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The Pharmacology of Prokinetic Agents and Their Role in the Treatment of Gastrointestinal Disorders

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The Pharmacology of Prokinetic Agents and Their Role in the Treatment of Gastrointestinal Disorders The Pharmacology of ProkineticAgents IJGE Issue 4 Vol 1 2003 Review Article The Pharmacology of Prokinetic Agents and Their Role in the Treatment of Gastrointestinal Disorders George Y. Wu, M.D, Ph.D. INTRODUCTION Metoclopramide Normal peristalsis of the gut requires complex, coordinated neural and motor activity. Pharmacologic Category : Gastrointestinal Abnormalities can occur at a number of different Agent. Prokinetic levels, and can be caused by numerous etiologies. This review summarizes current as well as new Symptomatic treatment of diabetic gastric agents that show promise in the treatment of stasis gastrointestinal motility disorders. For these Gastroesophageal reflux e conditions, the most common medications used in s Facilitation of intubation of the small the US are erythromycin, metoclopramide, and U intestine neostigmine (in acute intestinal pseudo- Prevention and/or treatment of nausea and obstruction). A new prokinetic agent, tegaserod, vomiting associated with chemotherapy, has been recently approved, while other serotonin radiation therapy, or post-surgery (1) agonist agents (prucalopride, YM-31636, SK-951, n ML 10302) are currently undergoing clinical o Blocks dopamine receptors in chemoreceptor i t studies. Other prokinetics, such as domperidone, c trigger zone of the CNS (2) A are not yet approved in the US, although are used in f Enhances the response to acetylcholine of o other countries. tissue in the upper GI tract, causing enhanced m s i n motility and accelerated gastric emptying a DELAYED GASTRIC EMPTYING OR h without stimulating gastric, biliary, or c G A S T R O E S O P H A G E A L R E F L U X e pancreatic secretions. Motor dysfunctions at the gastric or M - s duodenal level can result in gastric stasis. n Hypersensitivity to metoclopramide, or any i n a Symptoms typically associated with delayed o component of the formulation GI r i t t a gastric emptying include nausea, vomiting, early or n obstruction, perforation or hemorrhage c o i C easy satiety, bloating, and weight loss. Reflux is d p h e o c h r o m o c y t o m a , s e i z u r e characterized by impaired esophageal acid disorder(3) clearance, incompetence of the antireflux barrier s n o and delayed gastric emptying. Prokinetic drugs i Adverse reactions are more common/severe t c have been used in addition to proton pump a in dosages used for prophylaxis of inhibitors for suppression of significant symptoms. e chemotherapy-induced emesis. R e >10%: s r e Central nervous system:Restlessness, v d drowsiness, extrapyramidal reactions (high- A dose, up to 34%) - may be more severe in the George Y. Wu, M.D., Ph.D. ; Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-1845, USA. (860) 679-3185, (860) 679-3159 [email protected] 6 IJGE Issue 4 Vol 1 2003 George Y. Wu Gastrointestinal: Diarrhea (may be dose- G a s t r o i n t e s t i n a l h y p o m o t i l i t y : limiting) ) (gastroparesis): 7 ( Neuromuscular & skeletal: Weakness Oral. I.M., I.V.: 0.1 mg/kg/dose up to 4 n e l% to 10%: r times/day, not to exceed 0.5 mg/kg/day s d l n Central nervous system: Insomnia, i o h i t depression Antiemetic (chemotherapy-induced emesis): C c : a Dermatologic: Rash e I.V.: 1-2 mg/kg 30 minutes before e g R a Endocrine & metabolic: Breast tenderness, chemotherapy and every 2-4 hours s e o s prolactin stimulation Facilitate intubation: I.V.: <6 years: 0.1 r D e v Gastro intestinal: Nausea, xerostomia mg/kg 6-14 years: 2.5-5 mg d <1%: Methemoglobinemia (5), tachycardia A (6), hypertension or hypotension, tardive Gastroesophageal reflux: dyskinesia, fatigue, anxiety, agitation, Oral: 10-15 mg/dose up to 4 times/day 30 constipation min. before meals or food and at bedtime Single doses of 20 mg are occasionally Symptoms of overdose include drowsiness, needed for provoking situations ataxia, extrapyramidal reactions, seizures, Efficacy of continuing metoclopramide and methemoglobinemia (in infants) beyond 12 weeks in reflux has not been Disorientation, muscle hypertonia, determined y irritability, and agitation are common : g ) o 8 l M e t o c l o p r a m i d e o f t e n c a u s e s G a s t r o i n t e s t i n a l h y p o m o t i l i t y ( o s c extrapyramidal symptoms (eg, dystonic t fgastroparesis): i l x u o reactions) requiring management with Oral: 10 mg 30 min. before each meal and at d T A / diphenhydramine 1 -2 mg/kg (adults) up to a bedtime for 2-8 weeks : e e g maximum of 50 mg I.M. or I.V. slow push, g I.V. (for severe symptoms): 10 mg over 1-2 a a s followed by a maintenance dose for 48-72 s min.; 10 days of I.V. therapy may be o o d D r hours necessary for best response e v When these reactions are unresponsive to O diphenhydramine, benztropine mesylate I.V. Antiemetic (chemotherapy-induced emesis): 1-2 mg (adults) may be effective IV.: 1-2 mg/kg 30 minutes before These agents are generally effective within chemotherapy and every 2-4 hours to every 2-5 minutes. 