GI Diseases Pharmacology Flashcards
What is the route of the gastrointestinal tract?
Mouth, oesophagus, stomach, SI, LI
What are the accessory glands to the GI tract?
Salivary glands, pancreas, liver
Is the gut lumen internal or external to the body and why?
External
Food components enter the body after absorption
Due to conditions for digestion being tolerated in the gut (lumen) but not in the body
What are the conditions in the gut?
pH of stomach as low as 2.0, in the body is 6.8-8.0
Digestive enzymes would destroy body’s own tissue
MOs in lower intestine present but destructive/ lethal if entered body
Foods are foreign particles that would be attacked if entered body
What are the 4 digestive system processes:
Motility
Secretion
Digestion
Absorption
Describe motility in the GI tract:
Voluntary and involuntary
Skeletal muscle (voluntary) is responsible for chewing, swallowing and defacation
Smooth muscle (involuntary) contractions that mix and move forward content of the gut
Name the 2 types of smooth muscle contractions in the gut:
Tonic
Phasic
Describe tonic contractions:
In the absence of food
Constant low level of contraction
Tone maintains a steady pressure on contents of gut and prevents wall from being permanently stretched
Describe phasic contractions:
In the presence of food
Action potential induced bursts of contraction
-propulsive movements (moving forward)
-mixing movements
Describe secretion in the GI tract:
Digestive juices
Secretory cells extract large volumes of water and raw materials for secretion
GI hormones
Describe digestive juices in secretion:
Secreted by exocrine glands (from outside into lumen)
Contain water, electrolytes, and specific products for digestion or absorption e.g mucus, enzymes and bile salts
Where are mucus, enzymes and bile salts made?
Mucus: all through gut
Enzymes: pancreas and epithelial of lumen
Bile salts: liver for fat digestion
Describe secretory cells in secretion:
Secretion requires a lot of energy
Active transport of raw materials into cell
Synthesis of secretory products by ER
Neural or hormonal stimulation releases secretion
Secretions normally reabsorbed back into gut- gets back energy
Describe GI hormones in secretion:
Secreted by endocrine glands
Secreted into blood stream by EGs along tract wall
Regulate motility and exocrine gland secretion
Where does protein digestion begin and describe it:
Pepsinogen in gastric juice is converted to pepsin at low pH (acid)
Pepsin breaks down proteins to peptides
Describe protein digestion in the SI:
Trypepsinogen in pancreatic juice is converted to trypsin at a basic pH
Trypsin breaks down proteins into peptides
Peptidases (border of epithelial cells of SI) breaks down peptides to a.a, which are actively transported into epithelial cells of villi and from there to blood
Where are lipids digested?
Only broken down in duodenum and SI
Describe lipid digestion:
In the duodenum, lipids combine (emulsify) with bile salts to form fat droplets
Lipase from pancreas, digests emulsification drops triglyceride and monoglycerides and fatty acids
MGs and FAs diffuse into intestinal epithelial cells, where they recombine and join with proteins to form lipoproteins, called chylomicrons
These enter a lacteal (lymphatics), where they can travel to liver and other tissues where required
Describe polysaccharide digestion:
Starch is broken down by salivary amylase (mouth) and then pancreatic amylase (duodenum/ SI) to maltose-> glucose
Glycogen-> glucose
Cellulose and other indigestion carbs are not broken down by gut enzymes, but by microbes in the gut
Describe disaccharide digestion:
Enzymes in the SI break down simpler sugars
Sucrase-> sucrose -> glucose + fructose
Lactase-> lactose-> glucose + galactose
Glucose is AT into epithelial cells-> blood capillary
Name and briefly describe the structure of the digestive tract wall:
Mucosa- next to layer of SI
Submucosa- underneath mucosa
Muscularis- Muscle
Serosa- outer end
Describe the mucosa as part of the structure of the digestive tract wall:
Epithelial cells that line the lumen- simple columnar epithelium
Goblet cells that produce mucus
Lamina propria layer- capillaries are found, layer of connective tissue
Also contains lymphatic nodules
Muscularis mucosa aswell- responsible for changes in folds of mucosal layer, thin layer of nerve plexus
Describe the submucosa as part of the structure of the digestive tract wall:
Arterioles, veins, where branches of capillaries
Connective tissue, allowing tract to distend and be elastic
Contains larger blood and lymph vessels, sends branches to mucosa and muscularis external
Contains submucosa nerve plexus
Describe the muscularis as part of the structure of the digestive tract wall:
Major smooth muscle
Inner circular (contracts diameter of lumen) and outer longitudinal muscle (contracts length of gut)
Myenteric nerve plexus lies between these 2 layers- gut has own NS
Describe the serosa as part of the structure of the digestive tract wall:
Serous fluid, helps to keep the outer lubricated, preventing friction between tract to other tissues and organs
Outermost layer, connective tissue
Continuous with the mesentery- suspends digestive organs from nine wall of abdominal cavity like a sling
Describe what the folding is like in the mucosa:
Highly folded and varies in different parts of tract
Describe what the folding is like in the oesophagus:
Quite flat as don’t need to absorb so don’t need a high SA
Describe what the folding is like in the stomach:
Big (gastric) pits where acid, pepsin, other hormones are produced- protects stomach from acid
Describe what the folding is like in the SI:
Huge folds called villi which have microvilli
These increase SA for increased absorption
Describe what the folding is like in the LI:
Cribs- have stem cells
What are the 3 layers of the mucosa of the lumen?
