GI Flashcards

Question

Oesophagus role?

Answer 1

Fairly straight muscular tube, extends between pharynx and stomach. Sphincters at each end; pharynogoesophageal sphincter Gastroesophageal sphincter Perstaltic waves push food through oesophagus Swallowing centre controls progressions of wave Secretions of mucus are entirely protective.

Answer 2

J shaped sac like chamber between esophagus and small intestine Stomach consists of 3 parts: Fundus, body and antrum. 3 main functions: 1-Stores ingested food until it can be emptied into small intestine. 2-Secretes HCl and enzymes that begin protein digestion. 3- Mixing movements convert pulverised food to chyme. Pyloric sphincter barrier between stomach and upper part of the small intestine. Pyloric gland area thicker muscle bigger peristaltic movement pushes food towards pyloric sphincter but it won’t allow chyme in unless it is ready

Answer 3

Filling, storage, mixing and emptying. 1-Filling: involves receptive relaxation, enhances stomach ability to accommodate the extra volume of food with little rise in stomach pressure. Triggered by act of eating and mediated by vagus nerve. 2-Storage: takes place in body of stomach. 3-mixing: takes place in the antrum of stomach 4-emptying largely controlled by factors in the duodenum.

Answer 4

1-Factors in the stomach: Amount of chyme in the stomach is main factor that influences strength of contraction 2-Factors in duodenum: Fat digestion and absorption takes place only within small intestine, when fat is already in duodenum, further gastric emptying of additional fatty stomach content id prevented. Acid: In-neutralised acid in duodenum inhibits further emptying of acidic gastric contents until neutralisation can be accomplished Hypertonicity: Gastric emptying is reflexly inhibited when similarity of duodenal contents start to rise. Distension: Too much chyme in duodenum inhibits emptying of even more gastric contents.

Answer 5

1-Neural response: Mediated through both intrinsic nerve plexuses short reflex and autonomic nerves long reflex. This is ENTEROGASTRIC Reflex. 2-Hormonal response: Involves release of hormones from duodenal mucosa. This is ENTROGASTRONES, inhibit gastric emptying. Secretin (produced by S cell) Cholecystokinin (CCK produced by I cells) Additional factors that influence gastric motility Emotions: Sadness fear tend to increase motility Anger and aggression tend to increase motility Intense pain tends to inhibit motility.

Answer 6

Two distinct areas of gastric mucosa that secrete gastric juices: Oxyntic mucosa: *Lines the body and fundus Pyloric gland area *Lines the antrum Gastric pits at base of gastric glands There are 3 types of gastric exocrine secretory cells 1-Mucus cells lines gastric pits and entrance of glands Secrete thin watery mucus 2-Chief cells secrete enzyme precursor pepsinogen 3-Parietal oxyntic cells Secrete HCl and intrinsic factor for vitB absorption in terminal ileum if we don’t have intrinsic factor we get anaemia.

Answer 7

Gastrointestinal secretions play a crucial role in the digestion and absorption of nutrients. Here are some key components involved in the process: 1. Oxyntic Mucosa: This is the lining of the gastric glands in the stomach. It contains various types of cells that secrete different substances. 2. Gastric Pit: These are small depressions in the surface of the stomach lining that lead to the gastric glands. They help in the secretion and release of gastric juices. 3. Stomach Lumen: This is the inside space of the stomach where food and gastric secretions mix together for digestion. 4. Surface Epithelial Cells: These cells line the surface of the stomach and secrete mucus, which forms a protective barrier against the acidic environment of the stomach. 5. Mucous Cells: These specialized cells in the stomach lining secrete mucus, which helps lubricate and protect the stomach lining from the acidic gastric juices. 6. Chief Cells: These cells secrete pepsinogen, an inactive form of the enzyme pepsin. Pepsinogen is activated by the acidic environment of the stomach and helps in the breakdown of proteins. 7. Parietal Cells: These cells secrete hydrochloric acid (HCl) and intrinsic factor. HCl helps in the digestion of proteins and activates pepsinogen to pepsin. Intrinsic factor is necessary for the absorption of vitamin B12. 8. Enterochromaffin Cells: These cells produce and release various hormones, such as serotonin, that regulate gastrointestinal functions. 9. G Cells: These cells secrete the hormone gastrin, which stimulates the secretion of gastric acid and promotes gastric motility. 10. D Cells: These cells secrete the hormone somatostatin, which inhibits the release of gastric acid and other gastrointestinal secretions. These various secretions work together to create an optimal environment for digestion and absorption of nutrients in the gastrointestinal system.

Answer 8

• Functions of HCI - Activates pepsinogen to active enzyme pepsin and provides acid medium for optimal pepsin activity - Aids in breakdown of connective tissue and muscle fibers - Denatures protein by uncoiling Chief cell - Along with salivary lysozyme, kills most of the microorganisms ingested with food

Answer 9

Enables stomach to contain acid without injuring itself. The components of the gastric mucosal barrier enable the stomach to contain acid without injuring itself: 1-The luminal membranes of the gastric mucosal cells are impermeable to H* so that HCI cannot penetrate into the cells. 2-The cells are joined by tight junctions that prevent HCI from penetrating between them. 3- A mucus coating over the gastric mucosa serves as a physical barrier to acid penetration. 3-The HCO3, rich mucus also serves as a chemical barrier that neutralizes acid in the vicinity of the mucosa. Even when luminal pH is 2, the mucus pH is 7.

Answer 10

Pepsinogen - Stored in zymogen granules of chief cells - HCI 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 HCI in vicinity of gastric lining • Intrinsic factor - Secreted by parietal cells - Essential for vit-B12 absorption, allows binding to receptor in terminal ileum and absorption by receptor-mediated endocytosis

Answer 11

Endocrine/Paracrine Cells 1-Enterochromaffin- like (ECL) cells Histamine ACh gastrin stimulates parietal cells 2-G cells Gastrin Protein products,ACh stimulates parietal chief cells and ECL cells. 3-D cells Somatostatin Acid inhibits parietal G and ECL cells

Answer 12

• Cephalic phase Increased secretion of HCl and pepsinogen that occurs in response to stimuli acting in the head before food reaches stomach • Gastric phase - Begins when food actually reaches the stomach - Presence of protein increases gastric secretions - Presence of caffeine or alcohol • Intestinal phase - Inhibitory phase - acid, fat, hypertonicity, distension - Helps shut off flow of gastric juices as chyme begins to empty into small intestine

Answer 13

Pancreas has an exocrine and endocrine function, it’s located behind and below the stomach. Endocrine function Islets of langerhans Found throughout pancreas Secrete insulin and glucagon Exocrine function Secreted pancreatic juices 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

Answer 14

Exocrine secretion is regulated by hormones (entrogastrones) released by presence of chyme in duodenum Secretin stimulates NaHCO3 secretion from pancreatic duct cells CCK stimulates enzymes from acinar cells Proteolytic enzymes Digest proteins Trypsinogen converted to active form trypsin by enterokinase Chymotrypsinogen converted to active form chymotrypsin Procarboxypepridase converted to active form carboxypeptidase Pancreatic amylase: Converts polysaccharides into disaccharides amylase Pancreatic lipase Only enzyme secreted throughout entire digestive system can digest fat.

Answer 15

Once acid gets into duodenal lumen it stimulates secretin release from duodenal mucosa. Secretin is carried by the blood to pancreatic duct cells, this stimulates secretion of aqueous NaHCO3 solution into duodenal lumen. This neutralise the acid. Fat and protein products in the duodenal lumen stimulate CCK release from duodenal mucosa, CCK is carried by blood to pancreatic acinar cells. This increases secretion of pancreatic digestive enzymes into duodenal lumen. This starts the digestion of fat and protein. Hormones control pancreas secretions Summary: • Gastric endocrine glands - Gastrin, released by protein presence and Ach from G cells, stimulates HI and pepsinogen - Somatostatin, released from D cells, inhibits HCI, pepsinogen and gastrin • Duodenal endocrine glands - Secretin, released by presence of HCI, stimulates NaHCO, secretion - CCK, released by presence of fat and protein, stimulates pancreatic enzyme release

Answer 16

Main role of liver is digestion of fats, largest metabolic organ in the body. Body’s major biochemical factory and liver is important to digestion as it secreted bile salts. Has two sources of blood hepatic artery brings oxygenated blood and nutrient and hepatic portal vein brings in nutrient from gut and hepatic vein takes away CO2 away from liver to be excreted. Liver functions 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 The liver plays a vital role in digestion by performing several important functions: 1. Bile Production: The liver produces bile, a greenish-yellow fluid that helps in the digestion and absorption of fats. Bile is stored in the gallbladder and released into the small intestine when needed. Bile contains bile salts that aid in the emulsification of fats, making them easier to break down by enzymes. 2. Detoxification: The liver is responsible for detoxifying harmful substances in the body, including drugs, alcohol, and metabolic waste products. It processes and eliminates these toxins, preventing them from entering the bloodstream and affecting other organs. 3. Nutrient Processing: The liver processes and metabolizes nutrients absorbed from the intestines. It converts carbohydrates, fats, and proteins into forms that can be used by the body for energy or for storage. The liver also stores certain vitamins and minerals, such as vitamins A, D, E, K, and B12, iron, and copper. 4. Protein Synthesis: The liver synthesizes various proteins essential for the body's functioning. It produces blood clotting factors, albumin (a protein that helps maintain osmotic balance), and many other proteins involved in immune function and hormone regulation. 5. Storage and Release of Glucose: The liver maintains blood glucose levels by storing excess glucose as glycogen and releasing it when needed. This helps regulate blood sugar levels, ensuring a steady supply of energy for the body. 6. Production of Cholesterol: The liver synthesizes cholesterol, an essential component of cell membranes and a precursor for the production of certain hormones and bile acids. 7. Metabolism of Drugs and Hormones: The liver metabolizes drugs and hormones, altering their chemical structure to make them more easily excreted by the body. This process helps regulate the levels of hormones in the bloodstream and eliminates drugs from the system. Overall, the liver plays a multifunctional role in digestion, nutrient processing, detoxification, and metabolism, making it an indispensable organ for maintaining the body's overall health and well-being.

Answer 17

Actively secreted by liver and actively diverted to gallbladder between meals - Stored & concentrated in gallbladder - Aqueous alkaline fluid containing. Involved in emulsification of fats • Bile salts • Cholesterol • Lecithin • Bilirubin is also antioxidants - After meal, bile from gallbladder enters duodenum Gall bladder diseases gall stone calcification of stones which prevents gall bladder from releasing bile causes severe acute pain which causes lipid malabsorption.

Answer 18

Derivatives of cholesterol Converts large fat globules into a lipid emulsion forms Micelle has hydrophobic core and hydrophilic shell helps in breaking fat down as this allows lipase to enter and break down fat. After participation in fat digestion and absorption most are reabsorbed into the blood.

Answer 19

It is the site where most digestion and absorption occurs Consists of 3 segments Duodenum Jejunum Ileum Motility includes two parts Segmentation Migrating motility complex Small intestine is 15ft long, the mesentery holds together in the GI abdominal cavity and mesentery keeps it apart as it is part of the serosa which secretes mucus fluid to keep it form sticking together and if intestine gets stuck we get issues like hernia and damage like blood clot ischemia. Structure increases surface area of intestine because the finger like projection folds the villi and microvilli on the epithelial cells of the surface of intestine. Segmentation: Primary method of motility in small intestine Consists of ring like contractions along length of small intestine Within seconds contracted segments relax and previously relaxed areas contract Action mixed and propels chyme throughout small intestine lumen till it reaches the ileum and large intestine.

Answer 20

Segmentation: is primary method of motility in small intestine Initiated by pacemaker cells in the small intestine which produces basic electrical rhythm BER Circular smooth muscle responsiveness is influenced by distension of intestine, gastrin and extrinsic nerve activity Functions: Mixing chyme with digestive juices secreted into the small intestine lumen Exposing all chyme to absorptive surfaces of small intestine mucosa Migrating motility complex Sweeps intestines clean between meals

Answer 21

Secretion juices secreted by small intestine doesn’t contain any digestive enzymes Synthesised enzymes act within brush border membrane of epithelial cells Enterokinase Disaccharidases Aminopeptidases Digestion: Pancreatic enzymes continue carbohydrates and protein digestion. Brush boarder enzymes complete digestion of carbohydrates and proteins. Fat is entirely digested within small intestine lumen by pancreatic lipase. Absorption: Absorbs almost everything presented to it 9L/day Most of the absorptions occur in the duodenum and Jejunum. Adaptions that increase small intestine surface area: inner surface has permanent circular folds Microscopic finger like projections called villi Brush broader microvilli arise from liminal surface of epithelial cells Lining is replaced about every three days wear and tear Products of fat digestion undergo transformations that enable them to be passively absorbed and eventually enter lymph

Answer 22

Dietary carbohydrates starch glycogen Broken down by salivary amylase and pancreatic amylase by disaccharidases maltase lactase and sucrase into glucose, the monosaccharides enter cell by passive facilitated diffusion via GLUT-5 then enters the blood by simple diffusion to where its needed in the body SLGT symporter absorb Glucose, galactose, and fructose into epithelial cell by Na+ and active transport. The monosaccharides fructose enters the cell by passive facilitated diffusion via GLUT-5 Glucose, galactose and fructose exist exist cell at the basal membrane by passive facilitated diffusion via GLUT-2 These monosaccharides enter the blood by simple diffusion

Answer 23

Fat is broken down in the duodenum and it is emulsified via bile salts that is released by gall bladder then pancreatic lipase can hydrolyse the fat micelle droplets into monoglycerides and free fatty acids. They get absorbed into epithelial cell and reaggregate to form triglycerides that aggregate and coated with lipoprotein to form chylomicrons that transport lipids around the body. These passively diffuse through lipid bolster of the liminal membranes.

Answer 24

Dietary protein is broken down by pepsin and pancreatic proteolytic enzymes into small peptides and amino acids. 1-Dietary and endogenous proteins are hydrolyzed into their constituent amino acids and a lew small peptide fragments by gastric pepsin and the pancreatic proteclytic enzymes 2-Many small peptides are converted into their respective amino acids by the aminoceptidases located in the brush borders of the small-intestine epithelial cells. 3-Amino acids are absorbed into the epithelial cells by means of Na and energy-dependent secondary active transport via a symporter Various amino acids are transported by carers specific for them 4-Some small peptides are absorbed by a different type of symportor driven by H*, Na*-, and energy-dependent tertiary active transport 5-Most absorbed small peptides are broken down into their amino acids by intracellular peptidases 6-Amino acids ext the call at the basal membrane via various passive carriers 7-Amino acids enter the bicod by simple diffusion. (A small percentage of di- and tripeptides also enter the blood intact)

Answer 25

Primarily a drying and storage organ Consists of colon, cecum, appendix, rectum Chyme from small intestine consists of indigestible food residues unabasorbed biliary components and remaining fluids. Colon: Extracts more water and salts from contents Feces what remains to be eliminated Large intestine has mucosa submucosa and circular muscle but it has three strings of longitudinal muscle called taeniae coli, can contract and relax the haustra. Haustra pouches or sacs, actively change location as result of contraction of circular smooth muscle layer. Haustral contractions Main motility, initiated by autonomous rhythmicity of colonic smooth muscle cells. Mass movements via large contraction that moves colonic contents into distal part of large intestine. Gastrocolic reflex: 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. Defecation reflex: Initiated when stretch receptors in rectal wall are stimulated by distension. This causes internal anal sphincter to relax abs rectum and sigmoid colon to contract more vigorously. If external anal sphincter (skeletal muscle under voluntary control is relaxed, defecations occurs.

Answer 26

Secretion: Alkaline mucus protects and lubricates helps feces movement Digestion: No digestion occurs as no digestive enzymes exist in the large intestine but large intestine has colonic micro flora >500 species that can digest cellulose to short fatty acids Absorption: Salt and water Vitamin K synthesised by bacteria Excretion: Approx 2/3 water Undigested cellulose, bilirubin, bacteria and salt.

Answer 27

Gut microbe has different roles: 1-modulation of bone mass density 2-protection against epithelial injury 3-resistance to pathogens 4-breaking down food compounds 5-modification of the nervous system 6-metabolism of therapeutics 7-biosynthesis of vitamins and amino acids 8-Development and training of the immune system 9-promotion if angiogenesis 10- promotion of fat storage

Answer 28

Gastrin release is stimulated by presence of proteins in the stomach. Secretion is inhibited by accumulation of acid in the stomach. Functions: Acts in several ways to increase secretion of HCl and pepsinogen Enhances gastric motility, stimulates ileal motility, relaxes ileocecal sphincter, induced mass movements in the colon. Helps maintain well-developed, functionally viable digestive tract lining.

Answer 29

Secretin release is stimulated by the presence of acid in the duodenum. Functions: Inhibits gastric emptying in order to prevent further acid from entering duodenum until acid is neutralised Inhibits gastric secretion to reduce amount of acid being produced. Stimulates pancreatic duct cells to produce large volumes of aqueous NaHCO3 secretion. Stimulates liver to secrete NaCO3 rich bile which assist in neutralisation process. Along with CCK, is trophic to exocrine pancreas

Answer 30

Functions Inhibits gastric motility and secretion Stimulates pancreatic acinar cells to increase secretion of pancreatic enzymes. CCK causes contractions of the gallbladder and relaxation of sphincter of Oddi Along with secretin is trophic to exocrine pancreas Implicates in long term adaptive changes in the proportion of pancreatic enzymes in response to prolonged diet changes Important regulator of food intake.

Answer 31

Glucose dependent insulin trophic peptide Stimulates insulin release by pancreas Stimulated by presences of glucose in the digestive tract. GIP is a hormone that stimulates the release of insulin by the pancreas. It is primarily stimulated by the presence of glucose in the digestive tract. GIP helps regulate blood sugar levels by promoting the release of insulin, which facilitates the uptake and utilization of glucose by cells in the body.

Answer 32

Epidemiology Pathophysiology Aetiology Treatment of common upper GI conditions Define gastro-oesophageal reflux disease, peptic ulcer disease, gastritis and functional dyspepsia Lost alarm symptoms requiring referral Provide appropriate pharmaceutical and non-pharmaceutical advice for the management of common dyspeptic diseases

Answer 33

Occur due to Acid overproduction, faults with protective mechanisms (sphincters), dyspepsia and acid in the wrong location in oesophagus or duodenum. Symptoms: gastric reflex, heart burn, dyspepsia, abdominal pain, nausea and vomiting, wind. Treatment: Prevent acid from relocating, reduce acid production or neutralise it or remove the main cause.

Answer 34

Gastric-oesophageal reflux disease GORD 10-20% Duodenal and stomach ulcer disease PUD 10-25% Gastritis 30% Functional dyspepsia 30% Oesophageal and gastric cancer 2% Upper gastrointestinal (GI) conditions occur in the upper part of the digestive system, which includes the esophagus, stomach, and the first part of the small intestine (duodenum). These conditions can occur due to various reasons, including: 1. Gastroesophageal Reflux Disease (GERD): This occurs when the muscle at the end of the esophagus does not close properly, allowing stomach acid to flow back into the esophagus. Common symptoms include heartburn, chest pain, and difficulty swallowing. 2. Peptic Ulcers: These are open sores that develop on the lining of the stomach or the first part of the small intestine. They are often caused by a bacterial infection (Helicobacter pylori) or the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Symptoms may include abdominal pain, bloating, and nausea. 3. Gastritis: This is inflammation of the stomach lining, which can be caused by infection, excessive alcohol consumption, prolonged use of NSAIDs, or certain autoimmune disorders. Symptoms may include stomach pain, nausea, vomiting, and loss of appetite. 4. Hiatal Hernia: This occurs when a part of the stomach pushes up through the diaphragm into the chest cavity. It can cause symptoms such as heartburn, chest pain, and difficulty swallowing. 5. Esophagitis: This is inflammation of the esophagus, often caused by GERD, infections, or certain medications. Symptoms may include difficulty swallowing, chest pain, and heartburn. 6. Barrett's Esophagus: This is a condition in which the lining of the esophagus changes, increasing the risk of developing esophageal cancer. It is often associated with long-term GERD. Part 2: Upper gastrointestinal (GI) conditions occur in the upper part of the digestive system, which includes the esophagus, stomach, and the first part of the small intestine (duodenum). These conditions can occur due to various reasons, including: 1. Gastroesophageal Reflux Disease (GERD): This occurs when the muscle at the end of the esophagus does not close properly, allowing stomach acid to flow back into the esophagus. Common symptoms include heartburn, chest pain, and difficulty swallowing. 2. Peptic Ulcers: These are open sores that develop on the lining of the stomach or the first part of the small intestine. They are often caused by a bacterial infection (Helicobacter pylori) or the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Symptoms may include abdominal pain, bloating, and nausea. 3. Gastritis: This is inflammation of the stomach lining, which can be caused by infection, excessive alcohol consumption, prolonged use of NSAIDs, or certain autoimmune disorders. Symptoms may include stomach pain, nausea, vomiting, and loss of appetite. 4. Hiatal Hernia: This occurs when a part of the stomach pushes up through the diaphragm into the chest cavity. It can cause symptoms such as heartburn, chest pain, and difficulty swallowing. 5. Esophagitis: This is inflammation of the esophagus, often caused by GERD, infections, or certain medications. Symptoms may include difficulty swallowing, chest pain, and heartburn. 6. Barrett's Esophagus: This is a condition in which the lining of the esophagus changes, increasing the risk of developing esophageal cancer. It is often associated with long-term GERD.

Answer 35

Prevalence varies from 20-40%, quarter of these patients have peptic ulcer disease Majority of patients self medicate 90% self treat 9% see GP 1% see consultant Common community pharmacy problem Many patients self select treatment but this could mask potential serious conditions. Pharmacist plays key role in offering support and advice to patients: Life style changes Use of correct OTC meds Review prescribed medications Advice on referral and when should patient see a doctor Record adverse side effects of medication this is important due to risk of gastric cancer.

Answer 36

54% of cases are preventable If cancer is diagnosed within 1yr patient will have 42% survival rate in comparison to late diagnosis of 5yrs which means survival rate will only be 19% 7 in 10 cases at late stage Age and sex risk factor for gastric cancer Mid age 40-over 55 if patients comes for the first time with dyspepsia it is an alarm symptom so refer to GP Males at higher risk than females More common in smokers and drinkers Related to H.pylori infection 32% Slat intake Less common in vegetarians

Answer 37

Gastric stomach secretions Pepsinogen from chief cells: Breakdown proteins Hydrochloric acid from parietal cells Activate pepsinogen+ kills bacteria Intrinsic factor from parietal cells Acid absorption of vitamin B12

Answer 38

Acid secretions via parietal cells is controlled by: Nervous control: Cephalic phase, parasympathetic via thoughts smell taste or sight of food Local: Gastric phase parasympathetic Distension of stomach and chemical make up Hormonal: intestinal phase Food in the duodenum chyme causes secretion of somatostatin which inhibits acid production Basal phase occurs in times between the meals inter-digestive phase level of acid secreted is regulated by body weight, number of parietal cells genetic factor circadian rhythm. Secretion of H+ from parietal cells is stimulated by histamine, gastrin and acetylcholine ACh Gastrin is produced in response to vagal stimuli, rise in pH and ingested protein and calcium Stimulates growth of gastric mucosa Within parietal cell H+ is produced via the proton pump, exchanges H+ with K+ in the gastric lumen. AI: The production of acid in parietal cells of the stomach involves a complex biochemical and physiological process. Here is an overview of the steps involved: 1. Stimulation: Acid production in parietal cells is stimulated by various factors, including the release of the hormone gastrin, which is triggered by the presence of food in the stomach. Gastrin binds to specific receptors on the surface of parietal cells, activating a signaling cascade that leads to acid production. 2. Carbon Dioxide and Water Formation: Inside the parietal cell, carbon dioxide (CO2) and water (H2O) combine to form carbonic acid (H2CO3) with the help of an enzyme called carbonic anhydrase. This reaction occurs in the cytoplasm of the parietal cell. 3. Proton Pump Activation: Carbonic acid in the cytoplasm dissociates into bicarbonate ions (HCO3-) and hydrogen ions (H+). The bicarbonate ions are transported out of the cell in exchange for chloride ions (Cl-), which enter the cell. This exchange is facilitated by a protein called the chloride-bicarbonate exchanger. 4. Acid Secretion: The hydrogen ions (H+) generated within the parietal cell are actively transported across the membrane into the stomach lumen by an ATP-dependent proton pump called the H+/K+ ATPase. This pump exchanges the hydrogen ions with potassium ions (K+), which are taken up from the lumen into the parietal cell. 5. Acidification of the Stomach Lumen: The hydrogen ions that are pumped into the stomach lumen combine with chloride ions (Cl-) that passively diffuse into the lumen from the parietal cell. This combination forms hydrochloric acid (HCl), which is the main component of stomach acid. The overall process of acid production in parietal cells is tightly regulated to maintain the appropriate pH in the stomach for efficient digestion. Various factors, including hormones, neurotransmitters, and other signaling molecules, can influence this process. Disruptions in acid production can lead to conditions such as gastric ulcers, gastritis, or gastroesophageal reflux disease (GERD).

Answer 39

Acetylcholine act in M3 Histamine acts on H2 Gastrin acts on G cells ATP is converted to cAMP via Ca2+ ions to form Acid secretion can be decreased pharmacologically by blocking these receptors or blocking intracellular cAMP or blocking the proton pump inhibitor Parietal cells are a type of stomach cell found in the gastric glands. They have a distinctive structure that includes an extensive network of tubulovesicles and mitochondria. This structure allows parietal cells to perform their specialized function of acid production. The chemical reaction involved in H+ production within parietal cells is as follows: CO2 + H2O → H2CO3 → H+ + HCO3- Here's how the reaction proceeds: 1. Carbon dioxide (CO2) and water (H2O) combine in the cytoplasm of the parietal cell with the help of an enzyme called carbonic anhydrase. 2. This combination forms carbonic acid (H2CO3). 3. Carbonic acid then dissociates, releasing a hydrogen ion (H+) and a bicarbonate ion (HCO3-). To pharmacologically inhibit acid secretion and decrease H+ production, several approaches can be used: 1. Blocking Receptors: Certain medications, such as proton pump inhibitors (PPIs), histamine H2 receptor antagonists, or muscarinic receptor antagonists, can be used to block specific receptors on parietal cells. These receptors are involved in stimulating acid secretion, and blocking them can reduce acid production. 2. Inhibiting Intracellular cAMP: Cyclic adenosine monophosphate (cAMP) is a signaling molecule involved in the activation of acid secretion. Medications that inhibit cAMP production or its downstream signaling pathways can help decrease acid production. 3. Proton Pump Inhibitors (PPIs): PPIs are a commonly used class of drugs that directly target the proton pump (H+/K+ ATPase) in parietal cells. By irreversibly inhibiting this pump, PPIs can significantly reduce acid secretion and provide long-lasting acid suppression.

Answer 40

Parietal cells produce acid and directly stimulated by: Vagus nerve-Acetylcholine M3 receptors, due to though sight or smell Gastrin G receptors Due to content of stomach Histamine H2 receptors Stimulation of ECL cells by gastrin and vagus nerve Somatostatin prostaglandin Negative feedback due to content of duodenum

Answer 41

Auto-digestion of the stomach is prevented by a thin layer above the mucosa surface Complex matrix of bicarbonate and mucus pH7 unstirred layer. H+ taken away by sub-mucosal blood flow. Low blood pressure or low blood perfusion causes a Decrease in blood flow lead to necrosis of mucosa by increase if of H+ conc and decrease in O2 Stress ulcer in shocked or critically ill patients Prostaglandins COX-1 e.g. Somatostatin Increase mucus secretion, bicarbonates, blood flow, and decrease acid. NSAIDs especially COX-1 interfere with prostaglandin synthesis. Patient need protective drugs like PPI if they are on long term use of NSAIDs Oesophageal protection by lower oesophageal sphincter LOS permanent state of tonic contraction except when relaxed to allow passage of food.

Answer 42

Extremely prevalent amongst population and can be asymptomatic and symptoms can manifest as dyspepsia Gastritis precedes ulceration Gastritis inflammatory response of GI mucosa to H. pylori this leads to chronic gastritis and PUD which can develop into Gastric cancer Gastritis 40x increase risk of PUD and 6x at increased risk of gastric cancer

Answer 43

1-H.pylori protects themselves by hydrolysing urea to produce ammonia and this effectively buffers H+ ions. 2-Colonisation beneath the mucus layer in the antrum leads to chronic inflammation and decrease in somatostatin and increase in gastrin production which leads to increased acid production. 3- Increase in stomach acid production leads to chronic inflammation in the duodenum. H.Pylori moves into duodenum and reduces local protection which leads to duodenal ulcer. H.Pylori causes gastritis throughout stomach and this causes cell damage and decrease in acid production and decrease in mucosa which long term lead to gastric ulcer and gastric cancer. 50% of population over 60yrs old are infected, almost all over 80 Some strains more pathogenic than others

Answer 44

Identified breath test or stool antigen test: *given radio labelled urea and CO2 produced in breath *Stools need to be stored at -20C before testing stool. With these tests patient must avoid antibiotics 4 weeks before test to avoid false negative results. Blood test available but has poor sensitivity. Endoscopy is not recommended for H.Pylori testing In the UK, several clinical tests are commonly used to detect H. pylori infection. Here are three main types of tests: 1. Helicobacter pylori stool antigen (HpSA) test: This test detects the presence of H. pylori antigens in a stool sample. It is a non-invasive and reliable method, especially for monitoring treatment response. The sample can be collected at home and sent to a laboratory for analysis. 2. Helicobacter pylori breath test: This test measures the presence of H. pylori by analyzing the breath for the presence of specific gases produced by the bacteria. The patient consumes a special substance, usually urea, which is metabolized by H. pylori if present. Breath samples are collected at specific intervals and analyzed to determine the presence of H. pylori. 3. Helicobacter pylori blood test: This test detects the presence of antibodies against H. pylori in the blood. It is a serological test that can determine if a person has been exposed to H. pylori in the past or currently has an active infection. However, it cannot distinguish between a current or past infection, so it may not be the best method for monitoring treatment response. *Duodenal ulcer >90% H.Pylori infection Stomach gastric Ulcer 70-80% H.pylori infection. Eradication of infection improves healing rates and reduces relapse rates >50% to >10% in 3 years Eradication is a cure for H.pylori associated ulcers

Answer 45

10-15% of the population will suffer from peptic ulcer disease Gastric ulcers GU rare in under 40 Duodenal ulcers predominantly males between 20-50 *That is why it is important to ask patients for their age to determine the type of ulcer they have. Factors: gastric hyper-secretion genetic factor mainly Reduced mucosal resistance-occurs mainly in smokers as smoking reduces mucosal protective secretion DU- higher than average acid output GU- lower mucosal resistance Patients can be healed but not cured by suppression of acid secretion AI: Peptic ulcer disease (PUD) is a condition characterized by the formation of open sores, known as ulcers, in the lining of the stomach, upper small intestine, or esophagus. Peptic ulcers can occur when the protective lining of these areas is damaged, allowing stomach acid and digestive juices to irritate the underlying tissues. The primary cause of peptic ulcer disease is an infection with the bacterium Helicobacter pylori (H. pylori). This bacterium is estimated to be responsible for about 80% of peptic ulcers. Other factors that can contribute to the development of peptic ulcers include long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or aspirin, excessive alcohol consumption, smoking, and stress. The most common symptom of peptic ulcer disease is abdominal pain. The pain is usually described as a burning or gnawing sensation and may occur in the upper abdomen, often between meals or during the night. Other symptoms can include bloating, belching, nausea, vomiting, weight loss, and loss of appetite. Complications of peptic ulcer disease can include bleeding, perforation (when the ulcer creates a hole in the wall of the stomach or intestine), and obstruction (when the ulcer blocks the passage of food through the digestive system). These complications can be serious and require immediate medical attention. The diagnosis of peptic ulcer disease is typically made through a combination of medical history, physical examination, and diagnostic tests. These tests may include an upper gastrointestinal endoscopy, which allows the doctor to visualize the ulcer and take a tissue sample for biopsy, as well as tests to detect the presence of H. pylori infection. Treatment for peptic ulcer disease usually involves a combination of medications to reduce stomach acid production, eradicate H. pylori infection (if present), and protect the lining of the stomach and intestines. Lifestyle modifications, such as avoiding NSAIDs, reducing stress, and avoiding alcohol and smoking, may also be recommended. With appropriate treatment and lifestyle changes, most peptic ulcers heal within a few weeks to a couple of months. However, it's important to follow the prescribed treatment plan and attend regular follow-up appointments to monitor the progress and ensure complete healing.

Answer 46

Bleeding occurs in 10-15% of all PUD patients 5-10% of patients with duodenal ulcers will perforate. 1 in 7 of these will die. 5-10% of gastric ulcers eventually found to be malignant 60% of patients with PUD relapse after 1 year 50% of patients with GU relapse after 2 years

Answer 47

H.pylori major cause of PUD NSAIDS common cause of PUD More common in smokers Increase number of cigarettes in a day increases PUD prevalence Rate of healing slower in smokers and relapse is twice as common Genetic link with people with parents with PUD 3x more likely Stress related to PUD? No strong evidence

Answer 48

NSAIDs risk increased further if patient is elderly, has history of peptic ulcer disease or is a smoker. Sulfasalazine Iron preparations Corticosteroids Potassium particularly modified releases Bisphosphonates SSRI Some antibiotics These drugs predispose patients to PUD *Theophylline *Calcium antagonists *Nitrates These three drugs lower oesophageal sphincter pressure therefore predispose patients to GORD.

Answer 49

1/3 of patients with rheumatoid arthritis suffer with PUD *ibuprofen safest NSAID Even patients on 162.5mg aspirin a day get an increase risk of 1.5% NSAIDs inhibit prostaglandin synthesis via COX pathway COX-1 house keeping enzyme pathway protective prostaglandin eg GI mucosa COX-2 inflammatory prostaglandins Safer NSAIDs less inhibitory effect on COX-1 Celecoxib very little COX-1 activity

Answer 50

1-Gastric: Pain on eating Epigastric pain 2-Duodenal Localised pain occurring between meals and at night Relieved by eating (fatty food may aggravate) Other symptoms for both: *Bloating, nausea, anorexia, belching. *Haematemesis and melaena present if bleeding occurs.

