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Pharmacology of GIT - Peptic Ulcer

• Peptic ulcer pathogenesis involves aggressive factors and protective factors.
• Aggressive factors include acid, pepsin, bile salts, drugs (NSAIDs), and H. pylori.
• Protective factors include mucus, bicarbonate layer, blood flow, cell renewal, prostaglandins, and free radical scavengers.
• Therapy targets enhancing host defense by eliminating aggressive factors (e.g., H. pylori).
• Acid suppressants and lifestyle advice are used for treatment.
• Helicobacter pylori is a gram-negative bacillus.
• It only affects mucous layers, not cells.
• It disrupts mucosal defense, causing inflammation.

Drug Therapy for Peptic Ulcer

• Acid secretion reduction methods include H2 receptor antagonists, proton pump inhibitors, and anticholinergic drugs.
• Antacids neutralize stomach acid.
• Mucosal protective factors include sucralfate, colloidal bismuth, prostaglandins, and carbenoxolone.

Helicobacter pylori Eradication

• Infection diagnosis utilizes endoscopic biopsy of the gastric mucosa and serologic tests.
• Breath tests for urea are also used.
• Triple therapy involves a proton-pump inhibitor (PPI) along with metronidazole plus clarithromycin or amoxicillin.
• Quadruple therapy includes PPI, bismuth subsalicylate, metronidazole, and tetracycline.

H2-receptor Antagonists

• These are competitive antagonists of histamine, fully reversible, and have no effect on H1 receptors.
• Mechanism entails blocking histamine binding to H2 receptors, reducing intracellular cAMP, and decreasing gastric acid secretion.
• Preparations for H2-receptor antagonists include cimetidine, ranitidine, famotidine, and nizatidine.
• They potently inhibit basal, food-stimulated, and nocturnal gastric acid secretion.

H2-receptor antagonists: Therapeutic Uses

• Used in acute stress ulcers, peptic ulcers, GERD, and Zollinger-Ellison syndrome.
• High doses of intravenously injected medication are used for acute stress ulcers.
• Antacids are more efficient in neutralizing stomach acid, but their effect is short-lasting.
• Proton pump inhibitors (PPIs) are currently preferred in GERD treatment.

H2-receptor antagonists: Pharmacokinetics

• Orally administered H2 receptor antagonists distribute widely throughout the body.
• Dosage may need adjustment for hepatic or renal impairment.
• Cimetidine inhibits P450 enzymes and has anti-androgenic effects.
• Ranitidine does not inhibit P450 enzymes and is more potent.
• Famotidine and nizatidine resemble ranitidine in action and potency.

Proton Pump Inhibitors (PPIs)

• PPIs include omeprazole, lansoprazole, and pantoprazole.
• PPIs are substituted benzimidazoles.
• Omeprazole is the first of its class.
• Pantoprazole is available in IV form.
• Efficacy exceeds 90% in inhibiting basal and stimulated gastric acid secretion.
• Effect begins typically within 1-2 hours after administration.

Proton Pump Inhibitors (PPIs) - Actions

• These are prodrugs with acid-resistant enteric coatings.
• These coatings protect from premature gastric acid activation.
• The coating dissolves in the alkaline duodenum, and the prodrug is absorbed.
• The active form is then transported to parietal cells, where it induces irreversible inhibition of H+/K+-ATPase.
• Complete resynthesis of the enzyme requires about 18 hours.
• For optimal absorption, PPIs are administered on an empty stomach.

Proton Pump Inhibitors (PPIs) - Therapeutic Uses

• Used for treating erosive esophagitis, active duodenal ulcers, Zollinger-Ellison syndrome (long-term), and GERD.
• In animal studies, there's concern about long-term safety, especially regarding gastric carcinoid tumors and prolonged hypochlorhydria leading to secondary hypergastrinemia.
• Prolonged use with other drugs may lead to vitamin B12 deficiency.

Potassium Competitive Acid Inhibitors (PCABs)

• Vonoprazan, linaprazan, revaprazan, and soraprazan are NSAID-related ulcer preventive agents comparable to PPIs.
• PCABs competitively inhibit potassium on the luminal side of parietal cells.
• This rapid and reversible inhibition of H+, K+ ATPase prevents H+ and K+ exchange and, subsequently, acid secretion.

Antimuscarinic Agents

• Pirenzepine is an example.
• Primarily used in conjunction with peptic ulcers and Zollinger-Ellison syndrome.
• Side effects limit use, such as cardiac arrhythmias and urinary retention.
• Sucralfate and colloidal bismuth are cytoprotective compounds that prevent mucosal injury, reduce inflammation, and promote ulcer healing.

Sucralfate

• It forms complexes with aluminum hydroxide and sulfated sucrose.
• The complexes bind to damaged mucosal proteins, forming a physical barrier that reduces HCI diffusion and pepsin-induced mucus degradation.
• Sucralfate should not be taken with H2 antagonists or antacids as it requires an acidic environment for activation.

Colloidal Bismuth

• Effective in healing peptic ulcers due to its antimicrobial action.
• Inhibits pepsin activity and increases mucus secretion.
• It protects the ulcer crater by interacting with glycoproteins in necrotic mucosal tissue.

Prostaglandins

• Prostaglandin E2 (PGE2), produced by gastric mucosa, inhibits HCI secretion and stimulates mucus and bicarbonate secretion (cytoprotective effect).
• Misoprostol is a stable analog of PGE1, less effective than H2-receptor antagonists and PPIs in acute therapy.
• Prophylactic misoprostol use is helpful for NSAID-induced ulcers in high-risk individuals (elderly, pre-existing ulcer complications).
• Adverse effects include diarrhea and nausea, and use is contraindicated during pregnancy due to uterine contractions.