Mucous membrane
Lamina propria
Muscularis mucosa
Name the 4 process which regulates the digestive function:
Autonomic SM function
Intrinsic nerve plexus (gut NS)
Extrinsic nerves (CNS)
GI hormones
Describe the autonomic smooth muscle function:
Self induced electrical activity in digestive smooth muscle, prominently slow wave potentials (basic electrical rhythm)
Describe what triggers the autonomic smooth muscles self induced electrical activity:
Interstitial cells of Cajal:
-pacemaker cells that instigate cyclic slow wave activity
-located between circular and longitudinal muscle, allow whole sheets of sm cells to contract together when threshold reached
What does reaching the threshold in the autonomic sm to induce contraction depend on?
Mechanical, neural and hormonal factors e.g food present/ absent
What does the intensity (strength) of the contraction in the autonomic smooth muscle depend on?
Number of AP once slow wave potential threshold reached (depends on Ca2+)
Describe the intrinsic nerve plexus function:
Between the submucosa and myenteric nerve plexus
Enteric NS- entirely and throughout digestive tract wall-100 million neurones
Primarily co-ordinate local activities in tract
Using various types of neurones
Name and describe the types of neurones involved in the intrinsic nerve plexus:
Input neurones (sensory) respond to local stimuli
Excitatory and inhibitory output neurones- modulate motility or secretion of hormones or enzymes
-Ach promotes sm contraction
-NO and vasoactive intestinal peptide act together to relax sm
Describe the extrinsic nerve function:
Sympathetic and parasympathetic nerves influence motility and secretion by modifying activity of intrinsic nerve plexus
-altering secretion of GI hormones
-directly acting on sm and glands
What is the role of the parasympathetic ns in extrinsic nerve function?
Vagus nerve*- connected to all parts of digestive tract, can communicate from whats happening from mouth to gut
Increase SM motility
Promotes GI hormone and enzyme secretion
Co-ordinates activity between different regions of tract
Name the types of sensory receptors:
Chemoreceptors
Mechanoreceptors
Osmoreceptors- important in duodenum and SI
What is the effect of stimulation of sensory receptors:
Results in neural reflexes or secretion of hormones which alter activity of effector cells (sm cells, exocrine and endocrine gland cells)
Also effects on effector cells that are directly stimulated by GI hormones, neurotransmitters and local chemical mediators
What is the function of GI hormones in the digestive tract?
Endocrine gland cells in mucose of specific regions of tract release hormones into blood (not lumen) upon stimulation
Transported to other parts of digestive tract where stimulate or inhibit other exocrine gland cells or sm
Give examples of GI hormones secreted from the GI tract and where?
Duodenum- cholecystokinin- gall bladder contraction, pancreatic secretion
Stomach- gastrin- increase acid secretion
Pancreas- insulin/ glucagon
Describe the properties of the palate in the mouth:
Hard and soft
Forms roof of oral cavity (separates mouth from nasal passages)
Uvula (seals off nasal passages during swallowing)
How many teeth do adults have and describe their properties:
32 (28 without wisdom teeth)
Incisors/ premolar
Responsible for chewing (mastication)
Describe the property of the tongue?
Composed of skeletal muscle
Has around 10,000 taste buds:
sweet, sour, bitter, salty
Describe the properties of the pharynx:
Cavity at rear of throat, links mouth to oesophagus
– Common passageway for digestive and respiratory systems
– Tonsils
* Within side walls of pharynx * Lymphoid tissue
What are taste receptors?
Long spindly, modified epithelial cells
How much saliva is produced per day and what by?
1-2L per day
Produced by 3 main pairs of salivary glands (90%):
-Paratoid
-Sublingual
-Submandibular
What is the rate per min of saliva produced and how is it increased by?
Basal 0.5ml/min - stimulated by constant low level parasympathetic NS
Max 5ml/min, eg sucking on a lemon
Describe the composition of saliva:
99.5% H2O
0.5% electrolytes and protein (amylase, mucus, lysozyme, for antibacterial)
Bicarbonate ions- to have a neutral pH for amylase
What drugs can decrease the amount of salvia produced?
B blockers
Diuretics
Anticholinergics
Does digestion and absorption occur in the mouth?
Digestion yes
Absorption of food no, but sublingual/buccal drugs are absorbed
What are the functions of the saliva?
- Digestion of carbohydrates by salivary amylase
- Swallowing facilitated by moistening food
- Lubrication provided by mucus
- Antibacterial action
– Lysozyme destroys bacteria
– Saliva rinses away material that could serve as food
source for bacteria - Solvent for molecules that stimulate taste buds
- Aids speech by facilitating movements of lips and tongue
- Helps keep mouth and teeth clean
- Rich in bicarbonate buffers
Describe how eating can increase salvia production:
Pressure and chemoreceptors in the mouth, signals to salivary centre in medulla, signals to autonomic nerves-> salivary glands
Describe how a stimulus of seeing food (conditioned response) can increase saliva production:
Signals to cerebral cortex, to salivary centre in medulla, signals to autonomic nerves, salivary glands
What is swallowing?
