RCSI Upper GI Pharmacology 2024 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 Prof Will Ford Date Sept, 2024  Pha...

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 Prof Will Ford Date Sept, 2024  Pharmacology of upper GI tract disorders Peptic ulcer disease Gastro-oesophageal 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 Acid-induced damage to the mucosa Causes: i) Use of NSAIDs ii) Helicobacter pylori (H. pylori) infection Other factors, such as genetics, stress, spicy foods, smoking etc. Incidence: 1 in 10 individuals develop a peptic ulcer at some time - Duodenal ulcers usually appear between ages 30 and 50 (men > women) - Gastric 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 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 Trouble breathing Feeling faint Unexplained weight loss  Gastric acid secretion Schematic anatomy of the canaliculi in a parietal (oxyntic) cell  Control of gastric acid secretion Parietal cell Enterochromaffin-like cell (ECL) Adapted from Engevik et al. Physiol Rev. 2020;100(2):573-602. doi:10.1152/physrev.00016.2019 Regulation of gastric acid secretion Gastrin – Released from G cells into portal blood (endocrine) – Acts on CCK2R in parietal cells & ↑ [Ca2+] – ↑ Histamine release from ECLs Acetylcholine (ACh) – Released by mucosal nerves – Acts at M3 receptors on parietal cell & ↑ [Ca2+] – ↑ Histamine release from ECL cells Histamine – Released from ECL cells – Acts locally (paracrine) on H2 receptor of parietal cell – ↑[cAMP] → PKA* Inhibitory Factors Somatostatin – released from D Cells – (↓gastrin ↓histamine ↓acid) Prostaglandins (PGE2/PGI2) Prostaglandins and mucosal protection Prostaglandins are lipid mediators important in regulating inflammatory responses throughout the body Two important PGs produced in the stomach are PGE2 and PGI2: i) Inhibition of acid secretion from parietal cells ii) Stimulation of mucus and bicarbonate secretion from surface cells iii) Increased mucosal blood flow iv) 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 secretion Pepsin Mucosal bicarbonate secretion Bile salts Mucosal cell restitution Epithelial cell renewal Protection  Pathophysiology of peptic ulcers Mucosal Defense: Mucosal blood flow Aggressive Factors: Mucus secretion Gastric acid Mucosal bicarbonate secretion Pepsin Mucosal cell restitution Bile Salts Epithelial cell renewal H. pylori NSAIDs Ulceration  Drug-induced ulceration Non-steroidal anti-inflammatory drugs (NSAIDs) Commonly used to relieve pain, reduce inflammation, and lower fever e.g., aspirin, ibuprofen, diclofenac, naproxen 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 ↓ Mucus and bicarbonate secretion Promote ↓ Mucosal blood flow ulcers ↓ Epithelial restitution  Treatment NSAID-induced ulcers usually heal upon discontinuation of drug Additional treatment may be recommended to promote healing (PPIs) Withdraw NSAID? – Risk/Benefit considerations – why is the patient on NSAIDS – Risk profile of NSAID Naproxen vs ibuprofen COX-1 vs COX-2 Dose effect/duration Concomitant medication (low dose aspirin, steroid) Commence PPI (e.g., omeprazole) Patients with NSAID-induced GI events should be tested for H. pylori – Treat if present Problem for people with NSAID-induced peptic ulcers is how to manage patients with chronic pain when NSAIDs are discontinued  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 over 40s have H pylori in the stomach, >90% in ME) Lifetime risk of developing an endoscopic ulcer is 10-20% (H pylori positive individuals) H pylori can survive in stomach acid – Expresses urease which converts urea to NH4 and HCO3- – Results in acid neutralisation 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  Treatment of H pylori infection Triple therapy H pylori infections are usually treated with two different antibiotics at once, to help prevent the bacteria from developing resistance to one antibiotic. - common choices are amoxicillin, clarithromycin, metronidazole, or tetracycline Can be used in patients with allergy to penicillin An acid-suppressing drug will also be prescribed to help heal the stomach lining - common choices are, 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 second line therapy  Treatment of H pylori infection HSE recommendations First line of therapy – clarithromycin triple therapy is preferred: 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  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 adherence - Up to 20% of patients are non-adherent (mostly due to adverse effects) - Abdominal pain, diarrhoea, altered taste - Headache, vomiting If first line fails, initiate second line of therapy – should use different antibiotics to first line therapy  Summary When planning for H pylori eradication, must consider: i) Allergies to penicillin ii) Previous antibiotic exposure 14 Days Treatment is usually effective (85%) and failure is mostly due to: i) antibiotic resistance, or ii) poor adherence  Recap H pylori infection is common and a major cause of PUD Survives in the stomach due to Treatment involves triple therapy its ability to neutralise acid (two antibiotics, e.g., amoxicillin Attaches to epithelium and clarithromycin, and a PPI) secretes toxins (CagA and Success is dependent on lack of VacA) which damage the antibiotic resistance and patient epithelium and mucus layer, adherence allowing acid and enzymes to erode the mucosa Second line of treatment involves different antibiotics Diagnosed by urea breath test, (metronidazole) or bismuth faecal antigen test, endoscopy Treatment is effective in 85% or serology Gastro-oesophageal reflux disease Heartburn – (Very common) LOS does not close completely allowing stomach acid to reflux into the oesophagus Oesophagus Relaxed lower - Symptoms: burning, cough, hoarseness oesophageal sphincter When reflux is chronic and