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

Home , Prokinetic agent, Prucalopride, Tegaserod

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

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,

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]

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

/ 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

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. Some of r blood : D

IJGE Issue 4 Vol 1 2003 George Y. Wu : s

n clarithromycin, troleandomycin gastroparesis (16) and subacute/chronic o i

t Antidepressants: Nefazodone gastritis c e a s

r Antifungals: Oral or I.V. fluconazole, Prevention of GI symptoms associated with e U t

n itraconazole, miconazole, oral ketoconazole use of dopamine-agonist anti-Parkinson I

g Protease inhibitors: Indinavir, ritonavir, agents (17) u

r amprenavir D n o

i Peripheral dopamine receptor blocking

n t

e c r 0.15-0.3 mg/kg/dose 3-4 times/day; Increases esophageal peristalsis and lower d A l

i f l h maximum:10 mg/dose o esophageal sphincter pressure, increases

a C r m

s gastric motility and peristalsis, enhances i O

n :

Initial: 10 mg 4 times/day at least 15 a gastroduodenal coordination e h : g c s

min. before meals and at bedtime e Overall, facilitates gastric empting and a t l s M u o In some patients the dosage will need to decreases small bowel transit time d D A

be increased to 20 mg to obtain a - (18,19,20) s n i satisfactory result n a o r i t t GI hemorrhage, mechanical obstruction, a n c o Warnings/Precautions: Cisapride was voluntarily i perforation; prolactin secreting pituitary C withdrawn from the U.S. market in July 2000. This d tumor (21) decision was based on 341 reports of heart rhythm abnormalities including 80 reports of deaths. The s Increases prolactin levels (galactorrhea, n

o gynecomastia, amenorrhea, impotence) company will continue to make the drug available i t to patients who meet specific clinical eligibility u QTc prolongation tachyarrhythmias, cardiac a

c arrest may be precipitated in hypokalemic criteria for a limited-access protocol (contact 1- e r patients 800-JANSSEN). Serious cardiac arrhythmias P including ventricular tachycardia, ventricular Liver disease, breast cancer and patients on fibrillation, torsade de pointes, and QT MAO inhibitors prolongation have been reported in patients taking this drug. s 1 to 10%: n

o CNS: headache (1%); fewer CNS effects Patients should have a baseline ECG and an i t electrolyte panel (magnesium, calcium, potassium) c compared to metoclopramide a prior to initiating cisapride (see Contraindications). e Gastrointestinal: xerostomia (2%) R

Potential benefits should be weighed against risks e Less than 1%: abdominal cramps, s

r constipation, diarrhea, heartburn, dizziness, prior to administration of cisapride to patients who e v have or may develop prolongation of cardiac d dysuria, edema, extrapyramidal symptoms, conduction intervals, particularly QTc. These A insomnia, nausea, irritability, hot flashes, include patients with conditions that could palpitations, rash, regurgitation, urinary predispose them to the development of serious frequency : e g arrhythmias, such as multiple organ failure, COPD, a s o apnea and advanced cancer. d CNS effects (extrapyramidal reactions, r e

v disorientation) and cardiovascular effects Domperidone O (arrhythmias, hypotension) (21) :

This medication is not available in the US. s n o

i Anticholinergics may decrease domperidone t

Pharmacologic Category : dopamine c

a effects r

antagonist, peripheral e HIV protease inhibitors, azole antifungals, t n

I macrolide may increase plasma levels of

g e Symptomatic treatment of upper GI motility domperidone u s r

U disorder in association with diabetic Domperidone may increase the rate of D

The Pharmacology of ProkineticAgents IJGE Issue 4 Vol 1 2003 : s

n slowing absorption of drugs from the hypotension, or Parkinsonism o i

t stomach Contraindicated for IM or IV use due to a c a

r Use with caution in combination with l i k e l y s e v e r e c h o l i n e r g i c e t

n fluoroquinolones, type IA and III reaction I

g antiarrhythmic, and thioridazine because of u

r QT prolongation More common with S.C. Administration D s

n Cardiovascular: Hypotension, tachycardia, o i

GI motility disorders (16,17): 10 mg 3-4 t flushed skin c

times / day, 15-30 min. before meals a Central nervous system: Headache, malaise e e R g In severe/resistant cases 20 mg 3-4 times / Gastrointestinal: Abdominal cramps, e a s s day diarrhea, nausea, vomiting, salivation, r o e D

