1. Physiology and Pharmacology of the Large Intestine Professor John Peters e-mail j.a.peters@dundee.ac.uk

2. After this lecture, students should be able to:  Describe the structure and function of the large intestine and the patterns of motility that it exhibits  Provide an account of the defaecation reflex  Outline the causes of constipation and its treatment by purgatives  Describe water balance within the G.I. Tract  Understand the principles of oral rehydration therapy and the role of SGLT1 in this process  Outline the causes of diarrhoea and its treatment by antimotility agents Learning Objectives

3. The Large Intestine - General  Approximately 1.5 m long, 6 cm diameter  Comprises Colon o Ascending o Transverse o Descending o Sigmoid Caecum Appendix Rectum  Is primarily involved in: Absorption of fluids and electrolytes (Na +, Cl - ) Secretion of electrolytes (K + and HCO 3 - ) and mucus Formation, storage and periodic elimination of faeces  Normally receives approximately 500 ml of chyme (indigestible residues, unabsorbed biliary components, unabsorbed fluid) per day – entry permitted by the gastroilial reflex

4. Patterns of Motility in the Large Intestine (1)  Haustration  Peristaltic propulsive movements  Mass movement  Defaecation  Haustration - haustra are saccules caused by contraction of the circular muscle – similar to segmentation in function, but much lower frequency  Peristaltic propulsive movement – occur in both the aboral and oral directions. Oral movements occur principally in the ascending and transverse colon – contributes to long transit time (16 – 48 hours)  Mass movement – simultaneous contraction of large sections (about 20 cm) of the circular muscle of the ascending and transverse colon - drives faeces into distal regions Occurs about one to three times daily Typically triggered by a meal (often breakfast) via the gastrocolic response involving o gastrin o extrinsic nerve plexuses

5. Patterns of Motility in the Large Intestine (2)  Defaecation Mass movement - rectum fills with faecal matter Activation of rectal stretch receptors Activation of afferents to spinal cord Activation of parasympathetic efferents Activation of afferents to brain (urge to defaecate) Contraction of smooth muscle of colon and rectum – internal anal sphincter relaxes Relaxation of skeletal muscle of external anal sphincter Contraction of skeletal muscle of external anal sphincter Pelvic nerve Altered firing in efferents to spinal cord Pudendal nerve Defaecation assisted by abdomenal contraction and expiration against closed glottis Defaecation delayed – rectal wall gradually relaxes

6. CONSTIPATION and PURGATIVES Medically sound uses of laxatives include: when ‘straining’ is potentially damaging to health (e.g. patients with angina), or when defaecation is painful (e.g. haemorrhoids) predisposing to constipation to treat drug-induced constipation, or constipation in bedridden, or elderly patients to clear the bowel before surgery or endoscopy Numerous causes of constipation: e.g. improper diet, drugs, metabolic disorders Constipation is the presence of hard dried faeces within the colon  increase peristalsis and/or soften faeces causing, or assisting, evacuation  are resorted to far too readily in some societies by individuals obsessed by ‘regularity’  can be abused in eating disorders and may also disguise underlying disease Pugatives:

8. Absorption of Water in the GI Tract  Absorption of water is a passive process driven by the transport of solutes (particularly Na + ) from the lumen of the intestines to the bloodstream  Water ingested and secreted is normally in balance with water absorbed  Typical values are:  9.3 litre entering tract per day  8.3 litre absorbed by small intestine  1 litre enters large intestine of which 90% is absorbed Thus faeces normally contain 100 ml water along with 50 ml cellulose, bilirubin and bacteria Diarrhoea is defined as loss of fluid and solutes from the GI tract in excess of 500 ml per day

9. CAUSES OF DIARRHOEA (1) Diarrhoea can have numerous causes:  infectious agents – viruses, bacteria (e.g. traveller’s diarrhoea)  chronic disease  toxins  drugs  psychological factors Diarrhoea  may involve the small, or large, intestine  can result in dehydration, metabolic acidosis (HCO 3 - loss) and hypokalaemia (K + loss)  may be fatal if severe (e.g. cholera) Treatment of severe acute diarrhoea can include:  maintenance of fluid and electrolyte balance (first priority)  use of anti-infective agents (if appropriate)  use of non-antimicrobial antidiarrhoeal agents (symptomatic)

10. CAUSES OF DIARRHOEA (2)  Impaired absorption of NaCl Congenital defects Inflammation Infection (e.g. enterotoxins from some strains of E.coli and campylobacter sp.) Excess bile acid in colon  Non-absorbable, or poorly absorbable, solutes in intestinal lumen Lactase deficiency  Hypermotility  Excessive secretion Cholera provides a classic (and extreme) example Na + /K + ATPase Na + /K + /2Cl - co-tranporter Chloride channel (CFTR) cholera toxin enters enterocyte enzymatically inhibits GTPase activity of the Gs  subunit increased activity of adenylate cyclase increased concentration of cAMP cAMP stimulates CFTR hypersecretion of Cl -, with Na + and water following

11. Rehydration Therapy Exploits SGLT1 1.2 Na + bind 2.Affinity for glucose increases, glucose binds 3.Na + and glucose translocate from extracellular to intracellular 4.2 Na + dissociate, affinity for glucose falls 5.Glucose dissociates 6.Cycle is repeated Oral rehydration salts contain (for example) Glucose 20 g Sodium chloride 3.5 g Sodium bicarbonate 2.5 g Potassium chloride 1.5 g Dissolved in a volume of 1 L drinking water Absorption of Na + and glucose by SGLT1 cause accompanying absorption of H 2 0

12. ANTIMOTILITY AGENTS USED IN TREATMENT OF DIARRHOEA  Many morphine-like (or opiate) drugs have anti-diarrhoeal activity  The major opiates used in diarrhoea are: codeine diphenoxylate - low CNS penetration, low solubility in water (  abuse potential) loperamide – low CNS penetration, low solubility in water, undergoes enterohepatic recycling inhibition of enteric neurones (hyperpolarization via activation of  -opioid receptors) decreased peristalis, increased segmentation (i.e. constipating) increased fluid absorption constriction of pyloric, ileocolic and anal sphincters  The actions of opiates on the alimentary tract include: