large intestine, constipation, diarrhoea and lactose intolerance

why does gastrointestinal motility occur?

usually involuntary

• mostly due to the activity of smooth muscle (circular, longitudinal layers and the muscularis mucosa)

• BUT skeletal muscle is important in the mouth, pharynx, upper oesophagus and external anal sphincter

- food travels to digestive system and intestines start to absorb

what are the different types of smooth muscle involved in GI motility and what are each of their roles?

- Longitudinal muscle contraction: lumen becomes shorter and fatter - push the food to the intestine

- Circular muscle contraction: lumen becomes narrower and longer - squeeze food (digestion)

- Muscularis mucosae contraction: change in absorptive and secretory area of mucosa - enzyme release from glands

What is the enteric nervous system?

large network of neurons surrounding the digestive organs

- cell bodies of the neurones are located in ganglia, largely within the myenteric and submucous plexus. the interganglionic fibre tracts connect the two plexus

- these neurones regulate the activity of smooth muscles in intestinal tissue

- forms a reflex circuit that can operate independently of the rest of the NS, but is strongly modulated by hormones and extrinsic nerve input - also if under stress, influenced by the CNS

what is the enteric nervous system compromised of?

- Sensory neurons:(mechanoreceptors (by chewing food) , chemoreceptors (detecting sweet/salty), thermoreceptors)

- Interneurons: co-ordinating reflexes and motor programs

- Effector neurons: excitatory and inhibitory motor neurones

a trigger from the NS is required for contraction

what is the dominant autonomic innervation of the GI?

parasympathetic - rest and digest

what is the parasympathetic autonomic innervation of the GI?

- neurones released from spinal cord

- from ganglia close to target organ

- Preganglionic fibres (releasing ACh) synapse with postganglionic neurones within the enteric nervous system (ENS)

Excitatory influences (MAINLY)

• Increased gastric, pancreatic and small intestinal secretion, blood flow and smooth muscle contraction

Inhibitory influences:

• Relaxation of some sphincters, receptive relaxation of stomach - stomach gets wider to acccomadate food

REST AND DIGEST

what is the sympathetic autonomic innervation of the GI?

only occurs in some circumstances - when in danger/stress body does not want to focus on digestion

• Preganglionic fibres (releasing ACh) synapse in the prevertebral ganglia. Postganglionic fibres (releasing NA) innervate mainly enteric neurones

• Functionally less important than the parasympathetic

division

• Inhibitory influences

• Decreased motility, secretion and blood flow

adrenaline inhibits digestion

what is the spontaneous activity of the GI smooth muscle?

• Adjacent smooth muscle cells are coupled by gap junctions – allow spread of electrical currents from cell to cell forming a functional syncytium; hundreds of cells are depolarized and contract at the same time

• Spontaneous activity is modulated by:

a. Intrinsic (enteric) and extrinsic (autonomic) nervous system

b. Hormones

Spontaneous electrical activity occurs as slow waves - rhythmic patterns of membrane depolarization and repolarization that spread from cell to cell via gap junctions

what is the slow wave electrical activity of smooth muscles in GI?

• Slow waves are driven by the interstitial cells of Cajal (ICCs) which are pacemaker cells

• Contraction only occurs if the slow wave amplitude is sufficient to trigger action potentials (slow wave mediated mainly by triggering Ca2+ channel to open

- changes membrane potential of cell and may cause action potential (needed for muscle to contract)

-ICCs form gap junctions with each other and smooth muscle cells

- ICCs are located between the longitudinal and circular muscle layers and in the submucosa

in GI, what is the basic electrical rhythm?

Slow waves determine the basic electrical rhythm (BER) - not all slow waves trigger contraction

Whether slow wave amplitude reaches threshold depends upon (for example):

• Neuronal stimuli

• Hormonal stimuli

• Mechanical stimuli

BER frequency varies along GI tract

• Stomach - 3 slow waves per minute - low, not all generate contraction

• Small intestine- approx. 1-12 waves per minute in the duodenum; approx. 8 waves per minute in the terminal ileum- tends to drive luminal contents in the aboral direction

• Large intestine - favours retention of luminal contents facilitating absorption of water and electrolytes - retains food and solidifies faeces

what are the major motility patterns in the GI tract?

