GI Conditions (of Concern Here) PDF

GI conditions (of concern here) Heartburn is a burning feeling in the chest caused by stomach acid travelling up towards the throat (acid reflux). If it keeps happening, it's called gastro-oesophageal reflux disease (GORD). Dyspepsia/Indigestion Gastritis is when the lining of your stomac...

GI conditions (of concern here) Heartburn is a burning feeling in the chest caused by stomach acid travelling up towards the throat (acid reflux). If it keeps happening, it's called gastro-oesophageal reflux disease (GORD). Dyspepsia/Indigestion Gastritis is when the lining of your stomach becomes irritated (inflamed). It can cause pain, indigestion and feeling sick. Nausea and Vomiting Peptic Ulcer Disease Constipation and Defecation Problems Diarrhoea Gastroparesis chronic condition where the stomach cannot empty in the normal way. Food passes through the stomach slower than usual. It's thought to be the result of a problem with the nerves and muscles that control how the stomach empties. RECAP 1. The layout: 3. All parts of the alimentary Alimentary Canal: Mouth to anus canal have 4 layers: Accessory organs – liver/pancreas Mucosa (epithelium, lamina propria, muscularis mucosa) Submucosa 2. The 6-stages of dealing with Muscularis Externis food: Serosa 1. Ingestion 2. Mechanical Breakdown 4. Nerves of the digestive 3. Propulsion system: 4. Digestion Short axis (submucosal plexus) 5. Absorption & myenteric plexus Long axis (From the brain) – 6. Defecation Parasympathetic RECAP 5. Saliva can be secreted by 7. Stages of swallowing intrinsic or extrinsic glands Buccal phase Pharyngo-oesophageal phase (blocking off nasopharynx) 6. Saliva is made of: Pharyngo-oesophageal phase Amylase (blocking off trachea) Mucin Peristalsis Water Sphincter opening Protective elements (Defensin, IgA, Lysozyme) 8. Types of cell in stomach Mucus cells Parietal cells Chief cells Enteroendocrine cells RECAP 9. Regulation of gastric secretion 1. Cephalic 2. Gastric 3. Intestinal Gastric glands secrete gastric juices Mucous neck cells: in the duct portion Parietal cells: mid portion of glands secrete Enteroendocrine cells: HCl & intrinsic factor secrete multiple hormonal products; Chief cells: base of gland; secretes Gastrin (G cells) PYLORIC pepsinogen a precursor ATRUM, histamine, molecule to pepsin (an endorphins, serotonin, enzyme that digests cholecystokinin, & protein) somatostatin, which influence several digestive system organs Figure 23.15 Digestive Processes (Stomach) Acts as a holding vessel for ingested food Participates in mechanical & chemical digestion Propulsion: Delivers its product (chyme) to the small intestine Protein digestion: HCl denatures protein HCl activates pepsinogen to pepsin Pepsin breaks peptide bonds of proteins Rennin: an enzyme that breaks down casein (milk protein) secreted in infants Intrinsic factor: required for Vit. B12 absorption (needed to mature RBC) Mucosal barrier: protects the stomach from its own secretions Thin viscous mucus overlies a thick coating of HCO3- rich mucus Tight junctions between epithelial cell PM of glandular cells are impermeable to HCl Epithelium is replaced every 3-6 days Dyspepsia The British Society of Gastroenterology (BSG) defines dyspepsia as a group of symptoms that alert doctors to consider disease of the upper GI tract, and states that dyspepsia itself is not a diagnosis. 1. upper abdominal pain or discomfort,The aetiology of dyspepsia 2. heartburn, symptoms includes gastric and duodenal ulcers, gastro- 3. gastric reflux, oesophageal reflux disease 4. nausea, or vomiting. (GORD), oesophagitis, and oesophageal or gastric cancers Pharmacological treatments Antacids Mucosal strengtheners: Misoprostol Reduction of acid secretion: Proton pump inhibitors e.g. omeprazole Histamine H2 receptor antagonists e.g. ranitidine Muscarinc antagonists e.g. pirenzapine H pylori eradication regimes Dual therapy PPI and antibiotics This Photo by Unknown Author is licensed under CC BY-SA  Proton-pump inhibitors such as omeprazole bind Mechanism of action covalently to cysteine residues via disulfide bridges on the alpha subunit of the H+/K+ ATPase pump, inhibiting gastric acid secretion for up to 36 hours. This antisecretory effect is dose-related and leads to the inhibition of both basal and stimulated acid secretion, regardless of the stimulus PPI mechanisms PPIs are prodrugs – converted to active moiety (sulfenamide) in the presence of acid Sulfenamide binds covalently to exposed cysteine residues of the H+/K+ATPase pump Most of the PPIs have a pKa (pH 50% of molecule is protonated) that ranges from 3.8 to 5.0 A subset of patients may not gain the full therapeutic benefit of these drugs, or may develop treatment-related adverse events. The efficacy of PPIs to treat GORD and related conditions is closely linked to plasma concentrations. PPIs are metabolised by CYP2C19 (except rabeprazole) Omeprazole is a moderate inhibitor of CYP2C19, the major omeprazole metabolising enzyme. Oral dosing with omeprazole 20 mg maintains an intragastric pH of ≥ 3 for a mean time of 17 hours