Metoclopramide, Cisapride and Domperidone: Time to move on

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Metoclopramide, Cisapride and Domperidone Time
to move on ?

• Anish A. Sheth, MD
• April 13, 2007
• Faculty Preceptor Martin Floch, MD

2
Overview

• Gastric physiology motility 101
• Gastroparesis
• Functional Dyspepsia
• The Drugs
• Metoclopramide
• Domperidone
• Cisapride
• Other Agents Gastric Pacing
• The Pipeline

3
Gastric Physiology

• Fasting
• MMC
• Fed
• Accommodation
• Trituration
• Emptying

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Gastric Physiology - Fed
Functional Anatomy
Proximal
Accommodation
Trituration
Distal
Emptying
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Gastric Physiology - Fed

• Accommodation
• Fundus- high muscle tone at baseline
• Receptive Relaxation
• As food enters esophagus
• NO, VIP gtgt Ach
• Adaptive Relaxation
• As food enters stomach
• 40-60 minutes
• Defect linked to functional dyspepsia

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Gastric Physiology - Fed
Lag Phase

• Trituration
• Lower body, antrum
• Mix food with secretions
• Propel against closed pylorus
• 1-3 hours
• Emptying
• Pylorus
• 3-5 cc aliquots
• Liquids then Solids

Bowen, R. 2005
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Gastric Motility
5-HT
ACh
Extrinsic Intrinsic
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Gastric Motility
Central
Enteric
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Gastric Motility - Pacemaker

• Interstitial cells of Cajal
• Between outer/inner muscle layers
• Slow waves
• Background frequency
• 3 cycles/minute
• Do not generate contractions
• Neural Hormonal
• Modulate contraction

Schuster, MM. Atlas of Gastorintestinal
Motiltiy.1993
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Gastric Motility - Fasting

• Migrating Motor Complex (MMC)
• Motilin
• Cycles every 90-120
• Phase I
• Quiescent
• 45-60 min
• Phase II
• single contractions
• 45 min
• Phase III
• 3 cpm, forceful
• 5-10 min

I
II
III
Lacy. Surg Clinic NA, 2005
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Gastric Motility - Fed

• Interrupts fasting MMC
• High amplitude irregular contractions
• Stomach max 3 cpm
• Duodenum 12 cpm

Lacy. Surg Clinic NA, 2005
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Overview

• Gastric physiology motility 101
• Gastroparesis
• Functional Dyspepsia
• The Drugs
• Metoclopramide
• Domperidone
• Cisapride
• Other Agents Gastric Pacing
• The Pipeline

13
Gastroparesis

• Impaired transit of intraluminal contents from
  stomach to duodenum in absence of mechanical
  obstruction
• Lacy, B in S. Clin N.A, 2005

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Gastroparesis

• Diabetic
• 50 of cases
• Vagal neuropathy
• Decreased ICC
• Increased glucagon

Lacy, et al S Clin NA 2005
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Gastroparesis- Symptoms
GCSI Gastroparesis Cardinal Symptom Severity
Index
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Gastroparesis- Mechanisms

• Decreased fundal tone
• Antral hypomotility
• Antroduodenal dyscoordination (Pylorospasm)
• Pacemaker arrhythmias
• - Bradygastria, Tachygastria
• Excessive small bowel inhibitory feedback
• - Small bowel dysmotility

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Gastroparesis- Mechanisms

• Impaired fundal tone
• Decreased tone delays movement of bolus to antrum

Lacy. Surg Clinic NA, 2005
Regulation of fundic tone. Other mediators of
relaxation CCK, VIP, Dopamine
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Gastroparesis- Mechanisms

• Pylorospasm
• Increased phasic tonic contractions in diabetics

Malagelada, Gastroenterology 1986.
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A word about functional dyspepsia

• Rome III- Classification (formerly dysmotility
  vs. ulcer-like)
• Postprandial distress syndrome
• Epigastric pain syndrome
• Pathophysiology
• Gastroparesis (25-30)
• Impaired proximal gastric relaxation1
• vs. increased relaxation in gastroparesis
• 1 Janssens, et al Gastroenterology 1998