Gastroesophageal Reflux Disease (GERD)

• A condition involving stomach acid reflux into the esophagus, causing heartburn and irritation.
• Physiologic GERD is short-lived, postprandial, and asymptomatic.
• Pathologic GERD involves symptoms, mucosal injury, and typically includes nocturnal occurrence.
• Treatment goals encompass alleviating symptoms and recurrence frequency, promoting mucosal healing, and preventing complications.
• Pathophysiology encompasses factors like defective lower esophageal sphincter, hiatal hernia, esophageal clearance issues, and mucosal resistance issues.

Non-pharmacologic Interventions for GERD

• Dietary modifications include avoiding aggravating foods/drinks, high-fat diets, and meals before bedtime.
• Weight loss in overweight/obese patients can help.
• Nicotine cessation is recommended.
• Elevating the head of the bed by 6-8 inches may be beneficial.
• Avoid tight-fitting clothing.
• Avoid drugs that lower LES pressure, delay gastric emptying, and irritate the mucosa (e.g., α-adrenergic antagonists, anticholinergics, benzodiazepines, and certain others).

Medications for GERD

• Antacids (alginate preferred)
• H2-receptor antagonists
• PPIs
• Prokinetic drugs
• Surgical intervention if needed

Nausea and Vomiting

• Nausea is the conscious recognition of vomiting center stimulation.
• Vomiting is a physiological, bodily defense mechanism against toxic substances.
• It involves forceful expulsion of gastric contents with abdominal/chest muscle contraction.
• Often associated with cytotoxic drug administration (70-80% of patients experience it)

Treatment and Prevention of Nausea and Vomiting

• Removing underlying causes.
• Correcting dehydration and electrolyte imbalances.
• Using pharmacological agents that target receptors implicated in nausea and vomiting (e.g., dopamine, histamine, and serotonin inhibitors).
• Alternative delivery forms (intravenous infusions, subcutaneous injections, suppositories) might be necessary

Pharmacologic Agents for Nausea and Vomiting

• Corticosteroids
• Cholinergic antagonists
• Dopamine antagonists
• Serotonin antagonists
• Neurokinin 1 receptor antagonists
• Cannabiniod receptor antagonists

Serotonin (5-HT3) Antagonists

• These agents include dolasetron, granisetron, ondansetron, and palonosetron.
• They are highly effective in preventing cancer chemotherapy induced emesis (especially cisplatin-induced).
• Primarily block peripheral 5HT3 receptors on intestinal vagal afferents.
• Also affect CNS vomiting centers and CTZ.

Neurokinin (NK1) antagonists

• These agents include Aprepitant and Fosaprepitant
• These are primarily central in action, blocking substance P receptors.
• Effective in preventing acute and delayed phase chemotherapy-induced nausea and vomiting.
• Often combined with 5-HT3 antagonists and corticosteroids.

D2 receptor antagonists - Metoclopramide

• Metoclopramide blocks D2 receptors in the central vomiting center (CTZ).
• It increases release of acetylcholine from cholinergic neurons, enhancing intestinal smooth muscle sensitivity and tone.
• It strengthens the lower esophageal sphincter and facilitates gastric emptying.
• It is highly efficient against highly emetogenic cisplatin.

D2 receptor antagonists - Domperidone

• Domperidone is a selective D2 antagonist.
• It avoids the extrapyramidal side effects of other D2 antagonists due to limited penetration of the blood-brain barrier.

D2 receptor antagonists - Phenothiazines (Prochlorperazine, Promethazine)

• These drugs are effective against low to moderately emetogenic chemotherapy agents such as fluorouracil and doxorubicin.
• Use is limited due to side effects, particularly extrapyramidal side effects.

Corticosteroids as Antiemetics

• Dexamethasone and methylprednisolone are effective against mild-to-moderately emetogenic chemotherapies.
• Unknown mechanism of action, though an effect on prostaglandins (PGs) is suspected.
• Commonly used in combination with 5HT3 antagonists for prevention of chemotherapy-induced vomiting

Antimuscarinic drugs (Scopolamine)

• Antiemetic effect due to muscarinic receptor inhibition in the cerebellum.
• Rapid CNS distribution.
• Highly effective for motion sickness.
• High incidence of anticholinergic side effects; oral/parenteral forms result in high side effect incidence, so transdermal patch delivery is preferred.

H1 receptor antagonists (e.g., dimenhydrinate, diphenhydramine)

• Cause sedation, making them helpful antiemetics.
• H1 antagonism plus antimuscarinic activity are characteristics.
• Used for motion sickness, vertigo; however, adverse effects include sedation and anticholinergic effects (dry mouth, confusion, urinary retention).

Prokinetic Drugs

• Metoclopramide, domperidone, cisapride, and macrolide antibiotics (e.g., erythromycin)
• Increase GI tract motility.
• Affect gastric emptying.
• Increase LES pressure (useful in GERD).
• Metoclopramide and domperidone are D2 antagonists with additional CNS effects; domperidone avoids central side effects.
• Cisapride has serious side effects (arrhythmias); more modern forms are available now.

Prokinetic Agents: Therapeutic Uses

• Used in impaired gastric emptying, a common consequence of post-surgical procedures (vagotomy) and diabetic gastroparesis.
• Also useful in GERD.

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