This document discusses prokinetics, which are drugs that enhance gastrointestinal motility. It describes the normal control pathways of GI motility, including hormonal and neural pathways. It then discusses various phases of GI motility including the cephalic, gastric, and intestinal phases. The document outlines several prokinetic drug categories and examples, including muscarinic agonists, anticholinesterases, dopamine D2 blockers, 5-HT4 agonists, and motilin agonists. It discusses the mechanisms of action and advantages/disadvantages of various prokinetic drugs. Novel therapies for improving GI motility in critically ill patients are also mentioned.

1. PROKINETICS
By: Dr. Vahid Nikoui
Email: nikoui@razi.tums.ac.ir

2. Normal GI Motility

3. Control pathways
 Both hormonal and neural
 Short pathways: involves automatic regulation within the enteric
system itself
 Long pathways: involves the CNS (somatic and autonomic)
 Three phases: cephalic, gastric and intestinal phases

4. Cephalic phase: salivary and gastric secretions
 Salivary secretion stimulated by
parasympathetic NS by odors,
sight, taste  saliva fluid and
rich in enzymes
 Stimulated by sympathetic NS
thick secretion, rich in
proteins
 Gastric secretion: increase acid
and enzymes secretion in
response to sight, smell and
taste of food

5. Gastric phase
 Stimuli: presence of
food in the stomach
(both distention and
nutrients)
 Stimulation of the
parasympathetic NS
and secretion of gastrin
(hormone)
 Response: increased
motility and juice
secretion

6. Intestinal phase
 Arrival of nutrients in duodenum  decreased gastric
secretion and motility
 Promotes secretion of cholecystokinin (CCK) and secretin
- CCK promotes:
- increased pancreatic enzyme secretion
- gallbladder contraction and sphincter of Oddi
relaxation
- secretin promotes:
- bicarbonate ion secretion (pancreas)
- bile secretion

7.  Peristalsis:
 Waves of contraction of longitudinal muscle fibers
moving down the GI tract
 Segmentation:
 In small intestine for mixing chyme

8. Gastric motility
 Gastrin
 CCK
 Secretin
 Gastric inhibitory peptide (GIP)

9. Control mechanisms
 During fasting, ghrelin and peptide YY (PYY)
concentrations are abnormal
 Nutrient-stimulated concentrations of CCK
and PYY are markedly elevated  delayed
gastric emptying

10. Motility in the small intestine
 Segmentation and peristalsis increased by distention
of the wall
 Intestino-intestinal reflex:
 Severe distention or injury inhibits motility in the region
 Ileo-gastric reflex:
 Distension of ileum inhibits gastric motility
 Gastro-ileal reflex:
 Presence of chyme in stomach increases motility in ileum

11. Motility in the colon
 Haustration:
 Like segmentation
 Colono-colonic reflex:
 Distension in one part of the colon induces relaxation in other parts
 Gastro-colic reflex:
 A meal in the stomach increases colonic motility
 Defecation:
 Triggered by distention of the rectal wall
 Signal sent to sacral parasympathetic and cortex
 Smooth muscle of anal sphincter open
 If the person decides to go to the bathroom  open
voluntary muscle sphincter

12. Migrating motor complexes (MMCs):
☆Phase I:
 Quiescence
☆Phase II:
 Variable period of irregular contractile
activity
☆Phase III:
 Short period (5~10 min) of intense, frequent, regular
contractions (motilin receptor) clear bowel

14. Gastric emptying in the critically ill
 Delayed gastric emptying is more frequent in:
☆Burns
☆Multiple trauma
☆Severe sepsis
►80% of head injuries
►Hyperglycemia delays gastric emptying
 (pre-existing DM doesn’t affect)

15.  Drugs administered in ICU, particularly inotropes
and those used for sedation
 Opiates  μ-receptors

16.  High levels of circulating catecholamines commonly seen 
negative effect
 Adrenaline reduces gastric emptying by a β-adrenergic effect
 Dopamine reduces antral contractions and slows orocaecal
transit
 High-dose catecholamines may reduce the prokinetic effect of
erythromycin
 Anticholinergics and calcium channel blockers