of the 24-hour period in duodenal ulcer patients. Gastroparesis - Delayed gastric emptying in the absence of a mechanical obstruction Condition associated Diabetes mellitus Hypothyroidism Neurological conditions like Parkinson's disease Iatrogenic causes Viral infections Vagal nerve damage during surgery Opioids Autoimmune attack Alpha-2-adrenergic agonists e.g clonidine nausea, vomiting, Tricyclic antidepressants e.g upper abdominal pain, amitriptyline early satiety, bloating, Anticholinergics e.g atropine. and in severe cases, unintentional weight Treatment of gastroparesis is generally based on dietary loss. modifications and avoiding medications that delay gastric What are Promotility agents Prokinetic agents refer to a class of drugs that promote the passage of ingested material in the GI. Tx symptoms: dysmotility, visceral hypersensitivity and altered visceral tone Gastroparesis and constipation Gastroesophageal reflux Neurogastroenterology and motility disease Chemotherapy-induced Enteric neuro-modulation nausea and vomiting Diabetic gastroparesis (digestive condition caused by diabetes) Gastrointestinal dysmotility Important considerations: (muscles of the digestive system becomes impaired) 1. Is the simple stimulation of gut motility a valid target? Chronic constipation due to 2. Target disorders are poorly defined unknown causes 3. Non-selective drugs will have side effects How do Promotility agents work? Increase wave-like contractions in the esophagus Increase contractions in the stomach Promote emptying of stomach contents Increase wave-like contractions in the intestines 1. Stimulating excitatory chemical messengers (neurotransmitters) like acetylcholine (smooth muscle contractions) 2. Suppressing inhibitory neurotransmitters like dopamine and serotonin …which stimulate specific receptors on the smooth muscle cells in the GI tract, thus promoting muscle contractions. ….Four types of prokinetic drugs  2 - Dopamine antagonists first-line Maybe therapy added Metoclopramide and Domperidone (torsades de pointes) block the effects of dopamine in the CNS and at the chemoreceptor zone (anti-emetic). stimulate peristalsis by releasing acetylcholine adverse effects (~25%) Px for hypomotility disorders associated with nausea Metoclopramide GIT: ↑ gastric peristalsis, relaxes pylorus and duodenum → gastric emptying, independent of vagal innervation ↑ LES tone ↓reflux ↑ intestinal peristalsis to some extent, no significant action on colonic motility and gastric secretion. CNS: effective antiemetic; acting on the CTZ, blocks apomorphine induced Administration: vomiting. orally three to four times a day Domperidone less CNS Side effects: drowsiness, restlessness, and diarrhoea.effects doesn’t cross BBB  Mechanism Of Action: Metoclopramide acts through both dopaminergic and serotonergic receptors Multiple actions Dopamine D2 antagonist Serotonin (5-HT4) agonist Serotonin (5-HT3) antagonist ↑ amplitude and frequency of contractions inhibits fundic receptive relaxation coordinates gastric, pyloric, and duodenal motility moderate acceleration of gastric emptying Dopaminergic regulation of gastrointestinal motility and sites of action of metoclopramide and  3 - Serotonergic Agonists (substituted benzamides) Cisapride and Prucalopride Cisapride activate serotonin receptors (5HT4 receptors) to release acetylcholine Their actions are also blocked by atropine Treat mild to moderate gastroesophageal reflux, gastroparesis Minor side effects ------ serious cardiac risks Aim: ability to accelerate intestinal transit, reduce esophageal acid exposure, and promote gastric emptying ……………………………………………………………………………............................................Lots of drugs developed and withdrawn Prucalopride a selective serotonin 5HT4-receptor agonist with prokinetic properties Prucalopride is recommended as an option for the treatment of chronic Tx constipation only in women for whom treatment with at least two 4 - Motilides Erythromycin (macrolide antibiotic ) Indicated for GI stasis - enhance peristalsis by acting on motilin receptors or by releasing motilin Their actions appear to be mediated by acetylcholine since they are also blocked by atropine. Motilin agonists may increase gastric tone or inhibit gastric accommodation and, potentially, worsen symptoms, even when gastric emptying improves Description of the Condition Infrequent stools, difficult stool passage, or seemingly incomplete defaecation. Occurs at any age Common in women, during pregnancy, elderly. New onset constipation, especially in patients > 50 years of age, or accompanying symptoms such as anaemia, abdominal pain, weight loss, or blood in stools - risk of malignancy? Secondary constipation can be caused by a drug - Review. Figure reproduced from Here  Colon By the time the digested food (chyme) reaches the large intestine, most of the nutrients have been absorbed The primary role of the large intestine is to convert chyme into faeces for excretion Lacks villi and has many crypts of Lieberkühn The crypts consist of simple short glands lined by mucus- secreting goblet cells