Upper GI Pharmacology 2024-25-Moodle.pdf

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn UPPER GI PHARMACOLOGY Class Year 2 Module Gastrointestinal & Hepatology Title Upper GI pharmacology Lecturer Dr....

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn UPPER GI PHARMACOLOGY Class Year 2 Module Gastrointestinal & Hepatology Title Upper GI pharmacology Lecturer Dr. Stephen Keely Pharmacology of upper GI tract disorders Peptic ulcer disease Gastrooesophageal reflux disease Nausea and vomiting  Learning outcomes Describe the pathophysiology and pharmacology of peptic ulcer disease Explain the basis and application of ‘triple therapy’, to include role of antimicrobial agents Discuss the mechanism of action and adverse effects of proton pump inhibitors, histamine H2 antagonists, cytoprotective agents and antacids Describe the pathophysiology and pharmacology of gastro-oesophageal reflux disease Describe the pathophysiology and pharmacology of upper gastrointestinal motility and stimulatory agents Describe the pathophysiology and pharmacology of nausea and vomiting (emesis) Explain the mechanism of action and adverse effects of muscarinic anticholinergics, histamine H1 antagonists, dopamine D2 antagonists, serotonin 5-HT3 antagonists and cannabinoids  PEPTIC ULCERS Peptic ulcers = open sores that develop on the inside lining of your stomach and the upper portion of your small intestine. Gastric Ulcers Duodenal Ulcers Occur due to acid-induced damage the mucosa CAUSES: i) Use of NSAIDs ii) Helicobacter pylori (H. pylori) infection Other factors, such as genetics, stress, spicy foods, smoking etc. can contribute. INCIDENCE - 1 in 10 individuals develop a peptic ulcer at some time. - Duodenal ulcers usually appear between ages 30 and 50 (men > women) - Stomach ulcers occur later in life (60+) (women > men)  SYMPTOMS Mild Pain is the most common symptom – occurs in the abdomen Varies in severity (described as being burning or gnawing) Particularly between meals or at night Can last mins - hrs Eases with eating or antacid use Other Symptoms Feeling of fullness, bloating or belching Intolerance to fatty foods Heartburn Nausea Serious Dark blood in stools Vomiting or vomiting blood Shortness of breath Unexplained weight loss Gastric obstruction Perforation  Gastric Glands - basic secretory unit of the stomach Cells of the Gastric Mucosa - Mucus surface Cells – secrete mucus and HCO3- - Parietal Cells – secrete HCl - Chief Cells – secrete pepsinogen and lipase - Enteroendocrine Cells – found mostly in the antrum & secrete gastrin and somatostatin - Enterochromaffin-like cells – found in the lamina propria & secrete histamine in response to gastrin - Nerves: Effector and sensory neurons  Regulation of Acid Secretion When a food enters the stomach - Stretch activates the ENS – which releases ACh (acts at muscarinic M3 receptors). - Food particles stimulate the release of Gastrin from G cells in the body and antrum - Ach and gastrin act either directly on parietal cells, or indirectly through histamine release from enterochromaffin cells (histamine acts at H2 receptors to promote HCl secretion). - As HCl concentrations increase, D Cells are stimulated to produce somatostatin (inhibits parietal cells and G Cells) Molecular Pathway of Acid Secretion - Histamine, ACh, and gastrin binding to their receptors elevate levels of intracellular messengers, Ca2+ and cAMP. - Ca2+ and cAMP-induce K+ and Cl- secretion across the apical membrane into the lumen. - K+ binding to the outer face of the H+ /K+ ATPase activates the transporter – H+ is secreted into the lumen - Net activity of the transporters results in HCl being secreted into the stomach - aids in digestion - kill bacteria. - As pH rises – D Cells secrete somatostatin which inhibits acid secretion by blocking cAMP responses to histamine.  