Nausea/vomiting associated with dopamine - v eructation agonist anti-Parkinson agents: 20 mg 3 -4 d Genitourinary: Urinary urgency A times / day Ocular: Lacrimation, miosis Respiratory: Asthmatic attacks GASTROESOPHAGEAL REFLUX DISEASE M i s c e l l a n e o u s : :

In addition to acid inhibitory agents, and y

g Diaphoresis o promotility drugs mentioned above, in selected l o c cases cholinergic agonists may be helpful. i x Symptoms of overdose (25) include nausea, o T

vomiting, abdominal cramps,diarrhea, /

Bethanechol e

g involuntary defecation, flushed skin, a s hypotension, and bronchospasm o

Pharmacologic Category: Cholinergic d

r Treat symptomatically with atropine for e Agonist v severe muscarinic symptoms or epinephrine O to reverse severe cardiovascular or :

Gastroesophageal reflux (22, 23) s

n pulmonary sequelae o

Non-obstructive urinary retention and i t c

retention due to neurogenic bladder a

r Decreased effect: Procainamide, quinidine e e Treatment and prevention of bladder t s n Increased toxicity: Bethanechol and I

U dysfunction caused by g ganglionic blockers -> critical fall in blood u Phenothiazines r pressure D Diagnosis of flaccid or atonic neurogenic Cholinergic drugs or anticholinesterase bladder (24) ) 7 agents. 2

. n 6 o 2 i Stimulates cholinergic receptors in the t (

c Oral (administered 1 hour before meals or 2 n A

smooth muscle of the urinary bladder and e f hours after meals) r o

gastrointestinal tract resulting in increased d l

m Abdominal distention or urinary retention: i s i peristalsis, increased GI and pancreatic h

n 0.6 mg/kg/day divided 3-4 times/day C a :

h secretions, bladder muscle contraction, and e c Gastroesophageal reflux: 0.1-0.2 mg/ kg/ e increased ureteral peristaltic waves g a M

s dose given 30 min. to 1 hour before each meal (24) o to a maximum of 4 times/day D s

n S.C.: 0.15-0.2 mg/kg/day divided 3-4 times/ ) o i Mechanical obstruction of the GI or GU tract 8 t 2 day ( a

s c or when the strength or integrity of the GI or t i l d bladder wall is in question (25) u n d Oral: 10-50 mg 2-4 times/day i A a Hyperthyroidism, peptic ulcer disease, : r e t

epilepsy, obstructive pulmonary disease, g n a s o

bradycardia, vasomotor instability, o C D

IJGE Issue 4 Vol 1 2003 George Y. Wu

A C U T E C O L O N I C I N T E S T I N A L but this must be distinguished from PSEUDOOBSTRUCTION (OGILVIE'S myasthenic crisis SYNDROME) Anticholinesterase insensitivity can develop Is a disorder characterized by dilatation of the f o r b r i e f o r p r o l o n g e d cecum and right hemicolon (occasionally periods extending to the rectum) in the absence of a mechanical obstruction. Active intervention is Frequency not defined indicated for deteriorating patients; most patients Cardiovascular: Arrhythmias (especially will respond to neostigmine, administered during bradycardia), hypotension, decreased carbon close cardiovascular monitoring. Patients who monoxide, tachycardia, AV block, nodal have contraindications or are not responding rhythm, nonspecific EKG changes, cardiac should be decompressed with a colonoscopy. arrest, syncope, flushing Central nervous system: Convulsions, Neostigmine dysarthria, dysphonia, dizziness, loss of s

n consciousness, drowsiness, headache o i Pharmacologic Category: t Dermatologic: Skin rash, thrombophlebitis c

Acetylcholinesterase a e (I.V.), Urticaria R Inhibitor Gastrointestinal: Hyperperistalsis, nausea, e s

r vomiting, salivation, diarrhea, stomach e

Acute intestinal pseudo-obstruction(26) v cramps, dysphagia, flatulence Diagnosis and treatment of my asthenia d A Genitourinary: Urinary urgency e

s gravis Neuromuscular & skeletal: Weakness, U Prevention and treatment of postoperative fasciculations, muscle cramps, spasms, bladder distention and urinary retention arthralgias Ocular: Small pupils, lacrimation Reversal of the effects of non-depolarizing Respiratory: Increased bronchial secretions, neuromuscular-blocking agents after surgery laryngospasm, bronchiolar constriction,