Answer 51

1-Gastritis inflammation of stomach lining caused mainly by H..Pylori 2-Gastric ulcer occur in stomach prolonged exposure to H.Pylori causes inflammation, gastric atrophy predisposes to this but also NSAIDs and their effects on reducing gastric cytoprotection implicated. Stomach Prolonged exposure to H.pylori causing inflammation and gastric atrophy NSAIDs 3-Duodenal Duodenum post stomach Caused by genetic predisposition caused by Excessive acid secretion from stomach due to host factors h.pylori Treatment?

Answer 52

5-10% of western world adults have symptomatic reflux. Caused by gastric juice and occasionally duodenal contents in oesophagus Defective lower oesophageal sphincter may be most important abnormality that causes GORD Factors lowering pressure if the LOS: Dietary factors Fat Chocolate Caffeine Alcohol Cigarettes Endocrine factors: High level of oestrogen and progesterone Pregnancy HRT COC contraceptives Drugs SSRI NSAIDs AI: Gastroesophageal reflux disease (GORD), also known as GERD (gastroesophageal reflux disease), is a chronic condition characterized by the reflux of gastric juice, and sometimes duodenal contents, into the esophagus. It is estimated that 5-10% of adults in the Western world experience symptomatic reflux associated with GORD. The lower esophageal sphincter (LOS) is a muscular ring that acts as a barrier between the stomach and the esophagus. In individuals with GORD, the LOS is often defective and does not close properly, allowing the acidic stomach contents to flow back up into the esophagus. This can lead to symptoms such as heartburn, regurgitation, chest pain, and difficulty swallowing. There are several factors that can contribute to a decrease in the pressure of the lower esophageal sphincter, making it more likely for reflux to occur. These factors include: 1. Dietary factors: Certain foods can relax the LES and increase the risk of reflux. Examples include fatty foods, chocolate, caffeine (found in coffee, tea, and some sodas), alcohol, and cigarettes. 2. Endocrine factors: Hormonal changes can affect the function of the LES. High levels of estrogen and progesterone, which can occur during pregnancy or when using hormone replacement therapy (HRT) or combined oral contraceptive (COC) pills, may contribute to the development or worsening of GORD symptoms. 3. Drugs: Certain medications can weaken the LES or increase acid production, making reflux more likely. Examples include selective serotonin reuptake inhibitors (SSRIs) and nonsteroidal anti-inflammatory drugs (NSAIDs). The diagnosis of GORD is usually based on the presence of typical symptoms and response to treatment. However, in some cases, further diagnostic tests such as an upper gastrointestinal endoscopy or a pH monitoring test may be performed to assess the severity of the condition or rule out other possible causes. Treatment for GORD aims to relieve symptoms, heal any esophageal damage, and prevent complications. Lifestyle modifications such as avoiding trigger foods, losing weight if overweight, elevating the head of the bed, and quitting smoking may be recommended. Medications such as antacids, H2 receptor antagonists, proton pump inhibitors (PPIs), and prokinetics may also be prescribed to reduce acid production, improve LES function, or promote faster emptying of the stomach. In some cases, surgery may be considered if lifestyle modifications and medications do not provide sufficient relief. Surgical options for GORD include fundoplication, in which the upper part of the stomach is wrapped around the LES to strengthen it, and magnetic sphincter augmentation, where a magnetic device is implanted around the LES to help prevent reflux.

Answer 53

Hiatus hernia occurs when part of the stomach is pushed up through the diaphragm due to weakness in the diaphragm wall or muscles and this prevents the LOS from closing properly allowing stomach content to escape into the oesophagus Hiatus Hernia very prevalent 30-50% of population Majority of patients asymptomatic May present as GORD

Answer 54

It is important to investigate medication use when exploring symptoms of patients because many drugs lower the LOS pressure and this includes: 1-Anti-cholinergic 2-Beta-2 agonists 3-Calcium channel blockers 4-Diazepam 5-Nitrates 6-Alcohol 7-Progesterone 8-Oral contraceptives 9-Theophylline

Answer 55

Drugs which can cause oesophageal ulcerations: 1-NSAIDs 2-Bisphosphonates 3-Clindamycin 4-Clotrimoxazole 5-Doxycycline 6-Potassium 7-Theophylline 8-Tetracycline Antibiotics responsible for 50% of drug induced oesophagitis (especially Clindamycin in capsule form)

Answer 56

In diagnosed patients, Motility of oesophagus may be abnormal in patients with GORD. Gastric emptying delayed in 40% of patients with GORD Main symptoms is heartburn dyspepsia. May also suffer dysphagia or odynophagia (pain on swallowing) Complications include Barrett’s oesophagus, haemorrhage, stricture. Barrett’s is a risk factor cancer., this is when lining of the oesophagus change so it resembles that of intestine. Endoscopy only method of diagnosis.

Answer 57

Half of patients with chronic dyspepsia no evidence of organic disease Could be due to hypersensitivity to gastric acid? Four groups: Ulcer like Dysmotility like Reflux like Non-specific symptoms Psychological factors stress anxiety Eradicate H.Pylori if present Neutralise acid or prevent acid production (symptomatic relief) Periodic monitoring safety netting as NUD can be precursor for more or a serious condition.

Answer 58

Heart burn= pain immediately with or after food if no organic disease means it is functional dyspepsia but upon investigation if diagnosis proves GORD then treatment is needed not just OTC Epigastric pain check if pain is immediately with or after food could be functional dyspepsia but if diagnostic tests shows it’s gastritis or gastric ulcer Epigastric pain if pain is between meals or at night or pain relieved by eating it could be functional dyspepsia so no organic disease but if diagnostic test shows it is gastritis or duodenal ulcer. AI: Non-ulcer dyspepsia (NUD) and functional dyspepsia are terms used to describe a condition characterized by recurring or chronic upper abdominal pain or discomfort without evidence of an underlying structural or organic cause. Gastroesophageal reflux disease (GERD) is a separate condition that involves the reflux of gastric acid into the esophagus. While there may be some overlap in symptoms, there are differences between these conditions: 1. Symptoms: - NUD/Functional dyspepsia: The main symptom is upper abdominal pain or discomfort that is not related to specific meal times and may be described as a burning, gnawing, or aching sensation. Other symptoms may include bloating, early satiety (feeling full soon after starting a meal), and nausea. - GERD: The main symptom is heartburn, which is a burning sensation in the chest that may radiate to the throat. Regurgitation, the sensation of acid coming up into the throat or mouth, is also common. 2. Pathophysiology: - NUD/Functional dyspepsia: The exact cause is not well understood, but it is believed to involve abnormalities in the way the gastrointestinal tract functions and processes sensory information. Factors such as altered gastric motility, abnormal sensitivity to stomach acid, and psychological factors may play a role. - GERD: It is primarily caused by the reflux of stomach acid into the esophagus due to a weakened lower esophageal sphincter (LES) or increased pressure in the stomach. This can occur due to factors such as obesity, pregnancy, hiatal hernia, and certain medications. 3. Acid-related findings: - NUD/Functional dyspepsia: There is no evidence of significant acid-related findings on diagnostic tests such as endoscopy or pH monitoring. - GERD: Diagnostic tests may show evidence of esophageal inflammation, erosions, or strictures caused by the exposure to stomach acid. 4. Treatment: - NUD/Functional dyspepsia: Treatment focuses on managing symptoms and may include lifestyle modifications (e.g., dietary changes, stress reduction), medications to reduce acid production or relieve symptoms (e.g., antacids, H2 receptor antagonists), and psychological interventions if stress or anxiety is contributing to the symptoms. - GERD: Treatment aims to reduce acid reflux and relieve symptoms. Lifestyle modifications (e.g., dietary changes, weight loss, elevating the head of the bed), medications to reduce acid production (e.g., proton pump inhibitors, H2 receptor antagonists), and in some cases, surgical interventions may be recommended. It's important to note that these conditions can coexist in some individuals, and the symptoms can overlap. A thorough evaluation by a healthcare professional is necessary to differentiate between NUD/Functional dyspepsia and GERD and to develop an appropriate treatment plan.

Answer 59

Stomach, peptic & duodenal ulcer First of all identify organic cause of disease and treat it accordingly Step-1 Identify and eradicate H.pylori 7 day triple therapy to treat H.Pylori PPI and two antibiotic’s amoxicillin and erythromycin. Step-2 Stop inappropriate therapy like NSAIDs if use of NSAIDs is a must then ensure patient is on PPI for gastric protection Step-3 Reduce acid production to reduce gastritis and enable mucosa to repair Use drugs that will either block H2 or Proton Pump Offer PPI or H2 for 8 weeks and once ulcer is healed test for H.Pylori and if H.Pylori is present then offer eradication therapy as well. If we find patient doesn’t use NSAIDs or any other inappropriate medication and no presence of H.Pylori, then PPI or H2 will be prescribed for 4-8weeks Sometimes patient ulcer won’t be healed even after taking the appropriate treatment steps This could be due to their adherence as it is triple therapy, ahve they completed course, have they taken their medication appropriately, have they been able to stop the NSAIDs or are they taking NSAIDs over the counter or do they have crowns disease or malignancies. If patient heals and symptoms reoccurs a low dose PPI should be given to control symptoms

Answer 60

Remove causative agent Anything which lowers the LOS pressure Non-pharmacological advice Use rafting product like gaviscon Reduce acid production to enable recovery of oesophageal mucosa

Answer 61

Diet: Eat small meals Avoid food which lowers the LOS pressure like caffeine chocolate alcohol Avoid fatty foods- slow gastric motility Avoid eating within 4hrs and drinking within 2hrs of going to bed Avoid drugs which lower the LOS pressure Avoid tight fitting clothes Lose weight Attention to posture Avoid bending from the waist Don’t lie down after eating increases exposure of food to oesophageal lining Nocturnal heartburn symptoms raise the head of the bed 15-23com Stop smoking Reduce alcohol intake

Answer 62

We can manage the initial presentation of these symptoms OTC if there are no alarm signs and symptoms present. Symptomatic Neutralise acid Reduce flatulence Prevent dislocation of acid All treatment available over the counter

Answer 63

Aluminium, Magnesium, Sodium & Calcium salts. *Neutralise acid by combining with HCl, this gives relief and CO2 is released called Eructation *Eructation *Increase LOS pressure- by gastric alkalisation *Mucosal protection via stimulation of prostaglandin synthesis What affect do the two factors above have on gastric-release? its increased in response to increased pH after taking antacid, this results in an acid rebound. Although frequent high doses of these medications promote ulcer healing but they are only limited for short term use. Drug form tablets and liquid break tablet or chew better Liquids works quicker and have greater neutralising ability due to their smaller particle size but is shorter acting. Best to use after 1 hour of meal when gastric emptying is slow so they remain the stomach for longer and they act up to 3hrs in comparison to 30mins before meal Rapid relief of symptoms of heart burn and indigestion As per NICE guidance Avoid long term, frequent, continuous use: Only relieves symptoms in the short term, rather than prevention. Rennies/settlers /tums.

Answer 64

Side effects include constipation with aluminium based salts and diarrhoea with magnesium based salts? These effects can be useful if patient has diarrhoea or constipation as these products can help or products can be used in combination to counteract s/e. *Aluminium binds phosphate in the gut~~> osteoporosis *Aluminium may be absorbed ~~~> neurotoxicity Rebound gastric acid secretion with prolonged use Sodium avoided in patients with hypertension and cardiac problems, use BNF to check for relative sodium content of indigestion products and avoid sodium products in patients with hypertension or cardiac issues. Important drug interactions to consider, this is related to enteric coating of medications we can lose that protective effect of enteric coating and drug can be destroyed by stomach content so a lot of medication is not to be taken with indigestion products. Reduced absorption we get binding with tetracycline and iron based tablets. Generally safe in pregnancy but be mindful of sodium content as it can cause fluid retention. Low dose or no sodium product as heart burn indigestion is common in pregnancy,

Answer 65

Alginates formulated with antacid Forms a high pH viscid is mass (Raft), trapping air bubbles and CO2 from the reaction of antacid with the stomach contents. Floats to top of the stomach and protects oesophageal mucosa form the stomach contents Dimeticone or Simeticone: This is an anti-foaming agent Reduces surface tension of intragastric air bubble. Allows bubbles to escape- reduce bloating feeling.

Answer 66

Cimetidine Famotidine Nizatidine Ranitidine H2 receptor antagonists have longer duration of action than antacids. Competes for H2 receptor on parietal cells, H2 receptor antagonists effect is overridden by powerful stimulus such as large meal as this reverse block on H2 receptor. PUD: High healing rates, no reduction in relapse (has H.pylori been eradicated? As replaces suggests there is another underlying cause) GORD After 12 weeks 80-90% of patients with mild oesophagitis improved Not effective in moderate to severe GORD.

Answer 67

1-7% of patients suffer from ADR: *only headache and dizziness> placebo *Cimetidine- gynaecomastia 0.2% impaired libido *Nizatidine- swearing, abnormal dreams *Confusional states in elderly with H2 antagonist use Interactions Cimetidine binds to P450 cytochrome P450 inhibitor increases drug effect. Phenytoin, carbamazepine, theophylline, warfarin.

Answer 68

Symptomatic relief of heartburn, dyspepsia & hyperacidity. 6-days continuous treatment maximum Maximum dose of 2 tablets in 24 in comparison to prescription only dose of 150mg BD or 300mg ON patient should only use it for 6days only. Sub-therapeutic dosages Patients use them prophylactically.

Answer 69

1-Omeprazole 2-Lansoprazole 3-Pantoprazole 4-Esomeprazole Enteric coated preparations, absorbed in small intestine. PPIs take a day or 2 to reach their full effect so patients should be given antacid till PPI reach their full effect. Blocks hydrogen-potassium ATPase enzyme. Prolonged suppression of acid secretions. 20mg omeprazole causes 80% decrease in acid secretions for 24hours, 40mg 100%. Heal ulcers more rapidly than H2 antagonists. Healing rate same at 8 weeks. PPIs superior in the treatment of reflux/GORD. PPI licensed for preventing acid aspiration in surgeries when patient undergoes general anaesthesia as it has prolonged acid suppression.

Answer 70

Short term side effects include nausea, diarrhoea, flatulence, Epigastric pain, dry mouth & headache. Arthralgia and myalgia joint or muscle pain Concerns about bacterial overgrowth May increase risk of salmonella or helicobacter as acid in the stomach has antibacterial properties Lanzoprazole take before food- food decrease its bioavailability Rebound acid hyper-secretion may occur after stopping prolonged treatment with PPI. Therefore use lowest dose to control patients condition or use when needed.

Answer 71

Omperazole 10mg and 20mg indicated for adults over 18 Swallow with plenty of water 20mg daily until symptoms improved then 10mg Refer to GP *If after 2 weeks still no relief * If treatment required continuously for 4 weeks then refer *Patient is over 45 and present with new or changed symptom.

Answer 72

1-Metoclopramide, Domperidoneis prescription only drug due to risk of CVD *Increase gastric emptying and LOS tone. 2-Sucraflate *Polymerise below pH-4 to form a sticky gel *Protective barrier over ulcer (adheres strongly) Physical protection and allows bicarbonate to restablish pH 3-Bismuth 2nd line for H.pylori regimes May act similarly to sucralfate Strong affinity for mucosa, especially in ulcer craters. May blacken teeth and stools. 4-Misoprostol Promotes ulcer healing by stimulating protective mechanisms-sometimes used with NSAIDs.

Answer 73

Metoclopramide C Increases LOS tone And increase gastric emptying Alginates form a raft in the fundus that reduces reflux Antacids act on the fundus wall stomach walls to neutralise acid PPI and H2 antagonist block acid release from parietal cells act on lower part of the stomach pyloric antrum.

Answer 74

Functional dyspepsia, gastritis or PUD Removal of causative agents Dietary changes Symptomatic management H2 antagonist or PPI GORD Lifestyle & dietary changes Alginates products or PPI Not H2 antagonist

Answer 75

Patients over 45 with new/changed symptoms of heartburn or dyspepsia Continuous dyspepsia Increasing severity Weight loss, loss of appetite, sign of anaemia Pain in exercise- cardiac origin? Dysphagia (unexplainable pain on swallowing) Blood in vomit or stools Make sure you ask patients these questions so you can refer to GP or before giving them an OTC med.

Answer 76

Upper GI conditions common Most symptoms can be treated by community pharmacist Antacids and H2 antagonists Rafting agents and PPIs Refer: When symptoms don’t improve Symptoms present for first time over the age of 45

Answer 77

Parietal cell can be stimulated by Histamine Acetylcholine Gastrin Stimulation leads to formation of canaliculus invagination H+ is pumped out into the canacliculus Cl- flows through an ion channel HCl passes into the lumen of the stomach. When designing molecule to Intervene with response to stimulus by stopping natural ligands from binding to receptors on the parietal cells We can target M2 or CCK2 but most successful target is to antagonise H2 receptor.

Answer 78

1-Histamine natural ligand unlike any other natural ligands due to it is imidazole ring structure. This means it can exist as 2 different tautomers. Hydrogen can reside on either one of the nitrogens. Normal ratio is 1:4 showing favour to τ tautomer on the left. If you add a substitute to the ring you can change that ratio and make it in favour of π tautomer but this will make it have less of agonist action at H1 receptors. 2- At physiological pH histamine is charged, first charge occurs at aliphatic amine as it is most basic out of the other nitrogens. Overall the molecule is 99.6% ionised but of that 96% exist as mono-cation with charge on side chain and 3% exist as di-cation where the ring is charged.

Answer 79

Drug design was based on natural ligand Histamine SAR of both H1 and H2 to identify the similarities and differences for agonist binding. Both H1&2 require a ring structure that is separated form a positively charged nitrogen via a two carbon spacer. H1 receptor SAR for agonist is less specific with variation possible in heteroaromatic ring whereas H2 agonist the heteroaromatic ring has to contain this (amidine group)

Answer 80

Standard approach for an antagonist is to take an agonist molecule and made it bigger and more hydrophobic. Binds in the same way to agonist binding site. Additional binding steps the receptor being switched on Initial approaches unsuccessful but one agonist 4-methyl-histamine still an agonist selective for H2 Next step in design was to change the polar group NH3 N-alpha-guanylhistamine is partial agonist (postive charge of giants can be shared over 3nitrogens and can be further or closer to imidazole ring. Does this mean antagonist binding involves a different binding region for the polar group? It is proposed that the agonist binding site is closer to the ring binding site. Histamine is too short to bind to the antagonist binding site. N-alpha-guanylhistamine can access both sites acts as a poor agonist. Blocks the agonist and antagonist binding site. Now the focus is to build pure antagonist not partial and this is down by focusing on charged part of molecule. Thio derivative charge located at terminus (increased activity still as partial agonist) Methylthio derivative where charge is not located at terminus (partial agonist reduced antagonist behaviour) This gave rise to key model: Good agonist behaviour comes from maximising binding interactions through 2 points of contact. Increasing spacer length to maximise chelation interactions with a 3 carbon spacer chain and keep the same guanyl functional group. This forms a better antagonist. This activity was kept even if one of the nitrogen’s groups were replaced by another substituents. Example molecule is Isothiourea A chelation type binding by hydrogen bonds rather than a charged binding interactions. Derivatives shouldn’t be charged as this means molecule would have better pharmacokinetics properties. Also removing charge could help on distinguishing between agonist and antagonist binding sites. SKF-91581 important molecule as it was the first molecule to show pure antagonist behaviour. It so neutral at physiological pH and has same shape as guanyl grouo so it can do the same chelate binding. Further extension to carbon spacer and methylation gave Burimamide, has better activity and is selective but low bioavailability. Imidazole ring and optimising it’s binding interactions by identifying which tautomer would be best for binding and finding a way to maximise the presence of that tautomer for histamine. The pKa of the imidazole ring is 5.74 and at the physiological pH there is an an equilibrium between the two uncharged forms via charged intermediates. Tau form is predominant in histamine so it is involved Ik binding for both agonists and antagonists. Majority of histamine is uncharged on the ring. However the pKa of the imidazole ring in burimamide is not the same as the pKa as in histamine, because it is side chain is electron donating this makes the nitrogen more electron rich and therefore more likely to act as a base and become protonated. This means 40% of burimamide will be double charged at physiological pH, charged on the side chain and charged on the imidazole and in histamine this is only 3%. This led to this burimamide, inclusion of sulphur makes the side chain electron withdrawing, this reduces pKa of the ring so it is less likely to be charged. This gives better antagonist. If charge matters then does tautomer matter and does it have to be tau tautomer? In histamine the tau nitrogen is more basic because it is further away from the electron withdrawing side chain. This means it has bigger electron density and this is favoured. We can have this effect by introducing an electron donating group on the ring because it is going to pass electrons I got he ring and that increase in the electron density will be more pronounced at the tau nitrogen than the pi nitrogen. This gave rise a better molecule Metiamide was in clinical trial but got withdrawn as it cause a bad s/e of Agranulocytosis. So how can we keep the activity and lose this bad s/e? Research was done in range if substituted guanidines that were less likely to become charged at physiological pH. The cyano and the nitro derivatives were best for activity. This led to the first H2 antagonist Cimetidine. Then ranitidine although it was not toxic but it had drug interactions.

Answer 81

H2 antagonist were designed with limited knowledge of the biological process. The design is considered to be a classic in rational drug design gave rise to most important prescription drug Cimetidine.

Answer 82

Cimetidine is an inhibitor of many cytochrome P450 enzymes Significant drug interactions drugs from different classes Effects levels of other drugs (decrease and increase) Changed absorption of some drugs

Answer 83

1-The side-chain guanidine substituent interacted through a bidentate interaction. This is a two way interaction between two amines and a single amino acid residue on just 1 binding site. This hypothesis was revised because the structure of cimetidine can exist as one of 4 stereoisomers. These stereoisomers are different depending on the orientation of the amine substituents relative to the double bond. Only 2 stereoisomers are active and exist in equilibrium as Z,E and E,Z form. The E,E form you get a steric reaction between the methyl group and cimetidine. The Z,Z form we get an interaction between the methyl group and the cyano group CN. But if cimetidine only exists in the Z,E and E,Z form this means hypothesis can’t be right because the hydrogens are not pointing in the same direction meaning they can’t bind at the same binding site int he bidentate.

Answer 84

The hypothesis was updated, there are still 2 points of interactions, but this is to two separate hydrogen binding sites (2 binding sites). Evidence of this has been provided through the synthesis of molecules where conformation is fixed by including a ring structure, by putting the guanidine in a ring structure. The inclusion of isocytosine unit allowed additional hydrophobic derivatives and resulted in Oxmetidine drug.

Answer 85

Ranitidine was fed through patent busting by finding original loop holes in cimetidine SAR. Thsi resulted in a better drug, fewer side effects and no drug interactions as ranitidine didn’t inhibit the P450. Ranitidine has 2 major structural differences. It no longer has an Imidazole ring and the neutral polar group has been further modified further. As the imidazole ring is essential for an agonist but for an antagonist it’s not required. Also other nitrogen containing rings can be used and other hereto atoms rings. Making changes on imidazole ring and new rings has very different effects. If we put a methyl group at the same position on the imidazole ring, it increases activity and on the furan methyl decreases activity. Thsi means binding isn’t occurring at the same place or receptor.

Answer 86

Increased hydrophobicity, increases activity of molecule. This could be done by making the guanidine group less polar. How can we change the overall polarity of the guanidine group to make it more hydrophobic? This is done by changing the polarity by making it less polar while still retaining the 2 amines for binding. This is form by changing the nitrogen to a carbon. The addition of NO2 is essential as the electron withdrawing group then stabilises the desired tautomer where the 2 amines are available to do the binding interactions.

Answer 87

1-The structure activity relationship for ranitidine the ketoaminal group is optimal group binding. 2-If the sulphur is removed form the spacer chain activity will decrease. Activity also decreases if the sulphur position is moved. 3-If the ring is made more hydrophobic by making it a thiophene instead of the furan this would decrease activity. 4-The substitution pattern around the ring matters. Position is optimal at 2 & 5 position but we can change substituents, we can change the methylamino group significantly, so the actual properties of that group basicity and hydrophobicity are not crucial. Substitution can be varied without loss of activity, can be protonated. Nizatidine and Famotidine are two derivatives of Ranitidine with slight changes this gave them advantage in activity.

Answer 88

Parietal cells can be stimulated by histamine, acetylcholine & gastrin. Stimulation leads to formation of a canaliculus invagination, this is highly acidic (pH2). The parietal cell is stimulated to generate acid via the action of histamine and this process can be stopped by H2 antagonists. H+ ions are produced in the parietal cells by the action of the enzyme carbonic anhydrase from the reaction of H2O and CO2. The H+ ions produced are pumped into the canaliculus and this occurs against conc gradient and at the same time K+ are into the parietal cell against the gradient. This step requires energy and that is provided by the hydrolysis of ATP (ATP~~~>ADP+Pi) The 2 ion channels operate as well with Cl- ions and K+ ions flowing into the canaliculus with their gradient. The resulting HCl is passed in the canacliculus then into the lumen of the stomach.

Answer 89

Omperazole Esomeprazole Pantoprazole Iansoprazole Rabeprazole PPIs taken orally and pass through into the systemic circulation, they’re able to do this because they’re lipophilic and neutral (weak bases pKa-4) PPI reach the parietal cells and flow into the canaliculus. In the low pH of the canaliculus PPIs undergo a metabolic transformation and become charged molecules. This enables a cascade reaction where PPIs can be transferred into an active species. This active species is able to form a disulphide bond with one or more of the 3 available cysteine m residues on the proton pump. This leads to irreversible inhibition. Acid production restored if new proton pump is synthesised or by regeneration of inhibited cell through glutathione.

Answer 90

1-PPI picks up a proton H+ and the benzimidazole ring become protonated. 2-Intramolecular reactions occurs. The nucleophilic pyridine nitrogen can now attack the carbon adjacent to the charged nitrogen and that gives a 5 membered ring. This arrangement of the molecule is known as Spiro derivative. 3- The benzimidazole ring is reformed and that results in the cleavage of the carbon sulphur bond and the formation of sulphinic acid derivatives. 4-this is highly reactive and a second intramolecular reaction occurs. This generates a cationic pyrimidine molecule and that is the active species that can interact with the protein. 5- a disulphide bond is formed from the thiol on the proton pump giving us the inhibited enzyme.

Answer 91

Slide 10 So how were these molecules discovered? CMN 131 was the first molecule in the design process. As we've seen so many times before, this was not synthesised to interact with this biological system. It was designed as an antiviral. But testing against other disease models showed it to reduce acid secretion, but it's too toxic for human use. And it was proposed that the problem with the molecule was the thioamide. Thus research was undertaken to change that functionality and it resulted in H 77/67 where the thioamide is included within an aromatic ring structure. It keeps the same binding interactions, but it was a much less toxic molecule. It can be improved further by improving the hydrophobicity. So in the case of H 124/26, including another aromatic ring. Slide 11 Analysis of how that molecule worked indicated that it was actually metabolised in the body to a sulfoxide, and that sulfoxide was much more active. So that molecule now called timoprazole was investigated as a drug itself. Unfortunately, it didn't make it to market for two different reasons. Firstly, during clinical trials it was shown that it inhibited iodine uptake by the thyroid, but additionally it was also a known compound. It had been patented for the treatment of TB, which meant there was going to be no profit in it of taking this one to market. But the recognition of the importance of a sulfoxide group was a crucial step in developing the proton pump inhibitors we have today. The first real drug like molecule was picoprazole. So here the timoprazole structure has been slightly altered by the introduction of ring substituents. What's really interesting about picoprazole is it maintained activity, but the toxicity was lost. Picoprazole was developed in 1976. We didn't actually know what the target was, the proton pump, until 1977. Slide 12 Further changes could be made to picoprazole and H159/69 was an important advance. Here it was shown that having electron donating groups on the pyridine ring enhanced activity. So here we have a methoxy group. It achieves this by increasing the nucleophilicity of the pyridine nitrogen. This allows the first step of our reaction to occur more easily. But unfortunately, the molecule proved to be too chemically sensitive and readily degraded. But by changing the ester on the benzimidazole ring to an ether, the activity could be kept and the molecule was more stable. And that led to omeprazole being the first successfully marketed proton pump inhibitor. Slide 13 Omeprazole is a chiral molecule. Hang on. I'm pretty sure you don't believe me about that. It's a different sort of chirality to what you've seen before. And it's to do with the sulphur being tetrahedral. You can think of the lone pair being equivalent to a bond. So our sulphur has four different substituents on it. It was shown that the S enantiomer is the better drug molecule, more potent and with better pharmacokinetics because it's metabolised more slowly leading to a longer duration of action. The single enantiomer came onto the market in 2000. Slide 14 So in summary, why are proton pump inhibitors so good? They have a highly specific mechanism. It works regardless of the stimuli for acid production. The drug is inactive at a normal body pH. The target is only available in the canaliculus. And the canaliculus is the only area of the body where the active drug can be formed. The local concentration of the drug is high as once it becomes protonated, it cannot diffuse back into the parietal cell, so it's only activated once it’s at the site of action. It reacts quickly once it's activated because of the cascade reaction. So overall, the proton pump inhibitors are excellent drug molecules. If you want to find out more about this subject, you can read the relevant chapter in Patrick Medicinal Chemistry.

Answer 92

Chyme passes from small intestine and passes along caecum, colon and into rectum by peristalsis. Chyme passes from the small intestine through the ileocecal valve and into the cecum of the large intestine. Any remaining nutrients and some water are absorbed as peristaltic waves move the chyme into the ascending and transverse colons. This dehydration, combined with peristaltic waves, helps compact the chyme. Water and salts reabsorbed, resulting in drying of the stool, excess drying of the stool causes constipation. Bacteria role in the intestine and white GI: 1-ferment non-digestible polysaccharides, some metabolites absorbed like cellulose. 2-produce vitamin K and biotin (B7), which can be reabsorbed. 3-produce gasses from undigested polysaccharide. 4-essential for development of caecum and lymphatics Stool is stored in the rectum until urge for defection. Stools hard when stored in rectum for longer than normal so more water absorbed.