PROSTAGLANDINS AND MUCOSAL PROTECTION Prostaglandins - lipid mediators important in regulating inflammatory responses throughout the body. - synthesised from arachidonic acid by different cell types in the mucosa - epithelial, endothelial and immune cells - synthesis depends on the activity of a number of enzymes – including the cyclooxygenases, COX-1 and COX-2 - 2 important PGs produced in the stomach include PGE2 and PGI2: i) Inhibition of acid secretion from parietal cells ii) Inhibition of histamine release from ECL cells iii) Stimulation of mucus and bicarbonate secretion from surface cells iv) Increased mucosal blood flow v) Increased epithelial repair (restitution) PGs are very important in mucosal protection against gastric acid  PATHOPHYSIOLOGY OF PEPTIC ULCERS A physiological balance exists in healthy individuals between gastric acid secretion and gastroduodenal mucosal defense Mucosal Defense: Aggressive Factors: Mucosal Blood Flow Gastric acid Mucus Pepsin Mucosal Bicarbonate Secretion Bile Salts Mucosal Cell Restitution Epithelial Cell Renewal Protection  PATHOPHYSIOLOGY OF PEPTIC ULCERS A physiological balance exists in healthy individuals between gastric acid secretion and gastroduodenal mucosal defense Mucosal Defense: Mucosal Blood Flow Aggressive Factors: Mucus Gastric acid Mucosal Bicarbonate Secretion Pepsin Mucosal Cell Restitution Bile Salts Epithelial Cell Renewal H. Pylori NSAIDs Ulceration  NSAID-INDUCED ULCERATION Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) NSAIDs - commonly used to relieve pain, reduce inflammation, and lower temperature e.g., ibuprofen, diclofenac, naproxen, aspirin Mechanism of Action – Inhibit COX-1 and COX-2 mediated production of PGs COX-1: Constitutively Expressed Mediates synthesis of PGs that regulate acid and mucus secretion in the stomach COX-2: Inducible Mediates synthesis of PGs responsible for mediating inflammation and pain Chronic use of NSAIDS: ↑ Gastric acid Secretion ↑ Histamine release from ECL Cells ↓ Mucus and bicarbonate secretion ↓ Mucosal Blood flow ↓ Epithelial restitution } Promote Ulcers TREATMENT OF NSAID-INDUCED ULCERATION NSAID-induced ulcers usually heal upon discontinuation of drug – Risk/Benefit analysis is required if considering discontinuation Why is the patient on NSAIDS Can condition be managed if NSAIDS are discontinued (e.g., switch to paracetamol?) Could different NSAIDS be used (e.g., COX-2 specific) Are additional medications being used (e.g., aspirin/steroids) Commence proton pump inhibitors (PPIs) (e.g., omeprazole) Patients with NSAID-induced ulcers should be tested for H. pylori – Treat if present  SUMMARY Chronic NSAID use can cause the development of peptic ulcers Mechanism is due to inhibition of COX and mucosal PG synthesis – Increased gastric acid secretion and decreased barrier function Treatment usually involves withdrawal NSAIDs (if possible) & commence PPI Patients with NSAID-induced ulcers should be tested for H. pylori – Treat if present  H. PYLORI AND PEPTIC ULCER DISEASE Helicobacter pylori is a motile, Gram-negative, spiral bacillus Infection is common and usually occurs during childhood (~ 50% of all people have H. Pylori in the stomach) Lifetime risk of developing an endoscopic ulcer is 10-20% (H. pylori positive individuals) H Pylori can survive in stomach acid – Expresses an enzyme called urease which converts urea to NH4 and HCO3- – Results in neutralisation of acid H Pylori infects gastric epithelial cells – Causes inflammation and epithelial cell death leading to loss of barrier function – Allows access of acid and pepsin to the mucosa Ulceration  UREA BREATH TEST Tests for active H. pylori infection; >95% sensitive and specific – HSE recommended test – Patient ingests radiolabelled (C13 or C14) urea – If H Pylori is present, urease will hydrolyse the radiolabeled urea to produce NH4 and labelled CO2 – Labelled CO2 can be quantified in the expired breath  TREATMENT OF H PYLORI INFECTION Triple Therapy - HSE Recommended - 2 different antibiotics (amoxicillin, clarithromycin, metronidazole, or tetracycline) - A proton pump inhibitor common (omeprazole, pantoprazole, or esomeprazole) - Treatment is usually taken for 14 days - Repeat breath test at least two weeks after proton pump inhibitor treatment has finished and four weeks after completing antibiotic treatment - Infection is gone (& chances of re-infection within 3 years are ~10%) - Infection is still present - Progress to 2nd line therapy  TREATMENT OF H PYLORI INFECTION HSE RECOMMENDATIONS - 1st Line of Therapy – clarithromycin triple therapy is preferred, comprising i) PPI ii) clarithromycin iii) amoxicillin or metronidazole - If the patient is allergic to penicillin – use metronidazole & clarithromycin - If the patient has previously been treated with metronidazole for other infections – use clarithromycin & amoxicillin - If the patient has previously been treated with clarithromycin for other infections – use amoxicillin & metronidazole - If patient is allergic to penicillin and has previously been treated with clarithromycin for other infections, use Quadruple Therapy = PPI, metronidazole, tetracycline and bismuth. These regimens eradicate H. pylori in about 85% of cases.  