(27) respiratory muscle paralysis, dyspnea, m n s respiratory depression, respiratory arrest, i o i n t Inhibits destruction of acetylcholine by

a bronchospasm c h

A acetylcholinesterase, which facilitates c Miscellaneous: Diaphoresis (increased), f e o transmission of impulses across myoneural a n a p h y l a x i s , a l l e r g i c M :

junction g - reactions s o n l n i o o a c i i r t t

Hypersensitivity to neostigmine, bromides, x a Symptoms of overdose include muscle n o c i o T

or components of the formulation GI or GU

d weakness, blurred vision, excessive / C e

obstruction g sweating, tearing and salivation, nausea, a s

o vomiting, diarrhea, hypertension, d : Does not antagonize and may prolong the r bradycardia, muscle weakness, and paralysis s e n phase I block of depolarizing muscle v

o Atropine sulfate injection should be readily O i t relaxants (eg, succinylcholine) available as an antagonist for the effects of u

a Use with caution in patients with epilepsy, : c neostigmine (26,29,30) s e r asthma, bradycardia, hyperthyroidism, n o P i

/ cardiac arrhythmias, or peptic ulcer t

Anticholinergics: Effects may be reduced c s a g Adequate facilities should be available for with cholinesterase inhibitors Atropine r n e i

cardiopulmonary resuscitation when testing t

n antagonizes the muscarinic effects of n r I

a and adjusting dose for myasthenia gravis cholinesterase inhibitors (31) g W Have atropine and epinephrine ready to treat u Beta-blockers without ISA: Activity may r

hypersensitivity reactions D increase risk of bradycardia

The Pharmacology of ProkineticAgents IJGE Issue 4 Vol 1 2003 s c

Cholinergic agonists: Effects may be i It is absorbed rapidly after oral t e n

increased with cholinesterase inhibitors i administration, and is metabolized mainly k o

Corticosteroids: May see increased muscle c pre-systemically when absorbed, intact a

weakness and decreased response to m tegaserod is excreted as N-glucuronides via r a

anticholinesterases shortly after onset of h bile (32) corticosteroid therapy in the treatment of my P s : n s

asthenia gravis o Sever renal impairment, hepatic impairment i n t o a

i Deterioration in muscle strength, including (moderate or severe), history of bowel c i t d c

severe muscular depression, has been n obstruction abdominal adhesions, a i r a r e documented in patients with myasthenia symptomatic gallbladder, sphincter of Oddi t t n n gravis while receiving corticosteroids and o dysfunction I C

g anticholinesterases u

r Digoxin: Increased risk of bradycardia with Most common reported is diarrhea (9% vs. 4 D concurrent use % compared to placebo) (35)

Neuromuscular blockers: Depolarizing s In a majority of cases, a single episode, n

neuromuscular blocking agents effects may o mainly within the first week of treatment i t

be increased with cholinesterase inhibitors c Abdominal pain, flatulence, and headaches a

Nondepolarizing agents are antagonized by e had a rate comparable to placeb R

cholinesterase inhibitors (29) e Abdominal surgeries were increased in s

r patients treated with tegaserod (0.3 vs. 0.2 e : v e Acute intestinal pseudoobstruction - 2 mg percent), primarily cholecystectomy d g a A

s administered undiluted by slow I.V. injection Tegaserod was not found to be carcinogenic, o over several minutes (26, 29, 30) teratogenic or toxic to the fetus in animal D studies (36) IRRITABLE BOWEL SYNDROME : s

Irritable bowel syndrome (IBS) is a gastrointestinal n No clinically relevant or adverse drug - drug o i disorder characterized by chronic abdominal pain t interactions have been reported c a

and altered bowel habits in the absence of any r No dose adjustments are required for e t

organic disorder. Prokinetic drugs should be n concomitantly administration of drugs that I

considered only for short-term use in constipation g are metabolized via CYP1A2 (theophylline) u predominant IBS. r or digoxin D