Answer 93

Passage of hard stools faeces less frequently than patients own normal pattern. Constipation is a symptom not a disease. It’s characterised by difficulty in opening bowels. *going to the toilet less than 3 times a week *straining to open bowels more than 25% of occasions *hard or pellet like stool on more than 25% of occasions Chronic constipation- generally >12weeks in preceding 6months. Constipation is very common and affects all ages: 1 in 7 people 1 in 5 older people 1 in 3 children More common in women than men Late pregnancy Taking regular meds 10million prescriptions for laxities per year in England

Answer 94

Age elderly and young patients at higher risk. 1-Diet: Low fibre, high animal fat, inadequate fluid intake, caffeine, alcohol both alcohol and caffeine are diuretics so less fluid in body and stool will be dry. 2-Poor bowel habits *Ignoring urge to defecate 3-Imaginary constipation in elderly patients due to less food consumption which means less stool passage 4- Medications: Antacids: Al and Ca salts Antispasmodics because they contain anticholinergic API which reduces bowel motility. Antidepressants: amitriptyline, doxepin because they have anticholinergic affect reduces bowel motility. Iron tablets eg ferrous sulphate can bind up the bowel. Diuretics thiazides, bendrofluazide, reduce patients hydration rate. Opioid Painkillers: codeine, morphine Ca channel blockers: diltiazem, verampail ACE inhibitors eg enalapril, lisionpril Anticholinergic eg hyoscine, tolterodine Ulcer healing eg lansoprazole, Omperazole. Antipsychotics eg haloperidol, olanzipine. Laxative abuse. AI: The drugs mentioned can cause constipation due to various mechanisms: 1. Antacids (Aluminum and Calcium salts): These antacids can cause constipation by reducing bowel motility and slowing down the movement of stool through the gastrointestinal tract. 2. Antispasmodics (containing anticholinergic API): Antispasmodics that contain anticholinergic active pharmaceutical ingredients (API) can reduce bowel motility by blocking the action of acetylcholine, a neurotransmitter that promotes bowel movements. 3. Antidepressants (such as amitriptyline, doxepin): Some antidepressants have anticholinergic effects, which can lead to reduced bowel motility and constipation. 4. Iron tablets (e.g., ferrous sulfate): Iron tablets can bind up the bowel and cause constipation, especially when taken in high doses or for an extended period. 5. Diuretics (such as thiazides, bendrofluazide): Diuretics can reduce the hydration rate of patients, which can lead to dehydration and subsequently result in constipation. 6. Opioid painkillers (codeine, morphine): Opioid painkillers can cause constipation by slowing down the movement of stool through the gastrointestinal tract. They affect the smooth muscle contractions in the intestines, leading to decreased bowel motility. 7. Calcium channel blockers (such as diltiazem, verapamil): Calcium channel blockers can affect the smooth muscle contractions in the intestines, leading to decreased bowel motility and constipation. 8. ACE inhibitors (e.g., enalapril, lisinopril): ACE inhibitors are not typically associated with constipation. However, some individuals may experience constipation as a side effect, although it is relatively uncommon. 9. Anticholinergic drugs (e.g., hyoscine, tolterodine): Anticholinergic drugs, as mentioned earlier, can reduce bowel motility and contribute to constipation. 10. Ulcer healing medications (e.g., lansoprazole, omeprazole): Ulcer healing medications are not typically associated with constipation. However, some individuals may experience changes in bowel habits as a side effect. 11. Antipsychotics (e.g., haloperidol, olanzapine): Antipsychotic medications can cause constipation as a side effect, possibly due to their anticholinergic effects. 12. Laxative abuse: Overuse or abuse of laxatives can disrupt the natural bowel function and lead to dependence, making it difficult for the bowels to function properly without the use of laxatives. It's important to note that individual responses to medications can vary, and not everyone will experience constipation as a side effect. If constipation becomes persistent or bothersome while taking any medication, it's best to consult with a healthcare professional for further evaluation and guidance. Amitriptyline and doxepin are both tricyclic antidepressants that have been found to have anticholinergic effects. Anticholinergic effects refer to the ability of a drug to block the action of the neurotransmitter acetylcholine in the central and peripheral nervous systems. Amitriptyline and doxepin, like many tricyclic antidepressants, have a chemical structure that allows them to bind to and block certain receptors for acetylcholine. By blocking these receptors, they interfere with the normal functioning of the cholinergic system. Acetylcholine is involved in various physiological processes in the body, including regulation of muscle contractions, cognitive functions, and the autonomic nervous system. When the action of acetylcholine is blocked by drugs like amitriptyline and doxepin, it can lead to a range of anticholinergic effects, such as dry mouth, blurred vision, constipation, urinary retention, and cognitive impairment. It's important to note that the anticholinergic effects of these medications can vary from person to person and may depend on factors such as dosage, individual sensitivity, and other medications being taken There are several classes of drugs that have anticholinergic effects: 1. Antidepressants: Tricyclic antidepressants (e.g., amitriptyline, doxepin), selective serotonin reuptake inhibitors (SSRIs) at higher doses (e.g., fluoxetine, paroxetine), and some monoamine oxidase inhibitors (MAOIs) can have anticholinergic effects. 2. Antipsychotics: Some typical antipsychotics (e.g., haloperidol, chlorpromazine) and atypical antipsychotics (e.g., olanzapine, quetiapine) may have anticholinergic properties. 3. Antihistamines: First-generation antihistamines (e.g., diphenhydramine, chlorpheniramine) often have significant anticholinergic effects. Some second-generation antihistamines (e.g., cetirizine, fexofenadine) have fewer anticholinergic properties. 4. Antiparkinsonian medications: Certain medications used to treat Parkinson's disease, such as trihexyphenidyl and benztropine, have anticholinergic effects to help reduce tremors. 5. Antispasmodics/antimuscarinics: Medications like dicyclomine and oxybutynin, used to treat conditions like irritable bowel syndrome and overactive bladder, respectively, have anticholinergic effects. 6. Motion sickness medications: Some medications used for motion sickness, such as scopolamine, have anticholinergic properties. It's important to note that different drugs within these classes may have varying degrees of anticholinergic effects. Additionally, individual sensitivity to these effects can also vary. Anticholinergic drugs have several potential side effects due to their ability to block the action of acetylcholine in the body. These side effects can vary in severity and may depend on factors such as the specific drug, dosage, individual sensitivity, and duration of use. Some common side effects of anticholinergic drugs include: 1. Dry mouth: Anticholinergic drugs can reduce saliva production, leading to a dry, sticky feeling in the mouth. 2. Blurred vision: These drugs can cause blurred vision or difficulty focusing on nearby objects. 3. Constipation: Anticholinergic medications can decrease bowel movements and lead to constipation. 4. Urinary retention: These drugs may interfere with the normal bladder function, causing difficulty in urination or incomplete emptying of the bladder. 5. Confusion or cognitive impairment: Anticholinergic drugs can affect cognitive function, leading to confusion, memory problems, or difficulty concentrating. 6. Increased heart rate: Some anticholinergic drugs can cause an increase in heart rate. 7. Dizziness or lightheadedness: These drugs can sometimes cause dizziness or a feeling of lightheadedness. 8. Dry eyes: Anticholinergic medications can reduce tear production, resulting in dry and irritated eyes. 9. Increased sensitivity to heat: Anticholinergic drugs can interfere with the body's ability to regulate temperature, leading to increased sensitivity to heat and an increased risk of heat-related illnesses. Anticholinergic drugs primarily act by blocking the action of acetylcholine, a neurotransmitter that plays a role in various physiological processes. These drugs bind to and inhibit specific receptors known as muscarinic receptors, which are predominantly found in the parasympathetic nervous system. Muscarinic receptors are a subtype of cholinergic receptors, and there are five different subtypes (M1 to M5) that are distributed throughout the body. Anticholinergic drugs can bind to and block these receptors, preventing the binding of acetylcholine and inhibiting its effects. By blocking muscarinic receptors, anticholinergic drugs can have various pharmacological effects, including: 1. Decreased salivation: Anticholinergics reduce saliva production by blocking muscarinic receptors in salivary glands, leading to a dry mouth. 2. Bronchodilation: By blocking muscarinic receptors in the airways, anticholinergics can relax smooth muscles and promote bronchodilation, which can be beneficial in the treatment of respiratory conditions such as asthma or chronic obstructive pulmonary disease (COPD). 3. Reduced gastrointestinal motility: Anticholinergics can inhibit the activity of smooth muscles in the gastrointestinal tract, leading to decreased motility and potentially causing constipation. 4. Decreased urinary frequency: By blocking muscarinic receptors in the bladder, anticholinergics can reduce bladder contractions and increase bladder capacity, resulting in decreased urinary frequency. 5. Dilated pupils: Anticholinergic drugs can block muscarinic receptors in the iris muscles, causing dilation of the pupils (mydriasis). 6. Reduced sweating: Anticholinergic drugs can inhibit sweat gland activity by blocking muscarinic receptors, leading to decreased sweating. It's important to note that different anticholinergic drugs may have different affinities for specific muscarinic receptor subtypes, which can contribute to variations in their pharmacological effects and side effect profiles.

Answer 95

IBS contributes to constipation but this condition alternates between constipation and diarrhoea. Intestinal obstruction: 1-Scarring- from IBD, diverticulitis, or post surgery. 2-Adhesions 3-Intestinal cancers 4-Abdominal hernia 5-Gallstones wedged in intestine 6-Volvolus 7-Foreign bodies 8-Intussusception 9-Haemorrhoids 10-Fissures Other disease can cause constipation: Diabetic autonomic neuropathy Spinal cord injury or tumours Cerebro vascular accident Multiple sclerosis Parkinson’s disease Connective tissue disorder Hirschsprung’s disease Mechanical problems of the anus and rectum Eg rectal prolapse *poor thyroid function cause main role of thyroid is to maintain regular bowel habit. *lead poisoning *pregnancy *travel *immobility

Answer 96

Medical history of patient? History of symptoms: What is the patients Normal pattern of defecation? Do they have other symptoms Frequency of their bowel habit and consistency of their stool. Are they experiencing any faecal impaction or incontinence? How long/ intense are the symptoms? Impact on daily life? Are they taking other medications Changes in diet and life style. New job? Holiday? Diet?

Answer 97

Prevalent in 5-30% of children Aetiology unknown for children but diet changes from milk to new food impacts their GI and milk is a laxative. Symptoms: Foul smelling wind and stools, irregular stool structure and excessive flatulence, abdominal pain, distension and discomfort.Soiling/overflow.

Answer 98

Main causes Age related decline in GI motility Decreased mobility Poor diet, low solid and liquid intake. Wasting of pelvic floor muscles Side effects of medicines Faecal impaction may occur,

Answer 99

Constipation is a symptom not a disease It affects a high percentage of the population Many factors a cause constipation When constipation has been confirmed appropriate steps need to be taken to manage the problem. *lifestyle and dietary changes *short course of laxatives

Answer 100

1-Summarise the guidelines for managing constipation 1. **Guidelines for Managing Constipation:** - Encourage increased fiber intake through diet or supplements. - Promote adequate fluid intake. - Encourage regular physical activity. - Consider lifestyle changes such as establishing a regular bowel routine. - Offer laxatives as appropriate if lifestyle changes are ineffective or if there's an underlying cause of constipation. 2-Counsel a patient on appropriate lifestyle changes to help constipation symptoms. 2. **Counselling a Patient on Lifestyle Changes:** - Increase dietary fiber intake by consuming fruits, vegetables, and whole grains. - Ensure adequate hydration by drinking plenty of fluids, especially water. - Engage in regular physical activity, such as walking or jogging, to promote bowel movement. - Establish a consistent bowel routine by attempting to defecate at the same time each day. 3-Discuss the differences in the guidelines for particular patient groups 3. **Differences in Guidelines for Specific Patient Groups:** - For elderly patients or those with mobility issues, additional emphasis may be placed on maintaining hydration and physical activity. - Pregnant women may require tailored advice regarding fiber intake and suitable laxatives. - Patients with comorbidities may need careful consideration of medication interactions and contraindications. 4-Distinguish the key features of each laxative 4. **Key Features of Laxatives:** - Bulk-forming laxatives: Increase stool bulk and promote bowel movement. - Osmotic laxatives: Draw water into the bowel to soften stools and stimulate bowel movements. - Stimulant laxatives: Directly stimulate the bowel muscles to encourage movement. - Stool softeners: Soften stools by adding moisture to them, making them easier to pass. 5-Describe why one laxative is chosen over another 5. **Choosing Laxatives:** - Selection depends on factors such as the severity of constipation, patient preference, and any underlying medical conditions. - Bulk-forming laxatives are often recommended as first-line treatment due to their safety profile and effectiveness. - Osmotic laxatives may be preferred in cases of more severe constipation or when rapid relief is needed. - Stimulant laxatives are usually reserved for short-term use or when other treatments have failed due to the risk of dependency and side effects.

Answer 101

1-To achieve an individuals normal frequency of defecation 2-Establishing regular, comfortable defecation. 3-Preventing laxatives dependence 4-Relieving discomfort Bristol stool chart Type 1-7 Characterise stool Type 1 separate hard lumps Type-7 watery no solid stool Type -1 The longer the transit time the longer it takes food and waste products to make it is way through the GI system The greater opportunity body had to absorb water from the stool so stool is harder to pass and constipation occur. Type-7 less transit time so body hasn’t absorbed water from stool which means diarrhoea will occur Type 3-4 normal stool.

Answer 102

1-Bulking agents: Ispaghula husk, methyl cellulose 2-Stimulant laxatives: Bisacodyl (oral and rectal) Senna Dantron (in co-danthrathmer or co-danthrusate) Sodium picosulphate 3-Faecal softeners: Docusate (oral and rectal) Glycerol (suppository) Arachis oil (enema) 4-Osmotic laxatives: Lactulose Macrogols (inert polymers of ethylene glycol) Magnesium hydroxide and magnesium sulphate Phosphate (suppository and enema) Sodium citrate (microenema) **BOSS** 1. **Bulking Agents (B):** Ispaghula husk and methyl cellulose. 2. **Stimulant Laxatives (S):** Bisacodyl, Senna, Dantron, Sodium picosulphate. 3. **Faecal Softeners (S):** Docusate, Glycerol, Arachis oil. 4. **Osmotic Laxatives (O):** Lactulose, Macrogols, Magnesium hydroxide, Magnesium sulphate, Phosphate, Sodium citrate.

Answer 103

For both acute and chronic: 1-Lifestyle advice and manage any underlying cause. Fluid intake, exercise, diet high fibre fruit&veg. Medical history, medications eg opioids. 2-Bulk forming eg. Ispaghula husk gives some response within 1-3 days then add osmotic laxatives but if bulk forming laxative doesn’t yield benefit the use osmotic laxative alone. 3- (+/or) Osmotic: Macrogol use osmotic laxative for 1-3 days if not effective use stimulant eg. senna. 4-stimulant 6- Gradually titrate the laxative doses up or down aiming to produce soft, formed stool without straining at least 3 times per week. In acute step 5: Gradually reduce and stop after producing a soft, formed stool without straining at least 3 times per week. In terms of stopping these laxatives it must be done gradually over a period of months, starting with the stimulant laxatives first you may need to simultaneously increase dose of osmotic laxatives to off set this affect. In chronic step 5: if stimulant laxatives fails Next step is to use prucalopride (pro-kinetic serotonin agonist) stimulates GI motility (Prucalopride is a medication used to treat chronic constipation in adults who have not responded to at least two classes of other laxatives at maximum and recommended dose for at least 6 months and where symptoms are severe and when invasive treatment is used like suppository or enema or removal of stool. It works by increasing the movement of the gut, helping stools to pass more easily.)

Answer 104

Faecal loading is a generalised term to describe build up of faecal matter within the colon whereas impaction occurs when that matter has been present for a long period of time where body has reabsorbed water from stools. Impaction is characterised by dry hard matter that patient can’t evacuate from the bowel. Hard stools is seen in faecal impaction and soft stool is a symptom of faecal loading. The guidance for faecal impaction/hard stool states first step in treatment is high dose of oral macrgol like laxado or movacol. Aim to draw water into the stool via osmosis to make stool softer and easier to pass. If unsuccessful after 48hrs maximum. The next step is to treat with stimulant laxatives like senna or bisacodyl aim to get movement of the bowel working about 12hrs. if still unsuccessful at this stage or response is slow or inadequate. The next step is to consider using glycerols suppository either on it is own or suppository plus bisacodyl suppository gives quick bowel movement of 30mins to an hour should notice improvement in the patient symptoms. If this step fails, consider a sodium phosphate enema or a Arachis oil retention enema. Sodium phosphate is one of the strongest osmotic laxatives of previous measure fail we need to use more potent laxatives. If we got soft stools a symptom of faecal loading: First step in the pathway is to use stimulant pathway senna or bisacodyl reason for this unlike for hard stools we try to use osmotic laxative to soften stool, here the stool is already soft so there is limited benefit of osmotic laxatives. First step to use stimulant laxative if unsuccessful, next step consider Docusate which is a stool softener which also got stimulant effects or a sodium citrate mini enema and this is an osmotic laxative. If unsuccessful with both treatment then move to next step in the pathway is to use a sodium phosphate enema or Arachis oil enema.

Answer 105

***Avoid bulk forming laxatives*** Because their mechanism of action is that they increase faecal mass this causes the colon to be distended and that stimulates peristalsis but opioids reduce bowel contractions and this means reduction in peristalsis, have antagonist effects here. Avoid bulk forming laxatives like fybogel ispaghula husk. Use osmotic laxative movcol, laxdor or (Docusate) stool softener got mild stimulant activity as first line in treating opioid induced constipation. Second line is stimulant laxatives like senna or bisacodyl because stimulants work directly on the bowel in order to stimulate peristalsis. They are having an exact opposite effect on the bowel as the opioids, this helps the bowel to overcome inhibition of peristalsis. Osmotic and stimulant ideal combination soften and increases peristalsis combined effect. If this fails next step in the guidance is to use peripherally acting μ-opioid opioid receptor antagonist PAMORA. Peripheral means medication is not acting centrally Opioids are agonists at the opioid receptors in the brain I.e having central affect. The side effect of constipation is a peripheral side effect taking place in a location outside of the brain blocking of μ-opioid receptors in the GI tract and this is resulting in the constipation of the patient. The mechanism of action of PAMORA is blocking the the μ-opioid receptors in the GI tract without blocking the central effects, thus protecting the analgesic effects for the patient and relieving constipation. 1-Naloxegol: Peripherally acting μ-opioid receptor antagonist (PAMORA) Given orally When patient hasn’t responded to laxatives PAMORAs don’t antagonise the important opioid receptors. 2-Methylnaltrexone PAMORA Subcutaneous No evidence submitted to NICE not recommend by NICE 3-Naldemedine (NICE TA651) Sept 2020 PAMORA Oral A new option.

Answer 106

High fibre diet: 30g fibre/day with sufficient fluid (most only get 18g) Caution when increasing fibre intake due to obstructive symptoms or faecal impaction. Increasing fibre intake is Ineffective in slow transit constipation or defecatory disorders. Switch from white to whole meal Limit evidence but also recommend: Increased physical activity 2L of water per day Be cautious with increasing the fibre intake, take care if there's any obstructive symptoms or faecal impaction. also increasing the fibre intake is ineffective in slow transit Constipation or in patients who have got defecatory disorders so patients who are not going to benefit from having the high fibre diet will be people with these obstructive symptoms that we mentioned which can be caused by conditions like Crohn's diverticulitis cancer perhaps even having a foreign body within within the GI system and also then faecal impaction, this is when faeces have built up obstructive symptoms that's where the patient would experience abdominal pain nausea vomiting cramping and flatulence caused by the intestinal obstruction and some patients might have that as adhesion's after surgery possibly also after a hernia. the issue with fibre being ineffective and slow transit Constipation, this goes back to the Bristol stool chart so slow transit Constipation is where the food and waste products are moving through the GI system quite slowly or relatively slowly now if that is the case then increasing the fibre has no benefit for those patients because what we're looking to do is bulk up the contents of their stool but if they've already got slow transit Constipation that actually increasing the content of the colon is certainly not going to help the situation now likewise if the patient's has a defecatory disorder for example something like Hirschsprung's disease which is a nerve conduction problem with the bowel again in this particular case because the patient has gotten anatomical issue actually increasing the content of the colon is not going to bring about an improvement for that patient, for everybody else for whom they will benefit from a high fibre diet a simple switch they can make is to move from white foods for wholemeal foods so if we take the examples of rice bread pasta if we're moving from white versions of foods to wholemeal versions of those products they're going to have a much higher fibre content so that's an easy change that people can make there is limited evidence for some of the further interventions that we can make however all of the interventions that we will discuss are good lifestyle advice and things that we would be recommending people for as part of their overall health picture OK so we firstly would advise people to increase their physical activity for the simple reason that we know that patients who are predominantly bedbound are at much greater risk of developing Constipation OK so it stands to reason that we should increase our physical activity in order to ensure regular bowel movements and the patients also need to be advised to ensure they're getting an adequate fluid intake so minimum of two litres of water per day obviously if they're having increased physical activity or it's a particularly hot climate and that figure needs to go up accordingly

Answer 107

Obstructive symptoms refer to a set of symptoms that occur when there is a blockage or obstruction in the gastrointestinal (GI) tract, hindering the normal passage of food, fluids, or waste material. These symptoms can manifest in various ways and may include: 1. **Abdominal pain:** Often described as cramping or sharp pain, abdominal discomfort is a common symptom of GI obstruction. 2. **Nausea:** Feeling queasy or the urge to vomit is another typical symptom of obstruction. 3. **Vomiting:** In severe cases, vomiting may occur due to the body's attempt to expel the blockage or because of the build-up of gastric contents. 4. **Cramping:** Spasms or cramps in the abdomen may accompany obstruction, reflecting the body's attempt to move material past the blockage. 5. **Flatulence:** Excessive gas production and bloating can occur due to the obstruction, leading to discomfort and distention of the abdomen. Obstructive symptoms can result from various conditions affecting the GI tract, including: - **Mechanical obstruction:** Physical blockages caused by conditions such as tumors, strictures (narrowing of the intestine), adhesions (scar tissue), or foreign bodies can impede the normal flow of contents through the GI tract. - **Functional obstruction:** In some cases, the muscles of the GI tract may fail to contract properly, leading to a functional obstruction. Conditions like intestinal pseudo-obstruction or Hirschsprung's disease can cause this type of obstruction. - **Inflammatory conditions:** Inflammatory bowel diseases like Crohn's disease or diverticulitis can cause inflammation and swelling, leading to partial or complete obstruction of the intestine. - **Volvolus:** This occurs when a loop of the intestine twists around itself, causing a mechanical obstruction. Overall, obstructive symptoms in the GI tract can be caused by a wide range of conditions, each requiring specific diagnostic and treatment approaches to alleviate symptoms and address the underlying cause.

Answer 108

Faecal impaction occurs when a large, hardened mass of stool becomes stuck in the rectum or colon and cannot be passed naturally. This condition typically develops over time due to chronic constipation or prolonged periods of not having a bowel movement. As fecal matter accumulates and becomes compacted, it becomes increasingly difficult and painful to pass. Symptoms of fecal impaction may include: 1. Severe constipation 2. Abdominal pain or discomfort 3. Rectal pain or pressure 4. Difficulty or inability to pass stool 5. Nausea or vomiting 6. Bloating or abdominal distention 7. Loss of appetite 8. Leakage of stool or liquid stool around the impacted mass Fecal impaction requires medical attention to address and resolve. Treatment may involve a combination of methods, such as manual disimpaction (physical removal of the impacted stool), laxatives or stool softeners to help soften and loosen the stool, enemas or suppositories to stimulate bowel movements, and dietary changes or fiber supplements to promote regular bowel movements and prevent recurrence. In severe cases, hospitalization may be necessary for more intensive treatment and monitoring. It's essential to seek medical care promptly if symptoms of fecal impaction develop to prevent complications such as bowel obstruction or perforation.

Answer 109

Slow transit constipation is a type of chronic constipation characterized by delayed movement of stool through the colon (large intestine) and rectum. In individuals with this condition, the muscles of the digestive tract may not contract properly, leading to sluggish or ineffective movement of fecal matter. As a result, stools move through the colon at a slower-than-normal pace, causing difficulty in passing stools and infrequent bowel movements. Symptoms of slow transit constipation may include: 1. Infrequent bowel movements (typically fewer than three times per week) 2. Difficulty passing stools 3. Straining during bowel movements 4. Feeling of incomplete evacuation after bowel movements 5. Abdominal discomfort or bloating 6. Rectal pain or pressure 7. Excessive gas or flatulence 8. Abdominal distention The exact cause of slow transit constipation is not always clear, but it may be related to dysfunction of the nerves or muscles that control bowel movements. Risk factors for developing this condition include a sedentary lifestyle, inadequate dietary fiber intake, certain medications (such as opioids or anticholinergic drugs), neurological disorders, and hormonal imbalances. Diagnosis of slow transit constipation often involves a thorough medical history, physical examination, and diagnostic tests such as colonic transit studies, anorectal manometry, and defecography. Treatment typically focuses on relieving symptoms and may include dietary modifications (such as increasing fiber intake), lifestyle changes (such as regular exercise), laxatives or stool softeners, biofeedback therapy, and in severe cases, surgical options such as colonic resection or placement of a colonic stimulator. Overall, slow transit constipation can significantly impact an individual's quality of life, but with appropriate management and treatment, symptoms can often be effectively controlled and managed. It's important for individuals experiencing chronic constipation to consult with a healthcare professional for proper evaluation and management.

Answer 110

First step is to offer bulk forming laxative. Add or switch to an osmotic laxative. Can also consider a short course of a stimulant such a senna but it can’t be given OTC must be prescribed as stimulant laxatives can induce labour contractions. Never supply stimulant laxatives in a pharmacy setting in pregnancy or pregnant patients. Consider glycerol suppository 38% of pregnant women suffer from constipation as a result of increased progesterone and this causes the bowel smooth muscle to become relaxed and this reduces motility. Compression of the bowel from the uterus this will reduce motility. Many pregnant women take iron supplements this will cause constipation too. Check for haemorrhoids as it is common in pregnancy. Breastfeeding: Offer bulk forming laxatives Add or switch to an osmotic laxative Can consider a short course of a stimulant laxatives such as bisacodyl or senna. Glycerol suppository Laxatives in breastfeeding

Answer 111

Children may not go to the toilet as frequent and delaying stool passage causes excess drying of the stool and thus constipation, anal fissures, anal spasms. This leads to learnt behaviour of avoiding defecation. 1st line treatment- Macrogols paediatric version of movacol laxdor paediatric or cosmocol and negotiated and nonpunitive behavioural interventions suited to persons stage of development. 2nd line- add stimulant laxatives like senna Or if 1st line Macrogol was not tolerated or not beneficial change to stimulant laxatives 3rd line add lactulose or other softening laxatives like Docusate if Macrogol was not tolerated continue at maintenance dose (which may be for several months) Some paediatric Macrogol products are not licensed for children under 2 (such as Cosmocol paediatric) informed and documented verbal consent recommended for prescriber) Each product has different licensing age even though they contain macrogol before prescribing make sure and tell parents about unlicensed indication is known. NICE recommends Suppositories and enemas but not recommended for routine use in primary care. Parents pick glycerol suppository from pharmacy but complexity use is not recommended oral is much more convenient for children. Laxatives may be needed for several months to (overcome the learned behaviour)

Answer 112

1-Ispaghula husk: e.g. fybogel 3.5g/sachet *Hi-fibre brand is the same as the original! *1 sachet BD for children 12yrs and over *Sachets which you pour into full glass of water and take straight away. *Preferably after meals but not just before bed. *Take 1/2 to 1 hour before or after other medications *Remains effective despite long term use as they don’t act directly on the bowel itself 2-Methylcellulose e.g. Celevac *500mg tablets *3-6 tablets BD with at least 300ml of liquid *break tablets in the mouth before swallowing because this aids water absorption *Don’t take just before bed because these meds swell when in contact with water and the aim is to absorb fluid and this bulks up stool and this distends the colon which stimulates a bowel contraction. At night patient won’t have peristalsis as this slows down in sleep, don’t take before bed as this is against natural peristalsis in the body. *Ensure good fluid intake is maintained as these meds absorb water and if patient is dehydrated this reduces the effectiveness of the medication. If patient doesn’t have enough fluid or excess fluid, this can cause constipation for some patients *2-3 days for effect to be seen

Answer 113

* In these types of laxatives adequate water intake is essential* 1-Macrogol: e.g. Movicol, Cosmocol, Laxido 1-3 sachets daily, in divided doses Sachets to dissolve in 125ml of water Can be high in sodium so it’s contraindicated n hypertension, heart disease and renal impairment. Do not take other oral medicines 1 hour before or after dose because this affects absorption. Different flavours available- can mix with diluting squash if desired 1-3 days for effect. 2- Lactulose 15-45ml daily (single dose or in divided doses) Very sweet tasting liquid- sticky sweet can cause if intolerant to lactose. No issue for diabetic patients as Lactulose is not absorbed through gut wall. Up to 2 days for effect. 3-Magnesium hydroxide: e.g. Milk of Magnesia liquid Mainly seen as liquid: 30-45ml PRN Dose to be given at bedtime Can be abused as it is very purgative (strong effect) Old fashioned remedy - caution in elderly due to its purgative effect it can affect elderly more than younger patients. Can cause a strong laxative effect such as diarrhoea this can affect elderly worse than younger patients. Commonly seen as OTC (max 3days use) Research weak no RCT 3-6 hours for effect. 4- Docusate: e.g. DulcoEase, Dioctyl Up to 500mg daily in divided doses 12-72 hours for effect of tablets, suppositories 15min Softening agent with a stimulant effect May be useful alternative for people who find it hard to increase their fluid intake Generally well tolerated.

Answer 114

As pharmacist have to instruct patient on use of both enema and suppositories. 1-Suppositories: Position yourself comfortably. Lying on your left side with feet level or slightly elevated is the best position when in inserting a suppository When ready, take the suppository out of the package and hold it in between your thumb and middle finger. Be careful not to drop it Use water soluble lubricant to coat the blunt end of the suppository Be sure that the blunt shape is pointing toward the anus not the tip. Insert suppository directly into the anus. Insert it enough to avoid suppository from coming out. (Usually to the depth of your finger is sufficient) Lie still and hold suppository inside the back passage for 10-15 minutes. 2-Enemas: 1. Once you have warmed the enema in a bowl or sink of warm water, pull the lid off the nozzle. Hold the bottle upright so the contents do not spill. 2. The nozzle is already lubricated, but you can put on more lubricating jelly if you like. 3. Lie on your left hand side, on the towel, with your knees bent up toward your chest as far as comfortable. 4. Gently push the nozzle about 7cm (in) into your anus. 5. Slowly squirt the contents in. Remove the nozzle once you have finished and stay lying down. 6. Try to hold the liquid in your bottom for as long as you can - five minutes, if possible. Go to the toilet when you can no longer hold it and you really feel like emptying your bowels 8. Stay near the toilet for the next hour 9. Some people have stomach cramos for a short time after using the enema 10. Occasionally, you can feel faint or dizzy. If this happens, lie down until you feel better *both products have a quick onset of action, given when prescriber wants urgent solution or a quick acting method more than oral tablets. Used before hospitalisation to undergo procedure for bowel evacuation. These products licensed for constipation not faecal impaction. Arachis oil only exception given for faecal impaction but be aware of peanut allergy, warn patient.

Answer 115

Short term use 1-Senna/senokot Tablets and syrup 7.5mg daily max per dose 30mg daily Onset of action 8-13hours advice patient to take before bed at 6pm or 8pm and they should get bowel movement next morning. Syrup is unpalatable. 2-Dantron/ co-danthramer or co-danthrusate Co-danthramer includes PEG (Macrogol) Co-danthrusate includes Docusate Colours urine red but I harmful side effect. Avoid prolonged contact with skin as it can cause skin irritation advice patients who wear nappies to be cautious and to change nappy frequently Only used in terminally ill patients due to potential risk of ( potential carcinogen) Oral solution Onset of action 6-12 hours. Sodium picosulphate/ Dulcolax 5-10mg once daily Tablets and syrup Syrup is palatable Onset of action 10-14hours Bisacodyl: Duclolax Acts on small intestine 5-10mg once daily: increased if necessary up to 20mg OD Tablets act in 10-12hrs Suppositories act in 20-60mins but it can cause local inflammation

Answer 116

Prucalopride is a selective serotonin 5HT4- receptor agonist with pro kinetic properties. Prucalopride is a medication that is used to treat constipation. It works by specifically targeting and activating serotonin 5HT4 receptors in the gut. By doing so, it enhances the natural movement of the digestive system, known as peristalsis, which helps to facilitate the passage of stools through the intestines. This prokinetic effect of prucalopride helps to relieve constipation and improve bowel movements. Should only be prescribed by clinicians experienced in treating chronic constipation after careful review. 2mg tablets OD, review treatment if no response after 4 weeks (reduced dose in elderly) S/E Headache and GI disturbance Increased doses will not improve response 1-2 weeks for effect *Linaclotide for use for constipation in patients with IBS.

Answer 117

Peripherally acting μ-opioid antagonist PAMORA *Naloxegol e.g. moventig tablets and syrup *25mg OD to be taken in the morning Counsel on the risk of opioid withdrawal (shouldn’t occur but cases have been reported) Tablets can be crushed mixed with 120ml of water and taken immediately mixture can be administered via nasogastric tube if required. Take on empty stomach When naloxegol therapy is initiated it is recommended that all currently used maintenance laxative therapy should be halted until clinical effect if naloxegol is determined. Works within 12-72 hours *Naldemedine e.g. Rizmoic 200mcg tablets OD Counsel on risk of opioid withdrawal

Answer 118

Mostly of plant origin, including non digestible polysaccharides *cellulose and other components Mechanism of action depends on type: •typically polysaccharides increase osmolality in the gut when broken down, causing water retention. •Retention of water in the GIT, so expanding and softening the stool. •Bulkier stool distends the colon •Promotion of peristalsis via stimulating colonic mucosal receptors/stretch receptors •This leads to acetylcholine release which increases parasympathetic drive. ACh activates muscarinic acetylcholine receptors mostly M2 and M3 subtypes, this increases peristalsis. Also creates mucus layer in the intestinal lining, facilitating defecation.

Answer 119

*Poorly absorbed so they act as osmotic agents and that increases water retention in the gut lumen. *because they are hyperosmolar agents, they are absorbed into stools by osmosis, making it softer *Softer stools are easier to pass. *Many osmotic laxatives also contain Mg2+ *Mg2+ triggers release of cholecystokinin CCK *CCK increases intestinal secreations and colonic motility *Decreases transit time through gut. AI: Osmotic laxatives work by drawing water into the intestines, which helps soften the stool and promote bowel movements. They do this by increasing the osmotic pressure in the intestines, which prevents water from being absorbed and instead encourages water to be retained in the bowel. This increased water content in the intestines helps to stimulate bowel movements and relieve constipation. Osmotic laxatives can be helpful for short-term relief of constipation, but they should be used with caution and under the guidance of a healthcare professional.

Answer 120

*Stimulate local reflexes of myenteric nerve plexus of the gut. *Irritate nerve endings in wall of intestine * Motor effect on gut wall increases propulsion *Increases secretion of water into bowel *Increases gut motility and decreased transit time AI: The pharmacology of stimulant laxatives involves several mechanisms that promote bowel movements and relieve constipation: 1. **Stimulation of Myenteric Nerve Plexus:** Stimulant laxatives directly stimulate the local reflexes of the myenteric nerve plexus in the gut. This stimulation triggers rhythmic contractions (peristalsis) of the intestinal muscles, leading to increased propulsion of fecal matter through the intestines. 2. **Irritation of Nerve Endings:** Stimulant laxatives also irritate the nerve endings in the wall of the intestine. This irritation enhances the sensitivity of the intestinal muscles to nerve signals, further promoting muscle contractions and bowel movements. 3. **Motor Effect on Gut Wall:** The stimulation of the myenteric nerve plexus and the irritation of nerve endings in the intestine result in a motor effect on the gut wall. This effect increases the propulsive movements of the intestinal muscles, facilitating the movement of fecal matter towards the rectum. 4. **Increased Secretion of Water:** Some stimulant laxatives, such as bisacodyl and senna, also increase the secretion of water into the bowel. This additional fluid softens the stool, making it easier to pass, and helps to prevent constipation by promoting regular bowel movements. 5. **Increased Gut Motility and Decreased Transit Time:** Overall, the pharmacological actions of stimulant laxatives lead to increased gut motility and decreased transit time of fecal matter through the intestines. This accelerates intestinal transit, softens the stool, and promotes more frequent and easier bowel movements. By targeting multiple mechanisms involved in bowel function, stimulant laxatives effectively relieve constipation and promote regular bowel function. However, it's important to use them judiciously and under the guidance of a healthcare professional to minimize the risk of adverse effects and ensure optimal therapeutic outcomes.

Answer 121

Senna is an Anthraquinone laxatives, it combines with sugars to form glycosides. Glycosides are molecules where the sugar is attached to a functional group via glycosidic bond. Glycosides bond hydrolysed by colonic bacteria to release irritant anthracene glycoside derivatives, specifically sennosides A&B are absorbed and have direct action on myenteric nerve plexus, increasing smooth muscle activity. They also increase PGE2 secretion (which increases gut motility). Also reduces colonic water absorption. Also

Answer 122

Stool softener is known as emollient laxatives. Some work as surface wetting agents/surfactants (e.g. Docusate) Reduced surface tension allows water/fats to penetrate stool. This softens the stool, making it easier to pass. Docusate has stimulant activity too Arachis oil and paraffin creates a barrier between stool and intestinal wall. This eases passage of stool through intestine. Paraffin no longer popular due to concerns over carcinogenicities.

