Disorders Affecting Motility: Constipation, Diarrhea, and IBS

Contents Overview

• Constipation
• Haemorrhoids
• Diarrhoea
• Celiac disease
• Irritable Bowel Syndrome

Physiology of Intestinal Motility

• Muscular contractions and secretions controlled by the ANS.
• Enteric nervous system (ENS)
  • third branch of the ANS?
• Slow waves propagated by ICC's

(a) Action potential slow wave Membrane potential (mV) 0 T -50 Force of muscle contraction 0 Time Longitudinal Muscle Circular Muscle Muscularis Mucosae Mucosa 0 Endocrine Cell 0 o Vagus Nerve 0 O O 4 Mechano- receptors 14 4 E Chemo- receptors 4 4 4 4 Secretory Cells Sympathetic Ganglia º 4 Preganglionic Nerves Postganglionic Nerves Sympathetic System Myenteric Plexus Submucosal Plexus

• Neurotransmitters include:
  • Contractile: Acetylcholine, Histamine, 5-HT, ATP, Neuropeptide-Y
  • Relaxant: Noradrenaline, Dopamine, Prostaglandins, Nitric oxide.

Parasympathetic System 4• ENTERIC NERVOUS SYSTEM all these • are is a series of feedback and feedforward loops which reside within the enteric system. And then we have some input from the parasympathetic and sympathetic systems. • we have a submucosal plexus and a submucosal and myenteric plexus so essentially what the submucosal plexus does. It coordinates intestinal secretions. It's the myantaric plexus which coordinates the motor activity of the of the of the of the bowel. · So we can transplant barrels relatively, easily, easily. And they do function because they have chemoreceptors stretch receptors and so on, so that they can respond to the changes in the intestinal contents. It's just the finer changes like during the fight or flight response that don't really enable the bowel to switch off during that time. what they do is they depolarise at a set pace and a set rate. So that means that the rate of peristaltic contractions within any segment of barrel is reasonably is determined by the rate at which they depolarise, so that the pacemaker cells of the gut, the incidental cells of cajaline, the rate of depolarisation. So what that means is that we cannot really change the rate of those contractions. But what we can do is change the force of those contractions. And that's where the autonomic and enteric nervous systems come in. • the rate of those waves is determined by the Icc's depolarizing. And these action potentials are produced because of either the enteric system or the sympathetic system. So the neurotransmitters that are involved in this process for contractile purposes. - Contractile: Acetylcholine, Histamine, 5-HT, ATP, Neuropeptide-Y - Relaxant: Noradrenaline, Dopamine, Prostaglandins, Nitric oxide.Intracellular Signalling Pathways

Intracellular Signalling Pathways

Smooth muscle Agonists Ligand-gated CaC GPCR Ca2+ L-type CaC PLASMA MEMBRANE IP3 Ca2+ - , 1 1 IP3R 1 -RyR CaM Ca2+- CaM MLCK Ca2+ SR Myosin Myosin-P CONTRACTION Agonists that stimulate contraction of smooth muscle primarily achieve this through an increase in intracellular calcium concentrations. GPCR's are linked through Gq to PLC which activates PLC to convert PIP2 to IP3 and DAG. IP3 bins to receptors on the SR which when activated release Ca2+ into the cytoplasm. Ca2+ binds with Calmodulin, a calcium binding protein which then binds to MLCK. MLCK then phosphorylates myosin causing contraction. Alternatively, ligand gated calcium channels can be activated or L-type Ca2+ channels, both of which result in then increase in the intracellular calcium concentration.

Diagnosis of Dysmotility

• Depends upon the individual person!
  • Diet
• Fibre intake etc
• Normal frequency?
  • Ranges between:
• Three movements per week!
• Three movements per day!
• Recent medication use?
  • Antibiotics eg amoxicillin, metronidazole
• More common with high dose or x2 or more
• Alter normal commensal bacteria
• Contaminated food

When Can Antibiotics Cause Diarrhea?

€= More than one An ertibiotica period of time An antibistich taken at a higher down A powerful, brocs-apettrum very well

Bristol Stool Chart

Type 1 Separate hard lumps, like nuts (hard to pass) Type 2 Sausage-shaped but lumpy Type 3 Like a sausage but with cracks on the surface Type 4 Like a sausage or snake, smooth and soft Type 5 Soft blobs with clear-cut edges Type 6 Fluffy pieces with ragged edges, a mushy stool Type 7 Watery, no solid pieces. Entirely Liquid We shouldn't be pooping out little pallets, because that means that the stool is overly desiccated. It's resided in the colon for too long, and the fluid content is too low. Similarly, it shouldn't keep the imprint of your of your the rugi of the and the plic eye folds of the colon, so you can see here. This is almost like a cast taken of your colon. It shouldn't look like that again. That means an element of constipation. So it's still sausage shape, but it's quite lumpy, and all those are representing the folds of your large intestine. This one again still retains the the creases and the folds, but with cracks on the surface, so again represented as somebody with constipation. Now that we have type 4, which is the perfect stool, it's like a sausage or snake, but smooth and soft.