Tegaserod 6 mg orally BID with or without food

: May start with a single dose of medication e

Pharmacologic Category: Aminoguanidine g and titrate up to BID a indole derivative of serotonin that acts as s o Treatment has been approved for 4 to 6 weeks selective partial agonist of 5 - HT4 receptor D with another 4 to 6 weeks in responsive (32) patients (37)

e Constipation predominant irritable bowel s

U syndrome (33) CONCLUSIONS Several prokinetic agents have been of value in n o

i Activates 5 - HT 4 receptors located on treating GI disorders. Research into specific t c neurons of the gastrointestinal tract, A receptors, agonists and antagonists in the GI tract

f o

increasing the gastrointestinal motility have led to the development of new agents with m

s May reduce visceral sensitivity in more specificity and fewer side effects. It is likely i n

a experimental animal models (34) that in the future more of these tailored drugs will h c

e become available for the treatment of motility

M disorders.

IJGE Issue 4 Vol 1 2003 George Y. Wu

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J Pediatr Gastroenterol Nutr 5. Kearns GL, Fiser DH. Metoclopramide-Induced 1986; 5:47. Methemoglobinemia. Pediatrics 1988; 82(3):364. 26. Stephenson BM, Morgan AR, Salaman Jr. Ogilvie's 6. Malkoff MD, Ponzill, JJ, Myles GL. Sinus Arrest After syndrome: A new approach to an old problem. Dis Colon Administration of Intravenous Metoclopramide. Ann Rectum 1995; 38:424. Pharmacother 1995; 29(4): 381. 27. Payne JP, Hughes R, Al Azawi S. Neuromuscular 7. Low LC, Goel KM. Metoclopramide Poisoning in Blockade by Neostigmine in Anaesthetized Man. Br J Children. Arch Dis Child 1980; 55(3):310. Anaesth 1980; 52(1):69-76. 8. Schulze-Delrieu K. Drug Therapy. Metoclopramide. N 28. Orenstein SR, Lofton SW, Orenstein DM. Bethanechol Engi J Med 1981; 305(1):28. for pediatric gastroesophageal reflux: A prospective, 9. Cucchiara S, Staiano,A, Boccieri A. Effects of Cisapride on blind, controlled study. J Pediatr Gastroenterol Nutr 1986; Parameters of Oesophageal Motility and on the Prolonged 5:549. Intraoesophageal pH Test in Infants With Gastro- 29. Turegano-Fuentes F, Munoz-Jimenez F, Del Valle- oesophageal Reflux Disease. Gut 1990; 31(1):21. Hernandez E, et al. Early resolution of Ogilvie's syndrome 10. Barone JA, Huang YC, Bierman RH. Bioavailability of with intravenous neostigmine: A simple, effective Three Oral Dosage Forms of Cisapride, a Gastrointestinal treatment. Dis Colon Rectum 1997; 40:1353. Stimulant Agent. Clin Pharm 1987; 6(8):640. 30. Ponec RJ, Saunders MD, Kimmey MB. Neostigmine for 11. Tack J, Coremans G, Janssens J. A Risk-Benefit the treatment of acute colonic pseudo-obstruction. N Engl Assessment of Cisapride in the Treatment of J Med 1999; 341:137. Gastrointestinal Disorders. Drug Saf 1995; 12(6):384. 31. Fisher DM, Cronelly R, Miller RD. The Neuromuscular 12. Bran S, Murray WA, Hirsch IB. Long QT Syndrome Pharmacology of Neostigmine in Infants and Children. During High-Dose Cisapride. Arch Intern Med 1995; Anesthesiology 1983; 59(3):220. 155(7):765. 32. Degen L, Matzinger D, Merz M. Tegaserod, a 5-HT4 13. Lewin MB, Bryant RM, Fenrich AL. Cisapride-Induced receptor partial agonist, accelerates gastric emptying and QT Interval. J Pediatr 1996; 128(2):279. gastrointestinal transit in healthy male subjects. Aliment 14. Olsson S, Edwards IR. Tachycardia During Cisapride Pharmacol Ther2001; 15:1745. Treatment. BMJ 1992; 305(6856):748. 33. Prather CM, Camilleri M, Zinsmeister AR. Tegaserod 15. Rizwanuddin S, Wolfe SM. Cisapride and Torsade de accelerates orocecal transit in patients with constipation Pointes. Lancet 1995; 345:508. predominant irritable bowel syndrome. Gastroenterology 16. Van Eygen M, Dhondt F, Heck E. A double-blind 2000; 118:463. comparison of domperidone and metoclopramide 34. Camilleri M. Review article: Tegaserod. Aliment suppositories in the treatment of nausea and vomiting in Pharmacol Ther 2001; 15:277. children. Postgrad Med J 1979; 55 (Suppl 1):36. 35. Muller - Lissner SA, Fumagali I, Bardhan KD. Tegaserod, 17. Bines JE, Quinlan JE, Treves S. Efficacy of domperidone A 5-HT4 receptor partial agonist, relieves symptoms in in infants and children with gastroesophageal reflux. J irritable bowel syndrome patients with abdominal pain, Pediatr Gastroenterol Nutr 1992; 14:400. bloating, and constipation. Aliment Pharmacol Ther 2001; 18. Carroccio A, lacono G, Montalto G. Domperidone plus 15:1655. magnesium hydroxide and aluminum hydroxide: a valid 36. Fidelholtz J, Smith W, Radwis J. Safety and tolerability of therapy in children with gastroesophageal reflux. A tegaserod in patients with irritable bowel syndrome and double-blind randomized study versus placebo. Scand J diarrhea symptoms. Am J Gastroenterol 2002; 97:1176. Gastroenterol 1994; 29:300. 37. Scott LJ, Perry CM. Tegaserod. Drugs 1999; 58:491. 19. PMS-Domperidone product monograph, Pharmascience Inc. Quebec, October 1997. 20. Euler AR. Use of bethanechol for the treatment of gastroesophageal reflux. J Pediatr 1980; 96:321. 21. Levi P, Marmo F, Saluzzo C. Bethanechol versus antiacids in the treatment of gastroesophageal reflux. Helv Paediatr Acta 1985; 40:349. 13 IJGE Issue 4 Vol 1 2003 George Y. Wu The Pharmacology of ProkineticAgents IJGE Issue 4 Vol 1 2003