Pharynx and Oesophagus involved
Moves food from mouth through pharynx into stomach
Sequentially programmed all-or-none reflex – can’t be stopped once begun
Initiated when bolus is voluntarily forced by tongue to rear of mouth into pharynx
Swallowing centre briefly inhibits respiratory centre during swallowing
Swallowing is the beginning of peristalsis
In pharynx, bolus prevented from re-entering mouth, or entering nasal passages or trachea
What are the 2 phases in swallowing?
- Oropharyngeal – 1 sec
- Oesophageal – 5-9 sec
Describe the oesophagus:
Fairly straight muscular tube
Extends between pharynx and stomach
Sphincters at each end
Name the 2 sphincters in the oesophagus and what are their purpose?
Pharyngoesophageal sphincter- at the top, stops food entering the resp tract
Gastroesophageal sphincter- at bottom, stops food going back up from stomach
Is there any digestion/ absorption in the oesophagus?
No, there is not enough time
How does food move through the oesophagus?
Peristaltic waves push food through oesophagus, swallowing centre controls the progression of the wave
Mucus is secreted for lubrication/ protection
What are the 3 sections of the stomach and describe them:
Fundus- air
Body- food is there for a while
Antrum- thicker muscle than body, used for mixing, parastaltic wave to pyloric sphincter so pushes it back until it is ready, so pulverises it into chyme
What are the 3 main functions of the stomach?
Store ingested food until it can be emptied into small intestine
Secretes HCl and enzymes that begin protein digestion
Mixing movements convert pulverized food to chyme
What type of foods stay longer in the body of the stomach?
Fatty foods, 6-8 hrs
Why should food pass slowly through the stomach and what occurs if it doesn’t?
Need to give time for the SI to absorb, if not causes diarrhoea
Name the 4 aspects of GI motility:
Filling
Storage (body)- stomach
Mixing (antrum)- stomach
Emptying- (duodenum)
Describe the aspect of filling in GI motility:
Involves receptive relaxation (smooth muscle relaxed):
-Enhances stomach’s ability to accommodate the extra volume of food with little rise in stomach pressure
-Triggered by act of eating
-Mediated by vagus nerve
What factor in the stomach influences the strength of contraction for stomach emptying?
Amount of chyme in the stomach
What factors in the duodenum affect the amount of stomach emptying?
Fat
Acid
Hypertonicity
Distension
How does fat in the duodenum affect stomach emptying?
Fat digestion and absorption takes place only within small intestine
When fat is already in duodenum, further gastric emptying of additional fatty stomach contents is prevented
How does acid in the duodenum affect stomach emptying?
Un-neutralized acid in duodenum inhibits further emptying of acidic gastric contents until neutralisation can be accomplished
This is accomplished from bicarbonate from the pancreas to neutralise it
How does hypertonicity in the duodenum affect stomach emptying?
Gastric emptying is reflexly inhibited when osmolarity of duodenal contents starts to rise
How does distension in the duodenum affect stomach emptying?
Too much chyme in duodenum inhibits emptying of even more gastric contents
Is the stomach or duodenum more important in gastric emptying?
Duodenum
Which responses can occur in response to factors to gastric emptying?
Neural
Hormonal
Describe the neural response in gastric emptying:
Mediated through both intrinsic nerve plexuses (short reflex) and autonomic nerves (long reflex)
Collectively called enterogastric reflex
Describe the hormonal response in gastric emptying:
Involves release of hormones from duodenal mucosa collectively known as enterogastrones, inhibit gastric emptying
-Secretin (produced by S cells)
-Cholecystokinin (CCK, produced by I cells)
What is the function of intrinsic factor and where does it act?
Helps vit B12 absorption in the terminal ileum
What are additional factors which can influence gastric motility?
– Emotions
* Sadness and fear – tend to decrease motility
* Anger and aggression – tend to increase motility
– Intense pain – tends to inhibit motility
Name the 2 areas of the gastric mucosa that secrete gastric juice:
Oxyntic mucosa
-Lines body and fundus
Pyloric gland area (PGA)
-Lines the antrum
Name and describe the 3 types of gastric exocrine secretory cells:
Mucous cells:
-Line gastric pits and entrance of glands
-Secrete thin, watery mucus
Chief cells
-Secrete enzyme precursor, pepsinogen
Parietal (oxyntic) cells
-Secrete HCl and intrinsic factor
What stimuli promote mucous cells to secrete and what is the function of the secretion?
Mechanical stimulation by contents
Protects mucosa against mechanical, pepsin and acid injury
What stimuli promote chief cells to secrete and what is the function of the secretion?
Ach and gastrin
When activated, begins protein digestion
What stimuli promote parietal cells to secrete and what is the function of the secretion?
Ach, gastrin and histamine
Activates pepsinogen, breaks down connective tissue, denatures proteins, kills MO
What are the functions of HCl?