TREATMENT OF H PYLORI INFECTION Treatment failure usually indicates either: i) Antibiotic resistance - resistance to amoxicillin is rare - resistance to clarithromycin and metronidazole is common and can develop during treatment. ii) Poor compliance - Up to 20% of patients are non-compliant (mostly due to adverse effects) - abdominal pain - diarrhea - altered taste - Headache - Vomiting If 1st line fails, initiate 2nd Line of Therapy – should use different antibiotics to first line therapy SUMMARY H Pylori infection is common and a major Treatment involves triple therapy (2 cause of PUD Antibiotics and a PPI) 1st line treatment = clarithromycin, Survives in the stomach due to its ability to amoxicillin, and a PPI neutralise acid Treatment is effective in 85% but is Attaches to epithelium and secretes toxins dependent on lack of antibiotic resistance which damage the epithelium and mucus and patient compliance layer, allowing acid and enzymes to erode the mucosa 2nd line of treatment involves different antibiotics (metronidazole) or bismuth Diagnosed by urea breath test (or fecal antigen test, endoscopy or serology) Gastroesophageal Reflux Disease  Gastroesophageal Reflux Disease - Heartburn – (Very common) LES does not close completely allowing stomach acid to reflux into the esophagus. - Symptoms: burning in the chest, cough, hoarseness -.When reflux is chronic and frequent it is known as Gastroesophageal reflux disease (GERD) - GERD causes esophageal inflammation (esophagitis) and ulcers, and ultimately, Barrett’s esophagus Diagnosis – Upper GI endoscopy Treatment: Lifestyle changes: diet, eating habits, weight Oral medications: antacids, Histamine H2 antagonists, PPIs (e.g., esomeprazole)  PROTON PUMP INHIBITORS (PPIS) e.g. Omeprazole, esomeprazole, lansoprazole Most potent class of acid supressing drug Mainstay of treatment for acid suppression Peptic ulcer disease GERD Prophylaxis vs ulcer development (e.g., NSAIDs) Irreversibly inhibits the H+-K+ -ATPase – Weak base & absorbed in small intestine – Accumulates in canaliculi of parietal cells (1000 x higher conc than in the blood) – Activated by acid PPIs are prodrugs (converted to sulfenamide which covalently binds the pump) PROTON PUMP INHIBITORS Oral administration (take 30 minutes before food) High bioavailability (80-90%) PPIs have a short t1/2 (1-2 hours) – Rapidly metabolised in the liver Long duration of action (48-72 hours) – Irreversible inhibition (covalent binding) SIDE EFFECTS Well tolerated Headache, nausea, dizziness, rash Drug Interactions – PPIs increase gastric pH and therefore alter drug absorption ↑ Digoxin ↓ Ketoconazole Interaction with Cytochrome P450 system – Alter the metabolism of other drugs  H2 RECEPTOR ANTAGONISTS e.g. Cimetidine, Ranitidine, Famotidine Histamine – Released from ECL cells – Acts locally on H2 receptor of parietal cell – ↑[cAMP] → PKA Histamine Receptor 2 antagonists – Competitively inhibit H2 receptors – Reduce histamine stimulated acid secretion – ↓basal and food stimulated acid secretion (90%)  H2 RECEPTOR ANTAGONISTS Oral absorption is rapid from small intestine Peak concentrations occur 1-3 hours post administration Elimination is by hepatic metabolism, glomerular filtration and tubular secretion. Side Effects: Very safe Diarrhoea, Dizziness, Muscle pain Drug Interactions – Cytochrome P450 inhibition – alters metabolism of other drugs eg. Phenytoin, theophylline, warfarin – H2RAs increase stomach pH and can reduce absorption (and bioavailability) of drugs that need an acidic environment for absorption (e.g. Ketoconazole, aspirin) Can rarely cause nephrotoxicity/hepatotoxicity  CYTOPROTECTIVE AGENTS Cytoprotective agents i) stimulate gastric mucus production and mucosal blood flow ii) or by forming a coating that protects the ulcerated tissue e.g., misoprostol and sucralfate. MISOPROSTAL Stable orally delivered analogue of PGE2 ↓ acid secretion from parietals cells ↑ mucous and bicarbonate secretion ↓ histamine release from ECL ↑ blood flow Good for use in NSAID-induced ulcers – (bypasses inhibition of COX-2 to act at PG receptors) Side effects Diarrhoea, Abdominal cramps, uterine contractions (NB: contraindicated in pregnant women)  CYTOPROTECTIVE AGENTS SUCRALFATE Complex of aluminium hydroxide and sulfated sucrose Given orally & becomes activated in acid to form a paste Binds to proteins in ulcerated mucosa to form a viscous cytoprotective gel – Protects it from acid, pepsin and bile salts Induces an increase in mucosal PG concentration – maintain mucosal blood flow – Increase bicarbonate and mucus secretion. Side Effects - Is not absorbed from the GI tract and has few side effects - Constipation - Nausea - Hypophosphatemia - Can affect bioavailability of other drugs (e.g., tetracyclines, digoxin) BISMUTH SALT Given orally in a salt form, such as bismuth subsalicylate. MOA unclear – no significant acid-neutralizing capacity – Binds and protects mucosal lesions – inhibits the proteolytic action of pepsin – increases mucus secretion – Toxic against H. pylori (used in quadruple therapy) Side effects: – Nausea and vomiting – Reversible blackening of the tongue and faeces  ANTACIDS Relieve mild and infrequent symptoms associated with acid- related disease. – Calcium, magnesium, aluminium or sodium salts Directly neutralise acid resulting in ↑pH Quick acting (within minutes) Short duration of action – 30 minutes (empty stomach) – 3 hours (given with or within 1 hour of a meal) ↑pH can also inhibit activity of peptic enzymes Should not be used for more than 14 days – -consult doctor. ANTACIDS: SIDE EFFECTS Well tolerated (approx $10 bn in global sales in 2017) Magnesium salts can cause diarrhoea & aluminium salts can cause constipation – Combination product can maintain normal bowel function Aluminium and Magnesium may be absorbed systemically – Can cause toxicity in some patients (e.g., Renal Insufficiency) Calcium Salts (e.g. calcium carbonate) - potent antacids – Calcium is readily absorbed Can cause hypercalcemia, kidney stones, milk alkali syndrome (renal damage) All can bind phosphate in the gut causing hypophosphatemia – Bone demineralisation (rickets)  ANTACIDS: SIDE EFFECTS Sodium (e.g., sodium bicarbonate, Alka Seltzer) – Sodium retention (hypertension) – Should be avoided by patients requiring sodium restriction to control high bp – Systemic alkalosis (nausea, muscle spasms, tremors, confusion, difficulty breathing) Allergic Reactions – very rare Drug Interactions – ↓ absorption of acidic drugs (e.g., Digoxin & ketoconazole) – Chelation with divalent ions inhibits absorption of some drugs (e.g., tetracyclines and fluoroquinalones) – altered dissolution of pH-sensitive enteric coatings – urinary alkalisation alters elimination of many drugs (e.g. salicylates) NB: Separate antacid from interacting drug by at least two hours  Antacids with alginate Alginate (alginic acid) - anionic polysaccharide mainly found in brown algae – high viscosity, gelling properties Not acid neutralising Forms a viscous solution which floats on top of gastric contents preventing acid reflux = Raft-forming agent  SUMMARY GERD occurs due to chronic reflux of the stomach contents into the esophagus Medications aim to either – i) Neutralise Acid – antacids (e.g., Sodium bicarbonate, magnesium bicarbonate) – Ii) Inhibit Acid secretion PPIs (omeprazole, esomeprazole) H2 receptor antagonists (cimetidine, ranitidine) – Iii) Enhance protection – cytoprotective agents PG analogues (Misoprostal) – stimulate mucus, inhibit acid secretion & increase blood flow Sucralfate – binds ulcer and forms a protective gel Nausea and Vomiting  Nausea and vomiting Nausea - a stomach distress, with distaste for food and an urge to vomit Vomiting - disgorging the contents of the stomach (and sometimes the small intestine) through the mouth Vomiting is not a sickness but is a part of the body’s natural innate defence mechanisms - prevent poisoning and infection - can be a symptom of an underlying illness (e.g., appendicitis) - Other causes can include - Vestibular disturbances (vertigo, motion sickness) - Hormonal changes (pregnancy) - Drug treatments (chemotherapy)  Control of Vomiting - Vomiting is a reflex that is under control of the CNS - Structures involved in control of vomiting are found in the Vomiting Centre in the medulla oblongata Medulla Oblongata is the most primitive area of the brain and is responsible for regulating life- sustaining involuntary bodily functions (breathing, heart rate, etc.), and is the centre of basic instincts.  