peptic ukcers Flashcards
(5 cards)
what is the acid secretion pathway and how drugs fit into this for peptic ulcers
Peptic ulcer disease (PUD) is an upper gastrointestinal disorder involving the erosion of the mucosal layer of the GI tract in areas exposed to acid and pepsin. Ulcers result from an imbalance between mucosal defensive factors (such as prostaglandins, mucus, bicarbonate, and blood flow) and aggressive factors (such as NSAIDs, acid, bile salts, and H. pylori). Therapy aims to reverse this imbalance.
Acid Secretion Pathway
Gastric acid (HCl) is secreted at approximately 2 litres per day, with a pH of less than 1.0. This acid is produced by parietal cells in the stomach.
Several factors stimulate parietal cells to produce and secrete acid:
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Histamine: Stimulates acid secretion. Mast cells produce a basal level of histamine, which increases in response to acetylcholine and gastrin. H2 receptors are expressed on parietal cells and are the target for histamine.
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Gastrin: Stimulates acid secretion. Mast cell histamine also increases in response to gastrin.
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Acetylcholine: Stimulates acid secretion. Mast cell histamine also increases in response to acetylcholine. Acid secretion can be mediated by acetylcholine or gastrin alone.
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Food: Stimulates acid secretion.
These stimuli ultimately converge on the H+/K+ ATPase, also known as the proton pump, located in the parietal cells. The proton pump is responsible for the final step of acid secretion, pumping hydrogen ions into the stomach lumen in exchange for potassium ions.
Acid secretion is inhibited by Somatostatin, produced by D cells. Prostaglandins (specifically PGE2 via EP4 receptors) also play a protective role by preventing the activation of the proton pump, which reduces HCl production.
How Drugs Fit In
Different classes of drugs target various points in the acid secretion pathway or neutralise the secreted acid to treat peptic ulcers and related conditions like GORD.
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Antacids
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These are weak bases that work by neutralising gastric acid already present in the stomach lumen.
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They provide quick onset of relief but are short-lived and best for short-term use.
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Examples include aluminium hydroxide (which can cause constipation) and magnesium hydroxide (which can cause diarrhoea).
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Antacids can also promote gastric mucosal defence by stimulating the secretion of mucus, bicarbonate, and prostaglandins.
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H2 Receptor Antagonists (H2RAs)
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Examples include cimetidine, famotidine, and nizatidine.
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They act as competitive antagonists on the H2 receptors expressed on parietal cells.
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By blocking histamine’s action at these receptors, they inhibit acid secretion stimulated by histamine, gastrin, and meals.
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They are less effective at blocking acid secretion mediated solely by acetylcholine or gastrin.
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While historically important, H2 antagonists have largely been replaced by PPIs for PUD treatment.
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Proton Pump Inhibitors (PPIs)
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Examples include omeprazole, lansoprazole, pantoprazole, and rabeprazole. Esomeprazole is the S-isomer of omeprazole, offering improved properties.
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PPIs are lipophilic weak bases that are absorbed and delivered to the parietal cells.
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They are inactive at neutral pH but become activated (protonated) in the highly acidic environment (pH < 2.0) of the parietal cell canaliculae.
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The activated form then binds covalently and irreversibly to a cysteine residue in the proton pump (H+/K+ ATPase).
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By directly blocking the final step of acid production, PPIs achieve an almost total inhibition of gastric acid secretion.
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They are effective at inhibiting acid secretion stimulated by all stimuli (histamine, gastrin, acetylcholine) because they target the common final pathway - the pump itself.
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The block is irreversible, so acid secretion only recovers as the parietal cells synthesise new proton pumps. This leads to long-lasting effects, with inhibition lasting up to 48 hours.
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PPIs are the current drug of choice for GORD due to their efficacy over H2RAs. They are also indicated for PUD and Zollinger-Ellison Syndrome.
Understand why these drugs are likely to cause the SE associated with them.
Effect on drug absorption. By increasing gastric pH, PPIs can affect the absorption of other drugs. For example, they can increase the absorption of warfarin, diazepam, and phenytoin, potentially leading to increased drug toxicity.
Mucosal Protective Agents
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This category includes Bismuth, Sucralfate, and Misoprostol, which help protect the ulcer site or promote protective factors.
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Side Effects:
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Sucralfate: May bind with other drugs and interfere with absorption. The source states this effect but does not fully explain the mechanism (Sucralfate forms a sticky polymer in acidic environments, which presumably is why it binds to other substances, but this link isn’t explicitly made as the reason for drug interaction).
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Misoprostol: This is a prostaglandin analogue (PGE1). It can cause uterine contractions, which is why it is contraindicated in pregnancy. It can also cause menorrhagia. The source directly links these effects to its prostaglandin nature.
Stage of development - gord
Initial Event: GORD begins with the backflow of stomach acid (and bile) into the oesophagus.
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Initial Damage (Oesophagitis): The oesophagus is not equipped to handle stomach acid, and this exposure can lead to scaring (oesophagitis). Reflux oesophagitis is shown as a step in the progression diagram.
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More Severe Symptoms: As GORD progresses or becomes more severe, patients may experience symptoms like difficulty swallowing and chest pain.
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Complications (Representing Stages/Progression): Chronic GORD can lead to several complications, which can be seen as a progression of the disease:
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Oesophageal erosions.
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Oesophageal ulcer.
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Narrowing of the oesophagus (oesophageal stricture). Strictures are also shown as a complication in the diagram.
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Haemorrhage. Haemorrhage is shown as a complication in the diagram.
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Barrett’s oesophagus: In some patients, this develops. It has been linked to cancer of the oesophagus. Barrett’s oesophagus is also shown as a step in the progression diagram following Reflux oesophagitis.
symptoms of GORD
The primary symptom mentioned is Heartburn, which is an uncomfortable burning sensation behind the breastbone. The sources note that a Myocardial Infarction (MI) is often mistaken for GORD, highlighting the significance of this symptom.
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More severe symptoms that can occur include difficulty swallowing.
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Another severe symptom listed is chest pain.
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A sore throat is also mentioned as a potential symptom.
treatments for GORD
Acid Controlling Agents: This is considered central to GORD treatment.
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Proton Pump Inhibitors (PPIs): These are the current drug of choice for treating GORD. PPIs are indicated for Oesophagitis with GORD, and studies show that elevating pH in the lower oesophagus using PPIs is therapeutically advantageous. They have replaced H2 antagonists for many uses.
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H2 Receptor Antagonists (H2RAs): These drugs inhibit acid secretion stimulated by histamine, gastrin, and meals. While used, the sources indicate that PPIs are more effective for GORD.
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Antacids: These weak bases work by neutralising gastric acid. They provide quick onset of relief but have a short duration and are good for short term use. Long-term use is not recommended. Antacids can also promote gastric mucosal defence by promoting the secretion of mucus, bicarbonate, and prostaglandins.
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Future Interventions: Future treatments may include pro-motility drugs.