Activates pepsinogen to active enzyme pepsin and provides acid medium for optimal pepsin activity
Aids in breakdown of connective tissue and muscle fibres
Denatures protein by uncoiling
Along with salivary lysozyme, kills most of the microorganisms ingested with food
Describe the structure and function of the gastric mucosal barrier:
Enables stomach to contain acid without injuring itself:
-the luminal membrane of the gastric mucosal cells are impermeable to H+ so HCl can’t penetrate into cells
-cells are joined by tight junctions
-mucus coating over the gastric mucosa as a physical barrier
-bicarbonate ion rich mucus neutralises
Name and describe the other components of the gastric juice:
Pepsinogen:
-Stored in zymogen granules of chief cells
-HCl in stomach converts it to pepsin, which is autocatalytic
-Acts optimally in acid, breaking specific peptide bonds
Mucus:
-Protects mucosa against mechanical injury
-Protects stomach wall from digestion by pepsin
-Alkaline, neutralising HCl in vicinity of gastric lining
Intrinsic factor
What is the function of enterochromaffin- like cells (ECL) for regulation of gastric secretions by the endocrine system?
Produces histamine
Stimulated by Ach and gastrin
Which stimulates parietal cells
What is the function of G cells for regulation of gastric secretions by the endocrine system?
Produces gastrin
Stimulated by protein products and Ach
Which stimulates parietal, chief and ECL cells
What is the function of D cells for regulation of gastric secretions by the endocrine system?
Produces somatostatin
Stimulated by acid
Which inhibits parietal, G and ECL cells
Name the 3 phases of gastric secretion:
Cephalic
Gastric
Intestinal
Describe the cephalic phase:
Increased secretion of HCl and pepsinogen that occurs in response to stimuli acting in the head before food reaches stomach
Describe the gastric phase:
Begins when food actually reaches the stomach
Presence of protein increases gastric secretions Presence of caffeine or alcohol
Describe the intestinal phase:
Inhibitory phase - acid, fat, hypertonicity, distension
Helps shut off flow of gastric juices as chyme begins to empty into small intestine
Describe digestion in the stomach:
Carbohydrate digestion from salivary amylase continues in body of stomach as little mixing here
Protein digestion by pepsin begins in antrum as mixed with digestive juices in this region
Describe absorption in the stomach:
Alcohol – lipid-soluble, diffuses slowly through mucosa into blood
Aspirin and other weak acids – un-ionised, lipid-soluble so absorbed quickly
What is the exocrine function of the pancreas?
Secretes pancreatic juice containing:
-Pancreatic enzymes actively secreted by acinar cells that form the acini
-Aqueous alkaline solution actively secreted by duct cells that line pancreatic ducts -rich in NaHCO3 for neutralising HCl (pancreatic buffer)
What is exocrine secretion in the pancreatic glands regulated by?
Hormones (enterogastrones ) released by presence of chyme in the duodenum:
-Secretin stimulates NaHCO3 secretion from pancreatic duct cells
-CCK stimulates enzymes from acinar cells
Name the pancreatic enzymes and their function:
Proteolytic enzymes- digest protein
Pancreatic amylase- converts polysaccharides into the disaccharide amylase
Pancreatic lipase- only enzyme secreted throughout entire digestive system that can digest fat
Name 3 proteolytic enzymes released from the pancreas:
Trypsinogen - converted to active form trypsin by enterokinase
Chymotrypsinogen – converted to active form chymotrypsin
Procarboxypeptidase – converted to active form carboxypeptidase
Are the pancreatic enzymes active and why/not?
No as don’t want them to digest the duodenum, they are activated inside the duodenum
Name and describe the duodenal endocrine glands:
– Secretin, released by presence of HCl, stimulates
NaHCO3 secretion
– CCK, released by presence of fat and protein, stimulates pancreatic enzyme release
What is the blood supply like in the liver?
Hepatic artery
- Oxygen and metabolites
Hepatic portal vein
- absorbed nutrients from digestive tract
What are the functions of the liver not related to digestion?
– Metabolic processing of the carbohydrates, proteins and lipids after absorption
– Detoxifying or degrading body wastes and hormones, drugs, and other foreign compounds
– Synthesizes plasma proteins
– Stores glycogen, fats, iron, copper, and many
vitamins
– Activates vitamin D (along with kidneys)
– Removes bacteria and worn-out red blood cells
– Produces acute phase proteins and hormones, eg hepcidin, thrombopoietin and IGF-1
– Excretes cholesterol and bilirubin
Where is bile secreted from?
Actively secreted by liver (hepatocytes) and actively diverted to gallbladder between meals
Where is bile stored?
Gall bladder
What is the composition of bile?
Aqueous alkaline fluid containing:
* Bile salts
* Cholesterol
* Lecithin
* Bilirubin
Where does bile go after a meal?
It enters the duodenum
What is bilirubin?
A breakdown product from from RBCs when haem breaks down
Its an antioxidant
What are diseases of the gall bladder and what does this mean?
Gall stones, so can’t release bile, lipid malabsoprtion
What are the 3 segments of the small intestine?
Duodenum
Jejunum
Ileum
What is the motility like in the small intestine:
Segmentation
Migrating motility complex
What is the structure like in the SI to aid its function?
Big folds which have villi- finger like projections to increase SA
The the villi they have microvilli on epithelial cells which enzymes are produced at brush border to help with e.g protein digestion
What is segmentation in the SI?
– Primary method of motility in small intestine
– Consists of ringlike contractions along length of small intestine
– Within seconds, contracted segments relax and previously relaxed areas contract
– Action mixes and propels chyme throughout small intestine lumen
How does segmentation start in the SI?
