Use of novel prokinetic agents to facilitate return of gastrointestinal motility in adult critically ill patients

Current Opinion in Critical Care

Volumn 12, Issue 4, 2006, Pages 295-302

  Roberts, Derek J ^a   Banh, Hoan Linh ^b   Hall, Richard I ^c  

^a DALHOUSIE UNIVERSITY   (Canada)

^b DALHOUSIE UNIVERSITY   (Canada)

^c QUEEN ELIZABETH II HEALTH SCIENCES CENTRE   (Canada)

Author keywords

Alvimopan; Critical care; Critically ill patient; Dexloxiglumide; Loxiglumide; Prokinetic agents; Tegaserod

Indexed keywords

17 METHYLNALTREXONE; ALVIMOPAN; CHOLECYSTOKININ RECEPTOR BLOCKING AGENT; CISAPRIDE; CLOPAMIDE; CYTOCHROME P450 INHIBITOR; DEXLOXIGLUMIDE; DEXTROMETHORPHAN; DIGOXIN; DOMPERIDONE; DOPAMINE 2 RECEPTOR BLOCKING AGENT; ERYTHROMYCIN; FLUCONAZOLE; GLYCOPROTEIN P INHIBITOR; LOPERAMIDE; LOXIGLUMIDE; METOCLOPRAMIDE; MORPHINE SULFATE; MU OPIATE RECEPTOR ANTAGONIST; NALOXONE; OPIATE; ORAL CONTRACEPTIVE AGENT; PROKINETIC AGENT; SEROTONIN 2 ANTAGONIST; SEROTONIN 3 ANTAGONIST; SEROTONIN 4 AGONIST; TEGASEROD; THEOPHYLLINE; UNINDEXED DRUG; WARFARIN;

ABDOMINAL CRAMP; ABDOMINAL PAIN; ABDOMINAL SURGERY; CLINICAL TRIAL; CRITICALLY ILL PATIENT; DIARRHEA; DRUG EFFICACY; DRUG HALF LIFE; DYSTONIA; ENTERIC FEEDING; FLATULENCE; GASTROINTESTINAL MOTILITY; GASTROINTESTINAL MOTILITY DISORDER; GASTROINTESTINAL TRACT; HEADACHE; HEART ARREST; HEART VENTRICLE TACHYCARDIA; HUMAN; HYPOTENSION; HYPOVOLEMIA; ILEUS; INTESTINE INNERVATION; ISCHEMIC COLITIS; NAUSEA; OUTCOME ASSESSMENT; PAIN ASSESSMENT; PELVIS SURGERY; PERISTALSIS; QT PROLONGATION; REVIEW; STOMACH EMPTYING; SYNCOPE; TARDIVE DYSKINESIA; TORSADE DES POINTES; VOMITING;

ADULT; CRITICAL ILLNESS; GASTROINTESTINAL AGENTS; GASTROINTESTINAL MOTILITY; HUMANS; INDOLES; PENTANOIC ACIDS; PIPERIDINES;

EID: 33746050728     PISSN: 10705295     EISSN: 15317072     Source Type: Journal    
DOI: 10.1097/01.ccx.0000235205.54579.5d     Document Type: Review

References (77)