Answer 123

PAMORAs are competitive antagonist at mu-opioid receptors. Prevent opioid activation of intestinal receptors. Targeting underlying opioid induced side effects ie reduced GI motility, hypertonicity, increased fluid absorption. This results in normal propulsion and peristalsis.

Answer 124

Prucalopride is a 5HT4 receptor agonist: 5HT4 receptors are present on GI tract , especially myenteric plexus. 5HT4 activation leads to increased release of ACh this increases rest and digest parasympathetic drive and peristalsis and propulsion.

Answer 125

Red flags: 1-Pain on defecation- causing suppression of reflex. 2-Patient over 40 years with sudden changes in bowel habits (no obvious cause) 3-Greater than 14days duration (no obvious cause) 4-Associated fatigue 5-Presence of blood in stool 6-Repeated failure of laxatives 7-Suspected laxative abuse Children although there are laxatives licensed for children OTC, they require initial referral to a GP to have physical examination. Macrogols is 1st line laxdor Paediatric dose Macrogol is a POM, adult Macrogol is P med.

Answer 126

70% of men over 70 have some degree of prostate enlargement. Prostate is located above the rectum, enlargement of prostate puts pressure on rectum causes rectum to narrow affecting stool passage. These patients must use stimulant laxatives for long time POM only. Refer repeat requests and unexplained constipation in the over 40s but refer for prostate check too.

Answer 127

A change in normal bowel habit resulting in increased frequency of bowel movements and the passage of soft or watery stools. May be accompanied by colicky pain due to increased contraction of smooth muscle with additional production of gases. It is a symptom of different conditions but not a disease.

Answer 128

*Acute diarrhoea: Abrupt onset of >3 loose stools/day and lasts no longer than 14 days. Dietary insults like alcohol or spicy food Bacterial/viral infections Majority of cases resolve within 2-3 days without specific treatment. Use rehydration salt *Chronic diarrhoea: Pathological cause Lasts >14 days Possibly flare up of previously diagnosed condition eg IBS, UC, Crohn’s disease. Needs further investigation to get to underlying cause.

Answer 129

Difficult to quantify or determine as many cases are self limiting and not reported. Common in children under 5: Acute gastroenteritis most common Between 1-3 cases per year due to underdeveloped GI system makes them more prone. Adults: Just under 1 episode/yr 22% food related Travellers diarrhoea

Answer 130

Mortality from acute diarrhoea declining globally. Second highest cause of childhood mortality Age and nutritional status are most important host factors in determining severity and duration. The younger the child, the higher risk for severe, life threatening dehydration

Answer 131

Change in the balance between the absorption and secretion of water and electrolytes due to: Osmotic force that drives water into the gut lumen, eg after ingestion of nonabsorbable sugars Proportional to the intake and responsive to fasting. Or Enterocytes actively secreting fluid eg enterotoxin-induced diarrhoea. Not responsive to fasting Ion transport activated by bacteria resulting in pathogens invading enterocytes or producing enterotoxins which damage cells or inducing cytokine secretion to produce PGE which stimulates secretion. The passage is explaining the changes in the balance between the absorption and secretion of water and electrolytes that occur in the pathophysiology of diarrhea. There are two main mechanisms mentioned: 1. Osmotic Force: This refers to the presence of substances in the gut lumen that cannot be absorbed by the body, such as nonabsorbable sugars. These substances create an osmotic gradient that draws water into the gut, leading to diarrhea. The amount of water that enters the gut is proportional to the intake of these substances and can also be influenced by fasting. 2. Enterocyte Secretion: Enterocytes are cells lining the intestines that are responsible for absorbing nutrients and fluids. In some cases, these enterocytes can become overactive and start actively secreting fluid instead of absorbing it. This can be induced by enterotoxins, which are toxins produced by certain bacteria that specifically target the enterocytes. This type of diarrhea is not responsive to fasting. Additionally, the passage mentions that ion transport, which involves the movement of electrolytes across the intestinal lining, can be activated by bacteria. This can occur when certain pathogens invade the enterocytes or produce enterotoxins that damage the cells. The activation of ion transport can also be triggered by the production of cytokines, which are inflammatory molecules, leading to the secretion of prostaglandins. Prostaglandins further stimulate fluid secretion in the intestines, contributing to diarrhea. In summary, the passage explains that diarrhea can occur due to a change in the balance between the absorption and secretion of water and electrolytes in the intestines. This can be caused by the osmotic force created by nonabsorbable substances or by the active secretion of fluid by enterocytes, which can be induced by enterotoxins or bacterial invasion. •AI: Diarrhea is a condition characterized by the frequent passing of loose, watery stools. The pathophysiology of diarrhea involves disruption in the normal functioning of the gastrointestinal tract, leading to increased fluid secretion, decreased fluid absorption, or both. There are several mechanisms that can contribute to the development of diarrhea: 1. Increased Fluid Secretion: Certain infections, such as those caused by bacteria or viruses, can stimulate the release of toxins that activate chloride channels in the intestinal lining. This leads to increased secretion of chloride and water into the intestinal lumen, resulting in watery diarrhea. 2. Decreased Fluid Absorption: Inflammation or damage to the intestinal lining can impair the absorption of fluid from the gut. Conditions like inflammatory bowel disease, celiac disease, or radiation enteritis can disrupt the normal absorption process, leading to diarrhea. 3. Altered Intestinal Motility: Normal bowel movements rely on coordinated contractions of the intestinal muscles. Any disruption in this motility can affect the transit time of stool through the intestines. Conditions like irritable bowel syndrome or certain medications can cause abnormal motility patterns, leading to diarrhea. 4. Malabsorption: Some digestive disorders, such as lactose intolerance or pancreatic insufficiency, can interfere with the normal absorption of nutrients and water from the intestines. This can result in osmotic diarrhea, where undigested substances draw excess water into the intestinal lumen. 5. Microbial Imbalance: The balance of normal intestinal bacteria, known as the gut microbiota, plays a crucial role in maintaining gut health. Disruption of this balance, such as through the use of antibiotics, can lead to an overgrowth of harmful bacteria or yeast, causing diarrhea. It's important to note that the specific pathophysiology of diarrhea can vary depending on the underlying cause. Effective management of diarrhea involves identifying and addressing the underlying cause, as well as addressing fluid and electrolyte imbalances to prevent complications.

Answer 132

•Invasive bacteria causing diarrhoea: specific types of microorganisms can directly attack mucosal cells which cause diarrhoea. Stools will contain blood and pus. Patient will have fever, typical examples shigella, salmonella, yersinia, enteroinvasive E-coli. •Non invasive: don’t directly damage the gut, bacteria produce enterotoxins that disrupt secretion of water and electrolytes. Patient will present with watery diarrhoea, examples include: Staphylococcus aureus, B cereus, C perfingens, enterotoxigenic E. coli. •Virally induced diarrhoea: Mechanism not fully understood Enterocytes become secretory resulting in watery diarrhoea.

Answer 133

•Symptoms: Accompanying symptoms; temp, fever, blood in stool. Rapid onset Absence of stool formation •Trigger factors: Bad/unusual food, alcohol, drugs, contaminated water. Time/intensity: Dehydration in major risk groups, dehydration serious risk in elderly patients. Fecal studies and tests to identify pathogen. If bacterial infection it can be treated with antibiotics. Serum albumin Fecal alpha 1 anti-trypsin Both tests can identify protein loss as this suggests damage in GI tract, not specific test but aids in diagnosis. Intestinal biopsy used in severe diarrhoea.

Answer 134

Infants: infectious gastroenteritis, toddlers diarrhoea, food intolerance, coeliac disease. School age children: Infectious gastroenteritis, drugs (antibiotics) Adults: Infectious gastroenteritis, IBS, IBD, drugs, XS alcohol and spicy food, coeliac disease. Older people: Infectious gastroenteritis, large bowel cancer, faecal impaction (pseudo-diarrhoea) drugs, ischaemic colitis. Typical causing organisms causing diarrhoea: Children < 5: rotavirus most common and onset 12-48hrs. Adults: campylobacter (onset 2-5days) most common, followed by rotavirus. Other causes: E.coli 1-6days, salmonella 12-24hrs, shigella 1-7days, clostridium difficile (usually starts during AB therapy), clostridium perfringens (12-18hrs), bacillus cereus (1-16hours), staphylococcus aureus (1-7hours).

Answer 135

Antibiotics-most common-broad spectrum. Laxatives Metformin Ferrous sulphate (iron) NSAIDs Colestyramine Antacids-Mg Salts Beta blockers Digoxin Misoprostol

Answer 136

Good hygiene: wash hands After visiting the toilet Before touching food After gardening After playing with pets Between handling raw and cooked food SUMMARY: Diarrhoea is a change in normal bowel habit resulting in increased frequency and soft or watery stools. Considerations in treatment include: Age, frequency, duration Assess dehydration risk Anti-motility drugs have a role in the management of diarrhoea.

Answer 137

•List treatment options for different patients groups •Describe the pharmacology of the treatment options •Describe how to apply the guidance to over counter requests •List appropriate non-pharmaceutical advice •Identify and give details on the signs of dehydration •Describe the cause, symptoms and treatment of Clostridioides Difficile infection (C.Diff)

Answer 138

Treatment aims: *prevention and reversal of fluid and electrolyte depletion *Management of dehydration if present •Most settle spontaneously at around 3 days •Oral rehydration therapy ORT dioralyte rehydration salt. •Rapid control of symptoms required? Consider using Loperamide or branded Imodium peripheral opioid agonist (Loperamide acts as a potent opiate agonist in the intestine and reduces intestinal motility, causing a slowing of intestinal transport and increased resorption of water and electrolytes, actions that are helpful in treating diarrhea.) Difference between prescribed dose and OTC med GSL and P med. •Prescribed dose >12years: initially 4mg, followed by 2mg after each loose stool (for up to 5days max) usual dose 6-8mg daily; maximum16mg per day (8 caps). •GSL/P dose >12 years: initially 4mg, followed by 2mg after each loose stool (for up to 48hours max); usual dose 6-8mg daily; maximum 12mg per day (6 caps). Eat as soon as able bland food like soups, bread, pasta, rice, potatoes. Avoid caffeine, alcohol, carbonated drinks. All of these drinks are diuretics. Avoid anti-motility drugs in severe gastroenteritis or dysentery. These are more serious forms of diarrhoea due to blood/mucus in stools, fever. The concern is that loperamide can prolong the infection. Prevention and treatment of fluid and electrolyte depletion is primary importance.

Answer 139

Dioralyte >2 (if under 2 years only under medical supervision) Mainstay of treatment for acute diarrhoea, to prevent or correct dehydration. Advise patient to Maintain appropriate fluid intake once rehydration established. Mix sachet with *200ml water*. Dioralyte relief: contains rice starch (bulks when in contact with water, this helps retain water int he colon to bulk up stools and help patients lose leas water) Severe cases of diarrhoea require hospitalisation for IV fluids. If under 1 year old-only under doctor supervision and supply: Prescription doses For child 1-11months: 1-1.5 times usual feed volume to be given For child 1-11years 200ml, to be given after every loose motion For child 12-17 years 200-400ml to be given every loose motion, dose according to fluid loss. For adult 200-400ml to be given after every loose motion, dose according to fluid loss.

Answer 140

1-Determine underlying cause and treat as appropriate. •underplaying pathological cause like crohns or IBS. •foreign travel •laxative abuse •medications-PPIs or antibiotics •immunocompromised •family history of IBS/coeliac disease •lactose intolerance (if worsened by diary), excess caffeine/sorbitol •Refer for specialist investigation Oral rehydration therapy and loperamide must be given while ongoing investigations to identify cause.

Answer 141

Loperamide manufacturers advice to avoid in pregnancy (no info available) Weigh up risks to both baby and mum (if severe refer to professional) Loperamide appears in breast milk Amount probably too small to be harmful but it is still not licensed for OTC use in pregnancy or breast feeding. Give patient ORT and fluid essentials- avoid dehydration If symptoms warrant loperamide, refer in both instances from community pharmacy.

Answer 142

Feeding babies, continue with normal milk feeds. Breast milk has antibodies to fight infection or pathogen causing diarrhoea. Children: encourage plenty of fluids Use ORT Anti-diarrhoeals not recommended by NICE ( BNF states doses for children but not licensed in <12 year olds for most products, so never sell from community pharmacy. For <12 need prescription. Preventing spread of diarrohea Careful washing and drying of hands after using toilet, nappy changing and before meals. Don’t share towels 48hour exclusion from school following cessation of symptoms Avoid swimming for 2 weeks following last episode of diarrhoea.

Answer 143

1-Co-phentrope •atropine and diphenoxylate (anticholinergic and opioid) •licensed as adjunct to rehydration in acute diarrohea •Initially 4 tablets followed by 2 tablets every 6 hours until diarrhoea controlled. 2-Kaoline and Morphine •Not evidence based such small amount of morphine No evidence for kaolin in acute diarrhoea Historical use elderly patient Potential for abuse 3-Bismuth sub-salicylate PeptoBismol (never in less than 16yrs old due to Reye’s syndrome) Limited evidence not recommended by BNF or NICE Inhibits intestinal fluid secretion Suppresses intestinal inflammation Bactericidal action. 4-Probiotics •live bacteria •compete for available nutrients with pathogen •insufficient evidence for use on NHS

Answer 144

Synthetic opioid analogue-pethidine congener which doesn’t readily pass BBB. Binds to mu-opioid receptors in gut wall, this inhibits Acetylcholine and Prostaglandin release. ACh is the main excitatory neurotransmitter in the GI tract ACh binds to muscarinic/ nicotinic ACh receptors, increasing parasympathetic activity. ACh inhibition leads to: Decreased propulsive peristalsis Decreased sensitivity to rectal distension Increased sphincter tone of the ileocaecal valve and anal sphincter. •prostaglandin inhibiton leads to: Reduced gut secreations Reduced gut motility both mainly via inhibition of PGE2 Increased intestinal transit time (enhancing water and electrolyte reabsorption) Morphine/codeine are also sometimes used to treat diarrohea As opioids, they share this mechanism of action Problems with abuse/dependence.

Answer 145

100 parts diphenoxylate HCl to 1 part atropine sulphate. 1-Diphenoxylate •synthetic opioid- pethidine congener; doesn’t readily pass BBB. •Does not usually have CNS activity; large doses lead to typical opioid effects. •Insoluble salts mean that there is no potential for misuse by injectors. 2-Atropine •Muscarinic ACh receptors antagonist. •Reduction in ACh reduces parasympathetic drive PNS. •GI motility is inhibited. •Effect not marked as several as several excitatory transmitters, including ACh are important in the function. AI: Co-phenotrope is a combination medication that contains 100 parts of diphenoxylate HCl and 1 part of atropine sulphate. Here is the pharmacology of each component: 1. Diphenoxylate: - It is a synthetic opioid and a congener of pethidine. - Diphenoxylate does not readily pass the blood-brain barrier (BBB). - Typically, diphenoxylate does not have central nervous system (CNS) activity. However, at high doses, it can produce typical opioid effects. - The presence of insoluble salts in diphenoxylate reduces the potential for misuse by injectors. 2. Atropine: - Atropine is an antagonist of muscarinic acetylcholine (ACh) receptors. - By blocking the action of ACh, atropine reduces parasympathetic drive from the peripheral nervous system (PNS). - Inhibition of GI motility is one of the effects of atropine. - However, the effect of atropine on GI function is not as pronounced as several excitatory transmitters, including ACh, play a role in GI function.

Answer 146

Red flags to refer: •Recent travel abroad (especially to intermediate/high risk areas) •Blood or mucus in stools •Associated with severe vomiting and fever •Severe or persistent abdominal pain •Pregnancy and breast feeding •Signs of dehydration Referrals to GP when duration exceeds: >1days for infants and under 1yr old >2days for children under 3 and frail elderly patients >3 children over 3 and otherwise healthy adults

Answer 147

Absorption of medicines may be affected Drink plenty of clear fluids Avoid drinks high in sugar, alcohol or caffeine. Avoid carbonated fluids-causes bloating Avoid milk Eat light and easily digested food Advise not to return to work until they have been symptom-free for 48hours Hygiene Hand washing Cleaning toilet seats flush handles and basin.

Answer 148

3 or more loose stools in 24hrs with or without at least one symptoms of cramps, nausea, fever, or vomiting. Causes: •Bacteria (most common esp Ecoli? Viruses, protozoan parasites •Comparatively lower food hygiene and sanitation facilities in destination •Prevention: Food, water and personal hygiene Vaccines (hepatitis A, typhoid and cholera) •Treatment Maintain hydration Loperamide Antibiotic treatment

Answer 149

Appears unwell or deteriorating Altered responsiveness Decreases urine output Skin colour unchanged Warm extremities Altered responsiveness Sunken eyes Dry mucus meme brand except for mouth breather Tachycardia Tachypnoea Reduced skin turgor Normal blood pressure Normal peripheral pulses Clinical shock: Decreased level of consciousness Pale or mottled skin Cold extremities Tachycardia Tachypnoea Weak peripheral shock Prolonged capillary refil time Hypotension indicates decompensated shock

Answer 150

When patient is unwell with any of the following symptoms: Vomiting Diarrhoea Fever sweats and shaking Then the following medications must be stopped due to risk of acute kidney injury or failure as they increase the risk of dehydration ACE inhibitors; lisinopril, perindopril, ramapril. ARBs: losartan, candesartan, valsartan NSAIDs: ibuprofen, Diclofenac, naproxen Diuretics: furosemide, spironolactone, indapamide, bendroflumthiazide. Metformin lactic acidosis can occurs due to dehydration. This is a serious life threatening risk. Then resume when patient is treated for dehydration using ORT

Answer 151

C.Diff bacterium usually present int he gut. Broad spectrum antibiotics upset microbiome allowing C.Diff to flourish C.Diff releases toxins that damage lining damage of colon Highly contagious diarrhoea can develop can be fatal Risk factors include broad spectrum Abx use >65 years old prolonged stay in hospital care home, immunocompromised Sepsis can happen in severe infection of C.Diff Treatment= Vancomycin 125-500mg every 6-hours for 10days.

Answer 152

Describe the epidemiology of irritable bowel syndrome Describe the aetiology of IBS Describe the Pathophysiology of IBS Describe the symptoms of IBS List common treatments Describe pharmacology of common treatments Describe red flag symptoms of IBS

Answer 153

Onset most common at 20-30 years of age X2 more common in females than males Estimated to effect 10-20% of population but it is under reported X2 risk among 1st degree relatives Lack of reliable prevalence data

Answer 154

Exact cause of IBS is not understood Food intolerances eg lactose/gluten are precursors to IBS No lesions are present gut is not damaged or diseased Post infective bowel dysfunction, gut hypersensitivity, altered colonic motility and heightened pain sensation all implicated. Stress commonly implicated.

Answer 155

Structurally the gut is normal IBS is a functional GI disorder No detectable pathology using standard tests Blood tests/stools samples/ colonoscopy may be used to rule out other conditions Functional conditions require symptoms management

Answer 156

Abdominal cramping Diarrohea/ constipation/alternating Flatulence Bloating Urgency to defecate Acid indigestion Nausea Lethargy Eating May worsen symptoms Passing mucus in stools

Answer 157

•Abdominal pain present for at least 6months •Relieved by defecation or: •Increased/decreased bowel frequency or stools form •Plus at least 2 of the following: *Abdominal bloating/distension *Altered stool passage (straining, urgency, incomplete evacuation) •Worsened by eating •passing mucus Secondary care diagnosis: •The Rome IV criteria are sometimes used •Abdominal pain 1 day per week in the last 3months •symptoms began at least 6months prior •Alongside >2 of the following related to defecation Change in stool frequency Change in stool form

Answer 158

IBS-C >25% of stools are types 1/2, <25% are types 6/7 IBS-D >25% of stools are types 6/7, <25 are types 1/2 IBS-M >25% of stools are types 1/2 and >25% of stools are types 6/7 IBS-U Persons has IBS, but bowel habits can’t be categorised as above

Answer 159

Antispasmodic drugs Antidepressants Laxatives Loperamide Linaclotide

Answer 160

Preferable to use direct smooth muscle relaxants: 1-Alverine Citrate 60-120mg to TDS 2-Mebeverine 135mg TDS (20mins before food) or 200mg BD for MR prep 3-Peppermint oil capsules 1-2 caps to TDS •Hysocine butylbtomode and dicycloverine can also be used but tend to have more antimuscarinic effects •Contraindicated in intestinal obstruction or paralytic ileus.

Answer 161

Use is licensed for patients with IBS Patients who have not responded to typical treatments Doses given are lower than you would see for mental health disorders uses. TCA e.g Amitriptyline 10-30mg at night SSRI 2nd line (sertraline, citalopram, fluoxetine) BSG doesn’t specifically recommend one Pain modulators effects/peripheral on GI function Counsel patients as they may be shocked when reading PIL.

Answer 162

For IBS-C: •Laxatives from any class May be used aside for on Lactulose •Lactulose can increase gas production and worsen symptoms •Dose should be titrated according to symptoms •Review laxative advice from constipation notes •Avoid prolonged stimulant laxative use

Answer 163

Is used for IBS-D Review diarrhoea notes Remember P/GSL versions of loperamide can be used for acute diarrhoea in IBS but only for patients>18yrs old Must have been diagnosed with IBS monkey for attacks lasting up to 48hours refer if longer Can be used for 2 weeks maximum, as long as individual bouts are less than 48hours

Answer 164

•For moderate to severe IBS-C in adults •Person must have had IBS-C for at least 12months •Should only be used if max tolerated doses of laxatives haven’t helped •290mcg once daily 30mins before food •Avoid in GI obstruction/IBD

Answer 165

•Exact mechanism of action for Mebeverine unknown •It specifically acts on smooth muscle cells •Blocks voltage operated sodium channels •This prevents build up of intracellular calcium •This reduces symptoms of colonic hypermotility

Answer 166

•Guanylate Cyclase-c agonist •GC-C activation leads to increased production cyclic guanosine monophosphate cGMP •Increased 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 time is increased GC-C~~> |cGMP~~> |CFTR action~~> | intestinal chloride+bicarbonate

Answer 167

•Unintentional weight loss •Unexplained rectal bleeding •Family history of bowel/ovarian cancer •Loose stools for >6 weeks in patients > 60yrs old •Anaemia •Elevated inflammatory markers (IBD?) •Abdominal/rectal masses

Answer 168

Presence of diverticula (diverticulum) _pouches protruding outwards from the large intestine wall. _small mucosal herniations protruding through intestinal layers and smooth muscle. Diverticulosis: _condition where uninflammed diverticula _usually asymptomatic Diverticular disease: _symptomatic Diverticulitis _condition where one or more inflamed/infected diverticula AI: Diverticula are pouches that protrude outwards from the wall of the large intestine. They are small mucosal herniations that protrude through the intestinal layers and smooth muscle. Diverticulosis refers to the condition of having uninflamed diverticula. It is usually asymptomatic, meaning it doesn't cause any noticeable symptoms. However, when diverticula become symptomatic and cause various gastrointestinal issues, it is referred to as diverticular disease. Diverticulitis specifically refers to the condition where one or more diverticula become inflamed or infected. This can cause symptoms such as abdominal pain, fever, and changes in bowel habits.

Answer 169

Diverticulosis is a condition characterized by the presence of small pouches, called diverticula, in the lining of the colon or large intestine. It is a common condition that usually does not cause any symptoms or complications. Diverticular disease, on the other hand, refers to a range of conditions that can occur as a result of diverticulosis. These conditions include diverticulitis, which is inflammation or infection of the diverticula, and diverticular bleeding, which is bleeding from the diverticula. Diverticular disease can cause symptoms such as abdominal pain, bloating, changes in bowel habits, and rectal bleeding. In summary, diverticulosis is the presence of diverticula in the colon, while diverticular disease refers to the complications or symptoms that can arise from diverticulosis.

Answer 170

Diverticular disease is very common, particularly in industrialised countries. _Westernisation increases incidence _Lack of fibre _Prevalence Similar in females and males Increase with age Rare in people aged <40 1/3 people >65yrs and >65% people over >85. 80-85% patients remain asymptomatic Approximately 5% with diverticulosis develop diverticulitis. 15-25% patients with diverticulitis develop COMPLICATIONS requiring surgery. Mortality associated with these: 1.Abscess formation 2.Intestinal rupture 3.Fistulas 4.Peritonitis 5.Massive bleeding More common in patients who are immunocompromised on anti-inflammatories or have severe co-morbidities Sure, here are the explanations for each term: 1. Abscess formation: Abscess formation refers to the development of a localized collection of pus within the body. In the context of diverticular disease, it can occur when an infection within a diverticulum spreads and leads to the formation of an abscess. Abscesses can cause pain, swelling, and inflammation in the affected area. 2. Intestinal rupture: Intestinal rupture, also known as bowel perforation, is a serious complication that can occur when there is a hole or tear in the wall of the intestine. In the case of diverticular disease, if the inflammation or infection in the diverticula becomes severe, it can weaken the intestinal wall and potentially lead to rupture. This can result in the leakage of intestinal contents into the abdominal cavity, which can cause severe abdominal pain, infection, and other complications. 3. Fistulas: Fistulas are abnormal connections or passageways that form between two organs or between an organ and the skin. In the context of diverticular disease, fistulas can develop when an inflamed or infected diverticulum creates a tunnel-like passage to another organ, such as the bladder or the skin. This can lead to various symptoms and complications, depending on the location of the fistula. 4. Peritonitis: Peritonitis is a condition characterized by inflammation of the peritoneum, which is the thin tissue lining the inner wall of the abdomen and covering the abdominal organs. In diverticular disease, peritonitis can occur if there is a rupture or perforation of the intestine, leading to the release of intestinal contents into the abdominal cavity. This can cause severe infection, abdominal pain, fever, and other symptoms that require immediate medical attention. 5. Massive bleeding: Massive bleeding refers to significant and profuse bleeding that can occur as a complication of diverticular disease. In some cases, the blood vessels in the diverticula can rupture, leading to substantial bleeding. This can result in symptoms such as rectal bleeding, blood in the stool, dizziness, weakness, and potentially life-threatening situations if not promptly addressed. It is important to note that these complications are more commonly associated with diverticulitis, which is the inflammation or infection of the diverticula.

Answer 171

Causative agents unknown: 1-Increased intraluminal pressure and weakening of muscle wall thought to be the primary cause. Hypertrophy in the lining of large intestine due to low fibre diet. 2-Abnormal colonic motility due to opioid use analgesic or IBS. 3-Defective muscular structure. 4-Changes in collagen structure eg in aging. Factors: Genetics, left sided diverticula forte dominate in the west sigmoid colon but right sided predominant in Asians. Dietary factors: •Associated with a low fibre diet and constipation •Obesity

Answer 172

•Colonic muscular hypertorphy results in the narrowing of lumen and formation of small chamber with high pressure and subsequent diverticula. Diverticulitis: •Fecal material or undigested food collect in Diverticula and cause obstruction •Mucus secretions and normal bacterial overgrowth lead to distension of diverticula. This results in vascular compromise and perforations. •Increase in intraluminal pressure and stuck food particles may also damage diverticula wall, resulting in inflammation, necrosis & perforations. •Recurrent attacks leads to scar tissue formation and lumen narrowing.

Answer 173

Condition is asymptomatic so no need for routine follow ups. Maintain healthy balanced diet, high in fibre 30g per day Maintain adequate fluid intake If overweight advise about benefit if weight loss, exercise and also smoking cessation to prevent progression. If constipated-offer bulk forming laxatives.

Answer 174

•Intermittent pain in lower left quadrant (with constipation, diarrhoea, rectal bleeds). •Abdominal pain worsened by eating, relieved by passing stool or wind. •Flatulence •Lower left quadrant tenderness on palpation. •Asian populations develop symptoms may present right sided. •Symtpoms can overlap with other conditions like IBS. •No systemic symptoms

Answer 175

High fibre diet Bran supplements/Bulk forming laxatives Lifestyle advice as per diverticulosis Antispasmodics when colic eg Alverine, mebeverine, peppermint oil. Meds to Avoid: NSAIDs Anti-motility drugs to slow transit time eg codeine and loperamide should not be used these drugs Increase Risk of diverticular perforation. AI: Diverticular disease management typically involves a combination of lifestyle modifications and medications. Here are some key management strategies: 1. High-fiber diet: Consuming a diet rich in fiber can help prevent constipation and promote regular bowel movements, which can reduce the risk of diverticular disease progression. Foods high in fiber include fruits, vegetables, whole grains, and legumes. 2. Bran supplements/Bulk-forming laxatives: These can be used to increase dietary fiber intake and help soften the stool, making it easier to pass. Examples of bulk-forming laxatives include psyllium husk and methylcellulose. 3. Lifestyle advice as per diverticulosis: It is important to maintain a healthy lifestyle to manage diverticular disease. This includes regular exercise, maintaining a healthy weight, drinking plenty of fluids, and avoiding smoking and excessive alcohol consumption. 4. Antispasmodics: Antispasmodic medications, such as Alverine, Mebeverine, and peppermint oil, can help relieve colic or abdominal pain associated with diverticular disease by relaxing the muscles in the intestines. Medications to avoid in diverticular disease: 1. NSAIDs: Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, should be avoided as they can increase the risk of diverticular perforation and bleeding. 2. Anti-motility drugs: Drugs that slow down intestinal transit time, such as codeine and loperamide, should be avoided as they can increase the risk of diverticular perforation. These medications can delay the movement of the stool and potentially worsen the condition.

Answer 176

Constant lower left abdominal pain with: Fever Sudden bowel movement Blood mucus in stools Lower left quadrant tenderness Palpable abdominal mass distension Malaise Nausea and vomiting Increased WBC, if bleeding occurs increase in platelets, anaemia and increased CRP. AI: Diverticulitis is a condition characterized by inflammation or infection of small pouches called diverticula that develop in the lining of the colon, most commonly in the lower left side of the abdomen. It typically presents with the following symptoms: 1. Constant lower left abdominal pain: The pain is usually persistent and localized to the lower left side of the abdomen. It may be described as cramping or sharp in nature. 2. Fever: Inflammation and infection in diverticulitis can lead to an elevated body temperature, resulting in fever. 3. Sudden bowel movement: Diverticulitis can cause changes in bowel habits, including sudden urges to have a bowel movement or increased frequency of bowel movements. 4. Blood and mucus in stools: In severe cases, diverticulitis can lead to the presence of blood and mucus in the stools. This is known as rectal bleeding and may range from mild to severe. 5. Lower left quadrant tenderness: The affected area in diverticulitis is often tender to touch, particularly in the lower left quadrant of the abdomen. 6. Palpable abdominal mass distension: In some cases, a palpable mass or swelling may be felt in the lower left abdomen. This can occur due to an abscess (collection of pus) or inflammation in the diverticula. 7. Malaise: Diverticulitis can cause a general feeling of discomfort, weakness, or unease, known as malaise. 8. Nausea and vomiting: Inflammation and infection in diverticulitis can lead to nausea and vomiting. 9. Laboratory findings: Blood tests may reveal an increased white blood cell count (indicating the presence of infection) and elevated C-reactive protein (CRP) levels, which are markers of inflammation. If bleeding occurs, there may be an increase in platelet count and evidence of anemia. It is important to seek medical attention if you are experiencing these symptoms as diverticulitis can be a serious condition that requires proper diagnosis and management. Treatment may involve antibiotics, pain management, dietary modifications, and, in severe cases, hospitalization for intravenous antibiotics and possible surgical intervention.

Answer 177

Refer to hospital if: Patient is over 65years Co-morbidities Immunocompromised Can’t take oral Abx antibiotics at home so need IV in hospital setting Dehydrated at risk and can’t rehydrate at home Uncontrollable abdominal pain plus signs of complicated acute diverticulitis.

Answer 178

Signs of complicated acute diverticulitis: 1-Intra-abdominal abscess mass on examination 2-Diverticular haemorrhage 3-Peritonitis (rigidity, guarding upon examination) 4-Stricture (reduced GI motility, constipation, cramping) 5-Fistula formation (faecaluria, pneumaturia, passing faeces through bladder/vagina) A colovesical fistula is an open connection between the colon and bladder. A thick wall of tissue normally separates the two. Fecal matter from the colon can enter the bladder through this colovesical fistula, causing painful infections and other complications. 6-Intestinal obstructions (cramping, absolute constipation, distension) 7-Sepsis increase in resp and HR, decrease in systolic blood pressure and no urine output, skin discolouration, cognitive impairment.

Answer 179

Acute +systemically unwell but doesn’t need admission= Co-amoxiclav 500/125 TDS x5 days (Cefalexin if penicillin allergy) + Metronidazole 400mg TDS x5 Trimethoprim 200mg BD x5 days + metronidazole 400mg TDS x5 days Acute + systemically well= Consider no antibiotics strategy (antimicrobial stewardship) Analgesia paracetamol (avoid NSAIDs/Opioids) Re-present if symptoms worsen

Answer 180

2 inflammatory disorders of the gastro-intestinal tract _Crohns diseases _Ulcerative colitis Both of which are Chronic disease: _Follows an unpredictable relapsing & remitting course, varying severity When measuring inflammatory cytokines in patients blood even in remission phase results will show these inflammatory cells are primed to react again. Relapse can occur once a year or once in 5 years. _Extra-gastrointestinal manifestations •In 10-15% cases-UC & CD May be difficult to distinguish.

Answer 181

Crohn’s disease: Affects any part of the GI tract from mouth to rectum. Inflammation extends through all layers of the gut wall. Mucosa sub-mucosa, muscularis & serosa. If inflammation occurs through all these layers then fistulas can form and opening/leak from GI into other tissues or organs can occur. Inflammation is patchy in distribution Ulcerative Colitis: Affects the colon and rectum only Affects one layer mucosa and submucosa. Inflammation is diffuse/continuous in distribution.