– Initiated by pacemaker cells in small intestine which produce basic electrical rhythm (BER)
– Circular smooth muscle responsiveness is influenced by distension of intestine, gastrin, and extrinsic nerve activity
What is the migrating motility complex?
Peristalsis
Sweeps intestines clean between meals
Longitudinal muscle, few times a day, pushes all of chyme from SI to LI
What secretion occurs in the SI?
Juices secreted doesn’t contain any digestive enzymes
Synthesized enzymes act within brush-border membrane of epithelial cells
-Enterokinase
-Disaccharidases
-Aminopeptidases
What digestion occurs in the SI?
– Pancreatic enzymes continue carbohydrate and protein digestion
– Brush-border enzymes complete digestion of carbohydrates and protein
– Fat is digested entirely within small intestine lumen by pancreatic lipase
What absorption occurs in the SI?
– Absorbs almost everything presented to it – 9L/day – Most occurs in duodenum and jejunum
– Adaptations that increase small intestine’s surface area
– Lining is replaced about every three days
– Products of fat digestion undergo transformations that enable them to be passively absorbed
* Eventually enter lymph
How often is the lining of the LI replaced?
5-7 days
What glucose transporters are used to transport different monosaccharides?
SGLT- glucose and galactose (active)
GLUT5- fructose (passive)
GLUT 2- allows all to get into blood stream from epithelial cells
Describe fat digestion:
Large fat globules are emulsified by the detergent action of bile salts into a suspension of smaller fat droplets, increasing SA for pancreatic lipase
Lipase hydrolyse the TGC into MGC and fatty acids which are then resynthesised into TGC once into the epithelial cells
What is the large intestines main role?
Drying and storage organ
What does the large intestine consist of?
– Colon
– Cecum
– Appendix
– Rectum
What is the function of the colon?
Extracts more water and salt from contents
Feces, what remains will be eliminated
Describe a structure of the LI to be able to move chyme:
Taenia coli (longitudinal muscle)
Three strings of these made into haustra so can actively change location as result of contraction of circular smooth muscle layer so LI can move chyme
Name the 3 segments of the colon:
Ascending colon
Transverse colon
Descending colon
What are haustral contractions?
Initiated by autonomous rhythmicity of colonic smooth muscle cells
What is the gastrocolic reflex in the LI?
– Mediated from stomach to colon by gastrin and by
autonomic nerves
– Most evident after first meal of the day
– Often followed by urge to defecate
What is the defecation reflex in the LI?
– Initiated when stretch receptors in rectal wall are
stimulated by distension
– Causes internal anal sphincter to relax and rectum and sigmoid colon to contract more vigorously
– If external anal sphincter (skeletal muscle under voluntary control) is also relaxed, defecation occurs
Describe secretion in the LI:
Alkaline mucus- protects and lubricates
Describe digestion in the LI:
No digestion as no digestive enzymes
Colonic microflora (>500 species) digest cellulose to short chain fatty acids
Describe absorption in the LI:
Salt and water
Vitamin K synthesised by bacteria
Describe excretion in the LI:
Approx 2/3 water
Undigested cellulose, bilirubin, bacteria and salt
Explain the function of gastrin:
Release is stimulated by presence of protein in
stomach
Secretion inhibited by accumulation of acid in stomach
Functions:
-Acts in several ways to increase secretion of HCl and
pepsinogen
-Enhances gastric motility, stimulates ileal motility, relaxes ileocecal sphincter, induces mass movements in colon
-Helps maintain well-developed, functionally viable digestive tract lining
Explain the function of secretin:
Presence of acid in duodenum stimulates release
Functions:
-Inhibits gastric emptying in order to prevent further acid from entering duodenum until acid already present is neutralized
-Inhibits gastric secretion to reduce amount of acid being produced
-Stimulates pancreatic duct cells to produce large volume of aqueous NaHCO3 secretion
-Stimulates liver to secrete NaCO3 rich bile which assists in neutralization process
-Along with CCK, is trophic to exocrine pancreas
Explain the function of CCK:
-Inhibits gastric motility and secretion
-Stimulates pancreatic acinar cells to increase secretion of pancreatic enzymes
-Causes contraction of gallbladder and relaxation of sphincter of Oddi
-Along with secretin, is trophic to exocrine pancreas
-Implicated in long-term adaptive changes in proportion of pancreatic enzymes in response to prolonged diet changes
-Important regulator of food intake
What is GIP?