1. Ritz MA, Fraser R, Edwards N, et al. Delayed gastric emptying in ventilated critically ill patients: measurement by 13 C-octanoic acid breath test. Crit Care Med 2001; 29:1744-1749.
2. Ritz MA, Fraser R, Tam W, Dent J. Impacts and patterns of disturbed gastrointestinal function in critically ill patients. Am J Gastroenterol 2000; 95:3044-3052.
3. Mentec H, Dupont H, Bocchetti M, et al. Upper digestive intolerance during enteral nutrition in critically ill patients: frequency, risk factors, and complications. Crit Care Med 2001; 29:1955-1961.
4. Tryba M. The gastropulmonary route of infection-fact or fiction? Am J Med 1991; 91:135S-146S.
5. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 2001; 344:665-671.
6. Montejo JC. Enteral nutrition-related gastrointestinal complications in critically ill patients: a multicenter study. The Nutritional and Metabolic Working Group of the Spanish Society of Intensive Care Medicine and Coronary Units. Crit Care Med 1999; 27:1447-1453.
7. Montejo JC, Grau T, Acosta J, et al. Multicenter, prospective, randomized, single-blind study comparing the efficacy and gastrointestinal complications of early jejunal feeding with early gastric feeding in critically ill patients. Crit Care Med 2002; 30:796-800.
8. Person B, Wexner SD. The management of postoperative ileus. Curr Probl Surg 2006; 43:12-65. A current and extensive review of postoperative ileus.
9. Behm B, Stollman N. Postoperative ileus: etiologies and interventions. Clin Gastroenterol Hepatol 2003; 1:71-80.
10. Kehlet H, Holte K. Review of postoperative ileus. Am J Surg 2001; 182 (suppl):3S-10S.
11. Mythen MG. Postoperative gastrointestinal tract dysfunction. Anesth Analg 2005; 100:196-204. Informative review of the epidemiology, putative pathogeneses and etiologies, and generalized approach to treatment of postoperative gastrointestinal tract dysfunction.
12. Davies AR, Bellomo R. Establishment of enteral nutrition: prokinetic agents and small bowel feeding tubes. Curr Opin Crit Care 2004; 10: 156-161.
13. Doherty WL, Winter B. Prokinetic agents in critical care. Crit Care 2003; 7:206-208.
14. Booth CM, Heyland DK, Paterson WG. Gastrointestinal promotility drugs in the critical care setting: a systematic review of the evidence. Crit Care Med 2002; 30:1429-1435.
15. Galligan JJ, Vanner S. Basic and clinical pharmacology of new motility promoting agents. Neurogastroenterol Motil 2005; 17:643-653. A recent review that details 5-HT, motilin, cholecystokinin 1, and opioid receptor structure and function and the basic and clinical pharmacology of novel prokinetic agents, including tegaserod, renzapride, erythromycin, loxiglumide, dexloxiglumide, and alvimopan.
16. Hansen MB. Neurohumoral control of gastrointestinal motility. Physiol Res 2003; 52:1-30.
17. Pasricha PJ. Treatment of disorders of bowel motility and water flux; antiemetics; agents used in biliary and pancreatic disease. In: Goodman LS, Gilman A., Brunton LL, et al., editors. Goodman & Gilman's The pharmacological basis of therapeutics, 11th edn. New York: McGraw-Hill; 2006. pp. 983-1008. A general pharmacology text that reviews regulation of gastrointestinal motility and basic and clinical pharmacology of currently employed prokinetic agents and some novel prokinetic agents (mostly tegaserod).
18. Wood JD, Galligan JJ. Function of opioids in the enteric nervous system. Neurogastroenterol Motil 2004; 16 (suppl 2):17-28.
19. Murphy DB, Sutton JA, Prescott LF, Murphy MB. Opioid-induced delay in gastric emptying: a peripheral mechanism in humans. Anesthesiology 1997; 87:765-770.
20. Taniyama K, Makimoto N, Furuichi A, et al. Functions of peripheral 5-hydroxytryptamine receptors, especially 5-hydroxytryptamine4 receptor, in gastrointestinal motility. J Gastroenterol 2000; 35:575-582.
21. Talley NJ. Serotoninergic neuroenteric modulators. Lancet 2001; 358:2061-2068.
22. Beattie DT, Smith JA, Marquess D, et al. The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo. Br J Pharmacol 2004; 143:549-560.
23. Tonini M. 5-Hydroxytryptamine effects in the gut: the 3, 4, and 7 receptors. Neurogastroenterol Motil 2005; 17:637-642.
24. Lal S, McLaughlin J, Barlow J, et al. Cholecystokinin pathways modulate sensations induced by gastric distension in humans. Am J Physiol Gastrointest Liver Physiol 2004; 287:G72-G79.
25. Varga G, Balint A, Burghardt B, D'Amato M. Involvement of endogenous CCK and CCK1 receptors in colonic motor function. Br J Pharmacol 2004; 141:1275-1284.
26. Chou CC, Wu D. Torsade de pointes induced by metoclopramide in an elderly woman with preexisting complete left bundle branch block. Chang Gung Med J 2001; 24:805-809.
27. Bentsen G, Stubhaug A. Cardiac arrest after intravenous metoclopramide - a case of five repeated injections of metoclopramide causing five episodes of cardiac arrest. ActaAnaesthesiolScand 2002; 46:908-910.
28. Ellidokuz E, Kaya D. The effect of metoclopramide on QT dynamicity: double-blind, placebo-controlled, cross-over study in healthy male volunteers. Aliment Pharmacol Ther 2003; 18:151-155.
29. Drolet B, Rousseau G, Daleau P, et al. Domperidone should not be considered a no-risk alternative to cisapride in the treatment of gastrointestinal motility disorders. Circulation 2000; 102:1883-1885.
30. Claassen S, Zunkler BJ. Comparison of the effects of metoclopramide and domperidone on HERG channels. Pharmacology 2005; 74:31-36.
31. Drolet B, Khalifa M, Daleau P, et al. Block of the rapid component of the delayed rectifier potassium current by the prokinetic agent cisapride underlies drug-related lengthening of the QT interval. Circulation 1998; 97:204-210.
32. Camilleri M. Alvimopan, a selective peripherally acting mu-opioid antagonist. Neurogastroenterol Motil 2005; 17:157-165. Review of the pharmacology of the opioid receptor system in the gastrointestinal tract and the basic and clinical pharmacology of alvimopan.
33. Leslie JB. Alvimopan for the management of postoperative ileus. Ann Pharmacother 2005; 39:1502-1510. A review of the pharmacodynamics, pharmacokinetics, available clinical trial evidence, and safety of alvimopan in patients with postoperative ileus.
34. Schmidt WK. Alvimopan* (ADL 8-2698) is a novel peripheral opioid antagonist. Am J Surg 2001; 182 (5A Suppl):27S-38S.
35. Azodo IA, Ehrenpreis ED. Alvimopan (Adolor/GlaxoSmithKline). Curr Opin Invest Drugs 2002; 3:1496-1501.
36. Gonenne J, Camilleri M, Ferber I, et al. Effect of alvimopan and codeine on gastrointestinal transit: a randomized controlled study. Clin Gastroenterol Hepatol 2005; 3:784-791. Randomized, double-blind, placebo-controlled trial of healthy volunteers that found that alvimopan prevented the decrease in small-intestinal and colonic transit, but not gastric emptying, induced by codeine.
37. Paulson DM, Kennedy DT, Donovick RA, et al. Alvimopan: an oral, peripherally acting, mu-opioid receptor antagonist for the treatment of opioid-induced bowel dysfunction - a 21-day treatment-randomized clinical trial. J Pain 2005; 6:184-192. This randomized, placebo-controlled, multicenter trial was conducted to assess safety and efficacy of a single morning dose of alvimopan (0.5 or 1 mg) for treatment of opioid-induced bowel dysfunction in patients with chronic non-malignant pain or opioid dependence. The primary endpoint (the proportion of patients with at least one bowel movement within 8 h of study drug administration on each day, averaged across all patients) occurred in 54, 43, and 29% of patients on alvimopan 1 mg, 0.5 mg, and placebo, respectively. However, the median daily opioid consumption was higher in alvimopan groups versus the placebo group and the use of less potent laxatives was (overall) slightly higher in alvimopan groups at baseline.
38. Zimmerman DM, Gidda JS, Cantrell BE, et al. Discovery of a potent, peripherally selective trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine opioid antagonist for the treatment of gastrointestinal motility disorders. J Med Chem 1994; 37:2262-2265.
39. Cassel JA, Daubert JD, DeHaven RN. [(3)H]Alvimopan binding to the micro opioid receptor: comparative binding kinetics of opioid antagonists. Eur J Pharmacol 2005; 520:29-36. This animal study demonstrated that the receptor-binding kinetics of alvimopan involve rapid binding to the μ-opioid receptor, but a relatively slow dissociation rate. This may have implications for the increased potency of alvimopan when administered prior to exogenous opioids and the long duration of action of the drug in comparison to older μ-opioid receptor antagonists (naloxone, N-methylnaltrexone).
40. Liu SS, Hodgson PS, Carpenter RL, Fricke JR Jr. ADL 8-2698, a trans-3,4-dimethyl-4-(3-hydroxyphenyl) piperidine, prevents gastrointestinal effects of intravenous morphine without affecting analgesia. Clin Pharmacol Ther 2001; 69:66-71.
41. Taguchi A, Sharma N, Saleem RM, et al. Selective postoperative inhibition of gastrointestinal opioid receptors. N Engl J Med 2001; 345:935-940.
42. Wolff BG, Michelassi F, Gerkin TM, et al. Alvimopan, a novel, peripherally acting mu opioid antagonist: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial of major abdominal surgery and postoperative ileus. Ann Surg 2004; 240:728-734; discussion 734-735.
43. Delaney CP, Weese JL, Hyman NH, et al. Phase III trial of alvimopan, a novel, peripherally acting, mu opioid antagonist, for postoperative ileus after major abdominal surgery. Dis Colon Rectum 2005; 48:1114-1125. A large randomized, double-blind, placebo-controlled trial, which investigated the efficacy of alvimopan 6 or 12 mg compared with placebo on GI-3 (defined as the latter of the following two events: time that the patient first tolerated solid food and time that the patient first passed flatus or a bowel movement) after bowel resection or hysterectomy. The results were paradoxical, with the 6 mg dose being seemingly more effective than the 12 mg dose. Opioid requirements were increased with the 12 mg dose (but not the 6 mg) without an increase in VAS pain scores.
44. Viscusi ER, Goldstein S, Witkowski T, et al. Alvimopan, a peripherally acting mu-opioid receptor antagonist, compared with placebo in postoperative ileus after major abdominal surgery: results of a randomized, double-blind, controlled study. Surg Endosc 2006; 20:64-70. A large, randomized, double-blind, placebo-controlled trial that investigated the efficacy of alvimopan 6 or 12 mg compared with placebo on GI-3 (defined as the latter of the following two events: time that the patient first tolerated solid food and time that the patient first passed flatus or a bowel movement) after bowel resection or hysterectomy. The unadjusted hazard ratio for recovery of GI-3 did not achieve statistical significance. However, after adjustment for significant prognostic factors (sex/surgical duration) a small improvement was demonstrated.
45. Kellum JM, Albuquerque FC, Stoner MC, Harris RP. Stroking human jejunal mucosa induces 5-HT release and Cl- secretion via afferent neurons and 5-HT4 receptors. Am J Physiol 1999; 277:G515-G520.
46. Grider JR, Foxx-Orenstein AE, Jin JG. 5-Hydroxytryptamine4 receptor agonists initiate the peristaltic reflex in human, rat, and guinea pig intestine. Gastroenterology 1998; 115:370-380.
47. Vickers AE, Zollinger M, Dannecker R, et al. In vitro metabolism of tegaserod in human liver and intestine: assessment of drug interactions. Drug Metab Dispos 2001; 29:1269-1276.
48. Appel-Dingemanse S. Clinical pharmacokinetics of tegaserod, a serotonin 5-HT(4) receptor partial agonist with promotile activity. Clin Pharmacokinet 2002; 41:1021-1042.
49. Swan SK, Zhou H, Horowitz A, et al. Tegaserod pharmacokinetics are similar in patients with severe renal insufficiency and in healthy subjects. J Clin Pharmacol 2003; 43:359-364.
50. Prather CM, Camilleri M, Zinsmeister AR, et al. Tegaserod accelerates orocecal transit in patients with constipation-predominant irritable bowel syndrome. Gastroenterology 2000; 118:463-468.
51. Degen L, Matzinger D, Merz M, et al. Tegaserod, a 5-HT4 receptor partial agonist, accelerates gastric emptying and gastrointestinal transit in healthy male subjects. Aliment Pharmacol Ther 2001; 15:1745-1751.
52. Degen L, Petrig C, Studer D, et al. Effect of tegaserod on gut transit in male and female subjects. Neurogastroenterol Motil 2005; 17:821-826. Recent randomized, double-blind, placebo-controlled pharmacodynamic study that demonstrated that tegaserod accelerates gastric emptying, small bowel, and colonic transit in both male and female subjects.
53. Wooltorton E. Tegaserod (Zelnorm) for irritable bowel syndrome: reports of serious diarrhea and intestinal ischemia. CMAJ 2004; 170:1908.
54. Brinker AD, Mackey AC, Prizont R. Tegaserod and ischemic colitis. N Engl J Med 2004; 351:1361-1364.
55. Shetzline MA, Cohard-Radice M, Joelsson B. Ischemic colitis, irritable bowel syndrome, and tegaserod - an alternative viewpoint. Pharmacotherapy 2005; 25:1684-1685.