Answer 182

World-wide distribution of IBD _more common in industrialised countries _affects all races & both sexes Peak incidence occurs at 10-40years Can occur at any age 15% over 60yrs old 1/250 people are affected by IBD in the uk Rapid increases in incidence between 1955-1975 Particularly Crohn’s disease but now it is stabilised

Answer 183

CD •5-20 per 100,000 population per year. •Prevalence of 50-100 cases per 100,000 population. UC twice as much as CD •10-20 per 100,000 population per year •prevalence of 100-200 cases per 100,000 population Male:Female ratio: CD is slightly more common in females M:F= 1:1.2 Occurs at younger age Mean age at onset: 26 years UC slightly more common in males M:F = 1.2:1 Occurs at an older age Mean age at onset 34

Answer 184

Causative agents of IBD are unknown Numerous factors are though to have a role e.g Environmental: Diet Smoking Infection Drugs Diet: Several factors have been associated with IBD Fat intake, fast food ingestion, milk, fibre consumption, total protein and energy intake and refined carbohydrates Evidence is inconclusive •Many patients are able to identify foods that aggregate or exacerbates their symptoms Cows milk or spicy foods Smoking: Worsens clinical course of disease Increased risk of relapse & need for surgery. 40% of CD patients are smokers 10% UC Smoking may help to prevent onset of UC as chemicals affect colon smooth muscles: Alters gut motility and transit time. Infection: Evidence that exposure to Mycobacterium paratuberculosis can cause CD. UC can occur after episode of infective diarrohea, no definite association with single infective agent. Association with measles & mumps infections. Enteric microflora IBD patients loss of immunological tolerance to intestinal microflora. Can be manipulated by antibiotics, probiotics and prebiotics to balance favourably. How does the loss of tolerance to intestinal microflora occur in patients? The loss of tolerance to intestinal microflora in patients can occur due to various factors. One possible reason is a disturbance in the balance of gut bacteria, also known as dysbiosis. This can be caused by factors such as antibiotic use, poor diet, stress, or certain medical conditions. When the balance of gut bacteria is disrupted, it can lead to an overgrowth of harmful bacteria or a decrease in beneficial bacteria. This imbalance can trigger an immune response in the gut, leading to inflammation and loss of tolerance to the normal microflora. Other factors that can contribute to the loss of tolerance include intestinal infections, autoimmune diseases, genetic predisposition, and environmental factors. These factors can disrupt the normal immune response in the gut, leading to an abnormal reaction to the intestinal microflora. It's important to note that the loss of tolerance to intestinal microflora is a complex process, and the exact mechanisms are still being studied. However, maintaining a healthy diet, managing stress, and avoiding unnecessary antibiotic use can help promote a balanced gut microbiome and reduce the risk of developing intolerance to intestinal microflora. What is the difference between prebiotics and probiotics? Prebiotics and probiotics are both beneficial for gut health, but they have different roles. Probiotics are live bacteria or yeasts that are beneficial to the digestive system. They can be found in certain foods, such as yogurt, kefir, sauerkraut, and kimchi, or taken as dietary supplements. Probiotics help restore and maintain a healthy balance of bacteria in the gut. They can improve digestion, support immune function, and may even have other health benefits beyond the gut. On the other hand, prebiotics are non-digestible fibers that serve as food for the beneficial bacteria in the gut. They are found in certain foods, such as onions, garlic, bananas, and whole grains. Prebiotics help stimulate the growth and activity of beneficial bacteria in the gut. By nourishing these bacteria, prebiotics promote a healthy gut microbiome and can improve digestion, support nutrient absorption, and enhance overall gut health. In summary, probiotics are live bacteria that you consume directly, while prebiotics are fibers that nourish the beneficial bacteria already present in your gut. Both probiotics and prebiotics play important roles in maintaining a healthy gut microbiome, and they can complement each other when consumed together. Drugs: NSAIDs can exacerbate IBD as they inhibit the synthesis of cytoprotective prostaglandins like COX-1 Antibiotics can change enteric microflora and precipitate a relapse. Oral contraceptives pill: Increase risk of developing CD Possibly caused by vascular changes Isotretinoin- for acne- possible risk factor. Appendectomy: Has protective effects on CD and UC Immunologically based? People who have had their appendix removed are at higher risk. Stress: Can trigger a relapse in IBD Activates inflammatory mediators at enteric nerve endings in gut wall. Genetic factors influence the risk of IBD by causing: Disruption of epithelial barrier integrity. Deficits in autophagy Deficiencies in innate pattern recognition receptors Problems with lymphocyte differentiation, especially CD

Answer 185

Genetic factors influence the risk of IBD by causing: Disruption of epithelial barrier integrity. Deficits in autophagy Deficiencies in innate pattern recognition receptors Problems with lymphocyte differentiation, especially CD Inappropriate response of the immune system in the mucosa of the GI tract to normal enteric flora. Mutations of the gene CARD15/NOD2 located in chromosome 16 associated with small intestine CD in white populations The gene OCTNI on chromosomes 5 and DLG5 on chromosome 10 have also been linked to CD 70% of UC patients: Have anti-neutrophil cytoplasmic antibodies (p-ANCA) Autoimmune component: association between IBD ankylosis spondylitis & histocompatibility antigen HLA-B27 AI: Genetic factors play a significant role in influencing the risk of inflammatory bowel disease (IBD) by causing various disruptions and deficiencies in the body. Some of these factors include: 1. Disruption of epithelial barrier integrity: Genetic factors can affect the integrity of the epithelial barrier in the gastrointestinal (GI) tract. This disruption can lead to increased permeability, allowing harmful substances to enter the gut and trigger an immune response. 2. Deficits in autophagy: Autophagy is a cellular process that helps remove damaged cellular components and pathogens. Genetic factors can cause deficits in autophagy, leading to the accumulation of harmful substances and impairing the immune response in the GI tract. 3. Deficiencies in innate pattern recognition receptors: Innate pattern recognition receptors (PRRs) play a crucial role in recognizing and responding to pathogens in the gut. Genetic deficiencies in PRRs can weaken the immune response and increase susceptibility to IBD. 4. Problems with lymphocyte differentiation, especially CD: Genetic factors can affect the differentiation of lymphocytes, particularly CD4+ T cells, which play a significant role in regulating immune responses. Dysregulation of lymphocyte differentiation can lead to an inappropriate immune response in the mucosa of the GI tract. 5. Inappropriate response of the immune system to normal enteric flora: Genetic factors can contribute to an abnormal immune response in the gut, leading to inflammation and damage to the intestinal tissue, even in the presence of normal gut bacteria. Additionally, mutations in specific genes have been associated with IBD. For example, mutations in the gene CARD15/NOD2, located on chromosome 16, are linked to an increased risk of small intestine Crohn's disease (CD) in white populations. The genes OCTNI on chromosome 5 and DLG5 on chromosome 10 have also been identified as genetic factors associated with CD. It is important to note that while genetic factors play a role in IBD, they do not solely determine the development of the disease. Environmental factors, lifestyle choices, and the interaction between genes and the environment also contributes to the risk of developing IBD. In ulcerative colitis (UC), approximately 70% of patients have the presence of anti-neutrophil cytoplasmic antibodies (p-ANCA). These antibodies are directed against the cytoplasmic components of neutrophils and can be detected through blood tests. The presence of p-ANCA is often used as a diagnostic marker for UC. There is also an autoimmune component associated with inflammatory bowel disease (IBD) and ankylosing spondylitis. Ankylosing spondylitis is a type of arthritis that primarily affects the spine. It is characterized by inflammation and fusion of the spinal joints. Studies have shown an increased prevalence of ankylosing spondylitis in individuals with IBD, particularly those with UC. Furthermore, there is a genetic association between IBD, ankylosing spondylitis, and the histocompatibility antigen HLA-B27. HLA-B27 is a specific human leukocyte antigen (HLA) gene variant. It is more commonly found in individuals with ankylosing spondylitis and is also associated with an increased risk of developing IBD, particularly in individuals with UC. The exact mechanisms underlying the relationship between these conditions and HLA-B27 are not fully understood. However, it is believed that HLA-B27 may contribute to an abnormal immune response and inflammation in both UC and ankylosing spondylitis. It is important to note that while there is an association between these conditions, not all individuals with UC will have p-ANCA or develop ankylosing spondylitis, and not all individuals with ankylosing spondylitis will have UC or IBD. The presence of these factors can vary among individuals, and the development of these conditions is influenced by a combination of genetic, environmental, and immunological factors. Ethical factors: Jews are more prone than non Jews IBD incidence is lower in non-white races Familial factors: First degree relatives of those with IBD have up to 20% chance of developing IBD 15% greater concordance for IBD in identical twins than non identical twins.

Answer 186

IBD is a severe prolonged and inappropriate inflammatory response to trigger factors. Alters the normal architecture of the G.I tract. Could be due to: Increased inflammatory activity of effector lymphocytes and pro-inflammatory cytokines that override normal control mechanisms. Primary failure of regulatory lymphocytes and pro inflammatory cytokines. In CD, T cells are resistant to apoptosis after inactivation.

Answer 187

Affects any part of the gut: Involving one area or multiple areas Usually the terminal ileum and ascending colon. Discontinuous Affected areas are thickened, oedematous and narrow: Deep ulcers can appear Mucous membrane between fissures has Cobblestone appearance. Can progress to deep fissuring ulcers, fibrosis and strictures. Also can lead to bowel obstructions, abscess and gut perforations. Microscopically: Non-specific granulomatous inflammation. Inflammation extends throughout all layers of the bowel transmural Inflammatory cells are seen throughout lymphocytes and plasma cells Th1 associated Chronic inflammation leads to an increased risk of cancer.

Answer 188

Starts in the rectum (proctitis) and if it extend it’s called Universal. 40% rectum proctitis 40% sigmoid & descending colon (left sided colitis) 20% whole colon Only the mucosa & sub-mucosa are affected Continuous starting in the rectum Formation of crypt abscess & mucosal ulceration Mucosa looks red, inflamed & bleeds easily. Purulent & granular with superficial ulceration Pseudo-polyps in severe inflammation Microscopically: Inflammatory cells infiltrate the lamina propia and crypts. Th2 associated Dyspepsia can be seen from biopsies Can progress to carcinomas Difference between UC and CD UC is Th2 associated IL 4,5,10 Th2 associated. Dysplasia can be seen from biopsies changes to cells UC more bleeding than CD AI: Ulcerative colitis (UC) is a type of inflammatory bowel disease that primarily affects the colon and rectum. It typically starts in the rectum and can extend to other parts of the colon. The extent of involvement can vary, with approximately 40% of cases involving only the rectum (proctitis), 40% involving the sigmoid colon and descending colon (left-sided colitis), and 20% involving the entire colon. In UC, only the mucosa and submucosa layers of the colon are affected. The inflammation is continuous, starting from the rectum and progressing to other parts of the colon. This chronic inflammation leads to the formation of crypt abscesses and mucosal ulceration. The mucosa appears red, inflamed, and easily bleeds. In severe cases, purulent and granular changes with superficial ulceration can be observed, and pseudopolyps may develop. Microscopically, UC is characterized by inflammatory cell infiltration in the lamina propria and crypts. It is associated with a Th2 immune response, with the production of cytokines such as IL-4, IL-5, and IL-10. Dysplasia, which is the abnormal growth of cells, can be observed in biopsies and may progress to the development of carcinomas. One key difference between UC and another type of inflammatory bowel disease called Crohn's disease (CD) is the association with Th2 immune response. UC is specifically associated with Th2 cytokines, while CD has a more complex immune response. Dysplasia can also be seen in biopsies of UC, indicating changes in cell structure. Additionally, UC tends to cause more bleeding compared to CD.

Answer 189

IBD depends on site, extent and severity of active disease. Symptoms of both disease: Diarrohea Fever Abdominal pain Nausea & vomiting (more common in CD) Malaise Lethargy Weight loss more common in CD Malabsorption Growth retardation in children

Answer 190

Tends to be more disabling than UC Onset can be acute or insidious Other symptoms include: Pain particularly on LRQ Anaemia Palpable masses Small bowel obstructions Abscesses Fistulas Gut perforations

Answer 191

Symptoms: Diarrhoea with blood/mucus in stools Up to 10-20 liquid stools per day Abdominal pain cramps with fever Constipation due to narrowing due to seedling of colon or rectum. 50% of UC patients have a relapse each year Severe attacks can be life threatening

Answer 192

1-Skip areas common in CD never in UC 2-Cobblestone mucosa common in CD rare in UC 3-Transmural involvement common in CD and occasional in UC 4-Rectal sparing common in CD never in UC 5-Fístulas common in CD never in UC 6- Strictures common in CD and occasional in UC 7-Granulomas common in CD and occasional in UC 8-Perianal involvement common in CD and never in UC

Answer 193

Joints and bones: Arthropathies and osteopenia Skin: Erythema nodosum; tender hot red nodules subside over a few days to leave brown skin discolouration. Pyoderma gangrenosum; Pustule-develops into an ulcer. Ocular: 1-Episcleritis Intense burning and itching of blood vessels involved. 2-Uveitis Headache, burning red eye, blurred vision. Liver Sclerosing Cholangitis: Chronic inflammation of the biliary tree. Leads to progressive fibrosis & biliary strictures.

Answer 194

Quality of life generally lower in CD vs UC, especially because of recurrences after surgery. In UC surgery can be down to remove large intestine and fitting a stoma instead and large intestine juts forms stool and removed water whereas small intestine most absorption occurs and this where nutrient and absorption occurs. Increased risk of peritonitis due to inflammation especially in CD as it can occur over the whole bowel cavity and malignancy. Malnutrition and chronic anaemia common in long-standing CD.

Answer 195

Confirmed by clinical evaluation & a combination of investigations: Biochemical Endoscopic Radiological Histological Nuclear medicine based Hard to distinguish between CD and UC if they both are occurring in the same place in the GI like rectum or large intestine we can’t tell the difference between both. History of disease: Recent travel Medications Smoking Family history Details of symptoms including: Stool frequency & consistency Urgency Rectal bleeding Abdominal pain Fever Examinations: General well being Pulse Blood pressure Temperature weight loss Abdomen tenderness or distension Right iliac fossa mass Anus: Oedematous anal tags, fissures or perianal abscesses. •Blood tests: Anaemia is common Deficiency of iron and it folate also occurs Raised ESR &CRP& WCC Hypoalbuminaemia; protein loss occurring in the gut sue to leakage. LFTs May be abnormal •Microbiological testing for infectious diarrohea •Serological tests Saccharomyces cerevisae antibody usually present in CD P-ANCA antibody Negative in CD and positive in UC

Answer 196

Essential in the initial assessment of suspected severe IBD Excludes colonic dilations Helps assess disease extent in UC Identifies proximal constipation Gives an impression of right iliac fossa mass in CD Can show evidence of small bowel dilations.

Answer 197

Sigmoidoscopy: Internal examinations of the colon (lower third) using a sigmoidoscope. Used for all patients presenting with diarrhoea. Used to confirm diagnosis of UC Rectal Biopsy: Detects non-specific histological changes in the mucosa Colonoscopy: Internal examinations of the colon entire length using a colonscopen Used for mild or moderate disease to assess extent of disease Biopsy can be performed as well Double contrast barium enema: Inferior to colonoscopy Can detect early mucosal changes Small bowel radiology: Current standard for assessing small intestine Ultrasound: Sensitive and non-invasive Identifies thickened small bowel loops in the CD Computer tomography & magnetic resonance imaging Evaluates activity & complications of the disease.

Answer 198

• Know the key differences in the gross morphological features of UC and CD? • Be able to compare and contrast the healthy gut immune response and that in IBD? Understand the different immune responses involved in UC versus CD? Crohn’s disease: Affects any part of the GI tract from mouth to rectum. Inflammation extends through all layers of the gut wall. Transmural Inflammation is patchy in distribution Fissures, fibrosis and strictures Ulcerative colitis: Affects colon and rectum Only affects the mucosa and submucosa Inflammation is diffuse in distribution Psuedopolyps in severe inflammation Crypt abscesses and mucosal inflammation. To maintain healthy guts: 3-components must work together microbes, epithelium barrier function, and immune system.

Answer 199

Small intestine epithelium in healthy state goblet cells Preston in crypt epithelium secrete a layer of mucus and this limits exposure microbes to epithelial cells. Mucus layer forms a barrier. Paneth cells near stems cells secret antimicrobial peptides such as alpha defences that limit bacteria coming through into the lamina propria. The gut is largest producer of IgA immunoglobulin A which provides additional protection to the gut. Specialised epithelial cells called M cells are able to sample by endocytosis lumen antigens and pass this antigen to immune cells this causes tolerance in this harsh environment. This innate microbial sensing by epithelial, dendritic, and macrophages is mediated through pattern recognition receptors. PRR dendritic cells can also sample luminal antigens by passing dendrites through the epithelium and taking them up, these dendritic cells are able to present antigens to naive CD4 cells in secondary lymphoid organs such as Peyers patches and mesenteric lymph node. Where factors such as phenotype of the antigen presenting cells and the cytokine modulates differentiation of CD4 T cells subroots with different types of cytokine profiles. CD4 T cells can differentiate into T reg cells and T helper cells or Th-1,2,17 phenotypes. They also have entrotropic properties, be induced to hold the gut from systemic circulation. These activated T cells will recirculate back into lamina propria through systemic circulation to carry out their function AI: In a healthy state, the small intestine epithelium has several defense mechanisms to protect against microbial invasion. Goblet cells, located in the crypt epithelium, secrete a layer of mucus that forms a barrier and limits the exposure of epithelial cells to microbes. This mucus layer acts as a protective shield. Paneth cells, found near the stem cells, secrete antimicrobial peptides, such as alpha defensins, which further prevent bacteria from entering the lamina propria. These peptides have antimicrobial properties, helping to maintain a healthy gut environment. The gut is the largest producer of immunoglobulin A (IgA), an antibody that plays a crucial role in protecting the gut. IgA provides additional protection by binding to microbes and preventing their attachment to the intestinal epithelial cells. Specialized epithelial cells called M cells are responsible for sampling antigens from the lumen of the gut. These M cells can take up antigens by endocytosis and then transfer them to immune cells, triggering a tolerance response in the gut's harsh environment. This innate microbial sensing by epithelial cells, dendritic cells, and macrophages is mediated through pattern recognition receptors (PRRs). Dendritic cells, a type of PRR cell, can also sample luminal antigens by extending dendrites through the epithelium and taking up the antigens. These dendritic cells then migrate to secondary lymphoid organs, such as Peyer's patches and mesenteric lymph nodes, where they present the antigens to naive CD4 T cells. The phenotype of the antigen-presenting cells and the cytokine environment in the lymphoid organs influence the differentiation of CD4 T cells into different subsets with distinct cytokine profiles, such as T regulatory cells (Tregs) and T helper cells (Th1, Th2, Th17). These activated T cells, including Tregs and Th cells, recirculate back into the lamina propria through the systemic circulation to carry out their functions, including immune regulation and responses to microbial stimuli. This circulation allows for the coordination of immune responses within the gut.

Answer 200

The gut immune system plays a critical role in maintaining the balance between protecting the body from harmful pathogens and tolerating beneficial microbes and dietary antigens. Here is an overview of how the gut immune system functions: 1. Physical and Chemical Barriers: The gut has several physical and chemical barriers that prevent the entry of harmful pathogens. These include the epithelial layer, which acts as a physical barrier, tight junctions between epithelial cells, mucosal layer, and antimicrobial peptides secreted by various cells in the gut. 2. Gut-Associated Lymphoid Tissue (GALT): The gut is equipped with specialized lymphoid tissue known as Gut-Associated Lymphoid Tissue (GALT). GALT includes Peyer's patches, mesenteric lymph nodes, and isolated lymphoid follicles. These structures contain immune cells, including B cells, T cells, dendritic cells, and macrophages, which play a crucial role in immune surveillance and response within the gut. 3. Antigen Sampling and Presentation: M cells, specialized epithelial cells in the gut, sample antigens from the gut lumen and transfer them to underlying immune cells. Dendritic cells, present in the gut epithelium and lamina propria, can also sample luminal antigens. These immune cells process the antigens and present them to other immune cells, such as T cells and B cells, to initiate an immune response. 4. Tolerance and Immune Regulation: The gut immune system has mechanisms to induce tolerance and regulate immune responses to harmless antigens, such as dietary proteins and commensal bacteria. Regulatory T cells (Tregs) play a key role in maintaining immune tolerance by suppressing excessive immune activation and preventing inflammation. 5. Immunoglobulin A (IgA) Production: The gut is the largest producer of Immunoglobulin A (IgA), an antibody that plays a crucial role in mucosal immunity. IgA is secreted into the gut lumen and acts by neutralizing pathogens, preventing their attachment to the gut epithelium, and modulating the composition of the gut microbiota. 6. Interaction with Gut Microbiota: The gut immune system has a complex relationship with the trillions of beneficial bacteria residing in the gut, known as the gut microbiota. These bacteria stimulate and shape the development of the gut immune system and contribute to immune homeostasis. The immune system, in turn, helps maintain a balanced gut microbiota composition and prevents harmful microbial overgrowth. 7. Immune Response Activation: When harmful pathogens breach the gut barrier, the immune system mounts an immune response to eliminate the threat. This involves the activation of immune cells, such as T cells, B cells, and phagocytes, which work together to eliminate the pathogens and initiate an inflammatory response if necessary. Overall, the gut immune system is designed to maintain a delicate balance between protecting against pathogens and tolerating the beneficial microbes and dietary antigens within the gut. It relies on various immune cells, antibodies, and regulatory mechanisms to achieve this balance and ensure the overall health of the gut and the body.

Answer 201

1-In the healthy lamina propria, it normally consists of diverse immune cells and secreted cytokines. These include anti-inflammatory mediators. TGF-beta and interleukin-10. These downregukate immune responses. There are pro-inflammatory mediators from innate and adaptive immune cells that limit excessive entry of intestinal microbiota and defend against pathogens. Non inflammatory defences such as phagocytosis via macrophages defend against bacteria entering lamina propria while minimising the damage to the tissue. There is a homeostatic balance maintained between the regulatory T-cells and effector T-cells. 2-In intestinal inflammation: Several events contribute to increased bacterial exposure including disruption of mucus layer, dysregulation of epithelial tight junctions, increased intestinal permeability and increased bacterial adherence to epithelial cells. Inflammatory bowel disease innate cells produce increased levels of TNF-a, IL-6, 12, 23 and other chemokines. Marked expansion of immune cells in the lamina propria with increased number of CD4 T-cells especially the Pro-inflammatory T-cells sub-groups. These also secrete increased level of cytokines and chemokines. Increased production of chemokines results in recruitment of additional leukocytes resulting in a cycle of inflammation. Therapeutic approaches to treating IBD is Inhibiting pro-inflammatory cytokines or the entry of cells into intestinal tissues. Therapeutics approaches also focus on inhibiting T-cell activation and proliferation. Biological therapies focus on blockade of co-stimulatory molecules that enhance interactions between innate and adaptive cells. CD4 cells Th17 subtype express cell surface markers such as IL-23, IL-12 receptor 1 and CL-6 Interleukin 23 compromises of subunits P-19,40 secreted by antigen Presenting cells. Engagement of IL-23 with IL-23 receptor complex results in the activation of JAK-2 regulating transcriptional activations. Different cell types (innate and adaptive immunity) and cytokines are indicated in UC and DC NK cells express more active immune molecules in IBD such as CD28. Dendritic cells remain in hypo responsive tolerogenic state in healthy gut this when IL-10 and TGF-beta is produced this is the healthy tolerogenic state. Dendritic cells are activated with high level till like receptors that occurs in IBD patients when that barrier is broken they migrate to peripheral lymphoid tissues and generate antigen specific T-cell responses and induce adaptive responses. Blocking of interaction between dendritic cells and T cells that can prevent development of colitis. T cell responses associated with IBD: TH1~~~~> IFNgamma, TNF, IL-6~~> CD T-bet TH2~~~~>IL-5,6,13, TNF~~~~> UC GATA3 TH9~~~>IL-9~~~~> UC PU.1 TH17~~~~>IL-17A/F, IL-22,22~~>CD,UC RORC Treg~~~> IL-10,TGF-beta~~~> resolutions healthy response

Answer 202

1-Corticosteroids 2-Azathioprine 3-5-amino salicylates 4-Cyclosporin 5- Methotrexate

Answer 203

1-Corticosteroids are used in the treatment of IBD conditions such as UC & CD. 2-The glucocorticoid receptor complex can inactivate pro-inflammatory transcription factors such as NFKb and activator protein-1 AP1 and so prevent them activating inflammatory mediators such as IL-6 and leukotrienes. 3-Glucocorticoid are potent inhibitors of T-cell activation and pro-inflammatory cytokines and are highly effective treatment for active inflammatory bowel disease. Mechanism of action of glucocorticoids: Glucocorticoids mediate their anti-inflammatory responses by passively transporting themselves into target cells and binding the intracellular glucocorticoids receptors GR, also known as GR-alpha which is held in the cytoplasm due to being bound to the heat shock protein (hsp) complex which compromises chaperone molecules hsp90, hsp70 and immunophilin FKBP59. When the glucocorticoids ligand binds to GR-alpha it becomes activated. This allows the formation of a homodimer of 2 activated GRs which is transported into the nucleus of the target cell. This inhibits the promoter regions of genes such as nuclear factor kappa B NFkB and activator protein-1 AP-1 which are potent transcription factors for many pro inflammatory cytokines and adhesion genes. Central to the anti-inflammatory action of glucocorticoids is the induction of inhibitor kappa B alpha IkBa which binds to and inhibits NF-kB sequestering it in the cytoplasm.

Answer 204

Inhibits de novo purine synthesis and acts as an anti-proliferative agent by interfering with protein, DNA and RNA synthesis and promoting apoptosis. Azathioprine is an immunosuppressive anti-metabolite, it’s metabolite is 6-MP 6-methyl mercaptopurine activation of this molecules occurs via hypoxanthine-guanine phosphoribosyl transferase enzyme (HPRT) processes 6-MP to thio-IMP, which is then converted to thio-XMP and thio-GMP. TMPT and XO also converts 6MP to it is active metabolite TPMT converts 6-MP to other active metabolites, the 6-methylmercaptopurine ribonucleotides (6-MMPR), 6-MP is catabolized by Xanthine oxidase (XO) to the inactive metabolite 6-thiouric acid. The primary metabolic action is via the enzyme xanthine oxidase (XO), which metabolizes 6-MP to its inactive form, 6-thiouric acid (6-TU). TIMP is only active metabolite which HGPRT converts 6MP to TIMP 1-Azathioprine is an immunosuppressive anti-metabolite. 2-Azathioprine is metabolised to 6 mercaptopurine 6-MP. 3-Activation of 6-mercaptopurine occurs via hypoxanthise - guanine phosphoribosyltransferase HGPRT and a series of multi-enzymatic processes involving kinases ie TPMT thiopurine S-methyltransferase to form 6-thioguanine nucleotides 6-TGNs as major metabolites. The cytotoxicity of Azathioprine is due, in part to the incorporation of 6-TGN into DNA. Another inactivation pathway is oxidation, which is catalysed by xanthine oxidase XO, concentrated in the intestine and the liver to form 6-thiouric acid. 6-MP is a purine analog that acts as an antimetabolite immunosuppressive agent inhibiting T-cell proliferation by interfering with the synthesis of nucleotides. Azathioprine and it’s metabolites play a role in control of T-cell apoptosis by modulation of RAC1 activation upon CD28 co-stimulation. Specific blockade of RAC1 activation is achieved by Azathioprine generated 6-Thio-GTP that binds to RAC-1 instead of GTP. Consecutively the activation of RAC-1 targets genes such as MEK, NFkB, bcl-xL is suppressed by Azathioprine, leading to a mitochondrial pathway of apoptosis. Azathioprine therefore converts a costimulatory signal into an apoptotic signal by modulating RAC-1 activity. These findings may explain the beneficial immunosuppressive effects of azathioprine and have important implications for the design of nivel specific therapies for organ transplantation and autoimmune diseases. bcl-xL= antiapoptotic signal

Answer 205

5-Aminosalicylates 5-ASA (Mésalazine, olsalazine, sulphasalazine and balsalazide) are administered orally, rectally via a suppository or enema. 5-Aminosalicylates 5-ASA has effects in the prostaglandin synthesis/ cyclooxyegenase pathway. PGE2 prostaglandin synthesis occurs through a pathway involving cyclooxygenase enzymes. This pathway is up regulated during inflammation. It causes cell proliferation and increased cell survival as well as modulating immune cell differentiation and gut epithelial stem cell function. 5-ASA works on COX dependent pathways COX-1,2 (cell proliferation/ survival inflammation) and COX independent pathways PRAP gamma, NFkB, non COX targets ( cell survival). The precise mechanism of actions of 5-ASAs are unknown but appears to occur through inhibition of COX dependent ( inflammatory) and COX independent (non-inflammatory) processes. 1-Sulphasalazine is the Azo-bond prodrug of 5-ASA and sulphapyridine. Around 90% of a dose of sulfasalazine reaches the colon, where most of it is metabolised by anaerobic bacteria into sulphapyridine and mesalazine (5-ASA). Both metabolites are active most of the sulfapyridine is absorbed and then further metabolised, but most mesalazine is not and remains in the colon. 2-The 5-ASA drug mesalazine has a similar molecular structure to aspirin. It’s molecular targets are similar to other NSAIDs inhibiting cell proliferation through inhibiting cyclooxygenase and reducing prostaglandins synthesis and suppressing of pro-inflammatory cytokine production. 3- 5-ASA also effects the COX-independent pathway: reduces neutrophil chemotaxis to sites of inflammation and inhibit the survival of immune cells through NFkB signalling and inhibits TNF-mediated effects in epithelial proliferation. 4- 5-ASA effects on reactive oxygen metabolites ROM: there is an increased number of neutrophils and activated monocytes in IBD gut tissues. These cells are a source of reactive oxygen metabolites 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 patients. 5ASA can scavenge free radicals during superoxide anion generation in neutrophils I.e inhibits ROM generation so inhibiting oxidative DNA damage.

Answer 206

Modulates pro-inflammatory cytokine production and T-cell survival. Normally used in UC but not in CD patients. Can induce remission in UC. •CsA was first isolated from fungi •lipophilic cyclic peptide of 11 amino acids • immunosuppressive effects on cell mediated and humoral immune responses 1- interactions of antigen with a T-helper Th-cell receptors results in increased intracellular Ca2+. 2- Stimulation of a phosphatase, calcineurin. 3- Activation of various transcription factors that initiate IL-2 expression. 4- MOA Ciclosporin: binds to cyclophillin a cytosolic protein member of the immunophillin family ( a group of proteins that act as a intracellular receptors for such drugs) 5-CsA is a specific competitive inhibitor but calcineurin calcium and calmodulin-dependent phosphatase. Calcineurin normally acts in opposition to the many protein kinases involved in signal transduction. 6-Ciclosporin inhibits translocation of NF-AT transcription factors and reduced transcription of cytokine genes for IL-2, TNF-a, IL-3,4, CD30L, GM-CSF and IFN-gamma. 7-Reduction in IL-2 cytokines synthesis and IFN/IL-3 causes decreased clinal proliferation of T-lymphocytes and decreases expression of IL-2 receptors .

Answer 207

Folates are actively taken up into cells and then converted to poly-glutamates (Fglu). Folates are essential for synthesis of purine nucleotides and thymidylate. The hydro folate reductase enzyme DHFR is involved thymidylate synthesis and is important for transforming an inactive form of folic acid into active form which is necessary to make some of the building blocks needed for DNA production. Reaction is as follows: two step reaction is catalysed by DHFR which converts the substrate first to dihydrofolate FH2 and the FH4 FH4 functions as an essential co-factor carrying the methyl groups necessary for the transformation of 2-deoxyuridylate DUMP to 2-deoxythymidylate DTMP required for the synthesis of DNA and purines. Mechanism of action of MTX: MTX is an anti-metabolite of folic acid, it interferes with the normal metabolic activity of folic acid and it inhibits the DHFR enzyme as it has higher affinity for FH2 than DHFR. FH4 is then depleted. •MTX prevents de novo DNA and purine syntheses. Inhibiting proliferation of lymphocytes involved in the inflammation. •MTX blocks the survival of T cells by blocking proliferation and inducing apoptosis through the elevation of intracellular reactive oxygen species ROS •Suppresses production of pro inflammatory cytokines IL-6,13, TNF-a and IFN-gamma • Blocks leukocytes endothelial adhesion molecules E-selectin, ICAM-1,3, platelet endothelial cell adhesion molecules ( PECAM-1) and VCAM-1 expression.

Answer 208

TNF is elevated in the serum of IBD patients Immune cells isolated from the gut biopsies spontaneously produced increased amounts of TNF, which correlated with the degree of mucosal inflammation in the tissue. TNF is also produced by immune cells in the inflamed gut mucosa of IBD. E.g macrophages. T-cells, dendritic cells and non immune such as fibroblasts and fat cells and is only present in the paneth cells during IBD. Effects of TNF: TNF activates macrophages to produce pro-inflammatory cytokines, increase apoptosis of gut epithelial cells; regulated T cell apoptosis; causes paneth cells death via necroptosis. (Unprogrammed/ inflammatory cell deaths) •The effects of blocking TNF would be to induce T-cell and inflammatory cell apoptosis; reduce inflammatory cytokine production; reduce paneth cell necroptosis; reduce epithelial cell apoptosis; elevate regulatory macrophages m; reduce MMP-induce tissue destruction. •There are two forms of TNF, membrane bound TNF m-TNF which is cleaved by the soluble by TNF alpha converting enzyme TACE into soluble form of TNF sTNF. Both of these are correlated with disease activity in CD & UC patients.