Glucose-dependent insulinotrophic peptide
– Stimulates insulin release by pancreas
– Stimulated by presence of glucose in digestive tract
Describe the MoA of bulk forming laxatives:
Polysaccharides increasing osmolality in gut when broken down, causing water retention
Retention of water in GIT, so expansion and softening of stool
Bulkier stools distend the colon
Promotion of peristalsis via stim colonic mucosal receptor/ stretch receptors
This leads to Ach release (increasing parasympathetic drive)
Ach activates muscarinic Ach receptors (mostly M2/M3) which increases peristalsis
Also creates mucus layer in intestinal lining, facilitating defecation
Describe the MoA of osmotic laxatives:
Poorly absorbed so act as osmotic agents and increase water retention in the gut lumen
As hyperosmolar agents, they are absorbed into stools by osmosis, making it softer so are easier to pass
Many osmotic laxatives also contain Mg2+, which triggers the release of CCK
CCK increases intestinal secretions and increases colonic motility and decreases transit time through gut
Describe the MoA of stimulant laxatives:
Stimulate local reflexes of myenteric nerve plexus of the gut
Irritate nerve ending of intestine wall
Motor effect on gut wall, increases propulsion of bowel
2º effect as also increases secretion of water to bowel
Increases gut motility and transit time
Describe the structure of senna:
Anthraquinone structure
Combine with sugars to form glycosides
Glycosides are molecules where the sugar is attached to a functional group via a glycosidic bond
Describe how Senna works:
The glycosidic bond is hydrolysed by colonic bacteria to release irritant anthracene glycoside derivatives, sennosides A and B
Absorbed and have direct action on myenteric nerve plexus, increase sm activity
Also postulate to PGE2 secretion (increase gut motility)
Also decrease in colonic water absorption
Describe the MoA of stools softeners:
Sometimes known as emollient laxatives
Some work as surface wetting agent/surfactant (e.g docusate)
Reduce surface tension of stool, allows water/ fats to penetrate stool
This softens the stool, making it easier to pass
Docusate also has some stimulant activity
Arachis oil and paraffin creates a barrier between stool and intestinal wall
This eases the passage of stool through intestine
Paraffin no longer popular due to concerns over carcinogenicity
Describe the PAMORAs MoA:
Are competitive antagonists at intestinal mu-opioid receptor
Prevent opioid activation of intestinal mu-opioid receptors
Targeting underlying opioid induced SEs i.e GI motility, hypertonicity, increase fluid absorption
This results in normal propulsion and peristalsis
Describe the MoA of prucaloprid:
5HT4 receptor agonist
5HT4 receptors are present in GIT, especially myenteric plexus
5HT4 activation leads to increase release of Ach
Increase parasympathetic drive (rest and digest)
This increases peristalsis and propulsion
Describe the MoA of loperamide:
Synthetic opioid analogue- pethidine congener which doesn’t readily pass the BBB- peripheral effects
Binds to mu-opioid receptors in gut wall
This inhibits Ach and PG release
Ach is the main excitatory neurotransmitter in the GIT
Ach binds to muscarininc/ nicotinic Ach receptors, increase parasympathetic activity
What is the pharmacological consequence of the MoA of loperamide?
Ach inhibition leads to:
-decreased propulsive peristalsis
-decreased sensitivity to rectal distension
-increases sphincter tone of the ileocaecal valve and anal sphincter
PG inhibition leads to:
-decreased gut secretions
-decreased gut motility (both mainly via inhibition of PGE2)
-increase in intestinal transit time (enhancing water and electrolyte reabsorption)
What is the ileocaceal valve and how can it be involved in diarrhoea?
At junction from SI to LI
Food is passed through this valve, limits the rate of food passage into the cecum and prevents digested material from LI back into SI
If we increase muscle tone of IV, this limits rate of food through, decreasing gut motility, so gives body increased opportunity to increase absorption of water and electrolytes and decrease symptoms of diarrhoea
What is the anal sphincter and how can it be involved in diarrhoea?
Ring of muscles right at the opening of the anus, keeps the anus closed as stool is collecting in the rectum, pressure eventually increases so that the sphincter relaxed
Increasing muscle tone of the sphincter stops it from becoming relaxed as much
What is the MoA of diphenoxylate in co-phenotrope?
Synthetic opioid- diethidine congener, doesn’t readily cross the BBB
Doesn’t usually have CNS activity, large doses lead to typical opioid effects
Insoluble salts mean that there is no potential for misuse by injectors
What is the MoA of atropine in co-phenotrope?
Muscarinic Ach receptor antagnoist
Decrease in Ach decreases parasympathetic drive
GI motility inhibited
Effect not marked as several excitatory transmitters, including Ach are important in the function
Describe the MoA of antispasmodics:
Exact mechanism not known for mebeverine
It specifically acts on sm cells
Blocks voltage operated Na channels
This prevents build up of intracellular Ca (decrease in contractility of SM)
This decreases symptoms of colonic hypermotility
Describe the MoA of linaclotide:
Guanylate cyclase- C (GC-C) agonist
GC-C activation leads to increase in production of cyclic guanosine monophosphate (cGMP)
Increase cGMP stimulates the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel
CFTR ion channel increases secretion of chloride and bicarbonate into the intestinal lumen
GI transit increases
What cells are involved in the normal gut pathophysiology?
Goblet cells
Paneth cells
M cells
Dendritic cells
Lamina propria
Non inflammatory defences
How are goblet cells involved in the gut?
In the epithelium (crypt) secreted a layer of mucus, limits exposure of microbes to epithelial cells (barrier)
How are Paneth cells involved in the gut?
Located at base of crypt near stem cells, secrete antimicrobial peptide e.g a defensins which limits bacteria coming through lamina propria
What antibody does the gut mass produce and why?
IgA- additional protections to microbes
How are M cells involved in the gut?
Can sample luminal antigens and pass it to underlying immune cells leading to tolerance (innate)
How are dendritic cells involved in the gut?