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Overview

• Gastric physiology motility 101
• Gastroparesis
• The Drugs
• Metoclopramide
• Domperidone
• Cisapride
• Other Agents Gastric Pacing
• The Pipeline

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The Drugs Dopamine in the stomach

• Gastric smooth muscle relaxation
• Enhances fundic accommodation
• Impairs antroduodenal coordination
• Disruption of slow waves
• Baseline 3 cpm
• Retrograde propagation of slow waves

Schuster, MM. Atlas of Gastorintestinal
Motiltiy.1993
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The Drugs Metoclopramide

• Dopamine (D2) antagonist
• Stomach (Pro-motility)
• Chemoreceptor trigger zone
• (Anti-emetic)
• 5-HT4 agonist/ 5-HT3 antagonist
• Increases ACh release from myenteric neurons

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The Drugs Metoclopramide

• 1979 Approved for short-term use
• 4-12 weeks
• Effects
• - Increases gastric contraction amplitude
• - Improves antroduodenal coordination
• - Increases gastric emptying rate
• Prokinetic effect wanes after 2 months

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The Drugs Metoclopramide

• Other modes of action
• Corrects slow wave dysrhythmias1,2
• - Tachygastria (gt 3 cpm)
• - Bradygastria (lt 3 cpm)
• - Flat line
• Anti-emetic effects
• Block DA receptors in brainstem (CTZ)
• 1 McCallum Dig Dis 1995
• 2 Vasey Am J Gastro 1989

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The Drugs Metoclopramide

• Dosing
• Start 5-10 mg qid
• Max 20 mg qid
• Available in liquid/SQ forms

• Side Effects
• CNS
• Drowsiness
• Acute dystonia
• within 48 hr
• Tremor
• Tardive dyskinesia (gt3 mo.)
• Increased Prolactin
• Galactorrhea
• Menstrual Irregularities

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The Drugs Domperidone

• Dopamine (D2) antagonist
• Stomach
• Chemoreceptor trigger zone
• Peripherally-acting

Physiologic Effect Inhibits fundic receptive
relaxation Increases proximal gastric tone
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The Drugs Domperidone

• Symptomatic improvement in diabetic gastroparesis
• 260 patients
• 20 mg qid x 4 weeks
• 80 response
• No correlation with results of gastric emptying
  testing
• Prokinetic effect lost at 6 weeks
• Resolution of slow wave dysrhythmias
• Vasey Am J Gastro 1989
• Drug of choice in Parkinsons patients

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The Drugs Domperidone

• Dosing
• Start 10 mg qid
• Max 30 mg qid
• Must treat for 1 month to assess efficacy

• Side Effects
• Does not cross blood-brain barrier
• Increased Prolactin (anterior pituitary)
• Galactorrhea
• Menstrual Irregularities

Not FDA approved Can be obtained with IND
application and local IRB approval.
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The Story of Domperidone

• Janssen Pharmaceuticals
• Several attempts at gaining FDA approval
• Approved by FDA GI drugs section but rejected by
  FDA
• No reasons given

June 7, 2004
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D2 Antagonists Summary

• No long-term data on efficacy in gastroparesis
• Clinical benefit primarily due to anti-emetic
  properties (gt 4-6 weeks)
• Side effects limit tolerability of metoclopramide

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Serotonin in the gut

• 5-HT3
• Post-synaptic
• Motor Sensory neurons
• Ligand-gated ion channel

• 5-HT4
• Pre-synaptic
• Myenteric plexus
• Increases ACh release from motor nerve terminals

Bornstein Curr Opin Pharmcol 2006
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The Drugs Serotonin in the stomach

• Varying effects based on receptor subtype
  location
• Gastric body
• 5-HT1 NO release
• smooth muscle relaxation
• 5-HT4 Ach release
• smooth muscle contraction
• Pylorus
• 5-HT3 - decrease tone (increases gastric
  emptying)

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The Drugs Cisapride

• 5-HT4 agonist/ 5-HT3 antagonist
• Net effect increased acetylcholine release
• Distal esophageal contractions (GERD)
• Antroduodenal contractions (Gastroparesis)
• Blocks human K channels
• QT prolongation
• Over 100 deaths- Withdrawn 2000
• Torsade de pointes
• CYP450 3A inhibitors

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Long-Term Studies Cisapride

• Diabetic Gastroparesis
• Cisapride 10 mg tid v. Placebo
• 12 months
• Improvement in symptoms
• Dyspepsia score
• 4.1 v. 2.0
• Improvement in gastric emptying
• 13C-octanoate breath test
• 50 175 min v. 223 min.