1. Peristalsis - a series of wave-like muscle contractions that move food through the digestive tract - triggered by distension of the gut wall. It involves contraction of longitudinal muscle layers, making intestine shorter and wider and pushing food in direction

2. Tonic contraction- sustained contractions found in the sphincters of the G.I. tract - allowing digestion to occur

3. Segmentation - rhythmic contractions of the circular muscle layer that mix and divide luminal contents - narrow the lumen to increase enzyme contact

what is the main absorption of water process in the GI tract?

passive driven by transport of solutes (mainly Na+) from lumen of intestines to blood stream. movement of water BY OSMOSIS ➢ Is largely driven by absorption of Na+

➢ Intestinal fluid movement is always coupled to solute movement

➢ Water may move via transcellular, or paracellular, routes

➢ Absorption of Na+ provides a (local) osmotic force for the absorption of water

what is electrogenic water absorption?

when one group of Na+ moves from lumen to interstitial fluid, it becomes more positive - therefore charge has been changed

what is electroneutral water absorption?

when one group of Na+ is absorbed is compensated by H+ out, so charge is unchanged

what are the principle mechanisms/features of sodium/water absorption in the GI tract? where do they occur?

- Na+/glucose co transport: electrogenic, in SI

- Na+/AA co transport: electrogenic in SI

- Na+/H+ exchange: electroneutral powered by Bicarb, in duodenum and jejunum

- Parallel Na+/H+ and Cl-/HCO3- exchange: cAMP/cGMP and Ca dependnnt - in ileum and colon

- epithelial Na+ channels (ENaC): regulated by aldosterone, in distal colon

how and when is Cl- passively absorbed in the GI tract?

- when Na+ leaves the lumen it becomes too negative

- negativity of lumen repulses Cl

- therefore enters epithelial cells

this occurs:

• In the small intestine force provided by lumen negative potential due to electrogenic transport of Na+ (Na+/glucose and Na+/amino acid)

• In the large intestine force provided by lumen negative potential due to electrogenic transport of Na+ through ENaC

in Cl-/HCO3- exchange, and parallel Na+/H+ and Cl-/HCO3- exchange energy is required, and special channels are present for Cl-

what is the mechanism of Cl- secretion?

- occurs at basal (continuous) rate from crypt cells

- Low intracellular Na+ drives inward movement of Na+, K+ and 2Cl, all via NKCC1

- K+ recycles via K+ channels, but intracellular concentration of Cl- increases providing a gradient for Cl- to exit cell via CFTR (cystic fibrosis transmembrane regulator - which secrete Cl- from epi cell back to lumen) on the apical membrane

➢ CFTR channels are normally closed

➢ Lumen negative potential (negative Cl-) develops voltage-dependent secretion of Na+ through paracellular pathway, water follows this and causes diarrhoea

what is the role of CFTR in diarrhoea?

➢ Normally, little secretion of Cl- occurs because apical CFTR is either closed, or not present

➢ Secretion occurs when CFTR is activated by:

• bacterial enterotoxins

• hormones and neurotransmitters

• immune cells products

• some laxatives

all of these effect cAMP, cGMP and Ca2+ levels, which cause insertion of CFTR levels

- when CFTR opens: Cl- moves to lumen, Na+ and H2O attracted from intestinal fluid and diarrhoea occurs

what are the 4 main causes of diarrhoea?

1. Excessive secretion - secretory diarrhoea (eg E Coli)

2. Impaired absorption of NaCl - by:

- congenital defects in channels: less absorption of Cl-, increasing Na+ and H2O output

- infection or inflammation

- destruction of intestinal absorptive epithelium

3. Non absorbable or poorly absorbable solutes in lumen - ie lactose intolerance, lactase deficiency therefore water attracted to lactose and water stays in intestine as not absorbed

.4. Hypermotility - IBS, not enough time for absorption

how does E.Coli cause diarrhoea?

Cholera provides an additional classic example

• Cholera toxin enters enterocyte enzymatically inhibits GTPase activity of the Gsα subunit

- Gsa is couples with adenylate cyclase which activates cAMP

- cAMP stimulates CFTR

- causing hypersecretion of Cl-, with Na+ and water following causing diarrhoea

what is the consequences of diarrhoea?

• Can result in dehydration (Na+ and H2O loss) - loses water and electrolytes

• Metabolic acidosis (HCO3- loss) - usually absorbed, but here it increases acidity of lungs

• Hypokalaemia (K+ loss)

• May be fatal if severe (e.g. cholera)

what is the treatment of severe acute diarrhoea?

• Maintenance of fluid and electrolyte balance (first priority) - always hydrate and use ORT

treating the cause:

• Use of anti-infective agents (Abx - if appropriate)

• Use of anti-motility agents

what is the mechanism of rehydration therapy?