Classes of Drugs Affecting GI Motility

• Drugs that alter the motility of the gastrointestinal tract include:
  • Purgatives (laxative)
• which accelerate the passage of food through the intestine
  • Pro-motility agents
• increase motility of the gastrointestinal smooth muscle without causing purgation (so no pooping)
  • Antidiarrhoeal drugs,
• decrease motility
  • Antispasmodic drugs

And if you think about how smooth muscle tone is achieved? It's primarily because of the leakage of acetylcholine into the synapse. . And then the rate at which acetylcholine is break broken down. . So, what's happening when we have an increase in tone? Is that the rate of leakage of a release is greater than the rate of breakdown on normal metabolism, so essentially goes into partial state of contraction. And that really happens kind of in conditions like Ivs, so what we can do then is we don't change the rate of motility, but what we do is we stop the barrel from cramping. Essentially. · decrease smooth muscle tone.

Constipation Overview

Normal frequency of defecation 3 x per day 1 x per 3 days Normal stool volume 200-300 mL/day 200-300 g/day Constipation · Straining · Pain · Incomplete evacuation . Reduced frequency or volume · Hard stool

Bristol Stool Chart for Constipation

Type 1 Separate hard lumps, like nuts (hard to pass) Type 2 Sausage-shaped but lumpy Type 3 Like a sausage but with cracks on the surface Type 4 Like a sausage or snake, smooth and soft Type 5 Soft blobs with clear-cut edges Type 6 Fluffy pieces with ragged edges, a mushy stool Type 7 Watery, no solid pieces. Entirely Liquid

Factors Contributing to Constipation

Inhibition by cortical centres (e.g. move to strange environment) Reduced fluid and food intake (especially fibre) Sympathetic overactivity (e.g. stress) Enteric nerves and smooth muscle dysfunction e.g. idiopathic slow transit, ileus, hypokalemia, hypocalcaemia, drugs Spinal damage e.g. Multiple sclerosis Pelvic nerve damage e.g. autonomic neuropathy Mechanical obstruction e.g. hernia, tumour, stricture Absence of enteric nerves (Hirschsprung's Local pain e.g. fissure, anal ulcer Haemorrhoids

Constipation Definition and Causes

• Definition
  • Frequency: < 3 stools/
  • Consistency: Hard stools
  • Sensation of incomplete evacuation
  • Straining

TRANSVERSE COLON Right colic (hepatic) flexure Left colic (splenic) flexure Teniae coli ASCENDING COLON DESCENDING COLON Teniae coli Ileum Mesoappendix Omental appendices Haustra Ileocecal sphincter (valve) CECUM SIGMOID COLON VERMIFORM APPENDIX RECTUM ANAL CANAL ANUS

• Causes of Constipation
• Slow Transit
  • Ageing, chronic use stimulant laxatives
• Inadequate
  • Fluid/Dietary Fiber/Exercise
• Metabolic and Endocrine
  • Hypercalcaemia
  • Hypothyroidism
• Drugs
  • Opiates, TCA's, Calcium Resonium (hyperkalaemia)
• Physiological
  • Pregnancy
  • Iron containing medication for anaemia

Treatment of Constipation

• Lifestyle
  • Exercise
  • Advice on mechanism of defecation
• Diet
  • Fluid
  • Fibre
• Soluble (Pysllium, Ispaghula)
• Insoluble (Bran)
• Medical:
  • Laxatives

Types of Laxatives

12« Previous Stool bulking agents Fibre supplements (e.g. bran) Ispaghula husk, sterculia, methylcellulose Hide Labels Next » Increase stool bulk by drawing water around their fibres - require adequate fluid intake Osmotic laxatives Non-absorbed sugars (e.g. lactulose, lactitol) Polyethylene glycol Magnesium and phosphate salts Draw water into the intestinal lumen and may cause dehydration and electrolyte abnormalities in some people. Phosphate salts can be given rectally Stool softeners Liquid paraffin, arachis 으 . Retained in the stool. Ease passage of stools, defecation particularly with haemorrhoids and anal fissure Stimulant laxatives Senna, bisacodyl, dantron, sodium docusate Probably act by stimulating mucosal entero-endocrine cells, which in turn stimulate motility and fluid secretion Specific receptor agonists and antagonists 5HT4 agonists, e.g. prucalopride Stimulate motility, and may be particularly useful for constipation associated with abdominal pain in the irritable bowel syndrome

Specific Laxative Medications

Laxatives - Ispaghula husk; - Sterculia/Methyl cellulose; non-digestable polymers. - Lactulose - Macrogols (Movicol) - Magnesium hydroxide & magnesium sulfate - Docusate sodium (surfactant type action producing softer stools) - Arachis oil (enema) - Bisacodyl (oral; 10-12 hours or suppository: 15-30 min) - Senna (irritant-stimulates peristalsis) - Sodium picosulfate (orally) and docusate sodium (suppository) - Glycerol (Irritant suppository, 15-30 min) - Neostigmine (chronic pseudo-obstruction) - Prucalopride (Selective 5-HT4 agonist) · Last resort after others have failed!

Drugs that Increase GI Motility

• Domperidone (primarily used as antiemetic)
  • Increases GI motility
  • Increases tone of lower oesophageal sphincter
  • Useful in gastric stasis and GORD
• Metoclopramide (primarily used as antiemetic)
  • Stimulates gastric motility and increases gastric emptying.
  • Useful in gastric stasis and GORD but not paralytic ileus (common after GI surgery).
• Prucalopride (Selective 5-HT4 agonist)
  • Last resort after others have failed!