frequent it is known as gastro-oesophageal reflux disease (GORD or GERD) Inflamed oesophagus - GORD causes oesophageal inflammation (oesophagitis) and ulcers, and ultimately, Barrett’s oesophagus - 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) Most potent class of acid supressing drug Mainstay of treatment for acid suppression ­ Peptic ulcer disease ­ GORD (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 [ ] than in the blood) – Activated by acid PPIs are prodrugs (converted to sulfenamide which covalently binds the pump) e.g., omeprazole, esomeprazole, lansoprazole  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 (pKa) ↑ Digoxin ↓ Ketoconazole Interaction with cytochrome P450 system – Alter the metabolism of other drugs H2 receptor antagonists Histamine – Released from ECL cells – Acts locally on H2 receptor of parietal cell – ↑[cAMP] → PKA Histamine H2 receptor antagonists – Competitively inhibit H2 receptors – Reduce histamine stimulated acid secretion – ↓basal and food stimulated acid secretion (90%) e.g., cimetidine, ranitidine, famotidine  H2 receptor antagonists Oral absorption is rapid from small intestine Peak concentrations occur 1-3 hours post administration Elimination is by glomerular filtration and tubular secretion Side effects: Very safe Diarrhoea, dizziness, muscle pain Drug interactions – Cytochrome P450 inhibition* (cimetidine) – alters metabolism of other drugs e.g., phenytoin, theophylline, warfarin – H2 RAs 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 – contra-indicated in patients in hepatic failure or renal insufficiency (?)  Cytoprotective agents (i) Stimulate gastric mucus production and mucosal blood flow Misoprostol Stable analogue of prostaglandin E2 Given orally ↓ acid secretion from parietal cells ↑ mucous and bicarbonate secretion Inhibits histamine release from ECL Good for use in NSAID-induced ulcers – (bypasses inhibition of COX-2 to act at PG receptors) Side effects – Diarrhoea, abdominal cramps, uterine contractions  Cytoprotective agents (ii) Form a coating that protects the ulcerated tissue 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 – Not absorbed from the GI tract and has few side effects Constipation, nausea, hypophosphatemia – Can affect drug bioavailability (e.g., tetracyclines, digoxin)  Bismuth salts Given orally in a salt form, such as bismuth subsalicylate MOA unclear – No significant acid-neutralising capacity – Binds and protects mucosal lesions – inhibits the proteolytic action of pepsin – Increases mucus secretion – Toxic to 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 Well tolerated (~ $6.7 bn in global sales in 2022)  Antacids: side effects Magnesium salts may cause diarrhoea Aluminium salts may cause constipation – Combination product can maintain normal bowel function Aluminium and magnesium may be absorbed systemically – Normally not a problem, can cause toxicity in patients with renal insufficiency Calcium salts (e.g., calcium carbonate) - potent antacids – Calcium is readily absorbed Can cause hypercalcemia, kidney stones, and milk-alkali syndrome 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 their high blood pressure 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) N.B.: Separate antacid from interacting drug by at least two hours  Raft-forming agents Not acid-neutralising Form a viscous solution which floats on top of gastric contents preventing acid reflux Anionic polysaccharides Guar gum, xanthan gum, carrageenan, pectin, locust bean gum, alginates (alginic acid)  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 ­ sometimes it can be a symptom of an underlying illness  Control of vomiting Vomiting is a reflex that is under control of the CNS Structures involved in control of vomiting are found 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 Vestibular Pain, Fear, Disgust System Muscarinic Vestibular Histamine H1 nucleus GABA NK1 Vomit Dopamine D2 Muscarinic Centre (inside BBB) NK1 5-HT3 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 – information coming directly from the frontal lobes of the brain, the digestive tract and balancing mechanism of the inner ear 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 oesophageal sphincter and stomach Thus, DA antagonists can be used to promote motility DA antagonists are among the most commonly used anti-emetics 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, diarrhoea ­ Unlike metoclopramide does not cause dyskinesia  Prokinetics 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 ­ Chemotherapy-induced N&V ­ “Morning sickness” Can also cross the BBB ­ Acts on DA receptors in the CTZ Side effects Fatigue, diarrhoea, depression, dyskinesia ­ should not be taken for more than 12 weeks ­ contraindicated in patients with Parkinson’s disease  Anti-emetic drugs 5-HT3 antagonists Cannabinoids (e.g., ondansetron) (e.g., nabilone) Act in CTZ Synthetic form of delta-9- - used for chemotherapy- tetrahydrocannabinol induced N&V and for Acts on CB1 and CB2 receptors gastroenteritis scattered throughout the medulla - can be given orally or IV oblongata ­ chemotherapy-induced N&V Side effects ­ oral, 1-3 hrs before chemotherapy Constipation, headache, flushing, drowsiness Side Effects Vertigo, drowsiness, dry mouth, euphoria  Anti-emetic drugs Muscarinic antagonists H1 antagonists (e.g., hyoscine, scopolamine) (e.g., diphenhydramine, cyclizine) Act in vestibular nucleus and Act in vestibular nucleus vomit centre Used for motion sickness Used for Motion sickness – tablet (30-60 min prior to travel) - tablet (30 mins before travel) Side effects - transdermal patch (take 5- Drowsiness 6hrs before travel) Side effects Corticosteroids - CINV Blurred vision, dry mouth, (e.g., dexamethasone) tachycardia, constipation, drowsiness NK1 antagonists - CINV (e.g., aprepitant)