17. Intestinal absorption in critically ill
 Glucose absorption is substantially reduced
 Fat absorption may also be reduced
 The reasons for impaired absorption are unclear

19. Agents that enhance coordinated
contraction of the antrum & duodenum
Increases gastric emptying
Relief of gastric stasis
Decreases reflux oesophagitis / heart burn
Decreases regurgitation of gastric contents
& emesis

20. Achalasia (esophagus spasm, lower
esophageal sphincter (LES) fails to relax)
GERD (gastroesophageal reflux disease)
(insufficient LES pressure)
Gastroparesis (delayed gastric emptying,
often occurs in people with diabetes due to
vagus nerve damage)

21. CATEGORY PROTOTYPE MECHANISM OF
ACTION
Muscarinic agonists Bethanachol GI motility
Anticholinestrases Neostigmine GI motility, inhibit
ACh degradation
Dopamine D2 Metoclopramide & Blocks inhibitory
blockers Domperidone D2 receptor
Cisapride, Activates
5-HT4 agonists Metoclopramide excitatory 5-HT4
Tegaserod, receptors
Prucalopride
Activate neural &
Motilin Agonists Erythromycin smooth muscle
motilin receptor

22. Bethanachol & Neostigmine:
Disadvantages:
Non-specific effect
Increases salivation
Diarrhea, gastric & pancreatic secretion

23. Metoclopramide
D2 antagonist
5-HT4 agonist
5-HT3 antagonist
 Widely used in ICU
 Antagonizes the inhibitory effect of dopamine on motility
 Crosses the blood brain barrier
 Hyperprolactinemia
 Anti-emetic effect
 With repeated administration tachyphylaxis develops
 Ineffective and contraindicated in patients with head injuries

24. Domperidone
 D2 selective antagonist
 Does not cross blood brain barrier
 CNS related symptoms are least
 Causes hyperprolactinemia

25. Cisapride
 5-HT4 agonist
 Acetylcholine increase in enteric nervous system
(parasympathomimetic)  increase esophageal
sphincter tone and gastric emptying
 Has no D2 receptor activity, no CNS related side effects
 No hyperprolactinemia, no anti-emetic effect
 Causes upper G.I. motility, promote colonic hypermotility
 Relieves constipation
 Causes ventricular arrhythmia by torsades de pointes
 Block K+ channels in the heart & GIT

26. • Erythromycin
 Macrolide antibiotic & acts as a motilin agonist
 Low doses (1~3 mg/kg IV) of erythromycin act as a motilin
agonist, triggering phase III activity in the stomach and small
intestine
 In critically ill, it increases antral motility, accelerates gastric
emptying and improves the success of feeding
 Efficacy reduced after 7-day use
 Cardiac toxicity and bacterial resistance

27. Combination therapy
 Combination of erythromycin and
metoclopramide for failure of nasogastric
feeding, is superior to either drug alone and
with less tachyphylaxis

29. Novel Therapies

30.  Elevated cholecystokinin levels slow gastric emptying
and motility and are associated with feed intolerance in
critically ill patients
☆Dexloxiglumide
 Selective and highly potent CCK-1 receptor antagonist
 Inhibits gall bladder contraction
 Improves lower oesophageal sphincter function
 Hastens colonic transit

31. μ Receptor Antagonists
 Opiates slow gastric emptying  opiate
antagonist
☆Naloxone
 administered directly into the gut  avoid
antagonism of the central effects of parenteral
opiates
 improves the success of feeding and reduces
pneumonia

32. ☆Alvimopan
 High affinity for μ receptors
 Does not cross the blood–brain barrier
 No effect on gastric emptying
 hastened gut recovery and shortened time
to hospital discharge in patients after
bowel resection or hysterectomy

33. nhibit dopamine D2 receptors
Motor
neuron
hibit
Stimulate
HT3 receptors 5HT4 receptors

34.  Thank You !