Answer 209

Both TNF forms signal through two distinct TNF receptors TNFR-1 and TNFR-2. TNFR-1 is expressed on lymphocytes and endothelial cells and TNFR2 is ubiquitously expressed. mTNF signals through both receptors whereas sTNF signals with greater affinity through the TNFR-1. TNFR-1 receptor activation results in an intracellular signalling cascade with pleiotropic effects mainly apoptosis ( through a caspase-8 dependent signalling pathway via FADD), or cytokine secretion of e.g. IL-8,1,6 (through nuclear factor kappa B pathway). (Pleiotropic effects are defined as a single gene affecting multiple systems or determining more than one phenotype, Pleiotropic effects of a drug are actions other than those for which the agent was specifically developed. These effects may be related or unrelated to the primary mechanism of action of the drug, and they are usually unanticipated.) TNFR-2 receptor activation pathway does not contain a death domain and can result in cell proliferation, migration and cytokine production e.g. IL-1,6. Infliximab, golimumab (UC only) and Adalimumab are used in IBD. They are human monoclonal antibody that binds to both the soluble and trnaumemebrane bio-active forms of human TNF-a. This interaction prevents the binding of TNF-a to its receptors, thereby inhibiting the biological activity of TNF-a.

Answer 210

Effectiveness of TNF therapy is similar for both UC & CD. Non responders about a third of patients don’t respond to anti-TNF therapy. About 50% initially respond to anti-TNF therapy but then lose their response following continued treatment due to the production of anti-drug antibodies. The production of anti-drug antibodies in response to anti-TNF therapy can occur due to the immunogenicity of the drug. Immunogenicity refers to the ability of a substance to induce an immune response in the body. Anti-TNF drugs are biologic agents designed to target and inhibit tumor necrosis factor (TNF), a protein involved in inflammation. However, as these drugs are derived from biological sources, they can be recognized as foreign substances by the immune system. This recognition triggers the production of antibodies to neutralize and eliminate the drug from the body. The production of anti-drug antibodies can be influenced by various factors, including the specific characteristics of the drug, individual patient factors, and treatment-related factors. For example, the structure and formulation of the drug, the route of administration, and the frequency and duration of treatment can all impact the likelihood of antibody production. Once anti-drug antibodies are produced, they can bind to the anti-TNF drug and prevent it from effectively targeting TNF. This reduces the drug's therapeutic effect and can lead to a loss of response to the therapy. It is worth noting that not all patients develop anti-drug antibodies, and the extent of their impact on treatment response can vary between individuals. Monitoring for the presence of these antibodies and adjusting treatment accordingly is an important aspect of managing patients receiving anti-TNF therapy.

Answer 211

Adaptive immunity: T cell homing/ trafficking in IBD activated T cells migrate or home to the gut tissues where they accumulate in large numbers, secrete inflammatory cytokines (IL-6, IL-23, TNF-a) and results in an un-resolving chronic inflammation. T-cell homing from the blood to the site of inflammation in the gut requires the interaction of 2 molecules; one on the surface of T cells and one on the surface of endothelial cells of the vessels. T cells, Tregs, and T helper cells; TH1, TH2, TH17 and all express a common molecules necessary for emigration form blood vessels into gut tissues. Defects in the function fi these cells occurs in IBD. The cell surface integrin a4B7 is a gut specific adhesion molecule not found in the other sites/organs of the body. The integrin a4B7 specifically interacts with mucosal vascular addressing adhesion molecule (MAdCAM1) that is expressed on the endothelium. Retention: T cells are also retained within the gut tissues through the binding of a4B7 integrin to E cadherins on the basal membrane of the epithelial cells. (Integrin α4β7 mediates the homing of lymphocytes to gut tissues. Vedolizumab, a monoclonal antibody (mAb) antagonist of α4β7, has demonstrated efficacy and has been approved for the treatment of inflammatory bowel disease in humans.) Blocking T cell homing and retention to the gut is a potential therapeutic target for the treatment of IBD. 1-Vedolizumab: anti a4B7 antibody blocking homing of the T-cells to the inflamed gut. Initial studies suggest some difference between UC and CD with vedolizumab therapy with more rapid clinical remission with CD but similar rates if long term remission. Sphingosine 1-phosphate signalling. The S1P receptor controls egression of immune cells from lymph nodes through a concentration gradient of sphinosine-1-phosphate. S1PR1 agonists render lymphocytes sensing the S1P gradient and exiting lymph node therefore causing a reduction in lymphocytes. Currently being appraised by NICE: Ozanimod for UC immune cell trafficking: Ozanimod acts as a sphinogosine-1 phosphate receptor antagonists preventing the egression of immune cells from lymph nodes to inflammatory tissues.

Answer 212

Ustekinumab for UC and CD Monoclonal antibody targeting the p40 subunit of IL-12 and IL-23. IL-12 and IL-23 involved in activating a cascade of inflammatory mediators responsible for the pathogenesis of IBD. Inhibition of IL-12,23 suppresses the TH-1&17 cell lineage of cytokines and chemokine in IBD.

Answer 213

Tofacitinib & Filgotinib Appear in the guidance for UC. Small molecule Janus kinases JAK inhibitors also known as JAKinibs. Tofacitinib JAK-1and 3 inhibitors Filgotinib JAK1 mainly JAK1 from recent studies. Upadacitinib is currently under review by NICE Inhibit the JAK-STAT signalling pathway. JAK inhibitors suppress pro-inflammatory responses mediated by cytokine receptors such as IL-10 and IL-12. AI: Janus kinase (JAK) inhibitors are a class of drugs that work by targeting and inhibiting specific enzymes called Janus kinases. These kinases play a crucial role in the signaling pathways of various cytokines and growth factors involved in inflammation and immune response. By inhibiting JAK enzymes, these drugs interfere with the signaling process and help regulate the immune system. Here is a breakdown of the mechanism of action of JAK inhibitors: 1. Cytokine Binding: Cytokines, such as interleukins and interferons, bind to their respective receptors on the surface of immune cells. 2. Receptor Activation: This binding triggers the activation of receptor-associated Janus kinases (JAKs) that are associated with the cytokine receptor. 3. JAK Activation: The cytokine binding causes the JAK enzymes to become activated and phosphorylate themselves. 4. Signal Transduction: The phosphorylated JAK enzymes then phosphorylate specific tyrosine residues on the receptor, creating docking sites for signaling molecules called signal transducer and activator of transcription (STAT) proteins. 5. STAT Activation: The activated STAT proteins bind to the phosphorylated receptor and become phosphorylated themselves. 6. Nuclear Translocation: The phosphorylated STAT proteins dissociate from the receptor and translocate to the cell nucleus. 7. Gene Expression: Once in the nucleus, the phosphorylated STAT proteins bind to specific DNA sequences, thereby regulating the expression of various genes involved in inflammation and immune response. JAK inhibitors work by blocking the activity of JAK enzymes, which interrupts the signal transduction pathway described above. By inhibiting JAKs, these drugs prevent the activation and phosphorylation of STAT proteins, thereby reducing the expression of pro-inflammatory genes and modulating the immune response. It is important to note that different JAK inhibitors may have varying selectivity for specific JAK enzymes, and their precise mechanism of action can differ slightly. However, overall, their goal is to interfere with the JAK-STAT signaling pathway and provide anti-inflammatory effects.

Answer 214

Altered epithelial barrier and Dysbiosis Epithelial barrier function is compromised in IBD allowing contact of laminia propria immune cells with bacteria which caused inflammation and ulceration The epithelial barrier contains Paneth cells that secrete anti-microbial peptides such as B-defensins and mucus secreting Goblet cells. The mucus layer that helps prevent bacteria from penetrating beneath the gut epithelium BD patients have both alterations in their mucous layer and microbial dysbiosis i.e. a change or alteration in the normal microbial balance In IBD there is a decrease in microbial diversity, with slightly different findings between CD and UC. In CD: a decrease in Firmicutes including Faecalibacterium parusnitzi whereas in UC there are also reduced Bacteroides and Clostridium genera but an increase in Enterococcus for example Altered barrier Dysbiosis • Phosphatidycholine • raecal microbiota transter Flora, IEC. Paneth cell EMERGING THERAPIES A new treatment that could go some way towards restoring the mucous layer or the microbial composition are potential therapeutic targets for inflammatory bowel disease. The mechanism of action is not yet well defined with studies ongoing. There are some differences between UC and CD. Fecal Microbial Transfer (MT) and probiotic transfer MT involves the transfer of a stool suspension obtained from a healthy patient into the Gl tract of an IBD patient thus restoring essential components of the microbiota that could revert inflammation. Currently limited evidence but promising. Probiotics: Escherichi coli Nissle (EcN) non-pathogenic Gram-negative strain. A mixture of 4 stains of Lactobacillus, 3 strains of Bifidobacterium and one strain of Stretococcus. EcN has been used in UC patients is not yet know with conflicting evidence at present but in some studies it exhibits similar anti-inflammatory effects to 5-ASAs, directs anti-microbial effects on B-defensins; antimicrobial effect and strengthens tight junctions between epithelial cells there fore increasing barrier function. Suggested Mo; dedifferentiation of cells into new healthy intestinal tissue that are resitant to adverse inflammatory events N.B. There is a differential effect of probiotic preparations in UC versus CD highlighting the multifactorial nature of IBD in terms of severity and variety. Phosphatidylcholine Phosphatidylcholine (PC) is an essential protective component of colonic mucus. Patients with UC have a low mucus PC content that reduces the hydrophobic barrier function of the intestinal mucus. This finding was highlighted its potential as a DRUG TARGET LT-02 is the drug name for a modified / continuous release of but has shown limited effect in clinical trials. The modified release of PC helps reconstitute the low mucus PC reservoir and re-establish the mucosal barrier Some studies have shown efficacy using a modified release preparation of soy lecithin containing 30% PC OTHER: Helminth therapy and dietary polyphenols

Answer 215

State medical guidance used in clinical practise. Recall the NICE guidance and be able to apply that to variety of clinical care situations.

Answer 216

Reduce symptoms Induce remission Maintain remission Improve maintain the quality of life Minimise toxicity related to drugs (short & long term) Distinguish between Acute treatment and Maintenance therapy: •Acute treatment is often termed induction treatment I.e to induce remission •Maintenance therapy is that used to maintain remission/prevent relapse

Answer 217

Issues: There’s no fully agreed or validated definition of remission! Clinical patient reported absence of rectal bleeding and endoscopic remission is most appropriate to measure remission. 3 clinical assessment tools: •Montreal classification consists of Extent can be classified as proctitis left sided or extensive and Severity based on symptoms E1 proctitis E2 left sided E3 extensive S0 clinical remission= asymptomatic S1 mild= 4 or less stools +/- blood no systemic illness normal inflammatory markers S2 moderate= greater than 4 stools but minimal signs of systemic toxicity S3 severe= severe at least 6 stools per day pulse 90b/m increased temp of 37.5 low Hb and high ESR •Mayo score encompasses stool frequency rectal bleeding endoscopic of mucosa score and remission score •Truelove and witts severity index Some patients might be asymptomatic but endoscopy show active inflammation so use of these classifications scores to guide dose control remain unclear. Treat to target: Adjustment to therapy based on assessment (control of asymptomatic inflammation)

Answer 218

•Disease severity •Disease extent •Disease location •Previous response to therapy •Presence of complications •Risk factors for progression, complications, patient characteristics, risk:benefits, cost NICE treatment guidelines is based on severity and location only

Answer 219

Inducing remission in mild to moderate UC- proctitis 1-Topical amino salicylates (1st penetration or inflammatory exacerbation) suppositories are preferred over enemas as they deliver drug to rectum rather than higher up in the sigmoid and are better tolerated than foams or enemas and they achieve higher mucosal concentrations and work faster and better than oral aminosalicylates monotherapy if disease is confined to rectum. •If remission not achieved in 4 weeks consider adding oral amino salicylates high remission seen when oral and topical is used in combination. If further treatment needed consider adding topical or oral corticosteroids but this step must be time limited. Oral prednisolone 40mg OD for 6-8 can be sued to induce remission. Prednisolone 5mg suppository OD can be considered as appropriate topical corticosteroid For patients that decline topical treatment consider oral aminosalicylate (not as effective as topical treatment) With use of topical treatment it’s always important to consider adherence to therapy. Patient should be involved in the decision making process as this will help with adherence. Other factors should be implemented like having the divided dose as a single dose at night to maximise and increase adherence convenience and better retention of suppository increasing time of contact with area that needs treatment For patients that can’t tolerate aminosalicylates consider time limited oral or topical corticosteroids.

Answer 220

Proctosigmoiditis and left sided colitis (distal colitis) Topical aminosalicylate (first penetration or inflammatory exacerbation) use enemas not suppositories 1g per day. If remission not achieved in 4 weeks consider adding high dose oral aminosalicylate 2-3g per day Switching to high dose oral aminosalicylate and time limited topical corticosteroids If further treatment needed stop topical treatment and offer oral aminosalicylate and time limited oral corticosteroids For patients that can’t tolerate aminosalicylates consider time limited or oral corticosteroids. Once daily dosing is as effective as divided doses and doses greater or equal to 2g a day are effective in inducing remission for patients with mild to moderate UC responding well and if it then higher doses must be used if severe symptoms.

Answer 221

Topical aminosalicylates and high dose oral aminosalicylates (first presentation or inflammatory exacerbation) •If remisión is not achieved in 4weeks stop tooocal treatment and offer time-limited course of oral corticosteroids •For people who can’t tolerate aminosalicylates, consider a time limited oral corticosteroids.

Answer 222

Moderate to severe: Oral corticosteroids 40-60mg of prednisolone might be used 50% if patient experience short term adverse effects with corticosteroids such as acne oedema sleep and mood disturbances glucose intolerance and dyspepsia. It should be given as single daily dose and causes less adrenal suppression. Effectiveness can be seen within two weeks of treatment with corticosteroids. Time limited usage used and stopped, reduction of 2.5 to 10mg per week for 6-8 weeks till termination of med. Inducing remission in Moderate to severely active disease. Biologics and Janus kinases: •Infliximab, adalimumab, golimumab- after failure of conventional therapy •Vedolizumab (TA 342) inadequate responses/loss of response or intolerance to either conventional therapy or TNF alpha antagonists. •Tofacitinib when disease has responded inadequately/response been lost to conventional or biological therapy.

Answer 223

Inducing remission in acute severe UC all patients should be hospitalised. Patients classified according to Truelove and Witts criteria of greater than 6 bloody stools per day systemic toxicity high temp >37.5 pulse of 90bpm hb of less than 105g/l CRP greater than 30mg/l IV corticosteroids (methylpredinsolone 60mg or hydrocortisones 100mg QDS benefit by day 3 and assess likelihood of requiring surgery. Consider IV Ciclosporin or surgery in those intolerant/ decline corticosteroids. If symptoms worsen or little/ no improvement within 72hours, consider adding IV Ciclosporin to the corticosteroids. If Ciclosporin Cl/clinically inappropriate, infliximab is an option. Consider IV fluids and electrolyte replacement due to imbalance Get stool cultures sigmoidoscopy Risk of VTE so use of lower molecular heparin is important to prevent that. Nutritional support Use of anticholinergic drugs antidiarrhoeal drugs NSAIDs and opiates can lead to colonic dilatation and that would warrant surgery.

Answer 224

Maintaining remission mild to moderate Proctitis and Proctosigmoiditis 1-Topical aminosalicylates alone (daily or intermittent) 2-Oral aminosalicylates plus topical aminosalicylates (daily or intermittent) 3-Oral aminosalicylates explaining that this may not be as effective as combined treatment of intermittent topical aminosalicylates alone

Answer 225

Offer low maintenance dose of oral aminosalicylates

Answer 226

•Consider meracaptopurine or Azathioprine After 2 or more inflammatory exacerbations in 12 months that require systemic corticosteroids Or •If remission is not maintained by aminosalicylates Consider Azathioprine or mercaptopurine (or oral aminosalicylates if Azathioprine or mercaptopurine Ciclosporin) •To maintain remission after a single episode of acute to severe UC.

Answer 227

Reduce symptoms Induce remission Maintain remission Improve maintain the quality of life Minimise toxicity related to drugs (short and long term) Distinguish acute treatment and maintenance therapy: •Acute treatment is often termed induction treatment I.e to induce remission. •Maintenance therapy is used to maintain remission/prevent relapse. Poor outcomes are associated with untreated inflammation even if asymptomatic Tight control= achievement of clinical and endoscopic remission Treat to target= adjustment to therapy based on assessment

Answer 228

•Disease location •Disease activity and severity •Previous response to therapy •Presence of complications •Risk factors for progression and complications, patients characteristics risk benefits and cost. PROM patient reported outcome measures HPI <4 remission >8 severe disease CDAI <150 remission >300 severe active disease Don’t correlate well with objective measures or markers of inflammation and are therefore are complementary to objective measures obtained at endoscopy imaging surrogate markers faecal caloprotectin

Answer 229

BSG, ECCO differ to NICE guidance as NICE only considers severity of disease in use of biologics as it uses number of exacerbation as a guideline Inducing remission starts with mono-therapy with glucocorticoids (at first penetration or a single inflammatory exacerbation in a 12 month period) •Prednisolone, methyl Prednisolone, hydrocortisone IV use of Prednisolone 40mg daily with tapering of 5mg per week but this should be tailored to patient diseases severity and tolerability. if patient can’t take corticosteroids orally use hydrocortisone 100mg QDS daily IV Reducing corticosteroids over time helps prevent acute adrenal insufficiency and early relapse in patients. •Budesonide may also be considered in certain circumstances including but Not for severe presentations. And when Contraindications to or refusal of conventional glucocorticoids. Budesonide is used in patients who have one or more of distalileoal Crohn’s disease ileocecal or right sided colonic disease NICE states that patient should be informed that Budesonide is less effective than conventional glucocorticoids but has less S/E due to poor oral absorption and clearing by first pass metabolism. BSG states that for mild to moderate ileocolonic/proximal disease Budesonide 9mg OD is as effective as Prednisolone at 8 weeks but dose should be tapered over 1-2weeks but in severe diseases it’s not effective NICE recommends use of aminosalicylates for patients with first presentation or first relapse at 12months period if patient is contraindicated to steroids but BSG ECCO don’t recommend it

Answer 230

1-Consider adding Azathioprine or mercaptopurine to glucocorticoids or budesonide to induce remission (if two or more inflammatory exacerbations in 12 months or if glucocorticoids dose can’t be tapered) Azathioprine dose of 2 to 2.5mg per kilo per day maybe used and a dose of 1 to 1.5 mg per kilo per day of meracaptopurine might be used 2-Consider adding methotrexate to glucocorticoids or budesonide in those who can’t tolerate Azathioprine or mercaptopurine or low TMPT activity (if 2 or more inflammatory exacerbation in 12 months or if glucocorticoids dose can’t to be tapered)

Answer 231

1–•Infliximab and •Adalimumab are licensed for adults with moderately/severely active disease, whose disease has not responded to conventional therapy. •Should be given as planned course until treatment failure or 12months after initiation •Continue if there is clear evidence of ongoing active disease (symptoms , biological markers and investigations endoscopy) •You May also see this therapy with an Immunosuppressant Severe= very poor general health and 1 or more of the following weight loss, fever, severe abdominal pain, usually frequent 3-4 stools per day. 2– •Ustekinumab TA 456 recommended as an option for treating moderately to severely active Crohn’s disease, that is, for adults who have had an inadequate response with, lost response to or were intolerant to either conventional therapy or a TNF-alpha inhibitor or have medical contraindications to such therapies. •Vedolizumab TA352 recommended as an option for treating moderately to severely active Crohn’s disease only if: a tumour necrosis factor alpha inhibitor has failed ( that is the disease has responded inadequately or has lost response to treatment) or a tumour necrosis alpha inhibitor can’t be tolerated or is contraindicated. Vedolizumab is recommended only if the company provides it with discount agreed inpatient scheme.

Answer 232

*Treatment: •Offer Azathioprine or mercaptopurine when previously used in induction strategy or consider in those not previously receiving this •Consider methotrexate only in those who needed it at induction, tried and did not tolerate Cl Azathioprine or mercaptopurine. Maintaince dose of 15mg subcutaneous MTX *No treatment follow up •share plans for follow up (frequency and who it should be with) •symptoms of relapse are known and action required (unintentional weight loss, abdominal pain, diarrohea, ill health) •knowledge of how to access health care •smoking cessation

Answer 233

Maintaining remission after surgery After complete macroscopic resection in ileocolonic Crohn’s disease within the last 3 months consider Azathioprine in combination with metronidazole for up to 3 months post operatively •Azathioprine alone in those who are unable to tolerate metronidazole •Don’t offer biologics or budesonide

Answer 234

Risk of enteric infections is higher in IBD patients than in control •Norovirus, Campylobacter, E.coli, C-difficile •IBD patients with C.diff show increased colectomy and mortality •C.diff treatment required •Careful consideration of IBD treatment •In acute severe disease, corticosteroids can remain and MDT review of other treatment is required. •Cytomegalovirus CMV risk potentially associated with refractory disease, immunomodulatory therapy, corticosteroids. •IV ganciclovir followed by PO valganciclovir treatment.

Answer 235

Assess at diagnosis: •Infection history: HSV (oral/genital), VZV (chicken pox, shingles) •Immunisation status: BCG, tetanus, diphtheria, pertussis, haemophilus influenzae, polio, meningococos, measles, mumps, rubella, pneumococcus, HPV, rotavirus, influenza. •Serology should be tested if the history is unclear to check patients immunity to these disease •Treat active HPV, latent/active TB, HCV, or HIV to initiating immunosuppressive therapy.

Answer 236

•Effective at inducing clinical remission but no role in Maintaince: •Important to reduce dose to cessation. •Approximately 14.9% of the UK IBD patients have steroid excess or dependence •Prolonged steroid use is associated with increased infection risk, osteoporosis, adrenal suppression, diabetes, weight gain, cardiovascular disease •Monitoring of the following is important before and during therapy: FBC, glucose, HbA1c, lipids, BP, eyes cataracts, glaucoma, mood and sleep.

Answer 237

•35-40% of patients with IBD have osteopenia 15% osteoporosis •Risk factors include uncontrolled inflammation, malabsorption, weight loss, prolonged/ high dose steroids, lack of physical exercise (weight bearing and muscle building) alcohol intake. •All patients on corticosteroids 800-1000mg Ca and 800IU vitamin D daily •Patients should have their risks assessed check calcium and vitamin d levels •Low risk patients-retest in 3-5years •High risk patients -Bisphosphonates (alendronate, risedronate, ibandronate, zolendronate)

Answer 238

Malnutrition is common in IBD it compromises over and undernutrition Multidisciplinary approach involving dietician input Specific deficiencies are difficult to interpret as influenced by disease activity 13-88% suffer with Mg deficiencies due to intestinal losses PO or IV magnesium care Po can worsen diarrohea Calcium/Vit D as previously discussed Potassium IV or PO 1/3 of IBD patients have iron deficiency anaemia (fatigue, reduced QoL, delayed recovery) Annual FBC, ferritin, CRP monitoring Dietary improvements-iron fortified foods, non haem iron, haem-iron foods, promoters of iron absorption vit-C rich avoiding inhibitors (tannins, caffeine, calcium) Pharmacological interventions IV iron (iron sucrose, ferric carboxymaltose)-Active IBD PO up to 100mg elemental iron in mild anaemia in those with clinically inactive disease. Once anaemia is treated test every 3 months for a year and between 6-12months after to ensure patient is no longer anaemic. Not all anaemia is linked to iron deficiency it is important to consider in patients vitB12 and folates deficiencies bone marrow depression and anaemia of chronic diseases. In individuals with mild anemia and clinically inactive inflammatory bowel disease (IBD), oral iron supplementation is usually limited to a maximum of 100mg elemental iron per day. This limitation is due to the potential risks associated with higher doses of oral iron in individuals with IBD. One of the main concerns is that high doses of oral iron can worsen gastrointestinal symptoms in individuals with active IBD. Iron supplements can cause irritation and inflammation in the gut, exacerbating symptoms such as abdominal pain, diarrhea, and bloating. Furthermore, excessive iron absorption from oral supplements can increase oxidative stress and inflammation in the intestinal mucosa of individuals with IBD. This can potentially contribute to disease flares and worsen the underlying inflammation. In severe cases of IBD, where there is active inflammation and significant gut damage, oral iron supplementation may be contraindicated. This is because the impaired absorption and utilization of iron in these individuals can lead to iron overload and tissue damage. In such cases, alternative routes of iron supplementation, such as intravenous iron, may be considered under the guidance of a healthcare professional. It is important to note that the management of anemia in individuals with IBD should be individualized and guided by healthcare professionals who can assess the specific needs and risks associated with each case.

Answer 239

Advise of widespread harm and offer smoking cessation Smoking is more common in Crohn’s disease patients Continuation of smoking is linked to worse disease course, high risk e of surgery and worst outcomes after surgery. Continuation of smoking is linked to worse disease course, higher risk of surgery and worst outcomes after surgery. UC is more common in non-smokers and is more likely to arise in those who quit Smoking is linked to reduced surgery rates, less extensive disease, reduced need for therapy Should be encouraged to stop, inform of potential increase in treatment.

Answer 240

Data is conflicting regarding non specific NSAIDs May lead to increase disease activity esp in Crohn’s colitis May precipitate a relapse Short term low dose in patients with controlled disease in remission is potentially safe No evidence that COX-II inhibitors are safer than non specific NSAIDs Further studies are required

Answer 241

IBD is a known risk factor for bowel cancer (colon and rectal cancer) In UC the risk factors include, duration of disease, amount of bowel affected and severity of the inflammation. Cancer risk begins to develop 8-10 years after the start of symptoms Extensive> distal>>>proctitis Cumulative incidence 1% at 10yrs, 2-3% at 20yrs and 5-7%at 30yrs Crohn’s disease risk similar to UC if colon main area of disease. Small bowel, intestinal lymphomas, anal cancers, risk potentially increased. Reducing the risk: Receive and take appropriate treatment to manage inflammation Regular specialist review at least annually Regular colonoscopy frequency dependent on presence of additional risk factors FHx and specific disease characteristics (disease activity/presence of strictures) Usually 1-5 yearly Additional ways to reduce risk- physical activity high fibre reducing red/processed meat, limiting alcohol, supplementing vit-D if deficient.

Answer 242

IBD patients on immunosuppressants should not take vaccines •COVID-19 Patients should receive a covid vaccine •Aminosalicylates or no treatment the vaccine should work as well as in the general population •Those on immunosuppressants are thought to have a reduced antibody response clarity study showed this to improve with 2nd dose-ongoing research. •Influenza injection especially if on immunosuppressants but general increased risk annually •Pneumococcal 2 weeks before immunosuppressants initiation

Answer 243

Chronic disease with long term medical treatment: •Remission •Topical treatments •Need for monitoring •Adverse affects •Patients beliefs Worse patients outcomes increased disease activity, relapse, loss of response, higher morbidity and mortality, poor QOL, higher disability

Answer 244

Stoma-output monitoring, knowledge of the site and functioning bowel remaining Short gut syndrome—lack of functioning small bowel •May affect nutritional absorption-consider review and replacement •May affect oral medication absorption-review absorption profiles and alter therapy accordingly Drug considerations-pain control non opioids, EC/MR preparations avoid use of liquids or non-coated tablets used, loperamide/codeine anti motility drugs to reduce motility 64mg higher dose loperamide risk of QTprolongation, antisecretory drugs PPI/Somatostatin Thais reduce gastric acid secretion and reduce stoma output, fluids (sodium loses)/rehydration loses, risk of hypotonic fluid consumption orally and are not absorbed and end passing through to Stoma bag this will cause dehydration and loss of Na so restrict oral hypotonic fluids such as squash & tea 0.5-1L in 24hrs replace losses with ORT such as dyrolayte. Patient at risk of hypokalaemia due to digoxin/diuretics, increases risk of digoxin toxicity if patient is taking digoxin as hypokalaemia increases patient risk of toxicity. iron preparations, laxative should be avoid in ileostomy patients as they cause rapid loss of water but in patients with colostomy bulk forming can be used if it doesn’t work use small dose of stimulant laxative but at extreme caution. Some meds contain sorbitol which also cause s/e or diarrhoea. •Other pharmaceutical considerations: •Anxiety and depression It is common and associated with increased hospitalisation and poorer outcomes •Pain and fatigue •Pain-common even when asymptomatic, more common in females and those experiencing anxiety and depression •Need to rule out inflammation, strictures, adhesions, abscesses. •Long term opiate use is associated with poor outcomes for IBD and addictions. •Consider other options/low dose for short periods/ additional therapies •fatigue-common= poor QOL review for subclinical disease and modifiable factors Patients with underlying inflammation are at risk of VTE so VTE prophylaxis- hospitalised patients.

Answer 245

State common side effects, cautions and contraindications for certain drugs used in IBD. Consider drug characteristics in decision making about treatments in IBD and apply them to patient scenarios. Recommend appropriate drug monitoring for patients with IBD.

Answer 246

Mesalazine (5-ASA) bound to sulfapyridine via an azo bond Colonic bacterial azoreductase breaks the bond Sulfapyridine is absorbed by colon, metabolised by liver and excreted in the urine.Mainly responsible for adverase effects Mesalazine exerts therapeutic effects through topical effects on the mucosa : 30% of free mesalazine is absorbed Metabolised locally and in the liver to an active form and free/conjugated drug is excreted in the urine or faeces.

Answer 247

•Contraindications: Hypersensitivity to sulfapyridine/sulfonamides or 5-aminosalicylates/salicylates •Cautions: •History of asthma as it can cause cough and dyspnea •Risk of haematological toxicity as it can cause blood disorders •Renal and hepatic impairment due to metabolism route and drug excretions route via these mechanisms. •Glucose-6-dehydrogenase G6PD deficiency G6PD deficiency is an inherited condition. It is when the body doesn't have enough of an enzyme called G6PD (glucose-6-phosphate dehydrogenase). This enzyme helps red blood cells work correctly. A lack of this enzyme can cause hemolytic anemia. •slow acetylator status. Sulfapyridine, a component of sulfasalazine, is contraindicated in patients with slow acetylator status due to the increased risk of adverse reactions. Slow acetylators are individuals who metabolize drugs, including sulfapyridine, at a slower rate compared to fast acetylators. Sulfasalazine is a medication commonly used to treat inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease. It is composed of sulfapyridine and 5-aminosalicylic acid (5-ASA). Sulfapyridine is metabolized in the liver through acetylation, a process that helps eliminate the drug from the body. In slow acetylators, the metabolism of sulfapyridine is impaired, leading to higher levels of the drug and its metabolites in the body. This can increase the risk of adverse drug reactions, including hypersensitivity reactions such as rash, fever, liver toxicity, and blood disorders. Fast acetylators, on the other hand, metabolize sulfapyridine more efficiently, reducing the risk of adverse reactions. Therefore, sulfasalazine may be better tolerated in individuals with fast acetylator status. To minimize the risk of adverse reactions, healthcare professionals may consider alternative medications or adjust the dosage of sulfasalazine in individuals with slow acetylator status. It is essential to consult with a healthcare professional for personalized advice and guidance regarding the use of sulfasalazine or any other medications.

Answer 248

Headaches, nausea, fever, rash, raised temperature, reversible infertility in men, reduced WBC. Pancreatitis Hepatitis, pneumonitis, skin reactions (Steven Johnson syndrome) haemolysis, inflammation of the kidney.

Answer 249

Monitoring: FBC & LFT: Before initiation and every second week for 3 months, then monthly for 3 months then every 3 months. Creatinine/eGFR—monthly for 3 months then as indicated Patient to report- sore throat, fever, malaise, jaundice, and unexpected non-specific illness- may indicate myelosuppression, haemolysis, hepatotoxicity. It may colour urine and stain contact lenses yellow.

Answer 250

*Different delivery mechanisms exist other than sulfasalazine to change the release of mesalazine to the GIT due to inner carrier side effects on the body. Attachment to other carrier molecules like (olsalazine-mesalazine dimer; balsalazide-aminobenzoyl-beta-alanine) •pH dependent formulations (Asacol, Mersen, Salafalk/granules, Mesasal) •Time dependent formulations (pentasa/granules) •Multi matrix system (Mezavant) There is uncertainty whether individual mesalazine formulations have differential effects on IBD patient subgroups. However an appropriate formulation must be chosen for the patient dependent on: Disease distribution, efficacy, s/e profile, patient preference Agent selection is important

Answer 251

Enteric coat: with a specific agent to release at specific pH-prevent early disintegration in the stomach and upper GIT Eudragit S— methyl acrylate copolymer coating- dissolves > or equal to pH7 Eudragit L— methyl acrylate copolymer coating- dissolves>or equal to pH6 Jejunum is at pH of 6-7 and ileum/colon at >7 Potential issue, pH reduced in IBD/other factors can change pH. Time dependent-microspheres of mesalazine encapsulated in ethyl cellulose semi permeable membrane and these are time and moisture dependent release but pH independent. Theoretically releasing throughout the GIT, stomach/duodenum to rectum. •Multi matrix—mesalazine incorporated into lipophilic matrix and enterically coated (dissolution pH>7) Matrix swells to form gel (potentiating slow diffusion) enabling drug delivery to terminal ileum and to entire colon release.