- exploiting Na+ and gluycose channels in order for Pt to absorb Na+ and water

1. 2Na+ bind

2. affinity for glucose increases, so it binds

3. Na+ and glucose translocated from extracellular (lumen) to intracellular (interstitial fluid)

4. 2Na+ dissociate, affinity for glucose falls

5. glucose dissociates

6. cycle repeated

JUST GIVING WATER - IT WILL BE EXCRETED

what are antimotility drugs used for? how do they work?

- used for treatment of diarrheoa

- opiate drugs! as they bind to new opiate receptors and cause hyperpolarisation, which inhibits movement of intestine

actions of the alimemtary tract include:

• inhibition of enteric neurones (hyperpolarization via activation of u-opioid receptors)

• decreased peristalsis, increased segmentation (i.e. constipating)

• increased fluid absorption

• constriction of pyloric and anal sphincters

what are the anti motility agents used in treatment of diarrhoea?

➢ The major opiates used in diarrhoea are:

• Codeine - treats hypermotility but has CNS effects

• Diphenoxylate - low CNS penetration, blocks the release of acetylcholine in the synaptic cleft

• Loperamide–opiate:

• First choice for traveller’s diarrhoea

• Relatively selective for the G.I. tract.

• It reduces peristalsis, decrease the passage of faeces

• Atropine - blocks Ach receptors, decreasing intenstinal movement, causes side effects on eyes and heart

what is lactose intolerance?

Relatively common digestive problem resulting from the inability to adequately

digest lactose: caused by lactase insufficiency

- Human populations exhibit (worldwide) a variable degree of lactase persistence (LP)

- Partially due to polymorphisms in the MCM6 gene that regulates expression of the lactase gene

what can lactose intolerance result from?

• Primary lactase deficiency- due to lack of the lactase persistence (LP) allele - most common cause world wide

• Secondary lactase deficiency - caused by damage to/ infection of/ the proximal small intestine - inflammation causes damage

• Congenital lactase deficiency - rare autosomal recessive disease - no ability to digest lactose from birth

what is the consequences of lactase insufficiency?

• Hypolactasia causes no disturbance unless lactose-containing food is consumed and activity of remaining enzyme is overwhelmed

• If lactose is delivered to the colon from the ileum colonic microflora produce:

• Short-chain fatty acids (which can be absorbed)

• Hydrogen (H2- which can be detected in the breath of lactase deficient individuals following a lactose challenge)

• Carbon dioxide

• Methane

what are the symptoms of lactose intolerance?

Symptoms:

• Bloating

• Abdominal pain

• Diarrhoea due to H20 from hydroxyl groups

how is lactose intolerance diagnosed?

ased on diet observation:

• Association of symptoms with lactose consumption

• Hydrogen breath test - to know if lactose is fermented by LT bacteria

• Lactose/milk tolerance test - lactose should degrade to glucose and galactose, so blood sample should show increase glucose, but with lactose intolerance there will not be a glucose increase

what is the treatment of lactose intolerance?

Treatment:

• Reduction or elimination of consumption of milk products

• Use of milk products treated with lactase

• Use of milk lactose-free

what is constipation?

difficult/infrequent defecation

what are the causes of constipation?

• Neurogenic disorders of the large intestine leading to reduced persistalsis (E.g. Megacolon, hypothyroidism, IBD with constipation, cancer etc.)

• Abdominal muscle weakness - non exercisers

• Diet poor of fibres

• Sedentary life style

• Constant suppression of the urge to empty

• Antidepressant drugs -anticholinergics - decrease peristalsis

• Opiates

• Aging - as decreases muscle contraction and movement

how is constipation treated non pharmacologically?

- More water and less alcohol should be consumed

• Some wheat bran can be added to the diet - to create a bulky hybrid mass to increase bowel movement

• Increase your activity- exercise

• Improve your toilet routine - Keep to regular time and give yourself plenty of time to use the toilet

• Don't delay

• Feet can be rested on low stool while going to toilet

how is constipation treated pharmacologically?

• Bulk laxatives: e.g. methylcellulose -Polysaccharide polymers not digestible

• Osmotic laxatives (e.g magnesium hydroxide, lactulose): -Poorly absorbed solutes

• Faecal softeners (e.g. arachis oil, docusate sodium) -Enema

• Stimulant laxatives (e.g. senna, dantron) -Drugs that directly increase peristalsis, by increasing cAMP

- Drugs that increase G.I. motility without purgation - Antiemetics (e.g. domperidone, metoclopramide) -Increase gastrointestinal motility and gastric emptying