56. DiBaise JK. Tegaserod-associated ischemic colitis. Pharmacotherapy 2005; 25:620-625. Case report of tegaserod-induced ischemic colitis that provides an excellent discussion of the available evidence linking tegaserod with ischemic colitis and the proposed, but unproven, mechanisms by which this may occur.
57. Schoenfeld P. Review article: the safety profile of tegaserod. Aliment Pharmacol Ther 2004; 20 (suppl 7):25-30.
58. Schoenfeld P. Systematic review: incidence of abdominal/pelvic surgery amongst patients using tegaserod in randomized controlled trials. Aliment Pharmacol Ther 2004; 19:263-269.
59. Drici MD, Ebert SN, Wang WX, et al. Comparison of tegaserod (HTF 919) and its main human metabolite with cisapride and erythromycin on cardiac repolarization in the isolated rabbit heart. J Cardiovasc Pharmacol 1999; 34:82-88.
60. Morganroth J, Ruegg PC, Dunger-Baldauf C, et al. Tegaserod, a 5-hydroxytryptamine type 4 receptor partial agonist, is devoid of electrocardiographic effects. Am J Gastroenterol 2002; 97:2321-2327.
61. Chey WD. Review article: tegaserod - the global experience. Aliment Pharmacol Ther 2004; 20 (suppl 7):15-19.
62. Evans BW, Clark WK, Moore DJ, Whorwell PJ. Tegaserod for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev 2004; CD003960.
63. Kamm MA, Muller-Lissner S, Talley NJ, et al. Tegaserod for the treatment of chronic constipation: a randomized, double-blind, placebo-controlled multinational study. Am J Gastroenterol 2005; 100:362-372.
64. Tack J, Muller-Lissner S, Bytzer P, et al. A randomised controlled trial assessing the efficacy and safety of repeated tegaserod therapy in women with irritable bowel syndrome with constipation. Gut 2005; 54:1707-1713.
65. Johanson JF, Wald A, Tougas G, et al. Effect of tegaserod in chronic constipation: a randomized, double-blind, controlled trial. Clin Gastroenterol Hepatol 2004; 2:796-805.
66. Nyhlin H, Bang C, Elsborg L, et al. A double-blind, placebo-controlled, randomized study to evaluate the efficacy, safety and tolerability of tegaserod in patients with irritable bowel syndrome. Scand J Gastroenterol 2004; 39:119-126.
67. Kellow J, Lee OY, Chang FY, et al. An Asia-Pacific, double blind, placebo controlled, randomised study to evaluate the efficacy, safety, and tolerability of tegaserod in patients with irritable bowel syndrome. Gut 2003; 52:671-676.
68. Tegaserod Clinical Research Group. A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of tegaserod in Chinese patients with constipation-predominant irritable bowel syndrome [in Chinese]. Zhonghua Nei Ke Za Zhi 2003; 42:88-90.
69. Novick J, Miner P, Krause R, et al. A randomized, double-blind, placebo-controlled trial of tegaserod in female patients suffering from irritable bowel syndrome with constipation. Aliment Pharmacol Ther 2002; 16:1877-1888.
70. Banh HL, MacLean C, Topp T, Hall R. The use of tegaserod in critically ill patients with impaired gastric motility. Clin Pharmacol Ther 2005; 77:583-586. A case series involving three critically ill patients with gastroparesis refractory to conventional therapy that achieved the goal feeding rate within 3-5 days and a resolution of symptoms of gastroparesis within 24 h of tegaserod administration.
71. Feinle C, D'Amato M, Read NW. Cholecystokinin-A receptors modulate gastric sensory and motor responses to gastric distension and duodenal lipid. Gastroenterology 1996; 110:1379-1385.
72. Varga G. Dexloxiglumide Rotta Research Lab. Curr Opin Invest Drugs 2002; 3:621-626.
73. max and area under the curve. The discussion of the article provides an excellent review of dexloxiglumide pharmacokinetics and drug handling.
74. Tolle-Sander S, Grill A, Joshi H, et al. Characterization of dexloxiglumide in vitro biopharmaceutical properties and active transport. J Pharm Sci 2003; 92:1968-1980.
75. Hall M, Persiani S, Cheung YL, et al. Interaction of dexloxiglumide, a cholecystokinin type-1 receptor antagonist, with human cytochromes P450. Biopharm Drug Dispos 2004; 25:163-176.
76. Kunz P, Crelier GR, Schwizer W, et al. Gastric emptying and motility: assessment with MR imaging - preliminary observations. Radiology 1998; 207:33-40.
77. Schwizer W, Borovicka J, Kunz P, et al. Role of cholecystokinin in the regulation of liquid gastric emptying and gastric motility in humans: studies with the CCK antagonist loxiglumide. Gut 1997; 41:500-504.