Answer 252

Brand: Asacol MR/Mesren Formulation: enteric coat with Eudragit S Optimal drug release pH >7 Site of release terminal ileum and large bowel 2-Salofalk enteric coat with Eudragit L coating Optimal drug release >6 pH Mid terminal ileum and colon 3-Salofalk granules Matrix core with Eudrgit L coating Optimal drug release pH >6 Mid terminal ileum and colon 4-Octasa Enteric coat with Eudragit S Optimal drug release pH >7 Terminal ileum and large bowel 5-Pentasa/granules Ethyl cellulose semi permeable membrane microspheres Time dependent drug release Terminal ileum and colon

Answer 253

•Licensing is different for different preparations (doses and administration different) •Differences in formulations should allow different release profiles •Comparisons in efficacy and safety (mild-moderate UC) =well tolerated and equally effective •Systemic exposures from all oral formulations is comparable *Monitoring: •Renal function (creatinine/eGFR), urea, electrolytes, LFTs, FBC, prior to initiation and periodically until stabilised and routinely) •Renal function 6-monthly •Urea, electrolytes, LFTs, FBC- 6-monthly to annually

Answer 254

Topical= rectal & enemas Foam enemas usually treat up to the proximal sigmoid colon Liquid enemas can go up to the splenic flexure Equally effective in proximal UC Foam enemas preferred as easier to administer and to retain and are used to treat proximal sigmoid colon Topical= suppositories Indicated for use in disease up to the rectosigmoid junction Deliver drug more effectively to the rectum than enemas •*Table-1 enemas: Brand Formulation Strength Licensed indications Pentasa (2) Liquid enema in single use bottles. 1g in 100ml Treatment of UC affecting the distal colon and rectum. Adult dose frequency 1g (one enema) once daily at bedtime. Use in children Not recommended. Adverse effects related to administration BNFc: Not licensed for use in children under 18 years. For child aged 12-17 years dose as for adults (unlicensed use). (10) Pruritus, rectal discomfort and urge to defecate. Salofalk (4) Foam enema in a pressurised canister containing 14 doses. 1g per actuation Active, mild UC of the sigmoid colon and rectum. Two metered applications (2g) once daily at bedtime for 4-6 weeks. Can also administer in divided doses - 1 at bedtime and 1 during the night or in the morning if the patient has difficulty in holding in 2 doses at once. Little experience, only limited documentation for an effect in children. BNFc: Not licensed for use in children under 18 years. For child aged 12-17 years dose as for adults (unlicensed use). (10) Abdominal distension, anal discomfort, application site irritation, painful rectal tenesmus. Salofalk (6) Liquid enema in single use bottles. 2g in 59ml Treatment and prophylaxis ofacute attacks of mild UC in the rectum, sigmoid colon & descending colon. 2g (one enema) once daily at bedtime. Little experience, only limited documentation for an effect in children. BNFc: Not licensed for use in children under 18 years. For child aged 12-17 years dose as for adults (unlicensed use). (10) None listed in Summary of Product Characteristics. •Table 2 suppositories: Brand Strength Licensed indications Pentasa (3) 1g Treatment of ulcerative proctitis. Adult dose frequency Use in children Acute treatment: 1 suppository daily for 2-4 weeks. Maintenance treatment: 1 suppository daily. Not recommended. Little experience, only limited documentation for an effect in children. BNFc: Not licensed for use in children under 15 years. Child 12-17 years: dose as for adults. Dose unlicensed in children 12-14 years. (10) Adverse effects related to Pruritus, rectal discomfort and urge to defecate. administration Salofalk (5) 1g Treatment of acute mild to moderate UC of the rectum. 1 suppository daily, preferably at bedtime. Duration of use to be determined by the physician. Little experience, only limited documentation for an effect in children. BNFc: Not licensed for use in children under 15 years. No dose recommendations for children. (10) None listed in Summary of Product Characteristics. Salofalk (7) 500mg Management of mild and moderate episodes of UC of the rectum. 1-2 suppositories, 2-3 times daily. Dosage should be adjusted to suit the progress of the condition. Little experience, only limited documentation for an effect in children. BNFc: Not licensed for use in children under 15 years. Child 12-17 years: dose as for adults. Dose unlicensed in children 12-14 years. (10) None listed in Summary of Product Characteristics.

Answer 255

Meracaptopurine dose usually—1-1.5mg/kg daily Azathioprine dose usually 2–2.5mg/kg daily Prior to initiation check FBC, U&E and LFT Screen for HCV, HIV, HBV/VZV Vaccinate influenza and pneumococcal Ensure cervical screening up to date Check TPMT thiopurine methyltransferase- dose altered dependent on results Avoid in patients with very low TMPT Ongoing monitoring of FBC, U&E and LFT at least at 2,4,8 & 12 and then 3-monthly. •TPMT (thiopurine methyltransferase) is an enzyme that plays a crucial role in the metabolism of thiopurine drugs, such as azathioprine, mercaptopurine, and thioguanine. TPMT helps in the inactivation and elimination of these drugs from the body. The activity level of TPMT can vary among individuals due to genetic variations. Some individuals may have low or absent TPMT activity, while others may have high activity. This variability in TPMT activity can affect how individuals metabolize and respond to thiopurine drugs. In patients with very low TPMT activity, there is an increased risk of toxic side effects from thiopurine drugs. These side effects can include severe bone marrow suppression, which can lead to a decrease in the production of red blood cells, white blood cells, and platelets. To minimize the risk of these adverse effects, thiopurine drug dosages are usually adjusted based on TPMT activity levels. For patients with very low TPMT activity, thiopurine drugs may be contraindicated or require significant dose reductions. This is because individuals with low TPMT activity have a reduced capacity to metabolize and eliminate these drugs, leading to higher drug levels and an increased risk of toxicity. To determine the appropriate dosage of thiopurine drugs, healthcare professionals may perform TPMT genetic testing or measure TPMT enzyme activity in the blood. Based on the results, the drug dosage can be adjusted to optimize therapeutic efficacy while minimizing the risk of adverse effects. It is important to note that TPMT testing and dose adjustments are typically done under the guidance of a healthcare professional. They will consider various factors, including the individual's TPMT activity, medical history, and other medications being taken, to make informed decisions regarding the use of thiopurine drugs.

Answer 256

THIOPURINES • Mercaptopurine and Azathioprine • Contraindications - Hypersensitivity, serious infection, pancreatitis, impaired bone • Cautions - marrow Reduce TPMT Renal and hepatic impairment • Patients to inform the doctor of: ulceration of the throat, fever, infections, bruising, bleeding = signs of myelosuppression • Interaction with allopurinol - reduce azathioprine dose to ¼ of the usual dose • Reduce exposure to the sun, due to increased risk of skin cancers • Take with meals to reduce the risk of nausea - Reduce dose and give with allopurinol/switch to mercaptopurine

Answer 257

Define stoma Describe different types of stoma Describe some of the types of appliances available Describe psychosocial dimensions of stoma care Describe the common problems for stoma patients Discuss foods and drugs that can affect stoma output

Answer 258

Opening in front of abdomen Surgically created Bowel or bladder large or small intestine Enables elimination of contents Stitches attach bowel to the abdomen AI: A stoma is a surgical opening created on the surface of the body to divert the flow of bodily waste or fluids. It is typically performed when the normal route for elimination or drainage is no longer functional or needs to be bypassed. There are different types of stomas depending on the purpose and location. The most common types include: 1. Colostomy: This involves creating an opening in the abdominal wall to divert a portion of the colon (large intestine) to the stoma. It is often performed in cases of colorectal cancer, inflammatory bowel disease, or other conditions that affect the lower part of the digestive system. 2. Ileostomy: In an ileostomy, a portion of the ileum (the last part of the small intestine) is brought to the surface of the abdomen, creating a stoma. This procedure is usually done when the entire colon and rectum are removed or need to be bypassed. 3. Urostomy: A urostomy is performed when there is a need to divert urine away from the bladder. It involves creating an opening in the abdomen and connecting the ureters (tubes that carry urine from the kidneys to the bladder) directly to the stoma. Stoma care involves managing the stoma and the surrounding skin to maintain hygiene and prevent complications. This may include cleaning the stoma and changing the stoma appliance (a bag or pouch that collects the waste) regularly. It's important to note that living with a stoma can have a significant impact on a person's lifestyle and self-esteem. However, with proper education, support, and resources, many individuals are able to adapt and lead fulfilling lives with a stoma. Healthcare professionals, such as stoma nurses, are available to provide guidance and support to individuals with stomas.

Answer 259

Some diseases predispose patients: Inflammatory bowel disease IBD Diverticular disease Cancer if the large intestine Volvulus (twisting of loop of intestine due to lack of blood flow could’ve fatal if not treated) Perforations of colon Haemorrhage Toxic Megacolon acute enlargement of large intestine Growth retardations Colonic Polyps

Answer 260

1-Colostomy 2-Ileostomy 3-Urostomy

Answer 261

Most common Large intestine used to form stoma End colostomy one end of the colon is pulled through the abdomen and is stitched to the skin usually created from Descending colon~~> firmer stool left side of body Ascending or transeverse~~>more fluid stool Permanent or temporary Loop colostomy Support device sometimes used to hold loop colostomy till it heals One opening drains faeces, one opening drains mucus Often temporary to support healing

Answer 262

End of small intestine becomes the stoma Large intestine removed and if rectum and anal canal is removed then ileostomy has to be permanent Right hand sided Loop ileostomy Generally more fluids contents

Answer 263

Formed following bladder removal Output is urine Ileal conduit urinary diversion, small piece of bowel connected to the uréters which are detached from the bladder Acts as a channel for urine Not reversible Continuous flow Urostomy association

Answer 264

Different bags for different stoma types Lots of different makes Must be in drug tariff of HS otherwise can’t be prescribed Different advantages/disadvantages

Answer 265

Generally closed bag (disposable) Change once or twice a day Opaque/beige more discrete Normally use one or two piece system Two piece: Base plate change every 3-7days Pouch Flange provides secure attachment

Answer 266

Generally drainable bags reusable Change every 3-5days Also one or two more piece systems Integrated Clip or no closure systems Integrated tends to be preferred Can’t cuff the bag with integrated clips

Answer 267

Many different types available also one or two piece systems Tap outlet bags needs changing every 1-3days Specialist stoma nurse involvement Night drainage bags can be sued at home

Answer 268

Remove appliance gently Empty content of pouch down toilet Push skin down and away form appliance With other hand pull pouch up and away from stoma •Clean and prepare peristomal skin Soft tissue, warm tap water Gently remove any hair around the area Pat dry skin •Cut the correct hole to the shape of the stoma Apply appliance even pressure on baseplate If pouch is leaking change immediately Other items Available: Part IX of drug tariff Adhesives Adhesive removers Deodorants Skin fillers and protective skin Stoma caps and dressings

Answer 269

Diet Fluids Fibre rich food Dispelling gas Reducing odour Clothes Discrete Special designs Swimming/sports Cover filters in water sports Avoid contact sports and weightlifting Travel: forward planning, plenty of supplies, ORS, and anti-diarrohea medicines Travel certificates Consider air travel Personal life: Most resume normal sex life Smaller bag ir stoma cap Pregnancy can change stoma

Answer 270

Common Problems - Food •Gas producing Alcohol Asparagus Bananas Beans Broccoli Beef Cucumber Eggs Mushrooms Onions •Odour producing B vitamins Some cheeses Cauliflower Fish Garlic Green vegetable Onions Parsnips Turnips •Increase/ loosen stool Apples Bran Figs Prunes Spicy food Wholegrain cereals •Cause blockage Beef Broccoli Strawberries Celery Coleslaw Tomato sauce Grapes Lamb Mushrooms Nuts Sweetcorn Popcorn •Red stools Beetroot Strawberries Tomato sauce

Answer 271

•Diarrhoea: Antibiotics Furosemide Gold compounds Iron compounds Misoprostol NSAIDS Theophylline Laxatives Magnesiumions Fluoxetine •Constipation Anticholinergics Diuretics Iron Opioids TCA Verapamil Aluminiumions Fluoxetine/Paroxetine •Intestinal Dysmotility TCA Ca channel blockers Opiates Loperamide •GI Side Effects Aspirin NSAIDs Ca channel blockers, (amlodipine, diltiazem) Atenolol Nitrates Prednisolone Ferrous sulphate

Answer 272

•Constipation: Diet and medicines review Increase fluid and fibre Consider use of ispaghula Husk but not in ileostomy patients, increase water and salt loss so Refer to ileostomy nurse •Diarrhoea: Diet and medicine review ORS use Loperamide (liquid or dips tab don’t use energetic coating drugs use liquids and dispersible better absorption as capsules absorbed right away due to shortening of bowel Caps pass too quickly to be absorbed Suitable for ileostomy patients?

Answer 273

Pancaking: affecting colostomy patients, stools sit at top of bag, leads to leakage, too much air expelled through filter- block filter or use lubricant in bags. Bags not fitted properly or sticky faeces Ballooning: build up of gasses Filter use counsel on causes and how to prevent Skin problems Leakage Retraction Weight gain or pregnancy- stoma sinks below skin surface Prolapse Bowel prolapse through abdominal wall due to muscle weakness, no pain and continues to function Stenosis Narrowing of bowel, prevents stool passage Parastomal Hernia Detachment of abdominal wall muscles from stoma edges allowing protrusion through gap, causing hernia. Urinary crystals Alkaline urine-irritation and bleeding

Answer 274

Offer support (time, empathy, listen) Responding to symptoms Clinical check Signposting Appliance use reviews Stoma appliance customisation Resource: Manufacturers websites Coloplast Hollister Patients organisations and support groups Ostomy life styles The colostomy association The ileostomy and internal pouch support group Urostomy association Ostomyland Stomawise

Answer 275

A stoma is surgically created Part of bowel or bladder pulled from abdominal cavity through abdominal wall and attached to the skin Colostomy, ileostomy, Urostomy Medications and diet can affect effluent from stoma Psychological aspects need considerations Complications must be managed well.

Answer 276

•Describe malnutrition and its causes •Define parenteral nutrition PN and list its components •Describe how PN is administered •List the pharmaceutical issues associated with PN •Explain the assessment and monitoring of PN •State some common complications of PN

Answer 277

A deficiency or excess or imbalance of energy, protein, and other nutrients that causes measurable adverse effects on the tissue/body size, shape, composition & function & clinical outcome. Malnutrition is associated with abnormal nutrient intake due to deficiencies in: Nutrient intake Digestion Absorption Metabolism Excretion/Nutrient losses If untreated it can cause gross structural & functional changes. Health and quality of life seriously affected

Answer 278

•Acute malnutrition: Develops rapidly in the presence of Acute stress Injury Features short lived Resolves with improvement of patients condition •Chronic malnutrition: Develops in number of disease states Eg cancer, organ failure and IBD Requires long term monitoring and therapy.

Answer 279

•Impaired immunity •Decreased wound healing •Increased complications •Poor response to medical or surgical therapy •Reduced growth or development of infant or child •Death

Answer 280

PPN TPN Nasogastric tube Whole food by mouth Gastrostomy tube Jejunstomy tube Nasojejunal tube Nasodudodenal tube

Answer 281

Malnourished or at risk: Inadequate or unsafe oral intake A functional accessible gastrointestinal tract Use Enteral tube feeding Inadequate or unsafe oral or enteral intake A non functional or perforated gastrointestinal tract then use Parenteral nutrition enteral feeding (through a tube placed into the stomach or small intestine; parenteral feeding (through a tube inserted into a vein whereby nutrients enter the bloodstream directly)

Answer 282

Intravenous administration of nutritionally balanced, physiochemical stable and sterile combination of: Water Amino acids Glucose Lipids Vitamins Trace elements Electrolytes Can fulfil the total nutritional requirements can supplement an enteral feed or diet Reasons for using PN: •Short term inpatient Post surgery if patient is NBM gut rest >7days Obstruction in the gut Severe shock or gut infection Malnourished if unable to eat •Long term (home PN) Non-functioning gut Not enough gut to function eg surgery Some patients can eat small amounts May or may not be permanent

Answer 283

Consists of consultants Nutrition specialist nurse Dietician Pharmacist Roles: Take daily referrals from PN wards Assess patients suitability for TPN Assess patients nutritional requirements Work out what combination is required and order from pharmacy Assess inpatients on PN daily

Answer 284

Oral and equivalent PN source •Oral diet: Water volume Protein Carbohydrate Fats with essential fatty acids Vitamins Minerals Electrolytes •PN source: Water/volume L-amino acids mixture Glucose Lipid emulsion with essential fatty acids Vitamins Trace elements Electrolytes

Answer 285

Principal component of the body Accounts for approx 60-70% of the total body weight Risk of over or under hydration Consider fluid and electrolyte balance •An adult patient will require approx 20-40ml/kg/day Or calculated by: Maintaince fluid= 1500ml + (20ml x each kg of weight >20kg) And then adjust for losses What factors affect fluid requirements? •Dehydration: Fever Acute anabolic state High temperature Low humidity G.I losses Burns/wounds Blood loss •Fluid overload: High humidity Blood transfusions Drugs Cardiac failure Renal failure

Answer 286

20 required for protein synthesis and metabolism •8 essentials can’t be synthesised in the body has to be received from external source •5/12conditionally essential Patients needs exceed the synthesis in clinically stressed conditions Other needed for neonates and children Commercially available licensed solutions: Synthamin, Vamin, Vaminolact (paediatric) PN solutions prescribed in amount do nitrogen they provide Eg 9g, 11g, 14g, or 18g Most adults achieve nitrogen balance with 0.2g nitrogen/kg/day NB amino acids solutions are hypertonic to blood shouldn’t be administered alone in peripheral secretion

Answer 287

Requirements affected by: Age, activity & severity of disease Majority of adults maintained on 25-35 non-protein Kcal/kg/day Linked to basal metabolic rate Sourced form both lipid and glucose (dual energy) Minimise the risk of giving too much of either Can exceed metabolic capacity-complications

Answer 288

Recommended source of carbohydrates 1g anhydrous glucose provides 4kcal Concentration of glucose (eg 5%w/v) Selected: Provides glucose calories Meet the total volume Risk using of using glucose: Glucose not to be used alone as the energy source because: Risk of hyperglycaemia Fatty infiltration of liver (as excess glucose is converted to fatty acids) Excessive CO2 production Excessive consumption of oxygen Essential fatty acid deficiency

Answer 289

•Used as a source of energy and for provision of essential fatty acids •Energy rich 10kcal per gram of oil •Patients typically receive 2.5g lipid/kg/day •Monitor clearance in critically ill Mixture of soybean oil plus egg phospholipids Source of essential fatty acids Linoleic acid 52% Linolenic acid 8% Contains other fatty acids Oleíc acid 22% Palmitic acid 13% Stearic acid 4% Other fatty acids 1% • Intralipid 10%, Clinoleic 20% Advantages of lipid emulsions: Large amount of energy in small amount of fluid Allows peripheral administration Isotonic Venoprotective effect Contains some fat soluble vitamins E & K Prevents/reverses essential fatty acids deficiency

Answer 290

2 groups of micronutrients: •Trace elements •Vitamins Have a key role in intermediary metabolism as both co-factors and co-enzymes Affect enzyme activity and total metabolism Generally daily administration of all micronutrients is recommended in PN Factors affecting micronutrients requirements: •Baseline nutritional state on starting PN Acute or chronic onset of illness Dietary history Durations & severity of inadequate nutritional •Increased loss: Small bowel fistulae/aspirate-rich in zinc so zinc loss Biliary fluid loss rich in copper patient loses Cu Burn fluid loss- rich in zinc, copper, selenium (loss in Zn, Cu) •Increased requirement Increased metabolism Active growth •Organ function Liver failure-copper and manganese clearance reduced Renal failure-aluminium, chromium, zinc and nickel clearance reduced.

Answer 291

10 known trace elements: Iron Copper Zinc Fluorine Manganese Iodine Cobalt Selenium Molybdenum Chromium Commercially available products: Additrace, Decan *Vitamins* 2 main groups of fat soluble (stored in the body) and water soluble (renally cleared) Fat soluble (stored in the body): A retinol D ergocalciferol E tocopherol K1 Water soluble (renally cleared) B1 thiamine B2 riboflavin B6 pyriodoxine B12 C ascorbic acid Folic acid Panthothenic acid Biotin Niacin Preparations are available commercially: Vitilipid N adult- fat soluble vitamins Solivito N- water soluble vitamins These are added to the daily PN bag

Answer 292

Sodium Potassium Calcium Magnesium Phosphate Chloride Acetate Included to meet patients needs Can be adjusted according to blood results

Answer 293

Amino acids (nitrogen/proteins) Glucose and lipids (energy/fluid) Trace elements Vitamins Electrolytes Availability: Standard bags Scratch bags

Answer 294

How to administer PN •Central line is inserted into the chest here The line is tunnelled under the skin The line comes out here •Peripheral Fluids and med ones can be administered through catheter Peripheral administration considered first line for parenteral feeding Need good line care and low tonicity feeds Patients can be successfully maintained for many weeks Can be complicated by phlebitis Peripheral solutions have an osmolarity of approximately 800mOsmol/L Infused slowly into a large blood vessel with good blood flow

Answer 295

Indications: Duration likely to be short term Supplemental feeding Compromised access to central circulation No immediate facilites to insert central catheter High risk of fungal or bacterial sepsis Contraindications to central venous catherisation Contraindications: Inaccessible peripheral veins High osmolarity of the PN formulations High calorie/nitrogen requirements

Answer 296

Indicated when: Long term feeding is anticipated Peripheral route is inaccessible High tonicity formulations are required •Central solutions have an osmolarity of approximately 2000mOsmol/L •Solution is rapidly diluted into a central vein Inserted into either jugular or subclavian vein Position confirmed by x-ray Invasive & costly

Answer 297

Always administered under control of infusion pumps via a giving set Avoids overload of fluid, nutrition, electrolytes Should be administered at room temp Remove from refrigerator 3 hours before connection

Answer 298

Complex preparations: Contains over 50 chemicals entities Stability advice from manufacturers and third party experts Issues Physical stability Chemical stability Microbial stability Visual inspection before release and administration to the patient

Answer 299

•Precipitation: Potential to infuse solid particles fatal emboli Prescribed nutrients may not be infused Can’t be seen if bag contains lipids •Lipid destabilisation: Lipid globules may come together & coalesce Occlude the lung microvasculature-respiratory and circulatory blockages All PN fluids are passed through a filter when infused into patients

Answer 300

Vitamins: Readily undergo chemical degradations Often define the shelf life of the formulation Vitamin C is at least stable used as a marker for vitamin degradation All bags are protected from light during storage and infusions

Answer 301

Highly nutritional medium potential for microbial growth Manipulations performed using validated aseptic techniques Staff are trained in aseptic technique when connecting and disconnecting infusions

Answer 302

1-Does the patient need nutritional intervention? 2-What are their nutritional requirements? 3-How long will the underlying disease last? 4-Can the enteral route be used? 5-What are the routes PN can be administered?

Answer 303

Evaluate ongoing nutritional requirements, including fluid and electrolytes. Determine the effectiveness of nutritional intervention Facilitate early recognition of complications Identify any deficiency, overload or toxicity to individual nutrients Determine discrepancies between prescribed, delivered and received dose

Answer 304

Clinical symptoms Temperature Blood pressure Fluid balance Weight anthropometry Acid base profile Daily blood tests Liver function tests Electrolytes profiles Blood glucose Haematology CRP Calcium Albumin

Answer 305

Line blockage Can be caused by fibrin sheath forming around the line or a thrombosis blocking the tip Internal blockages of lipid, blood clots, or salts & drug precipitates Line kinking Blockages of a protective line filter Line sepsis Thrombophlebitis Refeeding syndrome: A metabolic complication occurring when the infused nutrition exceeds the tolerance of a previously malnourished patient Start feeding slowly I.e one bag over 48hours instead of 24hours Add thiamine if at risk acts as a coenzyme and helped prevent refeeding syndrome. Can cause significant mortality or morbidity (Refeeding syndrome is a potentially life-threatening condition that can occur when someone who is malnourished or has been fasting for a prolonged period suddenly starts to eat again. When the body is deprived of food for an extended period, it adapts by reducing its metabolic rate and utilizing stored energy sources, such as fat and muscle tissue. During this time, the body also experiences a decrease in certain electrolytes, vitamins, and minerals, including potassium, magnesium, and phosphorus. When a person with malnutrition or prolonged fasting starts to eat again, there is a sudden increase in insulin production, triggered by the intake of carbohydrates. This insulin surge leads to the uptake of glucose by cells, which in turn stimulates the uptake of potassium, magnesium, and phosphorus into the cells as well. The rapid repletion of these electrolytes can cause a shift in their distribution, leading to low levels in the bloodstream. This imbalance can result in various metabolic disturbances, including cardiac arrhythmias, muscle weakness, respiratory failure, seizures, and even death. To prevent refeeding syndrome, it is crucial to gradually reintroduce food and carefully monitor electrolyte levels during the refeeding process. Medical supervision and nutritional support are essential to ensure a safe and successful refeeding transition.) Characterised by generalised fluid and electrolyte imbalance in patients with a history of severe weight loss or chronic starvation

Answer 306

Nutrition support in adults Consider PN in those who are malnourished or at risk of malnutrition & either have: Inadequate or unsafe oral and or enteral nutritional intake A non-functional inaccessible or perforated leaking gastrointestinal tract Introduce PN progressively and monitor closely No more than 50% of estimated needs for 1st 24-48 hours Stop PN when adequate oral and or enteral support is established

Answer 307

Describe different fluid compartments in the body Describe how fluid balance is monitored and maintained Understand the indications for fluid replacement Determine the different types of intravenous fluids and their indications Summarise the factors involved in prescribing fluids

Answer 308

Intracellular fluid 25L: Cells Extracellular fluids 15L: Plasma 3L Interstitial fluid 12L

Answer 309

Intake: Fluids 1500ml Food 800ml Metabolism 300ml Output: Urine 1500ml Stools 200ml Insensible loses (eg lungs, skin) 900ml *Normal daily requirements: *25-30ml/kg/day Intravascular fluid and intracellular fluids, water and small molecules can be exchanged between them but not larger colloid substances and proteins due to the semi-permeable membrane. Proteins and larger colloids are present in the intravascular fluid and they maintain osmotic pressures must not pass out into intracellular membrane as this causes problems. This strict balance ensures vital nutrients will pass into cells and waste products will pass out. For electrolytes there sodium and potassium pumps on the surface of the membrane to maintain this balance of Na & K potassium passes into cells and sodium passes out of cell. Homeostatic balance is maintained via a number of homeostatic mechanisms.

Answer 310

Sodium plasma concentration 142 Sodium interstitial fluid concentration (mmol/L) 145 Sodium intracellular concentration (mmol/L) 12 Potassium plasma concentration 4 Potassium interstitial fluid conc (mmol/L) 4.1 Potassium intracellular concentration (mmol/L) 150 Chloride plasma concentration 103 Chloride interstitial fluid conc (mmol/L) 113 Chloride intracellular conc (mmol/L) 4 Bicarbonate plasma concentration 25 Bicarbonate interstitial fluid concentration (mmol/L) 27 Bicarbonate intracellular conc (mmol/L)12 Potassium levels higher inside cell 150mmol/L intracellular conc Sodium higher outside cell plasma conc of 142 and vice versa Total volume of fluids 40L in the body The extracellular volume depend on sodium conc is essential for maintaining volume If body intakes high load of Na this increases osmotic pressure of blood volume this stimulates the body thirst process to get water retention to balance out abnormal sodium balance to maintain appropriate extravascular volume of fluids in the plasma

Answer 311

Different types of fluids in the body have different electrolyte concentrations. The different electrolytes components of different fluids need to be considered if patient has any abnormality because their electrolytes requirements differ. •Saliva: Sodium 20-80 Potassium 10-20 Chloride 20-40 Bicarbonate 20-60 •Gastric juice: Sodium 20-80 Potassium 5-20 Chloride 100-150 Bicarbonate •Small intestine: Sodium 120-140 Potassium 5-15 Chloride 90-130 Bicarbonate 20-40 •Bile: Sodium 120-140 Potassium 5-15 Chloride 80-120 Bicarbonate 30-50 •Colonic diarrhoea: Sodium 60 Potassium 30 Chloride 45 Bicarbonate 45 •Sweat: Sodium 60 Potassium 10 All of the measurements above are in mmol/L

Answer 312

Maintaining the correct amount of fluid in the body Fluid input and fluid output Maintain normal daily requirements Replace additional loses Fluid balance is regulated by a number of homeostatic mechanisms regulated in the brain and kidney, two main homeostatic mechanism: •Anti Diuretic hormones which increase thirst, reduce renal excretion of water. ADH is synthesised in the hypothalamus and stored or released in the pituitary gland and it is main action on the kidney, reduces amount of renal excretion of water so causes water retention but stimulates in the brain thirst reflex to increase fluid intake. •Renin Angotenisn-Aldosterone system: Activated by falling renal perfusion Increase aldosterone —> increase sodium and water retention Dehydration reduces blood flow to kidneys this stimulates the RAAS which specifically increases production of aldosterone which causes increases in water and sodium retention by the kidneys to help restore fluid balance. These homeostatic mechanism don’t function properly after major injury/surgery or severe illness.

Answer 313

What fluid and how much fluid a patients needs? Is based on patients state! •Decreased fluid requirements in: Renal impairment Hepatic impairment Cardiac failure Head injury (intracranial pressure increased fluid intake can worsen this) •Increased fluid requirements: Vomiting/diarrohea High output stoma IBD Fistulas Burns

Answer 314

Correct acute losses or maintain homeostasis Blood volume Fluid levels Organ perfusions and function Mucositis inflammation of mucosa painful to swallow and this mainly occurs as a side effect of chemotherapy Prolonged failure of oral intake eg Mucositis Excessive losses NBM Special case patients—burns, brain injury, children.

Answer 315

If fluid is not administered correctly it can lead to: Electrolyte imbalance can lead to arrhythmia as consequence of electrolyte imbalance (role of K in cardiac function) cause by inappropriate fluid maintenance. Peripheral oedema Pulmonary oedema (severe shortness of breath) This is Base disturbance can cause many metabolic and respiratory problems Renal impairment Acid/base disturbances

Answer 316

Identifying dehydration: Thirst Reduced skin turgor (elasticity) Dry mucous membranes Increased capillary refill time (quick and easy assessment press finger it goes white and in 2seconds it should turn pink or red again in dehydrated patients it takes longer it might not happen) > 2seconds abnormal Altered level of consciousness Tachycardia fast pulse as a coping mechanism to maintain cardiac output Concentrated urine dark urine colour and lack of urine production=severe dehydration Consider alongside current medical conditions and drug therapy Some drug therapies can mask normal symptoms of dehydration like tachycardia like beta blockers or any medication that reduces heart rate

Answer 317

Observe: Weight in fluid depletion is reduced and in fluid overload is increased or weight gain is increased Blood pressure in fluid depletion is reduced and in fluid overload is normal or raised Respiratory in fluid depletion is rapid and shallow but in fluid overload is rapid moist coughs Pulse in fluid depletion is rapid weak but in overload is rapid Urine output in fluid depletion is reduced concentrated and in fluid overload is increased or decreased Skin in fluid depletion is dry less elastic and in fluid overload is oedematous Thirst in fluid depletion but not in fluid overload Temperature in fluid depletion might be raised but in fluid overload no disturbances to temp

Answer 318

Crystalloids Colloids Blood eg in patients with haemorrhage or major blood loss they will need blood replacement These fluids are characterised according to their physical composition and their mechanism of distribution. Can’t administer sterile water as it is not isotonic and could cause haemolysis breakdown of blood cells and is painful upon administer

Answer 319

Solutions of small molecules in water eg ions (Na+ and Cl-) and or glucose Eg 0.9% sodium chloride most commonly used 5% glucose Dextrose saline Hartmanns Crystalloids are isotonic with plasma Distribution in the body is determined by sodium content Higher Na content of Crystalloids the more fluid will be retained within the extracellular space plasma expander Lower Na content in crystalloid distributes more evenly through total body water TBW Caution over or prolonged use can lead to hypernatraemia

Answer 320

9g/150mmol of Na and Cl/100ml Distributes into the whole extracellular spaces (intravascular and interstitial spaces) Normal saline Can be given IV/SC Isotonic Used as a plasma expander Risk of hypernatraemia/ hyperchloraemic acidosis with excess use

Answer 321

Essentially water Distributes throughout the intravascular, interstitial and intracellular compartments Some calorie content if patient is diabetic? Glucose is primarily metabolised therefore doses not cause plasma expansions

Answer 322

Glucose and Sodium chloride Usually 4% glucose 0.18% sodium chloride Isotonic Glucose based fluid and sodium based fluid to boost intravascular volume Up to 3L over 24hrs if patient has no kidney dysfunction or hepatic problem Not long term as dose not contain other electrolytes

Answer 323

Balanced salt solution Most comparable to plasma Na+, K+, bicarbonate, Cl-, Ca2+, osmolarity No glucose Routine maintenance Resuscitation Particularly where large volumes requires or in patients with impaired compensatory mechanism ( e.g. critically ill)

Answer 324

Dispersions of large organic molecules in carrier solutions? Eg Albumin Dextran Gelatin Solutions of large insoluble molecules Provide more volume expansion than Crystalloids Characteristics depend on molecular size Contribute to oncotic pressure Oncotic pressure (colloid osmotic pressure) and this si defined as Osmotic pressure exerted by proteins in Blood plasma that usually tends to pull Water into the circulatory system.

Answer 325

Derived from human serum 4.5% isotonic 20% hypertonic (useful for plasmo expansion draws extra fluid osmotically into plasma) Short duration of action Expensive Shock: burns, haemorrhage, surgical losses and trauma. Used in ICU and emergency Synthetic collaids eg Dextrans Gelatin derivatives

Answer 326

Poly-dispersed solutions Dextran 70 larger molecular weight the longer it remains in the circulation but there are lower weight molecular dextrans used depending on patients needs. Interference with blood clotting, allergic reactions and cross matching with patient blood for blood transfusions. Anaphylaxis Renal excretion

Answer 327

Complex carbohydrates molecules Osmotic force causes water to enter blood vessel 2 main types Modified Gelatin (Gelofusion) Polygelines (Haemaccel) Differences in molecular size and duration of action in the two different brands gelofusine has larger molecular weight and longer duration of action Anaphylaxis due to animal collagen risk of reaction but not in synthetic product.