The epithelial cells contain almost no digestive enzymes The mucosa, like that of the small intestine, has a high capability for active absorption of sodium, Cl and water. The outer longitudinal muscle layer is modified to form three longitudinal bands called tenia coli visible on the outer surface. Since the muscle bands are shorter than the length of the colon, the colonic wall is sacculated and forms haustra. Secretion in the colon Mucus – neutralises any acid, protects against irritation, lubricates, and provides Absorbs water, a binding medium for faeces. NaCl, K, vit K Stimulation of the pelvic nerves (nerves of defecation reflex) cause: Increase in peristaltic motility of the colon Marked increase in mucus secretion Bacterial infection – mucosa secrete water and electrolytes & alkaline mucus to dilute irritating factors through rapid bowel movement (stimulant laxatives) Bacteria digest small amounts of fibre Absorption in the Bowel movements large intestines Poor motility causes greater absorbance and Water About 0.5- 1.5L/day is absorbed. Mush hard faeces in transverse colon Water and thus constipation Absorbs water, The net water loss is 100-200 NaCl, K, vit K ml/day Semi solid Sodiu In the presence of Na+-K+ ATPase m at the basolateral membrane, Na+ is actively absorbed and K+ is Semi-fluid Excess motility secreted into the lumen of colon causes less Chlorid Cl- is absorbed in exchange for absorbance and diarrhoea or e HCO3 - which is secreted Fluid loose faeces Vitami Vitamins as vit. K, biotin, B5 , folic ns acid and some aa and short chain FA Bacteria from bacterial fermentation of CHO digest CHO Bacteri a digest are absorbed small It does not absorb vitamin B12! amount s of Misc Certain drugs as steroids and aspirin fibre may be absorbed Reabsorption of organic wastes Control of motility in the colon Haustrations - Mixing Movement The motor events in proximal colon (cecum & ascending colon). Ring-like contractions (2.5 cm) of circular muscles divide the colon into pockets (haustra). (The longitudinal muscle also contracts at the same time) Uniform repetition of haustra occurs along the colon. Net forward propulsion happens when sequential migration of haustra occurs along the length of bowel. Segmenting contractions Propulsive - Mass Movement throughout the day The motor events in distal colon (transverse & Mass propagated descending colon). contractions 3 – Starts in the middle of transverse colon, 15 mins 10 time as day after breakfast. Constrictive ring occurs at a distended point, then 20 cm of the colon distal to constriction, contracts The desire of defecation as a unit forcing the faecal mass down the colon. is felt when a mass of Preceded by relaxation of circular muscle & faeces is forced into downstream disappearance of haustral rectum. contractions. Defecation – when its time to go Convenient timing Allow defecation reflex. Stretch of rectal wall is sent to SC by pelvic nerve. Efferent pelvic impulses cause reflex contraction of rectum & relaxation of internal anal sphincter. Followed by reduction in tonic impulses to external anal sphincter, so it relaxes voluntary. Faeces leave rectum assisted by voluntary straining & contraction of pelvic floor muscles. Inconvenient timing Inhibited defecation reflex from cerebral cortex Maintain voluntary tonic contraction of external anal sphincter. Override tonic contraction of internal anal sphincter Urge passes People who too often inhibit their natural 70-80% water by reflexes are likely to become severely weight constipated. Constipation Decrease in stool passage frequency = small, hard stools faecal impaction Difficulty initiating bowel movements (normal -3 x week on Western diet) Poor diet – lack of fibre (resists digestion – bulking agents) Decreased motility of GI tract – disorders: IBS, medications: opioids Blockage – colonic carcinoma, swollen diverticulum, anal fissures, Haemorrhoids (painful) Covered in Dr Amira Guirguis Medications: lecture on Further GI Conditions 1. Bulk-forming agents 2. Stimulant laxatives 3. Osmotic laxatives 4. Stool softeners Note Saline laxatives: Magnesium citrate and sodium phosphate can be used rectally to cleanse bowels prior to procedures Magnesium containing laxatives should be avoided in children, renal impairment, cardiac conditions, pre-existing electrolyte imbalance INCREASED risked of hypermagnesemia [heart block/ neuromuscular block/ CNS depression] INCREASED risked of hyperphosphatemia [acute renal failure, metabolic acidosis, hypocalcemia/ death] Diarrhoea - 3 liquidy stools in 24 hours 1. Inflammatory diarrhoea causes inflammation of the gastrointestinal epithelium and this usually happens with invasive pathogens or as a result of a chronic inflammatory bowel disease, and usually there are systemic symptoms like fever. 2. Non-inflammatory diarrhoea can be either secretory or osmotic Secretory water and electrolyte secretion and decreased absorption Osmotic ingested nutrients aren’t fully absorbed (e.g. lactose), and they remain in the intestinal lumen and pull in water through the process of osmosis ACUTE