Control of Vomiting Pain, Fear, Disgust Vestibular System Muscarinic receptors Vestibular Histamine H1 receptors nucleus NK1 GABA receptors receptors Vomit Dopamine D2 Muscarinic receptors Centre receptors (inside BBB) NK1 5-HT3 receptors receptors CTZ (outside BBB) Digestive tract Abdominal muscles diaphragm  Summary - How does vomiting occur 1. Stimulation of the vomiting centre located in the brain stem. -can be activated in 2 ways Chemical activation - mediated via the chemoreceptor trigger zone (CTZ) - sensitive to toxins and poisons in the blood stream. Neural activation occurs as a result of information coming directly from the frontal lobes of the brain, the digestive tract and balancing mechanism of the inner ear. 2. Through activation of both the PNS and SNS, the vomiting centre causes hypo-motility and reverse-motility of the digestive tract. - stomach contents forced out through the oesophagus. Anti-Emetic drugs act either by i) restoring normal gastrointestinal motility (prokinetic agents) ii) preventing signalling through the vomiting centre  Stimulants of upper GIT motility (Prokinetics) Dopamine has a direct relaxant effect on the gut by activating muscular D2 receptors in the lower esophageal sphincter and stomach. - Thus, DA antagonists can be used to promote motility (e.g., domperidone, metoclopramide) Metoclopramide D2 dopamine antagonist Also acts as a 5-HT4 receptor agonist - 5-HT promotes GI motility Stimulates gastric emptying – enhances contraction in stomach Speeds up transit of stomach contents Increases lower oesophageal sphincter tone Can also cross the BBB and act on DA receptors in the CTZ Side Effects: Fatigue, diarrhea, depression, dyskinesia - should not be taken for more than 12 weeks - contraindicated in patients with Parkinson’s disease (D2 antagonists worsen Parkinson’s symptoms)  Stimulants of upper GIT motility (Prokinetics) Dopamine antagonists are among the most commonly used anti-emetics Dopamine has a direct relaxant effect on the gut by activating muscular D2 receptors in the lower esophageal sphincter and stomach. - Thus, DA antagonists can be used to promote motility (e.g., domperidone, metoclopramide) Domperidone Peripheral D2 dopamine antagonist;– does not cross BBB Enhances contraction in stomach - Stimulates gastric emptying - Speeds up transit of stomach contents Increases lower oesophageal sphincter tone Side Effects: Headache, dry mouth, abdominal cramps, diarrhea Unlike metoclopramide does not cause dyskinesia as it does not cross the BBB)  Anti-Emetic Drugs Muscarinic antagonists (e.g., hyoscine, scopolamine) - act in vestibular nucleus and vomit centre - Used for Motion sickness - available as tablet (30 mins before travel) - transdermal patch (take 5-6hrs before travel) - Side Effects: blurred vision, dry mouth, tachycardia, constipation. H1 antagonists (e.g., diphenhydramine, cyclizine) – Act in vestibular nucleus – Used for Motion sickness – Tablet taken 30 – 60 min prior to travel – Side Effects: Drowsiness  Anti-Emetic Drugs Dopamine antagonists (e.g., Metoclopramide) - act in the CTZ – used for chemotherapy-induced N&V and for morning sickness in pregnancy – can be given orally or IV – Side Effects: Fatigue, diarrhea, depression, dyskinesia 5-HT3 Antagonists (e.g., Ondansetron) - Act in CTZ - used for chemotherapy-induced N&V and for gastroenteritis - can be given orally or IV – Side Effects: Constipation, headache, flushing, drowsiness Anti-Emetic Drugs Cannibinoids (e.g., Nabilone) - synthetic form of delta-9- tetrahydrocannabinol (Δ⁹-THC), the primary psychoactive component of cannabis - acts at CB1 and CB2 receptors scattered throughout the medulla oblongata – used for chemotherapy-induced N&V - given orally, 1-3 hrs before chemotherapy – Side Effects: Vertigo, drowsiness, dry mouth, euphoria  SUMMARY Vomiting is a part of the body’s natural innate defence mechanisms but can be a symptom of an underlying illness Vomiting co-ordinated by the Vomit Centre in the medulla with inputs from the CTZ, the vestibular system, the GI tract, and the brain Anti-Emetic drugs act either by i) restoring normal gastrointestinal motility (prokinetic agents) - D2 antagonists (metoclopramide, domperidone) ii) preventing signalling through the vomiting centre - Muscarininic anatgonists (e.g., hyoscine, scopolamine) - H1 antagonists (diphenhydramine, cyclizine) - 5-HT3 Antagonists (Ondansetron) - D2 antagonists (Metoclopramide) - Cannibanoids (Nabilone)