Review Article Gastrointestinal: Diarrhea (may be dose- Gastrointestinal hypomotility (gastroparesis): :

limiting) ) Oral. I.M., I.V.: 0.1 mg/kg/dose up to 4 7 (

Neuromuscular & skeletal: Weakness times/day, not to exceed 0.5 mg/kg/day n

l% to 10%: e

The Pharmacology of Prokinetic Agents and Their Role in r s d

Central nervous system: Insomnia, depression l Antiemetic (chemotherapy-induced emesis): n i o h the Treatment of Gastrointestinal Disorders i Dermatologic: Rash I.V.: 1-2 mg/kg 30 minutes before t C c :

a Endocrine & metabolic: Breast tenderness, chemotherapy and every 2-4 hours e e George Y. Wu, M.D, Ph.D. prolactin stimulation g Facilitate intubation: I.V.: <6 years: 0.1 mg/kg R a

s e

Gastro intestinal: Nausea, xerostomia o 6-14 years: 2.5-5 mg s r D

e <1%: Methemoglobinemia (5), tachycardia

INTRODUCTION Metoclopramide v

d (6), hypertension or hypotension, tardive Gastroesophageal reflux: Normal peristalsis of the gut requires A dyskinesia, fatigue, anxiety, agitation, Oral: 10-15 mg/dose up to 4 times/day 30 min. complex, coordinated neural and motor activity. Pharmacologic Category : Gastrointestinal constipation before meals or food and at bedtime Abnormalities can occur at a number of different Agent. Prokinetic Single doses of 20 mg are occasionally needed levels, and can be caused by numerous etiologies. Symptoms of overdose include drowsiness, for provoking situations This review summarizes current as well as new Symptomatic treatment of diabetic gastric ataxia, extrapyramidal reactions, seizures, and Efficacy of continuing metoclopramide agents that show promise in the treatment of stasis methemoglobinemia (in infants) beyond 12 weeks in reflux has not been gastrointestinal motility disorders. For these Gastroesophageal reflux Disorientation, muscle hypertonia, irritability, determined e

conditions, the most common medications used in s Facilitation of intubation of the small and agitation are common the US are erythromycin, metoclopramide, and U intestine Metoclopramide often causes extrapyramidal Gastrointestinal hypomotility fgastroparesis): neostigmine (in acute intestinal pseudo- Prevention and/or treatment of nausea and y

