Physiology and Pharmacology of the Large

Intestine

Professor John Peterse-mail

j.a.peters@dundee.ac.uk

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

The Large Intestine - General Approximately 1.5 m long, 6 cm diameter Comprises• Colon

o Ascendingo Transverseo Descendingo Sigmoid

• Caecum• Appendix• Rectum

Is primarily involved in:• Absorption of fluids and electrolytes (Na+, Cl-)• Secretion of electrolytes (K+ and HCO3

-) 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

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 involvingo gastrino extrinsic nerve plexuses

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

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 disordersConstipation 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:

Osmotic laxatives(e.g. magnesium sulphate / hydroxide – orally

sodium citrate – rectally)

PURGATIVES AND THEIR MECHANISM(S) OF ACTION

Bulk laxatives(e.g. methylcellulose -orally)

Retain H2OvolumeRetain H2Ovolume

Faecal softners(e.g. docusate sodium – orally)

Faecal softening

Stimulant purgatives(e.g. bisacodyl – oral or

suppository)

Stimulate peristalis; cause H2O and

electrolyte secretion

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

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 (HCO3

- 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)

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

Rehydration Therapy Exploits SGLT11. 2 Na+ bind2. Affinity for glucose increases,

glucose binds3. Na+ and glucose translocate from

extracellular to intracellular4. 2 Na+ dissociate, affinity for

glucose falls5. Glucose dissociates6. 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 gDissolved in a volume of 1 L drinking water

Absorption of Na+ and glucose by SGLT1 cause accompanying absorption of H20

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: