in humans. Gastroenterology 1986; minutes. A transient feeling of done in the treatment of GI motility 90: 1890-900. dizziness or faintness may occur disorders. Further comparative 12. Feldman M, Smith HJ. Effect of with rapid administration. As well, clinical trials and long-term expe­ cisapride on gastric emptying of IV infusions should be protected rience may allow cisapride to claim indigestible solids in patients with 1 gastroparesis diabeticorum. from light during administration . a prominent position in the therapy Gastroenterology 1987; 92:171-4. Metoclopramide is stable in 5% of patients with a variety of GI 13. Forbes D, Hodgson M, Hill R. The dextrose, 0.9% NaCl, 5% dextrose motility disorders. ~ effects of gaviscon and The Canadian Journal of Hospital Pharmacy Volume 44, No. 4, August, 1991 181

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