symptoms (eg, dystonic reactions) requiring : Oral: 10 mg 30 min. before each meal and at g obstruction). A new prokinetic agent, tegaserod, vomiting associated with chemotherapy, ) o 8

l management with diphenhydramine 1 -2 bedtime for 2-8 weeks (

has been recently approved, while other serotonin radiation therapy, or post-surgery (1) o s c

mg/kg (adults) up to a maximum of 50 mg I.M. t I.V. (for severe symptoms): 10 mg over 1-2 i agonist agents (prucalopride, YM-31636, SK-951, l x

or I.V. slow push, followed by a maintenance u min.; 10 days of I.V. therapy may be necessary n o d

ML 10302) are currently undergoing clinical o Blocks dopamine receptors in chemoreceptor T i t

dose for 48-72 hours A for best response / c studies. Other prokinetics, such as domperidone, trigger zone of the CNS (2) : e e A

When these reactions are unresponsive to g g are not yet approved in the US, although are used in f Enhances the response to acetylcholine of a o a

s diphenhydramine, benztropine mesylate I.V. 1- Antiemetic (chemotherapy-induced emesis): s other countries. tissue in the upper GI tract, causing enhanced o m o s d 2 mg (adults) may be effective IV.: 1-2 mg/kg 30 minutes before i D r

n motility and accelerated gastric emptying e a These agents are generally effective within 2-5 chemotherapy and every 2-4 hours to every 4-6 v DELAYED GASTRIC EMPTYING OR h without stimulating gastric, biliary, or c O e minutes. h o u r s ( a n d u s u a l l y g i v e n w i t h G A S T R O E S O P H A G E A L R E F L U X pancreatic secretions. M diphenhydramine 25-50 mg I.V./oral) Motor dysfunctions at the gastric or

- CYP1A2 and 2D6 enzyme substrate Postoperative nausea and vomiting: s

duodenal level can result in gastric stasis. n Hypersensitivity to metoclopramide, or any i n Decreased effect: Anticholinergic agents I.M.: 10 mg near end of surgery; 20mg doses a Symptoms typically associated with delayed o component of the formulation GI r i t t antagonize metoclopramide's actions. may be used a gastric emptying include nausea, vomiting, early or n obstruction, perforation or hemorrhage : c o i s Increased toxicity: Opiate analgesics may Facilitate intubation: IV.: 10 mg n 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 o

i increase CNS depression. characterized by impaired esophageal acid disorder(3) t c

a Gastroesophageal reflux: s clearance, incompetence of the antireflux barrier r e n t Gastroesophageal reflux: Oral: 5 mg 4 times/day (30 min. before meals o n i and delayed gastric emptying. Prokinetic drugs Adverse reactions are more common/severe I t

g Oral: 0.1-0.2 nig/kg/dose up to 4 times/day; and at bedtime) Increase dose to 10 mg 4 c u

have been used in addition to proton pump a in dosages used for prophylaxis of r e efficacy of continuing metoclopramide beyond times/day if no response at lower dose inhibitors for suppression of significant symptoms. chemotherapy-induced emesis. D R 12 weeks in reflux has not been determined e >10%: s : r Total daily dose should not exceed 0.5 Gastrointestinal hypomotility (gastroparesis): ) : e Central nervous system:Restlessness, 7 y v (

mg/kg/day l Oral: Initial: 5 mg 30 min. before meals and at d drowsiness, extrapyramidal reactions (high- r n e

A bedtime for 2-8 weeks Increase if necessary to e dose, up to 34%) - may be more severe in the d r l

d Gastrointestinal hypomotility (gastroparesis): 10 mg doses E l i :

Oral. I.M., I.V.: 0.1 mg/kg/dose up to 4 e I.V.: Initiate at 5 mg over 1-2 min.; increase to h

George Y. Wu, M.D., Ph.D. ; Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center, g C

times/day, not to exceed 0.5 mg/kg/day a 10 mg if necessary : s

263 Farmington Avenue, Farmington, CT 06030-1845, USA. e o (860) 679-3185, (860) 679-3159 g Antiemetic (chemotherapy-induced emesis): Postoperative nausea and vomiting (I): I.M.: 5 a D

[email protected] s I.V.: 1-2 mg/kg 30 minutes before mg near end of surgery; may repeat dose if o

D necessary 6 7