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  1. 1. PROKINETICS By: Dr. Vahid NikouiEmail:
  2. 2. Normal GI Motility
  3. 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. 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. 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. 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. 7.  Peristalsis:  Waves of contraction of longitudinal muscle fibers moving down the GI tract Segmentation:  In small intestine for mixing chyme
  8. 8. Gastric motility Gastrin CCK Secretin Gastric inhibitory peptide (GIP)
  9. 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. 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. 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. 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
  13. 13. 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)
  14. 14.  Drugs administered in ICU, particularly inotropes and those used for sedation Opiates  μ-receptors
  15. 15.  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
  16. 16. Intestinal absorption in critically ill Glucose absorption is substantially reduced Fat absorption may also be reduced The reasons for impaired absorption are unclear
  17. 17. Agents that enhance coordinatedcontraction of the antrum & duodenumIncreases gastric emptyingRelief of gastric stasisDecreases reflux oesophagitis / heart burnDecreases regurgitation of gastric contents& emesis
  18. 18. Achalasia (esophagus spasm, loweresophageal sphincter (LES) fails to relax)GERD (gastroesophageal reflux disease)(insufficient LES pressure)Gastroparesis (delayed gastric emptying,often occurs in people with diabetes due tovagus nerve damage)
  19. 19. CATEGORY PROTOTYPE MECHANISM OF ACTIONMuscarinic agonists Bethanachol GI motilityAnticholinestrases 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
  20. 20. Bethanachol & Neostigmine:Disadvantages: Non-specific effect Increases salivation Diarrhea, gastric & pancreatic secretion
  21. 21. MetoclopramideD2 antagonist5-HT4 agonist5-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
  22. 22. Domperidone D2 selective antagonist Does not cross blood brain barrier CNS related symptoms are least Causes hyperprolactinemia
  23. 23. 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
  24. 24. • 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
  25. 25. Combination therapy Combination of erythromycin and metoclopramide for failure of nasogastric feeding, is superior to either drug alone and with less tachyphylaxis
  26. 26. Novel Therapies
  27. 27.  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
  28. 28. 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
  29. 29. ☆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
  30. 30. nhibit dopamine D2 receptors Motor neuron hibit StimulateHT3 receptors 5HT4 receptors
  31. 31.  Thank You !