Answer 328

•Crystalloids Maintain osmotic gradient Widely available Low risk of ADRs Inexpensive •Colloids Smaller volumes 1L considered equivalent to 3L of Crystalloids Faster to give Longer half life Starches can reduce capillary leaks into interstitial space Colloids useful for plasma expansion of patients with renal or cardiovascular problems as 1L of colloids is equivalent to 3L of Crystalloids used in patients who are fluid restricted Faster to give less volume to give longer half life and starches in colloids reduce capillary leaks that occur in interstitial spaces during inflammation so use in sepsis or trauma shock burn Capillary leak occurs temporarily for 12hours but colloids reduce that leak in the initial 12hours

Answer 329

•Crystalloids Poor in maintains oncotic pressure Short half life •Colloids Maximum volume per day ADRs Expensive

Answer 330

Replace volume lost by haemorrhage Blood loss exceeds 20% of total blood volume Whole blood Packed cells Plasma Blood only used when haemorrhage is big and blood loss has exceeded 20% of patients total blood volume but up to 20% loss use colloids or Crystalloids. There are 3 types of blood products in market •Whole blood contains RBC platelets WBC etc •Packed cells removed platelets rich plasma and only left with packed RBC useful in patient with major blood loss who has heart or renal failure abs need more oxygen so fluid gives them oxygen carrying capacity but not volume associated with it •Plasma Contains water, electrolytes and proteins globulins clotting factors used in Patients with blood clotting deficiency or blood disorder.

Answer 331

Heart failure (excess preload) Acute respiratory distress syndrome Biochemical abnormalities Allergic reactions Haemodilutions Dilutional coagulopathy Renal impairment

Answer 332

Intravenous fluid therapy in adults in hospital is based on the 5R Resuscitation Routine maintenance Replacement Redistribution Reassessment

Answer 333

Required in patients who have acute circulatory shock or acute vascular depletion medical emergency! Patient needs fluid resuscitation to restore all circulating blood volume and restore increased cardiac output to get adequate oxygen delivery 500ml bolus of Crystalloids over 15mins—sodium containing (range 130-154mmol) eg NaCL 0.9% 500ml Repeat that as necessary up to 2L Continuous monitoring

Answer 334

25-30ml/kg/day fluid (max 2.5L—use IBW if obese) Up to 1mmol/kg/day K+/Na+/Cl- 50-100mg/day glucose Eg. 4% Glucose/0.18% sodium chloride + 20mmol potassium chloride 500ml over 8hrs x 2 some patients will need less or some more depends on patient case

Answer 335

Adjustment lV prescription for existing electrolytes Deficits/excesses and ongoing losses (eg gastrointestinal drains)—in context of patients conditions Adjust IV prescription for redistribution eg vascular leakage from intravascular compartment into Interstitial spaces during inflammation, ascities

Answer 336

Reassess needs and adjust at least daily Monitor for adverse effects eg fluid overload

Answer 337

Potassium chloride concentrate can be fatal Ampoules of 10%, 15%, 20% available- similar in appearance to WFI (water for injection) and NaCl ampoules so risk of error. Potassium chloride has critical role in cardiac function if administered inappropriately it can cause cardiac arrest death When added to bags of fluid must be mixed throughly as potassium is heavier and sits below solution Always use commercially available diluted preparations used where possible Distinguished labelling Separate storage Potassium treated same way as controlled drug so nurses are aware of risks

Answer 338

•Peripheral venous access Form arm Back of hand Small vein Short mid term length of use •Central venous access IV therapy >10days Poor peripheral access so central access must be used •Subcutaneous administration Hypodermoclysis Off label Prolonged administration of fluids Easier to insert line Unsuitable for rapid administration Used in palatine care end of life care

Answer 339

Patient should have an IV fluid management 24hour plan over suitable duration. Should be reviewed daily by an expert not bag by bag Review at same time as other prescribed medicines Only prescribe 24 hours at a time As pharmacist check fluids same as med review and check patient needs daily as fluid balance changes and patient needs change

Answer 340

•Nutrition requirements through the life cycle •Introduction healthy diet •Nutrition requirement throughout life •Micronutrient with a focus on Iron •Introduction to nutraceuticals •Malnutrition and related disorders •Enteral and parenteral nutrition •Malabsorption syndromes

Answer 341

Water Protein Carbohydrate Fat Dietary fibre Vitamins Minerals Electrolytes Trace elements Phytochemicals eg flavonoids protonoids Methylxanthines eg caffeine vasoactive amines found in some types of cheese Contaminants

Answer 342

Must provide sufficient energy and nutrients to maintain normal physiological functions and permit growth and replacement of body tissues Must offer the best protection against the risk of disease Healthy diet must provide protection against diseases

Answer 343

Prevents deficiencies and deficiency symptoms Optimises body stores Optimises some biochemical/ physiological functions Minimises a risk factor for some chronic disease Minimise the incidence of a disease.

Answer 344

Healthy eating The government’s Eatwell guide 1/3 fruit vegetables 5 portions 1/3 starch carbohydrates whole grain fibre Proteins Dairy Oil fat 6-8 cups of water Nutrient requirements depend on age, gender, physiological state eg (pregnancy) , genotype, environmental factors eg smoking smokers need higher levels of vitamin C

Answer 345

•RNI-reference nutrient intake: amount of a nutrient that is enough to ensure that the needs of nearly all the groups 97.5% are being met ie most require less. •EAR-estimated average requirement: Estimate of the average requirement for energy or a nutrient approximately 50% of people require less 50% require more SI-safe intake: where there is insufficient evidence to set another DRV-level or range of intake where no risk of deficiency of deficiency and below the level where there is a risk of undesirable effects. LRNI-lower reference nutrient intake: amount of nutrient that is enough for only the small number of people who have low requirements 2.5% ie most need more RDA (outside of uk) recommended dietary allowance or recommended daily amount Food labelling used by industries Front of pack Guideline daily amounts Traffic light system

Answer 346

Nutritional requirements of new born are high due to rapid growth and development. Breast milk vs formula mil both nutritionally complete for first months Breast feeding is the best form of nutrition for infants. Exclusive breast feeding tube a recommended for first 6months of an infants life as it provides all the nutrients a baby needs •Infant formula: Cows milk modified to mimic breast milk-huge range Newborn—birth to yr1 Sma pro or C&G first infant milk Follow on—6months to 1yr higher iron Sma pro or C&G follow on milk 6months+ Iron stores form birth are running low so formulas with higher iron content should be administered Toddler milk 1–3yrs SMA pro toddler milk 1+ •Prescribable formula: Soya based incase of cows milk protein allergy SMA soya infasoy Concerns with use before 6months due to allergy or tolerance Extensively hydrolysed formula—modified cows milk hypoallergenic Eg Althera and Nutramigen Others include lactose free, anti reflux, higher energy, colic, prem infants Weaning reasons for weaning? Increased requirements for energy, vitamins/minerals Growth and development—nutrient requirements no longer met by milk alone Variety of foods Six months recommended by DOH for introduction of solid food m Foods to avoid before 6months of age Wheat, gluten, fish, shellfish, fruit juices, soya, eggs, Before 1 year: salt, sugar, honey Care with textures to avoid choking

Answer 347

Requirements vary according to size and growth. Energy, proteins, vits and minerals requirements increase Important to have a Varied diet Small appetites—nutrient dense foods Whole milk until two years Common problems: Faddy eating Toddler diarrhoea Constipation Anaemia Dental caries

Answer 348

Healthy eating guidlines Varied diet with adequate energy and nutrients for various growth periods which are sometimes rapid during these years. Good supply of protein, calcium, iron, vit A&D particularly important School meals-controversial Physical activity important

Answer 349

Growth and development period, growth spurt during adolescence Peak bone mass occurs during adolescence so calcium and vitD requirements increase. Physical activity aids bone strength Energy and nutrient requirements in boys are greater than girls due to more muscle weight Growth spurt begins around age 10 in girls and 12 in boys Iron requirements increase in girls after onset of menstruation and continue to be higher through until menospause

Answer 350

Energy and nutrient requirements increase until 17yrs and then do not change too much between the age of 19 and 64yrs Requirements for energy 19-24yrs Average: Males 11.5MJ/day 2772kcal/d Females 9.1MJ/day 2175kcal/d Requirements for proteins RNI 0.75g protein/kg body wt Requirements for carbohydrates: 50% total from starch m <5% of total CHO- free sugars 30g/day fibre Requirements for fat 35% total energy, 11% of total as saturated, increases omega-3s Alcohol 2016 guidelines No more than 14mins per week in regular basis Spread evenly over 3 or more days Heavy drinking once or twice a week increases risk of death from long term illness and accidents/injuries. Risk of developing cancers increases Have several drink free days per week to cut down

Answer 351

Healthy varied diet during preconception/pregnancy Energy requirements increase by 0.8MJ/day 200kcal in the final trimester Small increase in proteins +6g/day For lactation larger increase in proteins +11g/day Avoid shark, swordfish and Marlon and limit tuna due to methylmercury is teratogenic Micronutrients 400micrograms folic acid/day during first trimester Iron rich foods and possibly supplements needed, particularly last trimester. Avoid vitamin A supplements and liver and liver products No alcohol and limit caffeine and stay active

Answer 352

Energy requirements decrease with age Requirements for other nutrients stay similar to adulthoods Malnutrition common problem in this age group due to: Inadequate intake of dietary energy loss of body weight, depletion of body fat stores and muscle wasting. Nutrient deficiencies Widespread metabolic physiological and functional adaptions occur

Answer 353

Infants have high nutrient needs which are given in form they can digest and metabolise. By age 5 and for the general adult population, healthy eating principles apply. Adolescence have high nutrient needs because of growth spurt and achieving peak bone mass. Energy balance is important to avoid obesity and under nutrition As we get older, energy requirements fall Malnutrition is a common problem among older people and in certain chronic conditions At times when oral feeding becomes affected, artificial nutrition may need to be considered

Answer 354

Define vitamins, minerals and trace elements and give example of each. Describe the basic functions and storage of some vitamins and minerals Discuss the functions, absorption, absorption, metabolism, regulations of iron. Discuss the consequences of iron overload and iron deficiency and how these are treated

Answer 355

Organic compounds required in small amounts for normal function of the body. They cannot be synthesised Beneficial effects of fruits and vegetables in relation to vitamins BNF: Prevention and treatment if deficiencies Not prescribable on NHS as dietary supplements Vitamin: body’s storage capacity depends on whether the vitamins are water soluble or lipid soluble for long time but water soluble shorter period of time. B12 3-6years A 6-10months D 2-4months Folic acid 1-3months C 2-4weeks B3 2-4 weeks K 1-2weeks B1 1-2weeks B2 1-2weeks B6 1-2weeks

Answer 356

Inorganic compounds required by the body Minerals >100mg/day Trace elements <100mg/day Functions Structural bones and teeth eg Ca Mg P components of biological fluids Nerves abs muscles eg calcium Iron requires for oxygen carrying Osmotic balance eg Na and Cl Enzymes eg Mn Cu Fe Hormones eg I for thyroxine

Answer 357

Water soluble vitamins are absorbed passively except: Vitamins B12 which requires intrinsic factor for receptor mediated endocytosis in the terminal ileum Fat soluble vitamins are carried in micelles and absoroped passively with end products of fat digestion Calcium and iron absorption is tightly regulated as they can damage cells Ca is an important second messenger and iron can be a pro oxidant if it is free so can damage tissues Other electrolytes unregulated

Answer 358

•Energy metabolism and cofactors B vitamins all •Antioxidants vits A, C, E, Zn, Se VitC is most potent antioxidant, vitE is a lipophilic antioxidant, vitA is pro vitamin which is beta carotene also an antioxidant and Zn and Se are incorporated into cellular antioxidants. Bone and other functions= vitD, vitK, Ca, P, Mg Iron

Answer 359

Fe is important for May aerobes Functions of Fe: Haemoglobin Myoglobin in muscle Cytochrome P450s important in the transfer of xenobiotics and drug metabolism. Catalase antioxidase role Peroxidases Cell growth and differentiation Stores are regulated by intestinal iron absorption only absorb what we need Only 10% of Fe from diet is absorbed by gut epithelial cells and this iron will be transported around the body as part of transferrin; is a protein that can carry iron to where its needed most importantly in the production of red blood cells precursors that are required int he bine marrow and then they become circulating RBC contain high amounts of Fe due to it is role on haemoglobin formation. RBC eventually get broken down by retículo-endothelial macrophages in the spleen and get incorporated back into the transferrin.

Answer 360

Iron absorption Only a portion of ingested iron is in a form that can be absorbed, either heme iron or ferrous iron (Fe2+). Iron is absorbed across the luminal membrane of small-intestine epithelial cells by different energy-dependent carriers for heme and Fe2+ like gene carrier protein 1 and divalent metal transporter 1 Dietary iron that is absorbed into the small-intestine epithelial cells and is immediately needed for red blood cell production is transferred into the blood by the membrane iron transporter ferroportin. In the blood, the absorbed iron is carried to the bone marrow bound to transferrin, a plasma protein carrier. Absorbed dietary iron that is not immediately needed is stored in the epithellal cells as ferritin which cannot be transferred into the blood. This unused iron is lost in the feces as the ferritin containing epithelial cells are sloughed. Dietary iron that was not absorbed is also lost in the feces. Sources of Fe: Haem red meat fish and poultry Non haem plant food eg lentils beans iron enriched fortified foods Increased absorption via Vit C red meat organic acids Decreased by phytates, tannins, calcium and soy! RNI 8.7mg/d males and 14.8mg/d females Recommended diet first but supplements if necessary at DRV levels

Answer 361

Most common deficiency in the world (WHO) Negative iron balance develops into iron deficiency anaemia—hb levels eventually drop after stores depleted Anaemia-hypochromic, microcytic (pale, small) RBC Women (childbearing & pregnant), prem and LBW infants, older infants and toddlers and teenage girls Patients with kidney failure, chronic malabsorption, GI diseases. Pallor, tired and weak, poor work performance Slow cognitive and social development in childhood Vitamin A deficiency limits use if iron stores Decreased immunity Heart failure if severe

Answer 362

When diet can’t restore stores within reasonable time or clinical deficiency. Supplement to restore stores abs then diet Supplemental iron: Ferrous salts (fumarate, sulphate, gluconate) Ferric iron Amount absorbed decrease with increasing doses, therefore often 3 equally spread doses/day Side effects: GI, nausea, vomiting, constipation, diarrhoea. To reduce start with half dose Not for this with normal iron stores because of iron overload and pro-oxidant effects.

Answer 363

Chronic iron toxicity: •Thalassaemias large group of genetic disorders of glob in chain synthesis where blood transfusions required often •Haemochromatosis genetic iron storage disease Treatment Iron chelators eg desferrioxamine-complex with ferric iron Desferiprone thalassaemias and deferisarox but this has more side-effects Role of globin chain int he production of Hb: In the context of chain synthesis, globin chains play a crucial role in the formation of hemoglobin, a protein found in red blood cells that is responsible for carrying oxygen throughout the body. Hemoglobin is composed of four globin chains, two alpha chains, and two beta chains, which are encoded by different genes. The role of globin chains in chain synthesis is to provide the structural framework necessary for the proper folding and function of the hemoglobin molecule. Each globin chain consists of a specific sequence of amino acids that determines its unique properties and interactions. During chain synthesis, globin chains are synthesized through a process called translation, where the genetic information encoded in the DNA is transcribed into messenger RNA (mRNA) and then translated into a sequence of amino acids. The mRNA is then transported to the ribosomes, where the actual synthesis of the globin chains occurs. Once the globin chains are synthesized, they undergo a series of post-translational modifications, including folding and assembly with other globin chains, to form the functional hemoglobin molecule. The proper folding and assembly of globin chains are crucial for the stability and function of hemoglobin. In summary, the role of globin chains in chain synthesis is to provide the structural framework for the synthesis and assembly of hemoglobin molecules. They play a vital role in the proper folding and function of hemoglobin, enabling it to carry oxygen and support various physiological processes in the body.

Answer 364

•Define nutraceuticals, dietary supplements and functional foods and give examples of each •Discuss types of nutraceuticals and the reasons for taking them •Discuss the factors affecting their activity •Briefly discuss best evidence for nutraceuticals

Answer 365

•Nutraceuticals food or ingredient that provides medical or health benefits, including prevention and treatment of disease Include dietary supplements and functional foods •Dietary supplements concentrated source of nutrients or other substances with a nutritional or physiological function Tablets, capsules, liquids, powders, pastilles, in addition to normal food intake to maintain health or prevent deficiency. •Functional food or beverage Any food or beverage containing an ingredient that gives it a health benefit beyond its usual nutritional value Health benefit: Improve physical or mental performance Decrease disease risk

Answer 366

Health benefits if nutraceuticals is to decrease disease risk or progression CVD, cancer, arthritis, gout, osteoporosis, neurological disorders, AMD, IBD&IBS, respiratory diseases. Improve physical or mental performance Well-being, aging skin Maintaince, gut function, weight loss, detoxification, immunity. Reasons for taking nutraceuticals Healthy lifestyle & increased awareness Prevent or decrease diseas Explosion in range and availability Media coverage Increasing scientific evidence linking diet and health or disease prevention Rising healthcare costs Ageing population Growing fixation with beauty

Answer 367

Naturally nutrient rich Medicinally active Processed Increases concentration of active ingredients Add component that is not normally present Eliminate/decrease a component Replace a component with one with known benefits Increase bioavailability or stability Genetically modified eg milk, rice, eggs and fortified cereals.

Answer 368

Anti-oxidants Amino acids Fatty acids and oils Bioflavonoids and phytoestrogens Probiotics Weight loss Glucosamine, chondroitin sulphate Stimulants

Answer 369

Vitamins A C E Selenium Zinc Carotenoids Flavonoids Function by counteracting free radicals but also anti-inflammatory, anti-tumorigenic, anti-coagulant, anti-aging Food beverages

Answer 370

Mainly fish oils—EPA&DHA Effects on skin, cholesterol levels and inflammatory mediators Health claim-heart and inflammation Because they produce resolvin lipid mediators so this lower inflammation Resolvins (RVs) are anti inflammatory lipid mediators that are biosynthesized from omega-3 polyunsaturated fatty acids (PUFAs) that are abundant in marine oil. Phytosterols Plant Stanols and sterols Margarines, mayonnaise, vegetable oils, yogurt, milk, soy, orange. Supplements Lower absorption of cholesterol 2g daily portion reduces LDL cholesterol

Answer 371

Live non pathogenic microorganisms that when administered in adequate amounts confer a health benefit on the host. Resistant to acid digestion Advocated for range of immune and gastrointestinal disorders

Answer 372

Population groups Menopause Vegetarians Pregnancy Children Disease prevention Joint Bone CVD Immune Eye Skin GI CNS General well-being Aging Sleep Mental alertness Detoxification

Answer 373

Nutraceuticals that benefit the heart health: Fruits and vegetables Garlic and onion Low fat foods Foods supplemented with plant sterols/stanols Breakfast cereals Whole grain Soy Oats and other beta glucan containing products Extra virgin olive oil Oily fish and foods supplemented with PUFA Nuts Tea Herbs Chocolate high in cocoa Has health benefits but doesn’t prevent disease from occurring

Answer 374

Products claims: Randomised controlled trials of some products in specific conditions Anecdotal or limited to in Vito or animal studies Safety and efficacy Many are safe if used appropriately Some can cause adverse effects Laboratory studies- in Vito and ex vivo effects on cell lines, cells and tissues Animal studies Observational studies Prospective cohorts RCTs Meta-analysis

Answer 375

Physiological state Genetic factors Drug interactions Processing Active file Bioavailability Nutrient interactions Adverse effects Behaviour Summary Nutraceuticals is broad term Used for a wide variety of reasons Broad range if specific and targeted supplements Regulation complex Product claims May lack evidence base to support them

Answer 376

Under nutrition and Cachexia loss of fat and muscles. The primary features of cachexia are inadequate nutrient intake, decreased or absent physical activity and altered metabolism due in part to a pathological systemic inflammatory response. Cachexia causes extreme weight loss and muscle wasting. It is a symptom of various chronic conditions such as cancer, chronic renal failure, HIV, and multiple sclerosis. Cachexia predominantly affects people in the late stages of serious diseases like cancer, HIV or AIDS, and congestive heart failure. Discuss the causes abs consequences of under nutrition Describe the different types of under nutrition Discuss how cachexia/clinical under nutrition is treated Describe the different types of prescribable and non prescribable nutritional supplements and give examples of each

Answer 377

Achieve optimum of weight if not risk of Overweight/obese or anorexic/cachectic tooth states could increase risk of disease. Protein energy malnutrition: deficiencies in any or all nutrients Micronutrients deficiencies: Deficiency of specific micronutrients Eg vitD Many causes of malnutrition: Reduced food intake Decreased absorption Decreased activity of co factors eg intrinsic factor and vitB12 Increased matbalism eg thyroid Underlying disease

Answer 378

•Physical: Impaired immune function Delayed wound healing Decreased muscle strength and fatigue Hypothermia Reduced respiratory muscle function and cough pressure, predisposing to chest infections Immobility predisposing to venous thrombosis and embolism and pressure sores Reduced final heigh in women leading to reduced pelvic size and small birth weight infants. •Psychological and behavioural: Depression Anxiety Reduced will to recover Self neglect Poor bonding with mother and child Loss of libido

Answer 379

Acute-acute inadequate nutrition leads to rapid wright loss or failure to gain weight normally Chronic malnutrition-inadequate nutrition over long period of time leading to failure of linear growth Acute and chronic malnutrition results of wasting, stunting or both Reduced food intake in adolescents and young people due to beauty stereotypes

Answer 380

Eating for Oder based on psychological disorder Very low weight Distorted body image Obsessive fear of gaining weight Older adults: Common particularly in institutionalised PEM and micronutrient deficiencies Decreased GI function with reduced absorption or metabolism underlying disease and interactions with drugs Reduced intake possibly due to: Dysphagia Poor appetite Poor mastication

Answer 381

Frequent in hospital populations Cachexia physical eating with loss of weight abs muscle mass caused by disease eg: Cystic fibrosis Inflammatory bowel disease AIDs Cancer Congestive heart failure COPD Sever schizophrenia Drug addiction

Answer 382

Food fortification to increase energy density of meals eg skimmed milk powder Small frequent meals and snacks Use of non prescription nutritional supplements eg Complan Often prescribable products/ supplements used eg Ensure, fortimel, fresubin All supplements should be used in adjunct to dietary fortification and snacking and not as meal replacement

Answer 383

Nasogastric and nasoenteric: Short term feeding Gastrostomy: Long term feeding at home eg stroke patients Jejunostomy: if unlikely to resume full oral intake after abdominal surgery or laparotomy Parenteral nutrition: if the gut is not functioning eg severe pancreatitis GI fistulas. Parenteral therapy has two forms, peripheral parenteral nutrition (PPN) and total parenteral nutrition (TPN). The main difference between PPN and TPN is the route of delivery. PPN is delivered through a large-bore peripheral IV catheter; TPN requires a central venous catheter.

Answer 384

•Nasal advantages abs disadvantages: Not invasive, quick, cheap. Irritation, risk of sinusitis, oesophagitis Dysphagia, risk of misplacement, risk of reflux, easy tube movement or removal, regular tube replacement, X-ray confirmation, stigmatising. •Abdominal advantages and disadvantages: Less stigmatising, less tube migration, less tube removal, less reflux, no nasal irritation, no dysphagia, no tube replacement. Invasive, sedation, antibiotics, irritation at site, leakage into abdomen, translocation of bowel, X-ray confirmation, tub clogging, hematomas causing bowel occlusion.

Answer 385

Nasogastric feeding: Short term feeding if <14days Unable to take any nutrition orally eg stroke, upper GI surgery Additional nutrition to improve an inadequate intake, eg burns, cystic fibrosis.

Answer 386

Standard polymeric 1kcal/ml eg Osmolite, jevity suitable for most feeding High energy 1.5kcal/ml eg Osmolite 1.5cal, ensure plus, jevity plus, jevity 1.5kcal/ml uses for high energy requirements/volume restriction Fibre added: All of jevity feed varieties for long term feeding, helps normalise bowels. Low sodium eg nutrition low sodium for hypertension, ascites Low electrolytes energy dense feed eg Nepro in renal impairment or fluid restriction Elemental peptide eg preative in mala absorption short bowel chrons

Answer 387

Diarrohea due to temp of feed, rate, check date/ fibre Constipation sue to fluid balance/ fibre Vomiting rate of feed/ position of pt/ infection? Blocked tube- feed/ meds/ not flushed

Answer 388

Shorter hospital stays Lower mortality and hospital admissions Improvement in immunity and fewer infections Improved wound healing Improved quality of life and well being Improved liver function in liver disease Improved clinical scores in CF and Crohn’s disease Lower consumption rate after surgery and liver disease.

Answer 389

Normal small intestinal absorption: Pancreas secretes digestive enzymes Liver secretes bile acids Surface area- mucosal folds, villi, microvilli and brush boarder enzymes Malabsorption occurs if one or more of these is dysfunctional Malabsorption syndromes encompasses numerous clinical entities Most common symptoms: Weight loss/failure to thrive Abdominal distension Diarrhoea Most common cause Western-coeliac disease Developing parasitic and work infestation

Answer 390

Coeliac disease: Coeliac sprue, gluten-sensitive enteropathy, gluten intolerance Characterised by: Atrophy of small intestinal villi due to abnormal sensitivity to gluten. Malabsorption of nutrients by damaged area of the small intestine. Prompt clinical and histological improvement following gluten withdrawal from diet. Normal smooth surface intact walls Coeliac endoscopic scalloping of mucosal folds Microscopic biopsy: Flattened villi

Answer 391

True prevalence is unknown as many people have mild or bisacodyl symptoms only 10-15% are diagnosed (NICE) Uk has high incidence 1/100according to coeliac society Increasing incidence in last 25 years Incidence in females is slightly higher than males Diagnosed at May age but particularly: 8-12months when children first weaned into gluten congaing foods Third ti fourth decades and beyond. Most prevalent in Western Europe and emigrants and Jews Incidence between 0.05% to approx 1.2% worldwide Rare in Africa far east and Caribbean Increasing in India, Middle East and Saharawui populations

Answer 392

Two factors lead to development of disease Genetic predisposition Consumption of gluten proteins Genetics: 95% of patients express HLA-DQ2 or DQ8 Receptors they encode bind gliadin peptides more tightly, activating T lymphocytes and initiating autoimmune response Gliadin is a protein found in gluten, which is a mixture of proteins found in wheat, barley, and rye. In individuals with coeliac disease, gliadin triggers an immune response in the small intestine. Gliadin is broken down into smaller peptides, which can then bind to the HLA-DQ2 or DQ8 receptors on immune cells called T lymphocytes. These receptors have a higher affinity for gliadin peptides, leading to a stronger binding and activation of the T lymphocytes. This activation of the immune response results in inflammation and damage to the lining of the small intestine, causing the characteristic symptoms and complications associated with coeliac disease. 75% concordance among monozygotic twins Up to approx 20% of first degree relatives affected Increase risk in type 1 diabetes, Down syndrome, Turner’s syndrome, autoimmune thyroid diseases and dermatitis herpertiformis. Dermatitis herpetiformis (DH) is a chronic skin condition characterized by itchy, blistering rashes. It is considered to be the skin manifestation of coeliac disease, which is an autoimmune disorder triggered by gluten ingestion. Both DH and coeliac disease share a strong association with gluten sensitivity. Similar to coeliac disease, DH is also caused by an immune reaction to gluten. In DH, the immune response is triggered by the deposition of gluten-derived antibodies (IgA) beneath the skin, leading to the formation of itchy and blistering skin lesions. These skin lesions are typically symmetrically distributed and commonly appear on the elbows, knees, buttocks, and back. Both coeliac disease and DH are closely linked to the HLA-DQ2 or DQ8 genes. In fact, nearly all individuals with DH also have coeliac disease, and the majority of them express HLA-DQ2. While coeliac disease primarily affects the small intestine, DH primarily affects the skin. However, both conditions are manifestations of the same underlying autoimmune response to gluten. Therefore, individuals with DH are typically advised to follow a gluten-free diet, similar to those with coeliac disease, to alleviate symptoms and prevent complications.

Answer 393

Gluten sensitivity chronic skin rash that involves limbs, trunk, and scalp. Characterised by blisters up to 1cm diameter filled with watery fluid intensely itchy. Accompanied by intestinal damage possibly asymptomatic indistinguishable from coeliac disease Gluten free diet leads to regression of both intestinal abs skin symptoms plus dapsone (di-aminodiphenyl sulfone) antibiotic that inhibits folic acid synthesis in bacteria can be given to treat this disorder.

Answer 394

Consumption of gluten: Gluten proteins sometimes incompletely digested Peptides are extremely immunogenic to affected patients Prolamines: alcohol soluble fractions of gluten absorbed in small intestine and presented to APC on lamina propria, resulting in immune response in mucosa. Gliadins in wheat Hordeins in barley Secalins in rye Possibly avidins in oats AI: The pathophysiology of gluten-related diseases, such as coeliac disease and dermatitis herpetiformis, involves an abnormal immune response to gluten, a protein found in wheat, barley, rye, and possibly oats. Here's an explanation of the passage you provided: When gluten is consumed, it is broken down into smaller protein fragments called peptides during digestion. However, in individuals with gluten-related diseases, these gluten peptides are not completely digested. These undigested peptides are highly immunogenic, meaning they trigger an immune response in individuals who are susceptible to these diseases. The prolamines are the alcohol-soluble fractions of gluten found in different grains. In the small intestine, these prolamines are absorbed and presented to antigen-presenting cells (APCs) located in the lamina propria, which is a layer of tissue in the intestinal wall. The APCs recognize the prolamines as foreign substances and initiate an immune response in the mucosa, the lining of the intestine. In wheat, the specific prolamines responsible for the immune response are called gliadins. In barley, the prolamines are known as hordeins, and in rye, they are called secalins. It is important to note that oats may also contain a protein called avidin, which could potentially contribute to the immune response, although the role of oats in gluten-related diseases is still debated. Overall, the consumption of gluten in individuals with gluten-related diseases leads to the incomplete digestion of gluten proteins, the formation of immunogenic peptides, and an immune response in the intestinal mucosa. This immune response is responsible for the characteristic symptoms and damage seen in these diseases.

Answer 395

Common: Diarrohea Fatigue Borborygmus Abdominal pain Weight loss Failure to thrive Abdominal distention Flatulence Uncommon or rare: Osteopenia Osteoporosis Abnormal liver function Vomiting Iron deficiency anemia Neurological dysfunction Constipation Nausea

Answer 396

Symptoms: Persistent diarrohea, malabsorption, weight loss, gas, abdominal pain, bloating or extra gastrointestinal manifestations. Restricted to mucosa of small bowel so can differentially diagnose from inflammatory bowel disease. Serological tests from blood sample: Tissue transglutaminase tTG antibodies Endomysial antibodies if both of these are negative then test for Total IgG antibodies if either of these negative but suspected disease. Home kits eg Biocard or own brand-approx £12-17 in pharmacy and online. Important to get a medical diagnosis. Endoscopy Macroscopic changes possibly visible eg scalloping Biopsy required to confirm diagnosis

Answer 397

Rarely lethal Increased risk of malignancy Most often T cell lymphoma of small bowel 3-6x risk Adenocarcinomas of the GIT-pharynx, oesophagus, SB. Untreated pregnant women have increased risk of: Miscarriage Baby with congenital malformation Short stature and malnutrition if undiagnosed in childhood.

Answer 398

Removal of gluten from diet No wheat, rye, barley Check whether tolerant to oats and use pure sources of oats. Bread and flour from wheat these cereals breakfast cereals pasta bakery cakes pastries biscuits Avoid manufactured products form flours Flans, custards, ice creams Malted foods Beer ale Sauces, gravy and thickening agents Sausages, pate, luncheon meats Cheese spreads Soups, chocolate and milk-flavoured drinks chocolate bars Any canned food Foods permitted: Milk, dairy products Fresh meats, fish, seafoods Eggs Rice, Corn, millet, sorghum, tapioca, soybean Fruits vegetables, margarine, oils and other fats Coffee, teas, and herbal infusions Homemade cakes and pastries not made from banned flours. Balanced diet Gluten free symbol better food labelling Gluten free foods available on prescriptions and market Coeliac societies Patients encouraged to join Up to date lists of g-f foods Recipes Restaurant guidance

Answer 399

Only 50-70% of patients maintain strict gluten free diet later in life. Non compliance frequent in children and adolescents Minority of patients do not improve with diet or symptoms relapse after time. Usually due to incomplete removal of gluten

Answer 400

Crohn’s disease and coeliac disease both affect the small intestine How are they different? How can they be differentially diagnosed? Crohn's disease and coeliac disease are both chronic conditions that can affect the small intestine, but they have different underlying causes and require different approaches for diagnosis. 1. Underlying Causes: - Crohn's Disease: It is an inflammatory bowel disease (IBD) characterized by chronic inflammation of the digestive tract. The exact cause is unknown, but it is believed to involve a combination of genetic, environmental, and immune system factors. - Coeliac Disease: It is an autoimmune disorder triggered by the consumption of gluten, a protein found in wheat, barley, and rye. In individuals with coeliac disease, the immune system reacts abnormally to gluten, leading to inflammation and damage to the lining of the small intestine. 2. Symptoms: - Crohn's Disease: It can affect any part of the digestive tract, from the mouth to the anus. Symptoms may include abdominal pain, diarrhea, fatigue, weight loss, and blood in the stool. In addition to the small intestine, Crohn's disease can also involve other parts of the digestive tract, such as the colon. - Coeliac Disease: The primary symptoms are related to the small intestine. They may include abdominal pain, bloating, diarrhea, constipation, weight loss, and malabsorption of nutrients. Coeliac disease can also cause symptoms outside the digestive tract, such as skin rashes, joint pain, and fatigue. 3. Diagnosis: - Crohn's Disease: Diagnosis typically involves a combination of medical history, physical examination, blood tests, endoscopy, and imaging studies (such as X-rays or CT scans) to assess the extent of inflammation and damage in the digestive tract. - Coeliac Disease: Diagnosis involves blood tests to detect specific antibodies associated with coeliac disease. If the blood tests are positive, a confirmatory diagnosis is made through an endoscopy with biopsy. During the endoscopy, a small tissue sample is taken from the small intestine to check for characteristic damage caused by gluten.

GI Flashcards

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