Can sample luminal antigens by passing dendrites through epithelium taking them up, can present antigen to naive CD4 T cell in 2º lymphoid organs i.e Payers patch, mesenteric lymph nodes which leads to a diffentiation of CD4 T cells into different types of T cells leading to systemic circulation then back into the lamina propria
Dendritic cells remain in a hyporesponsive and tolerogenic state
How is the lamina propria involved in the gut?
Diverse immune cells and cytokines i.e anti inflammatory mediators e.g TGF B, IL10 (these down reg IR)
Pro inflammatory mediators- limit excessive entry of intestinal microbiota and pathogens
How are the non inflammatory defences involved in the gut?
E.g phagocytosis
Homeostatic balance between T regs and T effector
What is the pathophysiology of the gut in IBD?
Disruption of mucus layer
Disregulation of epithelial tight junctions
Increase intestinal permeability
Increase bacterial adherence to epithelial cells
Innate cells produce increase levels of TNFa, IL6 and IL12
Pro-inflammatory cytokines- increase secretion and recruitment of leukocytes (major treatment area)
NK cells involved, more CD28
Dendritic cells activated when increased levels of toll like receptors IBD migrate to peripheral lymphoid tissue, generate antigen specific T cell responses (treatment area)
What type of immune and non immune cells does TNFa produce?
Immune cells- macrophages, dendritic cells
Non immune cells- fibroblasts, adipose
What does TNF activate?
Macrophages- cytokines that are pro inflammatory (IL1,IL6)
Epithelial cells- increase apoptosis of this, as helps keep luminal microbes at bay
Regulate T cell apoptosis
Causes death of paneth cells by necrosis- important for secretion against antimicrobial peptides
What would be the effects of blocking TNF?
Induce T cell and inflammatory cell apoptosis
Decrease inflammatory cytokine production
Decrease paneth cell necroptosis
Decrease epithelial cell apoptosis
Increase regulatory macrophages
Decrease MMP induced tissue destruction
What are the 2 forms of TNFa?
Membrane bound (mTNF)-cleaved by TNFa converting enzyme (TACE) into soluble form of TNF (sTNF)
What receptors does mTNF signal from?
Both TNFR1 and TNFR2 receptors
What receptors does sTNF signal from?
Signals more through TNFR1
Where is TNFR1expressed on?
Expressed on lymphocytes and endothelial cells
Where is TNFR2 expressed on?
Ubiquitously expressed
Describe TNFR1 activation:
Intracellular signalling cascade leads to apoptosis
Caspase 8 dependent signalling pathway via FADD
Or via cytokine secretion via NFkB
Describe TNFR2 activation:
Doesn’t have a death domain, results in cell proliferation, migration and cytokine production
Name the Anti TNF drugs used for IBD:
Infliximab
Adalimumab
Golimumab (UC only)
How does the antiTNF therapy work for IBD?
They are human mabs that bind to both soluble and transmembrane bioactive forms of human TNFa
This interaction prevents the binding of TNFa to its receptors therefore inhibiting biological activity of TNFa and decreasing intestinal inflammation
Describe the effectiveness for TNF therapy on both IBDs:
Effectiveness similar in both CD and UC
1/3 of patients don’t respond
50% of patients initially respond to treatment but then lose their response following continued treatment due to the production of anti-drug antibodies
Why would loss of effectiveness for anti TNF therapy be for?
Genetic background
Co-treatment
Disease status
How does Vedolizumab work?
Anti a4B7 antibody blocking homing of T cells to the inflamed gut
How are T cells involved in IBD?
Activated T cells migrate/or home to the gut tissues where they accumulate in large numbers, secrete inflammatory cytokines and result in an un-resolving chronic inflammation
How does T cell homing occur?
From the blood to the site of the inflammation in the gut required the interaction of 2 molecules, one on the surface of T cells and one on the surface of endothelial cells in the vessels
What T cells are involved and how do they emigrate and adhere to the gut from the BVs?
T reg, T helper and Th17 all express a common molecule (a4B7), a cell surface integrin
It is a gut specific adhesion molecule not found in any other sites/ organs in the body
The integrin specifically interacts with mucosal vascular dressin adhesion molecule (mAdCAM1) that is expressed on the endothelium
Once T cells are in the tissue (lamina propria), they are retained there as a4B7 bind there via E cadherin
Describe Sphingosine 1-phosphate signalling:
The S1P receptor controls aggression of immune cells from lymph nodes through a conc gradient of S1P
S1PR1 agonists stop lymphocytes sensing the S1P gradient and exiting lymph so decreasing lymphocytes
Name an S1P receptor antagonist and how does it work?
Ozanimod for UC
Immune cell trafficking, acts as a S1Pr antagonist preventing aggression of immune cells from lymph nodes to inflammatory tissues
Binds type 1 and 5 subtype of S1Pr
How does Ustekinumab work in IBD?
Targeting the p40 subunit of IL-12 and IL-23
Both IL involved in activating a cascade of inflammatory mediators responsible for the pathogenesis of IBD
Inhibition of IL, suppresses the Th1 and Th17 cell lineage of cytokines (NO, TNFa, INFg, IL-2) and chemokines (NO, IL6,17,22, INFg, TNFa) in IBD
Name the types if JAK inhibitors used in IBD and which JAK pathway do they inhibit?
Tofacitinib- JAK 1 and 3 inhibitors
Filgotinib- JAK 1 inhibitor
What type of IBD are JAKi used for?