Schaub, Aliment PharmTher 2002
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The Drugs Cisapride

• Role in Functional Dyspepsia
• 18 patients
• Cisapride vs Placebo
• Cisapride enhanced meal-induced fundic relaxation
• 270cc vs. 147cc (plt0.05)
• Mechanisms
• Enhanced antral tone shifts volume to fundus
• Enhanced gastric emptying into duodenum triggers
  increased fundic relaxation (vagus)
• Janssens, et al. Aliment
  Pharmacol Ther 1998

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Promotility Drugs

Abell, et al. Neurogast Motil 2006
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Overview

• Gastric physiology motility 101
• Gastroparesis
• The Drugs
• Metoclopramide
• Domperidone
• Cisapride
• Other Agents Gastric Pacing
• The Pipeline...

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Erythromycin

• Motilin receptor agonist
• Motilin released by duodenal mucosa
• Initiates phase III of MMC
• Motilin
• Activates smooth muscle calcium channels
• Stimulates cholinergic nerves

Lacy, Surg Clin NA 2003
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Erythromycin

• Physiologic Effects
• Elicits antroduodenal contractions
• Most potent stimulator of gastric emptying
• Clinical Use
• IV administration (3 mg/kg) for acute
  exacerbations
• Tachyphylaxis
• Abdominal pain, nausea
• Worsens FD
• Inhibits receptive relaxation

Gerken et al, Digestion 1999
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Tegaserod

• 5-HT4 agonist (partial)
• Open-label treatment of 163 patients with
  gastroparesis1
• Limited data on symptoms
• Enhanced gastric emptying
• Higher dose than in IBS
• 6 mg TID, 12mg BID
• 
  1 Tougas, et al, Gastroenterology 2003.

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Tegaserod

• Functional Dyspepsia
• Enhances fundic accommodation
• Increased pre and postprandial volumes
• Pre 140 cc vs. 200 cc
• Post 287 cc vs. 375 cc

Tack, et al. Aliment Pharmacol Ther 2003
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Tegaserod

• March 30, 2007
• Novartis suspends marketing of Tegaserod
• 11,600 patients
• 13 with serious CV events (1 in placebo group)
• Also linked to SEVERE diarrhea, ischemic colitis
• 4 deaths

www.yourlawyer.com
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Itopride

• Dopamine (D2) antagonist ACE inhibitor
• Enhances gastric emptying in animals

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Botulinum Toxin

• Pylorus injection
• Inhibits Ach release
• Decreases pyloric resting tone
• Prevents pyloric spasm
• Increases gastric emptying

• Gastroparesis Mechanisms
• Impaired fundal tone
• Antral hypomotility
• Antroduodenal dyscoordination (Pylorospasm)
• Pacemaker arrythmias
• Excessive small bowel inhibitory feedback

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Gastric Pacing Stimulation

• Two Approaches
• 1. Accelerate background gastric slow wave
• Serosal leads
• gt 3 cpm
• 2. Direct electrical stimulation
• Muscular leads

• Gastroparesis Mechanisms
• Impaired fundal tone
• Antral hypomotility
• Antroduodenal dyscoordination (Pylorospasm)
• Pacemaker arrhythmias
• Excessive small bowel inhibitory feedback

46
Overview

• Gastric physiology motility 101
• Gastroparesis
• The Drugs
• Metoclopramide
• Domperidone
• Cisapride
• Other Agents Gastric Pacing
• The Pipeline...

47
Coming down the Pipeline

• 5-HT4 agonists (w/o cardiac toxicity)
• Renzapride
• Mosapride
• Prucalopride
• Levosulpride ( D2 blockade)

• MotilinR agonists (w/o antibiotic properties)
• ABT-229
• KC 11458
• GM 611

• Miscellaneous
• Ghrelin (gastric stimulatory properties)

• CCK antagonist
• Loxiglumide