prokinetics
DESCRIPTION
.TRANSCRIPT
Normal GI Motility
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
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
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
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
Peristalsis: Waves of contraction of longitudinal muscle fibers
moving down the GI tract
Segmentation: In small intestine for mixing chyme
Gastric motility
Gastrin
CCK Secretin Gastric inhibitory peptide (GIP)
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
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
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
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
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)
Drugs administered in ICU, particularly inotropes and those used for sedation
Opiates μ-receptors
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
Intestinal absorption in critically ill
Glucose absorption is substantially reduced
Fat absorption may also be reduced
The reasons for impaired absorption are unclear
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
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)
CATEGORY PROTOTYPE MECHANISM OF ACTION
Muscarinic agonists Bethanachol
GI motilityAnticholinestrases Neostigmine GI motility, inhibit
ACh degradation
Dopamine D2 blockers
Metoclopramide &
Domperidone
Blocks inhibitory D2 receptor
5-HT4 agonists
Cisapride, Metoclopramide
Tegaserod, Prucalopride
Activates excitatory 5-HT4
receptors
Motilin Agonists Erythromycin
Activate neural & smooth muscle motilin receptor
Bethanachol & Neostigmine:
Disadvantages:
Non-specific effectIncreases salivationDiarrhea, gastric & pancreatic secretion
D2 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
Metoclopramide
Domperidone
D2 selective antagonist
Does not cross blood brain barrier
CNS related symptoms are least
Causes hyperprolactinemia
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
• 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 Useful in diabetic gastric paresis
Combination therapy
Combination of erythromycin and metoclopramide for failure of nasogastric feeding, is superior to either drug alone and with less tachyphylaxis
Novel Therapies
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
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
μ Receptor Antagonists
☆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
Stimulate 5HT4 receptors
Inhibit dopamine D2 receptors
Inhibit
5HT3 receptors
Motorneuron
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