UC
How do JAKi work?
They inhibit JAK-STAT signalling pathway
IL2/IL7 in JAK 1 or 3 signalling pathway and therefore inhibits STAT5 which leads to no pro-inflammatory effect
IL-10 on JAK 1 only
Describe the microbial diversity in IBD:
In IBD there is a decrease in microbial diversity
CD- decrease in firmicutes
UC- decrease in bacteroides and clostridium genera but increase in enterococcus
IBD patients have both altercations in their mucous layer and microbial dysbiosis
Name and describe a drug treatment for IBD that affects microbial diversity:
Fecal microbial transfer (FMT) and probiotic transfer
FMT involves transfer of a stool suspension obtained from a healthy patient into the GIT of a IBD patient, thus restoring essential components of the microbiota that could revert inflammation- limited evidence
What is phosphatidylcholine?
Essential protective component of colonic mucous
How do corticosteroids work for IBD?
Glucocoticoid receptor complex can inactivate pro-inflammatory transcription factors e.g NFkB and activator protein 1 (AP1), prevents them activating inflammatory mediators such as IL-6 and leukotrienes
They are also potent inhibitors of T cell activation and pro-inflammatory cytokines
How do glucocorticoids work to inhibit T cells and pro-inflammatory cytokines?
Passively transporting into cell and binding to intracellular glucocorticoid receptor, normally held in the cytoplasm as its bound to heat shock protein (HSP 90 and 70) complex and immunophilin FKBBP59
When glucocorticoid ligand binds to GRa receptor it becomes activated and leads to a homodimer of 2 activated GR into nucleus
Then inhibits promotor regions of genes e.g NFkB and AP1 which are potent TFs for many pro-inflammatory cytokines and adhesion genes
Glucocorticoids leads to induction of IkBa which binds to and inhibits NFkB by holding it into cytoplasm (so it can’t get into nucleus to be activated)
Why is azathioprine cytotoxic?
Due to the incorporation of 6-TGN into DNA
How does azathioprine work as a treatment for IBD?
Plays a role in T cell apoptosis by modulation of Rac1 activation upon CD28 co stim
Specific blockage of Rac 1 activation is achieved by azathioprine generated 6-Thio GTP that binds to Raf 1 (instead of normal GTP)
Normally the activation of Rac 1 target genes such as MEK, NFkB and bcl-xl, is suppressed by azathioprine, leading to mitochondrial pathway of apoptosis
Rac1 also activates STAT3- bcl-xl (antiapoptotic signal)
Inhibition of Rac1 activation stops this and therefore no apoptotic signal
How does sulfasalazine work in IBD?
Sulfasalazine is the azo-bond prodrug of 5-ASA and sulfapyridine
90% of sulfasalazine reaches colon where most of it is metabolised by anaerobic bacteria into sulfapyridine and mesalazine (both active)
How do 5-ASA’s work in IBD?
Have effects on PG synthesis/ COX pathway
This pathway (PGE2) is upregulated during inflammation, causes cell proliferation, cell survival as well as modulation immune cells, differentiation and gut epithelial stem cell function
5-ASA also affects the COX dependant pathway- reduces neutrophil chemotaxis to sites of inflammation and inhibit the survival of immune cells through NFkB signalling and inhibits TNF mediated effects on epithelial proliferation
How does mesalazine work in IBD?
Simular structure to aspirin, molecular targets are similar to other NSAIDs, inhibiting cell proliferation by decreasing COX and PG synthesis and suppressing pro-inflammatory cytokine production
What are the effects of 5-ASAs on ROM (reactive oxygen metabolites)?
Increase nº neutrophils and activated monocytes in IBD gut tissue, these cells are a source of ROM
ROM are produced during acute and chronic stage inflammation causing DNA and collateral tissue damage and oxidative products have been detected in the gut lumen of IBD
5-ASAs can scavenge free radicals during superoxide anion generation in neutrophils thus inhibiting damage
How does MTX work in IBD?
FH4 is essential for transformation from dUMP to dTMP
Needs DHFR to make FH4
T cell survival blocked, induced apoptosis, stop inflammatory cytokines and decrease leukocytes epithelial adhesion molecules
Describe the features of ciclosporin to be used in IBD:
Modulates pro-inflammatory cytokine production and T cell survival
Normally used in UC- can induce remission
Lipophilic cyclic peptide of 11 a.as
Immunosuppressive effects on cell mediated and humoral immune responses
How does ciclosporin work in IBD?
Interaction of antigen with TH cell receptor increases intracellular Ca2+
Stimulation of a phosphatase, calcineurin
Activation of various TF’s that initiate IL-2 expression
Inhibits translocation of NF-AT TFs and decreases transcription of cytokine genes for IL2, TNFa, IL3,IL4,CD30L,GMCSF and IFNg into nucleus
Decrease of IL2 cytokine synthesis (and IFN/IL3) causes decrease in clonal proliferation of T lymphocytes and decrease expression of IL2 receptors (gene expression)
Describe the MoA of cyclosporin:
Binds to cyclophillin, a cystolic protein member of the immunophillin family
CsA is a specific competitive inhibitor of calcuneurin, Ca and calmodulin dependent phosphotase
Calcineruin normally acts in opposition to many protein kinases involved in signal transduction