4-6 hours (and usually given with diphenhydramine 25-50 mg I.V./oral) : s n CYP1A2 and 2D6 enzyme substrate Postoperative nausea and vomiting: o i t c Decreased effect: Anticholinergic agents I.M.: 10 mg near end of surgery; 20mg doses a r e t antagonize metoclopramide's actions. may be used n I Increased toxicity: Opiate analgesics may Facilitate intubation: IV.: 10 mg g u r increase CNS depression. D Gastroesophageal reflux: : Gastroesophageal reflux: Oral: 5 mg 4 times/day (30 min. before meals ) : 7 y ( Oral: 0.1-0.2 nig/kg/dose up to 4 times/day; l and at bedtime) Increase dose to 10 mg 4 r n efficacy of continuing metoclopramide e times/day if no response at lower dose e d r l d beyond 12 weeks in reflux has not been E l i : e h determined G a s t r o i n t e s t i n a l h y p o m o t i l i t y g C a : Total daily dose should not exceed 0.5 (gastroparesis): s e o g mg/kg/day Oral: Initial: 5 mg 30 min. before meals and a D s o at bedtime for 2-8 weeks Increase if D necessary to 10 mg doses 7 The Pharmacology of ProkineticAgents IJGE Issue 4 Vol 1 2003 : y l I.V.: Initiate at 5 mg over 1-2 min.; increase to these events have been fatal. r e d 10 mg if necessary Cisapride is also contraindicated for patients l E : Postoperative nausea and vomiting (I): I.M.: with prolonged electrocardiographic QT e g a 5 mg near end of surgery; may repeat dose if intervals (QTc >450 msec), a history ofQTc s o necessary prolongation, or known family history of D congenital long QT syndrome(13). : Perform a periodic renal function test Clinically significant bradycardia, renal s g r n Monitor for dystonic reactions failure, history of ventricular arrhythmias, s e i t r n e Monitor for signs of hypoglycemia in ischemic heart disease, and congestive heart o o i t i m patients using insulin and those being treated t failure; uncorrected electrolyte disorders a a n r c o i a for gastroparesis (hypokalemia, hypomagnesemia) d M p n Monitor for agitation and irritable confusion i Respiratory failure; and concomitant a : r medications known to prolong the QT t n o n i Increases aminotransferase [ALT interval and increase the risk of arrhythmia, t t o s c e a C r (SGPT)/AST (SGOT)] (S), increases such as certain antiarrhythmics, certain T e t n amylase antipsychotics, certain antidepressants, I astemizole, bepridil, sparfloxacin, and Cisapride terodiline. Cisapride should not be used in patients with Pharmacologic Category : Gastrointestinal uncorrected hypokalemia or hypo- Agent. Prokinetic magnesemia or who might experience rapid reduction of plasma potassium, such as those Treatment of nocturnal symptoms of administered potassium-wasting diuretics gastroesophageal reflux disease (GERD) (9) a n d / o r i n s u l i n i n a c u t e e s has demonstrated effectiveness for settings U gastroparesis, refractory constipation, and non-ulcer dyspepsia s >5%: n o i Central nervous system: Headache t n c o Cisapride enhances the release of Dermatologic: Rash a i e t c acetylcholine at the myenteric plexus. Gastro intestinal: Diarrhea, GI cramping, R A e May increase gastrointestinal motility and dyspepsia, flatulence, nausea, xerostomia f s r o cardiac rate. e Respiratory: Rhinitis v m d s Increases lower esophageal sphincter <5%: i A n pressure and lower esophageal peristalsis Cardiovascular: Tachycardia a h c Accelerates gastric emptying of both liquids Central nervous system: Extrapyramidal e and solids (10) effects, somnolence, fatigue, seizures, M insomnia, anxiety Hypersensitivity to cisapride or any Hematologic: Thrombocytopenia, increased component of the formulations; GI LFTs, pancytopenia, leukopenia, s hemorrhage, mechanical obstruction, GI granulocytopenia, aplastic anemia n o i perforation, or other situations when GI Respiratory: Sinusitis, coughing, upper t a c motility stimulation is dangerous (11) respiratory tract infection, increased i d Serious cardiac arrhythmias, including incidence of viral infection : n s i n a ventricular tachycardia, ventricular o i r t t fibrillation, torsade de pointes, and QT c Concomitant oral or intravenous n a r o e prolongation (12, 13, 14, 15), have been t administration of the following drugs with C n I reported in patients taking cisapride with cisapride may lead to elevated cisapride g u other drugs that inhibit CYP3A4.
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